Pharmacology Flashcards
Give an overview of the pharmacology of drugs as organic molecules and relevance to anaesthesia.
Recognize the structure and nomenclature of common organic groups
Explain structure-activity relationships in anaesthetic practice
Organic molecules may be aliphatic or aromatic.
Aliphatic molecules consist of a root, plus various functional groups and side chains
Presence and position of functional groups determines the physical, chemical and pharmacological properties of a drug
The structure of organic molecules determines solubility, protein binding, potency and stability
Minor modifications to the chemical structure of a drug can have dramatic effects on its clinical activity
Give an overview of the aliphatic compounds and functional groups relevant to anaesthesia.
Each group of atoms that becomes attached to the carbon chain has its own characteristic set of reactions. The functional groups are commonly found in anaesthetic practice.
What is the name of this molecule?
2, 6-di-isopropyl phenol
Propofol
The number of bonds an atom has, in its uncharged state, is the valency. For example, hydrogen has a valency of 1 (Fig 1). Looking at the other atoms in Fig 1, in each case, what is the valancy? 1, 2, 3, or 4
A. Bromine
B. Carbon
C. Chlorine
D. Fluorine
E. Nitrogen
F. Oxygen
Is this molecule an acid or base?
Carboxylic acid is an acid, as it donates the ‘H’ from the COOH group.
Is this molecule an acid or base?
Amine is a base. The lone pair of electrons on the nitrogen can form a co-ordinate bond with a free hydrogen to form a positively charged ammonium group.
Is this molecule an acid or base?
Phenols are weak acids and can give up a hydrogen.
Which functional groups are present in Tetracaine?
Possible answers:
A. Amide
B. Amine
C. Aromatic group
D. Ester
E. Halide
F. Alcohol
G. Acid
A. Incorrect.
B. Correct.
C. Correct.
D. Correct.
E. Incorrect
F. Incorrect.
G. Incorrect.
Which functional groups are present in Lidocaine?
Possible answers:
A. Amide
B. Amine
C. Aromatic Group
D. Ester
E. Halide
F. Alcohol
G. Acid
A. Correct.
B. Correct.
C. Correct.
D. Incorrect.
E. Incorrect.
F. Incorrect.
G. Incorrect.
Select the drug that has greater potency.
Bupivicaine
Increasing the bulk of the side chain on the amine (a butyl group rather than a methyl group), increases the molecules lipid solubility and hence potency
Correctly identify the three molecules shown below?
A) 2-methylbutane
B) 2, 3-dimethylbutene
C) 3-chloro-2, 2-dimethylpropanol
Give an overview of the interaction between molecules and the role that it has on clinical anaesthesia.
Describe the forces that hold molecules together
Explain the concept of polarity
Explain the relevance of bonding to molecular properties
The physical and chemical properties of a drug are determined by the molecular bonds
Intramolecular bonds may be:
ionic due to transfer of electrons (water soluble)
covalent due to shared electrons (lipid soluble)
Intramolecular forces such as hydrogen bonds or Van der Waals’ forces also affect solubility and protein binding
Covalent bonds may be pure or polar
With regard to the properties of covalent compounds…
A. They have high melting and boiling points
B. They are soluble in water
C. They conduct electricity
D. Their bonds consist of shared electrons
A. False. The forces between the molecules are weak requiring little energy to break them. At room temperature they are likely to be gases or volatile liquids.
B. False. They usually dissolve in non-polar or organic liquids.
C. False.
D. True. In covalent bonding each atom donates an electron to a shared electron pair.
Is the oxygen atom in this molecule a negative or positive pole?
Possible answers:
A. Negative pole
B. Positive pole
A. Correct.
B. Incorrect.
Oxygen atoms have a higher electro-negativity than carbon or hydrogen, hence are the more negative pole of the molecules.
Place each type of bond in order of decreasing strength of attraction, starting with the strongest bond.
Give an overview of ionization and the role it plays on clinical anaesthesia.
Identify anaesthetic drugs that are weak acids and weak bases
Discuss the relationship between the pKa of a drug and the degree of ionization
Derive the Henderson-Hasselbalch equation for the bicarbonate-carbonic acid buffer pair
Describe the importance of pKa in determining pharmacokinetic behaviour of drugs
Many anaesthetic agents are weak acids and weak bases
Weak acids are ionized above their pKa and weak bases are ionized below their pKa
The pharmacokinetic behaviour of a drug is influenced by its tendency to ionize at plasma pH
Buffering is an important means of minimising pH changes both intracellularly and in the plasma
A buffer pair works most efficiently at its pKa
The bicarbonate-carbonic acid buffer system is important because it is open-ended: carbon dioxide can be excreted through the lungs
Many of the drugs we use are organic molecules with added functional groups that make them weak electrolytes (Fig 1a).
Question: Which two functional groups are most important in allowing small organic molecules to act as weak electrolytes?
The -COOH (carboxyl) and -NH2 (amine) groups (Fig 1b). Other groups may also allow dissociation, but not always at a pH relevant to human physiology.
Can you identify two groups that often dissociate outside the pH range 6.5-8.5?
A phenolic hydroxyl group, i.e. with an aromatic ring -OH, and an aldehyde group, i.e. R-CH = O; often called a keto-group (Fig 2).
Carboxyl (-COOH) and amine (-NH2) functional groups are of particular importance in allowing partial dissociation of small organic molecules in an aqueous environment.
Question: Can you identify the two commonly used analgesic drugs shown in Fig 1a?
A is aspirin and B is morphine (Fig 1b).
Which is a weak acid and which is a weak base? Related to this, can you identify the functional groups responsible?
Aspirin is a weak acid and has a carboxyl group; morphine is a weak base and has an amine group (Fig 1c).
When a weak acid, such as aspirin, dissociates it gives up a proton, i.e. a hydrogen ion, to its aqueous environment. In the case of aspirin, i.e. acetylsalicylic acid, the carboxyl group dissociates:
R - COOH ⇔ R - COO- + H+
The -COOH group is a proton donor. -COO- is the proton acceptor (Fig 1a).
Question: What two factors determine the degree of dissociation?
The pH of the environment and the dissociation constant for the above reaction (Fig 1b).
What is pKa?
pKa is the pH at which the concentration of the proton donor form is equal to that of the proton acceptor form.
Look at the drug structure. What is the single best explanation for why this is a weak acid?
A. It is an induction agent
B. It has two isopropyl groups
C. It is an aromatic molecule
D. It has a phenolic hydroxyl group
E. There are no amine groups
A. Incorrect.
B. Incorrect.
C. Incorrect.
D. Correct. This drug is propofol. The phenolic hydroxyl group can dissociate, but only at a high pH.
E. Incorrect.
The pH of a 2.5% solution of sodium thiopental is 11. What is the single best explanation of why this is necessary?
A. Thiopental is a weak acid
B. Sodium thiopental can only form at this pH
C. The pH is high enough to prevent precipitation of thiopentoic acid
D. Isomerism of thiopental to the thiol form occurs at this pH
E. Thiopental is highly lipid-soluble except at high pH
A. Incorrect.
B. Incorrect.
C. Correct. Thiopental acid has a pKa of 7.6 in water but the unionized form is insoluble, and so would precipitate out at a pH near 7.6. At pH 11 the ratio of ionized to unionized form is about 5000:1 so acid precipitation does not occur.
D. Incorrect.
E. Incorrect.
Which of these anaesthetic drugs are weak acids?
A. Aspirin
B. Etomidate
C. Fentanyl
D. Propofol
E. Thiopental
A. True.
B. False. Etomidate is a weak base.
C. False. Fentanyl is a weak base.
D. True.
E. True.
We have previously seen that:
[H+] = Ka([proton donor]/[proton acceptor])
This equation can be transformed to help us predict the relative proportion of a drug in its ionized form.
Question: What does the equation look like if we take logarithms of both sides and make both sides negative?
-log[H+] = -log(Ka) - log ([proton donor]/[proton acceptor])
or, more familiarly:
-log[H+] = -log(Ka) + log ([proton acceptor]/[proton donor])
-log[H+] = pH
If we now substitute this into our equation and allow the concentration of proton donor and proton acceptor forms to be equal, we get: pH = -log(Ka). The negative logarithm of the acid dissociation constant is known as the pKa: it is the pH at which the concentration of proton donor equals that of the proton acceptor.
The equation we have just derived can be written:
pH = pKa + log ([proton acceptor]/[proton donor])
What is the weak organic acid compound shown in Fig 1?
Carbonic acid.
It is a proton donor.
The proton acceptor form is Bicarbonate: HCO3- (Fig 2).
The Henderson-Hasselbalch equation describes how the pH of the environment influences the equilibrium between carbonic acid and bicarbonate.
We can calculate how the ratio of unionized (carbonic acid) to ionized (bicarbonate) form varies within a range of pH values around plasma pH using the Henderson-Hasselbalch equation (Fig 1).
Question: If we know that the pKa of a system is 6.1, what is the proportion of ionized to unionized form at each of the following pH values: 6.1, 7.1 and 8.1?
You should have calculated the following ratios: 1, 10 and 100.
The carbonic acid-bicarbonate system is just one of the buffer systems in the body. Proteins contain amino acids, some of which have functional groups that can ionize at body pH. Proteins are important intracellular buffers. This is particularly true of haemoglobin within the red blood cell.
Question: Can you name an intracellular buffer system that is not a protein?
The phosphate buffer system.
HPO42- + H+ ⇔ H2PO4-
The pKa of this system, 6.8, is closer to intracellular pH than the bicarbonate system is to plasma pH. Since intracellular pH is lower than plasma pH this buffer system is quite efficient.
The kidney is involved in the excretion of hydrogen ions and retention of bicarbonate in the carbonic acid-bicarbonate buffer system (Fig 1). We produce 30-40 mmol H+ daily and in order to eliminate this amount of acid the renal tubules need the assistance of urinary buffers.
Question: Which weak base is an essential part of urine buffering when excess hydrogen ions need eliminating?
Ammonia: ammonia-ammonium ion is a buffer pair, with ammonia production occurring optimally at low pH: NH3 + H+ ⇔ NH4+
In addition to bicarbonate and ammonia, which other buffer system is also important in renal excretion of hydrogen ions?
The phosphate buffer system (Fig 2). Ammonia and phosphate buffers are produced in the renal tubular cells. Excretion of ammonium ions and dihydrogen phosphate allow net loss of acid from the blood.
Morphine has a pKa of 7.9. Regarding the ionization of morphine:
A. At pH 7.4 the ratio of the ionized to the unionized form of morphine is approximately 30:1
B. At physiological pH morphine is more ionized than fentanyl
C. Morphine has a tertiary amine group
D. Morphine is a weak base that is 50% ionized at pH 7.9
E. In a patient who is severely acidaemic, more morphine exists in the unionized form than is found in a normal person
A. False. The ratio is approximately 3:1.
B. False. Fentanyl has a pKa of 8.4 so is more ionized than morphine at pH 7.4.
C. True.
D. True.
E. False. If plasma pH drops below normal, as is seen in acidaemia, then a greater proportion of morphine exists in the ionized form.
A drug needs to reach its site of action within the body. For many anaesthetic drugs this involves injection of a liquid containing the drug followed by transport within the blood to the brain.
Question: Which two chemical properties of a drug determine how rapidly an anaesthetic agent reaches the brain?
Lipid solubility and pKa.
Lipid solubility is important for crossing the blood-brain barrier but pKa determines what proportion of the unbound drug is in the unionized form.
The unionized form passes the blood-brain barrier (BBB) more rapidly.
The ionized form of a drug is more water-soluble than the non-ionized form, so ampoule contents are at a pH that favours that form, although high and low pH solutions can be very irritant to veins.
If the unionized form of the drug is not water-soluble, then the drug cannot be prepared as an aqueous solution and requires other means to solubilize it. Induction agents need to reach the brain quickly and so need to be very lipid-soluble, but for rapid onset they need to be given IV.
Question: What methods are used to produce an intravenous preparation of induction agents?
Propofol is prepared as an emulsion in intralipid; egg phosphatide is used as the emulsifying agent
Etomidate is solubilized with polyethylene glycol or intralipid
Sodium thiopental is produced as a powder under nitrogen
Indirect access to the bloodstream requires absorption through a body barrier. The non-ionized form of the drug is more lipid-soluble than the ionized form. Paracetamol, aspirin, ibuprofen and morphine liquid are all drugs that can both ionize and be given orally.
Question: What is the pH of the stomach and the small intestine?
In the stomach, pH is low at around 2-3; in the small intestine pH is high, closer to 8-9.
Can you order the drugs mentioned above (Paracetamol, aspirin, ibuprofen and morphine liquid) according to the proportion of unionized form, from the smallest to largest proportion, in (a) the stomach and (b) the small intestine?
Stomach: morphine, aspirin, ibuprofen, paracetamol. Small intestine: aspirin, ibuprofen, morphine, paracetamol.
Aspirin, ibuprofen and paracetamol are all weak acids and so are ionized above their respective pKa (3.5, 4.9, 9.4). Morphine is a weak base, and so is ionized below its pKa (7.9).
At pH 3 all the acids are unionized: the higher their pKa, the higher the unionized fraction. At this pH morphine is largely ionized, and so has the lowest proportion in the unionized form. The order in the stomach is therefore: morphine, aspirin, ibuprofen, paracetamol.
At pH 8 morphine is very slightly more unionized than ionized, but aspirin and ibuprofen are both mainly ionized, aspirin more so than ibuprofen. However, paracetamol is still largely unionized. The order in the small intestine is therefore: aspirin, ibuprofen, morphine, paracetamol.
Many anaesthetic drugs need rapid access to the CNS for their activity. Three important factors govern the speed of passive movement of a drug across the BBB:
Lipid solubility: Highly lipid-soluble drugs enter the CNS more rapidly than poorly lipid-soluble ones
Degree of protein binding: A high proportion of unbound drug creates a favourable concentration gradient for movement into the CNS
pKa: The unionized form favours passage across the BBB
Therefore drugs with high lipid solubility, low protein-binding and a low proportion in the ionized form have a more rapid onset of CNS activity. Morphine has a pKa of 7.9 but alfentanil has a pKa of 6.4. Both are weak bases and so are unionized at a pH above their pKa. Morphine is about 40% protein bound and alfentanil is about 90%.
Question: Which has the faster onset of action?
Alfentanil. Although it has a lower proportion of free drug than morphine, this difference is much smaller than the difference between the proportion of unionized drug in the bloodstream. Alfentanil is 100 times less ionized than morphine.
The pKa of a drug may also influence its duration of action, particularly when given by continuous infusion. Propofol and fentanyl are commonly given by continuous infusion. Both are very lipid-soluble but fentanyl has a pKa of 8.5, which is very much closer to physiological pH than the pKa of propofol. Propofol is effectively unionized in the body.
Question: When given by continuous infusion for several hours, how does the offset time compare for the two drugs, assuming they are given at therapeutic doses?
Propofol has a much more rapid offset time than fentanyl. Part of the reason is because of the difference in ionization.
Fentanyl is a weak base and is ionized below its pKa, and so is largely ionized at physiological pH, i.e. 10:1 in favour. This form is water-soluble and redistributes from lipophilic stores to maintain an effective plasma concentration. Propofol, on the other hand, is not ionized: once in a favoured lipid environment it does not rapidly re-enter the plasma, and so its effects wear off more quickly.
Regarding the buffer system:
H2CO3 ⇔ HCO3- + H+
Select true or false for each option, then select Submit.
A. This is the only buffer system present in red blood cells
B. Carbonic acid is the weak acid and bicarbonate the conjugate base
C. The pKa of this system is less than 0.5 pH units from normal plasma pH
D. This is the most abundant extracellular buffer system
E. Carbonic anhydrase in the plasma is essential for this system to operate
A. False. Haemoglobin is present in red blood cells and can also act as a buffer.
B. True.
C. False. The pKa of this system is around 6.4 compared with a normal plasma pH of 7.4.
D. True.
E. False. Carbonic anhydrase is present in the red blood cell not the plasma.
These drugs are weak acids:
A. Remifentanil
B. Naproxen
C. Meperidine
D. Diclofenac
E. Meloxicam
A. False. Opioids are weak bases.
B. True. NSAIDs are all weak acids.
C. False. Opioids are weak bases.
D. True.
E. True.
These drugs are 50% or more ionized at physiological pH:
A. Paracetamol
B. Etomidate
C. Remifentanil
D. Ibuprofen
E. Ketamine
A. False. Paracetamol is a weak acid with a pKa of 9.4, so is not ionized at pH 7.4.
B. False. Etomidate is a weak base with a pKa of 4.2, so is not ionized at pH 7.4.
C. False. Remifentanil is a weak base with a pKa of 7.1.
D. True.
E. True.
Remember that bases are ionized below the pKa.
Acids are ionized above their pKa.
Give an overview of isomers, and their relevance to anaesthesia.
Define the categories of isomers
Describe the properties of different isomers
Explain their relevance in anaesthesia
Isomers are molecules which have the same molecular formula but different arrangements of their atoms
Structural isomers may have very different chemical structures, resulting in drugs with different physical, chemical and pharmacological properties
Stereoisomers have the same chemical structure but a different spatial configuration. They have the same physical and chemical properties but rotate the plane of polarised light in opposite directions
Isomers are relevant to medical practice as their different actions may produce therapeutic results or unwanted side-effects
What is an isomer?
An isomer is a chemical compound with the same molecular formula as another compound but a different arrangement of atoms.
Structural isomers have the following properties (Fig 1):
The same molecular formula, i.e. the same numbers of hydrogen, carbon, oxygen, nitrogen atoms
Different chemical structures (different arrangements of the atoms)
They may have similar or completely different pharmacological properties
Question: Which common anaesthetic drugs are structural isomers?
Isoflurane and enflurane have the same molecular formulae but different chemical structures (Fig 2). Their structures are similar as they are both halogenated ethers and they both have similar physical, chemical and pharmacological properties.
What is the name of the compound shown in Fig 1?
Sodium thiopental.
This is a form of structural isomerisation called tautomerisation. Tautomerisation can be called dynamic structural isomerisation. It occurs when two structural isomers exist in equilibrium with each other.
Sodium thiopental is prepared buffered to a pH of 10.5: this allows ionisation of the thiol (-SH group) to form the sodium salt which is readily water soluble. However, at the more acidic physiological pH of 7.4 the sulphide anion attracts hydrogen ions to form the unionised thiol molecule (Fig 2). This structure rapidly undergoes tautomerisation (a hydrogen ion is transferred from the sulphur atom to the nitrogen atom). The resulting thione (-C=S) (Fig 3) is very lipid soluble and rapidly crosses the blood-brain barrier.
The structure of midazolam is also modified by changes in acidity (Fig 1).
It contains a primary amine group which at acid pH is ionized and water soluble. Once injected into plasma, pH-dependant ring closure occurs to form a benzodiazepine ring. The resulting molecule is lipid soluble and readily crosses the blood-brain barrier.
Question: Why is this not true isomerisation?
A molecule of water (H2O) is eliminated when the benzodiazepine ring is formed, the two forms consequently do not contain the same number of atoms and hence are not in fact isomers, however in many texts it is given as an example of tautomerisation.
Geometric isomers occur in compounds which have a carbon-carbon double bond.
Question: What is a –C=C- functional group called (Fig 1)?
A compound with carbon-carbon double bond is an alkene.
Whilst there is free rotation around a carbon-carbon single bond, there is no rotation about a double bond. This may result in two geometric isomers:
In the cis isomer (Fig 2), functional groups exist on the same side of the double bond
In the trans isomer (Fig 3), they are on opposite sides of the double bond
What is the relevance of isomerisation in anaesthetics?
Isomerisation is relevant in medicine because one isomer will often produce the desired effect in the patient whereas the other isomer may have no effect or even produce unwanted side-effects (Table 1).
Two enantiomers will have very different conformational relationships with a chiral receptor, which may result in different:
Potencies
Intrinsic activities, i.e. one isomer may be an agonist at a particular receptor while the other is an antagonist
Pharmacological responses, e.g. levorphanol is an opioid analgesic whereas the enantiomer dextromorphan is a cough suppressant
Understanding of isomerization has resulted in drugs now being produced as a single isomer to optimise the desired actions and minimise unwanted effects.
- Muscle relaxants
Aminosteroids: vecuronium and rocuronium contain many chiral centres but are synthesised as single isomers.
Isoquinolones: atracurium and mivacurium each have 4 chiral centres and 16 possible stereoisomers.
Atracurium is produced as a mixture of 10 isomers each with different pharmacokinetics and potencies.
One isomer, cisatracurium, has various clinical advantages, including:
Three times increase in potency
Minimal autonomic effects
Minimal histamine release
Reduced laudanosine levels
It is produced as a single enantiomer and available commercially
- Local anaesthetics
Mepivacaine, prilocaine, bupivacaine and ropivacaine all exist as pairs of optical isomers.
The S enantiomer is the most pharmacologically useful due to the following advantages:
Increased vasoconstriction resulting in prolonged duration of action and less systemic absorption
Reduced cardiotoxicity
Reduced motor blockade
As a result ropivacaine and bupivacaine are now produced commercially as single enantiomers.
Are the β-blockers practolol and atenolol, examples of structural isomerization or stereoisomer isomerization? Select the correct box.
Structural isomerisation.
Atenolol and practolol are structural isomers of each other. At the left-hand end of the molecule as drawn, the amine and alkyl groups have switched position.
However, both can also exist as two stereoisomers, as the carbon marked * has four different groups attached, and hence is chiral.
Select the type of isomerisation that is found in halothane.
Stereoisomer isomerisation
Stereoisomerization is found in halothane. Halothane can exist as two non-superimposable mirror images due to the presence of a chiral carbon.
Correctly label the two sets of structures as either cis isomers or trans isomers.
A. CIS-but-2-ene. CIS-butenedioic acid.
B. TRANS-but-2-ene. TRANS-butenedioic acid.
Select the volatile agent that does not exist as stereoisomers.
Sevofluorane.
Sevoflurane is not a stereoisomer
Select the chiral centre in each of the following four structures.
Halothane - 2nd carbon
Enflurane - 3rd carbon
Isoflurane - 2nd carbon
Desflurane - 2nd carbon
With regard to structural isomers:
A. They have the same molecular formula
B. They have the same structural formula
C. They have the same physical properties
D. They have the same pharmacological properties
E. Enflurane is a structural isomer
A. True. This is the definition of an isomer.
B. False. Structural isomers differ in the arrangement of their atoms – the building blocks of their chemical structure.
C. False. Structural isomers may be very different compounds with different physical and chemical properties.
D. False. Although some structural isomers have similar pharmacological properties, many do not.
E. True.
Sort the enantiomeric form of the following drugs into the most and least clinically useful?
Give an overview of mechanisms of specific and non-specific drug action, and the relevance to anaesthesia.
List examples of simple non-specific drug actions with reference to their physicochemical properties
Describe the key mechanisms by which drugs exert their highly specific action, including receptor, enzyme and voltage-gated ion channels interaction
Outline the key principles that govern drug-receptor interaction including affinity, specificity, efficacy, agonism and antagonism
Give examples of commonly-used anaesthetic drugs outlining their specific mechanism of action with regards to receptor binding
A drug must first bind to its target, most commonly a receptor, in order to initiate its physiologic effect
Non-specific drug actions are governed by physicochemical interaction and tend to be less potent. Specific drug action results from the binding of a protein target, most commonly a receptor. This typically leads to a predictable cellular response
Drugs display varying degrees of specificity for receptors with many being stereoselective
Receptors are complex proteins found within or on the cell membrane and can be categorised into groups accordingly to their molecular structure. These include G-protein coupled receptors, ion channels, enzymes and nuclear receptors. They are intrinsic to the process of cell-signalling which ultimately leads to an alteration in cell function
Receptor-effector coupling is often a multi-step process with both positive and negative feedback mechanisms
Key concepts that describe this drug-receptor interaction include affinity, specificity, efficacy, agonism and antagonism
Drug binding is not equivalent to drug effect. The ability for a drug-receptor complex to elicit its effect is governed by its efficacy and can be displayed using concentration-response curves
Drugs act to either increase or decrease the various functions of a biological system. They can be classified according to their concentration-effect relationships
Regarding the mechanism of drug action:
A. A drug is an exogenous chemical substance that is used to alter a physiological system
B. Physicochemical forces that form the basis of simple non-specific drug action and tend to be less potent
C. Sugammadex is a gamma cyclodextrin that is used to reverse the effects of the steroidal neuromuscular blocking agent rocuronium via neutralisation
D. The osmotic diuretic mannitol acts to reduce intracranial pressure by lowering the plasma osmolality
A. True. Drugs can be identical to an endogenous compound. Drugs can exert their effect in a number of different ways ranging from simple non-specific action to highly specific actions on protein targets, namely receptors. The majority of the drugs we use in anaesthesia act in a highly tissue specific manner.
B. True. Important physicochemical forces include covalent bonding, ionic bonds, hydrogen bonds and van der Waals’ forces.
C. False. Sugammadex is an encapsulating agent and is an example of chelation. Antacids and protamine are examples of neutralisation.
D. False. Mannitol is an alcohol derivative of the sugar mannose. It is freely filtered at the glomerulus acting as an osmotic diuretic resulting in intravascular depletion. It increases plasma osmolality which leads to a reduction in extracellular brain water and thus decrease intracranial pressure.
Regarding receptors:
A. Receptors are only found on the cell surfaces and display variable expression throughout the body
B. G protein-coupled receptors represent the largest superfamily of receptor. They are located on the cell surface and present a common binding site for hormones and neurotransmitters
C. Voltage-gated ion channels are ionotropic, being responsible for rapid synaptic transmission
D. Tyrosine kinases are receptors that are linked to cytoplasmic enzymes and mediate the first steps in the transduction of signals carried by insulin and a wide variety of growth factors
E. Cytoplasmic soluble guanylate cyclase is activated by nitric oxide resulting in vasoconstriction and platelet aggregation via cyclic GMP production in smooth muscle cells
A. False. At a cellular level, receptors can be located on the cell surface, be linked to cytoplasmic enzymes or be found within the cell nucleus. The activation of cell surface receptors typically leads to rapid, short-term effects, whereas those involving nuclear transcription factors tend to induce a slower, long-term physiological response.
B. True. Over 500 families of GPCR proteins have been identified to date. These are intrinsically linked to a diverse array of second-messenger molecules that modulate the function of downstream proteins.
C. False. Ionotropic receptors are ligand-gated, not voltage-gated, ion channels that open in the presence of an extracellular ligand. Voltage-gated ion channels open and close in response to changes in the voltage across the cell membrane.
D. True. Tyrosine kinases are part of a receptor class that are intrinsically linked to cytoplasmic enzymes. They have an extracellular domain that binds a specific ligand and a cytoplasmic domain that contains a protein tyrosine kinase. Receptor binding activates the tyrosine kinases resulting in auto-phosphorylation of enzyme domains.
E. False. Soluble guanylate cyclase activity triggers an increase in cyclic GMP production, leading to smooth muscle relaxation and subsequent vasodilatation.
Regarding the key principles that govern drug-receptor interaction including affinity, specificity, efficacy, agonism and antagonism:
A. Drug potency is governed by both its affinity for a given receptor and its efficacy
B. Affinity is probability to which a drug binds to its receptor and is reflected by its dissociation constant
C. Half-maximal effect concentration (EC50) is the most common measure of drug efficacy
D. Efficacy is an inherent property of an agonist and reflects its ability to activate the receptor and produce a maximal biological response
E. The inhibitory effect of a non-competitive antagonist is surmountable with the additional agonist
A. True. The overall effect for a given drug is dictated by both the fraction of receptors it is able to occupy and its ability to produce a biological effect.
B. True. A drug that avidly binds to a receptor is said to have a high affinity. The dissociation constant represents the concentration at which 50% of receptors are occupied. A drug with a low dissociation constant has a greater affinity. This results in a shift of the log dose-response curve to the left.
C. False. Half maximal affect concentration is the most common measure of potency. It represents the concentration at which a drug produces 50% of its maximal possible response. The more potent a drug the lower the EC50.
D. True. Efficacy is a property of the drug, not the receptor. Drugs that bind to a receptor but produce less than maximal activation are partial agonists whereas an inverse agonist displays negative efficacy.
E. False. Only the inhibitory effects of a competitive antagonist can be overcome by increasing the dose of an agonist. This is because increasing the agonist concentration effectively displaces the antagonist from its binding site. Non-competitive antagonists either bind irreversibly to the agonist binding site or to a distant site, reducing agonist binding via an allosteric mechanism. An example is ketamine with glutamate at the NMDA receptor with the CNS.
Regarding the actions of certain drugs:
A. The action of lidocaine is dependent on the blockade of the sodium voltage-gated ion channel
B. Noradrenaline is an endogenous neurotransmitter that causes vasoconstriction by stimulating alpha-1 adrenoceptors and positive inotropic / chronotropic effects via beta-1 adrenoceptors
C. Propofol is a non-barbiturate hypnotic intravenous agent that binds to the beta-subunit of the GABAA receptor resulting in cell hyperpolarisation via a reduction in chloride channel conductance
D. Opioid receptors are inhibitory G protein-coupled receptors that act to reduce pain transmission and are subject to desensitisation with chronic stimulation
E. Benzodiazepines modulate the effects of GABAA at GABAB receptors
A. True. Lidocaine crosses the phospholipid cell membrane in its unionized, lipid-soluble form and binds to the internal surface of a sodium channel, preventing it from leaving the inactivated state.
B. True. Noradrenaline activates Gq-proteins (via alpha-1 adrenoceptors) and Gs-proteins (via beta-1 adrenoceptors). This results in an increase in intracellular calcium and cAMP respectively.
C. False. The GABAA receptor is a ligand-gated chloride ion channel that is anion selective and inhibitory. Activation results in an increase in channel opening allowing increase chloride ion entry and cell hyperpolarisation.
D. True. Opioid receptors are G protein-coupled receptors linked to inhibitory G proteins. When stimulated by an opioid agonist, hyperpolarisation of the cell membrane and reduced levels of cyclic AMP result in the inhibition of neurotransmitter release
E. False. Benzodiazepines act on specific allosteric binding sites on the ionotropic GABAA receptor (ligand-gated ion channel) exerting their anxiolytic or sedative effects. GABAB receptors are metabotropic (acting via G protein and second messengers) and when stimulated increase potassium conductance, thereby hyperpolarising the neuronal membrane. The antispasmodic baclofen is an example of a GABAB receptor agonist.
Give an overview of agonists and antagonists, and their relevance to anaesthesia.
define the terms affinity, potency and efficacy
define the terms agonist and antagonist
describe the concepts of full and partial agonism
discuss inverse agonism
describe the concepts of competitive, non-competitive, reversible and irreversible antagonism
The law of mass action is fundamental in the relationship between drug and receptor. It states that the rate of the reaction is proportional to the concentrations of the reacting elements (drug, receptors, and drug-receptor complexes).
Affinity describes how avidly a drug will bind to its receptor. The dissociation constant (KD) refers to the tendency of the drug-receptor complex to dissociate back to its component parts. A drug with high affinity will have a low KD.
Potency describes the quantity (either concentration or dose) of a drug required to produce a maximal effect. Higher potency will result in lower values for EC50 and ED50.
Efficacy describes the maximum effect produced by a drug once it has bound to the receptor. Intrinsic activity provides a means of quantifying this on a scale from -1.0 to 1.0.
An agonist is a drug with affinity for a receptor that has intrinsic activity once bound. An antagonist is a drug that has affinity for a receptor but has no intrinsic activity once bound.
Regarding affinity:
A. Affinity describes how avidly a drug binds to its receptor.
B. The dissociation constant reflects the strength of the drug-receptor bond.
C. The dissociation constant has the symbol KD.
D. If a drug has a low affinity the KD will be small.
E. KD is the concentration of a drug when 50% of its receptors are occupied.
A. True.
B. False.
C. True.
D. False.
E. True.
The affinity constant reflects the strength of the drug-receptor bond. The dissociation constant reflects the tendency of the drug-receptor to dissociate back to its drug and receptor components. The dissociation constant is represented as KD. If a drug has a high affinity the KD will be small.
Regarding potency:
A. Potency describes the quantity of drug needed to activate a receptor.
B. The EC50 and ED50 refer to the same concept.
C. The EC50 is the concentration of a drug that produces 50% of the maximal response.
D. The ED is the dose of a drug that produces a response in 50% of the population.
E. A more potent drug will have a lower ED50.
A. False.
B. False.
C. True.
D. True.
E. False.
Potency refers to the quantity of drug needed to produce a maximal effect. Potency is compared using concentration (EC50) or dose (ED50). These two concepts are similar, but subtly different. A drug with a lower EC50 will have a higher potency.
Regarding efficacy:
A. The Emax is the maximum effect that can be expected from a drug.
B. Further doses of the drug will increase the Emax.
C. Intrinsic activity = Emax of a full agonist/Emax of the drug.
D. An intrinsic activity of 0 would represent an antagonist.
E. An intrinsic activity of 0.7 would represent a partial antagonist.
Submit
A. True.
B. False.
C. False.
D. True.
E. False.
The maximum effect that can be generated by a drug once it has bound to the receptor is the Emax, accordingly, further doses are unable to produce a greater effect.
Intrinsic activity is the drug’s maximal efficacy as a fraction of the maximal efficacy produced by a full agonist, i.e. intrinsic activity = Emax of the drug/Emax of a full agonist. It may lie between 1 (a full agonist) and -1 (an inverse agonist).
An intrinsic activity of 0.7 would represent a partial agonist.
Regarding agonists and antagonists:
A. An inverse agonist is a drug that produces an effect opposite to an endogenous agonist
B. Agonists can be either competitive or non-competitive
C. Increasing the concentration of the agonist will overcome the inhibitory effect of an irreversible competitive antagonist
D. Non-competitive antagonists bind at different sites to the receptor
E. Increasing the concentration of the agonist will not overcome the inhibitory effect of a non-competitive antagonist
A. True.
B. False.
C. False.
D. True.
E. True.
Antagonists may be described as either competitive or non-competitive. Competitive antagonists may be either reversible or irreversible. In the presence of a reversible competitive antagonist, increasing the concentration of the agonist will overcome any inhibitory effect.
The term that best describes the dose of a drug needed to produce a maximum effect is:
A. Affinity
B. Potency
C. Efficacy
D. Intrinsic activity
E. Full agonism
A. Incorrect. Affinity describes how avidly a drug binds to its particular receptor. Numerically it is the reciprocal of the equilibrium dissociation constant KD and represents the drug concentration at which 50% of the receptor population are occupied.
B. Correct. Potency describes the quantity of drug needed to produce a maximal effect. It is compared using concentration (EC50) or dose (ED50). The potency of a drug partly depends on its affinity for receptors and partly upon the efficiency with which it produces a response. Drugs that have high affinity for a particular receptor tend to produce a response at a lower dose, i.e. have a higher potency.
C. Incorrect. Efficacy, or Emax , is the maximum effect that can be expected from a drug once it has bound to the receptor. The maximum effect of a drug is reached when a further increase in the drug dose will not produce any greater magnitude of effect.
D. Incorrect. Intrinsic activity (IA) is the drug’s maximal efficacy as a fraction of the maximal efficacy produced by a full agonist. If no response is produced then the drug has an IA of 0, if it produces a maximal response it has an IA of 1.
E. Incorrect. A full agonist is a drug that produces a maximal response when bound to its specific receptor, i.e. it has an Emax of 1.0.
Fill in the blanks:
Once a receptor is occupied by a drug it may or may not result in activation of that receptor. Activation means that the receptor is affected by the bound drug in such a way as to elicit a tissue response, i.e. it has intrinsic activity. If the drug binds and results in activation it is an agonist. If, on the other hand, the drug binds but fails to result in activation it is an antagonist.
Please label the following dose-response curve:
A full agonist will produce a maximal (100%) response, i.e. have an Emax of 1.0. An agonist that, despite affinity for a receptor, produces a sub-maximal response is a partial agonist and will have an Emax that lies between 0 and 1.0.
Regarding inverse agonists:
A. They can have an intrinsic activity of 0.8
B. A full agonist will have a higher affinity than an inverse agonist
C. They produce an effect opposite to an endogenous agonist
D. An antagonist has an intrinsic activity of 0
E. They compete with endogenous agonists for the same receptor
A. False.
B. False.
C. True.
D. False.
E. False.
Inverse agonists will produce an effect opposite to an endogenous agonist. They will have intrinsic activity which will be expressed as a negative number. The affinity for a receptor cannot be determined based on whether it is a full or inverse agonist. Affinity refers to how easily the drug binds to a receptor, it does not provide information on the response produced.
Regarding the dose-response curve in Figure 1:
A. Agonist A has a lower Emax
B. Agonist B shows the agonist effect in the presence of a non-competitive antagonist
C. The EC50 of both agonists are identical
D. Line B shows the agonist effect in the presence of a competitive antagonist
A. False.
B. False.
C. False.
D. True.
Antagonists may be described as either competitive or non-competitive. Competitive antagonists are subdivided into those that are reversible or irreversible. In the presence of a reversible competitive antagonist, increasing the concentration of the agonist will overcome any inhibitory effect. This is not the case with irreversible antagonists. The Emax of the agonist will remain unchanged, although the EC50 will increase.
Non-competitive antagonists bind to a different site to the receptor, resulting in conformational change. Here the Emax will fall and the EC50 will increase.
Give an overview of partial agonists and inverse agonists, and the relevance to anaesthesia.
Define the terms partial agonist and inverse agonist
Draw log (dose) v response curves and relate the features of this curve according to the properties of the drug
List examples of partial and inverse agonists and recognise how their pharmacodynamics relate to their clinical use
A partial agonist is a drug which produces a sub-maximal response even when all the receptors are fully occupied. It has intrinsic activity of greater than 0 but less than 1
A partial agonist can reduce the potency of a full agonist when they act upon the same receptors and they are present simultaneously
Buprenorphine has partial agonist effects as MOP and NOP opioid receptors
Receptors are not necessarily quiescent when there is no agonist present. They can demonstrate constitutive activity
Inverse agonists suppress constitutive activity and therefore produce a negative response by the system
Inverse agonists have an intrinsic activity of less than 0
The term which best describes how well a drug binds to a receptor is:
A. Efficacy
B. Affinity
C. Potency
D. Intrinsic activity
A. Incorrect. Efficacy - describes the magnitude of receptor response produced by a drug at a defined receptor. The maximum effect of a drug is reached when a further increase in the drug dose will not produce any greater magnitude of effect.
B. Correct. Affinity - a unique, derived constant for each drug-receptor combination that is the measure of the drug’s ability to bind to that particular receptor. Numerically it is the reciprocal of the equilibrium dissociation constant (K[D]) and represents the drug concentration at which 50% of the receptor population are occupied. Receptor selectivity occurs due to differing affinity for different receptors based upon the drug structure. Selectivity is generally deemed to be favourable in drug development as it aids reduction of adverse effects caused by off-target drug actions.
C. Incorrect. Potency - the concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug’s maximal effect. The potency for a drug partly depends on its affinity for receptors and partly upon the efficiency with which it produces a response. Drugs that have high affinity for a particular receptor tend to produce a response at a lower dose, i.e. have a higher potency.
D. Incorrect. Intrinsic activity - the drug’s maximal effect presented as a fraction of the maximal efficacy (Emax) capable by a system with a full agonist acting through the same receptors under the same conditions. If no response is produced then the drug has an intrinsic activity (IA) of 0, if it produces a maximal response it has an IA of 1.
Drug A has an ED50 of 25 mg.
Drug B has an ED50 of 50 mg.
A. Drug A is half as potent as Drug B
B. Drug A is twice as potent as Drug B
C. Drug B is twice as potent as Drug A
A. Incorrect.
B. Correct. Although two drugs, A and B, may produce the same maximal system response, drug A produces a response at half the dose of drug B. Therefore drug A has twice the relative potency of drug B.
C. Incorrect.
D. Incorrect.
The graph demonstrates a log (dose) v response curve for several full agonists at a particular receptor. It demonstrates the effect of drug potency upon the curve; a less potent drug requires a higher concentration in order to produce the maximal effect (thereby shifting the curve to the right).
See if you can label this example log (dose) v response curve for full agonists:
Although all these drugs produce the same maximal response they do this at differing drug concentrations and their EC50s are different. Therefore potency is A>B>C>D.
Which statements are correct regarding the graph in Fig 1?
A. Drug B has an intrinsic activity of 0.65
B. Drug A is a partial agonist
C. If the dose of Drug B is increased it will achieve the same maximal effect as Drug A
D. Drug A is more potent than Drug
A. Correct.
B. Incorrect.
C. Incorrect.
D. Correct.
Drug B produces a response at 65% of that which is possible in the system when a full agonist is used. This equates to an IA of 0.65. Drug A has an EC50 lower than Drug B, therefore drug A is more potent than drug B.
When in the presence of a partial agonist, the full agonist log (dose) v response curve will:
A. Remain unchanged
B. Have reduced maximal effect
C. Move to the left
D. Move to the right
A. Incorrect.
B. Incorrect.
C. Incorrect.
D. Correct. This is demonstrated on the log (dose) v response graph below by the curve being pushed towards the right when both full agonist and partial agonist are present.
Regarding partial agonists:
A. A partial agonist has an intrinsic activity of 1
B. Buprenorphine shows partial agonism at MOP and NOP receptors
C. Partial agonists increase the potency of full agonists when present within the same system
D. A maximal system response can be produced by increasing the dose of the partial agonist
A. Incorrect. A partial agonist has intrinsic activity that lies between 0 and 1. It does not produce a maximal effect. A drug with an intrinsic activity of 1 is a full agonist.
B. Correct.
C. Incorrect. Partial agonists can have an antagonistic effect on full agonists, this effectively reduces the potency of the full agonist.
D. Incorrect. A partial agonist can never produce a maximal system response, regardless of dose.
Regarding inverse agonists:
A. An inverse agonist can have an intrinsic activity of 0.6
B. A full agonist will have higher affinity than an inverse agonist
C. An inverse agonist suppresses the constitutive activity in a system
D. An inverse agonist has an intrinsic activity of 0
A. Incorrect.
B. Incorrect.
C. Correct.
D. Incorrect.
Inverse agonists suppress the constitutive activity present in a system. They therefore have intrinsic activity which will be expressed as a negative number. We cannot determine which drug has greater affinity for a receptor on the basis of whether it is a full or inverse agonist. Affinity refers to how easily the drug binds to a receptor, it does not provide information on the response produced.
Label the graph, demonstrating the varying relative efficacies of an agonist, antagonist and inverse agonist.
Give an overview of Drugs Affecting Transmembrane Signalling, and the relevance to anaesthesia.
Understand the mechanisms of transmembrane signalling
Explain transmembrane signalling with regards to basic groups of drugs
Receptors use different mechanisms of transmembrane signalling
G protein-coupled receptors are affected by opioids
Ion channel receptors are affected by local anaesthetics
Insulin receptors are an example of enzyme-linked receptors
G protein-coupled receptors:
A. Constitute the largest family of transmembrane receptors
B. Depend for their activity on the dissociation of the G protein into its constitutive subunits
C. Are the predominant receptor category for anaesthetic drug action
D. Have seven transmembrane helices
E. Do not work via second messengers
A. True.
B. True.
C. False. Anaesthetic drugs predominantly target ligand-gated ion channels.
D. True.
E. False. G protein-coupled receptors synthesise second messengers, depending on which G protein is coupled to the receptor.
G protein-coupled receptors (GPCRs) are the largest family of integral membrane proteins. 50% of modern drugs target GPCRs. These include opioids.
The action of the GPCR depends on three elements:
Receptor (Fig 1a)
The receptor has seven transmembrane helices. Binding sites are in the extracellular regions or between helices. It has an intracellular binding site for the G protein.
G protein (Fig 1b)
A G protein is a heterotrimeric protein composed of three subunits – α, β and γ.
Effector molecule (Fig 1c)
The effector molecule is activated by the α subunit of the G protein. It synthesises second messengers, depending on which G protein is coupled to the receptor. For example, β adrenergic receptors stimulate production of cAMP, α1 adrenergic receptors stimulate inositol trisphosphate (IP3), diacylglycerol (DAG), and Ca2+.
Which of the following are ion channel receptors?
A. G protein-coupled receptors
B. GABA receptors
C. Sodium channel receptors
D. NMDA receptors
E. Insulin receptors
A. False. G protein-coupled receptors act via a second messenger.
B. True.
C. True.
D. True.
E. False. Insulin receptors are enzyme-linked receptors.
Ion channel receptors are multimeric proteins located in the cell membrane. Each of these proteins arranges itself to form a passage extending from one side of the hydrophobic membrane to the other. The amino acids that line the channel and the physical width of the channel determine which ions are able to pass through. Ion channels cause a much faster reaction within the cell.
Types of ion channels:
- Voltage-gated ion channels
Voltage-gated ion channels are responsive to changes in the local electrical membrane potential (Fig 1). They are critical for the function of excitable cells, such as neurons and muscle cells.
Calcium channel blockers are one example of a drug that acts on voltage-gated ion channels. Other examples are sodium channel blockers, class III antiarrhythmics and local anaesthetics.
- Ligand-gated ion channels
Ligand-gated ion channels mediate passive ion flux driven by the electrochemical gradient for the permeant ions. They are gated by the binding of a specific ligand to an orthosteric site(s) that triggers a conformational change.
They are responsible for fast synaptic transmission in the nervous system and at the somatic neuromuscular junction.
Examples of this group of ion channels are:
Nicotinic acetylcholine receptors (nAChRs)
5HT3 receptors
NMDA receptors
GABA receptors (Fig 1)
Drugs affecting these receptors include muscle relaxants and most anaesthetic induction agents.
- Other ion channels
Other ion channel families include the aquaporins (Fig 1) (which also includes aquaglyceroporins), a family of chloride channels, which includes the cystic fibrosis transmembrane conductance regulator (CFTR).
Drugs that act on these receptors are ivacaftor (CFTR potentiator) and lumacaftor (CFTR correcting).
Which receptors do the following drugs act on?
Give an overview of nuclear drug receptors, and the relevance to anaesthetics.
understand the concept of intracellular nuclear receptors
recall the main types of nuclear receptors
recall the basic mechanisms of action
explain the role these receptors play in protein synthesis and clinical response
Intracellular receptors target transcription and DNA sequencing.
They are found inside the cell membrane in the cytoplasm or nucleus of the cell.
Steroid receptors and thyroid hormone receptors are important examples of intracellular receptors.
Drugs can target these receptors causing gene expression and protein synthesis.
Which of the following are intracellular receptors?
A. G-protein coupled receptors
B. Ligand-gated channel receptors
C. Oestrogen receptors
D. Tyrosine kinase receptors
E. Thyroid hormone receptors
A. False. This is an example of a cell surface receptor.
B. False. This is an example of a cell surface receptor.
C. True. Oestrogen receptors are type 1 intracellular receptors.
D. False. This is an example of a cell surface receptor.
E. True. Thyroid hormone receptors are type 2 intranuclear receptors.
Intracellular receptors are receptors located inside the cell membrane. They can be cytosolic (in the cell cytoplasm) or intranuclear (inside the nucleus of the cell). There are 2 main types.
Type 1
Ligands bind to protein receptor in cytoplasm or nucleus (Figure 1). Some examples are:
sex hormone receptors (oestrogen, testosterone)
cortisol receptors
mineralocorticoid receptors
Type 2
Ligands bind directly to DNA proteins (Figure 2). Some examples are:
vitamin A receptors
vitamin D receptors
retinoid receptors
thyroid hormone receptors
Regarding intracellular receptors:
A. They are only found in the nucleus
B. They have intrinsic transcriptional activity
C. They have ligands that are small and lipophilic
D. They do not contain zinc loops
E. Only type 1 class intracellular receptors bind directly to DNA proteins
A. False. They can be cytosolic or intranuclear.
B. True.
C. True.
D. False. The DNA-binding domain has ‘zinc fingers’ which are phosphorylated during transcription.
E. False. Type 1 intracellular receptors bind to protein receptors in the cytoplasm or nucleus.
Intracellular receptors have intrinsic transcriptional activity (Figure 1). Structurally they have:
a transcription-activating domain
a DNA-binding domain
a ligand-binding domain
The DNA-binding domain has zinc-containing loops (‘zinc fingers’) which phosphorylate when binding occurs.
Ligands that bind to intracellular receptors are small lipophilic molecules which easily cross the phospholipid membrane, for example steroid hormones, thyroid hormones and vitamin D.
Regarding thyroid hormone receptors:
A. They are only found in the nucleus
B. They contain a DNA-binding domain
C. They are only activated by thyroxine
D. They are type 1 intracellular receptors
E. When activated, thyroid hormone receptors bind via the transcription activating domains
A. True. They are examples of intranuclear receptors.
B. True.
C. False. Thyroid receptors can be activated with or without ligand binding. Also, T4 is de-iodinated intracellularly in the cytoplasm to the more active form T3. rT3, however, is metabolically inactive.
D. False. Thyroid hormone receptors are type 2 intranuclear receptors.
E. False. The DNA-binding domain of the active TR binds via the thyroid response elements.
Thyroid hormone production is a system regulated by the hypothalamic-pituitary-thyroid axis (Figure 1). This system works via a negative feedback loop where the thyroid hormone (T3 or T4) sends a signal to the hypothalamus and anterior pituitary to decrease TRH (thyroid releasing hormone) and TSH (thyroid stimulating hormone) production respectively.
The thyroid hormone receptor (TR) is a type 2 intracellular receptor which is already inside the nucleus (Figure 2). They have an important role in the physiological functioning of the body and are responsible for growth, metabolism and development.
The effects of thyroid hormone are mediated by the changes in expression of T3 responsive genes in target tissues. These changes in gene expression can occur both with and without ligand binding, thus making these receptors unique.
When thyroid hormone binds to the TR it undergoes a conformational change. The DNA-binding domain (of the active TR) will then bind to the thyroid response elements (TREs) which are located in the promoter region of the T3-responsive gene. Subsequently, gene transcription and expression will occur (Figure 1).
When TR binds without its ligand, it recruits a co-repressor protein. This causes the gene to be silent and thus gene expression will not take place.
Regarding gene expression and protein synthesis:
A. Gene expression is a fast process
B. Gene expression and protein production occurs in minutes
C. Intranuclear receptors are important drug targets
D. Receptor activation causes protein production
E. Intranuclear receptors are important in gene transcription
A. False. It is a slow process.
B. False. It occurs in hours to days.
C. True. Many useful drugs target intranuclear receptors, for example exogenous steroids.
D. True. The ultimate aim of gene expression is the production of specific proteins.
E. TrueIt is important to understand how these receptors work, as they are frequently targeted in clinical practice.
Intranuclear receptors have a slow onset of action. This is why it can take hours to days to see clinical responses when drugs targeting these receptors are given. It takes time for gene expression and protein production to occur once the receptor is activated. Furthermore, once administered, these drugs can have longer durations of action, lasting beyond the drug’s presence in the body.
Think about the patient with an exacerbation of asthma; the steroids given will not work immediately. In order to produce the desired clinical outcome (decreased inflammatory immune response) it will take several hours to days.
Give an overview of Enzymes as Drug Targets Including Anticholinesterases, and the relevance to anaesthetics.
Describe anticholinesterases, their mechanism of action (including short- vs medium- vs long-acting) and their common uses
List carbonic anhydrase inhibitors and their uses
Identify NSAIDs and their mechanisms of action
Describe monoamine oxidase inhibitors and their uses
Enzymes are important for the body to be able to carry out fast chemical reactions, which allows complex multicellular organisms to exist
Carbonic anhydrase inhibitors are used for glaucoma and for mountain sickness. They achieves this by alkalinisation of urine to create a metabolic acidosis to cause further hyperventilation to improve oxygenation
NSAIDs are a group of anti-inflammatory agents that are used as opioid sparring pain killers
MAOi are rarely used as first-line drugs, although a certain proportion of patients are still on these and thus special attention needs to be paid to them to avoid potentially catastrophic complications
Regarding anticholinesterases:
A. They are divided into ultra-fast acting, medium-acting and long-acting subgroups
B. Tensilon test is a diagnostic test for Myasthenia Gravis
C. Neostigmine is hydrolysed in exactly the same way as acetylcholine, but takes much longer
D. Medium-acting anticholinesterases can be used as oral treatment of myasthenic crisis
A. False. Anticholinesterases are divided into short-, medium- and long-acting.
B. True.
C. True.
D. False. Myasthenic crisis is a complication of myasthenia gravis characterised by worsening of muscle weakness, resulting in respiratory failure that requires intubation and mechanical ventilation.
Anticholinesterases are agents that target the enzyme acetylcholinesterase by occupying its active site to prevent ACh breakdown (Fig 1).
They are used for a multitude of clinical scenarios. For anaesthetists they are most commonly used to reverse the effects of non-depolarising muscular blocking agents (NdMBA). By reducing the breakdown of ACh, anticholinesterases increase the competitive displacement of NdMBA from the neuromuscular junction (NMJ).
They are also used in the diagnosis and treatment of myasthenia gravis (MG) and are an ingredient in pesticides and nerve gases.
They are classified according to duration of action:
- Short-acting
Edrophonium (Tensilon) (Fig 1) is an example of a short-acting anticholinesterase:
Lasts 10-20 mins
Used to diagnose MG, where the strength of muscles improves after administration of Tensilon - Medium-acting
Neostigmine (Fig 2):
Lasts 1-2 hours
Carbamylates the active site of the enzyme and, once bonded, it is hydrolysed like ACh, but takes much longer
Inhibits the action of plasma pseudocholinesterases and so prolongs the effects of suxamethonium and mivacurium
Reverses competitive neuromuscular blockers and is used to treat constipation on the Intensive Care Unit (ICU)
Is added to glycopyrrolate to offset that drug’s parasympathetic anticholinergic effects, e.g. bradycardia, hypotension, bronchoconstriction
Pyridostigmine
Lasts 2 to 3 hours
An oral treatment of MG
Physostigmine
Lasts 30 minutes to 5 hours
Available as topical eye drops for treatment of glaucoma
- Long-acting
chothiophate (Fig 3):
Lasts weeks
Phosphorylates the active site of the enzyme in a covalent bond. The enzyme, therefore, takes weeks to hydrolyse the drug
Was historically used for treatment of glaucoma
This group also includes Sarin and VX nerve gases used in chemical warfare, and tetraethyl pyrophosphate (TEPP) which is an insecticide
In toxic doses, e.g. organophosphorus poisoning, anticholinesterases cause SLUDGE syndrome (Salivation, Lacrimation, Urination, Defecation, GI upset and Emesis) and can cause death by paralysis of the respiratory muscles. Treatment is with antimuscarinic agents such as atropine or pralidoxime
Regarding long-acting anticholinesterases:
A. They can last days, not weeks
B. They form an ionic bond with the enzyme that takes weeks to break down
C. They are used in chemical warfare and pesticides
D. SLUDGE syndrome includes sweating, lacrimation, uraemia, defecation, GI upset and erectile dysfunction
A. False. Long-acting drugs can last weeks.
B. False. They form a covalent bond that takes weeks to break down.
C. True.
D. False. Sludge syndrome is characterised by salivation, lacrimation, urination, defecation, GI upset and emesis.
Carbonic anhydrase enzymes are found in the following cells:
A. Gastrin cells of the stomach
B. Proximal convoluted tubules in the kidney
C. Red blood cells
D. Pancreatic cells
A. False. Carbonic anhydrase enzymes are found in the parietal cells of the stomach.
B. True.
C. True.
D. True.
Carbonic anhydrase is an enzyme that catalyses the following formulae:
CO2 + H2O H2CO3 ←→ H+ + HCO3
Acetazolamide is a carbonic anhydrase inhibitor which is used for the treatment of mountain sickness and as a weak diuretic, as well as for the prophylaxis and treatment of glaucoma.
These act on the proximal convoluted tubules. They are non-competitive inhibitors of the enzyme affecting the sodium/H+ exchanger, thus causing alkaline urine with metabolic acidosis.
Regarding NSAIDs:
A. NSAIDs can be classified by their structure or COX inhibition
B. They have no opioid sparing effect
C. NSAIDs all have anti-platelet activity
D. COX 2 inhibitors have no significant risks
A. True.
B. False. NSAIDs have opioid sparing effect.
C. False. Only aspirin has been used for its antiplatelet activity.
D. False. COX 2 inhibitors have less risk of bleeding, but still have significant side-effects. Some have been withdrawn due to their increased risk of thrombotic complications.
Regarding cyclo-oxygenase inhibitors:
A. COX 2 is found in most cells under normal conditions
B. They aim to reduce the inflammatory mediators produced by the COX enzyme
C. They cannot trigger an asthma attack in those susceptible
D. Prostanoids are in a fine balance with prostacyclin
A. False. COX 1 is found in most cells, COX 2 is found mainly in inflammatory cells.
B. True.
C. False. COX inhibitors are well known to cause deterioration in asthma of those susceptible to this, by increasing production of leukotrienes causing bronchospasm.
D. True.
Non-steroidal anti-inflammatory drugs (NSAIDs) exert their effects by inhibiting the action of cyclo-oxygenase (COX) enzymes, thus reducing the production of prostanoids, i.e. inflammatory mediators. There are three forms of COX:
COX-1 is constitutive and is found in most cells
COX-2 is inducible and is normally undetectable in normal tissues, but is found in abundance in macrophages and other inflammatory cells
COX-3 is an isoenzyme most likely to be a CNS variant of COX-1 (site of action of paracetamol)
Normally prostanoids are in a fine balance with prostacyclin, a vasodilator which also prevents formation of platelet plug, and thromboxane, a vasoconstrictor and potent platelet aggregator.
COX inhibitors block conversion of arachidonic acid to prostanoids and thus more of it is converted to leukotrienes, which can cause bronchospasm - this is the mechanism whereby some asthmatics may worsen on administration of NSAIDs.
COX inhibitors can be classified either by structure or by COX inhibition:
Structure:
Acetylsalicylic acid (aspirin)
Phenyloacetic acids (diclofenac)
Carboacetic acid (indomethacin)
Propionic acids (ibuprofen)
Enolic acid (piroxicam)
COX inhibition:
Non-selective, e.g. aspirin, diclofenac and ibuprofen
Selective, e.g. parecoxib
NSAIDs are used as anti-inflammatory and analgesic agents. They have opioid-sparing effects.
Aspirin has unique antiplatelet action and thus is used for the prophylaxis and treatment of arterial thrombosis.
COX-2 inhibitors cause less risk of bleeding and cause fewer ulcers, but some of these have been associated with increased incidence of thrombotic complications, especially myocardial infarction.
GI bleeding risk is due to decreased levels of circulating prostaglandins that are essential in maintaining gastric mucosal integrity.
NSAID-induced exacerbation of asthma occurs in 10-20% of asthmatics due to increase production of leukotrienes.
Regarding monoamine oxidase:
A. They are normally bound to the cell surface
B. They break down monamines in the body only from food sources
C. They can have a role in psychiatric conditions
D. The two main types are MAO-AB and MAO-RIMA
A. False. They are normally attached to mitochondria.
B. False. They help break down all monoamines, including ones from food, and thus can inadvertently lead to a hypertensive crisis.
C. True. They have been implicated in many neurological and psychiatric conditions.
D. False. They are classified as MAO-A, RIMA or MAO-B.
Monoamine oxidases are a group of enzymes that, as the name suggests, catalyse the oxidation of monoamines. This uses its oxygen molecule to remove an amine group from the drug in question. They are found in most cell types, normally bound to the mitochondria.
They breakdown monoamines in food and hence are found in the liver, aka tyramine oxidase. They are also vital in the breakdown of monoamine neurotransmitters, and as such have a big role in many neurological and psychiatric conditions, where monoamine oxidase inhibitors (MAOi) are used.
There are two types of monoamine oxidases found in humans:
MAO-A
MAO-A is found in high concentrations in the cortex, while the cingulate gyrus had an equal balance of both. These are found in areas where there is increased serotonergic neurotransmission
MAO-A is found in the liver, pulmonary vascular endothelium, GI tract and placenta
MAO-B
MAO-B is found in the striatum and Globus pallidus in high quantities, and correlates to areas of the brain where there is a high level of noradrenaline neurotransmission (norepinephrine)
There are equally high levels of both MAO in the hypothalamus and hippocampal uncus
MAO-B is found in platelets
MAO-A and MAO-B deaminate monoamines by oxidation, as described earlier, and as indicated by the name.
Oxygen is used to remove an amine group, and its adjacent hydrogen atom, from the molecule in question, resulting in a ketone, or aldehyde, and ammonia (Fig 1).
Monoamine oxidases are classified as belonging to the family of proteins known as flavin-containing amine oxidoreductases (flavoproteins). They have a covalently-bonded FAD (flavin adenine dinucleotide). Both types are very similar in structure and have hydrophobic substrate binding sites.
MAO-A breaks down:
Serotonin
Melatonin
Noradrenaline
Adrenaline
MAO-B breaks down:
Phenethylamine
Benzylamine
They both also breakdown:
Dopamine
Tyramine
Tryptamine
MAOi can be divided into non-selective (older) and selective agents, as well as Reversible Inhibitors of MAO-A (RIMAs)
Regarding MAO:
A. MAO are found in the brain, liver, lung and placenta
B. Only MAO-B is found from birth
C. They remove an amine from a molecule
D. They are part of the flavoprotein family
A. True.
B. False. Only MAO-A is found from birth
C. True.
D. True.
MAO-A breaks down:
A. Noradrenaline
B. Metformin
C. Adrenaline
D. Selegiline
A. True.
B. False.
C. True.
D. False.
A good way to remember this is: MAO-A breaks down MANS (melatonin, adrenaline, noradrenaline and serotonin).
MAOi:
A. Are used as first-line agents in depression
B. Can be used in combination with SSRI/SNRI
C. Can be used in Parkinson’s disease
D. Can sometimes be used as prophylaxis in migraines
A. False. These drugs are not routinely used as first-line agents due to their many interactions, especially with food products.
B. False. They should never be used in conjunction with SSRIs/SNRIs due to the unacceptable risk of increased neurotransmitter levels in the brain causing hypertensive crisis.
C. True.
D. True.
Monoamine oxidases are a group of enzymes that, as the name suggests, catalyse the oxidation of monoamines. This uses its oxygen molecule to remove an amine group from the drug in question. They are found in most cell types, normally bound to the mitochondria.
They breakdown monoamines in food and hence are found in the liver, aka tyramine oxidase. They are also vital in the breakdown of monoamine neurotransmitters, and as such have a big role in many neurological and psychiatric conditions, where monoamine oxidase inhibitors (MAOi) are used.
There are two types of monoamine oxidases found in humans:
MAO-A
MAO-A is found in high concentrations in the cortex, while the cingulate gyrus had an equal balance of both. These are found in areas where there is increased serotonergic neurotransmission
MAO-A is found in the liver, pulmonary vascular endothelium, GI tract and placenta
MAO-B
MAO-B is found in the striatum and Globus pallidus in high quantities, and correlates to areas of the brain where there is a high level of noradrenaline neurotransmission (norepinephrine)
There are equally high levels of both MAO in the hypothalamus and hippocampal uncus
MAO-B is found in platelets
MAO-A and MAO-B deaminate monoamines by oxidation, as described earlier, and as indicated by the name.
Oxygen is used to remove an amine group, and its adjacent hydrogen atom, from the molecule in question, resulting in a ketone, or aldehyde, and ammonia (Fig 1).
Monoamine oxidases are classified as belonging to the family of proteins known as flavin-containing amine oxidoreductases (flavoproteins). They have a covalently-bonded FAD (flavin adenine dinucleotide). Both types are very similar in structure and have hydrophobic substrate binding sites.
MAO-A breaks down:
Serotonin
Melatonin
Noradrenaline
Adrenaline
MAO-B breaks down:
Phenethylamine
Benzylamine
They both also breakdown:
Dopamine
Tyramine
Tryptamine
MAOi can be divided into non-selective (older) and selective agents, as well as Reversible Inhibitors of MAO-A (RIMAs)
MAOi can cause:
A. Red man syndrome
B. Psychosis
C. Nausea, diarrhoea and/or constipation
D. Headache, drowsiness and/or insomnia
A. False. Red man syndrome is a skin reaction most associated with by overstimulation of specific immune cells in the body in response to vancomycin. MAOi can cause serotonin syndrome.
B. True.
C. True.
D. True.
Which of the following drugs are irreversible enzyme inhibitors?
A. Penicillin
B. Diclofenac
C. Aspirin
D. Omeprazole
E. S-Warfarin
A. True. Penicillin and other beta-lactam antibiotics irreversibly inhibit transpeptidase in the bacterial cell wall, disrupting peptidoglycan cross-linking and cell wall synthesis.
B. False. Diclofenac is a reversible COX inhibitor.
C. True. Aspirin is an irreversible enzyme inhibitor of platelet cyclo-oxygenase for the platelet’s lifespan, requiring the formation of new platelets to recover their normal function.
D. True. Omeprazole is a proton pump inhibitor that irreversibly inhibits the hydrogen/potassium ATPase pump in gastric parietal cells to decrease acid secretion. The synthesis of new proton pumps is necessary to produce gastric acid again.
E. False. Warfarin inhibits vitamin K epoxide reductase, which is required to regenerate reduced vitamin K, which can then activate clotting factors.
Irreversible enzyme inhibitors either act via allosteric binding to alter the active site, or by binding directly to the active site of the enzyme.
This last mechanism is usually through the drug forming covalent bonds at the active site of the enzyme. This prevents it from binding its endogenous ligand, but also the drug-enzyme complex cannot dissociate so the degree of inhibition cannot be overcome by increasing the substrate concentration. Reversal, therefore, depends on the synthesis of new enzymes, e.g. the action of aspirin on cyclo-oxygenase.
Proton pump inhibitors, e.g. omeprazole, also irreversibly inhibit the hydrogen/potassium ATPase pump in gastric parietal cells to decrease acid secretion. The synthesis of new proton pumps is necessary to produce gastric acid.
Drugs may act as analogues to an endogenous ligand and can compete with them to transiently block the active site of the enzyme from being accessed, decreasing the rate of complex formation and reaction.
The degree of inhibition depends on the concentration of the drug relative to that of the endogenous substrate, so increasing inhibition as the drug concentration rises.
Inhibition may be overcome by increasing the amount of substrate present, therefore the Vmax eventually achieved remain the same, but are reached at a slower rate.
Most competitive inhibitiors act reversibly.
Examples of reversible competitive enzyme inhibitors include:
Acetylcholinesterase inhibitors, e.g. neostigmine
Cyclo-oxygenase inhibitors, e.g. non-steroidal anti-inflammatory drugs: ibuprofen and diclofenac
Phosphodiesterase inhibitors, e.g. theophylline
Angiotensin converting enzyme inhibitors, e.g. ramipril
GIve an overview of Enzyme Induction and Inhibition, and the relevance to anaesthesia.
Discuss enzyme kinetics
Define the drugs that target enzyme systems
Explain the processes of enzyme induction and inhibition
Describe common pharmacokinetic interactions occurring due to altered enzyme activity
Drugs may elicit their therapeutic effect through enzyme stimulation or inhibition
A number of commonly used drugs are direct enzyme inhibitors
Drug metabolism by the cytochrome P450 enzyme system is subject to Michaelis-Menten kinetics
Pharmacokinetic metabolic interactions can occur due to cytochrome P450 enzyme induction or inhibition leading to adverse drug effects
Examples of acetylcholinesterase inhibitors and their mechanism of action include:
Neostigmine and pyridostigmine
Neostigmine and pyridostigmine act as substrates to form a carbamylated enzyme complex with AChE, with a slow rate of hydrolysis over 30 minutes, preventing it from metabolising ACh.
Organophosphate compounds
Organophosphate compounds irreversibly inhibit AChE. They phosphorylate the esteratic site of AChE, making it resistant to hydrolysis and reactivation. It may be reactivated with pralidoxime. Pralidoxime binds to the anionic site of AChE, then cleaves the phosphate-ester bond. Thus the organophosphate dissociates from AChE.
Organophosphate poisoning produces a cholinergic syndrome featuring salivation, urination, diarrhoea, muscle weakness and bradycardia and requires resuscitation and organ support to allow time for enzyme recovery or synthesis, and elimination of the poison.
Edrophonium
Edrophonium acts by binding to the anionic site, reversibly inhibiting AChE. It has a fast onset of action with a short duration and is used clinically to differentiate a myasthenic crisis, where neuromuscular function should improve, from that of a cholinergic crisis.
Monoamine oxidases (MAO) are isoenzymes which deaminate neurotransmitters. Types A and B exist; MAO-A deaminates serotonin and catecholamines and MAO-B deaminates tyramine and phenyethamine. Both metabolise dopamine.
MAO inhibitors are used in the management of resistant depression, obsessive compulsive disorder, chronic pain and Parkinson’s disease.
The older non-selective monoamine oxidase inhibitors, phenelzine and tranylcypromine, act irreversibly. Moclobemide is a reversible selective MAO-A inhibitor and selegeline is an irreversible selective MAO-B inhibitor.
Question. Which antibiotic is a reversible MAO inhibitor?
Linezolid, used in the treatment of resistant infections such as vancomycin-resistant Enterococci and methicillin-resistant Staphylococcus aureus, is a reversible MAO inhibitor.
Any patient taking MAO inhibitors may exhibit pronounced hypertension and arrhythmias on administration of indirectly acting sympathomimetics which are metabolised by MAO and should be avoided. Directly acting sympathomimetic amines should also be used with caution as they may also have an exaggerated response, but they are additionally metabolised by catechol-o-methyl-transferase.
G protein-coupled receptors (GPCRs) act through second messenger systems, i.e they are metabotropic. GPCR stimulation triggers coupling with a specific G protein on the intracellular side of the membrane to activate or inhibit enzymes. G proteins Gs or Gi stimulate or inhibit respectively, the enzyme adenylyl cyclase that regulates cAMP formation (Fig 1). Gq activates phospholipase C.
Question: Can you give an example of a drug that works via a Gi protein-coupled receptor?
Morphine. Opioid receptors MOP, KOP and DOP are linked to Gi. When stimulated by opioid-receptor binding, it leads to the inhibition of adenylyl cyclase, reducing levels of cAMP, and therefore decreasing neurotransmitter release.
What are the potential effects of treating a patient taking diltiazem with clarithromycin?
Clarithromycin inhibits CYP 3A4 activity, reducing the metabolism of calcium channel blockers such as diltiazem, leading to increased serum concentrations with an increased risk of bradycardia, A-V blockade and hypotension.
In the case of pro-drugs, enzyme inhibitors reduce their conversion into active metabolites and decrease the drug’s effect. For example, inhibition of the CYP 2D6 isoenzyme that metabolises codeine results in the decreased production of codeine-6-glucuronide, norcodeine and morphine, and patients may experience less effective analgesia. This is seen with the co-administration of anti-depressants like fluoxetine.
Conversely, a patient taking an enzyme-inducer, such as carbamazepine, may demonstrate an increased analgesic effect.
Regarding mechanisms of enzyme inhibition:
A. Neostigmine and pyridostigmine competitively inhibit acetylcholinesterase
B. Non-competitive inhibitors can be overcome by increasing the substrate concentration
C. Aminophylline and theophylline are examples of selective PDE inhibitors
D. The cytochrome P450 enzyme system is not subject to dose-dependent kinetics
E. Genetic polymorphisms in CYP can influence the speed of dug metabolism and response
A. True. Neostigmine, pyridostigmine and physostigmine are reversible enzyme carbamylators that act as substrates binding to both sites of AChE to form a carbamylated enzyme complex, with a slow rate of hydrolysis over 30 minutes, preventing it from metabolising ACh.
B. False. Non-competitive inhibitors bind away from the active site of the enzyme, preventing it from being activated, inhibiting product formation. It decreases the Vmax achievable and cannot be overcome by increasing the substrate concentration.
C. False. Aminophylline and theophylline are examples of non-selective PDE inhibitors. They are used in the management of acute severe asthma and uncontrolled chronic asthma for their bronchodilatory effects.
D. False. CYP enzyme-drug reactions follow dose-dependent kinetics as described by the Michaelis-Menten equation influencing the plasma drug levels achieved.
E. True. There are poor, extensive and ultra-rapid phenotypes. Extensive and rapid phenotypes rapidly metabolise relevant drugs, leading to reduced plasma levels with loss of efficacy, necessitating increased doses to achieve a therapeutic response. However, they metabolise pro-drugs like codeine into their active metabolites faster, with a greater risk of opioid-related side-effects.
Regarding Michaelis-Menten kinetics:
A. They obey the law of mass-action
B. The Michaelis constant, Km is the concentration of substrate at which the reaction is occurring at 50% of its maximum velocity
C. They describe the affinity the enzyme has for its substrate
D. The addition of a competitive inhibitor to an enzyme reaction decreases the Vmax that can be achieved
E. They describe kinetics involving covalent bonding between enzyme and substrate
A. True. Michaelis-Menten kinetics obey the law of mass action between receptor saturation and drug concentration.
B. True. Km is the concentration of substrate at which the reaction is at 50% of its maximum velocity.
C. True. It is also a measure of the binding affinity between the enzyme and a specific substrate. A higher Km indicates a lower affinity of the enzyme for a substrate and a higher concentration of substrate is necessary to bind the enzyme to reach Vmax, which is approached more slowly.
D. False. Competitive inhibitors block the active site, therefore decreasing enzyme affinity and increasing the Km. Increasing the substrate concentration increases enzyme-substrate complex formation, so the Vmax achievable is not altered, whereas a non-competitive inhibitor decreases the Vmax that can be achieved.
E. False. Michaelis-Menten kinetics describe enzyme and substrate reactions which are weakly bonded and allow dissociation.
Enzymes are protein catalysts that increase the speed at which chemical reactions occur with substrates at physiological conditions, without being expended themselves. They lower the activation energy necessary to start a reaction and orientate molecules to allow the reaction to progress more rapidly.
They have an active site, which binds a specific substrate to form an enzyme-substrate complex. This reacts to either synthesise or release a product, subsequently leaving the enzyme intact for future reactions (Fig 1).
The rate of such chemical reactions can be described as follows:
First order reaction, whose rate depends on the concentration of the reacting substrate and is an exponential process approaching a maximum velocity
Zero order reaction; this is reached when the enzyme systems’ active sites have all become saturated. The rate then becomes constant and independent of any further changes in the substrate concentration
The Michaelis-Menten equation can be used to describe the rate or velocity of such reactions.
The Michaelis-Menten equation can be used to describe the rate or velocity of such reactions.
V = (Vmax [S]) / (Km + [S])
V is the velocity of the reaction.
Vmax is the maximum velocity of the reaction. This is reached when enzymes active sites have been saturated with substrate.
S is the substrate concentration.
Km is the Michaelis constant, specific to a single substrate-enzyme reaction. It is defined as the concentration of substrate at which the velocity of the reaction is half of the maximum velocity, Km = ½Vmax as demonstrated in Fig 1.
It is also the reciprocal of the enzymes affinity for a specific substrate. A small Km will have a high affinity for a substrate so less is required to reach ½Vmax at a faster rate.
Cytochrome P450 enzyme induction:
A. Increases the formation of new CYP enzymes
B. Produces a conformational change in the enzymes active site to increase substrate binding
C. May be caused by smoking
D. Is not associated with alcohol consumption
E. Develops immediately following drug binding
A. True. Enzyme induction involves increased transcription and production of more isoenzyme to increase metabolic activity.
B. False. There is no change in the active site. However, the presence of more enzyme increases its affinity for the substrate.
C. True. Polycyclic aromatic hydrocarbons in cigarette smoke can induce CYP1A2 and CYP2E1 expression with higher rates of metabolism of opioids and volatile agents.
D. False. Alcohol abuse strongly induces CYP2E1 enzyme expression.
E. False. Enzyme induction takes some time to develop.
Drug metabolism occurs mainly in the liver in two phases. Drugs generally undergo phase I followed by phase II reactions, but some are metabolised by phase II reactions only:
Phase I reactions include oxidation, reduction and hydrolysis and are catalysed by the cytochrome P450 (CYP) enzyme system. They are also required to convert pro-drugs such as codeine and ACE inhibitors into their active form
Phase II reactions include glucuronidation, sulfation, acetylation and methylation. These processes conjugate drugs to increase their water solubility and improve their excretion. They involve enzymes such as uridine-diphospho-glucuronosyl transferase, which have a role in the metabolism of drugs like codeine, morphine, and propofol. These may also be subject to enzyme induction
CYP is mainly found in the smooth endoplasmic reticulum of hepatocytes as well as many tissues throughout the body, including the gut mucosa, kidney and lung. They are classified into a number of families, subfamilies and isoforms, with some drugs being metabolised by more than one isoenzyme.
57 of these isoenzymes have been identified, with 30 being involved in drug metabolism, the majority of which is performed by only 6:
CYP 1A2
CYP 2C9
CYP 2C19
CYP 2D6
CYP 2E1
CYP 3A4
These are listed in Table 1, with some important drugs they metabolise.
These CYP enzyme-drug reactions follow dose-dependent kinetics as described by the Michaelis-Menten equation. Plasma levels of a drug may therefore be affected by the concurrent administration of other drugs undergoing metabolism by the same cytochrome P450 isoenzyme.
CYP2D6 is an important isoform with numerous polymorphisms and is involved in the metabolism of commonly encountered perioperative drugs such as codeine, tramadol, ondansetron, as well as antidepressants, neuroleptics, beta-blockers and anti-arrhythmics. Polymorphisms result in variable individual responses to opioids; 5-10% of Caucasians are poor metabolisers, 65-80% are extensive metabolisers and 5-10% are ultra-rapid metabolisers with a variable prevalence found globally. Ultra-rapid metabolism is seen in up to 29% of the population in Ethiopia, but only in 0.5% of the Chinese, where 30% may be poor metabolisers.
CYP3A is the most abundant subfamily and is responsible for metabolising opioids, benzodiazepines, tricyclic antidepressants, anti-arrhythmics, calcium channel antagonists and statins amongst many other drugs.
Regarding the Cytochrome P450 system:
A. Centrilobular hepatocytes contain low concentrations of CYP450
B. It is involved in phase 2 reactions
C. Drugs that are activated by CYP450 enzymes display an increased effect with enzyme induction
D. CYP450 isoenzymes metabolise specific substrates
E. The majority of all drug metabolism occurs through only 6 isoenzymes
A. False. Centrilobular hepatocytes contain high concentration of CYP 450 enzymes.
B. False. Phase I reactions include oxidation, reduction and hydrolysis and are catalysed by the cytochrome P450 (CYP) enzyme system.
C. True. Pro-drugs that require activation will demonstrate an increased effect in the presence of enzyme inducers.
D. True. Enzymes react with specific substrates.
E. True. 90% of foreign substances are metabolised by the following six isoenzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.
Drug metabolism occurs mainly in the liver in two phases. Drugs generally undergo phase I followed by phase II reactions, but some are metabolised by phase II reactions only:
Phase I reactions include oxidation, reduction and hydrolysis and are catalysed by the cytochrome P450 (CYP) enzyme system. They are also required to convert pro-drugs such as codeine and ACE inhibitors into their active form
Phase II reactions include glucuronidation, sulfation, acetylation and methylation. These processes conjugate drugs to increase their water solubility and improve their excretion. They involve enzymes such as uridine-diphospho-glucuronosyl transferase, which have a role in the metabolism of drugs like codeine, morphine, and propofol. These may also be subject to enzyme induction
CYP is mainly found in the smooth endoplasmic reticulum of hepatocytes as well as many tissues throughout the body, including the gut mucosa, kidney and lung. They are classified into a number of families, subfamilies and isoforms, with some drugs being metabolised by more than one isoenzyme.
57 of these isoenzymes have been identified, with 30 being involved in drug metabolism, the majority of which is performed by only 6:
CYP 1A2
CYP 2C9
CYP 2C19
CYP 2D6
CYP 2E1
CYP 3A4
These are listed in Table 1, with some important drugs they metabolise.
These CYP enzyme-drug reactions follow dose-dependent kinetics as described by the Michaelis-Menten equation. Plasma levels of a drug may therefore be affected by the concurrent administration of other drugs undergoing metabolism by the same cytochrome P450 isoenzyme.
CYP2D6 is an important isoform with numerous polymorphisms and is involved in the metabolism of commonly encountered perioperative drugs such as codeine, tramadol, ondansetron, as well as antidepressants, neuroleptics, beta-blockers and anti-arrhythmics. Polymorphisms result in variable individual responses to opioids; 5-10% of Caucasians are poor metabolisers, 65-80% are extensive metabolisers and 5-10% are ultra-rapid metabolisers with a variable prevalence found globally. Ultra-rapid metabolism is seen in up to 29% of the population in Ethiopia, but only in 0.5% of the Chinese, where 30% may be poor metabolisers.
CYP3A is the most abundant subfamily and is responsible for metabolising opioids, benzodiazepines, tricyclic antidepressants, anti-arrhythmics, calcium channel antagonists and statins amongst many other drugs.
Regarding cytochrome P450 enzyme inhibition:
A. Drugs may inhibit multiple classes of isoenzymes
B. Glucocorticoids are potent enzyme inhibitors
C. Competitive inhibition decreases as the drug plasma concentration falls
D. Penicillin is a reversible bacterial transpeptidase inhibitor
E. Neostigmine is a reversible competitive acetylcholinesterase inhibitor
A. True.
B. False. Dexamethasone is an inducer of CYP2D6.
C. True.
D. False. Penicillin and beta-lactam antibiotics are irreversible inhibitors of transpeptidase and inhibit peptidoglycan cross-linking, therefore weakening the bacterial cell wall.
E. True.
Drug metabolism occurs mainly in the liver in two phases. Drugs generally undergo phase I followed by phase II reactions, but some are metabolised by phase II reactions only:
Phase I reactions include oxidation, reduction and hydrolysis and are catalysed by the cytochrome P450 (CYP) enzyme system. They are also required to convert pro-drugs such as codeine and ACE inhibitors into their active form
Phase II reactions include glucuronidation, sulfation, acetylation and methylation. These processes conjugate drugs to increase their water solubility and improve their excretion. They involve enzymes such as uridine-diphospho-glucuronosyl transferase, which have a role in the metabolism of drugs like codeine, morphine, and propofol. These may also be subject to enzyme induction
CYP is mainly found in the smooth endoplasmic reticulum of hepatocytes as well as many tissues throughout the body, including the gut mucosa, kidney and lung. They are classified into a number of families, subfamilies and isoforms, with some drugs being metabolised by more than one isoenzyme.
57 of these isoenzymes have been identified, with 30 being involved in drug metabolism, the majority of which is performed by only 6:
CYP 1A2
CYP 2C9
CYP 2C19
CYP 2D6
CYP 2E1
CYP 3A4
These are listed in Table 1, with some important drugs they metabolise.
These CYP enzyme-drug reactions follow dose-dependent kinetics as described by the Michaelis-Menten equation. Plasma levels of a drug may therefore be affected by the concurrent administration of other drugs undergoing metabolism by the same cytochrome P450 isoenzyme.
CYP2D6 is an important isoform with numerous polymorphisms and is involved in the metabolism of commonly encountered perioperative drugs such as codeine, tramadol, ondansetron, as well as antidepressants, neuroleptics, beta-blockers and anti-arrhythmics. Polymorphisms result in variable individual responses to opioids; 5-10% of Caucasians are poor metabolisers, 65-80% are extensive metabolisers and 5-10% are ultra-rapid metabolisers with a variable prevalence found globally. Ultra-rapid metabolism is seen in up to 29% of the population in Ethiopia, but only in 0.5% of the Chinese, where 30% may be poor metabolisers.
CYP3A is the most abundant subfamily and is responsible for metabolising opioids, benzodiazepines, tricyclic antidepressants, anti-arrhythmics, calcium channel antagonists and statins amongst many other drugs.
The following drugs may display pharmacokinetic interactions causing adverse effects:
A. Rifampicin and warfarin
B. Paroxetine and metoprolol
C. Erythromycin and diltiazem
D. Ritonavir and methadone
E. Cimetidine and rocuronium
A. True. Rifampicin induces CYP2C9 with a risk of inadequate anticoagulation by warfarin.
B. True. Paroxetine inhibits CYP2D6, reducing the metabolism of beta-blockers.
C. True. Erythromycin inhibits CYP3A4, reducing the metabolism of diltiazem.
D. False. Ritonavir is a widespread enzyme inhibitor, but has not been shown to significantly affect methadone’s efficacy. Lopinavir induces metabolism of methadone and may lead to opioid withdrawal.
E. False. Cimetidine is an enzyme inhibitor, but does not influence rocuronium, which is largely excreted unchanged.
Give an overview of unwanted drug side effects, and the relevance to anaesthesia.
Define unwanted effects
Explain reactions that can occur in anyone and reactions that occur only in susceptible individuals
Discuss ways of categorising unwanted effects
Give examples of these unwanted drug effects
Discuss types of allergic reactions and common tests
Unwanted effects of the drugs we prescribe and administer are common and potentially life-threatening
Some of these unwanted effects can be predicted, or have their severity reduced, by careful history-taking, by having detailed knowledge of the pharmacology of the drug, and by being aware of potential issues and the rapid responses to those issues
There are several different ways to classify and define unwanted effects
Further testing, and obtaining specialist help in the case of some reactions, may be required to assess the risk of administration of a drug, e.g. if suxamethonium apnoea or malignant hyperthermia is suspected
Genetic variation between individuals and between ethnic populations can lead to unwanted drug effects.
Plasma pseudocholinesterase E1a gene
A mutation in plasma pseudocholinesterase E1a gene is associated with deficient enzyme activity and affects metabolism of suxamethonium and mivacurium.
Suxamethonium apnoea is one of the most common unwanted effects in anaesthesia.
4% of Caucasians carry this abnormal gene. This figure is higher in Asians and those from Middle Eastern descent and lower in Africans
Cytochrome P450 2D6 enzyme
Cytochrome P450 2D6 enzyme (CYP2D6) is responsible for converting codeine to its active metabolites.
Variations in this enzyme can affect the metabolism of codeine, tramadol, ondansetron and beta-blockers.
Poor metabolisers of codeine may have a poor analgesic result. There are extensive metabolisers, for example there is lower activity of the enzyme in Chinese populations compared to Caucasian populations. There are also ultrarapid metabolisers, such as the Saudi Arabian and Ethiopian populations, who metabolise these drugs faster and more completely.
Adverse Drug ReactionsReactions due to Genetic Variation
Genetic variation between individuals and between ethnic populations can lead to unwanted drug effects.
Select each label for more information.
CYP2C19 enzyme
In Chinese populations, a CYP2C19 enzyme deficiency affects response to diazepam and tricyclic antidepressants.
G6PD enzyme
G6PD enzyme deficiency results in haemolytic anaemia in susceptible individuals.
Such a deficiency is commonest in Mediterranean, African and Asian populations and it affects the use of sulphonamides and nitrofurantoin in susceptible individuals.
Porphobilinogen deaminase
Porphobilinogen deaminase deficiency causes acute intermittent porphyria.
It is commonest in Switzerland, Sweden and the Netherlands and affects barbiturates and nitrofurantoin use.
Regarding adverse drug reactions:
A. Suxamethonium apnoea is an example of a reaction that occurs in susceptible individuals
B. Suxamethonium apnoea is an example of a Type A reaction
C. Hypoglycaemia with aspirin is an example of a Type A reaction
D. Malignant hyperthermia is an example of drug idiosyncrasy
E. Anaphylaxtic reactions are mediated by IgE
A. True.
B. False. Suxamethonium apnoea is an example of a Type B (bizarre) reaction.
C. True.
D. True
E. True.
Type A (augmented)
Type A reactions make up 85-90% of all adverse drug reactions
They are often related to pharmacological effects of the drug
They are commonly dose-related
They can be further divided into:
Primary reactions due to an exaggerated response to the drug, e.g. hypoglycaemia with aspirin
Secondary reaction not related to the desired effect, e.g. tinnitus with aspirin
Type B (bizarre)
Type B reactions are bizarre, unpredicted, and not dose-related
They make up 10-15% of adverse drug reactions
Examples include suxamethonium apnoea, malignant hyperthermia and hepatic porphyria
These reaction types occur in susceptible individuals only:
A. Drug intolerance
B. Drug idiosyncrasy
C. Drug overdose
D. Drug side-effect
E. Drug interaction
F. Drug allergy
G. Pseudoallergic reaction
A. True.
B. True.
C. False. Drug overdose can occur in anyone.
D. False. Drug side-effects can occur in anyone.
E. False. Drug interactions can occur in anyone.
F. True.
G. True.
Regarding the classification of reactions:
A. Coombs’ types are a way of defining reactions by time of onset
B. Type A and Type B classification is a way of defining reactions by time of onset
C. Coombs types are a way of defining reactions by immunological type
D. DoTS classification is a way of defining reactions according to dose, timing and susceptibility
A. False. Coombs’ types defines reactions by immunological type, not by time of onset.
B. False. Type A and Type B classification is a way of defining reactions by augmented and bizarre reactions.
C. True.
D. True.
Regarding allergic reactions:
A. Pseudoallergy is immunologically medicated
B. Allergy is immunologically mediated
C. RAST is a test for diagnosis of allergy
D. Allergic reactions must happen within minutes to be a true allergy
A. False. Pseudoallergic reactions have the same clinical manifestations as an allergic reaction, due to histamine release, but are not immunologic reactions.
B. True.
C. True.
D. False. Allergic reaction can be described as immediate and delayed. Immediate reactions, i.e. Type I reactions, classically begin within one hour of the first administered dose. Delayed reactions are those appearing after one hour, although most of them begin after six hours, and typically after days of treatment. Drug-induced hypersensitivity syndrome (DiHS) can begin after weeks of continuous treatment.
The commonest triggers were:
Antibiotics (47%) - Teicoplanin comprised 12% of antibiotic exposures, but caused 38% of antibiotic-induced anaphylaxis
Muscle relaxants (33%) - Suxamethonium-induced anaphylaxis was twice as likely as with other NMBAs and mainly presented with bronchospasm. Atracurium-anaphylaxis mainly presented with hypotension
Chlorhexidine (9%)
Patent Blue dye (5%)
Commonest presenting features:
Hypotension (46%)
Bronchospasm (particularly in patients with morbid obesity and asthma) (18%)
Tachycardia (9.8%)
Oxygen desaturation (4.7%)
Bradycardia (3%)
Reduced/absent capnography trace (2.3%)
All patients were hypotensive during the episode. 15% of patients had a cardiac arrest. The elderly with cardiac disease and the obese were most at risk of cardiac arrest and death.
Immediate
This is intended to distinguish IgE-mediated, Type I reactions from other types. Type I reactions classically begin within one hour of the first administered dose. This period of one hour identifies the majority of IgE-mediated reactions, which carry the risk of anaphylaxis if the patient is re-exposed.
Delayed
Delayed reactions are those appearing after one hour, although most begin after six hours and typically after days of treatment. These reactions may be caused by several different mechanisms, but they are not IgE-mediated. Types II, III, and IV immunologic reactions are all considered delayed reactions.
Drug rash with eosinophilia and systemic symptoms (DRESS) also known as drug-induced hypersensitivity syndrome (DiHS) can begin after weeks of continuous treatment. It is characterised by fever, rash, and multiorgan involvement, with or without eosinophilia and lymphocytosis. Hepatitis and hypersensitivity myocarditis may also occur. These reactions can persist for weeks to months, even after the medication is stopped.
Diagnosis of allergic reactions may be through:
Skin prick tests
RAST (radioallergosorbent tests)
Mast cell tryptase
Provocation tests
Give an overview of drug tolerance and tachyphylaxis, with the relevance to anaesthetics.
Define the terms tolerance and tachyphylaxis
Describe a classification system for types of tolerance
Explain how tolerance and tachyphylaxis differ
List clinically relevant examples of tachyphylaxis and tolerance
Drug tolerance may be thought of as a decrease in pharmacological response following repeated or prolonged drug administration
Tachyphylaxis describes a hyper-acute form of tolerance in which rapidly increasing doses are necessary to maintain a clinical effect over a time frame
Pharmacodynamics describes how drugs interact at a molecular level to produce their effects.
When a drug is given frequently, particularly at high concentrations, a desensitisation effect can occur due to repeated binding interactions between the drug and its receptor. This is known as pharmacodynamic tolerance.
Question: What other possible mechanisms are there?
Other possible mechanisms include a reduction in receptor density, conformational changes in the receptor structure and changes to the action potential thresholds. Down-regulation of receptors and associated reduction in neurotransmitter release may also play a part. Changes typically occur over days to weeks.
Pharmacodynamic tolerance develops at different rates for different effects of any given drug, e.g. cocaine users can quickly become tolerant to the euphoric ‘high’ they experience and therefore need ever larger doses to achieve that effect again. However, tolerance to the toxic cardiovascular effects is less pronounced.
It would be beneficial if tolerance occurred quickly to the negative side-effects of any drug whilst sparing the main clinical use. However, in practice it is a variable and unpredictable phenomenon and risks accidental overdose and serious harm if care is not taken.
Regarding classification systems for types of tolerance:
A. Innate tolerance describes a lack of sensitivity to a drug the first time it is administered
B. Acquired tolerance can be subdivided into three main categories: pharmacokinetic, pharmacodynamic and behavioural tolerance
C. Pharmacodynamics is concerned with the absorption, distribution, metabolism and excretion of a drug
D. Pharmacokinetics is most commonly associated with orally ingested agents
A. Correct.
B. Correct.
C. Incorrect. Pharmacokinetics is concerned with the absorption, distribution, metabolism and excretion of a drug and is therefore sometimes referred to as ‘what your body does to the drug’.
D. Correct.
As tolerance develops, a series of both physiological and psychological behaviours occur alongside. These may take the form of compensatory responses that continue for as long as the drug is taken.
Question: What symptoms can these include?
They can include symptoms such as pain, discomfort or mood changes and are usually described as physical dependence. Intense cravings can sometimes accompany this, which in the past was felt to be psychological but has now been recognised as a complex neuro-hormonal response and the basis for addiction.
If a drug to which tolerance has developed and for which a physical dependence has resulted, is stopped abruptly, withdrawal symptoms may occur. These are often unpleasant for the patient and may include sweating, paranoia, tachycardia and mood disturbance. They usually last for days to weeks and can be avoided or at least minimalised by gradually tapering off the usual dose.
The difference between tolerance and tachyphylaxis is:
A. Tolerance is when larger doses of a drug are required to produce the same effect
B. Tachyphylaxis is when there is a rapid increase in response to repeated doses over a short time period
C. Tachyphylaxis describes a hyper-acute form of tolerance
D. Clinically noticeable tachyphylaxis can sometimes occur even between the first and second doses of a drug
A. True.
B. False. Tachyphylaxis is when there is a rapid decrease in response to repeated doses over a short time period
C. True.
D. True.
Tachyphylaxis describes a hyper-acute form of tolerance in which rapidly increasing doses are necessary to maintain a clinical effect over a time-frame that may be as short as minutes.
Clinically noticeable tachyphylaxis can sometimes occur even between the first and second doses of a drug.
It has been postulated that rapid occupation of almost all the drug binding sites after one dose may be the cause, although the exact mechanism is unknown.
Clinically relevant examples in anaesthesia include ephedrine and hydralazine.
Clinically relevant examples of tachyphylaxis and tolerance are:
A. Opiates are a good example of a drug to which tolerance occurs to the desired effects
B. Clinically relevant examples in anaesthesia for tachyphylaxis include ephedrine and hydralazine
C. Alcohol is a good example of a drug that exhibits tachyphylaxis
D. Genetic polymorphisms in the enzyme alcohol dehydrogenase play a significant role in the wide variety of tachyphylaxis demonstrated between different groups
A. True.
B. True.
C. False. Alcohol does not typically exhibit tachyphylaxis. Repeat dosing over either hours or days tends to result in progressively increasing effects such as euphoria, confusion, ataxia and vomiting. However, tolerance to these effects does develop over a period of months to years with repeated use.
D. False. Genetic polymorphisms affect an individual’s ability to metabolise alcohol. This can lead to more marked effects but not to the development of tachyphylaxis.
Opiates still form the basis of systemic analgesia for severe pain even 200 years after the discovery of morphine.
It is a good example of a drug to which tolerance occurs rapidly to the desired effect, i.e. analgesia, but much less so to the unwanted effects, e.g. nausea, itching, constipation. This leads to rapid dose escalation in chronic users with the attendant risks of chronic dependence and accidental overdose.
Opiates undergo extensive hepatic metabolism via phase 1 and 2 pathways, leading to acquired tolerance over time.
Polymorphisms in the cytochrome P450 system are an obvious source of individual variation in this process. In particular, the extremely polymorphic CYP2D6 can lead to metabolism of opiates over a wide range of time-frames. Such patients have been classified as either poor, intermediate, extensive or ultra-rapid metabolisers.
Poor metabolisers will not readily convert codeine into morphine and will therefore appear more tolerant, whilst the ultra-rapid metabolisers may experience profound clinical effects, a state that has been linked to unexpected deaths in a small group of such patients 2.
Opiates are also substrates of the efflux transporter P-glycoprotein. It is expressed in a number of tissues in which it regulates absorption or penetration of substances across cellular membranes. Up-regulation over time of this barrier transporter could limit central nervous system penetration and therefore contact with opioid receptors
A number of metabolites are derived from opiates. This is most well described with morphine, which is broken down in the liver to morphine-3-glucuronide and morphine-6-glucuronide. Whilst the latter is a potently active metabolite, the former has been associated with neuro-excitatory behavioural responses opposed to the analgesic effects of morphine at its receptors 4.
Pharmacodynamic mechanisms also contribute to opioid tolerance. These include receptor mediated changes, receptor polymorphisms and cross tolerance. The process of Mu-receptor activation for example is complex involving multiple sequential steps but is thought to differ depending on whether stimulation is acute or chronic.
Regarding tolerance and tachyphylaxis:
A. Tolerance is an increase in pharmacological response to a drug following prolonged or repeated exposure
B. Tachyphylaxis only occurs when a patient has been taking a drug for a long period of time
C. Tachyphylaxis describes an acute drop in blood pressure after administration of a drug
D. Innate tolerance describes the influence of our genetic make-up on the handling of drugs
A. False. Tolerance is a decrease in pharmacological response to a drug following prolonged or repeated exposure.
B. False. Tachyphylaxis is a rapid form of tolerance, it can occur after one dose.
C. False. Anaphylaxis describes an acute drop in blood pressure after administration of a drug.
D. True.
Tolerance can be classified in a number of ways, with the simplest initial division into
Innate tolerance
Innate tolerance results from the influence of our genetic make-up on the handling of drugs.
It describes a lack of sensitivity to a drug the first time it is administered. Put simply, everyone reacts differently to the administration of any drug but when the effects of that drug, either wanted or unwanted, are markedly reduced in an individual, then innate tolerance is said to occur.
This may be related to physical factors such as body mass index, total body fat content, the presence of frailty and acute illness, or genetic factors such as specific polymorphisms that alter drug metabolism or transport.
Acquired tolerance
Acquired tolerance can be subdivided into three main categories:
Pharmacokinetic tolerance
Pharmacodynamic tolerance
Behavioural tolerance
Give an overview of drug interactions, and the relevance to anaesthesia.
List the main types of drug interactions
Describe some classification systems for drug interactions
Give examples of some drug interactions
Describe potential interactions between drugs used in anaesthesia and commonly used herbal medications
You should be able to describe these types of drug interactions and give examples:
Physiochemical: neutralization, precipitation, chelation
Pharmacokinetic: absorption, elimination, metabolism, distribution
Pharmacodynamic interactions: summation, potentiation, synergism, and antagonism
The potential interactions between commonly used herbal medications and drugs used in anaesthesia.
Cytochrome p450: inducers and inhibitors
Pharmacokinetic interactions describe the relationship between rates of change of drug concentration in the different parts of the body. Reactions occur when absorption, metabolism or excretion of one drug is altered by the presence of another drug. It is the magnitude and duration of effect that are altered, rather than the type of effect
Absorption
Examples of absorption include:
The use of activated charcoal in poisoning cases to absorb the toxin and reduce systemic absorption
Prokinetics such as metoclopramide alter gastric emptying and therefore alter the rate of drug delivery to the absorption site and influence uptake
Muscarinic antagonists do the opposite and slow GI function, decreasing absorption
The use of local anaesthetics with adrenaline reduces local blood flow and allows larger doses to be more safely administered
Second gas effect seen with nitrous oxide and volatile agent alveolar concentrations
Distribution
Examples of distribution include:
Any drug which alters cardiac output will alter drug distribution
Beta-blockers reduce cardiac output and therefore increase the time taken for suxamethonium to reach the neuromuscular junction and take effect
Competition for binding sites alters distribution. An example would be warfarin, which is displaced by highly bound drugs such as erythromycin and amiodarone
Metabolism
Examples of metabolism include:
The liver has a hugely significant role in metabolism, and blood flow to the liver is key in this. Drugs with high intrinsic clearance, i.e. lidocaine, are flow-dependent. Increased blood flow increases clearance.
Elimination
Examples of elimination include:
Drugs affecting cardiac output affect the rate of elimination of opiates and benzodiazepines
Drugs affecting pulmonary ventilation affect the rate of elimination of inhaled agents
The water solubility of a drug is related to ionization and excretion. For example the administration of sodium bicarbonate makes urine more alkaline, which increases water solubility and excretion of weak acids, aspirin and barbiturates
Pharmacodynamics describes how a drug affects an organism. It is the relationship between drug concentration and drug response. Pharmacodynamic interactions can be described as interactions where one drug alters the sensitivity of tissues to another drug, either by having an agonistic (same) effect or an antagonistic (blocking) effect. These effects can be at the receptor level or intracellularly.
Summation
Summation is where the action of drugs is additive.
Examples include:
Premedication with a benzodiazepine and then propofol at induction. The dose of propofol required to achieve the same level of anaesthesia is lower
The use of nitrous oxide with other inhalation anaesthetics
Potentiation
Potentiation is when one drug increases the effect of another drug.
Examples include:
The potentiation of non-depolarising neuromuscular blockade by magnesium
Probenacid increasing the action of penicillin by reducing its renal excretion
Synergism
Synergism is when the combined action of two drugs is greater than the action that would be expected from summation alone.
Examples include:
Clonidine and opiates
Propofol and remifentanil
Antagonism
Antagonism is where two drugs have opposite effects.
Examples include:
Flumazenil, which is a competitive antagonist, reversing the effect of benzodiazepines
The use of neostigmine for reversal of non-depolarising muscle relaxants
Some drugs may alter electrolyte concentrations. Altered electrolyte concentrations may mediate some drug actions or alter intravascular volume
Hypokalaemia
Hypokalaemia causes increased cardiac excitability and lowers the arrhythmia threshold. Therefore it increases arrhythmia susceptibility with catecholamines and anticholinergics.
Drugs which can cause hypokalaemia include diuretics, corticosteroids and insulin.
Hyperkalaemia
Hyperkalaemia reduces cardiac automaticity.
Drugs that increase potassium concentration include suxamethonium, and potassium-sparing diuretics.
Hyponatraemia
Hyponatraemia potentiates local anaesthetics and is indicative of a depleted volume status.
Drugs causing hyponatreamia include diuretics and sulphonylurea.
Hypernatraemia
Hypernatraemia is common in the critical care population or in those unable to drink water. Common presentations include thirst, confusion and muscle spasms. This can lead to seizures.
Drugs causing hypernatraemia include mannitol, sodium bicarbonate and hypertonic saline.
Hypomagnesaemia
Hypomagnesaemia can cause cardiac arrhythmias.
Drugs that can cause hypomagnesaemia include diuretics and laxatives.
Hypermagnesaemia
Administration of magnesium can cause cardiovascular effects, prolong neuromuscular blockade and has effects on peripheral vascular tone.
The American Society of Anaesthesiologists recommends that patients cease herbal medications two weeks before surgery. This time frame probably errs on the side of caution, because some of these remedies are eliminated rapidly after discontinuation.
Echinacea
Echinacea is taken to improve the immune system.
Chronic use can result in hepatic failure, which can then enhance the hepatotoxic effects of drugs such as amiodarone, methotrexate and halothane.
Ephedra
Ephedra is used as a CNS stimulant, for weight loss and for the treatment of asthma.
Caution is advised when ephedra is used in combination with other sympathomimetic drugs. Long-term use of ephedra may deplete endogenous catecholamine stores, leading to further cardiovascular instability intraoperatively and tachyphylaxis to other sympathomimetic drugs. Fatal arrhythmias have also been reported in patients taking ephedra who were exposed to halothane anaesthesia.
Garlic is used as a treatment for hypertension, hyperlipidaemia, and atherosclerosis.
It can potentiate the anti-platelet effects of aspirin and NSAIDs.
Ginger is used as an anti-inflammatory and an antiemetic.
Caution is advised when taken in combination with NSAIDS and warfarin.
Gingko biloba
Gingko biloba is thought to be neuroprotective and to improve blood flow.
It should be avoided in combination with NSAIDs, aspirin, and warfarin.
GInseng
Ginseng is used as a mood enhancer and an aphrodisiac.
Caution is advised when used in combination with NSAIDS and warfarin.
St John’s Wort
St John’s Wort is used as an antidepressant.
It has similar precautionary measures to conventional monoamine oxidase inhibitors (MAOIs).
It is a potent inducer of hepatic cytochrome P450 CYP3A4 isoform and may significantly increase the metabolism of many concomitantly administered drugs such as alfentanil, midazolam, and lidocaine.
It induces the P450 2C9 isoform that results in the reduction in effect of warfarin and NSAIDs.
The sedative properties of St John’s Wort may potentiate or prolong the effect of anaesthetic agents.
Valerian
Valerian is used as an anxiolytic and a hypnotic.
It increases barbiturate-induced sleep times. Acutely stopping the drug may result in a withdrawal syndrome.
These are examples of physiochemical interactions:
A. Neutralization
B. Metabolism
C. Precipitation
D. Elimination
E. Chelation
F. Absorption
A. True.
B. False. Metabolism is an example of a pharmacokinetic interaction.
C. True.
D. False. Elimination is an example of a pharmacokinetic interaction.
E. True.
F. True. Direct absorption is a physicochemical interaction, although absorption can also be an example of a pharmacokinetic interaction when a substance alters the absorption interface.
Pharmaceutical incompatibility describes the situation in which two drugs are either physically or chemically incompatible. Pharmaceutical and physiochemical interactions can occur both inside and outside the body. Such interactions can cause significant harm, but can also be used for therapeutic purposes.
They can be divided into:
Neutralization - For example, heparin and protamine.
Precipitation - For example, thiopentone and suxamethonium.
Chelation - For example, sugammadex and rocuronium.
Heavy metal poisoning can be treated using chemicals which chelate and remove them from the GI tract, i.e. in Wilson’s disease penicillamine can be administered to remove copper deposits from the body.
Absorption - For example, halothane dissolving into rubber.
Pharmaceutical incompatibility can also occur between drugs and equipment. An example of this is the interaction between paraldehyde and plastic, which necessitates the use of a glass syringe for administration 1.
Regarding pharmacokinetic interactions:
A. The use of local anaesthetics with adrenaline to reduce local blood flow and allow larger doses to be given more safely is an example of absorption
B. The second gas effect is an example of distribution
C. Liver blood flow is an example of metabolism
D. Drugs affecting cardiac output, which alters the rate of elimination of opiates and benzodiazepines, is an example of elimination
A. True.
B. False. The second gas effect is an example of absorption.
C. True.
D. True.
These herbal medicines interact with NSAIDs:
A. Echinacea
B. Ephedra
C. Garlic
D. Ginger
E. Gingko biloba
F. Ginseng
G. St John’s Wort
H. Valerian
A. False. Chronic echinacea use can result in hepatic failure, which can then enhance the hepatotoxic effects of drugs such as amiodarone, methotrexate and halothane.
B. False. Ephedra is used as a CNS stimulant. Caution is advised when it is used in combination with other sympathomimetic drugs.
C. True.
D. True.
E. True.
F. True.
G. True.
H. False. Valerian is used as an anxiolytic and a hypnotic. It increases barbiturate-induced sleep times.
Regarding physiochemical interactions:
A. The reaction between heparin and protamine is an example of neutralization
B. The interaction between paraldehyde and plastic is an example of pharmaceutical incompatibility
C. The reaction between thiopentone and suxamethonium is an example of chelation
D. The reaction between sugammadex and rocuronium is an example of absorption
A. True.
B. True.
C. False. The reaction between thiopentone and suxamethonium is an example of a precipitation.
D. False. Chelation explains the reaction between sugammadex and rocuronium. An example of absorption would be the reaction when halothane dissolves into rubber.
Regarding pharmacodynamic interactions:
A. Summation is where the action of drugs is additive
B. Potentiation is when the combined action of two drugs is greater than the action than would be expected from summation alone
C. Synergism is when one drug increases the effect of another drug
D. Antagonism is where two drugs have opposite effects
A. True.
B. False. Synergism is when the combined action of two drugs is greater than the action than would be expected from summation alone.
C. False. Potentiation is when one drug increases the effect of another drug.
D. True.
Regarding electrolyte abnormalities and their possible causes:
A. Hypokalaemia can be caused by steroids
B. Hyperkalemia can be caused by insulin
C. Hyponatraemia can be caused by diuretics
D. Hypernatraemia can be caused by diuretics
E. Hypermagnesaemia can be caused by laxatives
A. True.
B. False. Drugs that increase potassium concentration include suxamethonium, and potassium-sparing diuretics.
C. True.
D. True. Drugs causing hypernatraemia include mannitol, sodium bicarbonate and hypertonic saline.
E. False. Diuretics and laxatives can cause hypomagnesaemia.
Drugs which induce the cytochrome p450 system include:
A. Rifampicin
B. Barbiturates
C. Amiodarone
D. Alcohol, in chronic use
E. Phenytoin
F. Carbamazepine
G. Itraconazole
A. True.
B. True.
C. False. Amiodarone is an inhibitor of the P450 system.
D. True.
E. True.
F. True.
G. False. Itraconazole is an inhibitor of the P450 system.
Give an overview of Absorption and Bioavailability, and the relevance to anaesthesia.
Define absorption, bioavailability and first-pass metabolism
Describe factors which can affect absorption
Calculate the bioavailability for a given drug
Absorption is the passage of a drug from its site of administration into the plasma
There are multiple factors affecting absorption, including drug formulation, route of administration, physicochemical properties of the drug and local blood flow
First-pass metabolism is a phenomenon whereby the concentration of orally administered drugs is reduced, primarily by the gut wall and liver
Bioavailability is the fraction of a drug dose that reaches the systemic circulation
Bioavailability (F) is calculated by dividing the area under a curve describing concentration versus time for a non-intravenously administered drug, by the area under the curve for the same drug administered intravenously
Local anaesthetics (LAs) are weak bases. Why do you think they are less effective when administered into inflamed tissues, e.g. around an abscess?
Inflammation produces chemicals which make tissue pH more acidic. Weak bases will become more ionized and therefore not be able to cross the membranes to their intended site of action.
Remember:
An aide memoire which might help is:
AIA - Acids ionize above (their pKa)
BIB - Bases ionize below (their pKa)
Because pH and pKa are logarithmic derivatives, a difference between the two values of 1 corresponds to 90% association or dissociation, a difference of 2 to 99% and a difference of 3 to 99.9%.
Regarding absorption:
A. Absorption is defined as the movement of a drug from its site of administration into the plasma
B. Pinocytosis is an important mechanism by which drug absorption occurs
C. Carrier-mediated transport describes the mechanism of absorption whereby a drug molecule combines with an integral membrane protein and is transported against a concentration gradient
D. If 10 mg of oral morphine is administered to a patient and first-pass metabolism reduces this by about 70%, the amount reaching the systemic circulation is 7 mg
E. Local pH has an important influence on drug absorption, mainly because most drugs are weak acids or bases
A. True.
B. False. Direct diffusion is by far the most important mechanism of drug absorption. Uncharged molecules dissolve freely across the lipid bilayer of cell membranes.
C. True. In carrier-mediated transport, a molecule is absorbed by combining with a membrane protein. This may occur down a concentration gradient in which case it is called facilitated CMT and does not require energy, or against a concentration gradient which requires energy. Energy is provided by the hydrolysis of ATP.
D. False. FPM reduces the active drug to 30% of the original dose, i.e. 0.3 x 10mg = 3mg.
E. True. pH affects the degree of ionization of weak acids and bases which in turn will affect their ability to diffuse across the non-polar lipid membranes of cells.
Cell membranes form the barriers between aqueous compartments in the body. The basic structure of a cell membrane consists of a phospholipid bilayer with embedded proteins and attached carbohydrates (Fig 1).
Epithelial surfaces, such as gastrointestinal tract (GIT) mucosa and renal tubules, consist of a layer of tightly connected cells across which molecules must traverse to pass from one side to another (Fig 2).
Vascular endothelium forms a cellular layer between intra and extravascular compartments. Its permeability varies between different tissues.
The cells lining blood capillaries have pores between them allowing relatively free passage of drug molecules (Fig 3).
In order to be absorbed, drugs commonly need to cross cell membranes, e.g. drugs administered orally have to cross the GIT epithelium.
The main mechanisms by which drugs commonly cross cell membranes are (Fig 1):
- Direct diffusion, the most important by far
Non-polar (i.e. uncharged) molecules diffuse readily across cell membranes, because they can dissolve freely in the lipid bilayer (Fig 1).
The degree and rate of absorption is determined primarily by the concentration gradient across the membrane, the surface area available for absorption, and the lipid solubility.
- Via channels that traverse the lipid bilayer
Absorption of small water-soluble drugs may occur by passive diffusion, i.e. down a concentration gradient, through aqueous channels.
This is an important mechanism of transport across capillary endothelium membranes, such as in glomerular filtration.
- Carrier-mediated transport
Drug molecules which are too large or too insoluble to diffuse through cell membranes can use integral carrier proteins that normally transport naturally occurring substances for absorption.
Drug molecules can bind with these carrier proteins, which then undergo a conformational change and release the molecules on the other side of the membrane.
This method of absorption is saturable and subject to competitive inhibition by other drugs which are able to bind to the same carrier.
Carrier-mediated transport (CMT) may be:
Primary active transport
This occurs against a concentration gradient and is energy dependent, with the energy provided by adenosine triphosphate (ATP). Examples include 5FU (fluorouracil) absorption through the gut wall, levodopa uptake into the brain, and the sodium-potassium pump (Fig 1).
Facilitated diffusion
Facilitated diffusion via carrier proteins enhances absorption of molecules with low lipid solubility (Fig 2). It occurs down a concentration gradient and is not energy dependent. It is of limited importance in drug absorption, but is the mechanism by which both vitamin B is absorbed in the GIT and glucose into red blood cells.
Another mechanism of absorption which plays a fairly insignificant role in drug transport, but is worth mentioning for completeness, is pinocytosis (Fig 1).
In this energy-dependent process, molecules are engulfed by a portion of the cell membrane forming a vesicle, which is then internalized.
Drug A is a weak acid with a pKa of 5 and drug B is a weak base with a pKa of 9.
How would each drug be affected at a pH of 3, e.g. in the stomach?
A. A would become more ionized and absorption increased
B. A would become less ionized and absorption increased
C. B would become more ionized and absorption decreased
D. B would become less ionized and absorption decreased
A. False.
B. True.
C. True.
D. False.
Remember AIA and BIB. At a low pH, weak acids are more unionized and therefore easily cross through the cell membrane, whereas weak bases become more ionized and are not able to cross by passive diffusion. At a pH of 3, drug A is about 99% unionized and drug B is completely ionized.
Regarding drug absorption:
A. Drugs with high first-pass metabolism are usually prescribed in small dosages when given orally
B. If a person becomes shocked due to massive blood loss, the intravenous route would be better for emergency drugs than the intramuscular route
C. In the treatment of angina, the onset time of action for GTN would be similar if given orally or sublingually
A. False. If a drug has a high FPM only a small amount reaches the systemic circulation, therefore a large dose is usually required.
B. True. Absorption from the IM route is dependent on an adequate blood supply locally, and this may be significantly reduced in shock.
C. False. GTN has a rapid onset of action when administered sublingually, because it is taken up rapidly into the systemic circulation and avoids FPM.
Which of these factors can influence drug absorption?
A. Route of administration
B. Drug formulation
C. Local blood flow
D. Degree of ionization of the drug
A. True.
B. True.
C. True.
D. True.
All of these factors can influence drug absorption.
Regarding bioavailability (BA):
A. BA is defined as the fraction of an administered drug that reaches the systemic circulation
B. BA relates to the percentage of a drug formulation which consists of therapeutically active molecules
C. The inhalational route of drug administration has the lowest BA
A. True. This is the definition of bioavailability and represents the amount of active drug which is available at the site of action.
B. False.
C. False. Oral administration of a drug has the lowest BA, due mainly to first-pass metabolism.
Bioavailability (BA) refers to the fraction (F) of an administered drug that reaches the systemic circulation intact and is therefore available to act at the site of action.
By definition, BA following an IV dose is 100%. For example, if x number of molecules of a drug are injected into a vein, all x molecules reach the systemic circulation.
If a drug is administered by a non-intravenous route, BA is reduced because of factors involved in the absorption process. Oral BA is reduced compared to an IV dose due to GIT absorption and first-pass metabolism.
Assessing bioavailability requires calculation of the area under a curve (AUC) which describes blood drug concentration versus time following administration via a defined route.
For drugs taken orally (PO), BA is equal to the ratio of the AUC (PO) compared to the AUC (IV).
BA (F) = AUC (PO) / AUC (IV)
BA can also be calculated for other routes of drug administration, again by comparing the measured AUC to the AUC (IV).
Referring to the given plasma concentration versus time curves for the drug in Fig 1, calculate oral bioavailability.
A. 0.2
B. 0.4
C. 0.6
D. 0.8
E. 1.0
A. Incorrect.
B. Incorrect.
C. Correct. BA = AUC (PO)/AUC (IV) = 48/80 = 0.6 or 60%.
D. Incorrect.
E. Incorrect.
When discussing body fluid, we are generally referring to intracellular fluid volume, interstitial fluid volume and plasma volume as the three major components of the overall fluid volume.
The 42 L of fluid is held in different spaces within the body:
Intracellular Fluid (ICF)
This is the fluid contained within cell walls.
Irrespective of cell type, the composition of ICF is very similar. For modelling purposes, this allows us to classify and treat it as one fluid volume, even though it is divided into the millions of individual cellular volumes.
The ICF makes up 2/3 or 28/42 L of the total body water and the physiological barrier containing it is the cell membrane.
Extracellular Fluid (ECF)
Extracellular Fluid (ECF) is the remaining 1/3 or 14/42 L, which exists outside the cell membrane. This can be further subdivided into:
Intravascular fluid (roughly 1/4 or 3 of 14 L)
Interstitial Fluid (roughly 3/4 or 10.5/14 L)
Transcellular
Interstitial Fluid
Interstitial Fluid (roughly 3/4 or 10.5/14 L).
This is the fluid which lies in the space between cells, external to both the cell membrane and the vascular endothelium.
Intravascular fluid (plasm)
Intravascular fluid (roughly 1/4 or 3 of 14 L).
The fluid component of the non-cellular contents of the vascular system, i.e. the plasma volume.
The physiological barrier containing it is the vascular endothelium.
Transcellular
Transcellular, a small remaining volume of fluid which lies between epithelial lined spaces (0.5 L).
This is typically actively produced by excretion or filtration (CSF, breast milk, pleural fluid).
Give an overview of Pharmacokinetics: Distribution, Protein Binding and Body Compartments, with relevance to anaesthetics.
Describe the different body compartments, and barriers to the movement of substances between compartments
Explain the concept of volume of distribution
Describe the factors which have an impact on the distribution of a drug within the body
Explain protein binding, and its implications for drug distribution
Distribution describes the reversible transfer of drugs from one location to another
Understanding the body fluid compartments and physiological barriers between them allows us to predict how a drug will distribute
There are numerous physicochemical properties which determine the distribution of a drug
Volume of distribution can be calculated to allow assumptions about patterns of distribution, as well as calculating loading doses
Plasma proteins can act as a drug reservoir, and in some circumstances must be taken into account when calculating drug levels and dosing
Let us use IV fluid to demonstrate an example. Think about the composition of the following 3 fluids: 5% Dextrose, NaCl 0.9% and Gelofusin. If they are administered intravenously to the intravascular compartment, can you determine where each fluid will distribute to, and how much of each fluid will pass into each compartment?
Hint: think about the contents of the fluid, and whether they would be able to penetrate the different barriers between compartments.
Place the barrier names, barrier descriptions and the fluid names in each strip.
Select the labels in the diagram for information about fluid compartments and inter-compartmental barriers.
Dextrose
The Dextrose in 5% dextrose solution is rapidly metabolised by the body, and therefore behaves similarly to free water once administered.
Free water is able to distribute evenly between all three body compartments because it contains no large molecules or charged particles, which would block its movement past the physiological barriers.
Therefore, it will disperse proportionally to the volumes of the body compartments.
Sodium chloride
Sodium chloride contains lots of charged particles – Na+ and Cl-.
The vascular endothelium will not block the movement of small polarised molecules, and so the NaCl solution can move freely out of the intravascular space into the interstitial spaces.
The cell membrane will, however, block the passage of charged particles, and so they will be unable to enter the Intracellular space. Therefore, NaCl will be distributed proportionally through the ECF volume.
Gelofusin
Gelofusin/equivalent colloid fluid contains large protein structures.
These will be blocked from passing through the vascular endothelium, and therefore the whole volume administered will be confined to the intravascular space.
What factors may mean that a drug is not evenly distributed?
There are a few factors which are not accounted for by our physiological fluid compartment model.
An example would be partitioning, e.g. into lipid stores.
Lipid can make up a large % of the body by mass and the lipid solubility of a drug is an important factor in determining drug distribution. The more lipid soluble a drug, the greater the amount that will be removed from the circulation and stored in the lipid cells.
Imagine adding a block of lipid into the fluid in our simple single container model of the body.
Now, if we add our drug to the container it has the opportunity to disperse through the fluid, and the lipid.
Scenario 1
If the drug is not lipid soluble, e.g. a very polar molecule like a muscle relaxant, then the concentration found in the fluid will be unchanged – as if the lipid was not present.
With our formula we can determine the volume of distribution:
Vd = dose/concentration
In scenario 1, non-lipid soluble drug:
Vd = 1000 mg/200 mg/L = 5 L
Scenario 2
If, however, the drug is very lipid soluble e.g. propofol, then a significant amount of the initial dose will be removed from the plasma/fluid (‘V’) and stored within the lipid. This results in a significantly lower plasma/fluid concentration of drug.
With our formula we can determine the volume of distribution:
Vd = dose/concentration
In scenario 2, lipid soluble drug:
Vd = 1000 mg/L mg/L = 1000 L
Clearly, the volume of fluid in the body/container is nowhere near 1000 L, but it allows us to make assumptions about the distribution of a drug.
Just as lipid tissue can absorb a drug and cause an increase in our calculated volume of distribution, other things can also cause partitioning effects which impact on Vd.
Other examples include:
Bone absorption: tetracyclines and bisphosphonates (increases the Vd)
Thyroid sequestration: iodine (increases the Vd)
Tissue binding: Digoxin is extensively bound to NA+/K+ ATPase. (increases the Vd)
Plasma protein binding: reduces the Vd
You calculate the loading dose of a drug by:
Loading dose = Volume of distribution x Target concentration
Question: What proportion of a drug is ionised?
Drugs which are weak acids or bases exist in equilibrium between an ionised and non-ionised form
The non-ionised/non-charged form may be able to penetrate the cell membrane or barrier whilst the charged form typically cannot pass through
One good example of this is local anaesthetics (LA):
Only the ionised form of LAs is active, but it works from inside the cell
There is no transporter for LAs and so they can only enter the cell by diffusion through the cell membrane in the unionised form
Once inside the cell, a proportion of the drug can then become ionised again and act on the internal surface of the sodium channels to block them
The pKa determines the proportion of polarised:non-polarised drug at a given pH
If the pH conditions are not favourable, e.g. in infected tissue, the pH is low/acidic, then there is minimal drug in the un-ionised form, and so it cannot enter the cell to work. Clinically, this explains why local anaesthetic does not work well in infected or inflamed tissues without the addition of alkalinising agents like bicarbonate, to raise the local pH
Whilst it takes longer for drugs to reach the lipid tissues (due to lower regional blood flow), a drug which is highly lipid soluble will gradually distribute to, and accumulate in, fat stores. This is relevant when thinking about redistribution phenomena, e.g. with propofol (Fig 1).
The initial bolus dose provides a high plasma concentration which is quickly delivered to the brain due to its high regional blood flow. The large concentration gradient results in rapid diffusion across the cell membrane (as it is lipid soluble), high neuronal concentrations, and acts to produce anaesthesia.
If plasma concentrations are measured over time, they rapidly drop to relatively low concentrations.
Question: Why is this?
Question: What is the clinical implication of this?
Propofol is a lipid soluble drug and so will cross any cell membrane.
The initial high plasma concentration will result in rapid diffusion into all cell types - the location of which is dependent on regional blood flow, resulting in a fast reduction in plasma concentration as the drug moves out of the plasma into the larger volume of the total body water.
The implication is that the concentration of propofol in the neurone is now higher than that in the plasma – a reversal of the initial concentration gradient. This results in drug diffusion out of the brain and back into the plasma, a reduction in neuronal concentration and, therefore, an anaesthetic effect.
Clinically, this can be seen as a ‘window’ of anaesthesia after a single bolus of propofol. The offset of action is not due to metabolism or excretion of drug from the body, but to re-distribution out of the plasma volume, into total body water volume and lipid stores.
Question: Some situations may arise where the amount of free drug could be significantly altered due to changes affecting protein binding. Can you think of any?
lasma albumin levels are reduced, e.g. liver injury, or renal dysfunction
Significant reduction in the overall number of available binding sites. If available binding sites are saturated then the amount of unbound drug in the plasma will rapidly rise
Competitive binding at the same site between two drugs
One drug (X) may competitively displace another (Y) from the protein binding site, resulting in a shift in the equilibrium of bound:unbound drug
This would cause an increase in plasma and tissue concentration of drug Y
Because there are fewer binding sites available to X, its plasma and tissue concentrations will also be higher than if Y were not present
So far in the models discussed we have seen that when a drug is sequestered into or soluble in extravascular structures such as lipid or bone, then the plasma concentration falls and therefore the Vd rises.
With intravascular protein binding the opposite is true. Because the drug is being held in the intravascular compartment by the plasma protein, plasma samples will show a higher concentration than if the drug was evenly distributed through the body. This means that the volume of distribution will be lower than expected.
Digoxin
Digoxin = 500 L – this molecule is extensively bound by cellular surface protein and so has a Vd significantly greater that total body water.
Warfarin
Warfarin = 8 L – note that this is smaller than ECF volume, but larger than the plasma volume, which must be due to the effect of intravascular sequestration.
Gentamicin
Gentamicin = 18 L – close to the ECF volume, which agrees with the fact that it is a small, highly charged molecule which does not cross cell membranes easily, but should distribute through the ECF.
Ethanol
Ethanol = 30-40 L – this is a non-polar water soluble small molecule that can distribute through the Total Body Water, crossing both the vascular endothelium and the cell membrane. It does not bind significantly to plasma proteins and has a Vd of around 40 L – similar to Total Body Water. This also implies that there is minimal tissue protein binding or sequestration.
Regarding SBA - volumes of distribution Qn:
A. A lipid soluble drugs will have a large volume of distribution
B. A highly protein bound drug will have a small volume of distribution
C. The volume of distribution can be many times the total volume of the body
D. The units of Vd are L/kg
E. Can be used to calculate the loading dose of a drug
A. True.
B. False. It depends on whether the drug binds to plasma proteins of tissue proteins. If the drug is highly bound to plasma protein, then the Vd will be very low as the concentration of drug in plama will be far higher than if the drug had distribute evenly through all compartments. If the drug is bound to tissue proteins (like receptors) then the Vd will be high – because most of the drug is held outside of the vascular space so plasma concentration would be lower than if the drug was distributed evenly through all compartments.
C. True.
D. True.
E. True.
When discussing body compartments:
A. The significant compartments are: Intracellular, transcellular, and intravascular compartments
B. An adult is roughly 60% water - or 42 L
C. The extracellular fluid volume is made up of the interstitial fluid, plasma volume and transcellular fluid volume
D. The vascular endothelium acts as a functional barrier between intracellular and extracellular fluid
E. A small polar molecule will be able to enter to all fluid compartments
A. False. Typically we are discussing the intracellular, interstitial and intravascular compartments. The transcellular compartment makes up an insignificant volume of the TBW.
B. True. TBW is roughly 60% of an adults mass. Though this percentage changes with age and sex.
C. True. Remember that a significant proportion of fluid within the intravascular space is actually intracellular fluid held within the RBCs.
D. False. The vascular endothelium separates intravascular fluid from interstitial fluid. The cell membrane separates intracellular from extracellular.
E. False. Small molecules can cross the vascular endothelium, but because it is charged it cannot transfer across the cell membrane therefore will only distribute through the extracellular fluid volume.
The body can be divided into a number of different fluid filled compartments, i.e. different fluid spaces which exist physiologically, separated from each other by functional barriers to the free movement of solute within the fluid.
The adult body, by mass, is 60% water, i.e. the Total Body Water of a 70 kg adult is 42 L.
The barriers to free distribution are:
Vascular endothelium
Variable depending on location, but generally blocks large molecules and cells, e.g. red blood cells, heparin or large proteins like albumin, from leaving the plasma/intravascular volume.
Cell membrane
A lipid bi-layer with multiple embedded protein structures, like receptors, channels and transport proteins.
It will allow the passage of lipid soluble molecules, e.g. thyroxine, which simply dissolve directly through the lipid membrane, or particles with specific transport carrier proteins, like glucose. However, it will mostly block the free movement of charged particles from entering the cells, e.g. sodium, unless specific channels, or transport systems, are present.
Protein binding:
A. Frequently involves strong bonds forming between drug and plasma protein
B. Can occur in the plasma, or in the tissues
C. Is a non-saturable process
D. A drug which is highly protein bound may show a clinically significant reduction in plasma concentration if a second highly plasma protein bound drug is administered
E. The main plasma proteins involved with drug binding are albumin and alpha1-acid-glycoprotein
A. False. It is a reversible process which typically involves the formation of weak bonds including Van der Waals, hydrogen and ionic bonds.
B. True.
C. False. There is a finite amount of protein and therefore number of binding sites. The system can be saturated.
D. False. Even with highly plasma protein bound drugs, it is uncommon for clinically significant changes in plasma concentration to occur due to protein binding alone. In any case, the second drug would displace the initial drug from plasma protein and raise, not lower, the plasma concentration.
E. True.
If drugs are extensively bound by protein in the plasma, then the amount of free drug is lower than it would be if it were unbound.
This, in turn means that there is a lower concentration gradient for diffusion into tissues, and so there will be slower distribution of drug.
SBA – if a dose of 8 milligrams of drug X is administered IV and the Vd of the drug is 50 L, what is the plasma concentration?
A. 16 micrograms/L
B. 1.6 micrograms/mL
C. 160 micrograms/L
D. 1.6 milligrams/L
E. 160 micrograms/mL
A. Incorrect.
B. Incorrect.
C. Correct. Concentration = mass of dose/Vd.
D. Incorrect.
E. Incorrect.
Give an overview of the Pharmacokinetics of inhalational drug administration, and the relevance to anaesthesia.
explain how the physical and chemical properties of inhalation agents influence the pharmacokinetics of these drugs
describe the pharmacokinetics of inhaled anaesthetic agents during onset, maintenance, and offset of anaesthesia
describe how the patient and equipment can affect the pharmacokinetics, including onset, maintenance and offset of anaesthesia
compare the anaesthetic inhaled drugs and draw the wash-in and the wash-out curves
explain the concentration and second gas effect
The pharmacokinetic properties of inhaled anaesthetic agents are determined by their physicochemical properties.
Speed of onset and offset of inhaled anaesthesia is predominantly determined by the blood:gas partition coefficient.
The physiological factors that increase speed of onset are increased minute ventilation and a low(er) cardiac output.
Nitrous oxide is unique in clinical practice because we can use it in sufficient concentrations to utilise the concentration and second gas effects to increase the speed of onset of anaesthesia.
Duration of inhaled anaesthesia does not affect the half-time of the drugs but does affect the 90% decrement time, which clinically slows wake-up time in long duration anaesthetics.
Most of an inhaled anaesthetic drug is exhaled unchanged, but a small proportion of the drug is oxidised in the liver by the cytochrome P450 CYP2E1 enzyme.
Inhaled anaesthetic drugs are greenhouse gases that contribute to global warming and ozone destruction and we have a responsibility to minimise the anaesthetic impact on climate change .
Pharmacokinetics is the study of the way in which the body handles administered drugs. It describes drug absorption, distribution, metabolism, and excretion.
Absorption
Inhalational drugs used in anaesthesia are said to exist in at least three compartments: alveoli, blood, and brain.
The uptake from the alveoli, across the alveolar membrane, to the arterial blood is the absorption of the drug and is highly affected by the physicochemical properties of the anaesthetic agent. Wash-in curves allow comparison of the onset of each of the anaesthetic agents.
Distribution
Once the drug enters the arterial circulation the distribution of the drug commences, to the effect site of the brain. Both the physicochemical properties of the anaesthetic drugs and the physiological parameters of the patient affect this pharmacokinetic component.
Metabolism
Metabolism is discussed later in the session but has limited effect on the offset of general anaesthesia of inhaled anaesthetic agents and is determined by the chemical structure of the drug.
Excretion
Excretion of the drug is demonstrated using wash-out curves and varies depending on the physicochemical properties of the drug and the physiology of the patient.
The chemical structures of the inhaled anaesthetic drugs determine their physicochemical properties; and the physical and chemical properties have a major effect on their kinetics.
Question: What specific properties are used when describing the kinetics of inhaled anaesthetic agents?
Properties include:
solubility: lipid for potency; water (blood) for speed of onset
partition coefficients: potency and speed of onset
chemical structure: degree of metabolism
All volatile anaesthetic agents are ethers, except for halothane - a halogenated hydrocarbon, that you are unlikely to see used in 21st century clinical practice.
Ethers are organic compounds characterised by an oxygen atom bonded by two alkyl (or aryl) groups (Fig 1).
They are large molecules that are less lipid soluble than halothane, which means halothane is more potent than all newer agents in clinical practice.
They are also unable to form hydrogen bonds, due to the lack of polarised O-H bond, and are therefore less water (blood) soluble. They can however form hydrogen bonds with other molecules using their nonbonding electron pairs in the oxygen atoms.
Changes in the chemical structure of the drugs alter the inhaled agents’ solubility, and the extent of metabolism.
Question: Can you think of some examples of these changes?
Substitutions in the chemical formula
Lowest blood:gas partition coefficient (lowest blood solubility) because fluorine is the only substitution for the hydrogen molecules in the hydrocarbon groups.
This single atom substitute increases desflurane resistance to metabolism and increases its volatility due to having the lowest boiling point of the inhaled anaesthetic agents.
Isomerism
Isoflurane and enflurane are isomers: same molecular formula, different arrangement of atoms in space.
The altered position of fluorine atoms between the molecules make isoflurane less water (blood) soluble, more lipid soluble, and less susceptible to metabolism than enflurane.
Potency is a measure of drug activity and expresses the amount of drug required to produce an effect. Highly potent drugs require small doses to produce their effect.
Potency of inhaled anaesthetic drugs is reflected in the minimum alveolar concentration (MAC) of each drug: the more potent the drug the lower the MAC.
Question: What is the definition of MAC?
MAC is defined as the minimum alveolar concentration of an inhaled anaesthetic drug at steady-state that prevents reactive movement to a standard surgical stimulus (skin incision) in 50% of non-premedicated subjects at 1 atmosphere.
In usual practice inhaled anaesthetic agents are given at 1 atmosphere and indexing MAC to atmospheric pressure may be forgotten and lead to the assumption that concentration is the key measurement, but partial pressure is the key measure of inhaled anaesthetic drugs. However, atmospheric pressure is approximately 100kPa and so when partial pressure is measured in kPa it is virtually the same as concentration, and these terms are often used interchangeably.
MAC is specific to each anaesthetic drug and is additive when drugs are used concurrently. This can be used deliberately in clinical practice, for example, sevoflurane and nitrous oxide mixture is used in obstetric general anaesthesia to reduce the dose of sevoflurane and its effect on uterine tone.
MAC correlates with lipid solubility: the more lipid soluble the drug the lower the MAC; therefore, the more lipid soluble the more potent the drug.
A potent drug does not necessarily have a fast onset of action.
Question: State the MAC of isoflurane and desflurane and describe what this means for each drug’s solubility and potency.
Isoflurane
MAC = 1.2, high lipid solubility, more potent, slower onset of action and slow to reach compartment equilibrium.
Desflurane
MAC = 6.6, low lipid solubility, less potent, faster onset of action and quick to reach compartment equilibrium.
What is a partition coefficient?
A partition coefficient is the ratio of the amount of substance present in one phase compared with another, where the two phases are of equal volume and exist in equilibrium; the temperature must also be specified.
In anaesthesia this means that the partition coefficient describes the relative solubility of a single substance (inhaled anaesthetic drug) in two different materials (lipid and water [blood]) relative to gas. It is expressed as a dimensionless number, as a ratio to 1, and allows comparison of inhaled anaesthetic drugs.
The two partition coefficients important in determining volatile anaesthetic drug behaviour are the oil:gas partition coefficient and blood:gas partition coefficient (Fig 1).
The oil:gas partition coefficient describes the relative solubility of an inhaled anaesthetic agent in lipid. This determines the potency and the MAC of the drug.
The blood:gas partition coefficient describes the relative solubility of an inhaled anaesthetic agent in blood (water). This determines the speed of onset and offset of anaesthesia.
Table 1 details the partition coefficients of inhaled anaesthetic drugs.
What physiological and pharmacological factors affect the MAC?
Inhalational drugs used in anaesthesia exist in three ‘compartments’ of the body in which they exert a partial pressure (Table 1).
Question: What is partial pressure?
Partial pressure is defined by Dalton’s law of partial pressures: in a mixture of gases the pressure exerted by each component gas is the same as that which it would exert if it alone occupied the container.
The inhaled anaesthetic drugs produce anaesthesia in the central nervous system (CNS) when their corresponding partial pressure is reached.
The partial pressure of the anaesthetic drug equilibrates between the alveoli, arterial blood, and the CNS over time, and we use the partial pressure measured in the alveoli as a surrogate for the partial pressure in the brain, i.e. the effect site.
The partial pressure required to produce the appropriate anaesthesia is the MAC and is specific to each drug (Table 2).
A highly potent drug needs a small dose to exert its effect, and for anaesthetic drugs to exert their effect they must cross the blood-brain barrier (BBB) - a lipid bilayer.
The inhaled anaesthetic drugs of higher potency are also highly lipid soluble, which allows them to cross the BBB and produce anaesthesia even with a small dose. The small dose required means their minimum alveolar concentration (MAC), and therefore minimum brain concentration, is low.
MAC decreases with increased potency.
High lipid solubility is described by the oil:gas partition coefficient and the anaesthetic drugs with a high coefficient have a high potency because they are highly lipid soluble. For example, isoflurane.
The Meyer-Overton hypothesis recognised the relationship between potency and oil:gas partition coefficient and demonstrated that the correlation between potency and oil:gas partition coefficient of an inhaled anaesthetic drugs was directly proportionate.
Fig 1 shows the correlation between MAC and the oil:gas partition coefficient, in logarithm scales.
Question: Will a higher potency cause a quicker onset of anaesthesia?
A high potency does not cause a quicker onset of anaesthesia.
The speed of onset relies on a quick build-up of anaesthetic drug partial pressure.
A highly lipid soluble drug is absorbed easily and takes longer to establish this partial pressure, therefore inhaled anaesthetic drugs with a high potency (low MAC) and high lipid solubility correlating high oil:gas partition coefficient have a slower onset of anaesthesia.
We can use the FA/FI ratio rates to compare anaesthetic drugs. These are known as wash-in curves.
Each agent has its own wash-in curve (Fig 1).
Question: What does the steepness of the graph indicate?
Question: From the graph which volatile agent has (a) the fastest and (b) the slowest onset? (excluding nitrous oxide (N2O))
The rate at which the curves approach an FA/FI ratio of 1.0, which indicates how quickly the drug reaches equilibrium between inspired concentration and alveolar concentration, and therefore how quickly it produces anaesthesia.
Note that it takes up to 6 hours (or more) to reach equilibrium.
(a) Fastest: desflurane (b) Slowest: halothane.
Fig 1 shows that the curve for nitrous oxide is steeper than the curve of desflurane despite desflurane’s lower blood:gas partition coefficient. This is because the rate of rise of FA/FI in N2O depends more on its inspired concentration (Fig 2).
Nitrous oxide is the only inhaled anaesthetic drug that can be used in such different inspired concentrations to demonstrate such considerable differences in rate of rise in FA/FI, and therefore affect onset. It also demonstrates the concentration effect and the second gas effect, which are explained on the next few pages.
Inhaled anaesthetic drugs with a low lipid solubility also have a low blood solubility. This means they have a low blood:gas partition coefficient. It also means they have a higher MAC, due to their lower potency and lipid solubility.
When anaesthetic drugs have a low blood:gas partition coefficient they can increase their partial pressure quicker, equilibrate the FA/FI quicker, and generate a partial pressure gradient.
These partial pressure gradients are created between the different compartments of the body (alveoli, arterial blood, and brain) and the lower the blood:gas partition coefficient of the drug the quicker the increase in partial pressure gradient and the greater the pressure gradient generated between compartments.
The wash-in curves previously described demonstrate the blood:gas partition coefficient effect on accumulation of the alveolar partial pressure. The concept of the wash-in curve can be applied to the different compartments of the body as the anaesthetic drug moves from high partial pressure area, such as in the arterial blood, down its gradient to the low partial pressure area, such as the brain, until equilibrium is achieved.
Fig 1 represents two anaesthetic drugs and their blood:gas partition coefficients.
Question: Which of the two volatile agents (blue or red drug) will have a faster onset of action?
The blue drug: it has a lower blood:gas partition coefficient so alveolar concentration will reach equilibrium quicker, creating a greater partial pressure gradient between blood and alveolar gas and leading to more rapid equilibration in the brain.
What is the concentration and second gas effect?
Nitrous oxide is unique in its use because we can use it at significantly higher concentrations clinically to demonstrate the concentration effect and the second gas effect, which rely on the relative increased solubility of nitrous oxide compared with oxygen and nitrogen. The linked descriptions of these demonstrate how they alter the pharmacokinetics and how this impacts on the onset of anaesthesia.
The concentration and second gas effects are phenomena only seen with nitrous oxide because the other inhaled anaesthetic drugs are unable to be used at high enough concentrations to demonstrate the same effects.
The concentration effect
Despite both N20 and N2 being relatively insoluble in blood, N20 is about 20-30 times more soluble in blood than N2 (despite its low blood:gas partition coefficient).
During induction of anaesthesia using high concentrations of N2O the initial transfer across the alveolar membrane and absorption in the blood is high. This occurs while a significantly smaller volume of N2 enters the alveoli from the blood, causing a reduction in total volume of the alveolus.
Decreasing the alveolar volume leads to a concentration of the remaining gases in the alveolus and an increase in their partial pressures and may include an increased partial pressure of other inhaled anaesthetic drugs. This is known as the concentration effect.
The second gas effect
The diminished volume of the alveoli from the concentration effect is replenished by gases from the dead space, which contains and delivers more anaesthetic drug to the alveoli.
The increased alveolar partial pressure of the inhaled anaesthetic drug(s), from both the concentration effect and the increased delivery from the dead space, leads to a higher FA/Fi ratio and induces a faster onset of anaesthesia.
This is the second gas effect.
We can take advantage of the second gas effect when performing a gas induction using O2, N2O and a volatile anaesthetic drug: the presence of nitrous oxide significantly increases the speed of induction.
There are several physiological parameters that affect the uptake and onset of inhaled anaesthetic drugs.
Question: What two physiological factors have the most influence on the onset time of inhaled anaesthetic drugs?
The two most influential physiological factors are:
minute ventilation (MV)
cardiac output
Other physiological factors that influence the onset of anaesthesia are functional residual capacity (FRC) and cerebral blood flow (CBF).
FRC is the lung volume remaining at the end of expiration when breathing normally (Fig 1). (FRC = ERV + RV)
A capacity is the sum of two or more lung volumes, and the FRC is the sum of the expiratory reserve volume (ERV) and the residual volume (RV).
The FRC acts as an oxygen reservoir when we pre-oxygenate the patient before the induction of anaesthesia, particularly important during a rapid sequence induction of anaesthesia.
FRC is altered in many clinical circumstances.
Question: Can you name at least two factors that increase FRC and two factors that decrease FRC?
Question: What is the effect of a high FRC on the speed of onset of the inhaled anaesthetic agent?
A high FRC is a high volume of gas to dilute the inhaled anaesthetic agent. This therefore dilutes the alveolar concentration (lowers the alveolar partial pressure) of anaesthetic drug and may slow the onset of anaesthesia.
A low FRC will dilute the anaesthetic gas less and increase the alveolar concentration of drug, increasing the partial pressure gradient, and increasing the speed of onset of anaesthesia.
Choosing an appropriate MV will help offset the dilutional effect of the FRC.
A lower cardiac output is associated with a faster onset of inhaled anaesthesia, and therefore a higher cardiac output is associated with a slower onset.
This is because a lower cardiac output causes a slower removal of anaesthetic drug from the alveoli and permits the alveolar partial pressure of the drug to increase quicker: the fraction of alveolar concentration (FA) equilibrates quickly with the fraction of inspired anaesthetic drug (FI).
The increased alveolar concentration maintains a larger partial pressure gradient between the alveoli and the blood, and between the blood and the brain, creating a faster rise in brain partial pressure down a steeper gradient, and increasing the speed of onset of anaesthesia.
Question: What is the other reason low cardiac output is associated with an increased onset time of anaesthesia?
Blood flow to the brain is well preserved in low cardiac output states. As proportionately more blood will flow to the brain it results in a proportionately higher flow of anaesthetic-containing blood, increasing the onset of anaesthesia.
Increases in CBF will speed onset of anaesthesia, as more agent is delivered to the brain per unit time.
CBF is autoregulated and tends to be well maintained with even moderate falls in blood pressure and cardiac output as discussed above but can also be manipulated if required.
Question: Can you name a respiratory factor that can influence CBF and alter onset-time for anaesthesia
Hyperventilation or hypoventilation.
CO2 is a cerebral vasodilator.
Hyperventilation reduces carbon dioxide tension and reduces CBF through vasoconstriction, thus slowing onset time.
Hypoventilation increases CO2 tension, causing vasodilation, therefore increasing CBF and speeding onset time.
Volatile agents usually cause cerebral vasodilatation, resulting in increased CBF. This may aid onset of anaesthesia but can also increase intracranial pressure (ICP). They should, therefore, be used judiciously in patients with known or suspected increased ICP but are normally safe at standard clinical doses with careful maintenance of blood pressure and ventilation to avoid hypercarbia.
Wash-out curves are drawn to show the progressive decline in the alveolar concentration of inhaled anaesthetic drugs over time that occurs after the vaporiser has been switched off.
Mathematically washout curves exhibit a negative exponential process. This means the rate of change in the y-axis decreases as the x-axis increases, and is the same mathematical process as the wash-in curves because even though the actual value on the y-axis is increasing in the wash-in curve the rate of change is decreasing.
Question: Why is the y-axis description in the wash-out graph (FA/FAE) not the same as the wash-in graph (FA/FI)?
After the vaporiser has been switched off FI (inspired concentration of inhaled anaesthetic agent) is zero so FA/FI, i.e. FA/0, is infinite, or undefined. The y-axis can be plotted as alveolar partial pressure (usually % concentration) against time but for a comparison of drugs we use FA/FAE, where FAE is the partial pressure in the lungs when the vaporiser is turned off.
In practice the gas reaching the alveoli from the inspiratory limb of breathing circuit may still contain some anaesthetic drug, i.e. a small FI, and is most pronounced when using a circle breathing circuit. Increased fresh gas flows should be used at the end of the anaesthetic to minimise the effects of the any residual anaesthetic agent, especially when using a circle system.
Inhalational anaesthetic drugs are distributed in a multi-compartment model and therefore could be considered able to be described in similar pharmacokinetic principles as the intravenous maintenance drugs: where multi-compartment models are subject to context-sensitive half-time.
Question: What is context-sensitive half-time?
Context-sensitive half-time (CSHT) is defined as the time taken for the plasma concentration of a drug to fall by half after the cessation of an infusion designed to maintain a steady plasma concentration, where context refers to the duration of infusion.
In clinical practice the time taken for the inhaled anaesthetic drugs to fall by half (50% decrement time) varies little (~5 min) between the drugs, regardless of duration. Therefore, CSHT offers a poor comparison of these drugs.
Wake-up occurs at much lower concentrations of inhaled drug, much less than at 50% decrement in alveolar concentration, towards 90% decrement, and there is a big difference in 90% decrement times between the inhaled anaesthetic drugs, particularly with increasing duration of anaesthesia. This means the context is sensitive for 90% decrement-time, rather than half-time.
The differences in 90% decrement time are a result of the drug’s physicochemical properties
Desflurane has the shortest decrement time (Fig 1) due to its low lipid solubility (oil:gas partition coefficient) and low blood:gas partition coefficient.
The low coefficients allow the desflurane effect site concentration to reduce by 90% quickly because it doesn’t saturate the additional lipid tissues (no additional ‘lipid’ compartment to a multi compartment model) and doesn’t generate a drug reservoir to alter the partial pressure gradient between the brain and blood.
A patient is anaesthetised for day case hysteroscopy. Intravenous induction with propofol is chosen followed by sevoflurane maintenance via a laryngeal mask.
Ten minutes after induction the MAC on the machine reads 1.2 but the patient moves at the start of the operation.
Question: Why did the patient move when the MAC is 1.2?
What strategies can be used to overcome this problem in clinical practice?
The end tidal concentration of sevoflurane is measured by the anaesthetic machine, and the MAC is calculated based on the end tidal concentration - a surrogate measure of alveolar concentration.
The anaesthetic effect of the inhaled anaesthetic drug relies on the concentration (or partial pressure) of the drug at the effect site, i.e. the brain.
The equilibrium of concentration of anaesthetic drug between alveoli, arterial blood and brain takes time, different for each anaesthetic drug, and the patient moved because the concentration of sevoflurane in her brain was too low.
Setting a higher inspired anaesthetic drug concentration (on the vaporiser dial) than is required for anaesthesia, i.e. dialling higher than the MAC for that anaesthetic drug. This is known as over-pressuring.
Deliberately setting a higher inspired concentration of inhaled anaesthetic drug will increase the partial pressure in the alveoli and increase the concentration gradient between the alveoli and the arterial blood, and therefore increase the gradient between the blood and the brain. This allows the CNS concentration of anaesthetic drug to increase more quickly, and therefore produce anaesthesia at the effect site quicker as it reaches the MAC of anaesthetic drug sooner.
When using inhaled anaesthetic drugs:
A. Measured end-tidal alveolar concentration is a good surrogate for brain concentration at the beginning of the case
B. Desflurane is a good drug for inhalational induction of anaesthesia because of its speed of onset
C. Recovery from anaesthesia is faster with sevoflurane than isoflurane
D. Desflurane is extensively metabolised
E. When the vaporiser is dialled to 4% sevoflurane it means that exactly 4% sevoflurane is delivered to the patient using a circle system
A. False. End-tidal concentration is the same as brain concentration at equilibrium, which takes time to achieve. Therefore it is not a good surrogate at the beginning of the case.
B. False. Desflurane does have a quick onset but is too pungent and irritant for awake patients to breathe.
C. True. Sevoflurane is less soluble in blood than isoflurane (low blood:gas partition coefficient), therefore it has a faster offset as well as onset.
D. False. Desflurane is 0.02% metabolised.
E. False. Vaporiser output is diluted by gas already in the breathing system, and monitoring of inspired and end-tidal concentration of volatile agent is mandatory and allows adjustments of vaporiser concentration as required.
Minute ventilation:
Increasing alveolar ventilation and FGF during offset increases the removal of drug from the lungs.
The increased drug removal from a higher respiratory rate (or tidal volume) increases the partial pressure gradient between the (pulmonary arterial) blood and alveolus, and speeds transfer to the lungs for removal.
The higher FGF ensures low to no residual anaesthetic drug remains in the inspiratory arm of the circuit and prevents it being re-delivered to the alveoli to reduce the pressure gradient.
If the PCO2 becomes low because of the increased minute volume it can cause cerebral vasoconstriction. This can delay the offset of anaesthesia by reducing blood flow to the brain, therefore reducing the transfer of drug from the brain to the blood.
A low PCO2 may also delay the return of spontaneous breathing because PCO2 is a trigger for breathing via the central chemoreceptors in the medulla. If reliant on spontaneous ventilation for anaesthetic drug removal this will delay offset of anaesthesia.
Other drugs commonly used in anaesthesia affect spontaneous ventilation, for example opioid analgesic drugs reducing respiratory rate, may also slow patient wake-up by delaying offset of anaesthesia through low minute ventilation.
Rank the following according to which agent reaches equilibrium between alveolar and inspired concentrations most rapidly.
Nitrous oxide reaches equilibrium more quickly at high concentrations because of the concentration effect.
Regarding the chemical properties and metabolism of inhaled anaesthetic drugs:
A. The ethers are more lipid soluble than hydrocarbons
B. Only nitrous oxide is used at a high enough concentration to produce the concentration effect
C. Sevoflurane is metabolised to trifluoroacetic acid
D. The blood:gas partition coefficient of desflurane is lower than the coefficient of nitrous oxide
E. The solubility of nitrous oxide in blood is lower than the solubility of nitrogen
A. False. The ethers are less lipid soluble than halothane, a halogenated hydrocarbon; halothane is the most potent volatile agent in use and has the highest oil:gas partition coefficient.
B. True.
C. False. This is the only anaesthetic drug that is not metabolised to trifluoroacetic acid; it is metabolised to hexafluoroiso-propanol. It also forms the degradation product Compound A when used with CO2 absorbers.
D. True.
E. False. Nitrous oxide is more soluble than nitrogen in blood and this property helps explain the alveolar concentration effect that occurs during induction when a volatile agent is administered with nitrous oxide and oxygen.
Regarding inhaled anaesthetic drugs:
A. MAC correlates with drug solubility in blood
B. Partition coefficients have no units
C. A more potent drug has a quicker onset of action
D. Halothane is the most potent of the halogenated inhaled anaesthetic drugs
E. Inhaled anaesthetic drugs have a constant 90% decrement time
A. False. MAC is a measure of potency and correlates with lipid solubility (and therefore oil:gas partition coefficient).
B. True. They are a ratio of two solubilities, therefore have no units.
C. False. A potent drug has a high lipid solubility and requires a small dose to cause its effect, but in inhaled anaesthetic drugs it takes a potent drug a longer time to produce its anaesthetic effect. Drugs with a quicker onset of action have a low blood solubility.
D. True. It has the lowest MAC of the drugs discussed but is not used in clinical practice in the UK. The most potent drug in current use in the UK is isoflurane.
E. False. The 90% decrement time varies between agents but is longer for those with both a higher blood:gas partition coefficient and oil:gas partition coefficient.
The following physiological changes slow the onset of anaesthesia using inhaled anaesthetic drugs:
A. Term pregnancy
B. Reduced alveolar ventilation
C. Reduced cardiac output
D. Emphysema
E. Hypovolaemic shock
A. False. There are several physiological changes in pregnancy: hyperventilation and reduced FRC will favour a faster onset, but an increased cardiac output would tend to oppose this. Overall the respiratory effects predominantly increase the speed of onset of anaesthesia.. but an inhalational induction at term pregnancty is generally contraindicated because of aspiration risk.
B. True. This reduces delivery of the agent to the alveoli.
C. False. Low cardiac output results in increased alveolar partial pressure of agent, therefore faster induction. Cerebral autoregulation preserves blood flow to the brain, so a higher proportion of cardiac output goes to the brain.
D. True. Emphysema increases the FRC volume and dilutes the agent in the alveoli.
E. False. This causes a low cardiac output.
Give an overview of Pharmacokinetics: Elimination, and the relevance to anaesthetics.
Describe the pathways of biotransformation
Explain factors influencing drug biotransformation
Describe different routes of drug excretion
Describe the dynamics of drug clearance
Know the difference between zero and first order kinetics
Drug elimination involves the processes of drug metabolism and excretion and is carried out mainly by the liver and kidneys including other organs.
Biotransformation of drugs is either by phase 1 and/or phase 2 metabolism leading to the excretion of the drug. Liver is the major organ for drug metabolism but there are certain drugs which undergo organ independent metabolism like Hoffman’s degradation for atracurium and cisatracurium, esterases metabolism for suxamethonium and remifentanil.
Excretion mainly occurs through kidney via glomerular filtration, active tubular secretion and tubular reabsorption.
Clearance is the volume of the plasma which is cleared of the drug per unit time and is related to the elimination rate constant (Ke).
Drug clearance occurs either via first order or zero order kinetics.
Drugs which are eliminated via first order kinetics, a constant fraction of the drug is eliminated per unit time. Most of the drugs follow first order kinetics.
Drugs following zero order kinetics have a constant amount of drug which is eliminated per unit time, for example Thiopentone, phenytoin.
Michaelis-Menten kinetics involves the interaction between the enzymes and the drug where the velocity of the reaction (v) increases as the drug/substrate concentration (S) increases until all the enzymes are occupied by the drug causing saturation and reaching the maximal rate of reaction. This is then followed by conversion of the first order kinetics to zero order kinetics where V = Vmax, i.e. the velocity of the reaction does not increase with increase in substrate concentration 3.
Regarding oxidation reactions:
A. A substrate gains electrons from an oxidation reaction
B. It is the most common Phase 1 reaction
C. Dehydrogenation is a type of oxidation reaction
D. Thiopentone is metabolised by oxidation
A. False. Oxidation is loss of electrons while reduction is gain of electrons.
B. True.
C. True. Oxidation reactions involve oxygenation or dehydrogenation or electron transfer.
D. True. Thiopentone is metabolised in the liver by oxidation to thiopental carboxylic acid, hydroxythiopental and pentobarbital.
Phase 1 metabolism is characterised as a functionalisation reaction, either adding or unmasking a functional group (-OH, -SH, -NH2) on the parent drug molecule on which phase 2 reactions can occur (Fig 1). The three types of reactions are:
oxidation (most common)
reduction
hydrolysis
Phase 1 metabolism can convert the drug to either an active or an inactive metabolite. However, phase 1 metabolism usually converts the drug into intermediate metabolites, which may be highly reactive and toxic.
Oxidation involves loss of electrons or gain of oxygen (removal of hydrogen).
Phase 1 metabolism is usually mediated by microsomal cytochrome p450 mono-oxygenases with the CYTP3A4 being the most common (responsible for metabolism of > 60% of the drugs).
Barbiturates, benzodiazepines, paracetamol, ropivacaine and omeprazole are some drugs metabolised by oxidation. Halothane undergoes mainly oxidative metabolism.
Which of the following enzymes are involved in Phase 1 reactions?
A. Monoamine oxidases
B. Glucuronyl transferases
C. Esterases
D. Monooxygenases
A. True.
B. False. Glucuronyl transferase catalyses the attachment of a sugar moiety to a functional polar group and is a type of phase 2 reaction (conjugation).
C. True.
D. True.
Reduction involves the gain of electrons and is the converse of oxidation. It can be mediated by CYT P450 reductase and usually takes place under anaerobic conditions, such as the reduction of prodrug prednisone to active drug prednisolone.
Halothane may also be metabolised by reduction reactions to more toxic metabolites, especially when the liver is hypoxic (Fig 1).
Hydrolysis involves the cleavage of drug molecule using a molecule of water, and catalysed by esterases and amidases. It usually occurs in liver, plasma, intestines and other tissues, for example hydrolysis of amides and esters (lidocaine, prilocaine, meperidine, oxytocin) (Fig 1).
There are some non-P450 phase 1 reactions:
Mitochondrial enzyme monoamine oxidase is involved in metabolism of monoamines like adrenaline, noradrenaline and dopamine.
Esterases metabolise esters like aspirin, remifentanil, etomidate and atracurium in liver and muscles.
Alcohol dehydrogenase present in cytoplasm metabolises ethanol to acetaldehyde and further to acetic acid.
Angiotensin-converting enzyme in the lung is responsible for conversion of AT1 to AT2.
Hoffmann’s degradation is a pH- and temperature-dependent process in plasma that breaks down atracurium and cisatracurium.
Both of these reactions are phase 1 reactions.
Which of the following are Phase 1 reactions?
A. Conjugation to alcohols
B. Oxidation of monoamines
C. Ester hydrolysis
D. Acetylation
A. False.
B. True.
C. True.
D. False.
Phase 1 reactions involve oxidation, reduction and hydrolysis.
Regarding phase 1 reactions:
A. They involve the addition of a polar molecule to a functional group already present on the drug, or its metabolite
B. Sulfation is an example of phase 1 reaction
C. They involve the addition of a polar group to the drug
D. All inhalational agents are metabolised by phase 1 reactions
E. Most phase 1 reactions inactivate the drug
F. They occur primarily in the gut wall and blood
A. False. Phase 1 metabolism is characterised as adding or unmasking a functional group (-OH, -SH, -NH2) on the parent drug molecule on which phase 2 reactions can occur.
B. False.
C. True.
D. False.
E. False.
F. False. Phase 1 reactions can occur in the gut wall or blood supply, but do not occur exclusively at these sites. Most of phase 1 reactions happen in the liver.
Phase 2 metabolism involves the addition of a polar molecule to a functional group placed by phase 1 metabolism. Most phase 2 reactions inactivate the drug or active metabolite formed from phase 1 reactions.
Regarding extraction ratios:
A. Hepatic clearance of a drug with high extraction ratio depends on the drug protein binding
B. The hepatic extraction ratio becomes equal to 1 (unity) when the drug that reaches the liver is completely extracted
C. When no drug is extracted by the liver, the extraction ratio is zero
D. Propofol, ketamine, etomidate and morphine all have a high extraction ratio
A. False.
B. True.
C. True.
D. True.
Hepatic clearance for drugs with high ER is independent of plasma protein binding. When hepatic extraction ratio approaches 1, clearance equals hepatic plasma flow. All intravenous induction agents have high extraction ratios.
The hepatic extraction ratio (HER) is the fraction of the drug which is removed (extracted) during one pass of the blood through the liver. It is the rate-limiting factor in first order kinetics.
HER = (Ci - Co) / Ci
Where:
Ci = Drug concentration in blood entering the organ
Co = Drug concentration in blood leaving the organ
Hepatic Clearance = Hepatic Blood Flow x Hepatic Extraction Ratio
Drugs with high HER (HER>0.7) are rapidly cleared from the blood by the liver and clearance depends mainly on hepatic blood flow (flow limited or high clearance drugs).
Drugs with low HER (<0.3) are not efficiently cleared by the liver and their clearance is dependent on the metabolising capacity of the liver and free fraction of the drug and is independent of hepatic blood flow (capacity limited or low clearance drugs).
Regarding phase 2 reactions:
A. They usually involve conjugation reactions
B. They are less likely to reach saturation (Vmax) levels than phase 1 reactions
C. They requires molecular oxygen (O2) and NADPH as cofactors
D. Phase 2 reactions are detoxification pathways
A. True.
B. False.
C. False.
D. True.
Glucuronide conjugation usually decreases toxicity. Elderly patients usually metabolise drugs via phase 2 metabolism and have decreased phase 1 metabolism
Phase 2 (synthetic phase) metabolism involves formation of a covalent linkage between a functional group on the parent compound (or on a phase 1 metabolite) with endogenously derived glucuronic acid, sulphate, glutathione, amino acids or acetate (Fig 1).
It includes:
glucuronidation (most common)
acetylation
sulphation
methylation
glutathione conjugation
Either drugs undergo phase 1 followed by phase 2 reactions, or some undergo only phase 2 reaction to metabolites, which are usually water-soluble, pharmacologically inactive and non-toxic to be excreted in urine.
Phase 2 (synthetic phase) metabolism mainly occurs in the liver, but is also found in other sites like the lungs, kidneys, GIT, red blood cells and the spleen.
The enzymes involved are transferases, which attach small polar molecules (glucuronate, glutathione, sulphate and acetate) to a drug to make it more water-soluble.
The following changes to drug metabolism occur in the elderly:
A. Reduced microsomal enzyme activity
B. Reduced hepatic blood flow
C. Decreased body fat
D. Increased protein binding
E. Increased cardiac output
A. True. There is a reduced content of phase 1 drug-metabolising enzymes.
B. True. Decreased hepatic blood flow leads to decreased clearance of high extraction ratio drugs (morphine, lidocaine) in elderly.
C. False. There is a 10-15% increase in total body fat.
D. False. There is decreased serum albumin leading to increased free fraction of albumin bound drugs.
E. False.
Regarding renal excretion:
A. Drugs which are weak acids are excreted faster in alkaline urinary pH
B. Drugs which are weak bases are excreted faster in alkaline urinary pH
C. Reabsorption occurs mainly in the proximal convoluted tubule of the nephron
D. Renal clearance of drugs is affected by drug secretion rate and presence of renal disease
A. True. Weak acids are excreted faster in alkaline urine as it promotes the dissociation of the weak acids into ions and lead to increased excretion in urine. The major driving force for glomerular filtration in glomerular capillaries is the hydrostatic pressure. Diet may have an influence on urinary pH, for example a high-protein diet results in acidic urine.
B. False.
C. True.
D. True.
The kidneys are the main route of excretion of all the water soluble drugs and this occurs via three mechanisms:
- Glomerular filtration
Glomerular filtration
Blood enters through the afferent artery and glomerular hydrostatic pressure drive the process of filtration across glomerular capillaries. Glomerular capillaries have large pores which allows free drug (non-protein bound) whether lipid soluble or insoluble to be filtered into the Bowman’s capsule and then enter the PCT. It is a passive process.
Factors affecting glomerular filtration:
Renal blood flow
Molecular weight: drugs that are low molecular weight <7,000 Daltons are readily filtered
Molecular charge: negatively charged particles are repelled by negatively charged glomerular basement membrane
Plasma protein binding: drugs like heparin which are bound to plasma proteins cannot be filtered and therefore do not get excreted by glomerular filtration. Propofol has a low molecular weight but has 98% protein binding capacity and therefore is not actively filtered
Age and renal disease: renal drug excretion decreases progressively after the age of 50 years and GFR is low in renal failure
- Tubular reabsorption
Tubular reabsorption occurs after glomerular filtration into the kidney tubules and can be active or passive, but mostly occurs via passive diffusion.
Factors affecting passive tubular reabsorption include drug concentration, lipid solubility, ionisation and urine pH.
Most of the lipophilic and non-ionized drug which was filtered at the glomerulus will be reabsorbed in the PCT. Tubular reabsorption and secretion are immature at birth and mature by the end of the first year of life. Therefore, the duration of action of many drugs is prolonged in neonates.
- Active tubular secretion
Renal excretion is the sum total of these processes.
It is responsible for the elimination of many drugs.
It is an active carrier-mediated process where drugs are transported against their concentration gradient to be secreted into urine.
This energy-dependent process is capacity limited (saturable) for each drug type, i.e. maximum clearance of one basic drug leads to reduced clearance of another basic drug, but it can be also blocked by metabolic inhibitors.
It involves two carrier systems:
Organic acidic carrier or anions for acidic drugs like penicillin, aspirin
Organic base transport or cations for basic drugs like lidocaine, dopamine, amiloride.
Renal excretion = (glomerular filtration + tubular secretion) - reabsorption.
Regarding elimination half-life:
A. Half-life is increased by an increase in the volume of distribution
B. Half-life is increased by an increase in the rate of clearance
C. In renal failure with oedema, Vd and renal clearance decreases leading to an unchanged half-life
D. It takes 4 half-lives for 87.5% of the drug to be eliminated
A. True.
B. False. t½ = 0.693*Vd/Cl. Therefore half-life is directly proportional to Vd and inversely proportional to Clearance.
C. False. In patients with renal failure with oedema Vd increases and renal clearance decreases.
D. False. It takes 3 half-lives for 87.5% of the drug to be eliminated.
Elimination half-life is the time taken for the plasma concentration of the drug to drop by 50% of its original value in a single compartment model or the time taken by the drug concentration to fall to half by processes such as redistribution, elimination, and metabolism (Fig 1).
Many drugs have an initial redistribution phase with a short half-life followed by elimination phase with a longer half-life.
A process is said to be complete after 4-5 half-lives.
The concentration drops to:
50% drug left after 1 half-life
25% drug left after 2 half-lives
12.5% drug left after 3 half-lives
And finally, after 5 half-lives 3.125% left or it takes about 5 half-lives for a drug to be roughly 97% eliminated.
Therefore it will take ~4-5 elimination half-lives of a drug for a constant-rate infusion to reach its final concentration.
t1/2 = 0.693 x (Vd / Cl)
Regarding Michaelis-Menten kinetics:
A. The substrate is the limiting factor
B. The enzyme is the limiting factor
C. If the enzyme concentration is reduced the reaction velocity at each substrate concentration will be reduced
D. Higher Km means higher substrate affinity for the enzyme
A. False. The substrate is not the limiting factor.
B. True. The enzyme concentration is negligible compared to the substrate concentration.
C. True. Velocity of the reaction or product formation is proportional to the enzyme concentration.
D. False. Km is a measure of the enzyme’s affinity for the substrate therefore low Km equates to higher substrate affinity.
The Michaelis-Menten kinetics equation relates the enzyme-mediated rate of reaction to drug concentration for non-linear drug pharmacokinetics.
It describes enzymatic reactions where 100% enzyme saturation is reached and therefore transition occurs from first order to zero order, such as with thiopentone, phenytoin or ethanol.
It has been described by the Michaelis-Menten equation where Vmax is the maximum rate of reaction and Km is the concentration required to achieve 50% of this maximum rate. It is given by the equation opposite.
The curve is rectangular hyperbola.
V = (Vmax x S) / (Km + S)
Where:
V = velocity of reaction
Vmax = the maximum rate of reaction
S = Substrate concentration
Km = substrate concentration at half max velocity
The velocity of product formation no longer depends on the substrate concentration, but depends on the enzyme present and hence V = Vmax and therefore becomes zero order.
Therefore if a substrate has high affinity for the enzyme then the Km will be lower.
Regarding zero order kinetics:
A. The rate of elimination of a drug is dependent on the initial drug concentration
B. The half-life is given by the following equation t1⁄2 = 0.693/k
C. The half-life of the drug is directly proportional to the initial concentration of the drug
D. The plot of drug concentration against time is a straight line with a gradient of 1⁄K
A. True.
B. False.
C. True.
D. False.
In zero order kinetics the rate of degradation is independent of the concentration of the drug. The half-life of first order kinetics is constant.
With zero order kinetics, the rate of elimination is constant irrespective of drug concentration, which means that a constant amount of drug is excreted per unit time.
For example, if we start with 100mg of drug in a given volume and, say, elimination is 20mg/hr, then after 1 hour we will be left with 80mg of the drug. Because the elimination rate is constant, we will be left with 60mg of the drug after another hour.
Clearance is variable in zero order kinetics because a constant amount of drug is eliminated per unit time (Fig 1) and (Fig 2).
The half-life in zero order kinetics depends on initial concentration of the drug (C0).
Consider the graph.
Question: Assuming a zero order reaction, how would you label the the x and y axis?
Question: What does the intercept on y axis correspond to?
Question: How would you determine the rate constant?
How would you plot the first order elimination kinetics on the same graph?
The y axis is drug concentration and the x axis is time.
The intercept corresponds to initial drug concentration C0.
The rate constant is given by the -ve of the slope.
In zero order kinetics, the same amount of drug is eliminated per unit time while in first order kinetics variable amount of drug is elimimated per unit time as a constant proportion or fraction of the drug is eliminated.
Regarding first order kinetics:
A. Concentration falls exponentially with time
B. Half-life is equal to 3 time constants
C. Rate constant = clearance x vol of distribution
D. Rate of elimination is inversely proportional to the concentration of the drug
A. True.
B. False. Half-life is the time taken for C to decline to half its initial value. Time constant is the time required for C to fall to 1/e of its former value. For an exponential decline C = C0e-k.t where C0 is the concentration at time t = 0 and c is the concentration at time t. Time constant is the time taken for the concentration to fall to 37% of its original value (1/e).
Therefore half-life = 0.693. In first order kinetics rate of metabolism is directly propotional to the drug concentration.
C. False. Clearance = Vol of distribution (Vd) x elimination rate constant (Ke).
D. False. Clearance = Rate of elimination/ C (drug conc).
First order kinetics can be defined as “a constant proportion or fraction of the drug is eliminated per unit time”.
The rate of elimination is not constant and is proportional to the amount of drug present in the body (plasma concentration).
We can demonstrate by the following example:
If the drug follows first order kinetics then, say, if we start with 100mg of the drug in a unit volume of 1L and the half-life is 1 hour, then after 1 hour we will have 50mg of the drug remaining.
The rate of elimination is 100-50/1 = 50mg/hr.
Because a constant fraction, or proportion, of the drug is eliminated per unit time, which in this case is 50% over 1 hour, it drops to half, i.e. 25mg from 50mg, in another 1 hour and, hence, the rate of elimination will be 50-25/1 = 25mg/hr.
Hence, we see here that as the plasma drug concentration drops the rate of elimination also drops (Fig 1) and (Fig 2).
t1/2 = ln 2 / k = 0.693 / k
Therefore the half-life of first order reaction is constant.
In the graph below please label the elimination rate constant K1, K2 and K3 if K1< K2 < K3 assuming first order kinetics.
t1⁄2 = 0.693⁄K and hence t1⁄2 ∝ 1⁄K
Therefore the lower the values of K slower is the elimination of the drug.
Following an IV bolus of a drug:
If it achieves a plasma concentration of 12mg/L after the 1st dose, then what would be the plasma level before the 5th dose, given both half-life and the dosing interval is 8 hours.
A. 11.25mg/L
B. 18mg/L
C. 21mg/L
D. 32.5mg/L
A. Correct.
After the 1st dose (8 hours), the drug concentration is going to be 6mg/L. And then adding a second dose would make it 6 + 12 = 18mg/L.
After another 8 hours drug conc is going to be 9 + 12 = 21mg/L with the 3rd dose.
It will become 10.5 + 12 = 22.5mg/L in another 8 hours with the 4th dose.
It will reduce to 11.25 in another 8 hours, before the 5th dose.
Therefore, with multiple IV dosings, drug tend to accumulate and reach steady state which is considered to be achieved when concentrations are within 10%.
B. Incorrect.
C. Incorrect.
D. Incorrect.
Fig 1 is a drug concentration versus time graph, showing the pharmacokinetics when an infusion of thiopentone is started and continued for up to 48 hours in a patient with status epilepticus. Which parts of the graph represent first order and zero order kinetics?
It is well-established that thiopental shows nonlinear (Michaelis-Menten or saturable) kinetics when administered in high doses for prolonged periods.
Initially the plasma concentration follows first order kinetics and therefore an exponential rise followed by a transition to zero order kinetics when all the enzymes are saturated and then the plasma concentration rises.
Give an overview of the Pharmacokinetics of drug metabolism and excretion, and the relevance to anaesthesia.
Pharmacokinetics describes what happens to a drug in the body. The processes which pharmacokinetics can broadly be split into are called ADME:
A - absorption
D - distribution
M - metabolism
E - excretion
The principles of A.D.M.E. are shown in Fig 1.
Pharmacodynamics describes the actions produced by the drug on the body. Therefore, the effects of a drug result from a combination of its pharmacokinetic and pharmacodynamic characteristics in that individual.
define drug metabolism
describe where metabolism occurs in the body
classify the phases of metabolism
describe the phases of metabolism
describe factors affecting metabolism
explain the clinical importance of drug metabolism with relevant examples
Drugs are in general lipophilic and poorly hydrophilic, making them difficult to excrete.
In order to make them easier to excrete, they are metabolised.
Metabolism takes place throughout the body, but the liver is the main organ of metabolism.
Metabolism is broadly split into phase 1 and 2 reactions.
The purpose of phase 1 reactions is to add functional groups which allow conjugation (phase 2) reactions to occur.
Phase 1 reactions include oxidation, reduction and hydrolysis. The most common is oxidative, catalysed by the cytochrome P450 enzyme system of the liver.
Phase 2 reactions are conjugation reactions, which involve a bond being created with the new functional site created by phase 1.
Phase 2 reactions generally create larger, more hydrophilic, more polar molecules which are excreted more readily in the urine or bile.
There are many factors, physiological and pathophysiological, affecting metabolism.
What is true regarding renal clearance of drugs?
A. It involves zero order kinetics
B. It can occur via glomerular filtration, which depends on drug protein binding and the glomerular filtration rate
C. It is not affected by carrier saturation
D. Dissociation of drug in the urine favours reabsorption
Submit
A. Incorrect.
B. Correct. Renal drug clearance is the sum of glomerular filtration and active secretion minus drug absorption. Only the free fraction of the drug is filtered in glomerular filtration and is affected by the renal blood flow, age and renal disease. Renal clearance can occur via active secretion, which is an active carrier-mediated transport process and hence saturable. Lipid-soluble drugs undergo passive diffusion, being reabsorbed into the bloodstream.
C. Incorrect.
D. Incorrect.
Question: What is drug metabolism?
Drug metabolism, or “biotransformation”, is the breakdown of drugs by living organisms, usually through specialised enzymatic systems.
Drugs can undergo one of several pathways on entry into the body:
they can change spontaneously into other compounds (for example, atracurium)
they can be excreted unchanged by the body (for example, vancomycin)
or they can be metabolised by enzymes to different compounds to facilitate excretion
The majority of drugs fall into this last pathway.
Many drugs need to be lipid-soluble in order to cross cell membranes to access their target site. Indeed, as you may have learnt in previous sessions, anaesthetic agent potency is related to lipid solubility. This, however, makes these drugs relatively insoluble in water, and therefore difficult to excrete. The overall aim of metabolism is to produce a more water-soluble compound to facilitate the excretion of the drug in body fluids such as urine and bile. Very few drugs are excreted without being metabolised.
Question: Consider if the following statement is true or false:
Metabolism of a drug always decreases its therapeutic effect.
It is false. Metabolism can increase or decrease a drugs therapeutic effect, or create metabolites with similar effect.
Metabolism of a drug generally decreases its therapeutic effect. Some drugs, however, are metabolised firstly into active intermediate metabolites before further metabolism to inactive compounds. Some drug metabolites have significant activity similar to the parent compound, for example; morphine and its metabolite morphine-6-glucuronide.
Question: What is a prodrug?
Drugs called prodrugs have no intrinsic activity before metabolism, for example; diamorphine, codeine, enalapril and prednisone. They are only active after initial metabolism into an active compound.
In biochemistry reduction refers to a chemical reaction in which the substrate gains electrons (Fig 1).
Frequently, the resulting amino compounds are oxidised which forms toxic metabolites. Some compounds can be reduced to free radicals, which are reactive with biological tissues. Reduction reactions therefore frequently result in activation of a drug rather than detoxification.
Reduction is often achieved by the addition of hydrogen to a molecule or the removal of oxygen from a molecule.
Reduction reactions are the second most common type of phase 1 reactions. They are also catalysed by the CYP450 system and often take place under anaerobic conditions. There are fewer specific reduction reactions than oxidizing reactions.
Question: Can you think of any of the specific reduction reactions?
The nature of these reactions is also described by their name. Some reducing reactions include:
azo reduction
dehalogenation
disulfide reduction
nitro reduction
n-oxide reduction
sulfoxide reduction
Match the following descriptions to the relevant part of the body.
Gut
Enzymes within the gut wall also contribute to “first-pass” metabolism after oral administration of some drugs.
Metabolism in the intestinal lumen of drugs and their metabolites (excreted via bile) can also reverse the effects of hepatic microsomal enzymes, rendering compounds less polar and therefore available for reabsorption. This leads to the establishment of “enterohepatic recycling”.
For example, the glucuronides of morphine are hydrolysed back to the parent drugs, which may then contribute to further activity after reabsorption.
Bacterial enzymes play a significant role in this process, and the anaerobic environment in which they exist encourages reductive reactions, which again tend to offset the largely oxidative changes of the CYP450.
Renal
The renal system has a well described role as a major excretory organ for drugs and their metabolites. Its involvement in drug metabolism, however, is relatively poorly understood.
There is an increasing body of evidence demonstrating that the kidney is metabolically active. The kidneys express an array of enzymes variably involved in metabolism, both CYP450 enzymes, and those involved in phase 2 reactions such as UDP-glucuronosyltransferases.
Studies have demonstrated that the maximal rate of propofol glucuronidation by renal microsomes is 3 to 4 times greater than that of liver microsomes, and unsurprisingly, total systemic clearance of propofol in humans can exceed hepatic blood flow. The kidneys have been identified as contributing almost one-third of total systemic clearance.
Similarly, studies have demonstrated that the systemic clearance of morphine in humans can exceed hepatic clearance by 38%. In the absence of evidence of gut wall metabolism, the authors concluded that the most likely site of extrahepatic metabolism is the kidney.
Lungs
The lungs are principally concerned with the uptake of oxygen, and excretion of carbon dioxide. The lungs are the major excretory organ for some compounds, notably the inhalation anaesthetics.
They are involved in the modification or uptake of many endogenous substances including serotonin, prostaglandins and noradrenaline.
The lungs also have a limited capacity for drug metabolism. The lung is particularly suited to function as a “chemical filter” as it receives 100% of cardiac output and has the largest capillary endothelial surface in the body.
Propofol and local anaesthetics can be metabolised in the lungs, but this probably does not contribute significantly to total body metabolism. Other drugs that are metabolised include budesonide, salmeterol, fluticasone, and theophylline.
Blood
The red blood cell (RBC) contains moderate CYP450-like activity, in addition to the ability to catalyse various other reactions across a range of drugs. Whilst there is no evidence demonstrating the RBC’s capacity for the more important phase II reactions (glucuronidation, sulphation), they are capable of some of the less common ones (methylation, acetylation).
Several commonly used IV agents used by anaesthetists are rapidly metabolised by enzymes found within the blood.
Suxamethonium, mivacurium, procaine and other related local anaesthetics are substrates of pseudocholinesterase, found mainly in plasma. Esmolol is metabolised by red cell esterases.
Remifentanil is rapidly degraded by red cell esterases, principally to a carboxylic acid derivative, remifentanil acid. This organ-independent elimination and predictable, rapid metabolism makes it a useful agent in the ICU setting.
Liver
The most metabolically active organ in the body, the liver is strategically placed between the port of entry for many drugs (the orogastric route) and the rest of the body. Following absorption from the GI tract extensive “first-pass” metabolism of drugs occurs here after uptake via the portal vein, significantly reducing their systemic availability. This phenomenon explains why many drugs have an oral bioavailability less than the equivalent parenteral dose.
The large size and proportion of received cardiac output also contribute to the liver’s capacity for metabolism. Most importantly, the liver has very high concentrations of drug metabolising enzymes, relative to other organs.
The smooth endoplasmic reticulum of the hepatocyte is the principal site of metabolism in the liver, with enzymes being contained within the microsomes. The cytochrome P450 system is the largest family of membrane-bound, nonspecific, mixed-function enzymes.
Non-cytochrome P450 enzymes in the liver are also involved in metabolism, including esterases and flavin-containing mono-oxygenase enzymes.
In biochemistry oxidation is a chemical reaction in which a substrate loses electrons.
There are a number of reactions that can achieve the removal of electrons from the substrate (Fig 1). The addition of oxygen, or oxygenation, was the first of these reactions discovered and thus the reaction was named oxidation.
However, many of the oxidising reactions do not involve oxygen. The simplest type of oxidation reaction is dehydrogenation, which is the removal of hydrogen from the molecule.
Another example of oxidation is electron transfer that consists simply of the transfer of an electron from the substrate.
Oxidation is the most common of the phase 1 reactions and usually involves the initial insertion of a single oxygen atom onto the drug molecule.
Question: Can you think of any of the specific oxidizing reactions?
The specific oxidising reactions and oxidising enzymes are numerous and are described by the name of the reaction or enzyme involved. Some of these oxidising reactions include:
alcohol dehydrogenation
aldehyde dehydrogenation
alkyl/acyclic hydroxylation
aromatic hydroxylation
deamination
desulfuration
n-dealkylation
n-hydroxylation
A drug that has undergone a phase 1 reaction is now an intermediate metabolite that contains a reactive group such as hydroxyl (-OH), amino (-NH2), and carboxyl (-COOH). Many of these intermediate metabolites are not hydrophilic enough to permit elimination, and therefore must undergo additional metabolism as a phase 2 reaction.
Phase 2 metabolism includes enzymatic reactions that conjugate (join together) the modified drug with another substance. The conjugated products are larger molecules than the substrate and generally polar in nature (water soluble). Thus, they can be readily excreted from the body. Conjugated compounds also have poor ability to cross cell membranes, reducing their bioactivity.
Phase 2 conjugation reactions involve the attachment of ionised groups to the drug and it is this process that significantly increases their water solubility, allowing excretion in the bile and urine. These reactions include:
glucuronidation
sulfation
acetylation
methylation
Question: Consider if the following statement is true or false:
Phase 2 reactions always result in a metabolically inactive compound.
This is false. This is most often the case, but there are some notable exceptions, such as morphine-6-glucuronide which is pharmacologically active.
Glucuronide conjugation is one of the most important and common phase 2 reactions (Fig 1). It is an important metabolic pathway for many anaesthetic drugs.
Glucuronic acid, derived from glucose, is used in this reaction - added directly to the drug or its phase 1 metabolite. The sites of glucuronidation reactions are substrates that have an oxygen, nitrogen, or sulphur bond. This applies to a wide array of drugs and endogenous substances, such as bilirubin, steroid and thyroid hormones.
The UDP-glucuronosyltransferases (UGTs) catalyse this reaction which requires UDP-glucuronic acid (UDPGA) as its group-donating co-substrate.
Currently there are 24 identified human UGT genes. One important member of this group of enzymes is the UGT2B7 variant, which plays a role in the metabolism of a range of endogenous substances including steroid hormones and bile acids well as a number of commonly used drugs such as the NSAIDs, morphine and codeine.
Question: What does glucuronide conjugation usually do?
Glucuronide conjugation usually decreases toxicity (although there are some notable exceptions). The glucuronide conjugates are generally quite hydrophilic and are excreted by the kidney or bile, depending on the size of the conjugate.
Each substrate is converted by one or several of the UGT enzyme forms. Therefore, competition for glucuronidation may occur for drugs; as yet there is little evidence that this plays an important role clinically.
Volatile anaesthetics are thought to decrease the hepatic UDPGA, and subsequently may impair glucuronidation of drugs and endogenous substances.
Propofol is rapidly metabolised in the liver by conjugation to glucuronide and sulphate, producing water-soluble compounds which are excreted mainly by the kidneys. Clearance of propofol is extremely high (greater than hepatic blood flow), suggesting additional, extrahepatic, metabolism
Opioids are metabolised mainly in the liver to both active and inactive compounds that are excreted in urine and bile. Morphine is partially excreted in bile as glucuronide conjugates. In the gut, these glucuronides are metabolised by the normal gut flora to the parent opioid compound and reabsorbed (entero-hepatic recirculation).
Metabolism occurs in the gut wall and the liver via glucuronidation to morphine-3-glucuronide (M3G) (70%), morphine-6-glucuronide (M6G) (10%). Some sulfation reactions occur. M6G is 13x more potent than morphine and is normally excreted in urine
Match the following reactions to the correct phase.
The purpose of drug metabolism is to:
A. Increase lipophilicity of a drug
B. Decrease potency of a drug
C. Increase polarity of a drug
D. Add a functional group to a drug
E. Make a drug easier to excrete
A. False. The purpose is to increase hydrophilicity.
B. False. Although this is a desirable by-product.
C. True. This makes it easier to excrete.
D. True. This is a phase 1 reaction, which allows phase 2 to occur.
E. True. This is the purpose of metabolism.
The following drugs have active metabolites:
A. Morphine
B. Pethidine
C. Diazepam
D. Atracurium
E. Pancuronium
A. True. Morphine is metabolised by hepatic glucuronidation to morphine-3-glucuronide and morphine-6-glucuronide, the latter of which is clinically active.
B. True. Pethidine is demethylated by the liver to norpethidine, which has half the analgesic potential of pethidine, but a longer elimination half-life.
C. True. Diazepam is metabolised to desmethyldiazepam, which is active.
D. True. Atracurium is metabolised primarily by Hoffman degradation, of its metabolites, laudanosine, can lower seizure trigger thresholds and cause seizure activity.
E. True. Pancuronium is largely excreted unchanged (80%), but its deacetylated metabolites (20%) are pharmacologically active.
The following drugs are mainly eliminated from the body by hepatic metabolism:
A. Isoflurane
B. Morphine
C. Atracurium
D. Vancomycin
E. Remifentanil
A. False. Hepatic metabolism of isoflurane is <1%, the vast majority is excreted unchanged by the lungs.
B. True. Morphine is metabolised by hepatic glucuronidation to morphine-3-glucuronide and morphine-6-glucuronide, the latter of which is clinically active.
C. False. Atracurium is an interesting drug who’s metabolism is dependent on ester hydrolysis in plasma and Hoffman degradation, making it a useful drug in liver and renal failure.
D. False. Vancomycin is excreted by the kidneys unchanged.
E. False. Remifentanil is rapidly degraded by non-specific red cell esterases.
The following are prodrugs:
A. Suxamethonium
B. Diamorphine
C. Captopril
D. Paracetamol
E. Enalapril
F. Prednisolone
A. False. Suxamethonium is an active drug.
B. True. Diamorphine (diacetyl morphine) is a prodrug with no intrinsic activity, it is rapidly de-acetylated in a two step process to form morphine – the active drug.
C. False. Captopril is an active drug.
D. False. Paracetamol is an active drug.
E. True. Enalapril is a weak inhibitor of ACE that is metabolically transformed to an active metabolite, enaloprilat, in the liver. Enaloprilat is 10–20 times more potent than enalapril.
F. False. Prednisolone is the metabolite of a prodrug – prednisone.
Give an overview of the pharmacokinetics of the cytochrome P450 system
define what the cytochrome P450 system is (location, structure and physical properties)
identify families of the cytochrome P450 system
describe its role in pharmacology and physiology
relate the effects of specific drugs on the cytochrome P450 enzymes and the significance in clinical practice (induction, inhibition and genetic variation)
Cytochrome P450 enzymes are a superfamily of haemoprotein enzymes which can be categorised according to their genetic similarities.
They have a multisystem role which extends into the synthesis and metabolism of endogenous compounds.
They are key to the metabolism of exogenous substrates, and can be altered by certain drugs, which may result in adverse or beneficial effects depending on the drug and its metabolites.
Inhibitors and inducers of the CYP450 enzymes are important to recognise, in order to anticipate interactions which may result during polypharmacy.
Here are some examples of the physiological roles of the enzymes according to their location.
Adrenals
11-beta-hydroxylase is a CYP450 enzyme required for the synthesis of cortisol and aldosterone, and therefore ion transport, fluid balance and glucose metabolism.
CNS
High concentrations of CYP450 enzymes are present in the brainstem and medulla. Roles involved in:
the processing of neurotransmitters, such as dopamine and serotonin
peptide hormone release from the hypothalamus and the pituitary
cerebrovascular tone via arachidonic acid metabolites
GIT or liver bile acid production
70% isoform 3A4 found in mucosa of small intestine.
Contributes to reducing the bioavailability of drugs.
Kidneys
Key location is the brush border of PCT cells.
Here, they have a role in the metabolism of arachidonic acid to metabolites which affect renal vascular tone, glomerular permeability and sodium transport (via Na/K/Cl and Na/K ATPase channels).
Lung
CYP1A has a protective function in hyperoxic lung injury.
Multiple CYP450 enzymes, expressed throughout lung tissue, are involved in bioactivation of carcinogens in tobacco smokers, which contribute to pulmonary malignancies and COPD.
What are the cytochrome P450 enzymes and why are they important?
The cytochrome P450 enzyme system is a super family of mono-oxygenase enzymes, which holds an important role in physiological and pharmacological systems.
They are primarily found in the liver, bound to the lipid bilayer of the endoplasmic reticulum of hepatocytes. Importantly, they are also found in the kidneys and adrenals.
The enzymes are fundamental to the biotransformation and metabolism of exogenous and endogenous compounds, as well as the synthesis of physiologically active substances.
In the liver, they have a pivotal role in phase one metabolism of drugs: by oxidising substrates, they produce more hydrophilic metabolites for excretion.
Altered function may result in unwanted and adverse effects of drugs, and must be considered in certain disease states and when co-administering certain drugs.
The CYP2 family is one of the largest families and is responsible for the majority of drug metabolism.
CYP2C Subfamily — CYP2C9 isoform
Metabolises s-warfarin, NSAIDS, phenytoin and prodrug (to active form) losartan.
Inhibited by fluconazole and amiodarone.
So patients taking amiodarone and warfarin will be at increased risk of bleeding
CYP2C Subfamily — CYP2C19 isoform
Metabolises diazepam, phenytoin and omeprazole.
Inhibited by PPIs, particularly omeprazole, antifungals, for example, ketoconazole, cimetidine.
CYP2D Subfamily — Isoform CYP2D6 (accounts for 25% of drug metabolism!)
Metabolises:
analgesics, for example, codeine
tramadol beta blockers, for example, atenolol
metoprolol antidepressants, for example, TCA and SSRIs
other, for example, flecainide, ondansetron
Inhibited by SSRIs, for example:
fluoxetine and paroxetine
quinidine
amiodarone
cimetidine
methadone. This means that administering drugs such as tramadol and codeine which are metabolised to morphine by CYP2D6, can prevent their beneficial effects. It can potentially lead to toxic levels of other substrates of this enzyme
CYP2E subfamily — CYP2E1 isoform (only isoform)
Metabolises volatile anaesthetic agents (for example, sevoflurane, enflurane, isoflurane), ethanol, benzodiazepines and paracetamol.
Induced by isoniazid and chronic alcohol.
Inhibited by disulfiram and acute alcohol.
So acute intoxication may result in prolonged effects of BZDs.
Disulfiram is used in the treatment of alcohol dependence. It inhibits CYP2E1, preventing the normal metabolism of ethanol (ETOH), leading to accumulation of metabolites which results in unpleasant side effects when ETOH is ingested.
The cytochrome P450 enzyme system is a super family of mono-oxygenase enzymes, which holds an important role in physiological and pharmacological systems. In the human body they are found in:
A. the heart, liver, and kidneys
B. the bloodstream
C. the liver, kidneys, and adrenals
D. only the liver
A. Incorrect.
B. Incorrect.
C. Correct. They are primarily found in the liver, bound to the lipid bilayer of the endoplasmic reticulum of hepatocytes. Importantly, they are also found in the kidneys, and adrenals.
D. Incorrect.
The function of the cytochrome P450 enzymes is:
A. the biotransformation and metabolism of exogenous and endogenous compounds
B. the synthesis of physiologically active substances
C. to oxidise substrates to produce more hydrophilic metabolites for excretion
D. phase II metabolism
A. True. The enzymes are fundamental to the biotransformation and metabolism of exogenous and endogenous compounds, as well as the synthesis of physiologically active substances.
B. True.
C. True. In the liver, they have a pivotal role in phase one metabolism of drugs: by oxidising substrates, they produce more hydrophilic metabolites for excretion. Altered function may result in unwanted and adverse effects of drugs, and must be considered in certain disease states and when co-administering certain drugs.
D. False.
The CYP3 family is a large family which metabolises endogenous and exogenous compounds. Exogenous (drugs) include erythromycin, lidocaine, diazepam and midazolam, fentanyl and alfentanil, nifedipine, chlorphenamine.
CYP3A3
3A3 and 3A4 are the most important in metabolism of drugs.
CYP3A4
CYP3A4 is the most abundant CYP enzyme in the liver. Induced by: rifampicin, phenytoin and phenobarbitone. Inhibited by erythromycin, ketoconazole, cimetidine and grapefruit juice.
Give an overview and introduction to Pharmacokinetics and Modelling, and the relevance to anaesthetics.
Identify the four phases of drug disposition in the body
Describe routes of drug adminstration
Define biovailable fraction, volume of distribution, clearance and time constant
Describe drug behaviour in a simple one-compartment model
Discuss why simple models do not fit observed drug behaviour
The one compartment model has a single volume to consider, with volume of distribution Vd
The equation describing how plasma concentration changes with time is a negative exponential
The rate at which drug is eliminated from this volume is the product of the concentration and the clearance
Clearance is the ratio of the volume of distribution and the time constant
The time constant is the inverse of the rate constant for elimination
The half-life is shorter than the time constant by a ratio of 0.693, i.e. ln2, to 1
It takes approximately five half-lives or three time constants to reach steady state - either for elimination or for infusion
The pharmacokinetic behaviour of very few drugs used clinically can be described by such a simple model
Regarding anaesthetic drugs and the CYP450 enzymes:
A. CYP3A4 is involved in the metabolism of fentanyl
B. Chronic alcohol use may increase the requirements of some volatile agents, due to inhibition of CYP450 enzymes
C. CYP2D6 displays genetic polymorphism in 1% of Caucasian population which can limit the effects of tramadol
D. Fentanyl and midazolam demonstrate competitive inhibition of CYP3A3
A. True.
B. False. It is due to inducing the CYP2E1 isoform, so it metabolises substrates, such as volatile gases more quickly, increasing the amount required.
C. False. 5-10% of Caucasian population. CYP2D6 is the best-known polymorphic isoform; slow metabolisers who express the mutation may experience a reduced effect from tramadol and codeine, which require metabolism to produce morphine for their analgesic benefit.
D. False. Fentanyl and midazolam demonstrate competitive inhibition of CYP3A4.
Analgesics
Analgesics, for example, codeine may not be effective in patients who are slow metabolisers.
Benzodiazepines
Benzodiazepines, for example, midazolam, when co-administered with fentanyl may result in prolonged activity of benzodiazepines.
ETOH
Depending on if intake is acute or chronic, the anaesthetic effect and degree of metabolism of volatiles may be different from that expected by age alone.
Anticoagulants
If warfarin is co-administered with inhibitors such as amiodarone or omeprazole there is an increased bleeding risk, and the dose may need to be reduced.
Liver failure
Patients with liver failure may have reduced synthetic function, meaning they have reduced CYP450 enzymes, and therefore reduced metabolic capacity, leading to accumulation of drugs.
There are many possible routes for drug administration.
Question: Before reading any further, can you make a list of ten or more of these routes?
Question: Can you think of two examples of routes of drug administration where the drug is not meant to reach the systemic circulation?
Here is a list of some possible routes - you may have thought of others too:
Inhalation
IV
Oral
IM
Intranasal
Sublingual
Buccal
SC
Intrathecal
Epidural
Spinal
Rectal
Intraosseous
Transdermal
Topical
Inhaled bronchodilators in asthma
Topical steroids for eczema
Intranasal decongestants (vasoconstrictors)
Which of the following correctly describe relationships between the parameters of a one-compartment model:
A. Clearance = Vd/k
B. Vd = dose/C0 for a single dose
C. τ = 0.693 . t1/2
D. Rate of elimination = clearance x plasma concentration
E. k = 1/τ
A. False. Clearance = Vd.k
B. True.
C. False. t1/2 = ln2 . τ = 0.693τ
D. True
E. True
The simple one compartment model assumes that the body is homogeneous and that all tissues behave the same as plasma.
Drug enters this single compartment and is then eliminated (Fig 1). Observation tells us that the rate of elimination is directly proportional to plasma concentration, so the rate at which plasma concentration falls must also decline with time.
This can be represented mathematically by a negative exponential relationship between plasma concentration (C) and time (t).
The relationship is written as: C = C0e-kt
The important elements are:
The size of the compartment - the volume of distribution
The type of input - bolus doses or infusions
The output - representing loss of drug from the plasma in an exponential fashion with k being the rate constant for elimination.
Drug elimination is described as “linear” or “first order” because the ratio between plasma concentration and rate of elimination is constant.
For the mathematically minded, rate of elimination can be written as a differential equation that can be integrated to give the equation introduced before: C = C0e-kt
Differential equation
The differential equation is: dC/dt = -kC
This is then integrated with respect to time t from 0 to infinity, knowing that only the exponential function integrates to itself, C must be expressed as an exponential function of time.
C = Ae-kt where A is a constant
Using the condition that at time t = 0, C = C0 this tells us that A = C0 and we get the exponential relationship: C = C0e-kt
After a single IV bolus dose the plasma concentration v time curve is modelled by a single negative exponential function:
C = C0e-kt
The features are that the intercept on the concentration axis is C0 and the constant of proportionality describing the decline is k (the rate constant of elimination).
This relationship can be expressed in a different way in order to find the constant of proportionality.
If we take natural logarithms of both sides and re-arrange then the above equation can be written as:
lnC = lnC0 - kt
This is the equation of a straight line with intercept on the lnC axis of lnC0, from which we can find Vd, and the slope of the line will be -k (Fig 1).
There are many factors that influence bioavailability of a particular drug.
Can you think of three factors that might influence bioavailability?
Can you think of three routes of administration that will bypass hepatic metabolism?
The type of preparation: for example enteric coated tablets prevent acid in the stomach from breaking down some compounds
The route of administration is important: avoiding pre-systemic metabolism will increase bioavailability.
Co-administered drugs may alter pre-systemic metabolism and either increase or decrease bioavailability
Inhalation, IV, IM, sublingual and rectal routes will avoid the first-pass metabolism associated with oral administration. You may have thought of others as well.
Patient factors are also important. Genetic factors and co-administered drugs may influence metabolism and hence bioavailability. The health of the patient is also important: hepatic failure in particular.
Using a different route for drug administration will result in a different profile of plasma concentration over time compared with the standard route.
The ‘gold standard’ route for access to the systemic circulation is IV. Drugs given by routes other than this may encounter enzymes that restrict the proportion of administered drug that can reach the systemic circulation.
The proportion (fraction) of drug, administered by a route other than IV, that reaches the systemic circulation is known as the bioavailable fraction (BF). If given IV the bioavailable fraction is considered to be 1.
Bioavailability is often quoted as a percentage: if given IV bioavailability is considered to be 100%: other routes may have a considerably lower bioavailability.
Table of drug and bioavailability fraction:
Naproxen
0.99
Isosorbide mononitrate (ISMN)
0.93
Paracetamol
0.9
Phenytoin
0.9
Ibuprofen
0.85
Nifedipine
0.5
Amiodarone
0.5
Morphine
0.25
Isosorbide dinitrate (ISDN)
0.2
In the ln(C) v time graph, the gradient of the straight line is -k.
Question: What is the gradient when logarithms to base 10 are used? (Hint: remember the equation for this straight line)
We saw that the equation for the ln(C) v time graph is:
lnC = lnC0- kt
We have just shown that ln(x) = 2.303.log(x), so:
2.303.logC = 2.303 logC0- kt
logC = logC0 - kt/2.303
The gradient is therefore -k/2.303, which makes it less steep than when natural logarithms are used.
If 100 mg of a drug is given intravenously a one-compartment model predicts it will have an initial plasma concentration of 50 mcg/ml. Which one of the following is the value of its volume of distribution?
A. 2 L
B. 5 L
C. 20 L
D. 50 L
E. 200 L
A. Correct.
B. Incorrect.
C. Incorrect.
D. Incorrect.
E. Incorrect.
Volume of distribution is given by the relationship: Dose/concentration at time t = 0
Here we have: 100 000/50 ml = 2000 ml = 2 L
In many texts the semi-logarithmic plot of concentration against time is done on a logarithmic scale to base 10. It is important to appreciate the differences between these two plots, although both can be used to find the constants Vd and k.
Question: What is the relationship between logarithms to base 10 and natural logarithms? (Hint: think how x can be expressed in both systems)
x = 10y = ez, where y is log(x) and z is ln(x)
Taking logarithms to base 10 this gives:
log(x) = y = log(ez) = zlog(e) = ln(x).0.434
log(x) = 0.434.ln(x)
Alternatively:
ln(x) = 2.303.log(x)
The plasma concentration of a drug is 20 mcg/ml five minutes after IV injection and 10 mcg/ml after 105 minutes. If it has a clearance of 70 ml/min which of the following is the closest approximation to its volume of distribution?
A. 500 ml
B. 1 L
C. 5 L
D. 10 L
E. 50 L
A. Incorrect.
B. Incorrect.
C. Incorrect.
D. Correct.
E. Incorrect.
The half life is 100 min, since this the time it takes the plasma concentration to halve.
The relationship between clearance (Cl) and Vd is:
Cl = Vd/τ
= Vd/(t1/2/0.693) = 0.693Vd/t1/2
Rearrangement gives:
Vd = Cl. t1/2 /0.693
So Vd approximates to 70 x 100/0.7 = 10 000 ml or 10 L
Which of the following are an essential part of the mathematical model describing a drug given IV in a simple one-compartment model:
A. Volume of distribution
B. Bioavailability
C. Plasma protein binding
D. Clearance
E. Time constant
A. True.
B. False. This is important for routes other than IV.
C. False. This may affect the value of the volume of distribution.
D. False. This is the ratio of the two important parameters: volume of distribution and time constant.
E. True.
Which one of the following is the clearance of a drug in a simple one-compartment model if it has an initial concentration of 5 mcg/ml after a dose of 50 mg and a time constant of 50 min?
A. 100 ml/min
B. 200 ml/min
C. 500 ml/min
D. 750 ml/min
E. 1000 ml/min
A. Incorrect.
B. Correct.
C. Incorrect
D. Incorrect.
E. Incorrect.
Clearance (Cl) is the ratio of volume of distribution (Vd) to time constant (τ).
Cl = Vd/τ
Vd = dose/C0, where C0 is the initial concentration
Vd = 50 000/5 ml or 10 000 ml
Cl = 10 000/50 ml/min
Cl = 200 ml/min
Instead of multiple doses, we can use an IV infusion to reach a steady plasma concentration. How can we predict what the plasma concentration will be when steady state is reached?
Question: What principle will help us answer this question?
At steady state input = output.
We know that the rate of drug elimination in the one-compartment model is given by: plasma concentration x clearance - this is the output in mg/min. Input is the infusion rate, in mg/min.
Which of the following can affect bioavailability:
A. Route of administration
B. Drug concentration
C. Plasma protein binding
D. Renal failure
E. Co-administered drugs
A. True.
B. False. This affects rate of absorption.
C. False. This affects free drug concentration.
D. True.
E. True.
Using a different route for drug administration will result in a different profile of plasma concentration over time compared with the standard route.
The ‘gold standard’ route for access to the systemic circulation is IV. Drugs given by routes other than this may encounter enzymes that restrict the proportion of administered drug that can reach the systemic circulation.
The proportion (fraction) of drug, administered by a route other than IV, that reaches the systemic circulation is known as the bioavailable fraction (BF). If given IV the bioavailable fraction is considered to be 1.
Bioavailability is often quoted as a percentage: if given IV bioavailability is considered to be 100%: other routes may have a considerably lower bioavailability.
Bioavailability is particularly important when oral medications can no longer be given by mouth because of illness, especially in the ICU or during anaesthesia.
When given intravenously, maximum drug concentration is reached very rapidly and then declines over time as drug is metabolised and/or excreted.
When given orally, drug may be metabolised by the gut wall before reaching the intestinal venous circulation, which then enters the portal circulation to the liver where further metabolism occurs.
From the table (Table 1) we see that NSAIDs and paracetamol have high bioavailability compared with morphine. Drug selection is important; the mononitrate ISMN has a high bioavailability but ISDN, the dinitrate, is extensively metabolised in the gut wall and has low bioavailability.
When changing from an oral to an intravenous route we need to know the bioavailable fraction. This can be measured by an AUC (area under the curve) method (Fig 1).
Give an overview of the pharmacokinetics of Two- and Three-Compartment Models, and the relevance to anaesthesia.
Describe the two and three-compartment models
Discuss the movement of drug between compartments during infusions
Compare the volumes of distribution for models of different drugs
Discuss drug clearance
Describe the three-compartment model for propofol
Compare models representing opioid pharmacokinetics
Most drugs require a two or three-compartment model to describe pharmacokinetic behaviour
The 2-C and 3-C models are linear, just as the 1-C model, since the rate at which plasma concentration falls with time is proportional to plasma concentration itself
In a 2-C model there is one and in a 3-C model there are two inter-compartmental clearances and each has just one elimination clearance
The values for compartment volumes and clearances are determined by many factors: physicochemical properties as well as rate of metabolism
Volume of distribution at steady state for propofol and fentanyl is many times greater than total body water, emphasizing that volume of distribution does not correspond to any physiological volume
3-C models are used to programme target-controlled infusion devices for propofol and remifentanil
We have values for volume of distribution and clearance for propofol: clearance is about 1.9 L/min for a 70 kg person and volume of distribution is about 230 litres.
Fig 1 shows what is observed clinically compared with what would be predicted from a 1-C model that used the known Vd and Cl.
Question: What is the most obvious difference between these two graphs?
Question: How can we model what is actually happening?
The initial rate at which plasma propofol concentration falls with time is very much faster than predicted by the simple model.
Introduce additional compartments into which drug moves rapidly.
The simple model does not explain the behaviour of most drugs, not just propofol. We know that physiologically the body is not homogeneous and that fat and water content of and blood supply to different tissues varies markedly. It is not surprising that a single compartment is insufficient to describe drug disposition in plasma.
An extension of the simple model uses a second compartment, V2, with movement between the compartments described by rate constants for distribution (k12) and re-distribution (k21). It is still assumed that drug enters the central compartment, now called V1, and is eliminated from the body only from this central compartment with a rate constant for elimination of k10.
This model will be referred to as a 2-C model, compared with the simple one-compartment (1-C) model.
Question: What factors determine the values of k12 and k21?
The physicochemical properties of the drug: its lipid and water solubilities and its pKa in particular. Blood supply and the presence of transport process
We saw with a 1-C model that a fixed-rate infusion reached a steady-state concentration that was determined by the input rate and the clearance of the drug.
In a 2-C model, the only difference is that as drug enters the central compartment some will be eliminated and some will distribute. The rate of distribution slows as the peripheral compartment fills and steady state is reached when the concentration in both compartments is equal. At this point there is no overall distribution/redistribution.
Question: What can we calculate from the concentration at steady state (Css) and the infusion rate?
Clearance from the body using the principle:
INPUT = OUTPUT
This is done in the same way as for the 1-C model:
Clearance = INPUT/Css
INPUT has units of mg/min, Css has units of mg/ml, consistent with clearance having units of ml/min.
In a 2-C model a hydraulic analogy can demonstrate what happens when we stop an infusion that has reached steady state.
Initially the concentrations in both compartments is the same. The only thing that can happen now is that the concentration in the central compartment will fall as drug is eliminated. This creates a concentration gradient between the peripheral and central compartments, favouring redistribution.
Question: What factors determine how long it takes for plasma concentration to fall below an effective level?
It depends on:
The difference between the steady state concentration and the minimum effective concentration
The relative values of the inter-compartmental and the elimination clearances
If the inter-compartmental clearance is low and the elimination clearance high, then recovery from drug effect may be rapid (Fig 1).
If inter-compartmental clearance is high and elimination clearance low, then recovery will be prolonged because of rapid redistribution (Fig 2).
Using the hydraulic model, think about what will happen when we stop an infusion before reaching steady state.
Question: If the infusion is stopped before steady-state is reached what happens initially?
he concentration in V1 falls: some drug will distribute into V2 and some will be eliminated. This continues until the concentration in V2 approaches that of V1. From this point on, the system behaves as described for stopping the infusion after steady state has been reached.
The extent of this initial distribution depends on how long the infusion has been running and the ratio of inter-compartmental to elimination clearance values. If elimination clearance is very fast compared with inter-compartmental clearance, then elimination will predominate and the distribution phase will be relatively short.
Which of the following correctly identify the relationship among parameters of a two-compartment model?
A. There are three exponential processes
B. Elimination clearance is given by V1.k10
C. Inter-compartmental clearance is given by V2.k12
D. The peripheral compartment must have a larger volume than the central compartment
E. The volume of distribution is that of the central compartment only
A. Incorrect. There are two exponential processes.
B. Correct.
C. Incorrect. Inter-compartmental clearance is given by V1.k12 or V2.k21.
D. Incorrect. It is very common for this to be the case, but the model does not demand this.
E. Incorrect. The volume of distribution at steady state is the sum of both the peripheral and central compartment volumes.
Label the two compartment model.
Which of the following are true of a three-compartment model?
A. There are three exponential processes
B. Elimination clearance is given by V3.k31
C. There are three inter-compartmental clearances
D. Terminal elimination half-life is the same as elimination clearance
E. The volume of distribution is the sum of the three compartment volumes
A. True.
B. False. This is the inter-compartmental clearance between the central and third compartments. The elimination clearance is given by V1.k10.
C. False. There are two inter-compartmental clearances, not three.
D. False. It is related to elimination and re-distribution rate constants.
E. True.
Which of the following are true of a two-compartment model?
A. It is a second order process
B. Clearance occurs between compartments
C. The two exponential processes have half-lives of ln2/k12 and ln2/k21
D. Inter-compartmental clearance is always faster than elimination clearance
E. Elimination of drug from the model can occur from both compartments
A. False. It is a first order process because the rate of decline of plasma concentration is still proportional to plasma concentration.
B. True.
C. False. The two exponential processes have half-lives of t1/2α and t1/2β, which are both dependent on all rate constants in a complex way.
D. False. It may be true but the model does not demand this.
E. False. Elimination occurs only from the central compartment.
In the 1-C model we saw that the half-life of the single exponential process could be found from the gradient of a semi-logarithmic plot of concentration against time.
Question: The 3-C model has three exponential processes. How many half-lives can we describe?
Question: What are the three half-lives and what do they represent?
Three: related to the rate constants α, β, and δ. These are the gradients of the three lines that comprise the semi-logarithmic plot of concentration against time.
Rapid initial distribution t1/2α = ln2. 1/α;
Intermediate elimination and distribution t1/2 β = ln2. 1/β
Terminal elimination half-life t1/2δ = ln2. 1/δ, which represents re-distribution and elimination.
The inter-compartmental clearance between the central and third compartments is, by convention, slower than that between the central and second compartments.
Question: How do we use the rate constants and volumes to describe the inter-compartmental clearance between the central and third compartments (Cl13)?
Question: What form do you expect the mathematical equation that describes the 3-C model to take?
Cl13 = V1.k13 = V3.k31
This is exactly analogous to the inter-compartmental clearance between the central and peripheral compartment in the 2-C model.
The sum of three exponential processes:
C = Ae-αt + Be-βt + De-δt
Although the 2-C model is useful for predicting the behaviour of many drugs, it does not work well for many anaesthetic drugs that are given by continuous infusion for several hours in the operating theatre or even for several days in an intensive care setting.
Propofol, in particular, is an extremely lipid soluble drug that has a very large volume of distribution. Although a 2-C model can be used for predicting plasma concentration after bolus dose administration or for short-duration infusions, it is not adequate in the context of longer infusions.
A three-compartment (3-C) model has been shown to be the best predictor of plasma propofol levels.
The principles underlying a 3-C model are very similar to those of a 2-C model. The major differences are the existence of a third compartment and another inter-compartmental clearance (Fig 1).
The arrangement of compartments is called ‘mammillary’ since both peripheral compartments are in communication with the central compartment.
The 3-C model identifies three volumes that behave differently: the central compartment represents the behaviour of plasma, the second and third compartments represent peripheral tissues. In general the third compartment is very large for lipid soluble drugs.
The model is still a linear model since all elimination rates are linearly dependent on plasma concentration just the same as in the 1-C, and 2-C models met before.
The equation describing the concentration in the central compartment is now:
C1 = Ae-αt + Be-βt + De-δt
The slow, terminal phase has a rate constant δ, which is a hybrid rate constant as we described for the two rate constants for the 2-C model.
In anaesthetic practice the 3-C model is used to programme target-controlled infusion pumps for propofol and remifentanil. This will be covered in a later session.
Match the values to a parameter to construct the Marsh model for propofol.
A three compartment model is used to model the behaviour of propofol.
Which of the following correctly describe such a model:
A. Propofol elimination occurs only from the third compartment
B. Propofol moves directly between the second and the third compartments
C. The central compartment volume is smaller than the second compartment volume
D. The third compartment has a volume equivalent to total body water
E. Clearance by elimination is faster than both inter-compartmental clearances
A. False. Elimination occurs only from the central compartment, V1.
B. False. A mammillary model provides the best fit where drug moves from second to third compartments indirectly through the central compartment.
C. True.
D. False. The volume of the third compartment is in excess of 200 L, whereas total body water is only 42 L.
E. True. The inter-compartmental clearance from central to second compartment is almost as fast (1.78 L/min compared to 1.9 L for a 70 kg person).
Alfentanil, remifentanil, morphine and fentanyl are commonly used by infusion in theatre and in the ICU. They are all opioid agonists but have very different physicochemical properties and as a result require quite different models to predict their behaviour.
Question: What are the pKas of these opioids and how might this influence kinetic behaviour?
Question: How will this be reflected in the model?
Alfentanil 6.5; remifentanil 7.1; morphine 8.0; fentanyl 8.4. The lower the pKa the higher the proportion of unionized drug, which is associated with faster access to the CNS across the highly lipid blood-brain barrier and also into adipose tissue.
If lipid solublity and metabolism were all equal, then this difference in pKa would be associated with faster inter-compartmental clearances for lower pKa.
Which of the following are true of compartmental models for drug behaviour?
A. Most drugs behave according to a one-compartment model
B. Volume of distribution at steady state is the sum of all the compartment volumes
C. The second compartment volume is always smaller than the third compartment volume
D. The third compartment has a smaller inter-compartmental clearance than the second compartment
E. Inter-compartmental clearance between the central and second compartment may be greater than elimination clearance
A. False. Most drugs require a 2-C or 3-C model to describe their behaviour.
B. True.
C. False. This is often the case, as for fentanyl and propofol, but is not necessarily true - as for remifentanil.
D. True. This is the convention, as drug distributes more quickly to the second than the first compartment of a 3-C model.
E. True. This is true for fentanyl.
Which of the following are true of pharmacokinetic models for opioid drug behaviour?
A. Morphine has a lower volume of distribution than remifentanil
B. Alfentanil has a faster inter-compartmental clearance, Cl12, than elimination clearance
C. Fentanyl and morphine both have steady-state volumes of distribution greater than 3 ml/kg
D. The volume of the third compartment directly reflects lipid solubility
E. Morphine has a faster elimination clearance than fentanyl
A. False. Remifentanil has the smallest volume of distribution of the four opioid drugs described in this session.
B. True.
C. True.
D. False. Morphine is much less lipid soluble than fentanyl, but it has a similar volume of distribution. Lipid solubility can be important, but the model parameters are all highly inter-related and prediction of their relative values is impossible: the model will reflect observed behaviour.
E. True.
Before comparing the models for the opioids, consider the information in Table 1 and how it might influence the compartment volumes and inter-compartmental clearances.
Which of the following describe the pharmacokinetics of a drug that distributes according to a two-compartment (2-C) model?
A. It is a linear model
B. The rate at which plasma concentration falls with time is constant
C. Inter-compartmental clearance is given by V1.k12
D. At steady state, the elimination clearance can be calculated if plasma concentration is known
E. Only drugs given intravenously can be modelled this way
A. True.
B. False. There is a constant proportionality between concentration and rate at which concentration falls: dC/dt = -kC.
C. True.
D. True. Input is known from infusion rate and concentration of solution being infused; output is the product of clearance and concentration at steady state.
E. False. As long as bioavailability is known, then drug behaviour can be modelled.
Give an overview of the pharmacokinetics of Clearance and Volume of Distribution, and the relevance to anaesthesia.
Discuss drug clearance and its relationship to metabolism
Describe the non-compartmental method for measuring clearance
Discuss the variability in volume of distribution for anaesthetic drugs
Identify methods for measuring volume of distribution
Clearance is the elimination of parent drug from plasma. It may be due to excretion unchanged or metabolism or a combination of these two processes
In a one-compartment model, clearance is the ratio of volume of distribution to time constant
In a multi-compartment model clearance is found using the area under the concentration-time curve (AUC) method
Volume of distribution varies widely among drugs used in anaesthesia and intensive care
The physicochemical properties of a drug influences its volume of distribution and the physiological spaces into which it can distribute
The best estimation of volume of distribution is the ratio of the bioavailable administered drug dose to the clearance found from the AUC method
Comparing the pharmacokinetic behaviour of fentanyl and propofol:
A. Propofol is more lipid soluble than fentanyl
B. For fentanyl, inter-compartmental clearances are greater than for propofol
C. Propofol has a lower pKa than fentanyl
D. Both fentanyl and propofol distribute rapidly to peripheral tissues after a bolus dose
E. After constant-rate infusions lasting several hours, propofol and fentanyl both show a rapid decline in central compartment concentration
A. True.
B. True.
C. False. Propofol has a high pKa but, unlike fentanyl, it is a weak acid, so mainly unionized at plasma pH.
D. True.
E. False. Fentanyl redistributes very rapidly after long infusions, which maintains plasma levels much higher than for propofol.
Propofol and fentanyl are both very lipid soluble drugs with rapid metabolism. Both have rapid offset of effects after a single dose.
They might therefore be expected to have a similar pharmacokinetic model to describe their behaviour. However they differ in one important physicochemical property: fentanyl has an ionisable group and is largely in the ionized form in plasma whereas propofol is effectively unionized. In addition, propofol is more heavily protein bound, which accounts for a larger central compartment volume.
When comparing the models it can be seen that fentanyl has much greater inter-compartmental clearances than propofol, which reflects this difference in ionization. In addition, the clearance of propofol is greater than that of fentanyl. These two differences mean that, despite a larger central compartment and even after prolonged infusions, the plasma level of propofol will fall more quickly than for fentanyl.
In a later session we will expand on this context-sensitive behaviour of the two drugs.
Clearance represents elimination of drugs from the body. It may be due to metabolism or excretion unchanged or a combination of these. It has units of ml/min or L/h.
Question: In a simple one-compartment (1-C) model, how is clearance defined and found?
It is the ratio of volume of distribution (Vd) to time constant (τ).
Cl = Vd/τ
Both Vd and τ are found from the semi-logarithmic plot of concentration against time, as seen previously.
As we have noted in a previous session, few drugs behave as if they distribute into a single volume and the concentration vs time curve can be described by the sum of two or three exponential processes.
The concentration v time curve for most drugs can be described by the sum of two or three exponential processes.
The area under the concentration v time curve represents the clearance of the entire dose reaching the systemic circulation. The theory underlying this comes from non-compartmental models and applying the concept of statistical moments. You do not need to know about this in any detail.
Clearance can be measured from a bolus dose given intravenously and measuring the area under the curve, assuming all the dose given reaches the systemic circulation.
Cl = dose/AUViv
When given orally, only part of the dose will reach the systemic circulation.
Question: What do we call that fraction of drug taken orally that reaches the systemic circulation?
Question: How can we use bioavailable fraction (BF) to find clearance after an oral drug dose?
The bioavailable fraction. We can still calculate clearance from an orally administered dose, as long as we know the bioavailable fraction.
BF = AUCo/AUCiv
AUCiv = AUCo/BF
The clearance can then be calculated from:
Cl = dose x BF/AUCo
For a small number of drugs the KM is close to clinically relevant concentrations. In this case a small increase in substrate concentration will increase activity a small amount but a larger rise in plasma concentration may cause the substrate concentration to exceed that at which enzyme activity is maximal.
Question: What happens if substrate concentration exceeds that for maximal metabolic activity?
If this is the only enzyme that can metabolise the substrate then the rate of metabolism remains constant, at maximum capacity, independent of substrate concentration. This is the phase of zero order kinetics (Fig 1 and Fig 2).
When substrate concentration falls below that at which maximum metabolism occurs first order kinetics is re-established.
Thiopental, when given by infusing for prolonged periods, will saturate its enzyme system and display zero kinetics. Similarly phenytoin can also saturate enzyme capacity leading to adverse clinical effects that can be prolonged.
For most drugs first order kinetics prevail over the whole range of plasma concentrations. For some drugs the KM is many orders of magnitude above plasma concentration; hepatocyte concentration of drug is maintained effectively at zero.
Question: What limits rate of drug metabolism under these conditions?
Question: What anaesthetic drug is metabolised so rapidly that its metabolism is determined by hepatic blood flow?
Delivery of substrate: hepatic blood flow.
Metabolism of propofol is very dependent on hepatic blood flow: it has a very high extraction ratio. Fentanyl also has a high hepatic extraction ratio (ER).
Phenytoin, and other drugs where the enzymes are working at concentrations of substrate above their KM, has a low ER since the intracellular concentration is close to plasma.
Clearance represents elimination of drug from the body.
Question: How many ways can drug be eliminated?
Question: What can alter clearance?
Metabolism, particularly hepatic, excretion through the kidneys, lungs and other routes.
Changes in elimination and volume of distribution. People differ in their metabolic and excretory rates, which accounts for inter-individual variation. Illness will also alter clearance by altering volume of distribution. Drug interactions will alter metabolism and therefore clearance.
We will return to the effects of hepatic and renal failure later in this session.
Not all drugs need to be metabolised to be eliminated from the body.
Highly polar drugs will be excreted unchanged through the kidneys by filtration. Only unbound drug is filtered, unlike the hepatocyte, where capilliary sinusoids are freely permeable.
Many drugs are weak acids and weak bases and can be secreted into the proximal tubule by secondary transporters.
Renal elimination of drugs is therefore complex.
Question: What other route of excretion is of importance in anaesthesia?
The inhalational route for volatile agents.
The degree of protein binding differs widely among clinically useful drugs. Drugs compete for binding sites on albumin and globulins and one drug may displace another.
Question: What may happen if competition occurs?
It depends on the ER of a drug and its therapeutic ratio. Drugs with a high ER would still be entirely metabolised, so changes in plasma binding have no effect.
For most drugs with moderate ER, an increase in free drug concentration would increase hepatic uptake and enzyme activity increases so as to maintain effective plasma levels.
For a small number of very highly bound drugs with very low extraction ratios, such as warfarin and phenytoin, a small change in protein binding results in a very large increase in free drug concentration. Since both ER and intrinsic clearance are low, plasma concentrations will rise and the toxic threshold may be exceeded.
For drugs that are only moderately plasma protein bound, a small change in binding has little effect on plasma concentration and metabolism increases just a little to maintain levels.
These effects are best illustrated using Blaschke’s triangle (Fig 1).
In the 1-C model there is a single volume that represents the apparent volume into which the drug disperses.
Question: How do the two- and three-compartment models differ from the 1-C in terms of volume of distribution?
There is a central volume of distribution and one or two peripheral compartments, each of which has a volume that will contribute to the overall volume into which drug can disperse.
This reminds us that drug is initially given into the central compartment and then distributes to the peripheral compartment(s) later.
The central compartment volume represents the initial volume of distribution.
Question: Why might it be important to know the value of this initial volume of distribution?
Question: Can you think of any drugs where loading doses are used then smaller, maintenance doses keep plasma levels within therapeutic range?
To calculate a loading dose. There are several considerations when determining how to load a patient with a drug, particularly if the therapeutic window is small.
Warfarin and digoxin require loading doses for oral administration and amiodarone for intravenous use. TCI propofol also uses a loading dose. You may have thought of others.
You know that the initial volume of distribution of propofol is about 16 L; if you wish to establish an initial plasma concentration of 6 μg/ml, what loading dose would you use?
A. 13 ml of a 2% solution
B. 4.8 ml of a 1% solution
C. 18.2 ml of a 2% solution
D. 9.6 ml of a 1% solution
E. 26 ml of a 1% solution
A. Incorrect.
B. Incorrect.
C. Incorrect.
D. Correct.
E. Incorrect.
The initial volume of distribution (Vd) is 16 000 ml.
The required plasma concentration (Cp) is 6 μg/ml.
The total amount of propofol required to fill the initial volume of distribution is:
Cp x Vd
= 16, 000 x 6 μg
= 96 000 μg or 96 mg
A 1% solution of propofol has 10 mg/ml and a 2% solution 20 mg/ml.
The correct answer would either be 9.6 ml of 1% or 4.8 ml of 2% propofol.
A drug behaves according to a single-compartment model. Experimentally you find that it has a half-life of 70 min and a clearance of 100 ml/min. Which one of the following is its approximate volume of distribution?
A. 7 L
B. 10 L
C. 70 L
D. 100 L
E. 1000 ml
Submit
A. Incorrect.
B. Correct.
C. Incorrect.
D. Incorrect.
E. Incorrect.
In a simple one-compartment model clearance is the ratio of volume of distribution (Vd) and time constant (τ).
Cl = Vd/τ
Time constant is related to half-life:
t 1/2 = ln2.τ = 0.693 τ
⇒ Vd = Cl.τ = Cl.t1/2 /0.693
Vd is approximately 100 x 70/0.7 ml = 10,000 ml = 10 L
When a drug is given it will distribute through the body, carried in blood. Its physicochemical properties determine how easily it passes passively through lipid barriers and membrane.
When considering physiological volumes, there is the intravascular space and the interstitial space, which are part of the extracellular volume, as well as the total body water.
Question: If a drug was restricted to the vascular volume, what would you expect its volume of distribution to be?
The vascular space has a volume of 70-80 ml/kg, so a drug restricted to this space would have a small volume of distribution less than 10 L.
It is often said that highly protein-bound drugs have a small volume of distribution: this is not necessarily true. Only unbound drug can distribute, so highly protein bound drugs will simply distribute more slowly. Propofol is more highly bound than fentanyl (98% compared with 83%) but both distribute throughout a large volume of distribution, fentanyl more rapidly than propofol.
The intravascular space is small compared with total body water (42 L).
Question: What characteristics would you expect of a drug that is restricted to the intravascular volume?
Question: Can you think of a commonly used drug that has these characteristics?
A large, polar molecule that cannot pass through the endothelial gaps in the capillary vessels. It may be highly protein bound.
Heparin is a good example, it has a volume of distribution of about 40-70 ml/kg - very similar to blood volume.
The extracellular space (14 L) is about one third the total body water (42 L). Some drugs can distribute from the capillaries into the extracellular space, but not into the total body water.
Question: What characteristics would you expect of a drug that is restricted to the extravascular volume?
Question: Can you think of a class of drugs used commonly in our anaesthetic practice that has these characteristics?
A small, polar molecule that cannot pass through cell membranes.
Muscle relaxants are permanently charged molecules that do not pass through cell membranes and exert their action extracellularly. They have low protein binding and can easily pass out out of the capillaries, but not into cells - particularly not into adipocytes. Their volumes of distribution are around 14 L.
Total body water is around 42 L in an adult. Some drugs can distribute from the capillaries into the extracellular space and then pass into the cell.
Question: What characteristics would you expect of a drug that can access the intracellular volume?
Question: Can you think of a commonly abused drug that has these characteristics?
Low molecular weight drugs that can readily pass through cell membranes.
Ethanol can distribute through the total body water. Deuterium (‘heavy water’) can be used to measure this volume as it distributes freely.
If a drug can be described by a 1-C model, then volume of distribution is easily measured from the concentration-time curve.
Question: What is the best graph to plot for finding the volume of distribution in a 1-C model?
Question: How do you find the volume of distribution from this initial concentration?
A semi-logarithmic plot, which gives a straight line; the intercept on the y-axis is the concentration at time t=0.
Vd = dose/concentration, with units of mL or L.
Total body water is around 42 L in an adult. Some drugs have volumes of distributions many times this value.
Question: Can you think of two or more reasons why drugs could have large volumes of distribution?
Very lipophilic drugs that are poorly water soluble will preferentially enter adipose cells and be retained, such as propofol. Some drugs are actively transported into cells and concentrated by physiological processes, such as iodine. Some drugs enter cells and are then bound strongly to protein or nucleic acids within the cell, such as chloroquine.
This wide variation in volume of distribution for drugs is summarised in Table 1.
In hepatic failure there is a change in the distribution of body water with the development of ascites.
Question: How might a large volume of ascites affect clearance and hence drug administration?
The initial volume of distribution generally increases so loading dose needs to increase.
There is also a reduction in synthesis of plasma proteins that bind drugs, such as albumin, which complicates calculation of loading dose. Metabolism will decline, so maintenance dose will be reduced.
Loss of metabolic function is not equal for all drugs: not all drugs are metabolised in the liver. Moderate liver failure may not affect metabolism of all drugs requiring hepatic transformation equally, this depends on intrinsic clearance and hepatic blood flow.
Severe, end-stage hepatic failure is associated with poor drug metabolism in general for all drug biotransformed in the liver.
Earlier in the session we identified several factors that can influence how individuals vary in their handling of drugs. There can be very wide differences in clearance even among healthy people.
Question: Can you think of four factors, other than hepatic or renal failure, that could influence inter-individual variability in drug clearance?
Age - this alters the proportion of body water
Gender - lean body mass depends on gender and affects volume of distribution
Genetic disposition - possession of a different isoform of an enzyme may alter metabolism and clearance
Co-administration of other drugs: drugs can induce or inhibit enzyme activity
In renal failure, as in hepatic failure, there is a change in the distribution of body water.
Question: How might renal failure affect clearance?
Question: What drugs are excreted unchanged by the kidney?
The initial volume of distribution generally increases, since there is an increase in extracellular volume. A loading dose needs to be greater.
Hepatic metabolism is not necessarily affected, but some drugs are dependent upon renal excretion.
Those drugs that are highly polar: permanently charged drugs, such as muscle relaxants, may partly be excreted unchanged. Active metabolites that have been initially biotransformed in the liver will be poorly excreted, which might be important - for example morphine-6-glucuronide, which is more potent than morphine.
The clearance of a drug is 1.4 L/min. The initial half-life is 10 min. What loading dose is required to give a plasma concentration of 10 mcg/ml?
A. 100 μg
B. 200 μg
C. 200 mg
D. 10 g
E. 200 g
A. Incorrect.
B. Incorrect.
C. Correct.
D. Incorrect.
E. Incorrect.
The loading dose is the product of the concentration required and the volume of distribution. The initial volume of distribution is found from clearance:
Cl = Vd/τ and t1/2 = 0.693 τ
Vd = Cl. t1/2/0.693
Vd = 1.4 x 10/0.7 (approximately)
Vd = 20 L
Dose = Vd x concentration
= 20 000 x 10 μg
= 200 000 μg
= 200 mg
The initial volume of distribution of a drug is 20 L.The effective dose is 5 μg/ml. What loading dose is required?
A. 100 μg
B. 1 mg
C. 10 mg
D. 100 mg
E. 1 g
A. Incorrect.
B. Incorrect.
C. Incorrect.
D. Correct.
E. Incorrect.
The loading dose is the product of the concentration required and the volume of distribution.
Dose = Vd x concentration
= 20 000 x 5 μg
= 100 000 μg
= 100 mg
Which of the following correctly describe the pharmacokinetics of drug distribution?
A. In a 1-C model, clearance equals volume of distribution divided by half-life
B. In a 3-C model, clearance is dependent upon plasma concentration
C. In a 2-C model, terminal elimination half-life can be used to estimate volume of distribution
D. In a 2-C model the slower terminal rate constant represents elimination
E. Non-compartmental kinetics can be used to find clearance
A. False. Clearance is the ratio of volume of distribution to time constant, not half-life.
B. False. Clearance is independent of plasma concentration.
C. True.
D. False. The terminal rate constant, β, is a hybrid rate constant and depends, in a complex way, upon elimination and inter-compartmental transfer rate constants.
E. True.
Regarding pharmacokinetics:
A. Half-life is longer than time constant
B. Non-compartmental kinetics can be used to calculate bioavailable fraction
C. Terminal elimination half-life is dependent only on excretion
D. In a 2-C model inter-compartmental clearance is the product of V2 and k21
E. When measuring clearance after an oral dose, bioavailable fraction must be known
A. False. Time constant is longer than half-life by a factor of 1.443 since t1/2 = 0.693τ.
B. True.
C. False. It is also dependent upon re-distribution.
D. True.
E. True.
Give an overview of Target Controlled Infusions, and the relevance to anaesthetics.
Identify the difference between targeting plasma and effect-site
Describe the three-compartment models for propofol and remifentanil
Discuss the implications of duration of infusion on recovery times
Identify ideal properties for a drug to be used in a TCI system
Microprocessor driven infusion pumps can be used to induce and maintain anaesthesia with propofol and remifentanil
It is possible to target either plasma or effect-site
The Marsh model was designed to target plasma propofol concentration
The Schnider model was designed to target effect-site propofol concentration: this model is very different from the Marsh model
The time it takes for plasma concentration to fall to half of its value at the end of a targeted infusion is known as the context sensitive half-time (CSHT)
The context of the CSHT is the duration of the infusion
Propofol has a maximum CSHT of just under 20 min
Remifentanil has an almost constant CSHT due to its rapid metabolism
Fentanyl has a very long CSHT if infused for many hours
In an earlier session the three-compartment model (3-C) was introduced. This model can be used to predict the behaviour of both propofol and remifentanil.
Question: What are the pharmacokinetic parameters needed to describe a 3-C model?
Question: How can this model be applied to clinical use?
: A central volume of distribution and clearance together with two peripheral compartments and two inter-compartmental clearances.
An infusion pump can be controlled by a microprocessor that calculates the volume of drug to be delivered.
Which of the following can alter pharmacokinetic behaviour of a given drug in a particular patient?
A. Increasing age
B. Co-administered drugs
C. Onset of renal failure
D. Increase in body mass index (BMI)
E. Developing hepatic failure
A. True.
B. True.
C. True.
D. True.
E. True.
The first 3-C model described for use in an infusion device was the Marsh model.This allowed the plasma concentration to be targeted, with a pump delivering the calculated amount of propofol.
The plasma concentration required for induction of anaesthesia is around 6 μg/ml. The concentration to maintain anaesthesia varies between 3-10 μg/ml, depending on how stimulating the surgery is.
Question: What information does the pump need to deliver the appropriate amount of propofol?
In the Marsh model the initial volume of distribution is 15.9 L for a 70 kg patient.
Question: What loading dose will be delivered to achieve a plasma concentration of 6 μg/ml?
Question: If the pump delivers at a maximum rate of 1200 ml/h, for how long will the pump run before delivering this amount of propofol if a 1% solution is used?
The weight of the patient and the plasma concentration required.
Loading dose is the product of Vd and concentration so loading dose is:
15 900 x 6 = 95 400 μg or 95.4 mg
95.4 mg is 9.54 ml of a 1% solution. The pump runs at 1200 ml/h or 20 ml/min so this volume should be delivered in 9.54/20 min or just under 30 seconds. In practice a small amount more is given to compensate for the elimination and distribution taking place over this short time.
Consider a target-controlled infusion of propofol maintaining a plasma concentration of 6 μg/ml:
A. After a 30 min infusion the context sensitive half-time is 5 min
B. If the CSHT is 8 min then it will take 16 min for the concentration to fall to 1.5 mcg/ml after stopping the infusion
C. After an infusion lasting 10 h the CSHT is constant
D. At steady state infusion rate is equal to elimination rate
E. The context of CSHT is the duration of the infusion
A. True.
B. False. It will take longer for the concentration to fall from 3 μg/ml to 1.5 μg/ml than from 6 to 3 μg/ml.
C. False. It takes around 70 h before the CSHT is constant.
D. True.
E. True.
An ideal anaesthetic agent suitable for use by TCI will have the following properties:
A. It will behave according to a one-compartment model
B. It must be much more water than lipid soluble
C. It will be eliminated more rapidly than it is re-distributed
D. It will be cardiovascularly stable
E. It will have no active metabolites
A. False. Very few drugs behave this way, certainly not anaesthetic agents.
B. False. It needs to be lipid soluble to cross the blood-brain barrier.
C. True.
D. True.
E. True. This allows its effects to be predicted from its plasma concentration.
A patient on the ICU is receiving a constant-rate infusion of fentanyl:
A. The plasma concentration of fentanyl will not become constant until the infusion has been running for an hour
B. If the infusion has been running for less than 30 min then fentanyl has a short CSHT
C. The volume of distribution of fentanyl is more than 300 L
D. If a TCI infusion is used, then after a 6 h infusion the CSHT will be shorter than for a similar duration of infusion of propofol
E. If the infusion is stopped, the duration of its hypnotic effect depends only on the CSHT
A. False. It takes around 60 hours for steady state to be reached.
B. True.
C. True.
D. False. Propofol will have a much shorter CSHT after a 6 h infusion.
E. False. It also depends on the infusion rate: if low, then the effect may wear off before the concentration in plasma has halved. Patient pathology also influences pharmacodynamic response.
A patient is being anaesthetised with TCI propofol and remifentanil, both targeting the effect site:
A. On induction, the bolus dose of propofol will be larger than if an identical plasma concentration had been targeted
B. Remifentanil reaches steady-state at the same time as propofol
C. The effect-site is not appropriate to target when using the Minto model for remifentanil
D. The Schnider model would be appropriate to use for propofol in TCI effect mode
E. The CSHT of remifentanil is always shorter than that for propofol when they are used together
A. True.
B. False. Remifentanil has a smaller volume of distribution and reaches steady-state more rapidly than propofol.
C. False. The Minto model was designed to target the effect-site.
D. True.
E. True.
Which of the following statements are true for pharmacokinetics in older patients?
A. Oral absorption of most drugs in older patients is altered due to reduced gastric emptying
B. Absorption in older patients is the same as it is for other adults
C. The increase in total body water affects the distribution of drugs in older patients
D. Plasma and tissue concentrations are increased due to reduction in volume of distribution of water soluble drugs
E. The reduction of hepatic blood flow leads to increased systematic bioavailability of drugs dependent on hepatic clearance
F. The decrease in glomerular filtration rate and tubular function prolongs the elimination of drugs dependent on this route of elimination
A. False. Ageing is associated with changes in gastric pH, slowing of gastric emptying, and reduced small bowel surface area.
B. False. Drug absorption in older patients is slower than other adults.
C. False. There is an overall decrease in total body water in older patients. Younger patients have higher total body water content.
D. True.
E. True.
F. True.
Depending on the route of administration, the absorption of some drugs may be reduced in the elderly.
The decrease in body water affects the distribution and serum concentration of water soluble drugs. The half-life of lipid soluble drugs is increased and unbound drug concentration is increased due to changes in body fat and serum protein content.
The decrease in liver blood flow affects the rate of drug clearance. Re-accumulation of drugs normally eliminated by the kidneys can occur due to decreased renal function.
The relative reduction in body protein corresponds with loss of muscle bulk. This is also associated with reduced muscle blood flow and reduced metabolism of certain drugs such as remifentanil.
Which of the following statements are true for pharmacokinetics in neonates and infants?
A. Absorption is slower because of longer gastric emptying time
B. Hepatic enzyme activity is very similar to adults
C. Adult rates of metabolism can be reached with most drugs 6 weeks postnatally
D. Glomerular filtration rate is 20-40% of adult rate
E. Scaling down an adult dose of a water-soluble drug in proportion to body weight can result in a lower plasma concentration in neonates
A. True.
B. False. This is false for neonates and infants but may be true for older children.
C. False. Adult rates of metabolism for some drugs, such as barbiturates and phenytoin, can occur 2-4 weeks postnatally.
D. True.
E. True.
As with other special population groups, absorption is a key factor requiring consideration in neonates and infants.
Absorption will depend on the route of administration. Tissue sites of drug administration may lead to unreliable absorption due to vasomotor instability.
There are three different routes of administration which must be considered:
- Enteral route
There are several key facts to remember about absorption via the enteral route of administration in neonates:
Rate of absorption is slower because of the prolonged gastric emptying time and the increased intestinal transit time
Gastric pH is less acidic in neonates
Contact time - because of the longer gastric emptying time, there is greater contact time with the mucosa and thus an increased amount of drug absorption
- Rectal route
The site of placement of the drug within the rectal cavity may influence absorption. This is because of the difference in venous drainage systems. The rectal route of administration should be considered less reliable than IV.
The rectal route may be appropriate in certain out-of-hospital emergencies such the treatment of status epilepticus with rectal diazemuls.
- Transdermal route
In neonates the transdermal route of administration may be associated with rapid absorption because the stratum corneum is thin.
The ratio of body surface area to weight is much greater in neonates and infants than for older children and adults.
Total body water (TBW) plays an important role in distribution of drugs in neonates and infants (Fig 1).
TBW is 80% of total body weight in a preterm baby.
Doses of water soluble drugs based on scaling down adult doses in proportion to body weight can result in lower tissue concentrations.
There is a marked difference in the body fat content of neonates and infants, older children, adults (Fig 2) and older patients (Fig 3). This will influence the distribution of drugs.
Lower body fat and increased permeability of the blood-brain barrier can lead to increased concentrations of lipid soluble drugs in the brain.
There is a decrease in protein binding of drugs causing increased availability of the unbound drug. This leads to enhanced pharmacological action.
Metabolism of drugs in neonates depends on the size of the liver and activity of microsomal enzyme systems.
In neonates and infants:
Enzyme activity is immature
Phase I metabolism activity is reduced in neonates but increases progressively during the first 6 months of life and can exceed adult rates by the first few years for some drugs. It slows again during adolescence, and usually attains adult rates by late puberty
Adult rates of metabolism, however, may be achieved for some drugs 2-4 weeks postnatally
Phase II metabolism varies considerably
The glomerular filtration rate in neonates and infants is 20-40% of adult rate and therefore drugs removed by this route are eliminated slowly.
How would you expect the rate of absorption, distribution, metabolism and elimination to change in older patients when compared with neonates?
A. These factors would remain unchanged
B. These factors would change due to decrease in body water content
C. There would be some changes but generally they would be the same as for younger adults
A. Incorrect.
B. Correct.
C. Incorrect.
There is a marked difference between neonates and older adult patients in all aspects of pharmacokinetics. A number of factors differ in older people when compared with neonates. These include:
Total body water
Enzyme activity
Renal function
Hepatic blood flow
Level of body fat
Protein binding
Give an overview of Pharmacokinetic Principles in Different Patient Groups, and discuss the relevance to anaesthesia.
Define the concept of pharmacokinetics with reference to absorption, distribution, metabolism and elimination
Explain the absorption, distribution, metabolism and elimination of anaesthesia in key patient groups including neonates and infants, the elderly, the obese, pregnant patients and the critically ill
Neonates
Geriatric
Pregnant
Obese
Critically-ill
Which of the following statements best defines the concept of pharmacokinetics?
A. The study of the biochemical and physiological effects of drugs on the body
B. The study of the interactions that occur between the body and a drug following administration
C. The study of how the body absorbs and metabolises drugs, how long this takes and how the drugs are eliminated from the body
A. Incorrect. This is the definition of pharmacodynamics.
B. Incorrect. This is the definition of pharmacology.
C. Correct.
Pharmacokinetics can be defined as the study of the mechanisms of absorption and distribution of an administered drug, the rate at which a drug action begins and the duration of the effect, the chemical changes of the substance in the body and the routes of elimination.
The literature on basic pharmacokinetics may convey an impression that it is an exact science governed by rules and definitions. If the underlying laws can be elucidated, the disposition of a drug in any patient should be predictable. There is, however, a very wide interindividual variability in the way anaesthetic agents are dealt with by the body. This session will look at how pharmacokinetics varies in different patient groups and why.
Which of the following factors would you expect to influence drug absorption, distribution, metabolism and elimination in neonates and infants?
A. Total body water
B. Enzyme activity
C. Renal function
D. Hepatic blood flow
E. Amount of body fat
F. Protein binding
A. Correct.
B. Correct.
C. Correct.
D. Correct.
E. Correct.
F. Correct.
All of these factors influence pharmacokinetics in extremely young patients.
Which of the following factors would you expect to be relevant in the pharmacokinetics of a pregnant woman?
A. Hepatic blood flow
B. Hormone levels
C. Placental enzymes
D. Cardiac output
E. Protein binding
A. Correct.
B. Correct.
C. Correct.
D. Correct.
E. Correct.
All of the following factors are pertinent when considering pharmacokinetics in pregnant patients:
Hepatic blood flow
Hormone levels
Placental enzymes
Cardiac output
Protein binding
This part of the session will discuss how they are relevant.
A lady in her 39th week of pregnancy has gestational diabetes. Which, of the following statements, is correct regarding pharmacokinetics in this patient?
A. Gastric motility is unaffected due to an increase in serum progesterone levels
B. A decrease in serum albumin levels increases the free fraction of local anaesthetic drugs
C. Substances produced by the placenta metabolise hormones and drugs
D. Clearance of all drugs is enhanced by an increase in renal blood flow
A. Incorrect.
B. Incorrect.
C. Correct.
D. Incorrect.
Absorption in pregnant patients is affected by gut motility and has been related to increased progesterone levels and changes in the relative amounts of gastric acid and mucous secretion.
Gastric emptying is also delayed and this leads to increased uptake of drugs absorbed in the stomach and decreased uptake of drugs absorbed in the upper part of the intestines.
An increase in total body water and fat stores increases the volume of distribution. This may lead to lower total plasma concentrations with pre-pregnancy doses of drugs.
Protein binding of drugs is variable during pregnancy. Albumin levels are reduced due to plasma dilution. The binding of acidic drugs to albumin is also affected by the increase in free fatty acids which compete for alkaline binding sites. This leads to a larger free fraction of the drug.
Alkaline drugs, such as local anaesthetics and opioids, bind to α-acid glycoprotein whose concentrations are fairly consistent during pregnancy.
Metabolism
Metabolism in pregnant patients is affected by the increase in cardiac output. The clearance of many drugs may be enhanced because of this, as well as the increase in hepatic blood flow. The increase seen in enterohepatic circulation may lead to potentiation of certain drugs. The enzymes produced by the placenta are responsible for metabolism of various neurotransmitters and endogenous compounds.
Of note, is the production of placental lactogen which degrades insulin causing decreased sensitivity to insulin.
Elimination
The increased volume of distribution seen with certain drugs leads to prolongation of their half-lives, as clearance remains unchanged.
When considering pharmacokinetics in obese patients, which of the following is most important?
A. The ratio of adipose tissue to total body mass
B. The relative reduction in total body water
C. The relative reduction in muscle mass
A. Correct.
B. Incorrect.
C. Incorrect.
All these are true, but the most important is the increase in the percentage of adipose tissue.
Which of the following describe changes in pharmacokinetics in the obese population?
A. Drug absorption is increased in obesity
B. Volume of distribution of lipophilic drugs is increased
C. Serum albumin level decreases
D. Body mass index differentiates between adipose tissue and muscle mass
E. Considering actual body weight leads to overestimation of clearance
A. Incorrect.
B. Correct.
C. Incorrect.
D. Incorrect.
E. Correct.
The variation in drug response seen in this population is partly due to changes in pharmacokinetics.
The following links provide further details:
Absorption
Changes in absorption in obese patients could be expected because of:
Increased body surface area
Increased cardiac output
Increased gut perfusion 2
However, despite the theoretical rationale for altered absorption in obese patients, there is no difference when comparing oral drug absorption in obese patients with non-obese patients
Distribution
There are changes in drug distribution in obese patients because:
The increase in adipose tissue mass will increase the volume of distribution of drugs with lipophilic properties 4
The kinetics of hydrophilic drugs is also affected by an increase of organ mass, lean body mass and blood volume in obesity
Sub-therapeutic or supra-therapeutic concentrations can occur due to the physiologic changes which influence the volume of distribution of administered drugs
Metabolism
It is worth considering Phase I and Phase II metabolism, as well as liver function in obese patients:
Phase I - metabolism can remain unchanged or can increase
Phase II - drug biotransformations are increased leading to suboptimal serum concentrations of drugs metabolised by this route. There is an increased metabolism of lorazepam and oxazepam which undergo conjugation which leads to decreased sedation
Liver function - changes in liver function are not routinely seen despite fatty changes in the liver observed in obese patients
Elimination
Three factors to consider are:
Renal clearance correlates with creatinine clearance which is altered compared with non-obese patients
Use of conventional clearance equations may be inaccurate in the obese
Overestimation or underestimation of clearance can occur in obesity when considering actual body weight versus ideal body weight respectively
Which of the following statements are correct with regard to absorption in critically ill patients?
A. Absorption of drugs by the enteral route is decreased in a state of shock
B. Intestinal enzyme activity is always maintained
C. Absorption of enterally administered drugs is enhanced by the use of opioids
D. Phenytoin bioavailability is decreased when administered together with enteral nutrition
A. Correct.
B. Incorrect.
C. Incorrect.
D. Correct.
The bioavailability of orally or enterally administered drugs is highly variable, and usually significantly reduced in the critically ill.
Usually, the preferred route of administration is intravenous because of predictable bioavailability.
The pathophysiological changes caused by critical illness include:
Perfusion abnormalities
Decreased perfusion of the gastrointestinal system occurs due to redistribution of blood flow to vital organs.
Thus there is a reduction in the absorption of drugs from the periphery and intestines.
Intestinal atrophy
Intestinal atrophy can occur in the critically ill patient as a result of starvation 5.
The enzymatic activity may also be reduced thus further impairing absorptive function.
Motility dysfunction
Gut dysmotility can be due to early hypoperfusion. The use of opioid analgesics may further impair GI motility.
This leads to impaired absorption of enterally administered drugs.
Which of the following statements is correct regarding absorption of drugs?
A. The intramuscular route is reliable in neonates
B. Obesity markedly decreases enteral absorption of drugs
C. The intravenous route of administration is preferred in the critically ill as it achieves 90% bioavailability
D. Hyperperfusion of gut in septic shock leads to increased absorption
E. Opioid analgesics may lead to impaired absorption of enterally administered drugs
F. The transrectal route of drug administration is a reliable route
A. Incorrect.
B. Incorrect. There is no difference between obese and non-obese population.
C. Incorrect. Intravenous route achieves 100% bioavailability.
D. Incorrect. Hypoperfusion occurs in septic shock.
E. Correct.
F. Incorrect.
Which of the following statements is correct regarding the metabolism of drugs?
A. Phase I reactions are decreased in obesity
B. Changes in hepatic blood flow in critically-ill patients affects metabolism
C. Hepatic enzyme activity is increased in the critically-ill
D. Enzyme activity is mature in a term neonate
E. Phase II metabolism in a neonate is unchanged for all the drugs
A. Incorrect. Phase I reactions remain unchanged.
B. Correct.
C. Incorrect. Enzyme activity may vary in the critically-ill.
D. Incorrect. Enzyme activity is immature at birth.
E. Incorrect.
A 45-year-old female patient is admitted to the intensive care unit in septic shock. Which of the following statements best describes pharmacokinetics in this patient?
A. Delayed enteral feeding causes intestinal mucosal hypertrophy
B. Starting stress ulcer prophylaxis does not interfere with drug absorption
C. Increase in capillary permeability decreases the volume of distribution
D. Decreased protein leads to an increase in unbound fraction of all drugs
E. Hepatic blood flow decreases in the hyperdynamic stage of shock
F. Acute phase proteins decrease the hepatic enzyme activity
A. Incorrect. Delayed feeding causes atrophy.
B. Incorrect. pH changes in the stomach can affect absorption.
C. Incorrect. Increase in capillary permeability leads to an increase in volume of distribution of hydrophilic drugs.
D. Incorrect. Decreased protein leads to an increase in unbound fraction of protein bound drugs.
E. Incorrect. Hepatic blood flow increases in the hyperdynamic state.
F. Correct.
pH changes
The change in pH seen in the critically-ill patient affects the ionized state of drugs.
The non-ionized fraction of the drug is known to penetrate cellular membranes more effectively and the concentration of this fraction of the drug can affect the extent of distribution of the drug.
Fluid shifts
Administration of fluids in the critically-ill can cause leakage of large volumes into the interstitium.
The contributing factors can be an increased capillary permeability and decreased oncotic pressure which are seen in septic states. This increases the volume of distribution of hydrophilic drugs such as aminoglycosides.
The changes in blood concentration seen as a result emphasizes the need to monitor drugs, with narrow therapeutic indices, closely.
Protein binding
The concentration of plasma proteins may decrease in the critically-ill.
The unbound fraction of a protein bound drug increases as the protein concentration decreases.
This increases the volume of distribution of the drug.
Hepatic metabolism is dependent upon:
Hepatic blood flow (HBF)
Enzyme activity
Protein binding
Hepatic extraction ratio is dependent on these variables and knowledge of the ratio is useful in predicting changes in drug metabolism.
The metabolism of drugs dependent on hepatic blood flow (extraction ratio >0.7) is affected by the status of the cardiovascular system. An increase in hepatic blood flow, as seen in the early phases of sepsis, increases clearance. The reverse is true in conditions with poor perfusion 6.
Drugs with low hepatic extraction ratio are dependent on metabolic enzyme activity for their clearance. The enzyme activity is decreased by the cytokines and acute phase proteins. A diet with increased protein is known to increase enzyme activity and hence clearance.
Many drugs and their metabolites are eliminated by the renal route.
Renal dysfunction is common in critically ill patients, which has clinical implications for drugs or active metabolites that are eliminated through the kidneys.
The dose modifications for patients with renal dysfunction are widely available (e.g. manufacturer’s information, British National Formulary). Frequent blood concentration monitoring of drugs is required for drugs which need minimum drug levels to be effective (such as antimicrobials) or have narrow therapeutic indices.
Which of the following is correct regarding the distribution of drugs?
A. The volume of distribution of lipophilic drugs is increased in obesity
B. A relatively low volume of total body water in neonates affects distribution
C. Concentration of ionized drug changes in all critically-ill patients
D. Decreased protein concentration increases the unbound fraction of drug in the obese
E. There is a decrease in the free fraction of the drug in pregnancy
A. Correct.
B. Incorrect. There is an increase in body water.
C. Incorrect. The ionized drug concentration changes with change in plasma pH.
D. Incorrect. Changes in protein concentration are not noted commonly in the obese.
E. Incorrect. There is an increase in the free fraction of the drug.
A 35-year-old male patient with a body mass index of 40 kg/m2 is to undergo laparoscopic cholecystectomy. Which of the following statements best describes the pharmacokinetics of this patient?
A. The absorption of oral premedication is enhanced
B. The volume of distribution of fentanyl is decreased
C. Fatty changes in the liver routinely affects liver function
D. Volume of distribution of propofol is unchanged
E. Intravenous fluids administered during the procedure leads to delay in elimination of lipid soluble drugs
F. Increased metabolism of lorazepam leads to decreased sedation
A. Incorrect.
B. Incorrect. There is an increase in the volume of distribution of lipid soluble drugs.
C. Incorrect. Fatty changes have minimal effect on liver function.
D. Incorrect.
E. Incorrect. Intravenous fluids have no effect on elimination of lipid soluble drugs.
F. Correct.
A 60-year-old patient is admitted to the intensive care unit with acute renal failure as a result of septic shock. Which of the following statements is correct regarding drug distribution in this patient?
A. pKa of administered drugs is affected
B. The ionized fraction of the drug affects distribution
C. Lipophilic drugs have an increased volume of distribution due to ‘third spacing’
D. Decreasing albumin levels decrease volume of distribution
A. Incorrect. pKa is not influenced by external factors.
B. Correct.
C. Incorrect.
D. Incorrect.
Give an overview of the Pharmacokinetics of Intravenous Anaesthesia, and the relevance to anaesthesia.
Describe the mechanism of ‘target control infusion’ (TCI) and the various pharmacokinetic models used
Pharmacokinetics of target controlled infusions (TCI)
Various pharmacokinetic models used in TCI practice
Practical aspects of TCI
Which of the following statements best describe a pharmacokinetic model?
A. A pharmacokinetic model is a mathematical model that can be used to predict the blood concentration profile of a drug after a bolus dose or an infusion of varying duration
B. A pharmacokinetic model is a model predicting the rates of metabolism of induction agents
C. A pharmacokinetic model is a table of infusion rates corrected for age and gender and is useful for total intravenous anaesthesia
A. Correct.
B. Incorrect.
C. Incorrect.
A pharmacokinetic model is a mathematical model that can be used to predict the blood concentration profile of a drug after a bolus dose or an infusion of varying duration.
Arterial or venous blood/plasma concentrations of a drug are measured after a bolus or infusion in a group of patients or volunteers.
Standardized statistical approaches and software are used to estimate model parameters in that population.
For most anaesthetic agents in common use there are several published models. Each model describes the:
Number of compartments and their volumes
Rate of drug metabolism or elimination
Rate of drug transfer between the different compartments
The following pages provide further information on the various pharmacokinetic models.
Which of the following statements are true regarding pharmacokinetic models used in target controlled infusion (TCI)?
Select one or more options from the answers below.
A. Marsh model incorporates age as a covariate
B. The Schnider model has a fixed central compartment volume
C. The Minto model can be used for both remifentanil and propofol
D. The Domino model is used for thiopentone TCI on ICU
E. The central compartment volume in the Schnider model is a linear function of weight of the patient
F. The Marsh model can be used on any infusion pump
G. Lean body mass is used as a covariate in the Marsh model
A. Incorrect. The Schnider model incorporates age as a covariate.
B. Correct.
C. Correct.
D. Incorrect. There is no clinical model for thiopentone TCI.
E. Incorrect. The central compartment volume is fixed in the Schnider model.
F. Incorrect. A microprocessor with an appropriate model is needed for TCI.
G. Incorrect. Lean body mass is used as a covariate in the Schnider model to calculate clearance.
Match the most appropriate TCI model to each agent:
Maitre developed a three compartmental model that is the most commonly used model for TCI alfentanil systems. The model incorporates weight, age and gender as covariates.
The model developed by Shafer is most commonly used for TCI fentanyl administration. This model has no covariates.
The three compartment Domino model is the model used for TCI ketamine administration.
For propofol, the Marsh model requires actual body weight; the more recent Schnider model requires age, height, and total body weight to calculate lean body mass.
The model most commonly used for remifentanil is a three compartment model described by Minto. Covariates include weight, height, gender and age.
Appropriate effect site targets to set initially for a spontaneously breathing 40 year old man undergoing a GA for a minor procedure are:
A. Propofol 4 ng/mL
B. Remifentanil 4 mcg/mL
C. Propofol 5 mcg/mL
D. Remifentanil 8 ng/mL
E. Propofol 2 mcg/mL
F. Remifentanil 3 ng/mL
A. False. This is the correct number, but the wrong units.
B. False. This is the correct number, but the wrong units.
C. True. Although this should then be adjusted to clinical effect and appropriate processed EEG value.
D. False. This is likely to be too high to maintain spontaneous breathing.
E. False. This target is more appropriate for a more elderly patient.
F. True. Although this should then be adjusted to clinical effect and appropriate processed EEG value.
Give an overview of Interindividual Variation in Drug Response, and the relevance to anaesthesia.
Describe the underlying mechanisms of genetic variation
Describe the genetic variations of plasma cholinesterase
Identify which cytochrome P450 enzymes show significant genetic variability
Discuss the implications of gene multiplication
Identify receptors for which genetic variation has clinical significance
Identify those drugs for which genetic polymorphism contributes significantly to therapeutic efficacy
Regarding human chromosomes:
A. 50% of DNA codes for genes
B. Pre-mRNA from introns is spliced to form mRNA
C. The human karyotype has 22 pairs of autosomes
D. The ‘start’ codon also codes for methionine
E. Each amino acid is coded for by more than one codon
A. False. The 30 000 genes are coded for by just 20% of DNA.
B. False. Pre-mRNA from exons is spliced to form mRNA.
C. True. Humans have 23 pairs of chromosones, 22 autosomal pairs and one pair of sex chromosomes.
D. True. There is just one ‘start’ codon.
E. False. Methionine and tryptophan are both coded for by just one codon.
We all have 23 pairs of chromosomes, 22 autosomal pairs and the pair that determine sex (Fig 1). This complete diploid set of chromosomes is known as the human karyotype. There are about 30 000 genes encoded across these chromosomes.
On each chromosome are many genes; each gene is represented on both chromosomes so an individual has two representations of each gene: one is inherited from each biological parent (Table 1). For each gene we therefore have two alleles. There may be several variants of these alleles. The combined expression of the two alleles determines our phenotype for that gene.
Both alleles are usually transcribed when a gene is activated. Frequently, the expression of one allele dominates and determines the inherited phenotype (the dominant allele): the other allele is then referred to as recessive. If both alleles contribute equally to phenotype, then the term co-dominant is applied to the gene.
Some of these alleles may contain abnormalities. If the gene is autosomal dominant and just one allele is abnormal (heterozygous) then the phenotype will be normal, only if both alleles are abnormal (homozygous) will the phenotype be abnormal.
In your anaesthetic practice you may encounter genetic differences that can alter a patient’s response to the drugs we use routinely.
Question: Can you think of one very important inherited condition that affects your choice of anaesthetic drugs during emergency surgery?
Question: What enzyme is affected and where is the gene coding for it located?
Succinylcholine (suxamethonium) apnoea occurs with an incidence of around 1 in 2500 for the commonest homozygous abnormality.
Plasma (or pseudo-) cholinesterase, more correctly called butyrylcholinesterase (BChE), is coded by the BCHE gene located on the long arm of chromosome 3.
In addition to pseudocholinesterase, there are other genetic polymorphisms affecting enzymes that can alter a patient’s response to the drugs we use routinely.
Question: Can you think of two examples of enzymes demonstrating genetic variation?
Question: Which family of CYP450 enzymes have particularly important genetic variants?
Two good examples are:
The enzyme that acetylates hydralazine
Certain cytochrome P450 (CYP450) enzymes
The CYP2 family: CYP2C9, CYP2C19 and CYP2D6 have significant genetic polymorphisms.
Fig 1a shows the clotting cascade.
There is very strong evidence that the considerable variation in patient sensitivity to warfarin has a genetic basis. Two of the enzymes involved in warfarin activity and metabolism show genetic variability.
Question: Which cytochrome is responsible for metabolism of S-warfarin?
Question: How does warfarin block the activity of vitamin K-dependent factors in the coagulation cascade?
CYP2C9.
Warfarin inhibits the enzyme vitamin K epoxide reductase (VKOR), specifically subunit 1 (VKORC1). This enzyme is essential for recycling vitamin K, which is an essential part of post-transcriptional carboxylation of factors II, VII, IX and X and proteins S and C (Fig 1b).
Which of the following CYP450 enzymes demonstrate important pharmacogenetic variation?
A. CYP1B1
B. CYP1C19
C. CYP2C9
D. CYP2D6
E. CYP2E1
A. Incorrect. CYP1B1 does have pharmacogenetic variants, but they are associated with susceptibility to ovarian and other cancers.
B. Incorrect. CYP2C19 shows pharmacogenetic variation but CYP1C19 does not.
C. Correct.
D. Correct.
E. Incorrect. Although it belongs to the CYP2 family of enzymes, there are no important pharmacogenetic variants.
Which of the following drugs are metabolized mainly by enzymes that demonstrate important pharmacogenetic variation?
A. Losartan
B. Mivacurium
C. S-warfarin
D. Tramadol
E. Vecuronium
A. Correct. Losartan is a pro-drug so may not be effective in patients with abnormal CYP2C9.
B. Correct. Mivacurium is metabolized by plasma cholinesterase, which shows significant genetic variation.
C. Correct. S-warfarin (the more potent enantiomer) is metabolized by CYP2C19.
D. Correct. Tramadol is converted to an active metabolite that works through opioid receptors by CYP2D6.
E. Incorrect. Vecuronium is metabolized by CYP3A4.
Regarding pharmacogenomics:
A. 75% of patients with malignant hyperthermia have a SNP in the gene for the ryanodine receptor
B. The wild-type gene for the metabolism of S-warfarin is CYP2C9*10
C. Ultrafast metabolizers of codeine have multiple copies of the CYP2D6 gene
D. Splice variants of the μ-opioid receptor are found in different areas of the CNS
E. Hypertensive patients who are hetereozygous for SNPs in both amino acids at positions 49 and 389 respond to metoprolol
A. False. About 25% of MH patients have a demonstrable SNP in the ryanodine receptor.
B. False. The wild-type always has 1 as its final designation, so CYP2C91 is the wild-type.
C. True.
D. True. Splice variants are less widespread than the normal gene product and appear to be more localized.
E. False. Those who respond to metoprolol can be heterozygous for a SNP at just one of the two contributing amino acid positions, but not both.
All of the drugs below show pharmacogenetic variation. Match the drugs to the enzymes that are responsible for their metabolism.
An 19-year-old university student presents with severe abdominal pain and is scheduled for an emergency appendicectomy. He has not eaten for 48 hours and has not been vomiting. He gives a vague history of his father having had a ‘bad reaction’ to anaesthesia and needing care on an ICU. He knows no details, but it was before he was born. His parents cannot be contacted and the surgeon wants him to go to theatre now.
A. Cancel surgery until his parents can be contacted
B. Go ahead with surgery but avoid succinylcholine
C. Arrange a blood test to look at his plasma cholinesterase activity before proceeding
D. Go ahead with surgery using a volatile-free anaesthetic machine and total intravenous anaesthesia
E. Go ahead with surgery but avoid muscle relaxants and volatile agents
Submit
You should go ahead with surgery but avoid muscle relaxants and volatile agents.
It is not uncommon for patients to report ‘reactions’ to anaesthesia and in an emergency there is always pressure to get on with surgery. The most common adverse reactions requiring ICU admission are:
Anaphylaxis, particularly to muscle relaxants, which is idiosyncratic
Malignant hyperthermia and
Succinylcholine apnoea
Malignant hyperthermia and succinylcholine apnoea are both inherited conditions. You should always contact your senior for advice.
The safest option, if considering just the history of an adverse reaction in a close family member, is to delay surgery but in this case there is a significant risk of peritonitis.
By avoiding all muscle relaxants and using total IV anaesthesia (TIVA) in a careful way, with senior assistance at hand, the risk of a significant adverse reaction is minimized.
This case went ahead as discussed, with no adverse consequences. It later transpired that the student’s father had had succinylcholine apnoea but his mother had never been tested. The entire family was subsequently offered screening and his mother found to be heterozygous for the silent gene.
Concerning genetics:
A. mRNA has just a single helix
B. tRNA is formed from A,G,T and C nucleotides
C. The result of a SNP is always a single aminoacid substitution
D. μ-opioid receptors are formed from several genes
E. Monozygotic twins have the same genotype for plasma cholinesterase
A. True. DNA is a double helix, but mRNA just a single helix.
B. False. In tRNA, as in mRNA, T is replaced by U.
C. False. SNPs can have three possible outcomes: no change in amino acid sequence, a single amino acid substitution or a ‘stop’ codon may result with premature truncation of the amino acid sequence.
D. False. There is a single gene: MOR1, but more than one promotor and several possible splice variants.
E. True. Identical (monozygotic) twins have the same genotype.
Give an overview of Halogenated Volatile Agents and Unwanted Effects of Volatile Agents, and reference and application to anaesthetic.
List the important pharmacokinetic properties of anaesthetic agents and concepts such as MAC and oil:gas solubility
Describe the structure of the halogenated volatile agents
List the pharmodynamic properties of the agents including the unwanted clinical effects
Explain the synergistic effects of anaesthetic agents and the influence of differing ages on the clinically observed effects
Halogenated volatile agents are liquids at room temperature, which easily vaporise and have a low boiling point and high saturated vapour pressure
MAC is inversely related to potency and MAC increase is inversely proportional to the oil:gas solubility
The blood:gas partition coefficient describes the solubility of an inhaled gas in blood and the lower the solubility the faster the speed of onset of the agent
The volatile agents all have some adverse physiologically effects and all pose the rare but significant risk of the patient developing malignant hyperthermia
Question: From the knowledge that the boiling point of xenon is -108°C what can you deduce about the nature of this element at room temperature?
It will all be in the vapour phase and with the additional information that the critical temperature is 16.5°C and the critical pressure is 5.84 MPa, at standard room temperature and pressure, it will all be gas.
The critical temperature of a substance is the temperature at and above which vapor of the substance cannot be liquefied, no matter how much pressure is applied.
The critical pressure of a substance is the pressure required to liquefy a gas at its critical temperature.
Which of these volatile agents is the most potent?
A. Isoflurane (MAC 1.1)
B. Sevoflurane (MAC 2.0)
C. Desflurane (MAC 6.6)
Isoflurane is the most potent; potency is inversely related to MAC and is a measure of dose of drug required to exert a clinical effect.
MAC is the minimum alveolar concentration of an anaesthetic agent that prevents movement in response to a standard skin incision in standard conditions in 50% of subjects, when breathing in 100% oxygen and in the absence of other analgesic or anaesthetic agents.
It is useful to allow comparisons between different agents and as a guide for the percentage anaesthetic required for anaesthesia. It is also a measure of potency and can be compared to the ED50, i.e. the dose of a drug which produces a biological effect.
MAC is inversely related to potency.
Potency is the ability of a drug to produce an effect. The more potent the drug the smaller the dose required.
So, considering the values in Table 1, you can see that halothane is the most potent agent, i.e. requires the smallest concentration to produce a clinical effect.
MAC is also useful clinically as it can readily be measured by anaesthetic gas analysers.
It is far from clear how anaesthetic agents work, however with the observation that MAC increase was inversely proportional to the oil:gas solubility, Meyer and Overton hypothesised that inhalational agents must work non-specifically on the lipid rich neuronal cells of the central nervous system. They also proposed that potency increases with oil:gas solubility.
More recent research suggests the theory that agents work on CNS receptors such as potentiation at GABAA, glycine receptors and potentially inhibition at MNDA receptors as well as newer evidence for the role of two-pore domain potassium channels.
A 12-year-old patient is having an elective orthopaedic procedure to her ankle, requiring a general anaesthetic. She is given an IV induction agent, a supra-glottic airway is inserted and anaesthesia is maintained on sevoflurane at a MAC of 1 (ET Sevo of 2.0).
Question: Why did the anaesthetist choose sevoflurane? Should they have chosen a different vapour?
Question: During a stimulating part of the operation she moves and coughs, why might this be?
Sevoflurane is a liquid at room temperature and can be readily vaporised in a plenum vaporiser, with a relatively high SVP of 21 kPa.
It has the advantage of being non-irritant to the airways and has a pleasant odour so is suitable for use with an LMA and because of this, it can also be used for inhalational induction. A further factor facilitating this is the low blood:gas solubility resulting in a rapid speed of onset of anaesthesia.
Arguments for the use of a different agent would be that you could consider isoflurane, which has a similarly low MAC and high SVP but is somewhat cheaper. It does however have a more pungent odour and is a respiratory suppressant causing coughing and breath holding, so is not suitable for gaseous induction.
After checking the delivery of the anaesthetic agents and finding no issues it was felt that the level of anaesthesia was insufficient. The MAC value of any of the agents is affected by numerous variables. Specific to this case MAC is affected by young age (needing an increased MAC).
MAC is additive within the group of inhalational agents, so a mixture of agents with a cumulative alveolar concentration of 1 MAC has the same effect as 1 MAC of a single agent. This is most commonly seen with the use of nitrous oxide but also apples to xenon, e.g. If 60% nitrous oxide (MAC 105%), is added to a volatile agent in 40% oxygen the volatile agent requirement is reduced by 57%.
Regarding important pharmacodynamic properties of the volatile agents:
A. The MAC required for a neonate is higher than that for a 5-year-old
B. A higher MAC is required for an acutely intoxicated patient
C. MAC is inversely related to potency
D. The use of midazolam preoperatively decreases the MAC requirement
A. False. As per the table both the elderly and neonates require a lower MAC.
B. False. Higher MAC is required for patients who have a chronic consumption of alcohol whereas an acutely intoxicated patient will have a lower requirement.
C. True.
D. True. Midazolam is a sedative drug and will therefore decrease the MAC requirement.
Properties of an ideal anaesthetic agent include:
A. Low MAC
B. High latent heat of vaporisation
C. Boiling point around room temperature
D. Low blood:gas coefficient
E. Low oil:gas coefficient
A. True. A low MAC allows delivery with a high concentration of oxygen. Compare sevoflurane (MAC 2) with N2O (MAC 104).
B. False. A low latent heat of vaporisation facilitates easy vaporisation.
C. False. The inhalational agent must be predictably vaporised at room temperature to ensure reliable delivery of gas concentration, e.g. desflurane’s boiling point is at around room temperature. Therefore, it needs its own specialised vaporiser to ensure 100% saturation of the gas flow.
D. True. A low blood:gas coefficient allows for a rapid onset and offset of anaesthesia.
E. False. A high oil:gas coefficient relates to a high drug potency and therefore a more efficacious anaesthetic agent.
Which of the agents in Table 1 would you expect to be the least potent?
A. Sevoflurane
B. Isoflurane
C. Desflurane
D. N20
E. Xenon
N20 has the lowest oil:gas solubility.
Isoflurane has the highest oil:gas solubility therefore using Meyer-Overton hypothesis this is the most potent of these agent.
The agents are inhaled by the patient via the breathing circuit and uptake is via the alveoli of the lungs, where the small volatile molecules readily pass through the alveolar membranes to enter the bloodstream. Another important concept in the speed of onset of an anaesthetic agent relates to its solubility in blood.
The blood:gas partition coefficient describes the solubility of an inhaled gas in blood (Table 1).
The blood:gas coefficient is the ratio of the concentration of agent in one solvent compared to another solvent at equilibrium.
It would be easy to assume that the greater the solubility in blood the faster the speed of onset, however the converse is true as it is the partial pressure of agent in the blood and subsequently the brain (PB) which produces a more rapid onset of action (and offset).
Simply put, the anaesthetic agents exert their effects on brain tissue and the less soluble the agent is in blood the greater the partial pressure of gas which is available to exert its effect on the brain.
The higher the blood:gas coefficient the higher the uptake of gas that is required, i.e. there will be a longer induction time. Thus, it follows that the lower the blood:gas coefficient, the faster the onset of action.
A wash-in curve (Fig 1) illustrates that the lower the blood:gas coefficient, the faster the volatile agent exerts its clinical effect. Note clinical effect would be expected at 1.0 MAC.
Whereas the wash-out curve (Fig 2) shows the converse; the lower the blood:gas coefficient the faster the offset time and the quicker the patient will regain consciousness.
Place these anaesthetic agents at the correct point on the graph.
Regarding malignant hyperthermia:
A. Susceptibility to MH is carried by an autosomal recessive gene with variable penetrance
B. It can only be triggered in susceptible patients by volatile agents
C. The initial dose of dantrolene in the immediate management of MH is 2.5 mg/kg by IV bolus
D. It is carried on a gene on the X chromosome
E. The first clinical sign is a steady rise in the patient’s temperature
A. False. Autosomal dominant.
B. False. It can also be triggered by suxamethonium
C. True. And in a 70 kg man this requires 9 vials for the initial dose; each being 20 mg and being mixed with 60 ml of sterile water for injection.
D. False. It is carried on a gene on chromosome 19.
E. False. The first clinical signs are tachycardia, increasing ETCO2 and increased oxygen consumption. Pyrexia is a late sign.
Give an overview of Nitrous Oxide and Xenon, and the relevance to anaesthetics.
Describe the production, purification and storage of N2O
Define the relevant physicochemical properties of both N2O and xenon
Describe the Concentration Effect and the Second Gas Effect
List the side-effects, potential for toxicity and contraindications of N2O
State the similarities and differences between N2O and xenon
Both N2O and xenon are general anaesthetic agents
The values of the physicochemical properties for N2O should be committed to memory
The Concentration Effect accounts for the more rapid rise of FA/FI for higher as opposed to lower concentrations of N2O
The Second Gas Effect is caused by the Concentration Effect
Xenon is produced by fractional distillation of liquid air, a by-product of oxygen manufacture
Xenon costs approximately 2000 times that of N2O, hence its slow introduction into mainstream anaesthetic practice
N2O is most commonly produced by heating ammonium nitrate (NH4NO3) to 250oC.
Question. N2O is not the sole product derived from using this heating process. Can you name other ones?
The other products derived from this process are:
NO (nitric oxide)
NO2 (nitrogen dioxide)
NH3 (ammonia)
N2 (nitrogen)
HNO3 (nitric acid)
H2O (water)
The temperature of the reaction has to be very carefully controlled to minimise N2O contamination. These toxic impurities are removed by cooling and passing the raw products through alkaline gas washes. During this process, NO and NH3 are also removed but this occurs by acidic washes.
Regarding critical temperature:
A. This is the temperature above which it is not possible to return N2O to a liquid, regardless of the pressure
B. This definition should be quoted at one atmosphere
C. Above 36.5 oC N2O is defined as a vapour
A. Correct. Well done. This is the definition of critical temperature.
B. Incorrect. Critical temperature is the temperature above which it is not possible to return N2O to a liquid regardless of the pressure.
C. Incorrect. Above its critical temperature N2O is a gas. A vapour can be compressed to a liquid but a gas cannot.
For a saturated vapour pressure of 5200 kPa:
A. The gauge pressure of a cylinder of N2O should therefore be 5.2 atmospheres
B. This value falls in line with temperature
C. This may be defined as the pressure of a vapour at equilibrium that exists above its liquid and is independent of temperature
A. Incorrect. It should be 52 atmospheres or 52 bar at 20oC. (100 kPa = 1 bar = 1 atmosphere).
B. Correct. SVP is usually quoted at 20oC. The value will alter with temperature.
C. Incorrect. It is dependent on temperature – otherwise this definition is correct.
Critical temperature
This is the temperature above which it is not possible to return a substance into a liquid regardless of the pressure applied. Above its boiling point (-88.5oC) N2O is a vapour and with sufficient pressure may be ‘squashed’ into a liquid state but once the critical temperature (36.5oC) is exceeded the liquid state becomes impossible. Of academic note, N2O is therefore inhaled as vapour but exhaled as a gas.
Saturated vapour pressure
This is the pressure that exists above its liquid phase at equilibrium and is dependent on temperature, but independent of other gases present. The pressure gauge on a cylinder of N2O indicates its saturated vapour pressure which is constant while the cylinder contains N2O liquid.
The filling ratio is the ratio of the mass of liquid in the cylinder compared with the mass of water that the cylinder can hold. In temperate regions this is 0.75, while in the tropics it is 0.67. Why is the filling ratio higher in temperate regions?
Select one answer from the options, then select Submit.
Possible answers:
A. The cylinders are smaller
B. The temperature in temperate regions never rises above the critical temperature of N2O
C. The cylinders are made to a higher standard and can cope with the higher filling ratio
A. Incorrect. The size of the cylinders has nothing to do with the filling ratio.
B. Correct. If a full cylinder of N2O with a filling ratio of 0.75 reaches >36.5 ° C, all the N2O would convert to gas and exceed the pressure that the cylinder is designed to cope with. This would lead to an explosion. When the filling ratio is reduced to 0.67, even at temperatures >36.5 ° C, the cylinders are able to withstand the pressure of N2O gas.
C. Incorrect. The cylinders used in the tropics are made to the same exacting standards.
Regarding N2O:
A. It is not possible to anaesthetize anyone with N2O alone
B. 103 kPa of N2O prevents patients moving to a surgical stimulus
C. One MAC of N2O prevents patients from waking up during a simple operation
D. N2O is not very potent
A. Incorrect. It is not possible to anaesthetize anyone with N2O alone at one atmosphere, but in a pressurized chamber it is possible.
B. Incorrect. 103 % of N2O prevents 50 % of patients moving to a standard surgical stimulus.
C. Incorrect. The effects of one MAC refer to movement, not waking up.
D. Correct. Well done. A high MAC value indicates low potency while a low MAC value indicates high potency, e.g. isoflurane’s MAC is 1.17 % at one atmosphere.
MAC = 103 %
MAC is defined as the minimum alveolar concentration required to prevent 50 % of patients moving to a standard surgical incision, at one atmosphere.
The MAC value of N2O is 103 %. At first glance it therefore appears impossible to produce anaesthesia with N2O alone because using 100 % N2O is clearly a hypoxic mixture, never mind the extra 3 % required.
However, thinking in ‘percentages’ can result in missing the point because you should be thinking in ‘percentages of one atmosphere’ which leads to partial pressure - the key. Partial pressure is independent of atmospheric (or ambient) pressure so that for N2O it can be seen that 103 kPa are required for anaesthesia.
So it is possible to produce anaesthesia with N2O alone, you just need a hyperbaric chamber to allow 103 kPa of N2O and some additional oxygen.
Remember, for any anaesthetic agent, anaesthesia results from exposure to a partial pressure (which is independent of atmospheric or ambient pressure) rather than a percentage (which varies with atmospheric or ambient pressure).
Regarding blood: gas solubility coefficient:
A. The blood: gas solubility coefficient of N2O is much lower than other commonly used inhaled agents
B. A high blood: gas solubility coefficient results in a fast onset of action because agent gets into the blood quickly and can therefore get to the brain quickly
C. Ether has a blood: gas solubility coefficient of about 12. This means that at equilibrium the amount of ether in the blood will be 12 times that in the gas phase
A. Incorrect. Its value is 0.47, which is only slightly lower than other commonly used agents.
B. Incorrect. Agents with a high blood: gas solubility take a long time to generate a sufficient partial pressure so therefore have a slow onset of action.
C. Correct. Ether’s blood: gas solubility coefficient is high (12) resulting in the proportions as described.
Blood: gas solubility coefficient = 0.47
The blood: gas solubility coefficient is defined as the ratio of the amount of anaesthetic in blood and gas when the two phases are of equal volume, pressure and in equilibrium at 37 ° C. So in relation to N2O, roughly half as much exists in the blood phase compared to the gas phase.
A value of 0.47 may be regarded as low (however all modern anaesthetic agents have low values).
A low value results in a rapid onset of action as it equilibrates rapidly with the pulmonary capillaries and what little enters the blood generates a high partial pressure causing a rapid effect.
Agents with high values may enter the blood rapidly but the blood acts like a bottomless pit and so it takes a long time for the agent to reach a sufficient partial pressure to have an effect.
Entonox ® is a 50:50 mixture of N2O and O2. It takes on certain properties that mark it out as distinct from the properties of its constituents. This is called the Poynting effect.
The temperature below which Entonox ® separates back into N2O and O2 is pressure dependent and is known as the pseudocritical temperature.
It is stored at 137 bar in cylinders, but may also be delivered via pipes in hospitals at 4.1 bar.
Question: If a cylinder of Entonox ® were to fall below its pseudocritical temperature, would the gas initially withdrawn contain more O2 than N2O or more N2O than O2?
It would initially contain more O2 than N2O. This is because N2O would come out of Entonox ® as a liquid, while the O2 would remain as a gas. As time progresses, the mixture will contain less oxygen and may then eventually become hypoxic.
In which of the following situations is Entonox ® a useful analgesic?
A. Labour
B. Dressings change
C. Post major joint replacement
D. Fractured ribs
E. Removal of drains
A. True. This is due to its fast onset.
B. True. It is useful on wards to assist in painful procedures of short duration.
C. False.
D. False. There are two reasons Entonox ® is not suitable. There may be underlying pneumothorax which would get worse. Secondly, fractured rib pain is not short-term.
E. True. As with dressings change, Entonox ® can be used to assist pain relief.
It is important the phenomenon is clearly understood before looking at the mechanism behind it, so consider this question before moving on.
When the curves for FA/FI of the commonly used anaesthetic agents are plotted against time, their order follows the blood:gas solubility coefficient, the largest approaching an FA/FI of one most slowly whilst the smallest approaches an FA/FI most rapidly.
Question: So why is the curve for N2O usually shown above that for desflurane, given their blood: gas coefficients? (N2O = 0.47; desflurane = 0.42)
The Concentration Effect! The curve for N2O that lies above that of desflurane represents N2O at high concentration. If a low concentration of N2O were to be plotted, this would indeed be below that of desflurane.
This is not obvious because FA/FI is a ratio and the curves are not normally labelled to indicate the percentage used.
The Concentration Effect can be defined as the disproportionate rate of rise of FA/FI when high concentrations of N2O are used compared with when low concentrations are used:
It relates only to N2O because it is the only anaesthetic agent used in sufficiently high concentrations
Despite being relatively insoluble, large amounts of N2O are absorbed into the pulmonary capillaries
The main driving force is the large concentration gradient generated by high concentrations of N2O
It is helpful to split the phenomenon from the mechanism when considering the Concentration Effect.
The phenomenon describes the disproportionate rate of rise of FA/FI when high concentrations compared to low concentrations of N2O are used.
The Concentration Effect is also responsible for the observation that the FA/FI for other inhaled gases rises more rapidly in the presence rather than absence of nitrous oxide. This is known as the Second Gas Effect and applies to both volatile anaesthetic agents and oxygen. For obvious reasons it is particularly useful during gaseous induction of anaesthesia.
Question: From the image, what are the second gases?
Oxygen and sevoflurane.
In this sequence you will compare the properties of xenon and N2O. Look for a pattern that will develop as you answer the questions.
Xenon has no smell or colour, properties it shares with N2O. It does not support combustion.
Question: Does N2O support combustion?
Question: Is this lower than the boiling point of N2O?
Question: The critical temperature for xenon is 16.6oC. Is this higher or lower than the critical temperature for N2O?
Question: The blood: gas solubility coefficient for xenon is 0.114. Is this lower than the blood: gas solubility coefficient for N2O?
MAC for xenon is 65-70 % at one atmosphere. Is this higher or lower than the MAC for N2O?
Question: Bearing in mind the previous answers, compared to N2O does it take less or more time for the effects of xenon to be observed?
Yes. N2O supports combustion.
The boiling point for Xe is -108.1oC.
Answer: Yes. The boiling point of N2O is -88oC.
Lower, the critical temperature for N2O is 36.5oC.
Yes, the blood: gas solubility coefficient for N2O is 0.47.
Lower, the MAC for N2O is 103 %.
Less time.
Which ion channel pore does each ionotropic receptor control?
The mechanism of action of the gases can be subclassified into:
Macroscopic: brain and the spinal cord
Microscopic: synapses and axons
Molecular: pre and post-synaptic membranes
Macroscopic
On a macroscopic level, the transmission of ascending noxious afferent signals to the cortex via the thalamus is decreased following administration of inhalation anaesthetics. Movement response to pain is also reduced due to inhibition of spinal efferent neuronal activity.
Inhalation anaesthetics suppress cerebral blood flow and glucose metabolism, contributing to hypnosis and amnesia
Microscopic
Inhaled anaesthetics reduce neuronal and synaptic signal transmission through inhibitory actions on excitatory presynaptic channels and modulation of the inhibitory activity of the GABA-A and glycine receptors
Molecular
Modulation of two-pore domain potassium channels which are present both pre- and post-synaptically throughout the CNS. Inhalation anaesthetic action on these channels is thought to result in hyperpolarization and therefore influence the likelihood of action potential generation 198.
The action of inhaled anaesthetics on GABA-A receptors prolongs the inhibitory chloride current, which inhibits post-synaptic neuronal excitability.
These have the effect of decreasing the MAC of a volatile agent:
A. Fentanyl
B. Clonidine
C. Acute amphetamine intoxication
D. Chronic alcohol consumption
E. Midazolam
A, B and E: True. C and D: False.
These anaesthetic agents bind to the GABA-A to exert their effect:
A. Etomidate
B. Thiopental
C. Ketamine
D. Propofol
E. Volatile gases
A. True.
B. True.
C. False. Ketamine is an NMDA receptor antagonist.
D. True.
E. True.
The following statements describe the action of benzodiazepines:
A. Inhibition at the GABAA receptor
B. Increased frequency of GABA channel opening
C. Depolarization of the postsynaptic membrane
D. Increased sodium entry postsynaptically
E. Antagonist to GABA
A. False. Benzodiazepines are positive allosteric modulators at the GABAA receptor.
B. True.
C. False. Hyperpolarization is associated with benzodiazepine action.
D. False. Increased chloride entry is responsible for hyperpolarization.
E. False. Benzodiazepines enhance GABA activity.
Benzodiazepines (Fig 1) are drugs where a benzene ring(read a full definition of this term) has fused with a diazepine ring(read a full definition of this term). They are aromatic(read a full definition of this term), lipophilic(read a full definition of this term), amines(read a full definition of this term) 1. They act by potentiating the action of GABAA receptors 2.
Benzodiazepines have five broad actions 3:
Sedation
Amnesia
Anti-convulsant
Anxiolysis
Skeletal muscle relaxation
Gamma-aminobutyric acid (GABA) (Fig 1) is the main inhibitory neurotransmitter of the central nervous system, acting on two types of receptor:
GABAA
GABAB
Benzodiazepines act on GABAA receptors
GABAA receptors are:
Ligand-gated, anion channels
Pentamers – they are made up of five subunits – 2 alpha, 1 beta, 1 delta and 1 gamma. Together they form a central chloride ion channel 2
Predominantly post-synaptic receptors
When GABA binds to the receptor (at the interface between the alpha and beta subunits), the receptor is activated. Activation increases the opening frequency for chloride ions to enter the cell, hyperpolarising the neuronal membrane 2, 5
Once hyperpolarised, it becomes more difficult for an action potential to be generated
Benzodiazepines bind to separate binding sites to GABA, on the GABAA receptor. The sites exist on the interface between the alpha and gamma subunits 4.
Once bound, the affinity of GABA for its receptor increases, thus increasing the opening frequency for chloride ions to hyperpolarise the cell membrane 4.
19 GABAA receptor subunits have been cloned (Fig 1). Different benzodiazepines have different affinities for the various GABAA subtypes, which dictate the action of each drug 4. There are two benzodiazepine receptor subtypes 2:
BZ1 – found in the spinal cord and cerebellum (anxiolysis)
BZ2 – found in the spinal cord, hippocampus and cerebral cortex (sedation and anti-convulsant)
The pharmacological properties of the following benzodiazepines include:
A. Clonazepam is a short-acting benzodiazepine
B. Lorazepam is water-soluble
C. Diazepam is metabolised to oxazepam
D. Midazolam has an active metabolite
E. Temazapam is conjugated by acetylation
Submit
-Image
A. False. Clonazepam is a long-acting benzodiazepine.
B. False. Lorazepam is solubilised is propylene glycol.
C. True.
D. True.
E. False. Temazapam is glucoronidated.
Benzodiazepines result from fusion between a benzene ring and a diazepine ring.
The diazepine ring has a carbonyl group and another benzene ring attached (Fig 1).
The benzene ring has a halogen attached
Benzodiazepines are classed by their duration of action:
The pharmacological properties of the following benzodiazepines include:
A. Midazolam is water soluble at PH 3
B. Diazepam has an elimination half-life of 24 hours
C. The clearance of lorazepam is slower than that of diazepam
D. Oxazepam is metabolised to tempazepam
E. Diazepam is metabolised to nordiazepam and temazepam
A. True.
B. False. Diazepam has a terminal elimination half-life in excess of 36 hours.
C. False. The clearance of temazepam is faster than that of lorazepam.
D. False. Temazepam can be metabolised to oxazepam.
E. True. Diazepam undergoes N-demethylation to nordiazepam (60%) and 3-hydroxylation to temazepam (40%). Both are then further oxidated/conjugated to soluble products.
Benzodiazepines are strongly plasma protein bound, lipid soluble drugs. They have good oral bioavailability and cross the blood-brain barrier.
Benzodiazepines are metabolised in the liver (Fig 1, Table 1), with some having active metabolites with long half-lives, increasing the risk of cumulative effects of the drug. They are predominantly excreted in the urine.
As the drugs that you are most likely to face in your practice, this session will discuss diazepam, lorazepam and midazolam in greater depth. Absorption and distribution of these benzodiazepines are shown in Table 2.
Benzodiazepines are highly protein bound. As only the free drug is pharmacologically active, states such as hypoalbuminaemia may result in a reduction in protein binding and therefore increase the effects of the drug.
Following a single dose of benzodiazepine, drug activity is limited by redistribution 10.
The soluble derivatives from metabolism are predominantly excreted in the urine as shown in Table 1.
Following repeated doses/infusions, clearance has a greater impact on drug levels. Midazolam is therefore preferable when used as an infusion compared to diazepam or lorazepam.
Clearance:
Diazepam 0.4 ml/kg/minute
Lorazepam 1 ml/kg/minute
Midazolam 6-9 ml/kg/minute
You are called to ED-resus to review a 45-year-old woman. She was brought in by ambulance after being found in bed at home, appearing very drowsy. There were empty packets of diazepam on the bedside table and she smelt strongly of alcohol. It is unknown if the patient regularly takes any other medications, none were found at the scene. You are called because the patient seems to have become increasingly drowsy.
SpO2 94% (15L NRB), snoring sounds, respiratory rate 7/minute
BP 115/62
HR 69/minute
GCS E2/M5/V2
Question: How would you manage this patient?
The first step is to manage the patient through an ABCDE approach. Ensure the airway is maintained and securing the airway, insertion of an oral ETT if necessary. Once appropriate, ensure intravenous access and perform fluid resuscitation and maintaining normothermia (hypothermia is a risk of benzodiazepine toxicity) and normoglycaemia.
Investigations ought to be undertaken, including screening for other common co-ingested toxins (such as paracetamol) and a 12-lead ECG (prolonged QRS/QTc maybe a feature of concurrent tricyclic antidepressant overdose) 13.
Administration of antidotes
In this case, the patient has a delayed presentation, and with the additional risk of aspiration, activated charcoal would not be appropriate.
Flumazenil is a benzodiazepine antagonist, and can be considered in benzodiazepine toxicity where there is respiratory depression or significantly impaired consciousness.
lumazenil is an imidazobenzodiazepine 3. It is presented as a colourless, aqueous solution.
It is administered as 0.1 mg boluses, to a maximum dose of 2 mg.
Pharmacokinetics
Flumazenil is 40-50% protein bound to albumin, volume of distribution 0.9 L/kg, with an elimination half-life of 50 minutes. It is metabolised in the liver to inactive metabolites via de-ethylation and conjugation. Metabolism is impaired by liver impairment.
It is predominantly eliminated in the urine, with a clearance of 15 ml/kg/m.
Flumazenil is a cardiostable drug, with little direct respiratory affect. Vomiting, anxiety, sweating/flushing and hypertension are potential side-effects.
Contraindications are shown in Table
A dose of flumazenil has been administered, and the GCS improved briefly, but then falls again. How would you proceed?
ntubation and ventilation until the patient has eliminated the drugs would typically be first-line management.
A flumazenil infusion may be considered, as the termination half-life of benzodiazepines and their metabolites often exceeds flumazenil. The rate is initiated at 500 mcg/hour, and titrated to effect, between 100-2000 mcg/hour
The decision from the team was to ventilate the patient in critical care and she was safely extubated the following day.
Clinical effects of benzodiazepines include:
A. Reduced REM and slow-wave sleep
B. Anti-emesis
C. Reduced SVR
D. Retrograde amnesia
E. Reduced tidal volume
A. True.
B. False.
C. True. Benzodiazepines have minor depressant effects on SVR, preload, cardiac output and blood pressure.
D. False. Antegrade amnesia.
E. True. At non-toxic doses, this is countered by a slight increase in respiratory rate.
Unwanted effects
Features of acute toxicity:
Ataxia
Reduced motor coordination
Drowsiness
Severe:
Respiratory depression
Hypotension
Bradycardia
Hypothermia
Tolerance develops following regular long-term use.
Dependence can occur within weeks of regular use.
Withdrawal syndrome may have a slow onset due to the long half-life of benzodiazepines and their metabolites, occurring as late as 3 weeks after stopping long acting formulations (Table 1).
Regarding the presentation and structure of propofol:
A. Propofol is a phencyclidine derivative
B. Propofol is presented as a 1% or 2% lipid emulsion
C. Propofol is light-sensitive
D. Propofol is stable at room temperature
E. Propofol is a weak base
F. Propofol has a pKa of 11
A. False. Propofol is a phenolic derivative.
B. True.
C. False. Propofol is not light-sensitive and can be stored in clear glass vials.
D. True.
E. False. Propofol is a weak acid.
F. True.
Fig 1 shows the chemical structure of propofol (a useful way to remember it is that it resembles a snowman).
Propofol is presented as a 1% (10 mg.ml-1) or 2% lipid emulsion containing egg lecithin, soya bean oil, and glycerol. There is a risk of bacterial growth with this presentation, and disodium edetate is added as a chelating agent to mitigate this risk 3.
The National Audit Project (NAP) 6 looked at allergy to propofol, given concerns about allergy in patients with egg and soya bean allergies.
Read more about the Project’s results here.
Table 1 describes the physical properties of propofol.
Regarding the pharmacokinetics of propofol:
A. Propofol has a volume of distribution of 2.5 L.kg-1
B. Propofol is 90% protein bound
C. Propofol has an elimination half-life of 5-12 hours
D. Propofol is largely metabolised in the liver
E. Emergence following propofol infusion is relatively slow
A. False. Propofol has the largest volume of distribution of the induction agents at 4 L.kg-1.
B. False. Propofol is 98% protein bound.
C. True.
D. True.
E. False. Due to relatively rapid clearance via both hepatic and renal metabolism.
Propofol is metabolised in the liver (40% conjugated to glucuronide, 60% metabolised to quinol) and excreted as glucuronide and sulphate conjugates in the urine.
Clearance is very high, suggesting a degree of additional extrahepatic metabolism. Liver and renal dysfunction have little effect on metabolism.
The context-sensitive half-time (CSHT) is the time taken for the concentration of a drug to reduce by half once an infusion is stopped (Fig 1).
As in the three-compartment model, a drug will move from the plasma (V1) to peripheral tissues (V2 and V3). Once an infusion has been given for long enough, equilibrium will be reached between plasma and tissues, and there will be no net movement between compartments provided infusion rate equals rate of elimination.
Once the infusion is stopped, the concentration in plasma will fall as the drug is metabolised. The concentrations in tissues will now be relatively higher than in plasma, and therefore the drug will begin to redistribute. The longer the infusion has been running, the more drug will have accumulated in tissues, allowing for plasma levels to remain high until the drug is metabolised and excreted.
This gives the context-sensitive half-time.
For propofol infusions lasting up to 8 hours, the CSHT is about 20 mins 2. This has clinical relevance as emergence from either anaesthesia or sedation via propofol infusion remains relatively fast
Propofol:
A. Reduces systemic vascular resistance
B. Causes bronchoconstriction
C. Increases cerebral oxygen requirement
D. Is an antiemetic due to D2 receptor agonism
E. Is laryngeal reflex sparing
A. True.
B. False. Propofol causes bronchodilation.
C. False. Propofol reduces cerebral oxygen requirement.
D. False. Propofol is a D2 receptor antagonist.
E. False. Propofol blunts the laryngeal reflex.
CVS effects include:
Reduced systemic vascular resistance
Reduced blood pressure
Reduced myocardial contractility
Bradycardia
Respiratory effects include:
Reduced laryngeal reflexes
Reduced tidal volume
Bronchodilation
CNS effects include:
Hypnotic
Smooth and rapid induction of anaesthesia
Reduced cerebral perfusion pressure (CPP)
Reduced intracerebral pressure (ICP)
Reduced cerebral oxygen requirement
Occasional dystonias
Gastrointestinal effects include:
Antiemetic (D2 receptor antagonist)
Pain effects include:
Painful injection
Immediate due to direct irritant effects
Delayed (>10s) due to bradykinin release as kallikrein-kinin system is stimulated
Metabolic effects include:
Propofol infusion syndrome
Green hair and urine (from phenolic metabolites)
What?
Propofol infusion syndrome (PRIS, Fig 1) is the term used to describe the adverse effects of propofol when used for long-term sedation in critically-ill patients. This was originally termed propofol-related infusion syndrome, hence PRIS remains the commonly accepted abbreviation. It is usually associated with infusion rates of >4mg.kg-1.hr-1 for >24 hours and children are at higher risk of developing PRIS. Propofol is therefore not licensed for use as a sedative infusion in paediatric ICU settings.
Why?
PRIS is thought to be due to an imbalance between energy demand and utilisation; impairment in mitochondrial oxidative phosphorylation and free fatty acid utilisation leads to lactic acidosis and cardiac and skeletal myocyte necrosis.
Early recognition is key:
Monitor creatinine kinase (CK)
Stop propofol
Start alternative sedatives
Supportive - cardiovascular support (vasopressors/ inotropes) as required
Prevention involves:
Maximum infusion rate 4 mg.kg-1.hr-1
Regular CK and triglyceride monitoring
Regarding the pharmacology of the barbiturates:
A. Thiopental is the sulphur analogue of pentobarbital
B. All barbiturates are derived from barbituric acid
C. Thiopental is an oxybarbiturate
D. Barbituric acid is a condensation product of urea and lactic acid
E. The solubility of barbiturates increases on transformation from the keto to enol form, called tautomerism
A. True.
B. True.
C. False. Thiopental is an thiobarbiturate. Methohexital is an oxybarbiturate.
D. False. Barbituric acid is a condensation product of urea and malonic acid.
E. True.
Barbiturates are substances derived from barbituric acid, which is a condensation product of urea and malonic acid (Fig 1).
Barbituric acid is not a central nervous system (CNS) depressant. However, by altering the chemical structure of its ring, substituting a hydrogen ion with an alkyl or aryl group, the drug has hypnotic activity.
The substitution of hydrogen, oxygen, sulphur and a methyl group at positions 1 and 2 on the six-membered pyrimidine nucleus provide the structure of:
Fig 1: The thiobarbiturate thiopental
Fig 2: The methylbarbiturate methohexital, an oxybarbiturate
Fig 3: Phenobarbital
Methohexital has a methyl group at position 1 on the barbituric acid ring, whereas thiopental differs by the substitution of sulphur at the C-2 position
Barbiturates can exist in the enol and keto forms. However, they are more soluble in their enol form. Transformation from the keto to the enol form is favoured by alkaline solutions and is called tautomerism.
Thiobariturates, e.g. thiopental, are highly lipid-soluble and protein-bound, and are completely metabolized in the liver. Oxybarbiturates, e.g. phenobarbital, are less lipid-soluble and less protein-bound 1.
Barbiturates facilitate inhibitory synaptic transmission by enhancing and mimicking GABA-mediated Cl- influx at the GABAA receptor. They also inhibit excitatory post-synaptic transmission by blocking non-N-methyl-D-aspartate (non-NMDA) subtype glutamate receptors. Their neuroprotective effects are mediated via block at voltage gated Na+ and Ca+ channels and free radical scavenging effect. Finally, they block K+ channels and nicotinic ACh receptors.
Barbiturates cause the increased production of porphyrin and this may cause neurotoxic porphyrin levels. Other drugs to avoid in such patients are steroids, benzodiazepines, etomidate, enflurane, halothane, cocaine, lidocaine, prilocaine, clonidine, metoclopramide, hyoscine, diclofenac and ranitidine.
Regarding the pharmacokinetics and mechanism of action of the barbiturates:
A. Thiopental has a pKa of 7.6 and a pH 10.5 in solution
B. Thiopental can undergo tautomerism from the enol to the keto form, which is more water-soluble
C. Methohexital has a faster clearance than thiopental
D. Barbiturates suppress the action of GABA
E. Methohexital is 60% protein-bound, mainly in albumin
A. True.
B. False. The enol form is more water-soluble in alkaline solutions.
C. True.
D. False. Barbiturates enhance the action of GABA by direct receptor binding and augmentation.
E. True.
Thiopental, also known as thiopental sodium and thiopentone, is a thiobarbiturate, and is the sulphur analogue of pentobarbital (Fig 1). It was first used in 1934 by Lundy and Waters 4. It is a racemic mixture with a faint garlic smell, and contains 6% anhydrous sodium carbonate in an atmosphere of nitrogen (Fig 2). It is stored as a pale yellow powder. Sodium carbonate is used to produce the alkaline pH, which prevents precipitation of the free acids through acidification from atmospheric CO2.
After readily dissolving in water to produce a 2.5% solution with pH 10.5, it can be used as an induction agent. Sodium carbonate maintains the pH between 10-11. Therefore, the solution consists of the more soluble enol isomer of thiopental as it favours an alkaline environment (Fig 3) 1. The pKa is 7.6 and it is 99.9% ionized until injection, at physiological pH 7.4. An unstable unionized protonated sulphide is formed, which rapidly isomerizes into the stable highly lipid-soluble unionized enol form, thereby enabling passage across the blood-brain barrier to the brain tissue.
Thiopental is an IV anaesthetic agent, but also used in status epilepticus. It is also on the WHO essential drug list for a basic healthcare system 6.
Table 1 compares the pharmacokinetics of thiopental with those of other induction agents.
After an induction dose of thiopental, the short duration and rapid emergence is caused by redistribution of the drug to less vessel-rich areas of the body, and not by metabolism. After a single IV induction dose, on waking, only 18% has been metabolized.
Metabolism occurs in the liver to inactive metabolites, and liver enzyme cytochrome P450 induction occurs after a single dose. However, after repeated administration of the drug, the metabolism and clearance play a more important role in duration of action than redistribution. At this point, the drug displays zero‑order kinetics, which results in a longer lasting effect and delayed recovery. This is why thiopental, unlike propofol, is not used for the maintenance of anaesthesia.
Thiopental should not be mixed with acidic solutions or oxidizing agents as they may cause IV agent precipitation. Examples include vecuronium, rocuronium, lidocaine, morphine and calcium chloride. Always flush through with saline after thiopental has been administered to avoid precipitation.
Both thiopental and methohexital can cause complications. Categorize the complications listed below.
Ketamine is a phencyclidine derivative. There are four main important physicochemical properties of ketamine:
Molecular weight 238 g.mol-1
Ketamine is a relatively small molecule. Therefore, it has improved diffusion across membranes.
High lipid solubility
Ketamine has 5-10 times the lipid solubility of thiopental, so it crosses the blood-brain barrier faster.
Two optical isomers
Ketamine has a chiral centre with two optical isomers, S(+) and R(-), which display both pharmacological and clinical differences.
pKa 7.5
pKa is the pH at which a drug is 50% ionised:unionised. With weak bases, such as ketamine (pKa 7.5), the closer the pKa to physiologic pH (7.4) the more rapid the onset time. This is due to the fact that at physiological pH, more of the drug is in its unionised form. This increases the lipid-solubility and transfer by passive diffusion through the membrane, resulting in faster onset time.
The action on the NMDA receptor (NMDAR) is of particular relevance. Ketamine acts through non-competitive antagonism of the NMDAR. The NMDAR plays a role in opioid tolerance, hyperalgesia and allodynia.
Ketamine’s principal mode of action is non-competitive antagonism of the NMDA receptor (Fig 1). It acts by binding to specific sites within the ion channel, thus blocking it. However, it also has actions at many other sites. These include:
Opioid receptors with a preference for mu and kappa receptors - which may account for some of its use in chronic pain and opioid hyperalgesia
Thalamo-neocortical projection system
Antagonism of monoamine, muscarinic, cholinergic, nicotinic, purinergic and adrenoreceptor systems
Inhibition of neuronal sodium channels, which at high doses may produce local anaesthetic effects
Ca2+ channel
Calcium flux through NMDARs is thought to play a central role in synaptic plasticity, a cellular mechanism for learning and memory.
Ligand
The NMDA receptor is distinct in that it is both ligand-gated and voltage-dependent. Voltage-dependent calcium channels are prevalent in excitable tissue such as neurons and permeable to calcium ions.
The NMDAR exhibits voltage-dependent activation due to extracellular magnesium blocking the ion channel, resulting in a flow of calcium and sodium intracellularly and an efflux of potassium extracellularly.
Glutamate
The NMDAR is an ionotropic glutamate receptor.
Ca2+ Na+ / K+
NMDA is the agonist for this receptor. Activation of NMDARs results in the opening of an ion channel, resulting in the flux of Na+ and Ca2+ ions into the cell and K+ out of the cell.
The NMDA receptor is an ionotropic glutamate receptor to which NMDA binds selectively.
When glutamate and glycine are bound to the receptor, the receptor remains open (‘activated’). Antagonists are chemicals that ‘deactivate’ the receptor. Full activation of the NMDA receptor is both voltage- and ligand-gated. Opening and closing of the ion channel is primarily gated by ligand binding, whilst the current flow through the ion channel is voltage-dependent.
Magnesium (Mg2+) and zinc (Zn2+) can bind to specific sites on the receptor, blocking the passage of other cations through the open ion channel. Depolarisation of the cell dislodges the Mg2+ and Zn2+ ions allowing a voltage-dependent flow of sodium (Na+) and calcium (Ca2+) ions into and potassium (K+) out of the cell.
A 15-year-old polytrauma victim presents to A&E after falling off a horse. He requires urgent debridement of an open tibial fracture before transfer to a tertiary centre.
Vital signs are shown in Table 1.
Which of the following statements would you agree with in your initial assessment and management of this patient?
A. Volume resuscitation with crystalloid fluid is inappropriate prior to surgery
B. Ketamine would provide adequate analgesia
C. Ketamine is contraindicated in hypotension
D. When ketamine is used for sedation, supplementary oxygen is unnecessary
E. Benzodiazepine co-administration is contraindicated
F. When using ketamine, morphine should be avoided
A. Incorrect. Initial resuscitation with IV fluid is essential.
B. Correct. Ketamine has potent analgesic properties.
C. Incorrect. Ketamine stimulates the sympathetic nervous system.
D. Incorrect. Ketamine may suppress respiratory drive and, therefore, supplementary oxygen is indicated.
E. Incorrect. Benzodiazepine co-administration will reduce emergence reactions.
F. Incorrect. Co-administration is not contraindicated; however, morphine does cause respiratory depression and, therefore, close monitoring of respiratory rate is essential.
Ketamine typically increases heart rate, blood pressure, cardiac output and as a consequence increases myocardial work and oxygen consumption. Despite these typical clinical manifestations, ketamine is actually a direct myocardial depressant (negative inotropy). However, due to a dose-dependent CNS stimulation, leading to sympathetic outflow stimulation and release of catecholamine, negative inotropy is not usually seen apart from at high doses or in the critically-ill patient in whom endogenous catecholamines and sympathetic tone are exhausted.
This makes ketamine an ideal induction agent in the severely shocked patient, as part of a ‘cardio-stable’ induction. Adverse increases in myocardial oxygen consumption can be attenuated by co-administration of opiate or benzodiazepine. Negative inotropy can be avoided by dose reduction in critically-ill patients in whom this may be anticipated.
The racemic solution is available as 10, 50, and 100 mg/ml with a preservative, benzathonium hydrochloride (potentially neurotoxic). Typical doses are:
Induction of anaesthesia: 0.5-2 mg/kg IV or 4-10 mg/kg IM
Maintenance of anaesthesia: 10-30 mcg/kg/min via IV infusion
Sedation and analgesia: 0.2-0.75 mg/kg IV or 2-4 mg/kg IM, followed by continuous infusion of 5-20 mcg/kg/ min
Ketamine can be administered via multiple different routes including IV, IM, intranasal and oral and the bioavailability depends on the route (Table 1). IV onset of action is rapid, at approximately 30 second
Regarding the physiochemical properties of ketamine:
A. It has a molecular weight of 300
B. It has high lipid solubility
C. R(-) is more potent than S(+)
D. S(+) has greater affinity for the NMDA receptor
A. False. Its molecular weight is 238, making it relatively small and easier to diffuse across membranes.
B. True.
C. False. S(+) is 3 times more potent.
D. True.
The chemical structure of ketamine contains one chiral centre, so there are two possible optical isomers (Fig 1).
S(+) ketamine has a number of beneficial pharmacokinetic properties with clinical implications (Table 1) 3.
S(+) ketamine has greater affinity than R(-) ketamine at phencyclidine binding sites on the N-methyl-D-aspartate (NMDA) receptor, with a resultant doubling of potency compared to the racemic mixture (equal amounts of R(-) and S(+) isomers) in producing anaesthesia and analgesia.
S(+) ketamine also has a reduced recovery time and, since the incidence of psychological sequelae are equal at equal plasma concentrations, the lower dose required of S(+) ketamine results in fewer psychological side-effects.
Regarding mechanism of action and the NMDA receptor:
A. Ketamine’s main action is via interaction at NMDA receptors
B. Full activation of an NMDA receptor is only ligand-gated
C. Magnesium also has an effect on the NMDA receptor
D. The NMDA receptor is a type of glutamate receptor
A. True.
B. False. It is ligand- and voltage-gated.
C. True.
D. True.
Ketamine’s principal mode of action is non-competitive antagonism of the NMDA receptor (Fig 1). It acts by binding to specific sites within the ion channel, thus blocking it. However, it also has actions at many other sites. These include:
Opioid receptors with a preference for mu and kappa receptors - which may account for some of its use in chronic pain and opioid hyperalgesia
Thalamo-neocortical projection system
Antagonism of monoamine, muscarinic, cholinergic, nicotinic, purinergic and adrenoreceptor systems
Inhibition of neuronal sodium channels, which at high doses may produce local anaesthetic effects
The NMDA receptor is an ionotropic glutamate receptor to which NMDA binds selectively.
When glutamate and glycine are bound to the receptor, the receptor remains open (‘activated’). Antagonists are chemicals that ‘deactivate’ the receptor. Full activation of the NMDA receptor is both voltage- and ligand-gated. Opening and closing of the ion channel is primarily gated by ligand binding, whilst the current flow through the ion channel is voltage-dependent.
Magnesium (Mg2+) and zinc (Zn2+) can bind to specific sites on the receptor, blocking the passage of other cations through the open ion channel. Depolarisation of the cell dislodges the Mg2+ and Zn2+ ions allowing a voltage-dependent flow of sodium (Na+) and calcium (Ca2+) ions into and potassium (K+) out of the cell.
Regarding the pharmacokinetic properties of ketamine:
A. It has a slow IV onset time
B. It is 20-50% protein bound
C. It has a large volume of distribution
D. It has an elimination half-life of 100 mins
E. It has a large clearance of 890-1227 ml/min
F. It can be delivered as a TCI
G. It follows a one-compartment model
H. It is hepatically metabolised
A. False. It is rapid, at ~30 seconds.
B. True.
C. True. Its volume of distribution is 3 L/kg.
D. False. Its elimination half-life is 2-3 hours.
E. True.
F. True.
G. False. It follows a three-compartment model.
H. True.
The racemic solution is available as 10, 50, and 100 mg/ml with a preservative, benzathonium hydrochloride (potentially neurotoxic). Typical doses are:
Induction of anaesthesia: 0.5-2 mg/kg IV or 4-10 mg/kg IM
Maintenance of anaesthesia: 10-30 mcg/kg/min via IV infusion
Sedation and analgesia: 0.2-0.75 mg/kg IV or 2-4 mg/kg IM, followed by continuous infusion of 5-20 mcg/kg/ min
Ketamine can be administered via multiple different routes including IV, IM, intranasal and oral and the bioavailability depends on the route (Table 1). IV onset of action is rapid, at approximately 30 seconds
Ketamine is 20-50% protein bound and has a relatively large volume of distribution (3 L/kg) which is increased in the critically ill, with a distribution half-life of 10 minutes. It is metabolised in the liver by cytochrome P450, undergoing demethylation and hydroxylation of the cyclohexanone ring to metabolites norketamine (20% relative activity) and dehydronorketamine. The metabolites are conjugated and excreted in the urine with a relatively large clearance of 890-1227 ml/min. Elimination half-life is 2-3 hours.
The pharmacokinetics of ketamine have been described using simple single- and two-compartment models to more complex three- and multi-compartment models. Fig 1 illustrates a three-compartment model, as an IV dose enters the central compartment (plasma), before distributing to peripheral compartments, e.g. fat, muscle, organ tissues, and then being eliminated.
Ketamine is suitable for administration as a low-dose target-controlled infusion (TCI, Fig 2), using standard pharmacokinetic models
What three pharmacological responses do you think should be exhibited by the ideal agent?
Onset - A rapid, smooth and predictable onset within the CNS to produce anaesthesia with no unwanted effects
Recovery - A rapid and clear headed recovery with no unwanted effects such as postoperative nausea and vomiting
Additional effects - No unwanted responses in either the CNS or in other physiological systems
How do current agents match the pharmacological requirements of the ideal agent:
- Thiopental sodium
Advantages:
Provides a smooth, rapid induction of anaesthesia
There is an absence of unwanted movements. Injection is pain free
Disadvantages:
It has a low therapeutic index – especially in the elderly or debilitated
Vasodilatation and cardiac depression may result in a significant reduction in arterial pressure and cardiac output
Slow metabolism may result in delayed recovery with repeated administration
Extravasation or intra-arterial injection will result in severe pain and tissue damage
Must be avoided in porphyria
- Propofol
Advantages:
Rapid and usually smooth loss of consciousness
Rapid recovery due to a high clearance of the drug
Low incidence of PONV
Improved therapeutic index over thiopental
Obtunded respiratory reflexes minimize incidence of laryngospasm, particularly with use of laryngeal mask
Disadvantages:
Pain on injection although this is reduced by a lipuro formulation with long and medium chain triglyceride in soya bean emulsion
Dose related myocardial depression and vasodilatation
Incidence of excitatory effects results in some epileptiform movements
- Etomidate
Advantages:
A high therapeutic index results in a significant reduction in cardiovascular effects at the appropriate dose
Does not release histamine and has a low incidence of hypersensitivity reactions
Disadvantages:
The significant incidence of pain on injection is reduced by lipuro formulation with long and medium chain triglyceride in soya bean emulsion
Significant incidence of excitatory movements with all formulations
Impairs function of adrenal cortex particularly after prolonged infusion which is contraindicated
There is an increased incidence of nausea and vomiting
- Ketamine
Advantages:
Analgesic
Bronchodilator
Positive inotropic effects from indirect beta responses due to inhibition of norepinephrine uptake
May be administered by intramuscular route (with slow onset)
Disadvantages:
Maintains cerebral blood flow and therefore raised oxygen consumption and raised intracranial pressure
Emergence phenomena due to hallucinations or delirium may be particularly unpleasant even if reduced by premedication with benzodiazepine
Onset may be slower and result in dissociative anaesthesia
Present in different concentrations and as isomer
Match the physiochemical to the agents.
The physiology of nerve conduction is important in the understanding of how drugs act to inhibit or delay the conduction of the action potential. Label this diagram of a neuronal axon to identify the component parts.
The axon consists of:
A phospholipid bilayer consisting of hydrophilic heads and hydrophobic tails
Proteins embedded within the membrane to bind messenger chemicals, e.g. hormones and neurotransmitters
Transmembrane proteins that form a central pore or channel, or a transport mechanism to transport ions
The typical structure of a nerve cell comprises a cell body at one end with dendrites, the ‘finger-like’ projections that communicate with other cells.
Extending from this cell body is the neuronal axon down which the action potential passes.
Axons can be myelinated or non-myelinated, with myelination providing faster propagation of the potential, which occurs at the spaces in the myelin sheath called nodes of Ranvier
Local anaesthetic agents block the sodium channels of the phospholipid membrane in order to stop propagation of the action potential (Fig 1). The local anaesthetic agent must cross intracellularly in order to exert its effect, hence the uncharged proportion enters the cell.
Once intracellular, the local anaesthetic becomes ionized in order to bind to specific proteins within the sodium channel, rendering them in their inactive state and preventing further depolarization.
The degree of action is thought to be due to the number of ‘open’ sodium channels to which the anaesthetic is able to bind, and thereby bring about a conformational change. Therefore, it follows that local anaesthetic agents have a lesser affinity for resting-state neurones.
As the local anaesthetics bind, there is a failure to generate an action potential through:
Increases in the threshold for excitation
A slowing of impulse conduction
Decreases in the rate of rise and amplitude of the action potential
Question: How might the physical properties of the nerve affect speed of blockade onset?
Speed of blockade onset can be further affected because:
Smaller-diameter neurones are affected prior to larger-diameter neurones
Myelinated fibres are blocked before unmyelinated fibres of the same diameter
In clinical practice, both amides and esters are used.
Sort these local anaesthetics into the appropriate group.
Local anaesthetics are weak bases. Therefore, at physiological pH, there is a degree of ionized and unionized drug available. This is dictated by the Henderson-Hasselbalch equation.
The pKa defines the amount of drug at a given pH that exists in its ionized state. When at physiological pH, all local anaesthetics exist in a greater proportion at an ionized state. This proportion depends on the drugs and their own individual pKa. For example at pH 7.4, lidocaine has a pKa of 7.9 and is 75% ionized and bupivacaine has a pKa of 8.1 which means that more of the drug is ionized, approximately 85%.
Question: Why is the coexistence of the ionized and unionized states important to the activity of local anaesthetics?
Only the unionized molecules are able to pass through the axonal membranes. Lidocaine, with a lower pKa than bupivacaine, therefore has a faster onset due to this higher proportion being unionized.
The effect of pH is important and any changes in physiological pH have a marked effect on the activity of these drugs and their speed of onset.
The pharmacokinetics of local anaesthetic agents are explained under the headings in the diagram
Absorption
Local anaesthetics are typically administered directly to the area in which the effect is needed. Therefore, their systemic absorption depends on the blood flow to that specific area, be it subcutaneous, epidural or intrathecal. The more vascular the area, the higher the caution regarding the drug dosage employed, e.g. the epidural space is more vascular than subcutaneous administration, so higher caution is necessary.
Absorption is also influenced via the properties of the drugs. Some local anaesthetics have vasoconstriction or vasodilatory effects, e.g. Ametop® causes erythema to the applied region due to its vasodilatory effects on the local vasculature and cocaine causes vasoconstriction.
Adrenaline is often co-administered with local anaesthetics to counteract their vasodilator actions and potentiate the effects in the area needed. The slower the absorption from the site of administration, the longer lasting are the desired effects.
Distribution (binding)
Local anaesthetic drugs are heavily bound to plasma proteins at specific binding sites. The degree of binding affects the speed of onset and duration of action because it is the free portion of the drug that exerts its effect. Therefore, drugs that are more heavily bound have a longer duration of action as the free portion of drug is used, and more drug leaves the proteins as part of its concentration gradient.
This is evident when bupivacaine and lidocaine are compared:
Bupivacaine is 95% bound with a duration of action of several hours
Lidocaine is 70% bound with a maximum duration of action of 90-120 minutes
Metabolism and excretion
The metabolism of local anaesthetics is dependent on their group, and influences their half-life and, therefore, duration of action.
Ester local anaesthetics undergo hydrolysis at their ester linkage site by plasma esterases, namely pseudocholinesterase. This hydrolysis is rapid, hence the shorter half-life of these agents. Their breakdown also leads to the production of para-aminobenzoic acid (PABA), which carries a potential for anaphylaxis in a small group of individuals.
Amide local anaesthetics undergo metabolism in the liver. Therefore, their metabolism is dependent on both renal function and blood flow and, in turn, affects the elimination half-life. Amides are then excreted renally, with approximately 5% of the drug remaining unchanged.
Use Table 1 to help you assess these statements about safe doses of local anaesthetics.
A. A local infiltration of 20 ml 0.25% Chirocaine® (levobupivacaine) in a 60 kg male following inguinal hernia repair provides a safe dose of 50 mg
B. A spinal anaesthesia of 3 ml 0.5% heavy Marcaine® (bupivacaine) for a 75 kg female for a hysteroscopy and D&C provides a safe dose of 15 mg
C. A transverse abdominis plane (TAP) block in an 82 kg male for a laparotomy using 60 mls 0.375% Chirocaine® provides a safe dose of 225 mg
D. An epidural top-up in a 56 kg female for lower segment Caesarean section (LSCS) of 25 mls 0.5% chirocaine® 15 minutes after a rescue dose of 10 ml 0.25% chirocaine provides a safe dose of 140 mg
A. True. Chirocaine 0.25% = 2.5 mg/ml.
Total dose given = 20 x 2.5 mg = 50 mg
Maximum safe dose for 60 kg patient = 60 x 2.5 mg = 132 mg
B. True. Marcaine 0.5% = 5 mg/ml.
Total dose given = 3 x 5 mg = 15 mg
Maximum safe dose for patient = 75 x 2 = 150 mg
C. False. Chirocaine 0.375% = 3.75 mg/ml.
Total dose given = 3.75 x 60 = 225 mg
Maximum safe dose = 2.5 x 82 = 205 mg
D. False. Chirocaine 0.5% = 5 mg/ml, 0.25% = 2.5 mg/ml.
Top up for LSCS = 25 x 5 = 125 mg
Earlier top up = 2.5 x 10 = 25 mg
Total dose given = 150 mg
Maximum safe dose for 56 kg patient = 56 x 2.5 = 140 mg
Regarding the structure and groups of local anaesthetics used in practice:
A. Local anaesthetics have two distinct parts, a lipophilic aromatic ring and a hydrophilic tertiary amine group
B. The structure of the aromatic ring and hydrocarbon chain dictates the lipid-solubility of the drug
C. Ester local anaesthetics can be stored for longer than amide local anaesthetics
D. All local anaesthetics exist in a greater proportion at an unionized state at physiological pH
E. The structure of link between the lipophilic aromatic ring and the hydrophilic tertiary amine group determines the class of local anaesthetic
A. False. Local anaesthetics have three distinct parts, a lipophilic aromatic ring, a hydrophilic tertiary amine group and a link that defines it as either an ester or an amide.
B. True. The structure of the aromatic ring and hydrocarbon chain dictates the lipid-solubility of the drug, which in turn influences potency.
C. False. The ester link is less stable and, therefore, cannot be stored for the same length of time as amide local anaesthetics.
D. False. At physiological pH, local anaesthetics exist in a greater proportion at an ionized state.
E. True.
Local anaesthetics have three distinct parts:
Fig 1a: A lipophilic aromatic ring
Fig 1b: A hydrophilic tertiary amine group, which is charged
Fig 1c: A link
It is the structure of this link that determines the class of local anaesthetic:
Fig 1d: An ester link
Fig 1e: An amide link
Each component of the molecule confers the different properties of the local anaesthetic. The structure of the aromatic ring and hydrocarbon chain dictates the lipid-solubility of the drug, which in turn influences potency. The more lipid-soluble a drug, the less is required to penetrate the neuronal membrane and exert an effect. Therefore, it is more potent as smaller amounts are used.
The ester link is less stable than the amide link. Therefore, ester local anaesthetics cannot be stored for the same length of time as amide local anaesthetics. The local anaesthetic activity is conferred from protonation of the nitrogen within the amine group, which occurs as soon as the anaesthetic is intracellular.
Regarding local anaesthetic toxicity and its treatment:
A. Local anaesthetics may cause allergy, an increase of methaemoglobin in the blood, acidosis in cases of fetal stress and cardiotoxic side-effects
B. When using local anaesthetics, a high degree of suspicion of local anaesthetic toxicity is needed when unusual or unexpected neurological or cardiovascular symptoms present
C. Early neurological symptoms of local anaesthetic toxicity include altered taste, perioral tingling and tinnitus
D. Cardiovascular symptoms of local anaesthetic toxicity present as cardiac arrhythmias that respond well to early treatment
E. Treatment of local anaesthetic toxicity involves the use of Intralipid®, which prevents the local anaesthetic agent from being absorbed
A. True.
B. True. There are several factors that increase the risk of local anaesthetic toxicity. Blocks involving large volumes such as epidural or Bier’s blocks increase this risk. The vascularity of the site also increases or decreases the risk.
C. True. The early neurological excitatory symptoms of local anaesthetic toxicity include altered taste, perioral tingling and tinnitus. Symptoms of the progression of the toxicity includes motor twitching, grand mal seizures and coma.
D. False. Cardiac arrhythmias can occur and these may be prolonged and refractory to traditional treatment. Ultimately, complete cardiovascular collapse and cardiac arrest can result.
E. True. The treatment of local anaesthetic toxicity involves seizure management, airway protection, life support strategies and a regimen of Intralipid® as part of adjuvant treatment specific to the local anaesthetic plasma levels.
The nature of toxicity
Local anaesthetics are, on the whole, very safe to use. However, in circumstances of increased systemic absorption, there is a risk of progression to local anaesthetic toxicity, which can be lethal. Although it is rare, all anaesthetists should have a good knowledge of the risk factors and management of this clinical scenario and be familiar with the AAGBI guidelines 11.
Local anaesthetic toxicity should always be considered when unusual or unexpected neurological or cardiovascular symptoms present themselves within a clinical scenario involving the use of local anaesthetics. There are several factors that increase the risk of local anaesthetic toxicity. Blocks involving large volumes, such as epidural or Bier’s blocks, increase this risk. The vascularity of the site may increase or decrease the risk. Sites that are more vascular such as epidurals or those next to large blood vessels, e.g. cervical plexus, axillary and intercostal nerve blocks, are all higher risk.
Local anaesthetic choice also influences the propensity for local anaesthetic toxicity. Agents with prolonged duration of action bind more avidly to myocardial sodium channels and can induce prolonged, refractory arrhythmias.
Management
Management of local anaesthetic toxicity involves prompt recognition. The condition manifests as initial excitatory symptoms as levels rise, before cardiovascular collapse and neurological deterioration occurs. Early neurological excitatory symptoms include altered taste, perioral tingling and tinnitus, which then progresses to motor twitching, grand mal seizures and coma.
Cardiovascular symptoms ensue as plasma levels rise, with a dose-dependent myocardial depressive effect. As levels rise further, cardiac arrhythmias can occur that may be prolonged and refractory to traditional treatment. Ultimately, complete cardiovascular collapse and cardiac arrest can result.
Regimen
As per the AAGBI published guideline, as soon as local anaesthetic toxicity is suspected, injection of the agent should cease, urgent help should be sought and symptoms should be managed appropriately 11. This may include seizure management and airway protection, or following adult-life support algorithms. While this is ongoing, Intralipid®; should be sought as part of adjuvant treatment specific to the local anaesthetic plasma levels, following the dose recommendations of the AAGBI guideline. Intralipid® (20%) is a fat emulsion that binds free local anaesthetic within the plasma, preventing it from being able to enter the cells and further block sodium channels centrally, or in the myocardium.
The current regimen is:
An initial bolus of 1.5 ml/kg over 1 minute. Simultaneously start an infusion of 15 ml/kg/hour
Reassess after 5 minutes. If there is no improvement, repeat the bolus and double the infusion to 30 ml/kg/hour
At 10 minutes, reassess again and repeat the bolus dose, for the last time, with no change in the infusion rate
Do not exceed the maximum cumulative dose of 12 ml/kg
Case example
A 70 kg patient develops local anaesthetic toxicity following a simple procedure on his knee.
The current Intralipid® regimen is shown below, together with the doses appropriate for this patient:
In the treatment of a female paediatric patient weighing 8 kg who presents with local anaesthetic toxicity, the Intralipid® regimen (Table 1) is:
A. Initial bolus: 8 ml
Initial infusion rate: 120 ml/hour
Increased infusion rate: 200 ml/hour
B. An initial bolus: 12 ml
Initial infusion rate: 120 ml/hour
Increased infusion rate: 200 ml/hour
C. Initial bolus: 12 ml
Initial infusion rate: 120 ml/hour
Increased infusion rate: 240 ml/hour
D. Initial bolus: 8 ml
Initial infusion rate: 120 ml/hour
Increased infusion rate: 250 ml/hour
E. Initial bolus: 12 ml
Initial infusion rate: 12 ml/hour
Increased infusion rate: 240 ml/hour
A. False.
B. False.
C. True. The initial bolus is 8 kg x 1.5 ml/kg = 12 ml. The initial infusion is 8 kg x 15 ml/kg/hour = 120 ml/hour. The increased infusion rate is 8 kg x 30 ml/kg/hour = 240 ml/hour.
D. False.
E. False.
The main principles of the analgesic ladder are:
A. Drugs should be prescribed according to the patient’s level of pain
B. Oral administration is preferred
C. Analgesics should only be given at regular intervals if PRN doses do not control pain
D. Dosing should not be based on the medications’ half-life
E. Benefits and side-effects should be regularly reviewed, and medications adjusted accordingly
F. If a patient has severe uncontrolled pain, you may jump immediately to step 3
A. True.
B. True.
C. False. Analgesic should be prescribed regularly.
D. False. Dosing is based on the medications’ half-life.
E. True.
F. True.
The model encourages up titration of analgesics with increasing pain. At each level there is an opportunity to step up or down depending on pain levels or side-effects experienced.
There have been several suggested modifications to the original WHO ladder as advances in the pharmacology of pain have been made. These include addition of anaesthetic interventions such as nerve blocks at a proposed step four.
Several analgesic adjuvants commonly used in anaesthetics for acute pain management are not included in the WHO model.
These include:
Gabapentinoids
Steroids
Anxiolytics, antidepressants
Membrane stabilisers
Sodium channel blockers
N-methyl-d-aspartate receptor antagonists
These adjuvants can be utilised at any step on the updated analgesic ladder to improve pain control.
Place the following drugs onto the appropriate step on the analgesic ladder.
Match the dosage to the correct column in the table.
Regarding paracetamol:
Paracetamol is an atypical NSAID. It has actions on both COX 1 and 2 enzymes, but selectively inhibits COX-2. This inhibition leads to a reduction in prostaglandin synthesis.
Presence of high concentrations of hydroperoxide overcomes (as seen atsites of inflammation) overcome the effects of paracetamol.
The affinity for COX-2>COX-1 is thought to be due to lower levels of hydroperoxide produced by flow through this pathway
Granisetron and Tropisetron have been shown to block the analgesic action of paracetamol. This is not seen with Ondansetron.
Paracetamol was first synthesised in 1878 by Morse et al and introduced for medical usage in 1883. It has been shown to work via central mechanisms 4:
Inhibition of cyclo-oxygenases (both COX-1 and COX-2 enzymes), therefore inhibiting prostaglandin synthesis:
It has a relatively weak anti-inflammatory action, though there is some dispute over this
More recently, it has been reported that paracetamol inhibits COX-3 which was described as recently as 2002
COX-3 enzyme (thought to be a splice varient of COX-1) is found predominantly in the brain. It is this inhibition of prostaglandin synthesis in the central nervous system that produces its good antipyretic and analgesic effect
Activation of descending serotonergic pathways
Increased cannabinoid receptor activation
Although the benefit of gastric decontamination is uncertain, activated charcoal should be considered if the patient presents within 1 hour of ingesting paracetamol of 150 mg/kg.
Patients at risk of liver damage and therefore requiring N-acetylcysteine can be identified from a single measurement of the plasma-paracetamol concentration related to the time from ingestion, provided this time interval is not less than 4 hours.
Question: In which patients should N-acetylcysteine commence?
N-acetylcysteine should commence in the following patients:
Serum paracetamol concentration falls on or above the treatment line on the nomogram
Ingested doses of >150 mg/kg paracetamol
Acute liver injury, even if paracetamol level below treatment line
Presenting >24 hours after ingestion if:
Jaundiced
RUQ tenderness
ALT elevated or INR >1.3 (in the absence of another cause)
Paracetamol concentration is still detectable
NAC stimulates glutathione, which is essential in the metabolism of NAPQI (the toxic paracetamol metabolite).
NAC is hydrolysed intracellularly to cysteine, which replenishes glutathione stores. It also supplies thiol groups, which directly bind with NAPQI in hepatocytes and enhances non-toxic sulphate conjugation
Fig 1 is adapted from Accidental paracetamol poisoning.
NAC has four possible modes of action:
- Increased glutathione synthesis
- Direct binding of NAPQI
- Provision of inorganic sulphate
- Reduction of NAPQI back to paracetamol
A 20-year-old female attends the ED 5 hours after taking 36 x 500 mg paracetamol tablets during an intentional overdose. She is 60 kg.
Is she at high risk of toxicity?
Would you administer activated charcoal?
Are liver function tests indicated in this case?
In Fig 1a, plasma paracetamol level shows a level of 125 mg/L.
Does this patient require treatment with N-acetylcysteine?
Yes. She would be in an at risk group as ingestion has been of >10 g or >150 mg/kg.
No. Activated charcoal appears to be ineffective if time since ingestion is >1 hour, unless there is delayed gastric emptying. It is not recommended after 2 hours since ingestion.
Yes, all patients should have AST, ALT and paracetamol levels checked.
Paracetamol levels should be plotted on the treatment nomogram if time from ingestion is >4 hours (Fig 1b). Prognostic accuracy is not known after 15 hours, but if the level remains above the treatment line NAC should be administered.
The paracetamol level lies above the treatment line so the patient would require IV NAC.
Aspirin can be used for:
A. Mild to moderate pain
B. Anti-inflammatory in rheumatoid arthritis
C. Anti-inflammatory in osteo-arthritis
D. Secondary prevention in myocardial ischaemia
E. Prevention of all strokes
F. Deep vein thrombosis prophylaxis
G. Pre-eclampsia
A. Correct.
B. Correct.
C. Correct.
D. Correct.
E. Incorrect. Only prevents TIA/ischaemic stroke.
F. Correct.
G. Correct.
Aspirin is licensed for patients over 16 years of age. It should not be prescribed to patients below the age of 16 years due to the risk of Reye’s syndrome.
Aspirin (acetylsalicylic acid) is a non-steroidal anti-inflammatory drug (NSAID) (Fig 1).
It works as an irreversible, non-selective cyclo-oxygenase (COX) enzyme inhibitor, which inhibits the production of prostaglandins, prostacyclin and thromboxanes.
Prostaglandins are involved in inflammation and pain whilst thromboxanes are involved in platelet aggregation in the process of haemostasis
Aspirin has many other effects throughout the body:
Stimulation of the chemoreceptor trigger zone and respiratory centres in the medulla lead to nausea and vomiting and a respiratory alkalosis
Changes in cellular metabolism lead to a metabolic acidosis
Salicylates uncouple oxidative phosphorylation in the mitochondria; this generates heat and may increase body temperature
The following aids in the excretion of paracetamol:
A. Raising urinary pH
B. Activated charcoal
C. NAC
D. Renal dialysis
E. Repeated IV fluid boluses
A. False. Useful in salicylate excretion, not for paracetamol.
B. False. Activated charcoal binds to paracetamol to reduce absorption, not excretion. It is most effective if taken within 1 hour of paracetamol ingestion.
C. False. NAC increases glutathione synthesis, binds to NAPQI, reduces NAPQI back to paracetamol and provides inorganic sulphates for paracetamol conjugation (see slide 18)
D. False. NAC is the first-line treatment but renal dialysis can also be used.
E. False. Supportive treatment, does not affect excretion.
Paracetamol is metabolised in the liver by two pathways:
Glucuronidation and Sulphation to non-toxic conjugates (90%)
Cytochrome P450 system to N-acetyl-p-benzoquinone imine (NAPQI) (10%)
NAPQI is a toxic metabolite which is usually conjugated with glutathione to form non-toxic metabolites.
In exceptional circumstances, glutathione stores are insufficient or overwhelmed, so excess NAPQI generated causes adverse systemic effects. In these patients, paracetamol doses should be reduced. These include:
Paracetamol overdose
Extremes of ages
Starvation
Malabsorption
Genetic polymorphism (CYP-2D6 ultra-rapid/extensive metabolisers)
One of the mechanisms of actions of paracetamol is:
A. Inhibiting descending serotonergic pathways
B. Activating dopaminergic pathways
C. Inhibiting prostaglandin synthesis
D. Inhibiting MOP and KOP receptors
E. Inhibiting cannabinoid receptors
A. Incorrect. Not known to target this pathway. Paracetamol activates descending serotonergic pathways.
B. Incorrect. Not known to target it.
C. Correct. Irreversible COX enzyme inhibitor.
D. Incorrect. These are opioid receptors.
E. Incorrect. Not known to target this pathway. Paracetamol activates cannabinoid recepetors.
Paracetamol was first synthesised in 1878 by Morse et al and introduced for medical usage in 1883. It has been shown to work via central mechanisms 4:
Inhibition of cyclo-oxygenases (both COX-1 and COX-2 enzymes), therefore inhibiting prostaglandin synthesis:
It has a relatively weak anti-inflammatory action, though there is some dispute over this
More recently, it has been reported that paracetamol inhibits COX-3 which was described as recently as 2002
COX-3 enzyme (thought to be a splice varient of COX-1) is found predominantly in the brain. It is this inhibition of prostaglandin synthesis in the central nervous system that produces its good antipyretic and analgesic effect
Activation of descending serotonergic pathways
Increased cannabinoid receptor activation
Regarding physiology and the pharmacology of NSAIDs:
A. COX-1 is inducible
B. COX-1 is found in high concentration in the stomach
C. COX-1 inhibition is responsible for the desired therapeutic effects of NSAIDs
D. COX-2 inhibitors lead to increased cardiovascular risk
E. Arachidonic acid is derived from the cellular phospholipid bilayer
A. False. COX-2 is inducible.
B. True.
C. False. COX-2 is largely responsible for the beneficial therapeutic effects.
D. True.
E. True.
The pharmacology of NSAIDs revolves around the inhibition of the cyclo-oxygenase (COX) pathway (Fig 1).
The cyclo-oxygenases catalyse the conversion of arachidonic acid, derived from the cellular lipid bilayer, to biologically active prostaglandins. Active prostaglandins have a variety of physiological functions including:
Protection of the gastrointestinal tract
Renal homeostasis
Uterine function
Embryo implantation and labour
Regulation body temperature
Give an overview of the pharmacology of opioid Drugs: General Properties and Mechanisms of Action, and relevance to anaesthetics.
Classify opioid analgesics
Describe the role of opioid receptors in pain control
List the pharmacological actions of opioids
Recognise the importance of the physical properties of opioids
Explain the ways in which opioid drugs can be administered
Identify the major side effects of opioids
Opioids can be classed as natural, synthetic and semi-synthetic
Opioid receptors are G protein-coupled receptors
There are three types of opioid receptors: µ , κ and δ
The neurotransmitter action of opioids is always inhibitory in nature
The physicochemical properties of opioids influence the onset time of their analgesic effect
Most clinically useful opioids are agonists at the µ -receptor
There are many side effects associated with the use of opioids
Metabolism primarily occurs in the liver.
Morphine is converted to morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G), which have significant activity themselves.
Remifentanil is unique in being metabolised by non specific esterases in red bloods cells and tissues.
In the kidneys, M6G and M3G are excreted by glomerular filtration and so chronic renal failure can lead to the accumulation of these metabolites.
Endogenous opioids are peptides produced in the body and are widely distributed throughout the CNS. These endogenous opioids act as both neurotransmitters and neuromodulators.
The endogenous opioids are derived from precursor proteins. These precursors are present at high concentrations in the hypothalamus, pituitary, the periaqueductal gray, the brainstem and the substantia gelatinosa of the spinal cord.
The endorphins
The endorphins produced by the hypothalamus and pituitary gland primarily bind to the mu receptor with some action at the delta receptor. They produce analgesia and euphoria.
The enkephalins
The enkephalins bind to the delta and mu receptors and are involved in nociception.
The dynorphins
The dynorphins bind primarily to the kappa receptor and are involved in analgesia, appetite regulation and control of the circadian rhythm.
There are three classical opioid receptors which are distributed throughout the brain and spinal cord. They are also found outside the CNS in vascular tissue, heart, airways/lungs, gut and cells of the immune system.
Question: What type of receptors are these?
The G proteins linked to the opioid receptors are of the Gi/o type:
There is inhibition of adenylyl cyclase activity reducing cyclic adenosine monophosphate (cAMP) formation
There is reduced opening of voltage-gated calcium channels reducing presynaptic neurotransmitter release
There is increased potassium efflux resulting in hyperpolarisation of the cell
Overall there is reduced neuronal cell excitability leading to a reduction in transmission of nerve impulses and inhibition of neurotransmitter release (substance P, glutamate and calcitonin gene-related peptide).
In which areas of the central nervous system do opioids act?
Both endogenous and exogenous opioids act at different sites in the central nervous system to reduce the activity of the ascending nociceptive pathways.
There is reduction in afferent signalling (Fig 1) in the substantia gelatinosa of the dorsal horn of the spinal cord:
- Pre-synaptic inhibition
Activation of presynaptic opioid receptors on the terminals of neurones results in diminished release of transmitter from the terminals.
This is the mechanism whereby opioids reduce Substance P and Glutamate release from afferent neurones in the substantia gelatinosa
- Post-synaptic inhibition
Activation of post-synaptic receptors results in hyperpolarisation of the membrane, thereby reducing the likelihood of transmission of the nociceptive impulse.
There is enhanced activity of descending inhibitory pathways from the periaqueductal gray in the pons via the nucleus raphe magnus in the medulla to the dorsal horn (Fig 1).
Disinhibition
In the periaqueductal gray GABAergic interneurones reduce activity in descending inhibitory pathways. Opioids inhibit GABA release by presynaptic inhibition so removing the inhibitory effect on the descending pathway: so-called disinhibition.
This will reduce activity in afferent nociceptive pathways from the dorsal horn through release of noradrenaline and serotonin from the descending inhibitory neurones.
Opioids may also produce analgesia through a peripheral mechanism.
Immune cells infiltrating inflammatory cells may release endogenous opioid-like substances that act on peripheral opioid receptors located on the primary afferent sensory neurone.
The physiochemical properties of opioids influence their rate of absorption and speed of onset. Table 1 summarises the physiochemical properties of opioid drugs used in anaesthesia and intensive care. Opioids are weak bases, so they are more ionised below their pKas.
Question: Why does alfentanil have a more rapid onset of action compared to fentanyl, despite being less potent?
The pKa of alfentanil is one pH unit below plasma pH, so it is 90% unionised; fentanyl has a pKa of one pH unit above plasma pH, so only 9% is unionised. This is a 10-fold difference and, since alfentanil is less potent, a higher dose of drug is needed. This creates a very large concentration gradient for the unionised drug to cross the blood-brain barrier.
Match the opioids to their classification.
Have a look at the adverse effects of opioid drugs.
Central nervous system
Euphoria and dysphoria
Addiction and dependence
Tolerance
Sedation
Seizures (meperidine)
Skin and eyes
Pruritis
Miosis
Respiratory
Respiratory depression
Direct suppression of rhythm generation in the ventrolateral medulla
Reduce sensitivity of brainstem chemoreceptors to CO2
Reduce sensitivity of carotid and aortic chemoreceptors to hypoxia
Cough suppression
Chest wall rigidity (particularly with remifentanil)
Cardiovascular
Mild bradycardia
Anaphylaxis
Peripheral vasodilatation due to histamine release
Gastrointestinal and biliary
Nausea and vomiting
Constipation
Spasm of sphincter of Oddi
Genitourinary
Urinary retention
The following can be considered as opiates:
A. Fentanyl
B. Codeine
C. Remifentanil
D. Oxycodone
E. Morphine
A. False.
B. True.
C. False.
D. False.
E. True.
Morphine, Codeine and Thebaine are examples of opiates. The term opiate refers to all naturally occurring drugs derived from opium.
Regarding opioids:
A. They act via G protein-coupled receptors to open voltage-gated calcium channels, increase potassium efflux and reduce production of cAMP
B. Partial agonists are capable of producing the full effect when bound to a receptor
C. Naloxone is an example of a drug which binds to the receptor and has no intrinsic activity
D. Opioid receptors are found only in the central nervous system
E. Pentazocine is an example of an agonist/antagonist which antagonises the action of morphine at mu receptors
A. False. Opioids do act through G protein-coupled receptors to close voltage-gated calcium channels, increase potassium efflux and reduce production of cAMP.
B. False. Partial agonists such as buprenorphine produce sub-maximal effect when bound to the receptor.
C. True.
D. False. Opioid receptors can be found in the GI tract and peripheral tissue.
E. True.
Give an overview of the pharmacology of Morphine and Other Opioids, and the relevance to anaesthesia.
Describe the pharmacodynamics of opioids: both anti-nociceptive actions and side-effects
Describe the pharmacokinetics of the opioids commonly used to treat acute pain
Employ appropriate modes of administration to achieve analgesic efficacy
All opioids share the same mode of action, via the μ receptor, and have similar major side-effects: respiratory depression, nausea and vomiting, euphoria, somnolence, tolerance and dependence
In equi-analgesic doses, the opioids all cause these side-effects to a similar extent
Differences between opioids are due to differences in pharmacokinetics, action at other opioid receptors (κ, δ), action on other receptors and miscellaneous actions, such as histamine release
There are very large interindividual differences in response to opioids; both pharmacodynamics and pharmacokinetics
Opioids attach to proteins called opioid receptors (Fig 1). These are present in the central nervous system (brain and spinal cord), on peripheral nerves, and in the digestive tract.
Opioid receptors are a group of inhibitory G protein-coupled receptors. There are four major opioid receptors. These have been classified as:
DOP (delta-) or OP1
KOP (kappa-) or OP2
MOP (mu-) or OP3
NOP (nociceptin/ orpanin FQ) or OP4
DOP, KOP and MOP are classical opioid receptors and they are antagonised by naloxone.
NOP are morphologically similar to the classical opioid receptors but exhibit different clinical effects and are not sensitive to naloxone. It is therefore thought of as the ‘non-opioid branch of the opioid receptor’.
All opioids share the same mode of action, via the μ receptor (Fig 1). This mediates the principal effects associated with opioids.
Question: Can you identify three clinically useful effects of opioids?
Those you might have remembered are:
Analgesia
Sedation
Cough suppression (antitussive)
Antispasmodic for the gastrointestinal (GI) tract
All opioids share these effects, but not necessarily to the same degree: loperamide has little analgesic effect, but is effective at relieving spasm in the GI tract.
Unfortunately, not all effects seen with opioids are beneficial.
Morphine has low lipid solubility and crosses the blood-brain barrier slowly after intravenous administration (Fig 1a). Peak effect after IV bolus dose occurs after about 10 min.
It is metabolised in the liver and gut by glucuronidation to water-soluble metabolites, which are excreted, and small amounts are demethylated (Fig 1b) to normorphine (Fig 1c).
The principal metabolite (70%) is the 3-glucuronide M3G (Fig 1d), which is inactive. It is excreted in urine and bile. It may be broken down by gut bacteria to morphine and reabsorbed (enterohepatic recirculation).
The 6-glucuronide, M6G (Fig 1e), has greater potency than the parent compound. This accumulates in patients with impaired renal function. With long-term morphine administration M6G is responsible for a significant proportion of the pharmacological activity.
The elimination half-life of morphine is about three hours, but is very variable.
Question: Given a normal subject, can you estimate, in minutes, the range of the elimination half-life of morphine?
The elimination half-life can range from 100 to 400 min.
Remifentanil is a derivative of fentanyl, and is a μ agonist with similar potency to fentanyl.
The speed of onset of action of remifentanil is similar to that of fentanyl.
Question: Unlike fentanyl or alfentanil, remifentanil has two ester linkages within its structure (Fig 1). How might this influence the duration of action of this opioid?
Esters can be hydrolysed rapidly, so remifentanil has a very short duration of action. The image identifies which ester linkage is rapidly hydrolysed by non-specific plasma and tissue esterases.
Note: These are not plasma cholinesterase; they are not subject to genetic variation and are unaffected by anticholinesterases. This makes its elimination half-life very short (10-20 min), predictable and independent of hepatic or renal function.
For this reason remifentanil is administered by IV infusion.
The context sensitive half-time of remifentanil is the time for the plasma concentration to halve when an infusion is discontinued. It is approximately five minutes and, unlike other opioids, is independent of the duration of infusion.
Tissue esterase activity declines with age; remifentanil infusion rates must be adjusted accordingly.
The main breakdown product is a carboxylic acid derivative, which has only 0.1% of the potency of the parent compound, and thus has clinically insignificant pharmacological effects. This is excreted by the kidney.
Remifentanil is used by infusion for intraoperative analgesia. It can be administered via target-controlled infusion (TCI), in which a pharmacokinetic model programmed into a microprocessor-controlled infusion device is used to generate the target plasma concentration (Cpt) or effect site concentration (Cet). The effective Ce varies with age, and is dependent on other drugs, such as propofol, N2O and volatile agents, administered in combination. In combination with TCI propofol administered to a Cet of 4 µ g/ml, the Ce50 to obtund the pressor response to laryngoscopy is 5 ng/ml.
Similar clinical results to this TCI regimen can be achieved by an infusion of 0.5 µ g/kg/min for 1 min, followed by a continuous infusion of 0.2 µ g/kg/min. The administration of bolus doses can result in bradycardia, hypotension and cardiac arrest, and is best avoided.
At the end of surgery the IV line used for infusion should be flushed to prevent the inadvertent administration of a bolus dose, which may cause respiratory arrest.
Consideration should be given to the administration of other drugs for the provision of postoperative analgesia.
The use of remifentanil for postoperative analgesia is not established, and its safety is unproven.
Which categories do the drugs listed below belong to?
Intravenous drug doses result in all of the dose entering the plasma immediately. This avoids the time taken to absorb drugs in the gut when given orally, and also avoids first pass metabolism of drugs by the liver. The amount of a drug that reaches the systemic circulation is called the bioavailability.
Fig 1 shows the plasma concentration of a drug administered IV compared to orally over time. The oral bioavailability of the drug can be calculated by using the equation: Oral bioavailability = area under the curve oral or area under the curve IV.
Question: What properties are needed for agents to be administered transdermally, intranasally or sublingually?
Sometimes the oral or IV route of administration are not available because the patient is unable to tolerate it, or gastric emptying or absorption is not possible due to concomitant disease. The transdermal, intranasal or sublingual routes can avoid first pass metabolism of drugs by delivering them direct to the systemic circulation, while offering less invasive and well tolerated routes for patients.
All of these routes are able to deliver drugs to the systemic circulation by absorption across membranes into highly vascular areas. In order to do this, they require drugs which are relatively small molecules, potent (requiring low doses to be administered), and lipophilic in order to cross the membranes. There are disadvantages to these routes including:
Pain or irritation to the skin or nose by the drugs
Variable absorption of drug related to patient temperature, ability to administer or maintain drug in specific area, patient temperature
Drug limitations, e.g. a bitter taste, does not possess properties amenable to absorption, volume required too high
Regarding the principles of agonism, antagonism, and different routes of administration of opioids:
A. Patients with fentanyl patches for chronic pain are likely to need lower opioid doses to control acute pain
B. High molecular weight drugs are more amenable to transdermal delivery than low molecular weight drugs
C. Fentanyl and buprenorphine patches can be used for chronic pain and cancer pain
D. Morphine can be delivered by transdermal patches
E. Only molecule size affects transdermal drug delivery
A. Incorrect. Patients with chronic pain who are already on opioids are likely to have tolerance to opioids, and therefore will need higher opioid doses to control acute pain.
B. Incorrect. Low molecular weight drugs are able to cross the cell membranes for absorption.
C. Correct.
D. Incorrect.
E. Incorrect. Transdermal drug delivery is affected by molecule size, polarity, temperature, barrier thickness, not just size of molecules.
A full agonist (e.g. morphine, fentanyl) produces a maximal response. A partial agonist (e.g. buprenorphine) is able to produce a response, but not a maximal response.
If a full agonist is in the presence of a partial agonist, the partial agonist acts as a competitive antagonist – more of the full agonist is need to produce the maximal response.
A competitive antagonist (e.g. naloxone) competes with the agonist to occupy the receptor space. They both act at the same receptor site. Adding more agonist can overcome competitive antagonism. The agonist displaces the antagonist from the receptor site if the agonist concentration is higher than the antagonist concentration.
In contrast, non-competitive or irreversible antagonists cannot be overcome by increasing the agonist concentration. Irreversible antagonists bind at a different site to the agonist and cause a change in the conformation of the receptor site, which prevents the agonist from binding.
Affinity is a drug’s ability to bind to a receptor. This can be thought of as attraction – the drug is a metal and the receptor is a magnet. The more magnetic the drug is, the more avidly it binds to the receptor. A drug with high affinity binds strongly to a receptor. A drug with low affinity will still bind but not as tightly, so if a drug with higher affinity for the same receptor comes along, it will displace the lower affinity drug and bind to the receptor.
Potency is the amount of drug needed to produce the desired effect. The more potent the drug is, the lower the dose that is needed to produce the effect. Different drugs can be compared by looking at the EC50 (effective concentration/dose 50%).
Efficacy is the ability of a drug to produce a maximal response. Different drugs can have the same potency, but different efficacies. This can be demonstrated by looking at the EC50 again:
All three drugs (A, B and C) have the same EC50, but they do not all produce a maximal response because their efficacy is different. Drug A has high efficacy and is able to produce a maximal response. Drug C has a much lower efficacy. Drugs like drug B, C and D are known as partial agonists because they can bind to the receptor but are not able to produce a maximal response.
Increasing the dose of a weak opioid will increase the effect seen, as these drugs are capable of producing a maximal response. Increasing the dose of a partial agonist will not increase the effect beyond a certain point as these drugs are unable to produce a maximal effect no matter how much drug is given.
An important aspect of anaesthesia is the production of muscle relaxation appropriate for the surgical procedure.
Skeletal muscle is innervated by alpha motor neurons arising from the anterior horn of the spinal cord. For muscle contraction to occur, there must be successful depolarisation of the muscle membrane followed by release of calcium from the sarcoplasmic reticulum.
A motor neuron and the skeletal muscle fibres it contacts form a motor unit. All the fibres in a motor unit must fire together in order to produce co-ordinated movement. The number of fibres contacted by a single motor nerve varies between fewer than 10 to more than 100, depending on the need for precision and fine movement.
A single α-motor fibre has a diameter of about 10 μm and is surrounded by a myelin sheath that is produced by the plasma membranes of Schwann cells wrapping around the nerve many times.
Question: What is the speed of conduction down a motor nerve?
Very fast, around 50-100 m/s, which is much faster than would be expected from the diameter of the nerve: a squid giant axon with a diameter of 500 μm still only conducts impulses at 25 m/s.
The myelin insulates parts of the fibre so that conduction jumps between the gaps between adjacent Schwann cells. These bare areas are about 1 μm long and are known as nodes of Ranvier. A concentration of voltage-gated sodium channels at the nodes of Ranvier allows depolarisation to occur, then ‘jump’ to the next node. This known as saltatory conduction.
The motor neuron terminates at a specialised area of the myofibril: the motor endplate. The NMJ at the endplate allows close opposition of the terminal bouton of the nerve and the folded post-synaptic membrane of the muscle.
Depolarisation of the nerve terminal activates voltage-gated calcium channels on the pre-synaptic membrane of the nerve. The entry of calcium triggers the release of the neurotransmitter, ACh, from the synaptic vesicles.
The post-synaptic membrane at the endplate is highly folded, with nicotinic ACh receptors present on the crests of the folds.
Neuromuscular transmission must be rapid and ACh must be removed from the synaptic cleft because it can produce neuromuscular blockade. Associated with the membrane of the clefts is acetylcholinesterase (AChE), which allows rapid metabolism of ACh before it can produce flaccid paralysis.
ACh is synthesised within the motor neuron and packaged into vesicles in readiness for release upon depolarisation.
Question: What are the precursors for ACh synthesis and where do they come from
As the name suggests, ACh (Fig 1a) requires a source of choline (Fig 1b) and acetyl groups (Fig 1c). Choline is an essential nutrient found particularly in meat and eggs: some is present in vegetables, although at a much lower concentration. Acetyl-CoA, produced during aerobic decarboxylation of pyruvate, donates the acetyl group.
The enzyme responsible for synthesis of ACh is choline acetyltransferase. This is a product of the CHAT gene on the long arm of chromosome 10 (location 10q11.2).
During neuromuscular transmission:
A. Motor nerves conduct at 5-10 m/s
B. Nodes of Ranvier contain ligand-gated ionic channels
C. Schwann cells provide insulation of the nerve fibre
D. Saltatory conduction involves the opening of sodium channels
E. NAChRs are present in the clefts of the post-synaptic membrane
A. False. Motor neurones conduct faster than this at 50-100 m/sec.
B. False. There are voltage-gated ion channels at the nodes of Ranvier.
C. True.
D. True.
E. False. The nicotinic receptors are on the shoulder and crests of the post-synaptic membrane.
On depolarisation of the terminal bouton, voltage-gated calcium channels allow entry of calcium. These calcium channels are of the N‑type, i.e. neuronal, sometimes known as Cav2.2 channels. They differ in their subunit composition from the L-type calcium channels found post‑synaptically in the T-tubules.
N-type calcium channels are the target for certain toxins including omega conotoxin, produced by the marine cone snail. Interestingly, this is a very potent analgesic and a synthetic analogue, ziconotide, has been marketed as a potent non-opioid, non-NSAID analgesic for intrathecal infusion in chronic pain.
Calcium entry is then responsible for allowing fusion of the vesicle with the presynaptic membrane, exocytosis and release of ACh into the synaptic cleft. Patients with Lambert-Eaton syndrome have antibodies against these presynaptic calcium channels and demonstrate initial muscle weakness that increases in strength with repetitive action.
The presynaptic area of the NMJ is important for controlling release of the neurotransmitter ACh.
Once synthesised, ACh is stored in vesicles, some of which are free in the cytosol and others that are tethered to the presynaptic membrane, held there by specific proteins in the membrane called Soluble N-ethylmaleimide-sensitive factor Attachment protein REceptors, or SNAREs, (Fig 1). These proteins incorporate adenosine triphosphate (ATP) dependent enzyme activity involved in fusion of two membranes as is required in exocytosis.
Calcium binding to synaptotagmin encourages association with the SNARE protein complex.
The amount of ACh released in response to an action potential is known as a quantum. The quantal size, the exact amount of ACh released, depends on the number of vesicles docking with the presynaptic membrane and varies depending on the frequency of nerve stimulation.
Release of ACh is regulated by presynaptic nicotinic acetylcholine receptors (NAChRs). These are structurally different from those found on the post-synaptic membrane.
Activation of presynaptic nicotinic receptors increases the release of ACh, whereas inhibition reduces ACh release.
It is thought that the characteristic ‘fade’ in the train-of-four seen with non-depolarising muscle relaxants, and phase II block with succinylcholine, is due to blockade of presynaptic nicotinic receptors. These receptors are composed of different α and β subunits
Regarding presynaptic motor nerve terminals at the NMJ:
A. Ligand-gated calcium channels regulate vesicle exocytosis
B. L-type calcium channels are found presynaptically at the NMJ
C. ACh provides presynaptic feedback-inhibition
D. NAChRs are found presynaptically
E. In Lambert-Eaton syndrome, there are antibodies against presynaptic calcium channels
A. False. Voltage-gated calcium channels mediate vesicle release.
B. False. N-type calcium channels are present presynaptically at the NMJ.
C. False. ACh mediates increased release of ACh presynaptically.
D. True.
E. True.
The presynaptic area of the NMJ is important for controlling release of the neurotransmitter ACh.
Once synthesised, ACh is stored in vesicles, some of which are free in the cytosol and others that are tethered to the presynaptic membrane, held there by specific proteins in the membrane called Soluble N-ethylmaleimide-sensitive factor Attachment protein REceptors, or SNAREs, (Fig 1). These proteins incorporate adenosine triphosphate (ATP) dependent enzyme activity involved in fusion of two membranes as is required in exocytosis.
Calcium binding to synaptotagmin encourages association with the SNARE protein complex.
The amount of ACh released in response to an action potential is known as a quantum. The quantal size, the exact amount of ACh released, depends on the number of vesicles docking with the presynaptic membrane and varies depending on the frequency of nerve stimulation.
Regarding the motor endplate:
A. The resting potential of skeletal muscle is -70 mV
B. MEPPs reflect spontaneous release of ACh
C. Current flow through a single ion channel is around 50 pA
D. The Nernst potential for sodium is -50 mV
E. The muscle depolarises when the EPP reaches +15 mV
A. False. The resting potential of skeletal muscle is between -90 mV and -85 mV.
B. True.
C. False. Current flow through a single ion channel is around 5 pA
D. False. The Nernst potential for sodium is around +50 mV.
E. False. Muscle depolarises when the EPP reaches the threshold for voltage-gated sodium channels to open, around -70 mV.
On each NAChR there are two binding sites for ACh molecules: one at the interface between the first α subunit and the ɛ subunit and the second between the second α subunit and the δ subunit (Fig 1). Both sites should be occupied for the necessary conformational change to take place. Binding of ACh causes the α subunit conformation to change by rotation of the inner pore-facing surface, opening the pore to cation traffic (Fig 2).
The major cation carrying the inward current is sodium. There is a large chemical gradient between the low concentration of sodium inside the membrane(5 mmol/L) and the high concentration outside (145 mmol/L). The membrane is relatively impermeable to sodium in the resting state. The Nernst potential for sodium is approximately +50 mV, so inward movement of sodium increases the muscle membrane potential from -85 mV, in its resting state, to around +15 mV. Potassium ions can also move through these channels, but the concentration gradient favours outward movement of potassium.
Channel opening is transient, lasting one millisecond or less.
At the motor endplate there is a very large safety margin for successful transmission of the signal from nerve to muscle. A relatively small proportion of NAChR need to be activated to reach threshold. To produce any observable block of neuromuscular transmission, more than 80% of the receptors must be made unavailable to ACh.
At the post-synaptic membrane of the NMJ:
A. AChE is found in the clefts of the folded membrane
B. Individual AChE molecules are free in the synaptic cleft
C. NAChR have four different subunits
D. ACh binds to the β subunit of the nicotinic receptor
E. Only sodium ions pass through the opened ion channel
A. True.
B. False. AChE tends to form clusters and is loosely anchored to the membrane.
C. True. NAChR has five subunits, but two α subunits.
D. False. ACh binds to the α subunits.
E. False. Potassium ions can also pass through, but move outward.
n the absence of nerve stimulation, occasional random vesicle exocytosis occurs with individual quanta being released. Each causes a small influx of cations and a small, very transient depolarisation (0.4 mV) of the endplate as individual nicotinic receptors are activated then closed. The current carried by a single open NAChR is around 5 pA or 3 x 107 ions/s.
These small depolarisations are known as miniature endplate potentials (MEPPs). They are insufficient to reach the threshold for endplate depolarisation (Fig 1a).
When a stimulus arrives, many more quanta of ACh are released, opening nicotinic channels until a threshold is reached and the endplate is transiently depolarised: the endplate potential (EPP). This wave of depolarisation, the muscle action potential, spreads across the muscle membrane by activation of voltage-gated sodium channels, and down into the T-tubule system.
MEPPs recorded at the endplate occur randomly and occasionally produce additive effects, but not sufficient to reach threshold. Depolarisation of the endplate occurs when an action potential triggers discharge of large numbers of vesicles and the EPP increases until the threshold is reached and depolarisation is sufficient to trigger voltage-gated opening of the sodium channel in the muscle membrane (Fig 1b).
The signal sent by the motor neuron is a chemical signal in the form of ‘packets’ or quanta of ACh molecules. For excitation‑contraction coupling to take place, there must be an electrical signal from the muscle endplate. Thus a chemical-to-electrical form of transmission must take place: the signal needs to be transduced.
The post-synaptic receptors responsible for signal transduction are ligand-gated NAChR. These belong to the pentameric family of receptors (Table 1) and the mature form has two α subunits and one each of β, δ and ε subunits. There are several types of these subunits and composition varies from site to site. As shown earlier the presynaptic NAChRs have different α and β subunits from those at the post-synaptic site.
The receptors are held together in a cluster at the endplate by a scaffold of proteins.
Question: How are the non-depolarising NMBAs, such as pancuronium and atracurium, classified?
They are classified according to their chemical structure (Table 1).
Both types bind to the same sites as ACh, between the α subunits and their adjacent ɛ and δ subunit, and prevent ACh binding. Because of the safety margin for transmission, more than 80% of NAChR must be blocked before depression of the twitch height can be seen.
The presynaptic effects of the non-depolarising NMBAs are responsible for ‘fade’ of the twitch height during a train-of-four stimulus.
The onset and offset of action of these agents is very much longer than that of the depolarising NMBA, succinylcholine.
Pre-synaptically at the NMJ:
A. Calcium entry is essential for vesicle exocytosis
B. SNARE proteins provide the mechanism for membrane fusion
C. Nicotinic receptors have the same subunit composition as at the autonomic ganglia
D. The calcium channel is of the same type as found in myocardial muscle
E. All vesicles are anchored to the presynaptic membrane
A. True.
B. True.
C. False. Nicotinic receptors and autonomic ganglia have different types of α and β subunits.
D. False. T-type and L-type calcium channels are found in cardiac muscle and N-type pre-synaptically.
E. False. Some vesicles are attached awaiting release, but some are free in the cytoplasm.
On depolarisation of the terminal bouton, voltage-gated calcium channels allow entry of calcium. These calcium channels are of the N‑type, i.e. neuronal, sometimes known as Cav2.2 channels. They differ in their subunit composition from the L-type calcium channels found post‑synaptically in the T-tubules.
N-type calcium channels are the target for certain toxins including omega conotoxin, produced by the marine cone snail. Interestingly, this is a very potent analgesic and a synthetic analogue, ziconotide, has been marketed as a potent non-opioid, non-NSAID analgesic for intrathecal infusion in chronic pain.
Calcium entry is then responsible for allowing fusion of the vesicle with the presynaptic membrane, exocytosis and release of ACh into the synaptic cleft. Patients with Lambert-Eaton syndrome have antibodies against these presynaptic calcium channels and demonstrate initial muscle weakness that increases in strength with repetitive action.
The presynaptic area of the NMJ is important for controlling release of the neurotransmitter ACh.
Once synthesised, ACh is stored in vesicles, some of which are free in the cytosol and others that are tethered to the presynaptic membrane, held there by specific proteins in the membrane called Soluble N-ethylmaleimide-sensitive factor Attachment protein REceptors, or SNAREs, (Fig 1). These proteins incorporate adenosine triphosphate (ATP) dependent enzyme activity involved in fusion of two membranes as is required in exocytosis.
Calcium binding to synaptotagmin encourages association with the SNARE protein complex.
The amount of ACh released in response to an action potential is known as a quantum. The quantal size, the exact amount of ACh released, depends on the number of vesicles docking with the presynaptic membrane and varies depending on the frequency of nerve stimulation.
Release of ACh is regulated by presynaptic nicotinic acetylcholine receptors (NAChRs). These are structurally different from those found on the post-synaptic membrane.
Activation of presynaptic nicotinic receptors increases the release of ACh, whereas inhibition reduces ACh release.
It is thought that the characteristic ‘fade’ in the train-of-four seen with non-depolarising muscle relaxants, and phase II block with succinylcholine, is due to blockade of presynaptic nicotinic receptors. These receptors are composed of different α and β subunits (Table 1).
The muscle membrane has:
A. Ligand-gated sodium channels that depolarise when the EPP is reached
B. T-tubules that fold into the cell
C. L-type voltage-gated calcium channels in the T-tubules
D. Ryanodine RyR2 receptors
E. Voltage-gated calcium channels with pore-forming domains in the α1 subunit
A. False. Voltage-gated sodium channels are responsible for depolarisation when the endplate potential is reached.
B. True.
C. True.
D. False. Ryanodine RyR1 receptors are in the membrane of the sarcoplasmic reticulum; RyR2 are found in myocardial cells.
E. True.
Depolarisation of the muscle membrane is transmitted down the T‑tubules where voltage-gated L-type calcium channels are opened and calcium enters the myocyte (Fig 1). The α1 subunit is composed of four membrane-spanning elements, I - IV, each of which has six transmembrane domains (S1-6) with domain S4 responsible for sensing voltage changes and domains S5 and S6 being the pore-forming elements. The other subunits (α2, β, γ, δ) are regulatory.
Apparently, there is a direct physical connection between these L-type calcium channels in the T-tubule membrane and ryanodine receptors, RyR1, in the sarcoplasmic reticulum (SR). Under resting conditions calcium is stored in the SR attached to the binding protein calsequestrin. Entry of calcium triggers the opening of RyR1 (Fig 2) in the SR membrane which in turn allows release of this stored calcium that can now interact with contractile elements in the myocyte.
The conformational change associated with calcium binding to troponin allows the myosin heads to bind to actin and contraction can take place.
One of the elements of successful anaesthesia is muscle relaxation. The neuromuscular blocking agents (NMBAs) in clinical use can be classified according to their action at the post-synaptic NAChR into:
Depolarising NMBAs
The only depolarising NMBA in clinical practice is succinylcholine (SCh). This is structurally similar to ACh, two ACh molecules joined back-to-back, and is an agonist at the NAChR. It is not metabolised by AChE in the synaptic cleft, so is present for much longer than the natural transmitter.
There is initial fasciculation due to activation and then rapid onset of paralysis.
There is a much longer refractory period in the presence of SCh with desensitisation of the NAChR and flaccid paralysis.
Plasma cholinesterase rapidly metabolises SCh as it diffuses from the synaptic cleft and muscle function starts to recover within 5 min of a dose of 1 mg/kg and full recovery is complete within 15 min.
Non-depolarising NMBAs
The non-depolarising muscle relaxants act as competitive inhibitors at the NAChR at the NMJ.
At the NMJ:
A. ACh acts exclusively through nicotinic receptors
B. Neostigmine is a competitive inhibitor at nicotinic receptors
C. Nicotine causes receptor up-regulation
D. Plasma cholinesterase is present in the synaptic cleft
E. Organophosphates increase ACh levels in the synaptic cleft
A. True.
B. False. Neostigmine inhibits AChE.
C. False. Nicotine causes down-regulation of receptors.
D. False. Plasma cholinesterase is not present at all.
E. True. Organophosphates increase ACh levels in the synaptic cleft and lead to flaccid paralysis.
The activity and density of NAChRs at the motor endplate is partly determined by the effectiveness of signal traffic through the NMJ.
There are several clinical situations of importance to anaesthetists where the number and activity of NAChRs can be affected (Table 1). This influences the choice and dose of neuromuscular blocking agents:
Receptor numbers can increase: up-regulation
Receptor activity/numbers can decrease: down-regulation
Receptors may be blocked by antibodies, as in myasthenia gravis, with reduced activity
Up-regulation
Receptor up-regulation occurs when there is a reduction in signal traffic, such as is seen in denervation injury and burns. In response to this there is a proliferation of receptors inserted into the muscle membrane in the extrajunctional regions.
The receptors inserted are of the fetal type, with a γ subunit instead of ε, which have a longer channel opening time.
If succinylcholine is used as a muscle relaxant under conditions of receptor up-regulation, then there is a risk of arrhythmias and cardiac arrest due to hyperkalaemia because potassium efflux is much greater than under normal conditions.
In contrast, there is resistance to non-depolarising NMBAs and higher doses are required.
Down-regulation
Receptor down-regulation occurs when there is increased frequency of neuromuscular traffic.
The use of nicotine, present in cigarette smoke, can produce down-regulation of NACh function. However, this mostly affects neuronal nicotinic receptors in the CNS.
It has also been postulated that CNS down-regulation of NACh receptors occurs early in Alzheimer’s disease, which is why the use of centrally-acting inhibitors of cholinesterase are efficient in reducing mental deterioration in early, but not late Alzheimer’s.
Organophosphorus poisoning increases ACh availability and is also associated with receptor down-regulation.
Myasthenia gravis
Myasthenia gravis is an autoimmune condition in which there are antibodies to the NACh receptor at the NMJ. This results in increased sensitivity to competitive NMBAs and relative resistance to agonists, such as succinylcholine.
There are two important inherited conditions that require consideration for patients undergoing anaesthesia requiring muscle relaxation:
Succinylcholine apnoea, which is encountered when a patient is homozygous for two abnormal alleles of the gene for plasma cholinesterase (BCHE). This prevents breakdown of succinylcholine that allows development of flaccid paralysis, similar to that seen in the presence of organophosphate poisoning for several hours
Malignant hyperthermia (MH), which is an inherited condition in which there is abnormal calcium release from the sarcoplasmic reticulum and increased metabolism and contractility in skeletal muscles in response to triggering agents. There are several possible genetic associations including abnormalities of the skeletal RyR1 receptor and L-type calcium channels. Triggering agents include succinylcholine and the halogenated volatile agents, which should be avoided if this condition is suspected. Treatment of established MH involves the use of the muscle relaxant properties of dantrolene, which blocks RyR1 receptors
Regarding ligand-gated ion channels:
A. There are five subunits in a 5HT-3 receptor
B. NMDA receptors are activated by glycine
C. Nicotinic receptors belong to the cys-loop family of receptors
D. AMPA receptors are tetramers
E. P2X receptors are pentamers
A. True.
B. False. NMDA receptors are activated by glutamate and regulated by glycine
C. True.
D. True.
E. False. P2X receptors are trimers.
The signal sent by the motor neuron is a chemical signal in the form of ‘packets’ or quanta of ACh molecules. For excitation‑contraction coupling to take place, there must be an electrical signal from the muscle endplate. Thus a chemical-to-electrical form of transmission must take place: the signal needs to be transduced.
The post-synaptic receptors responsible for signal transduction are ligand-gated NAChR. These belong to the pentameric family of receptors (Table 1) and the mature form has two α subunits and one each of β, δ and ε subunits. There are several types of these subunits and composition varies from site to site. As shown earlier the presynaptic NAChRs have different α and β subunits from those at the post-synaptic site.
The receptors are held together in a cluster at the endplate by a scaffold of proteins.
Which of these features are characteristic of neuromuscular blockade, following a single dose of SCh?
A. A T4:T1 ratio of 1
B. Post-synaptic antagonist at nicotinic receptors
C. ‘Fade’ with a tetanic stimulus
D. Phase II block
E. Pre-junctional inhibition of nicotinic receptors
A. True. The T4:T1 ratio remains 1 with a single dose of SCh.
B. False. SCh is an agonist at post-junctional nicotinic receptors.
C. False. There is no fade of the tetanic response.
D. False. Phase I block is characteristic of a single dose of SCh.
E. False. SCh does not inhibit pre-junctional nicotinic receptors after a single dose.
SCh is the only ultra-short-acting neuromuscular blocking agent that is available in clinical practice. It is used to provide muscle relaxation during rapid sequence induction or for short interventions such as electroconvulsant therapy (ECT).
There are two types of neuromuscular blockade seen with SCh:
Phase I block, which occurs during normal use
Phase II block, which occurs after infusion or multiple doses of SCh
Phase 1 block
When given intravenously, SCh first causes activation of the nicotinic receptor. This allows entry of sodium and subsequent depolarisation of the post-synaptic membrane.
The activation and depolarisation of the muscle membrane accounts for SCh being described as a ‘depolarising’ blocker. Depolarisation block is also known as phase I block.
Fasciculation stops when depolarisation of the post-synaptic membrane occurs due to activation of nicotinic receptors.
The train-of-four (TOF) response to SCh phase I block shows no fade, unlike that seen with non-depolarising blockade (Fig 1).
Phase I block cannot be reversed by the use of anticholinesterases, such as neostigmine, and the block may be increased.
Once activated, NAChRs transition to a desensitized state in which they are unresponsive to agonists. In the presence of SCh or high concentrations of ACh, the proportion of NAChRs in the desensitized state increases. This is sometimes referred to as ‘desensitization block’. Return to the responsive state is time-dependent.
SCh has the fastest onset of neuromuscular blockade of all the available agents. However, it has many undesirable properties.
Question: Can you list six problems with the use of SCh?
Your list of recognised unwanted effects of SCh may include:
Bradycardia and arrhythmias
Hyperkalaemia
Myalgia
A rise in intraocular pressure
A rise in intragastric pressure
A rise in intracranial pressure
Pharmacogenetic variation in response
Allergic reactions
Malignant hyperthermia
Masseter spasm
Which of these features are characteristic of neuromuscular blockade following a single dose of vecuronium?
A. A T4:T1 ratio of 1
B. Post-synaptic antagonist at nicotinic receptors
C. ‘Fade’ with a tetanic stimulus
D. Post-tetanic potentiation
E. Pre-junctional inhibition of nicotinic receptors
A. False. The T4:T1 ratio is less than 1 with non-depolarising relaxants.
B. True. There is competitive inhibition. Vecuronium acts as a post-synaptic antagonist at nicotinic receptors.
C. True. ‘Fade’ with a tetanic stimulus is a characteristic of neuromuscular blockade following a single dose of vecuronium.
D. True. Post-tetanic potentiation is a characteristic of neuromuscular blockade following a single dose of vecuronium.
E. True. Pre-junctional inhibition of nicotinic receptors can prevent fasciculations with SCh.
Phase II occurs after repeated boluses or a prolonged infusion of SCh. The block is characterised by fade in the TOF and tetanic response along with post-tetanic potentiation (Fig 1), all of which are seen with non-depolarising neuromuscular blockers.
Despite the continued presence of SCh, the membrane potential gradually returns toward the resting state but neurotransmission remains blocked.
There is some debate over the exact mechanism of phase II blockade. Desensitization is considered contributory, although inhibition of nicotinic pre-synaptic receptors may occur.
Management of Phase II block may involve waiting for spontaneous recovery.
In patients with abnormal metabolism of SCh, phase II block may be observed after a single dose. Therefore, the use of SCh is contraindicated in these patients.
Nicotinic pre-synaptic receptors
Nicotinic receptors have five subunits, with exact subunit composition dependent on location. There are several types of α and β subunits and location determines which type is present. SCh inhibits presynaptic nicotinic receptors but only at high concentrations.
Post-synaptic NMJ = α1β1
Presynaptic NMJ = α3β2
Ganglia = α3β4
Management
During phase II block the anticholinesterases, such as neostigmine, may produce some reversal of blockade, although this may not be complete and it is better to wait for spontaneous recovery.
Therefore, treatment is supportive with continued sedation and mechanical ventilation. Neuromuscular blockade should be monitored and sedation should be continued until ‘fade’ disappears and normal neuromuscular transmission is re-established.
Opening of the cation channel at the NMJ allows the entry of sodium ions but potassium ions can also move out through the channel (Fig 1).
Question: Why do sodium cations enter the post-synaptic membrane but potassium cations go out into the synaptic cleft?
In the NMJ, sodium and potassium follow their electrochemical gradient: the concentration gradient for sodium favours movement into the muscle cell, whereas that for potassium favours movement out of the muscle cell.
After a normal intubating dose, a rise in plasma potassium concentration up to 0.5 mmol/L may occur. This rarely causes problems in adults, but arrhythmias can be seen more frequently in patients with renal failure, where plasma potassium levels are already elevated. In those patients where extrajunctional receptors are present, hyperkalaemia can be much greater and cardiac arrest can occur.
Move the corresponding number to the appropriate part of either molecule to identify it.
The benzylisoquinolinium group of relaxants includes atracurium and mivacurium (Fig 1a). They are composed of two quaternary ammonium groups (Fig 1b). These are linked by a chain of methylene groups (Fig 1c). In the case of mivacurium, this is a carbon-carbon double bond.
It is the quaternary ammonium groups of the NDMR molecules that cause the histamine release associated with these compounds. The ester group in ACh is hydrolysed by AChE. It is the position of the ester groups in benzylisoquinolinium NDMRS that permit hydrolysis to occur in plasma – by non-specific esterases in the case of atracurium, and by plasma cholinesterase in the case of mivacurium (Fig 1d).
The aminosteroid group of relaxants, such as vecuronium (Fig 1a) are composed of one or two quaternary ammonium groups (Fig 1b) inserted into the steroid nucleus (Fig 1c).
They have a smaller structure than their benzylisoquinolinium counterparts and are associated with less histamine release.
Certain aminosteroids possess an acetyl-ester link at the 3-C position that allows metabolism by deacetylation in the liver, e.g. pancuronium, vecuronium (Fig 1d). Other compounds, e.g. rocuronium which has a 3-OH group, undergo a lesser degree of metabolism and are predominantly excreted as unchanged drug in the bile and urine.
Show how these factors and characteristics affect depolarising and non-depolarising block by completing the table.
During neuromuscular monitoring of a partial non-depolarising block, specific features allow differentiation from a partial depolarising block.
Administration of a single twitch stimulus produces a reduced amplitude twitch for both depolarising and non-depolarising blocks.
If the nerve is stimulated at 1 Hz, i.e. a stimulus every second, then a non-depolarising block demonstrates fade (Fig 1).
Fade, or decrement, is the progressively decreasing twitch amplitude with successive stimuli. It is caused by a reduction in ACh release with each successive stimulus. The mechanism is thought to involve NDMR binding to presynaptic ACh receptors, which blocks the positive feedback mechanism described earlier in the session. As a result recruitment of reserve vesicles to the immediately active pool is reduced.
If the nerve is stimulated using a train-of-four (TOF) pattern, a non-depolarising block shows the ratio of T4 to T1 reduced below 0.7 (Fig 1).
In a depolarising block, the twitch amplitudes are similar from T1 to T4 and the TOF ratio is >0.7.
Post-tetanic potentiation or facilitation is the phenomenon where, following a tetanic stimulus of 50 Hz for 5 s, there is a temporary increase in the twitch amplitude (Fig 2).
It is thought that the tetanic stimulus augments the positive feedback mechanism, recruiting ACh vesicles to the docking sites for release. NDMRs exhibit post-tetanic potentiation; depolarising muscle relaxants do not.
Finally, the administration of an anticholinesterase reverses a non-depolarising block.
Give an overview of Aminosteroid Neuromuscular Blocking Agents, with relevance to anaesthesia.
List the neuromuscular blocking agents (NMBAs) available in the UK that are aminosteroid compounds
Discuss the relationship between the chemical structure of these compounds and their distribution and elimination
Explain the relationship between potency and onset time
Describe how pancuronium, vecuronium and rocuronium are eliminated
Specify the intubating dose, onset time and clinical duration of action of pancuronium, vecuronium and rocuronium
The aminosteroid NMBAs are pancuronium, vecuronium, rocuronium, pipecuronium and rapacuronium
The aminosteroid NMBAs depend on renal and hepatic function for their elimination, and some have active metabolites
Aminosteroid NMBAs rarely cause histamine release, the exception being rapacuronium, and their administration does not tend to cause any haemodynamic instability
The ED95 is the dose required to depress the twitch response by 95%, the intubating dose is typically 2 x ED95
The rapid onset of rocuronium is related to its low potency
The recommended intubating dose is 2 x ED95.
The onset time is the time from a single bolus of 2 x ED95 to 95% depression of the first twitch of the TOF.
The clinical duration of action is the time from injection of the NMBA to 25% recovery of the twitch response, i.e. T1/T0 25%, when the twitch height of the first twitch of the TOF is 25% of the control twitch height.
The recovery index is the time from 25% recovery to 75% recovery, i.e. the time for T1/T0 to recover from 25% to 75%.
Regarding the structure and function of the aminosteroid NMBAs:
A. Vecuronium is the bisquaternary analogue of pancuronium
B. Aminosteroid NMBAs compete with acetylcholine for binding to the alpha-subunit of the nicotinic receptor
C. Three minutes after the administration of rocuronium to a woman in the third trimester of pregnancy, the concentration of rocuronium in the umbilical vein is similar to that in the maternal plasma
D. Aminosteroid NMBAs are lipid soluble compounds that easily cross the blood-brain barrier
E. Monoquaternary aminosteroid NMBAs undergo greater biliary secretion than bisquaternary compounds
A. False. It is the monoquaternary analogue.
B. True. The quaternary ammonium group binds to the alpha-subunit. These agents are competitive antagonists of acetylcholine.
C. False. The quaternary ammonium group is positively charged and therefore these agents are not lipid soluble and cross the placenta to a very limited extent.
D. False. The quaternary ammonium group is positively charged and therefore these agents are not lipid soluble and do not cross the blood-brain barrier.
E. True. Monoquaternary ammoniums, having only one fixed positive charge, are slightly more lipid soluble than bisquaternary compounds and undergo greater biliary excretion.
The aminosteroid NMBAs have an androstane skeleton (Fig 1). Androstane is the tetracyclic hydrocarbon steroid nucleus, C19H32. It is the parent structure of the androgens.
Acetylcholine-like moieties are introduced at the A and D ring. This involves several modifications. The structure of acetylcholine is shown in Fig 2.
Moieties:
To the androstane skeleton (Fig 1a), hydroxyl groups are inserted at positions 3 and 17 (Fig 1b)
Acetyl groups may be added to the 3-OH and 17-OH groups by esterification (Fig 1c)
Nitrogen containing groups are added at positions 2 and 16. At position 2, this may be a tertiary amine, which is uncharged (Fig 1d) or a quaternary ammonium cation, with a fixed positive charge (Fig 1e). At position 16 there is a quaternary ammonium cation
The combination of an acetyl-ester group at position 3 and a quaternary ammonium substituent at position 2 gives a similar structure to acetylcholine (Fig 2). The same effect is produced at positions 16 and 17. The quaternary ammonium group binds to the α-subunit of the postjunctional nicotinic receptor. These drugs act as competitive antagonists of acetylcholine and compete for binding to the α-subunit. Each nicotinic receptor has two α-subunits
Vecuronium (Fig 1) and rocuronium (Fig 2) have one quaternary ammonium group and are referred to as monoquaternary compounds. Pancuronium (Fig 3) has two quaternary ammonium groups and is a bisquaternary compound.
Distribution
The quaternary ammonium group is positively charged, and therefore, these agents are not lipid-soluble. Thus they are not absorbed from the gastrointestinal tract, do not cross the blood-brain barrier and cross the placenta to a very limited extent. Their volume of distribution is similar to the extracellular fluid volume.
Excretion
Monoquaternary ammonium compounds, having only one fixed positive charge, are slightly more lipid-soluble than bisquaternary compounds and undergo greater biliary secretion.
Bisquaternary ammonium compounds tend to be renally excreted.
What is the ED95?
A. The dose that blocks neuromuscular transmission in 95% of the population
B. The dose that blocks 95% of the nicotinic receptors at the NMJ
C. The dose that suppresses the twitch response by 95%
D. The same for all aminosteroid NMBAs
E. The dose that provides the best conditions for intubation
A. Incorrect.
B. Incorrect.
C. Correct. ED95 is the dose required for 95% depression of twitch response, where ED stands for effective dose.
D. Incorrect.
E. Incorrect.
Studies investigating the pharmacodynamic properties of aminosteroid NMBAs typically involve stimulation of the ulnar nerve and measure the resulting twitch response of the adductor pollicis muscle.
Supramaximal square wave impulses of 0.2 ms duration at 2 Hz are administered every 12 s. The first response (T1) of the train-of-four (TOF) is used as the parameter for pharmacodynamic measurements. The control response is measured prior to the administration of the NMBA; this is denoted T0. Twitch response or twitch height may then be measured after various incremental doses of NMBA and the response compared to T0 (T1/T0).
The dose required for 95% depression of twitch response is the ED95, where ED stands for effective dose. Quoted ED95 values are the mean ED95 values from a representative sample of the population. Following the administration of ED95 of a NMBA, the twitch height would be expected to be 5% of the control response.
Which is the agent with the greatest potency?
A. Pancuronium
B. Vecuronium
C. Rocuronium
D. Pipecuronium
E. Rapacuronium
A. Incorrect.
B. Incorrect.
C. Incorrect.
D. Correct. Pipecuronium is the most potent aminosteroid NMBA with an ED95 of 0.045 mg/kg.
E. Incorrect.
For all the non-depolarising NMBAs, even the less potent agents, the vast majority of the drug in the junctional cleft is bound to nicotinic acetylcholine receptors (Fig 1).
Also there is a ‘margin of safety’ which means that almost all the postjunctional receptors must be blocked before neuromuscular transmission is affected. A neuromuscular block only becomes evident when 70-80% of receptors are occupied.
Therefore, the total number of molecules of any agent that must reach the NMJ is similar. Table 1 shows that for an agent of lower potency a greater mass of drug is administered, generating a greater concentration gradient from the plasma to the NMJ and a more rapid onset (Fig 2).
Which is the agent with the most potent active metabolite?
A. Vecuronium
B. Rocuronium
C. Pancuronium
A. Correct. A small fraction of vecuronium is metabolised to 3-hydroxyvecuronium which is active at the NMJ and nearly as potent as the parent drug, i.e. ~80% as potent.
B. Incorrect. A small fraction of rocuronium is metabolised to 17-desacetylrocuronium, which is 20 times less potent than the parent compound and has very little neuromuscular blocking activity.
C. Incorrect. Five to ten percent of the injected dose of pancuronium is metabolised to 3-hydroxypancuronium which has half the neuromuscular blocking potency of the parent compound.
The recommended intubating dose is 2 x ED95.
The onset time is the time from a single bolus of 2 x ED95 to 95% depression of the first twitch of the TOF.
The clinical duration of action is the time from injection of the NMBA to 25% recovery of the twitch response, i.e. T1/T0 25%, when the twitch height of the first twitch of the TOF is 25% of the control twitch height.
The recovery index is the time from 25% recovery to 75% recovery, i.e. the time for T1/T0 to recover from 25% to 75%.
Regarding this agent:
A. This is a bisquaternary amine
B. This agent is lipid-soluble
C. This agent undergoes predominantly biliary excretion
D. This is pancuronium
E. The 17-hydroxy metabolite is half as potent as the parent compound
A. True. The two nitrogen atoms each have four substituent groups.
B. False. The quaternary ammonium groups are ionized and therefore the compound is not lipid-soluble.
C. False. It is mainly excreted unchanged in the urine.
D. True.
E. False. 3-hydroxypancuronium has half the neuromuscular blocking potency of the parent compound.
Non-depolarising muscle relaxants act by competitively antagonising the action of acetylcholine at the neuromuscular junction by binding to the (α-)subunits of the nicotinic acetylcholine receptor on the post-junctional membrane (Fig 1).
The end-plate potential decreases until it is too small to activate an action potential, with resultant muscle relaxation.
The post-junctional membrane is generously supplied with nicotinic acetylcholine receptors.
Question: What percentage of nicotinic acetylcholine receptors need to be blocked before any clinical effect is observed?
More than 75% of all receptors need to be blocked.
Atracurium, cisatracurium and mivacurium are all non-depolarising agents and therefore share certain pharmacodynamic properties.
Onset of action is relatively slow. None of these drugs is suitable for rapid sequence induction
They are free from a number of the adverse side-effects of succinylcholine:
No fasciculations
No rise in intragastric, intracranial or intraocular pressure
No postoperative muscle pain
No potassium release
No triggering of malignant hyperthermia
To quantify the action of these drugs, a stimulus is applied to a motor nerve and the evoked muscle twitch is measured, either mechanically with a force transducer, using an electromyograph, or by using an accelerometer on a part that moves as a result (Fig 1).
Question: What is the ED95 of a drug?
The effective dose of drug that depresses the measured twitch strength in response to a single stimulus of the motor nerve by 95% is called the ED95. After this dose, the twitch height is just 5% of the pre-drug value. Intubation of the trachea requires twice the ED95 of the drug.
The action of NMBA can be quantified by onset time
and clinical duration.
The action of NMBA
The action of the non-depolarising NMBAs can be quantified by:
Onset time: The time from a single bolus of 2 x ED95 to 95% depression of the first twitch of the train-of-four
Clinical duration: The time from injection of the NMBA to 25% recovery of the twitch response
Table 1 shows ED95, intubating dose, onset time and clinical duration for benzylisoquinoliniums.
Regarding the onset time and duration of action of the benzylisoquinolinium NMBAs available in the UK:
A. At equipotent doses, atracurium has the fastest onset time
B. Following a dose of 2 x ED95, the onset time of all available benzylisoquinolinium NMBAs is less than 3 minutes
C. After equipotent doses, the duration of action of atracurium and cisatracurium is similar
D. After equipotent doses, the duration of action of mivacurium is approximately one-third that of cisatracurium
E. Mivacurium has a rapid onset of action and can be used for rapid sequence induction
A. True.
B. True.
C. True.
D. True.
E. False. Onset of action is relatively slow. None of these drugs is suitable for rapid sequence induction.
Regarding the elimination of atracurium:
A. The Hofmann elimination is only dependent on pH and temperature
B. Atracurium is stored at 4°C and a pH of 7.4
C. At a pH of 7.4 and 37°C the in vitro half-life of atracurium is 50 minutes
D. Atracurium should be avoided in patients with hepatic and renal dysfunction
E. In addition to Hofmann elimination, atracurium also undergoes breakdown by plasma cholinesterase
. True.
B. False. The drug is stable at 4°C and pH 3.4 - the conditions of storage.
C. True. In vitro at 37°C and pH 7.4 it has a half-life of 50 minutes.
D. False. The unique feature of atracurium that is different from any previous neuromuscular blocking drug is that it undergoes spontaneous decomposition by a chemical reaction that is dependent only upon the pH and temperature. Consequently, atracurium can be used in patients with deranged organ function in the absolute certainty that neuromuscular blockade will wear off.
E. False. It also undergoes ester hydrolysis.
The unique feature of atracurium that is different from any previous neuromuscular blocking drug is that it undergoes spontaneous decomposition by a chemical reaction that is dependent only upon the pH and temperature.
This is Hofmann elimination and it is not dependent on liver or kidney function. The drug is stable at 4ºC and pH 3.4, i.e. the conditions of storage. In vitro at 37ºC and pH 7.4 it has a half-life of 50 minutes.
Consequently, atracurium can be used in patients with deranged organ function in the absolute certainty that neuromuscular blockade will wear off.
Atracurium is also partially eliminated by ester hydrolysis catalysed by non-specific esterases.
There are several points to note about the structure of atracurium:
The structure is symmetrical (Fig 1a)
At each end of the molecule there is a tricyclic structure with a chiral C and N+ atom (Fig 1b)
There are two ester groups (Fig 1c)
The quaternary ammonium groups make these drugs highly ionized. This charge makes them highly water-soluble and they are not lipid-soluble.
Question: How does being highly ionized affect the drug?
They have a relatively small volume of distribution that is equal to or slightly larger than the extracellular fluid volume, and they are not absorbed from the gastrointestinal tract and do not cross the blood-brain barrier. They cross the placenta only in small quantities.
The highly ionized nature means that these drugs and their metabolites are partially renally excreted.
Table 1 compares the pharmacokinetic parameters of atracurium and cisatracurium.
The major routes of elimination are:
Mivacurium: ester hydrolysis catalysed by plasma cholinesterase
Atracurium and cisatracurium: Hofmann elimination and non-specific ester hydrolysis, i.e. not dependent on plasma cholinesterase
Question: How is atracurium metabolised?
Question: Is the elimination of atracurium affected by changes in pH?
Hofmann elimination and ester hydrolysis.
45% of atracurium undergoes Hofmann elimination to laudanosine and a mono-quaternary acrylate.
The remainder of the drug is metabolised by non-specific ester hydrolysis to a mono-quaternary alcohol and a mono-quaternary acid.
Up to 10% of atracurium is excreted unchanged in the urine.
Variation of pH in the clinical range does not significantly affect atracurium elimination.
None of the metabolites display any neuromuscular or cardiovascular effects and are excreted via the kidneys.
However, laudanosine is a tertiary amine that has epileptogenic properties (Fig 1).
In animal studies, at plasma levels greater than 17 μg/ml, epileptic activity has been reported.
Electroencephalography changes have been reported at levels in excess of 4.4 μg/ml.
It is not thought that laudanosine causes seizures in humans even when they have received an atracurium infusion for a prolonged period of time.
Table 1 shows the pharmacokinetics of atracurium in health, renal failure and liver disease.
One of the unique properties of atracurium is Hofmann elimination.
It is the two-carbon separation between the quaternary nitrogen and ester group that allows for Hofmann elimination.
Regarding atracurium and isomerism:
A. Atracurium displays geometric isomerism, but not stereoisomerism
B. Atracurium has four chiral centres
C. The commercial preparation includes 16 isomers
D. Cisatracurium is the C1-R-cis isomer of atracurium
E. 15% of an ampoule of atracurium is cisatracurium
A. False. It displays both geometric and stereoisomerism.
B. True.
C. False. The commercial preparation includes 10 isomers.
D. True.
E. True.
Fig 1a shows the chemical formula of atracurium. The C1 carbon is a chiral centre, having four distinct substituents. It can therefore exist in R and S forms.
The quaternary nitrogen atom is also chiral (Fig 1b).
The C1 carbon and the quaternary nitrogen are linked by a bond that cannot rotate freely because it is part of a ring structure. Because each atom has one large and one small group outside the ring, the arrangement can be designated cis, i.e. both small substituents on the same side of the plane of the ring, or trans, i.e. the small substituents on opposite sides of the ring (Fig 1c).
There are four possibilities at each end of the molecule:
C1-R - N cis
C1-R - N trans
C1-S - N cis
C1-S - N trans
Because the molecule is symmetrical, there are in fact 10 isomers of atracurium in the commercial preparation.
One of these, the isomer with the C1-R-cis configuration at each end of the molecule, is cisatracurium. (Fig 2).
Cisatracurium comprises about 15% of atracurium. In general, the cis-cis group of isomers are slightly more stable and more potent than the others.
In mivacurium, the C1 carbons are both in the R configuration.
The quaternary ammonium, however, is a chiral mixture. Therefore, at each end of the molecule the C1-N bond can be in the cis or trans configuration.
Thus there are three isomers:
trans-trans, which comprises 58% of the mixture
cis-trans, which is 36% of the mixture
cis-cis, which is 6% of mivacurium
Regarding the elimination of atracurium and cisatracurium:
A. 77% of a dose of atracurium is eliminated by Hofmann elimination
B. 77% of a dose of cisatracurium is eliminated by Hofmann elimination
C. 10% of atracurium is eliminated unchanged in the urine.
D. A greater proportion of atracurium is eliminated in the urine than cisatracurium
E. A greater proportion of cisatracurium undergoes ester hydrolysis, by non-specific plasma esterases, than atracurium
A. False. 45% of atracurium undergoes Hofmann elimination to laudanosine and a mono-quaternary acrylate.
B. True
C. True
D. False
E. False. 77% of a dose of cisatracurium is eliminated by Hofmann elimination as versus the 45% of atracurium. The remaining percentage is eliminated by ester hydrolysis.
Which of these statements best describes the graph?
A. 95% of nicotinic acetylcholine receptors are blocked
B. The TOF ratio is 0.5
C. If this trace were recorded at the ulnar nerve, there would be full neuromuscular recovery at the diaphragm
D. If this trace represents recovery from neuromuscular block, it would be the earliest time point for safe administration of an acetylcholinesterase inhibitor
E. Four twitches are visible
A. Incorrect. 95% of receptors blocked represents a deep level of neuromuscular block and there would be no visible twitches.
B. Incorrect. In order to have a TOF ratio there must be four twitches. In the diagram there are only two.
C. Incorrect. It is impossible to determine from the trace whether it has been obtained during onset, or recovery, from neuromuscular block. Furthermore, whilst the diaphragm recovers ahead of the abductor pollicis, it would be impossible to determine from this recording of partial recovery from neuromuscular block whether full recovery had occurred at a different site.
D. Correct.
E. Incorrect. There are only 2 twitches visible.
Prior to administration of a non-depolarizing muscle relaxant, the twitches of the train of four are of equal amplitude. The TOF ratio is 1.0 (Fig 1).
During onset of a non-depolarizing block there is reduction in twitch amplitude. T4 is the first to be affected, followed in order by T3, T2 and T1 (Fig 2).
Eventually T4 disappears completely. This occurs when T1 is 25% of its original amplitude. T3 disappears when T1 has fallen to 15-20% and T2 disappears when T1 is 5-10% of its initial value.
During complete neuromuscular block no twitches are observed. This deep level of block requires >90% of ACh receptors to be occupied by the non-depolarizing muscle relaxant.
During recovery from neuromuscular block, T1 is the first twitch to reappear. When T2 reappears it is smaller than T1. Reversal of neuromuscular block with an acetylcholinesterase inhibitor can be achieved safely if it is administered when the TOF count is 2 or greater (Fig 1).
Eventually there is return of all four twitches and this allows the TOF ratio, i.e. the T4/T1 ratio, to be measured (Fig 2). It is of interest to note that for any given T1 amplitude the TOF ratio is greater during onset compared to recovery from neuromuscular block: a phenomenon known as ‘fade hysteresis’.
With regards to the assessment of neuromuscular block:
A. A sustained head lift guarantees full recovery of neuromuscular function
B. Mechanomyography is an assessment tool in routine clinical practice
C. When using a peripheral nerve stimulator to assess residual neuromuscular block, double burst stimulation is more accurate than train of four
D. When using acceleromyography to assess residual neuromuscular block, a TOF ratio of 0.9 is the gold standard to be achieved
E. When using a nerve stimulator to assess depth of block, absence of adductor pollicis twitches from ulnar nerve stimulation suggests full neuromuscular block is present in the diaphragm
Submit
A. False. Sustained head lift can occur with a TOF ratio of <0.6.
B. False. It is primarily a research tool. Acceleromyography is the objective assessment tool more likely to be encountered in clinical practice.
C. True. DBS is superior to train of four in the visual and tactile assessment of fade. However, acceleromyography is superior to both.
D. True.
E. False. The diaphragm has a high density of ACh receptors and is thus more resistant to neuromuscular block than peripheral muscles such as abductor pollicis. In addition, by virtue of its better blood supply it is quicker to recover function than peripheral muscles. However, the absence of twitches at adductor pollicis suggests a sufficient depth of block exists that it would be an unsafe time point at which to administer anticholinesterase reversal agent.
Many clinical methods of assessing residual block can be used and include:
Sustained head lift for five seconds
Tidal volume size
Tongue protrusion and grip strength
The sustained head lift is perhaps the most established marker, but has also been shown to be insensitive, because patients can achieve this goal at train of four (TOF) <0.6.
Clinical signs of inadequate recovery can be more reliably detected, such as:
Poorly sustained, twitchy movements
Feeble cough
Inability to sustain a head lift and hypoxaemia
The train of four (TOF) pattern of nerve stimulation involves the repeated delivery of four successive supramaximal stimuli to the ulnar nerve at a frequency of 2 Hz, with a 10 second gap between trains. Ulnar nerve stimulation causes contraction of adductor pollicis, resulting in thumb twitches (Fig 1).
The facial and lateral popliteal nerves can also be stimulated using a TOF and the corresponding muscle twitch observed.
The twitch is usually subjectively assessed by visual or tactile means, but these are insensitive methods because it is impossible to detect fade once the TOF ratio is >0.4.
Another option to assess minor degrees of residual neuromuscular block is double burst stimulation (DBS). DBS uses two short 50 Hz tetanic bursts 750 ms apart delivered at supramaximal current, with each burst composed of three impulses. DBS is more accurate than TOF in the tactile assessment of residual block.
- In this trace it is evident that the first twitch is of greater amplitude than the fourth twitch. However, the ratio of T4 to T1 is much greater than 0.4 and thus fade could not be determined by visual or tactile methods.
- There is a large margin of safety in neuromuscular transmission which is achieved in part by high numbers of receptors on the post-junctional membrane. In order to have no visible twitch >90% of receptors have to be occupied by NDMR.
- This trace could be consistent with a partial depolarizing block as there is no fade.
- See answer 2.
Regarding reversal agents:
A. Neostigmine forms a weak hydrogen bond with the esteratic binding site on AChE
B. Neostigmine reacts with AChE to form a carbamylated enzyme which requires regeneration to yield active enzyme
C. Acetylcholinesterase inhibitors are safely administered as sole agents
D. Sugammadex encapsulates rocuronium to cause rapid reversal of neuromuscular block
E. Sugammadex alone has no action at the NMJ
A. False. Edrophonium forms such a bond with which ACh is readily able to compete. As such, edrophonium is little used in clinical practice and only for very shallow degrees of block.
B. True. The half-time is 30 minutes.
C. False. Anticholinesterases are not specific to the neuromuscular junction. They also block acetylcholinesterase in the autonomic nervous system leading to muscarinic side-effects. They should routinely be co-administered with an antimuscarinic agent.
D. True. This drug reverses a similar depth of block significantly faster than neostigmine.
E. True.
Neostigmine, pyridostigmine and physostigmine are carbamate esters that bind to AChE. Similar to ACh when bound to AChE, the resulting complex undergoes hydrolysis (Fig 1a).
The metabolic product is a carbamylated enzyme which has a much slower rate of hydrolysis (Fig 1b), i.e. the half-time is approximately 30 minutes, and regeneration of active enzyme is necessary before further breakdown of ACh can occur (Fig 1c).
Neostigmine is a quaternary amine and is the agent most commonly used to reverse neuromuscular block.
Regarding suxamethonium:
A 55-year-old man is listed for an emergency laparotomy for peritonitis secondary to colonic perforation from a suspected tumour.
He has marked abdominal distension causing diaphragmatic splinting and respiratory embarrassment with oxygen saturations 93% despite supplemental oxygen therapy.
In addition, he has had multiple episodes of vomiting despite a functioning nasogastric tube and thus has a significant potential for regurgitation and aspiration during induction of anaesthesia.
Suxamethonium
In many respects suxamethonium fulfils the essential requirements of the ideal agent. At a dose of 1.0-1.5 mg/kg it acts within 45 seconds to produce the best possible intubating conditions. It remains the most commonly used neuromuscular blocking drug in rapid sequence inductions.
However, suxamethonium acts as a depolarising muscle relaxant. It causes opening of the central pore of the post-synaptic nicotinic ACh receptor and maintains the membrane in a depolarized state, rendering nearby voltage-gated sodium channels inactive.
The open acetylcholine receptors allow an efflux of potassium ions through their central pores, which triggers uncoordinated muscle contraction, i.e. fasciculations, and may result in postoperative myalgia.
Rocuronium
An alternative strategy could be to ‘flood’ the receptors on the post-junctional membrane with a non-depolarising neuromuscular blocking agent.
Drugs with a low potency, e.g. rocuronium (Fig 1), require an increased mass of drug to exert the same biological effect as a more potent drug like vecuronium. But both drugs need to block nearly all the nicotinic acetylcholine receptors to produce full neuromuscular blockade. The increased mass of rocuronium given results in a steeper concentration gradient for diffusion between the intravascular compartment and effector site of the neuromuscular junction, and hence a more rapid onset of neuromuscular block.
At a dose of 1.0-1.2 mg/kg rocuronium produces intubating conditions within 60 seconds. As a non-depolarising muscle relaxant it avoids the risk of malignant hyperthermia and the muscle fasciculations and myalgia associated with suxamethonium. However, the increased dose of rocuronium results in a block lasting well over an hour.
Other agents
Similarly, when more potent agents such as atracurium and vecuronium (Fig 1) are used at higher doses, this same ‘mass effect’ also induces a more rapid onset of neuromuscular block. However, the time to achieve intubating conditions remains inferior to rocuronium.
Again, duration of block would be prolonged as a consequence of the increased dose.
A 75-year-old lady with a known benign oesophageal stricture presents to the A&E department on a Sunday afternoon.
She gives a history of progressive dysphagia to solids with acute onset of retrosternal discomfort following her Sunday roast. The surgical team diagnose an oesophageal food bolus obstruction and wish to take her to theatre for a rigid oesophagoscopy. The surgeon assures you it is going to be “a two-minute job”.
Suxamethonium
Suxamethonium (Fig 1) not only has a rapid onset of block but is also rapidly hydrolysed by plasma cholinesterase to succinylmonocholine, which has only weak neuromuscular blocking activity, and choline, allowing a rapid offset of action.
Recovery from neuromuscular block starts within 3 minutes and is complete within 12-15 minutes. However, the duration of block produced by suxamethonium can be prolonged when plasma cholinesterase activity is reduced and the breakdown of suxamethonium is slowed, or when the obsolete techniques of incremental dosing or continuous infusion are used.
There is no agent available to antagonise the action of suxamethonium.
Mivacurium
Mivacurium (Fig 1) is a benzylisoquinolinium ester and is structurally related to atracurium. It is formulated as a mixture of three stereoisomers: cis-trans 36%, trans-trans 58%, and cis-cis 6%.
Although onset of neuromuscular block is slow, duration of action is relatively short because of its rapid metabolism by plasma cholinesterase. However, it is subject to the same potential for variations in plasma cholinesterase activity that can result in prolonged duration of block as suxamethonium. When spontaneous recovery has begun, it proceeds rapidly. Administration of neostigmine generally accelerates recovery and is recommended.
It should be remembered that neostigmine inhibits plasma cholinesterase and prolongs the metabolism of mivacurium.
An alternative strategy would be to administer a longer-acting muscle relaxant with the ability to reverse from deeper levels of neuromuscular block, such as:
Rocuronium, which has a terminal half-life 85 minutes
Vecuronium, which has a terminal half-life 60 minutes.
Sugammadex is a newly available drug that encapsulates the aminosteroid compounds rocuronium and vecuronium and is capable of reversing deep levels of neuromuscular block (Fig 1).
A 25-year-old brittle asthmatic is admitted to the A&E department. She is well known to the hospital and has had several admissions to the ICU for ventilatory support.
Despite initial therapy her acute exacerbation is failing to settle and she fulfils the criteria for a life-threatening asthma:
She has a silent chest with SpO2 98% on a mask with reservoir bag
A tachycardia of 130 bpm
Systolic blood pressure 85 mmHg
She is starting to tire
She requires immediate intubation and ventilation.
Of all the muscle relaxants, vecuronium is the most cardiovascularly stable (Fig 1). It has no effect on heart rate or blood pressure. Histamine release is rare and the drug appears to have low immunogenicity. When a muscle relaxant is mandated for atopic individuals, vecuronium is the drug of choice.
Rocuronium is associated with minimal cardiovascular instability and few side-effects. It is weakly vagolytic and can cause tachycardia.
Atracurium is a benzylisoquinolinium compound composed of 10 stereoisomers. It has relatively few side-effects, but administration can be associated with histamine release. Atracurium is metabolised to laudanosine, but the risk of convulsions from accumulation is theoretical.
Cisatracurium is one of the 10 stereoisomers of atracurium. It is associated with decreased histamine release and has a better side-effect profile than atracurium. However, it has a slower onset of action and a slightly longer duration of block than atracurium. In this case, its side-effect profile would be good, but the onset of action would be too slow to get rapid control of this patient’s airway. It cannot really be considered as a short-acting muscle relaxant.
Mivacurium is more commonly associated with histamine release than either rocuronium or atracurium.
Suxamethonium has the least cardiovascular stability and the least clean side-effect profile. It can produce bradycardia, especially after a second dose; ventricular arrhythmias; and increased salivation. Intraocular, intragastric and intracranial pressure may be increased. Of all anaesthetic drugs it is the one most commonly implicated in anaphylactic reactions.
Furthermore, suxamethonium may cause a dangerous hyperkalaemia in patients with burns, spinal cord injuries and neuromuscular disorders such as Guillain-Barré syndrome due to potassium release from an abnormal proliferation of extra-junctional fetal-type acetylcholine receptors.
Regarding the autonomic nervous system:
A. It provides conscious control of skeletal muscle contraction
B. It is anatomically divided into three divisions
C. Sympathetic and parasympathetic efferent pathways each contain two neurons
D. Postganglionic sympathetic efferent pathways tend to be short
E. Preganglionic parasympathetic efferent pathways tend to be long
A. False. The autonomic nervous system does not control skeletal muscle, it controls visceral function but this is involuntary.
B. False. An important function of the autonomic nervous system is cardiovascular homeostasis.
C. True. The sympathetic and parasympathetic efferent pathways contain two neurons: preganglionic and postganglionic.
D. False. In the sympathetic nervous system, the autonomic ganglia tend to be distant from the effector organs while in the parasympathetic nervous system, the ganglia are very close to, or in, the effector organs.
E. True.
The peripheral nervous system consists of the somatic nervous system and the autonomic nervous system.
The main difference between the two systems is what target tissues are effectors. The somatic responses consist of motor neurons that only stimulate skeletal muscles. In contrast, the autonomic system targets smooth muscles, cardiac muscles, and glands. Although the basic circuit in both systems is a reflex arc, there are differences between somatic and autonomic reflexes.
The autonomic reflex arc is a system whereby afferent impulses from receptors travel to the central nervous system (CNS) via autonomic and somatic nerves, and integrate at various levels. These efferent impulses then travel to effector organs via preganglionic and postganglionic autonomic neurons.
All output from the CNS, except the nerve supply to skeletal muscle, is via the autonomic nervous system
The autonomic nervous system is divided anatomically into the sympathetic system and the parasympathetic system (Fig 1). Both systems function through reflex arcs that pass through and are integrated in the CNS.
The enteric nervous system is sometimes referred to as a third division. This system consists of the intrinsic nerve plexi of the gut and communicates with both the sympathetic and parasympathetic systems, even though it can function independently of the CNS.
The term autonomic was originally used because it was believed that the autonomic nervous system was controlled ‘autonomously’ and not by the CNS. Strictly speaking, this term is inaccurate.
Sympathetic and parasympathetic efferent pathways contain two neurons: preganglionic and postganglionic. The cell bodies of preganglionic neurons are located in the visceral efferent intermediolateral (IML) grey column of the spinal cord and in motor nuclei of some cranial nerves.
Preganglionic neurons are myelinated B fibres, which are smaller and conduct more slowly than A fibres and leave the CNS to synapse with postganglionic neurons at autonomic ganglia. In the sympathetic nervous system, the autonomic ganglia tend to be distant from the effector organs while in the parasympathetic nervous system, the ganglia are very close to or in the effector organs (Fig 1).
Each preganglionic axon diverges to an average of eight to ten postganglionic neurons and this causes the output of ANS to be more diffuse compared with the somatic system. The axons of the postganglionic neurons are mostly unmyelinated C fibres and terminate on the visceral effectors.
The adrenal medulla is a special case. It may be considered a sympathetic ganglion as the cells of the medulla are modified postganglionic cells. These release catecholamines into the circulation rather than innervate effector cells.
Select the four highlighted areas in the image for more information on each region of the sympathetic chain.
The cervical region
The cervical region consists of the superior, middle and inferior cervical ganglia.
The inferior cervical ganglion is called the stellate ganglion and is fused with the first thoracic ganglion.
Postganglionic nerves from the superior cervical ganglion innervate the head.
Postganglionic fibres from the middle and inferior cervical ganglia innervate the upper limbs and thoracic viscera including the heart.
The lumbosacral region
The lumbosacral region lies on either side of the lumbar and sacral vertebrae.
Some preganglionic fibres pass through the lumbar ganglia forming the lumbar splanchnic nerve. The fibres then synapse in the inferior mesenteric ganglion, which is another prevertebral ganglion.
Other preganglionic fibres from all levels synapse with postganglionic fibres. These then run with spinal nerves to supply structures in the lower body.
The splanchnic nerves
Preganglionic fibres from the lower seven thoracic segments pass through the sympathetic ganglia without synapsing. These fibres then converge to form the greater and lesser splanchnic nerves.
The splanchnic nerves synapse in the coeliac and superior mesenteric ganglia, which are prevertebral, i.e. in front of the vertebral column and not part of the sympathetic chain.
Preganglionic fibres in the splanchnic nerves also synapse in the adrenal medulla.
The sympathetic chain is formed from sympathetic ganglia and the fibres running between them. They lie adjacent to the vertebral column on each side.
The ganglia are connected by the axons of preganglionic sympathetic nerves passing to different levels in the chain.
There are usually 22 ganglia in each chain: 3 cervical, 11 thoracic, 4 lumbar and 4 sacral, although the chain only receives preganglionic fibres from the thoracic and lumbar segments of the spinal cord.
Regarding the autonomic nervous system:
A. Sympathetic ganglia are found exclusively in the sympathetic chains adjacent to the spinal cord
B. Preganglionic sympathetic nerves leave the spinal cord via grey rami communicantes
C. Postganglionic parasympathetic nerves supplying the head and neck originate in the stellate ganglion
D. The splanchnic nerves contain preganglionic sympathetic nerve fibres
E. The parasympathetic outflow from the CNS is via cranial and sacral spinal nerves
A. False. The coeliac and hypogastric ganglia are usually thought of as sympathetic.
B. False. Preganglionic sympathetic nerves leave the spinal cord via white rami communicantes which are myelinated.
C. False. Parasympathetic ganglia are situated within or close to effector organs. The stellate ganglion contains only sympathetic ganglia.
D. True.
E. True.
Within the parasympathetic division, the preganglionic fibres are relatively long so that ganglia are close to effector organs. Postganglionic nerves are short (Fig 1).
Parasympathetic preganglionic nerve fibres leave the CNS via two routes:
With cranial nerves
With sacral spinal nerves
The parasympathetic output is therefore often described as being craniosacral.
Select the two α receptors in the image for more information.
α1 receptors
α1 receptors stimulation causes coupling with Gq protein to activate membrane bound phospholipase C to produce inositol triphosphate (IP3) and diacylglycerol (DAG) as secondary messengers, which produces changes in Ca2+ concentration and binding. They cause:
Effects on smooth muscles:
Constriction of vascular smooth muscle
Bronchoconstriction
Relaxation of gastrointestinal smooth muscle
Contract gastrointestinal sphincters
Uterine contraction
Contract bladder sphincter
Contract iris (radial muscle)
Stimulation of salivary secretion
Hepatic glycogenolysis
Transmitters and ReceptorsAlpha Receptors
Select the two α receptors in the image for more information.
α2 receptors
α2 receptors interact with Gi- proteins to inhibit adenylyl cyclase, reducing cyclic adenosine monophosphate (cAMP) and Ca2+ channels, but activate K+ channels.
α2 receptors differ from α1 receptors as they are predominantly found on presynaptic nerve terminals at the junctions of sympathetic nerves with effector organs where they inhibit the release of noradrenaline by negative feedback. This inhibits sympathetic outflow from the brainstem. When noradrenaline or adrenaline bind to α2 receptors, further release from the nerve terminal is inhibited. However, α2 receptors are also present on some post-synaptic membranes, mediating constriction of vascular smooth muscle. Other effects include:
Relaxation of gastrointestinal smooth muscle (presynaptic effect)
Decreased insulin secretion
Platelet aggregation
The three subtypes of β receptor are all coupled to Gs proteins, which activate adenylyl cyclase and results in the formation of cAMP. cAMP activates intracellular enzyme pathways to produce changes in cell function.
β1 receptors
Actions of β1 receptors include:
Increased heart rate
Increased contractility
Renin release
Stimulate amylase filled salivary secretions
β2 receptors
Actions of β2 receptors include:
Smooth muscle relaxation at various sites, i.e bronchi (bronchodilation), vasodilatation of blood vessels, the relaxation of visceral smooth muscle, uterine relaxation, bladder detrusor muscle relaxation
Muscle tremors in skeletal muscles
Glycogenolysis
Inhibition of histamine release from mast cells
Stimulates insulin secretion
β3 receptors
β3 receptors are found in adipose tissue and skeletal muscle. They mediate lipolysis and thermogenesis.
Match the drugs to the receptors and agonists and antagonists.
How much do you already know about α1 receptors?
A. Stimulation of α1 receptors elicits the contraction of smooth muscle in all locations
B. The most obvious effect of α1 stimulation results from its effect on the tone of vascular smooth muscle
C. The distribution of α1 receptors determines the degree of regional vasoconstriction
D. Long-term α1-receptor stimulation produces a trophic response
E. Alpha receptors have no effect on heart function
A. False. In the gastrointestinal (GI) tract, the stimulation of α1 receptors produces smooth muscle relaxation.
B. True. The most significant effect is on the tone of vascular smooth muscle, where constriction of large veins, arteries and arterioles occurs, particularly in the skin and the splanchnic vessels. The resulting increase in blood pressure is usually associated with a decrease in cardiac output because of the increased afterload and activation of the baroreflex, which may cause bradycardia.
C. True. The distribution of α1 receptors determines the degree of regional vasoconstriction, with minimal effect on the vasculature of the heart and brain. The density of α1 receptors is much greater in the radial artery than the internal mammary artery, which has obvious clinical relevance to postoperative management of some cardiac surgical patients.
D. True. Long-term α1-receptor stimulation produces a trophic response, involving smooth muscle proliferation. In particular, this occurs in blood vessels, receptor subtype α1B, and in the prostate gland, receptor subtype α1A. Tamsulosin is used in the treatment of benign prostatic hypertrophy, relieving obstruction and thus improving urinary flow, because of its selectivity for the receptor subtype α1A.
E. False. Changes in afterload have an indirect effect of cardiac function, but alpha receptors make up 10% of the total adrenoceptor population of the normal human heart. They are inotropic but have little effect on coronary flow.
α2 receptors are widely distributed in the body (Fig 1). The greatest number are extrasynaptic, although the greatest density is found presynaptically, and they are inhibitory. Other receptors, e.g. postsynaptic and extrasynaptic, cause vasoconstriction and platelet aggregation. Agonists cause sedation in the CNS and they are widely used in veterinary anaesthesia, e.g. xylazine and medetomidine.
The clinically important effects are those due to CNS-receptor stimulation, which cause sedation and a reduction in sympathetic outflow, and presynaptic receptors on cholinergic and noradrenergic nerve terminals, which reduce transmitter release. Thus α2-receptor stimulation is associated with a slower heart rate and lower blood pressure.
Many α1 agonists are also α2 agonists, e.g. noradrenaline and methoxamine, but the subtle α2 effects are swamped by the α1-mediated vasoconstriction. Even the weak α1 stimulation by clonidine can cause transient hypertension before the α2 effects become apparent; dexmedetomide is much more α2-selective.
Regarding the stimulation of specific agonists:
A. Stimulation of α receptors results in an increase in systemic vascular resistance
B. Stimulation of α1 receptors results in the contraction of all smooth muscle except GI tract muscle
C. Circulating catecholamines are the main source of stimulation of α2 receptors
D. Stimulation of β1 receptors stimulates the heart
E. Stimulation of β2 receptors results in constriction of skeletal, bronchial and uterine smooth muscle
A. True.
B. True.
C. True.
D. True.
E. False. Stimulation of β2 receptors results in relaxation of skeletal, bronchial and uterine smooth muscle.
β-adrenergic receptors have been subdivided into β1, β2 and β3 receptors. In contrast to α receptors, stimulation of β receptors generally leads to the relaxation of smooth muscle.
β2 receptors mediate smooth muscle relaxation in blood vessels throughout the body and especially in skeletal muscle. The mechanism of action is endothelium-dependent and involves the release of nitric oxide. Anaesthetists frequently use drugs that modify vascular tone via β2-adrenergic receptors in vessel walls:
Effect on the heart
Stimulation of cardiac β receptors results in increased force of contraction (inotropy), and increased heart rate (chronotropy) (Fig 1). In healthy hearts, 80% of these receptors are the β1 subtype, but they decouple and depopulate in response to continued stimulation so that, in failing hearts, the β2 receptors may make up 50% of the β-receptor complement. In this situation, positive inotropy through β2 stimulation becomes important. Cardiac output increases at the expense of greater oxygen demand and reduced cardiac efficiency.
In higher doses, catecholamines predispose to cardiac arrhythmias, which may include ventricular fibrillation. These complications are more likely in patients with concurrent myocardial ischaemia.
Effect on metabolism
Catecholamines, via β1 receptors, elicit the conversion of:
Glycogen stores to glucose
Fat stores to free fatty acids
Lipolysis is also achieved via β3 receptors.
Attempts have been made to develop selective β3-receptor agonists in an attempt to treat obesity, although to date these have been unsuccessful.
Effect on skeletal muscle
Stimulation
Although less significant than with cardiac muscle, β2-receptor agonists also stimulate receptors on skeletal muscle:
β2 agonists, including adrenaline, increase the twitch tension of fast-contracting (white) muscle fibres
The twitch tension of slow (red) fibres is reduced by adrenaline
Although this mechanism is poorly understood, it is thought to involve the contractile proteins.
Tremor
β2 agonists cause tremor by:
Increasing muscle spindle discharge
An effect on the contraction kinetics of fibres, which produce an instability of fibre length, e.g. salbutamol, used by asthmatic patients
Vasculature
β2 stimulation dilates the skeletal muscle bed via a mechanism involving nitric oxide.
Effect on bronchial muscle
Activation of β2 receptors causes dilatation of bronchial smooth muscle. Therefore, selective β2-receptor agonists are very important bronchodilatatory agents in the treatment of asthma (Fig 2).
Effect on uterine muscle
Selective β2-receptor agonists have a similar relaxing effect on uterine smooth muscle, and can be used to prevent premature uterine contraction (Fig 3).
Identify the chemical structure shown in Fig 1.
A. Adrenaline
B. Noradrenaline
C. Tyrosine
D. Phenylalanine
E. Dopamine
A. Correct. The chemical structure shown is adrenaline.
Identify the chemical structure shown in Fig 1.
A. Adrenaline
B. Tyrosine
C. Phenylalanine
D. Dopamine
E. Noradrenaline
E. Correct. The chemical structure shown is noradrenaline.
Identify the chemical structure shown in Fig 1.
A. Adrenaline
B. Tyrosine
C. Phenylalanine
D. Dopamine
E. Noradrenaline
D. Correct. The chemical structure shown is dopamine.
Regarding tyrosine:
A. Tyrosine is an essential amino acid
B. In phenylketonuria, there is a congenital absence of phenylalanine hydroxylase
C. It is found in the adrenal medulla
D. It is metabolised to L-Dopa by tyrosine kinase
E. L-Dopa differs from tyrosine by the addition of a single hydroxyl group
A. False. As well as dietary sources, it is also synthesized in the liver from phenylalanine.
B. True. This leads to accumulation of phenylalanine.
C. True. Tyrosine is manufactured by the chromaffin cells in the adrenal medulla.
D. False. It is metabolised to L-Dopa by tyrosine hydroxylase; this is the rate-limiting step of the synthetic pathway.
E. True.
The key substance for catecholamine synthesis is tyrosine, an amino acid, which is obtained from protein-containing foods such as meat, eggs, dairy products and wheat (Fig 1). Tyrosine is concentrated in the cells of the adrenal medulla, i.e chromaffin cells, and in the catecholamine-secreting neurons.
However, tyrosine is ‘non-essential’ in that it is also synthesised endogenously from phenylalanine.
Phenylalanine is converted in the liver to tyrosine by phenylalanine hydroxylase (Fig 2). The congenital absence of hepatic phenylalanine hydroxylase causes the condition phenylketonuria (PKU), where the accumulation of phenylalanine is associated with abnormal neurodevelopment.
Conversion to dopamine occurs within the cytoplasm. Tyrosine hydroxylase converts tyrosine to L-Dopa and then dopa decarboxylase converts this into dopamine (Fig 1a).
The rate-limiting step in the whole synthetic pathway is the tyrosine → L-Dopa conversion.
Dopamine, and noradrenaline, exert negative inhibition on tyrosine hydroxylase and thus accurately control catecholamine production in the short term (Fig 1b). Tyrosine hydroxylase requires a cofactor, tetrahydrobiopterin, which is converted to dihydrobiopterin during enzyme action.
Dopamine now enters the granulated vesicles where dopamine β-hydroxylase (DBH) converts it into noradrenaline (Fig 1c).
Finally, within the cytoplasm of selected neurons, but mainly within the chromaffin cells of the adrenal medulla, phenylethanolamine-N-methyltransferase (PNMT) catalyses conversion of noradrenaline to adrenaline (Fig 1d).
Regarding endogenous catecholamines:
A. The adrenal medulla releases 80% noradrenaline and 20% adrenaline
B. The half-life of adrenaline is 10 minutes
C. Phenylethanolamine-N-methyltransferase (PNMT) catalyzes conversion of noradrenaline to adrenaline
D. The clinical difference between noradrenaline and adrenaline arises from their different affinity for the β1 adrenoceptor
E. Beta receptors are G protein-coupled
A. False. The adrenal medulla releases 80% adrenaline and 20% noradrenaline.
B. False. It is only 1-3 minutes.
C. True.
D. False. Adrenaline and noradrenaline differ mainly in their effects at β2 adrenoceptors, to which noradrenaline has a much lower affinity.
E. True. Alpha receptors are also G protein-coupled.
α and β receptors are divided into subtypes.
α receptors are divided into two subtypes:
α1 receptors
α1 receptors activate phospholipase C (PLC). They produce with PLC phospoinositol triphosphate (PIP3) in the cell membrane to produce the following as second messengers:
Inositol triphosphate (IP3)
Diacyl glycerol (DAG)
The main effects of α1 receptors are:
Constriction of vascular smooth muscle
Relaxation of gastrointestinal smooth muscle
Stimulation of salivary secretion
Hepatic glycogenolysis
α2 receptors
α2 receptors inhibit adenylyl cyclase and thus reduce cyclic adenosine monophosphate (AMP) formation. They differ from α1 receptors in that they:
Are predominantly found on pre-synaptic nerve terminals at the junctions of sympathetic nerves with effector organs
Provide a negative feedback system for control of transmitter release. When noradrenaline or adrenaline bind to an α2 receptor, further noradrenaline release from the nerve terminal is inhibited. Thus, α2 receptors mediate relaxation of gastrointestinal smooth muscle
However, α2 receptors are also present on some post-synaptic membranes mediating constriction of vascular smooth muscle and are found on platelets where they mediate aggregation.
β1 receptors
β1 receptors are found in the heart where they mediate increased heart rate and force of contraction.
They are also found in the salivary gland where they mediate secretion of amylase.
β2 receptors
β2 receptors are found on smooth muscle at various sites.
They mediate bronchodilatation and relaxation of visceral smooth muscle including sphincters. They also stimulate nitric oxide-mediated vasodilation in skeletal muscle and splanchnic vessels.
In the liver and skeletal muscle, they mediate glycogenolysis and muscle tremor whilst on mast cells they mediate inhibition of histamine release.
β3 receptors
β3 receptors are found in adipose tissue and skeletal muscle. They mediate lipolysis and thermogenesis.
Note: the sweat glands are an exception in that they are innervated by sympathetic fibres. However, the transmitter at the neuroeffector junction is acetylcholine, which acts on a muscarinic receptor on the effector cell membrane.
Give an overview of Drugs and the Parasympathetic Nervous System, and the relevance to anaesthetics.
Describe the functions of the parasympathetic system
Identify the neurotransmitters involved
List the drugs clinicians use to affect parasympathetic activity
The mechanism of cholinergic transmission can be interrupted in several ways
Modulation of parasympathetic function by cotransmission is now well recognised
Drugs that inhibit or stimulate the parasympathetic system are essential to anaesthetic practice
Presynaptic agents can be categorised according to the process they inhibit.
ACh synthesis
The rate-limiting step in the synthesis of ACh is transport of choline into the neuron. Hemicholinium is an analogue of choline that blocks the choline transporter, thereby inhibiting ACh synthesis. Existing ACh stores become slowly depleted.
Hemicholinium is not used in clinical practice, owing to its slow onset and the frequency dependent nature of the block.
Vesicular packaging of ACh
Cholinergic vesicles actively accumulate ACh, by means of a specific amine transporter. Accumulation of ACh is coupled with the large electrochemical gradient for protons that exists between intracellular organelles and the cytosol.
This is selectively blocked by the experimental drug vesicamol.
ACh release
ACh is released via exocytosis. This process is triggered by entry of calcium into the nerve terminal. Magnesium and aminoglycoside antibiotics antagonise this step and, although parasympathetic effects are not reported, they can, rarely, cause neuromuscular blockade by this mechanism. Muscle paralysis is a rare but recognised side-effect of aminoglycoside antibiotics and magnesium. It can be reversed by the administration of calcium salts.
Botulinum toxin and bungarotoxin are potent neurotoxins that specifically inhibit ACh release.
Botulinum toxin is a protein produced by the anaerobic bacillus Clostridium botulinum. This organism multiplies in preserved food and can cause botulism.
Botulinum toxin contains several peptidases that cleave specific proteins involved in exocytosis. The result is prolonged block of synaptic function. Botulism causes progressive parasympathetic and motor block, with a dry mouth, blurred vision, dysphagia and progressive respiratory paralysis.
Treatment with the antitoxin is only effective if it is administered before symptoms develop. Once the toxin is bound, its actions cannot be reversed. Acetylcholinesterase inhibitors are ineffective at restoring cholinergic transmission.
The administration of botulinum toxin by injection may be useful in the following conditions:
Sialorrhoea: excessive salivary secretion
Spasticity: excessive extensor muscle tone, usually associated with a birth injury
Urinary incontinence: associated with bladder instability, intra-vesical injection is used
Squint: intraocular muscle injection
Blepharospasm
Muscarinic receptor agonists have a reduced susceptibility to hydrolysis because of their choline ester structure. They act at nicotinic and muscarinic ACh receptors. Their relative activity at each is determined by their structure.
Research is underway with selective muscarinic agonists in the treatment of CNS disorders including dementia.
Termed parasympatholytic drugs, muscarinic receptor antagonists are competitive antagonists at muscarinic ACh receptors, blocking the effects of endogenous parasympathetic stimulation.
Their structure consists of an ester and a basic group, in the same relationship as acetylcholine. However, muscarinic antagonists have a bulky aromatic ring in place of the acetyl group. They can be subdivided on the basis of their structure into:
Tertiary ammonium compounds that are lipid soluble and penetrate the blood-brain barrier, gastrointestinal and conjunctival mucosa. Drugs used clinically include atropine and hyoscine, cyclopentolate and tropicamide-eye drops
Quaternary ammonium compounds that do not penetrate the blood-brain barrier, and the peripheral actions of which are similar to atropine. Drugs used clinically include hyoscine butylbromide, propantheline and ipratropium
List the clinical effects from the diagram.
CNS effects
Muscarinic receptor agonist:
None.
Muscarinic receptor antagonist:
Atropine has excitatory effects, e.g. restlessness, agitation and disorientation.
Hyoscine has depressant effects, e.g. sedation, amnesia, anti-emetic and anti-parkinsonian effects.
Ophthalmic effects
Muscarinic receptor agonist:
Pupillary constriction
Ciliary muscle contraction
As a result, intraocular pressure is reduced.
Muscarinic receptor antagonist:
Pupillary dilation and relaxation of ciliary muscle may occur.
As a result, intraocular pressure is raised, which may be detrimental in patients with narrow-angle glaucoma.
Glandular effects
Muscarinic receptor agonist:
Increased exocrine glandular secretion.
The combination of bronchial smooth muscle contraction and increased bronchial secretion can cause significant airway obstruction.
Muscarinic receptor antagonist:
Inhibition of exocrine glandular secretion. Mucociliary clearance is inhibited and residual secretions become thick and difficult to clear from the airway.
Ipratropium does not produce this effect.
Atropine and glycopyrrolate are used as premedication, e.g. in management of the difficult airway, to inhibit salivation and reduce bronchial secretions.
Smooth muscle effects
Muscarinic receptor agonist:
Relaxation of vascular smooth muscle
Contraction of all other smooth muscle, including bronchial, gastrointestinal and bladder smooth muscle.
Muscarinic receptor antagonist:
Reflex bronchoconstriction, e.g. during anaesthesia, is prevented by atropine.
Bronchoconstriction precipitated by local mediators, such as histamine and leukotrienes, is unaffected.
Relaxation of bronchial, biliary and urinary tract smooth muscle occurs, and incontinence secondary to bladder overactivity may be treated with muscarinic antagonists.
Cardiovascular effects
Muscarinic receptor agonist:
Bradycardia
Reduced myocardial contractility:
atrial > ventricular
The ventricles have sparse parasympathetic innervation and, therefore, low sensitivity to muscarinic agonists
Vasodilation
These effects reduce cardiac output and blood pressure.
Muscarinic receptor antagonist:
Blood pressure is unaffected as most resistance vessels do not have cholinergic innervations.
Heart rate is usually increased but, at very low doses, atropine can cause a paradoxical bradycardia, possibly due to its central actions.
Gastrointestinal effects
Muscarinic receptor agonist:
None.
Muscarinic receptor antagonist:
Gastrointestinal smooth muscle relaxation-motility is inhibited by atropine.
Pirenzipine is a selective M1 receptor blocker. It inhibits gastric acid secretion.
Decide whether each of the clinical uses listed below should be classified under muscarinic receptor agonism or antagonism.
A. Pilocarpine and cevimeline that stimulate salivation and lacrimation in patients with a dry mouth or eyes, secondary to irradiation or Sjögren’s syndrome
B. Darifenacin used in the treatment of urinary incontinence to relax the bladder
C. Tiotropium and ipratropium used as bronchodilators for the treatment of asthma and COPD
D. Pilocarpine eye drops that cause a reduction in intraocular pressure and are used in the treatment of glaucoma
E. Agents used to reduce salivation and bronchial secretions as premedication for anaesthesia
F. Agents used for pupillary dilation to facilitate ophthalmoscopic examination
Regarding the neurotransmitters that affect the parasympathetic nervous system:
A. Ganglionic receptors are exclusively nicotinic
B. Botulinism results from the toxin preventing synthesis of acetylcholine
C. Neurotransmission in the parasympathetic system is terminated by re-uptake of transmitter
D. The main neurotransmitter throughout the parasympathetic system is acetylcholine
E. Peripheral benzodiazepine receptors are an important site of modulation for the parasympathetic system
F. ATP and VIP are examples of NANC transmitters
A. False. Neurotransmission at autonomic ganglia is predominantly nicotinic, but muscarinic receptors are present and increase excitation.
B. False. Botulism prevents the release of the acetylcholine stores.
C. False. The parasympathetic neurotransmitter is ACh and its effects are terminated by metabolism, not re-uptake.
D. True.
E. False. The benzodiazepine receptor may influence central control of the the autonomic system, but there is no peripheral effect.
F. True.
ACh is the main neurotransmitter in the parasympathetic nervous system (Fig 1). It acts upon nicotinic ACh receptors in the parasympathetic ganglia and upon muscarinic ACh receptors at the target cells of effector organs.
There are several important processes involved:
Synthesis
ACh is synthesised within the nerve terminal, from choline (Fig 1). Choline enters the neuron from the synaptic cleft, via carrier-mediated transport. It is acetylated to form ACh by choline-acetyl-transferase, a cytosolic enzyme found exclusively in cholinergic neurons. This requires acetyl co-enzyme A (CoA) to donate an acetyl group.
The rate-limiting step in the synthesis of ACh is transport of choline into the neuron. This process is determined by the rate of release of ACh from the nerve terminal.
Packaging
Most of the ACh synthesised within a nerve terminal is packaged and stored in synaptic vesicles (Fig 1).
Accumulation of ACh within these vesicles occurs via a specific amine transporter. This is associated with a large electrochemical gradient for protons, between intracellular organelles and the cytosol.
Release
ACh is released via exocytosis. This process is triggered by entry of calcium into the nerve terminal (Fig 1). Depolarisation of the nerve terminal by an action potential causes voltage-gated calcium channels to open and an influx of calcium ions. ACh then diffuses across the synapse and binds to:
Post-synaptic nictonic ACh receptors in the parasympathetic ganglia
Post-synaptic muscarinic ACh receptors on the effector cells of the target organ
Receptor binding
Nicotinic receptors are part of the pentameric ligand-gated ion channel family and their stimulation increases membrane permeability to Na+ and K+ actions (Fig 1). Although there is great diversity in detail, they form three main groups: ganglionic, neuromuscular and CNS.
Muscarinic ACh receptors belong to the seven-transmembrane domain G protein-coupled family of receptors. Five molecular subtypes exist (Fig 2). Although they have some physiological selectivity1, all muscarinic agonists and antagonists used in anaesthetic practice are non-selective.
M2 is the main cardiac subtype. M3 receptors are involved with exocrine glands and smooth muscle. M4 and M5 receptors are found in the CNS only.
1 An example of physiological selectivity is the stimulation of M1 receptors which causes slow excitation in ganglia where the major cholinergic receptor is nicotinic, stimulates the CNS and also increases gastric secretion.
Clearance
Once released at cholinergic synapses, the actions of ACh are rapidly terminated. ACh is hydrolysed to form choline and acetic acid by cholinesterases, which are serine hydrolase enzymes (Fig 1).
There are two main forms of cholinesterase:
Acetylcholinesterase is mainly membrane-bound and is specific for ACh. It is responsible for rapid hydrolysis of ACh at cholinergic synapses. The active site of acetylcholinesterase consists of two distinct regions: An anionic site, which binds the basic (choline) moiety of ACh and an estertic (catalytic) site
Pseudocholinesterase is relatively non-selective for ACh and has broader substrate specificity. It is found in several tissues of the body, e.g. the liver, brain, gastrointestinal tract smooth muscle and skin, and it exists in soluble form in the plasma. It is not particularly associated with cholinergic synapses
Give an overview of The Cardiovascular System and Sites for Drug Effects, and the relevance to anaesthetics.
Describe the basic anatomy of the cardiovascular system
Understand the different sites of action for drugs to target the cardiovascular system
Understand how some drugs have these effects
Drugs used in anaesthesia can have positive or negative chronotropic and inotropic effects.
Drugs can have direct or indirect effects on the heart
The renin angiotensin aldosterone system regulates blood pressure by regulating blood volume and systemic vascular resistance
The cardiovascular system is controlled by the autonomic nervous system via both the parasympathetic and the sympathetic nervous systems, affecting the heart directly.
The renin-angiotensin-aldosterone system (RAAS) and peripheral vascular system also have an indirect contribution to the cardiovascular system.
Regarding antagonists:
A. Doxazocin is an example of an alpha-1 blocker
B. Beta-blockers all block the same receptor
C. Calcium channel blockers decrease systemic vascular resistance, myocardial contractility and cardiac output
A. True. Doxazocin binds to, and inhibits the action of, alpha-1 receptors, which in turn reduces systemic vascular resistance by inhibiting vascular smooth muscle contraction.
B. False. Each beta-blocking drug has an affinity for a particular receptor.
C. True.
Some alpha antagonists, such as doxazocin, are used as an adjunct to treatment of hypertension. These bind to alpha-1 receptors and inhibit their action, therefore inhibiting vascular smooth muscle contraction and reducing systemic vascular resistance.
Beta-blocking drugs bind to a beta receptor, inhibiting their effects, and so have negative chronotropic and inotropic effect. Each beta-blocking drug has an affinity for a particular beta receptor.
Calcium channel blockers block calcium entry into the cells and inhibit its release from the sarcoplasmic reticulum, which in turn decreases the contractility of the myocardium and smooth muscle tone in the arterial vessels. Therefore, these drugs (such as verapamil and diltiazem) cause arterial dilatation and very little venous dilatation, in turn decreasing the blood pressure by decreasing the systemic vascular resistance, myocardial contractility and cardiac output.
Regarding indirect effects on the cardiovascular system:
A. Stimulation of the parasympathetic nervous system increases heart rate and contractility of the heart
B. Baroreceptors are receptors which are stimulated in response changes in the vessel walls
C. Fibres from aortic and carotid sinus baroreceptors travel within the vagus nerve
D. Nitrates cause vasodilation via smooth muscle dilation
E. ACE inhibitors reduce blood pressure by affecting the renin angiotensin aldosterone system
Submit
A. False. Stimulation of the sympathetic nervous system increases contractility and heart rate. Stimulation of the parasympathetic nervous system reduces these.
B. True. Baroreceptors are mechanoreceptors which are stimulated by stretch within the wall of the vessel they are found in.
C. False. Fibres from aortic baroreceptors travel within the vagus nerve (X), whereas fibres from the carotid sinus are within the glossopharnygeal nerve (IX).
D. True. Nitric oxide binds to guanylyl cyclase, which converts GTP to cGMP, which activates protein kinase G. This then leads to a reduction in calcium levels and smooth muscle relaxation.
E. True. They inhibit angiotensin converting enzyme from converting angiotensin-1 to angiotensin-2.
When considering adrenergic drugs for inotropic or vasoconstrictive effect, it is enough to consider their effects on the α1, β1 and β2 receptors. Remind yourself of the effect of stimulating these receptors.
The clinical importance of dopaminergic receptors remains a matter of dispute, but most authorities believe that any small benefits of renal and splanchnic vasodilation are outweighed by adverse endocrine effects.
If the clinical situation demands an inotrope, then a drug with β1 and possibly β2 activity is indicated. If vasoconstriction is called for then an α1 agonist is required, and β2 stimulation is better avoided.
It is essential that an estimation of cardiac output is made before starting vasoconstrictive therapy even if it is only a simple clinical examination, e.g. peripheral temperature and capillary refill time, in order to avoid tissue ischaemia. Fluid administration or an inotrope may be more appropriate than a vasoconstrictor.
Adrenaline:
Adrenaline is the archetypal adrenergic drug and the most important drug in real emergencies. It is out of favour in intensive care because it is associated with more acidosis and possibly worse outcomes. β2 activity potententiates the glycolytic pathway and increases lactate production. The tachycardia and inotropism increases myocardial oxygen consumption.
Receptors: α1, β1 and β2
Noradrenaline
More than just a vasoconstrictor, noradrenaline is still the drug most commonly used to increase vascular tone, though fluid status must always be ascertained and corrected first.
It differs from adrenaline mainly at the β2 receptor, so it lacks vasodilatory properties and, in sicker hearts that rely on β2 agonism, it is a less effective inotrope.
Receptors: α1 and β1
Isoprenaline
There is no vasoconstriction with this drug but it is a very powerful inotrope that results in unfettered tachycardia. Therefore, it is mostly used to treat bradycardia.
Receptors: β1 and β2
Dopamine
Dopamine is a natural catecholamine and precursor of the others. There are still many who believe its effects on dopaminergic receptors gives it a special place in renal protection. Others believe that the associated hyperprolactinaemia and immune deficiency is responsible for increased mortality. It seems to be coming back into favour on mainland Europe.
Receptor: α1 and β1
Dobutamine
Dobutamine is a relatively β1-selective agonist, used for cardiac stress testing. It causes less tachycardia than isoprenaline for a given degree of inotropy because of its α activity, which generates inotropy directly and causes bradycardia indirectly through the baroreflex. It is the first choice of inotrope in many general ICUs.
Receptors: α1 and β1
Match the receptors to their effects.
Vasopressin (Fig 1), also known as arginine vasopressin (AVP), Pitressin® and antidiuretic hormone (ADH), differs from oxytocin (Fig 2) in only two amino acids.
Substituting the arginine for the unnatural dextro-arginine slows its enzymatic destruction, and deaminating the terminal cysteine affects receptor affinity. This is desmopressin (Fig 3) (DDAVP®).
When the glycine tail is enzymatically cleaved, the remaining peptide is identical to porcine vasopressin, with the substitution of lysine for arginine again slowing its breakdown in humans. This is terlipressin (Fig 4) (Glypressin®).
In normal circumstances the function of vasopressin is to regulate plasma osmolarity. It has little effect on blood pressure. However, in hypovolaemic shock, the plasma concentration increases markedly and contributes to the restoration of blood pressure. When osmolarity increases, plasma vasopressin concentration increases in step, but when blood volume reduces there is little effect until loss is significant, approximately 10% of blood volume, after which plasma vasopressin concentration increases exponentially
Therapeutic vasoconstriction
Vasopressin, and particularly terlipressin, have a clear place in the management of bleeding from oesophageal varices. Portal venous pressure is reduced by splanchnic vasoconstriction.
The use of vasopressin as a vasoconstrictor is not routine practice in other situations. Noradrenaline is usually used as first-line therapy, and that drug’s inotropic action may bring advantages, but it may also increase pulmonary vascular resistance. Vasopressin has been advocated as the vasoconstrictor of choice in patients with pulmonary hypertension.
Vasopressin also has been used in haemorrhagic shock, cardiac arrest, hypotension after cardiac surgery and sepsis, without finding a clearly defined place. Many would regard a low dose of vasopressin (0.5-1 units/hour) as a reasonable way to allow a reduction in intense adrenergic therapy, but survival data are lacking.
Other uses
Desmopressin, rather than vasopressin, is used to treat diabetes insipidus of extrarenal origin.
Its effects on clotting factors has prompted efforts to reduce perioperative bleeding, but results have been inconsistent and there are suggestions that it may have adverse effects on outcome.
Regarding the pharmacology of inotropes and vasoconstrictors:
A. α-adrenoceptor stimulation causes bradycardia in healthy individuals
B. Vasopressin is vasoconstrictive in all vascular beds
C. Noradrenaline is a powerful inotrope
D. A phosphodiesterase inhibitor usually increases blood pressure
E. A slow bolus of levosimendan usually increases blood pressure in patients with cardiac failure
A. True. The hypertension from increased systemic vascular resistance (SVR) causes a bradycardia through the baroreflex.
B. False. Vasopressin receptors are not found in the pulmonary vasculature.
C. True. Noradrenaline is a potent β1 agonist.
D. False. PDE inhibitors increase cardiac output but the decrease in SVR usually leads to a reduction in blood pressure. They are often given in combination with noradrenaline.
E. False. As with PDE inhibitors, the increase in cardiac output is insufficient to outweigh the reduction in SVR. This is especially obvious with bolus administration.
Levosimendan is the first of a new class of inotropes, although it is also categorized as an inodilator. Its primary action is as a ‘calcium sensitizer’ within the myocardium. It binds to calcium-saturated troponin C and stabilizes the complex, inhibiting troponin I effects. This facilitates actin-myosin crossbridge formation and improves myocardial contraction.
During diastole, when intracellular calcium concentrations are reduced, levosimendan dissociates from troponin C and relaxation is unimpeded. Its main metabolite has similar pharmacological actions so a 24-hour infusion of levosimendan has an effect for several days. Levosimendan is also vasodilating, being an antagonist of the adenosine triphosphate (ATP)-associated potassium channel and a phosphodiesterase III inhibitor. This is particularly noticeable during bolus administration.
The drug is extremely expensive and prospective, randomized trials have been small so its clinical value is not yet clear. Evidence of benefit is probably better for levosimendan than other inodilating drugs. However, there is no clear improvement in survival
Which of the following are modifiable and non-modifiable risk factors?
Match the drugs to the descriptions.
Give an overview of the Classifications for Antiarrhythmic Drugs, with relevance to anaesthetics.
There are four mechanisms of arrhythmia generation:
Enhanced normal automaticity
Abnormal automaticity
Triggered activity
Re-entry (circus movement)
Describe the cardiac action potential
Briefly describe the mechanisms of arrhythmia generation
List the methods of classifying antiarrhythmics
Explain the benefits and problems with each classification method
The normal cardiac potential consists of up to five phases. Each phase is vulnerable to one of four methods of arrhythmia generation
Abnormal cardiac electrophysiology promotes the development of arrhythmias
As there are several mechanisms of arrhythmia development, a number of antiarrhythmic drug classification systems have arisen
The most common system is the Vaughan-Williams system but it is not all encompassing. Perhaps the most clinically useful system is based on clinical efficacy. The Sicilian Gambit is the most recent attempt at bringing drug action together at all levels of action
Question: How many phases does the cardiac action potential have?
The rapid depolarization of action potentials is made possible by fast, voltage-gated sodium channels. These exist in three states: closed, open and inactivated, as determined by the status of the voltage-controlled activation and inactivation gates that lie in the channel of the ion-selective pore. At rest, the activation gate is closed and the inactivation gate open (Fig 1a). When excitation causes sufficient depolarization to open the activation gate, sodium ions pour down the concentration gradient into the cell and raise the trans-membrane potential (Fig 1b), but when the potential becomes too positive the inactivation gate closes, terminating depolarization (Fig 1c).
The process of repolarization is a delicate balance between dozens of pumps moving Na+, K+, Cl- and Ca2+ ions. There is much more opportunity here for physiological control of the action potential, e.g. in response to a change in heart rate, but also more situations where disease and drugs can affect it.
When repolarization is achieved, the activation gate of the fast sodium channel closes and the inactivation gate opens, changing the state of the channel from inactivated to closed, ready to generate the next action potential
There are five phases of the cardiac action potential, from phase 0 to phase 4.
Depolarization is the result of the net inward movement of positively charged ions. Repolarization occurs from net outward movement of positively charged ions.
The ion fluxes are different in non-pacemaker (Fig 1) and pacemaker cells (Fig 2) but the overall ion movement is the same.
Phase 0 - Rapid depolarization
The depolarizing stimulus raises the resting membrane potential from -90 mV to -65 mV. At this point the threshold potential has been reached and an ‘all or none’ action potential response occurs.
Subsequently, the rapid inflow of sodium ions (Na+) raises the transmembrane potential from -65 mV to +20 mV
Phase 1 - Initial repolarization
This is the early steep part of repolarization. The voltage-gated Na+ inward current terminates rapidly when the membrane potential becomes sufficiently positive. The phase 1 ‘notch’ in the action potential is caused by activation of transient outward K+ and inward Cl- currents
Phase 2 - Plateau phase
This is produced by a balance between the inward movement of calcium ions through slow calcium channels (L-type) and slow outward movement of K+ ions
Phase 3 - Repolarization
Shown by the downward curve, the calcium influx slows and the cell starts to repolarize.
The rapid period of repolarization is from outward potassium movement down its concentration gradient through open K+ channels.
This is the relative refractory period
Phases 3 and 4 - Resting potential
The resting membrane potential is re-established by two K+ moving inwards for every three Na+ moving outwards to give a net outward movement of positive charges
Automaticity is the property of cardiac fibres to initiate a spontaneous impulse.
Question: Automaticity results from depolarization during which phase
Automaticity results from depolarization during Phase 4 secondary to an inward Na+ current.
This slow depolarization can be enhanced by a number of factors e.g. adrenergic stimulation. Examples include inappropriate sinus tachycardia and atrial tachycardia.
Ventricular tachycardia may be treated by:
A. Amiodarone
B. Lidocaine
C. Verapamil
D. Flecainide
E. Digoxin
A. True.
B. True.
C. False.
D. True.
E. False.
Verapamil and digoxin are used to treat supraventricular tachycardias.
Flecainide, like lidocaine, can be used for ventricular tachycardias but can also be used for junctional re-entry tachyarrhythmias.
Clinical efficacy, as a classification system divides drugs into the type of arrhythmia they can affect.
Generally, arrhythmias are classified as:
Supraventricular, or
Ventricular
Note however, that some drugs may act on both types of arrhythmia (Table 1).
This is a simple classification that may allow the selection of a drug once the diagnosis is made.
Regarding the Sicilian Gambit:
A. The Sicilian Gambit is based on the clinical effect of the drug
B. Molecular targets in this classification include Na+ channels
C. Muscarinic receptors are targets for antiarrhythmic drugs
D. α-adrenoceptors and β-adrenoceptors are examples of second messengers
E. Some antiarrhythmic drugs target pumps and carriers
A. False. It is based on the molecular target of the drug.
B. True.
C. True.
D. False. These are receptors of the autonomic nervous system.
E. True.
Antiarrhythmics interact with cellular structures that alter electrophysiological function. The cellular structures are:
- Ion channels
These are large glycoproteins that span the membrane bilayer and, when stimulated, allow ions to cross the membrane rapidly to create an ion current.
The channels may carry inward currents, e.g. Na+ or Ca2+ or outward currents, e.g. K+.
- Pumps/carriers
Pumps are involved in the active transport of ions across the cell membrane e.g. Na+/K+-ATP pump and calcium pump.
Carriers are membrane proteins that facilitate exchange of ions or substrates or pumps them using energy.
Examples of cardiac cell carriers are the Na+/Ca2+ counter transport system and the Na+/K+/Cl- cotransporter.
- Receptors
The autonomic nervous system (ANS) is an important regulator of the cardiac rhythm.
The ANS receptors include:
α-adrenoceptors
β-adrenoceptors
Muscarinic M2 cholinergic receptors
Purinergic A1-receptors
- Cytoplasmic regulators of second messengers
By regulating second messengers, molecules may influence ionic currents within the cell.
The second messengers thought to be involved include:
Cyclic adenosine monophosphate (cAMP)
Inositol trisphosphate (IP3)
Diacylglycerol (DAG)
This classification is known as the Sicilian Gambit and was provided by the European Society of Cardiology as an alternative to the Vaughan-Williams classification.
Regarding the classification of antiarrhythmic agents:
A. Class I agents are beta-blockers
B. Lidocaine is a calcium channel blocker
C. Amiodarone is a class 4 agent
D. Class V agents include digoxin and adenosine
E. Sotalol belongs to class II and III
A. False. Class 1 agents are sodium channel blockers.
B. False. Lidocaine is a sodium channel blocker.
C. False. Amiodarone is a class 3 agent.
D. True.
E. True.
Antiarrhythmic drugs comprise many different drug classes and have several different mechanisms of action. Furthermore, some classes, and even some specific drugs within a class, are effective with only certain types of arrhythmias. Therefore, attempts have been made to classify the different antiarrhythmic drugs by mechanism.
Although different classification schemes have been proposed, the first scheme (Vaughan-Williams) is still the one that most physicians use when describing antiarrhythmic drugs. There are five classes described in the classification (Table 1).
Regarding the induction of hypotension:
A. Autoregulation maintains flow in cerebral, coronary and renal circulations down to a MAP of about 50 mmHg
B. NO acts directly on vascular smooth muscle through activation of GC, which converts mADH2 to cGMP
C. SNP is contraindicated in heart failure
D. In practice, most vasodilators affect both the arterial and venous circulation
E. Haemophilia is a condition where induced hypotension carries a significant risk
A. True.
B. False. NO acts directly on smooth muscle through activation of double GC which converts GTP to cGMP.
C. False. SNP is useful in heart failure.
D. True.
E. False. Conditions where induced hypotension carries significant risks include: ischaemic heart disease, cerebral vascular disease, peripheral vascular insufficiency, pregnancy and anaemia.
It is generally accepted that a MAP as low as 50-60 mmHg is tolerated well in healthy patients (Fig 1). Autoregulation maintains flow in the cerebral, coronary and renal circulations through a MAP range of 50-140 mmHg in healthy patients, but evidence that hypertension, and also diabetes and age, shift this curve to the right is weak and confounded by the effect of treatment with different classes of antihypertensive medication.
However, conditions where induced hypotension carries significant risks include:
Ischaemic heart disease
Cerebral vascular disease
Peripheral vascular insufficiency
Pregnancy
Anaemia
The effect of hypotension on individuals may thus be unpredictable.
Agents used to induce hypotension are divided into groups based on their site of action:
Direct vasodilators
α-adrenergic blockers
β-blockers
Opioids
Calcium antagonists
α2 adrenoceptor agonists
Anaesthetic agents
Ganglion blockers
A 45-year old woman presents for removal of a phaeochromocytoma. Her preoperative medication includes phenoxybenzamine and labetalol. During the operation she becomes hypertensive with a heart rate of 60 and many ventricular ectopics.
Which is the single most appropriate agent to control her blood pressure?
A. Esmolol
B. Sevoflurane
C. Magnesium
D. Phentolamine
E. Hydralazine
A. Incorrect.
B. Incorrect.
C. Correct.
D. Incorrect.
E. Incorrect.
This is a patient undergoing surgery for phaeochromocytoma. She is already both α-blocked and β-blocked with phenoxybenzamine and labetalol, respectively, so esmolol and phentolamine offers little extra to this control, although some doctors still use phentolamine.
Both phentolamine and hydralazine are likely to reduce the blood pressure but do nothing to suppress the ectopic beats. The most appropriate choice is magnesium. This produces the best control of blood pressure using a rapidly acting agent that can be manipulated independently of depth of anaesthesia.
Magnesium is the 4th most plentiful cation (after Na, K, Ca) in the body. The ionised fraction is physiologically active. An arteriolar vasodilator with minimal effects on the venous circulation.
Magnesium has proven particularly useful in the management of blood pressure during surgery for phaeochromocytoma
2 ml, 5 ml and 10 ml ampoules of of 50% magnesium sulphate are available.
2 ml = 1 g = 4 mmol MgSO4.
A loading dose of 40-60 mg/kg of the sulphate followed by an infusion of 1-2 g/h, is designed to achieve serum magnesium concentrations between 2-4 mmol/L.
Magnesium is a physiological antagonist of calcium at the presynaptic adrenergic terminal and in vascular smooth muscle cells.
Magnesium exerts a direct depressant effect on myocardial and vascular smooth muscle. It inhibits the release of catecholamines from the adrenal medulla and peripheral adrenergic terminals, and directly blocks catecholamine receptors. As a result, cardiac output and vascular tone are reduced, resulting in hypotension and decreased pulmonary vascular resistance.
Other effects include antiarrhythmic activity, anticonvulsant activity, muscle weakness, bronchodilation, respiratory muscle weakness, reduced uterine tone and impaired platelet activity.
Phaeochromocytomas are neoplasms of chromaffin tissue that synthesise catecholamines. Symptoms include the classic triad of headache, palpitations, and sweating. Hypertension is present in around 90% of cases, although it is paroxysmal in 35-50% of these (Fig 1).
Preoperative medical therapy focused on reducing the physiological impact of excess circulating catecholamines.
There is no universally accepted regimen and clinical practice varies. Combined α- and Β-adrenergic blockade is the most commonly implemented strategy.
Alpha blockade is initiated first
For patients with tachycardia or arrhythmias, beta blockade is typically added cautiously several days before surgery. The Β-adrenergic blocker should never be started before the α blocker as further elevation in blood pressure and even cardiac failure can be precipitated by blockade of vasodilatory peripheral Β2-adrenergic receptors with unopposed α-adrenergic stimulation
Calcium channel blockers, e.g. nicardipine, are sometimes used to supplement combined alpha and beta blockade
Describe the pharmacology of Therapeutic Antihypertensives, and the relevance to anaesthetsia.
Describe the pharmacology of commonly used antihypertensive drugs
Describe how to manage hypertensive patients presenting for elective surgery
Hypertension is important as it may lead to end-organ damage and can increase cardiovascular risk
NICE guidelines suggest management of hypertension with lifestyle modifications and the following medications:
ACEI/ ARB
Calcium channel blockers
Diuretics
AAGBI guidelines aim to prevent the diagnosis of hypertension being the reason that planned surgery is cancelled or delayed
The AAGBI have published guidelines for the measurement of adult blood pressure and the management of hypertension before elective surgery 6.
These aim to ensure that patients admitted to hospital for elective surgery are known to have blood pressure below 160 mmHg systolic and 100 mmHg diastolic in primary care. Secondary care should not attempt to diagnose hypertension in patients who are normotensive in primary care.
In patients with no documented primary care blood pressure, elective surgery should proceed if clinic blood pressures are below 180 mgHg systolic and 110 mmHg diastolic.
Give an overview of the pharmacology of anticoagulants, and relevance to anaesthetics.
describe the physiology of the clotting cascade
describe the classification and pharmacology of anticoagulants
explain the reversal of anticoagulation
The clotting cascade is a complex process which forms a clot with the integration of clotting factors and platelets.
With an appropriate stimulus, for example breaching of a vessel wall, the clotting factors get activated and follow 2 distinct enzymatic pathways, namely intrinsic and extrinsic, to form non-soluble fibrin mesh.
With the incorporation of platelets, the definitive clot is formed.
This pathway can get activated in a number of pathological conditions such as deep vein thrombosis, pathologies of cardiac valves, atrial fibrillation, cancers and during post-surgical period.
Drugs which include heparin, LMWH, warfarin and direct oral anticoagulants are invented and designed to overcome these problems.
Individual pharmacokinetic and pharmacodynamic properties govern the administration of these drugs at different scenarios and for different patients.
Give an overview of the clotting cascade.
Classically, the pathways of coagulation activation were defined as shown in Figure 1:
the intrinsic pathway, known as the contact pathway
the extrinsic pathway, known as the tissue factor pathway
A description of each of these pathways appears on the following tabs.
Because these pathway definitions came about as the result of laboratory testing, the roles of individual clotting factors were more discretely defined, while platelets and the role of natural anticoagulants and clot lytic pathways were not included. However, in vivo, all the factors interact to achieve coagulation.
The intrinsic pathway is activated when factor XII (Hageman factor) is exposed to tissues after damage, or contact with negatively charged surfaces or substances such as glass surfaces.
The pathway can be prompted by damage to the tissues, resulting from internal factors such as arterial disease. However, it is most often initiated when factor XII comes into contact with foreign materials, such as when a blood sample is put into a glass test tube. This in turn activates factor XI (anti-haemolytic factor C or plasma thromboplastin antecedent), which activates IX and VIII.
Finally, factor VIII (anti-haemolytic factor A) from the platelets and endothelial cells combines with factor IX (anti-haemolytic factor B or plasma thromboplasmin) to form an enzyme complex that activates factor X (Stuart-Prower factor or thrombokinase), leading to the common pathway.
Activation of the extrinsic pathway begins when damage occurs to the surrounding tissues, such as in a traumatic injury. Upon contact with blood plasma, the damaged extravascular cells, which are extrinsic to the bloodstream, release factor III (thromboplastin).
Sequentially, Ca2+ then factor VII (proconvertin), which is activated by factor III, are added, forming an enzyme complex.
This enzyme complex leads to activation of factor X (Stuart-Prower factor), which activates the common pathway.
The events in the extrinsic pathway are completed in a matter of seconds.
Regarding parenteral anticoagulants:
A. Protamine sulphate is equally effective as an antidote for haemorrhaging caused by heparins and LMWHs
B. Heparins do not cross the placenta or enter breast milk
C. Due to their narrow therapeutic window, heparins and LMWHs need to be monitored by the activated partial thromboplastin time
D. Unfractionated heparin forms a complex with antithrombin III in the inactivation of factors IXa, Xa, XIa and XIIa
E. LMWH inactivates factor Xa to a greater extent (4 times greater) than heparins
A. False.
B. True.
C. False.
D. True.
E. False.
Heparins and LMWH target factors 11a, 9a, 7a and 2a.
Vitamin K antagonists target factors 11, 7, 10 and 2.
Direct thrombin inhibitors target factor 2a.
Factor 10a inhibitors target factor 10a.
The main use of parenteral anticoagulants is to prevent thrombus formation or extension of an existing thrombus in the slower-moving venous side of the circulation, where the thrombus consists of a fibrin web enmeshed with platelets and red cells.
They have little or no intrinsic anticoagulant activity, and exert their anticoagulant activity by potentiating antithrombin (AT), an endogenous inhibitor of various activated clotting factors.
Doses of anticoagulants differ based on their activity and indication and the weight of the patient. Standard texts such as the BNF, as well as local guidelines, must be followed when prescribing.
Heparin and its derivatives (unfractionated heparin (UFH), low-molecular-weight heparins (LMWH), fondaparinux, heparinoids) act by potentiating antithrombin, which is an endogenous inhibitor of various activated clotting factors. Hirudin, bivalirudin and argatroban act by directly inhibiting thrombin.
Heparin Also called UFH
LMWHs:
Dalteparin sodium
Enoxaparin sodium
Tinzaparin sodium
Fondaparinux
Heparinoids Danaparoid sodium
Direct thrombin inhibitors
Hirudin
Bivalirudin
Argatroban
Warfarin:
A. Is a vitamin K antagonist
B. Specifically inhibits epoxide reductase enzyme
C. Is metabolised by the microsomal P450 enzyme
D. All of the above
D. All of the above
Warfarin competitively inhibits the vitamin K epoxide reductase complex 1 (VKORC1), which is an essential enzyme for activating the vitamin K available in the body.
Warfarin can deplete functional vitamin K reserves and therefore reduce the synthesis of active clotting factors. The hepatic synthesis of coagulation factors II, VII, IX, and X, as well as coagulation regulatory factors protein C and protein S, require the presence of vitamin K.
Indications are:
mechanical cardiac valves (after replacement)
atrial fibrillation, DVT, pulmonary embolism (as for DOAC)
Loading dose Day 1: 10mg
Day 2: 5mg
Day 3: 5mg
Monitoring INR usually between 2 and 3
Check INR day 4
Day 7 onwards: check INR twice weekly and adjust dose
For DVT and PE
Dalteparin: od sc injection (dose is weight dependent)
Continued until INR is in therapeutic range on 2 consecutive days
he most common side-effects related to warfarin treatment include:
alopecia
diarrhoea
nausea and vomiting, abdominal pain, bloating
rash
minor bleeding or bruising
The most serious adverse effect related to warfarin treatment is the risk of major bleeding. A meta-analysis of warfarin studies in AF found the incidence of major bleeding varied from 1.4 to 3.4% per year. The risk of bleeding is greater in patients recently initiated on warfarin and is related to the degree of anticoagulation, meaning that bleeding risk increases significantly with INR results >5.0.
The BNF and British Society of Haematology (BCSH) guidelines recommend vitamin K to reverse anticoagulation in patients whose INR is excessive.
arfarin interacts with many other drugs. It has a narrow therapeutic range.
Drugs may:
Potentiate the effect of warfarin
Examples of drugs which potentiate the effect of warfarin include:
allopurinol
disulfiram
azole antifungals (ketoconazole, fluconazole)
omeprazole
paracetamol (prolonged regular use)
propafenone
amiodarone
tamoxifen
methylphenidate
zafirlukast fibrates
statins
erythromycin
sulfamethoxazole
metronidazole
Antagonise the effect of warfarin
Examples of drugs which antagonise the effect of warfarin include:
barbiturates
primidone
carbamazepine
griseofulvin
oral contraceptives
rifampicin
azathioprine
phenytoin
Alcohol
Acute ingestion of a large amount of alcohol may inhibit the metabolism of warfarin and increase INR. Conversely, chronic heavy alcohol intake may induce the metabolism of warfarin. Moderate alcohol intake can be permitted.
Regarding heparin:
A. It affects the coagulation pathway mainly by binding to antithrombin; it has no antiplatelet activity
B. It binds to antithrombin and increases the inactivation of clotting factors
C. It inhibits the vitamin K dependent carboxylation of glutamate residue of clotting factors
D. Haemorrhage and heparin induced thrombocytopenia are the commonest adverse drug reactions occurring after heparin therapy
E. LMWH is only partly reversed by protamine
F. Unlike warfarin, the INR is not a good indicator of action of LMWH; the APTT ratio is far more reliable
G. Heparin-induced thrombocytopenia can occur after the first dose of heparin as it is not dose-dependent
A. False.
B. True.
C. False.
D. True.
E. True.
F. False.
G. True.
Heparin works as a catalyst for the natural anticoagulant antithrombin (Figure 1). It acts by:
inhibition of factor X, then by inhibition of XII, XI, IX, VIII, V with incremental doses
inhibition of platelet adhesion to vWF
activation of lipoprotein lipase, which reduces viscosity of blood and stagnation
When monitoring, test APTT for lower doses, and activated clotting time (ACT) for high-dose, for example in cardiothoracic surgery.
Reversal is achieved with protamine sulphate, a basic protein derived from fish sperm that binds to heparin to form a stable salt. This is cleared from the circulation with a half-life of about 7 minutes, therefore an infusion may be necessary.
The indication for heparin is a requirement for anticoagulation in various medical and surgical settings, such as acute limb ischaemia, post-vascular surgery, cardiopulmonary bypass and on extracorporeal lines.
The advantage of heparin is that its action is short-lasting with a half-life of 1 hour, and it can be easily reversed with protamine. However, in certain conditions, such as prevention and secondary treatment of deep vein thrombosis (DVT) and post-myocardial infarction, heparin has recently been replaced by LMWH and direct oral anticoagulants (DOACs), which have more predictable action, greater ease of administration and which do not require monitoring.
Regarding direct oral anticoagulants:
Select true or false for each option, then select Submit.
Multiple rows with several possible answers per question
Question True Result False Result
A. The bioavailability of rivaroxaban is considerably increased on taking it on an empty stomach
B. Rivaroxaban, apixaban and dabigatran are factor Xa inhibitors
C. There is currently no reversal agent for apixaban
D. Andexanet alfa is a recombinant form of human factor Xa protein which binds specifically to dabigatran
E. DOACs have a predictable anticoagulant effect and are administered at a fixed dose, they do not require routine monitoring
A. False.
B. False.
C. False.
D. False.
E. True.
Direct oral anticoagulants (DOACs) include:
rivaroxaban
dabigatran
apixaban
edoxaban
Rivaroxaban, apixaban and edoxaban inhibit platelet activation and fibrin clot formation via direct, selective and reversible inhibition of factor Xa (Figure 1). A dose-dependent inhibition of factor Xa activities is observed with rivaroxaban. All these drugs influence antifactor Xa activity. Additionally apixaban inhibits free and clot-bound factor Xa.
As a result all these drugs may prolong PT, aPTT and HepTest.
These drugs directly bind to the active site of factor Xa, thereby inhibiting both free and clot-associated factor Xa. These drugs also inhibit prothrombinase activity.
Dabigatran etexilate is a prodrug that is converted to the active dabigatran in vivo. Dabigatran is a specific reversible direct thrombin inhibitor.
Table 1 describes the pharmacokinetics of these drugs.
Discuss the management of a patient on a DOAC requiring surgery
In an acute emergency procedure when you need to operate within minutes, begin with blood sampling, including full coagulation panel with PT, aTPP, anti-FXa, dTT, for example. Then proceed to reversal of NOAC (if necessary, available or approved). Then proceed to operation, then repeat the coagulation panel, then finally targeted haemostatic intervention based on coagulation panel results and clinical picture.
In an urgent procedure when you need to operate within hours, begin with blood sampling, including full coagulation panel with PT, aTPP, anti-FXa, dTT, for example. Then, if deferral of surgery for 12 to 24 hours is not safe, change to the acute emergency procedure management. If deferral of surgery for 12 to 24 hours is safe, defer and repeat the coagulation panel. If there is a relevant residual effect, begin the urgent procedure management from the start. If there is no residual effect, proceed to operation and then finally targeted haemostatic intervention based on coagulation panel results and clinical picture.
In an expedited procedure when you need to operate within days, begin with blood sampling, including full coagulation panel with PT, aTPP, anti-FXa, dTT, for example. Then, if deferral of surgery is not feasible as for planned interventions, change to the urgent procedure managements. If deferral of surgery is feasible as for planned interventions, proceed to a multidisciplinary decision, based on patient and surgical factors.
Give an overview of antiplatelet agents, and the relevance to anaesthetics.
Recall basic facts about platelets
Explain the key pharmacological points about antiplatelet drugs
Describe how to manage patients presenting for surgery while taking antiplatelet drugs
Antiplatelet drugs are useful in a number of specific patient groups including patients:
With history of stroke or TIA
With ACS
With coronary stents
Who are post-coronary artery surgery
With 10-year cardiovascular risk of >20%
There are many sites of action of antiplatelet drugs including:
COX inhibition
P2Y12 receptor blockade
Phosphodiesterase inhibition
GP IIb/IIIa receptor antagonism
Perioperative management may involve stopping a drug for a minimal period, depending on the balance between the risk of surgical bleeding if it is continued and the risk of thrombosis if it is stopped
Identify the correct site of action for each of the drugs listed.
COX-1 inhibitor
Irreversible P2Y12 inhibitor
Reversible P2Y12 inhibitor
PDE inhibitor
GP IIb/IIIa inhibitor
A. Abciximab
B. Aspirin
C. Clopidogrel
D. Dipyradimole
E. Eptifibatide
F. Prasugrel
G. Tirofiban
H. Ticagrelor
Risk factors for VTE include:
A. Pelvic surgery
B. Obesity
C. Asthma
D. Recent long-haul air travel
E. Hypertension
A. True. These patients are high risk.
B. True. BMI >30 is a weak risk factor.
C. False.
D. True. Any air travel in the month pre-surgery or post-surgery increases risk.
E. False.
Patient and surgical factors can increase VTE risk (Table 1) 3, and these risks are additive. For example:
Patients should be warned that air travel 4 weeks before surgery increases the risk of postoperative VTE
In fact, any long-haul journey increases the risk of DVT 4. See ‘DVT prevention for travellers’ in the NICE Clinical Knowledge Summaries.
Air travel is also associated with a greater risk of VTE for up to 4 weeks after surgery
Patients taking an oral contraceptive should consider stopping it for 1 month prior to surgery, although this only reduces VTE risk if pregnancy is avoided
Several organizations have published guidelines on reducing the risk of VTE, e.g. NICE 5, the Scottish Intercollegiate Guidelines Network 6, the American College of Chest Physicians 7,8 and the Royal College of Obstetricians and Gynaecologists 9. They universally recommend that all surgical inpatients should be individually assessed preoperatively and informed of their risk of developing VTE, and that thromboprophylaxis should be discussed.
Details vary, but most Trusts have their own protocols, usually based on the NICE guidelines. NICE recommends that patients having day surgery under general anaesthesia should be managed in the same way as inpatients. Not all surgery presents the same risk to patients (Table 2) 8. Procedures under local anaesthetic with no subsequent impairment of mobility do not require VTE prophylaxis.
The advantages of LMWH over unfractionated heparin include:
A. Lower incidence of thrombocytopaenia
B. More accurate laboratory monitoring
C. Reduced hospital stay
D. Fewer bleeding complications
E. More reliable dose-response relationship
A. True.
B. False. Laboratory monitoring of LMWH is actually harder, but fortunately is not required.
C. True. As the LMWH may be administered at home by the patient or district nurse.
D. True. LMWHs are safe and cause no excess bleeding.
E. True.
LMWHs also consist of a variable number of alternating glucuronic acid and N-acetyl glucosamine residues. However, clinical preparations have about only 4-30 residue-length oligomers with mean MW 4 500 daltons.
LMWHs produce indirect inhibition of FXa by enhancing antithrombin III (ATIII) activity by a factor of 1 000 (Fig 1). They lack the long chain of disaccharide units present on unfractionated heparin and needed to bring thrombin and antithrombin together and so generate little anti-thrombin activity; this gives them a more predictable pharmacokinetic profile.
LMWHs, unlike unfractionated heparin, do not significantly alter the APTT and do not require laboratory monitoring.
Side-effects: As for unfractionated heparin although the incidence of thrombocytopenia and osteoporosis is very much less. Bleeding is still a concern although less frequent than with unfractionated preparations.
The key target in thromboprophylaxis is to prevent clot formation and propagation.
Unfractionated heparin is a glucosaminoglycan consisting of a variable number of alternating glucuronic acid and N-acetyl glucosamine residues. Clinical preparations have about 20-60 residue-length oligomers with mean MW 12 000 daltons.
The main action of heparin is indirect inhibition of thrombin, FIXa and FXa by binding to and enhancing antithrombin III (ATIII) activity by a factor of 1000 (Fig 1). Antithrombin binds to the activated factors and blocks their active site. Heparin also enhances the activity of other inhibitors including tissue factor pathway inhibitor (TFPI).
Side-effects: bleeding; thrombocytopenia; abnormal hepatic transaminase levels; osteoporosis (long term therapy only). Unlike warfarin, heparin is not teratogenic as it does not cross the placenta.
Fondaparinux:
A. Is a direct-acting thrombin inhibitor
B. Has potent direct anti-Xa activity
C. Has potent indirect anti-Xa activity
D. Can be given orally
E. Is given at a dose of 10 mg, once daily for thromboprophylaxis
A. False.
B. False.
C. True.
D. False. Fondaparinux is given subcutaneously.
E. False. The dose is 2.5 mg daily.
Fondaparinux is a synthetic pentasaccharide that resembles part of the heparin molecule to which ATIII binds. This binding enhances ATIII activity. It is approved by NICE for thromboprophylaxis.
Like heparin, it is a potent indirect inhibitor of FXa acting by enhancing ATIII activity. Unlike heparin, it has no effect on thrombin activity. It appears at least as effective as the LMWHs and may be used as an alternative. Unlike heparin, it does not induce thrombocytopenia.
It has a half-life of about 17 hours so is given once a day, the first dose given six hours post surgery.
Dose: 2.5 mg subcutaneously once daily. Duration of therapy: Nine days following knee surgery and four weeks following hip fracture surgery.
You want to insert an epidural for postoperative analgesia on a patient undergoing surgery. The patient is receiving LMWH thromboprophylaxis. How long after the previous dose should you wait before epidural insertion?
A. 4 hours
B. 12 hours
C. 24 hours
D. When the INR is <1.5
E. When the APTT is 35-45 seconds
A. Incorrect. This is the correct time to wait for patients receiving unfractionated heparin.
B. Correct.
C. Incorrect. This is how long you should wait before inserting an epidural in a patient receiving therapeutic dose LMWH, or twice daily prophylaxis.
D. Incorrect. For patients on warfarin the INR should be <1.5 before regional anaesthesia is performed. The INR is not a measure of LMWH activity.
E. Incorrect. APTT measures unfractionated, not low molecular weight, heparin activity.
Central neuraxial blockade reduces the incidence of postoperative DVT. However, these blocks are contraindicated in patients who are coagulopathic or anticoagulated because of the risk of vertebral canal haematoma.
The risk of spinal haematoma is estimated to be 1 in 150 000 epidural anaesthetics and 1 in 220 000 spinal anaesthetics. It is higher in those who have received drugs that impair coagulation.
Patients receiving LMWH thromboprophylaxis can have neuraxial blocks. To reduce haematoma risk, these should be timed to occur when coagulation status is optimal (Table 1 and Table 2) 13.
Regarding fluid distribution and the glycocalyx model:
A. Isotonic fluid distributes within the ECF and the ICF
B. Colloid osmotic forces act between the intravascular and interstitial spaces
C. In health, hydrostatic forces are the sole determinants of the direction of fluid movements
D. The space between the glycocalyx and the endothelial cells is rich in protein
E. Increasing protein concentration in the plasma reduces tissue oedema
A. False. Isotonic fluid distributes only in the ECF. (Glucose 5% is isotonic but metabolism of the glucose component renders it effectively hypotonic and then the water component equilibrates between ICF and ECF).
B. False. Colloid osmotic forces act between the intravascular and sub-glycocalyx spaces.
C. True.
D. False. The space between the glycocalyx and the endothelial cells is protein free, which creates a colloid osmotic gradient between it and the plasma.
E. False. As long as the glycocalyx is intact, fluid cannot be drawn from the interstitial space into the plasma under colloid osmotic forces. Therefore, increasing protein concentration in the plasma does not reduce tissue oedema.
Some inconsistencies can be explained by the realisation that the composition of the interstitial space is not constant. For instance, if acute haemorrhage reduces the capillary pressure, fluid will indeed pass into the capillary, but in doing so the interstitial hydrostatic pressure will reduce while the osmotic pressure will increase as interstitial proteins are concentrated, opposing further flow. Conversely, the transient transfer fluid to the interstitium caused by an acute rise in capillary pressure will reduce the interstitial osmotic pressure and increase the interstitial hydrostatic pressure, thus restoring the status quo.
However, the revolution in understanding has come with the discovery of the endothelial glycocalyx.
The discovery of a glycocalyx layer between the endothelial cells and the plasma (Fig 1) necessitates a revision of Starling’s model 1, 2. The layer is formed from a mesh of glycoproteins and proteoglycans (protein structures with polysaccharide side chains such as syndecan-1) with embedded glycosaminoglycans (long, hydrophilic polysaccharide chains such as chondroitin and heparan) that give the layer bulk. It is similar to the layer covering the scales of fish. The name has Greek origin: glyco for sweet, calyx for husk (coating).
This endothelial glycocalyx layer is impermeable to proteins. It ultrafilters fluid driven out of the capillary by hydrostatic pressure and leads to a protein free sub-glycocalyx space with no colloid osmotic pressure. This sub-glycocalyx space is only a potential space because the colloid osmotic pressures in its surroundings (the capillary lumen and the interstitial space) keep it dry. The glycocalyx offers resistance to flow that explains why equilibration of crystalloid infusions between the intravascular and interstitial spaces is longer than expected. Dye penetrates into the glycocalyx but red cells do not, explaining the difference in intravascular volume derived by the two dilution techniques.
In the revised model, osmotic forces cannot draw fluid from the interstitium to the vascular compartment because of the intervening sub-glycocalyx space. Osmotic effects will tend to drive fluid from the sub-glycocalyx space into both the capillary lumen and the interstitial fluid. As a consequence, the hydrostatic pressure gradient is the sole determinant of the direction of fluid movement across the capillaries. Osmotic forces do nevertheless act to oppose outward movement of fluid from the intravascular space. The steady-state relationship between capillary pressure and filtration rate into the interstitium differs markedly from the traditional Starling model, but it is in agreement with experiment (Fig 1).
The above considerations apply to ‘typical’ capillary endothelium, but some specialised tissues are different. For example, endothelium in hepatic sinusoids have discontinuities in the glycocalyx and fenestrations in the endothelium that allow equilibration between plasma and interstitial fluid, and capillaries in the kidney are able to continuously reabsorb interstitial fluid.
Give an overview of intravenous fluids, and the relevance to anaesthetics.
Describe the rational use of intravenous fluids for plasma volume expansion
Explain the physiology of fluid distribution
Compare crystalloids and colloids as plasma volume expanders
Choose an appropriate fluid type based on available evidence, cost and side-effects
Explain how to give a safe, dynamically-assessed fluid challenge
Optimal fluid resuscitation involves giving the right fluid type in the right volume at the right time
Both crystalloids and colloids are equivalent plasma volume expanders in hypovolaemic patients
Large meta-analyses do not favour one fluid type over another, although recent doubts have been cast over the safety of colloids in intensive care
It is advisable to choose a fluid type that minimises the chloride load and takes into account other recognised adverse effects and cost
Fluid challenges should involve rapid infusion of small volumes, titrated to physiological endpoints appropriate for the clinical setting
Patients with evidence of tissue hypoperfusion who are unresponsive to fluids should be discussed with the critical care team
Regarding fluid dynamics in different clinical contexts:
A. In hypovolaemic patients, initial fluid resuscitation leads to a negligible rise in capillary hydrostatic pressure
B. In hypovolaemic patients, plasma expansion with colloids is superior to crystalloids
C. In health, plasma expansion with crystalloids is inferior to colloids
D. Damage to the glycocalyx layer increases the risk of tissue oedema formation
E. In critical illness, the glycocalyx layer can be disrupted
A. True.
B. False. In hypovolaemic patients, plasma expansion with crystalloids and colloids are equivalent.
C. True. The glycocalyx offers only modest resistance to crystalloids so they equilibrate with the ECF, while colloids are retained within the vascular lumen.
D. True. Damage to the glycocalyx reduces resistance to crystalloid flow into the ECF, flooding the interstitial space faster than lymph flow can remove it. Retention of colloid within the vascular lumen is also impaired, and extravasated colloid will aggravate oedema formation.
E. True. This may explain high fluid requirements and tissue oedema.
Volunteers
Healthy volunteers for physiological experiments have capillary pressure greater than the infection point of the curve in Fig 1. Crystalloid infusions increase capillary pressure further and fluid is lost more rapidly from the circulation into the interstitial space (t½ about 8 min, slower than the expectations of classical physiology because of the resistance of the glycocalyx). Thus, within half an hour, the infused fluid is spread throughout the extracellular space. The modest volume expansion is short-lived as it is eliminated from the body as urine (t½ approx. 30 minutes).
In this situation, most of a colloid infusion remains within the circulation, making colloid a more effective volume expander than crystalloid solutions, and volume is eliminated more slowly (t½ 2 or 3 hours).
Anaesthetised patients
Anaesthetised patients have reduced capillary pressure with minimal fluid efflux to the interstitium. This effect is likely to be due to the accompanying hypotension than the level of consciousness or the drugs used. Plasma expansion with small volumes (3 ml.kg-1) of intravenous fluids is unlikely to raise capillary pressure significantly so, in this situation, equal volumes of crystalloids and colloids have a similar duration of effect on volume expansion which is prolonged (t½ 3-6 hours) compared to volunteer studies. However, larger volumes of crystalloid will diffuse to the interstitium, and the expansion of interstitial fluid by very large crystalloid infusions may change the visco-elastic properties of the gel matrix, increasing the interstitial compliance, aggravating oedema formation and making the oedema more refractory to treatment.
Ill patients
Capillary endothelium in inflamed tissue forms large pores that increase fluid conductance, and inflammatory cytokines cause the structural proteins of the interstitial matrix to relax, increasing interstitial compliance and so reducing interstitial pressure. The glycocalyx is also damaged by proteases, as indicated by the presence of syndecan-1 and glycosaminoglycans in plasma.
Damaged glycocalyx allows large molecules to pass and its resistance to fluid transfer is reduced. Fluid passes into the interstitial space at a rate that exceeds the capacity of the lymphatic system, resulting in tissue oedema. Furthermore, colloid molecules diffuse into the interstitial tissue, increasing its capacity to retain fluid and delaying resolution of oedema.
The endothelial glycocalyx can be damaged by sepsis, hyperglycaemia and possibly even by the rapid infusion of intravenous fluids. Experimental measures to minimise injury to the glycocalyx or restore its function include the use of volatile anaesthetics, hydrocortisone and the infusion of glycosaminoglycans.
Regarding histamine:
A. It is made up of an imidazole ring and an amino acid side chain
B. It is an acidic molecule
C. It acts to decrease bronchial mucosal secretions
D. It is produced via the carboxylation of histidine
E. Histamine release from mast cells is mediated via Ig
A. True.
B. False. Histamine is a basic molecule
C. False. It increases bronchial mucosal secretions; therefore, a side-effect of some antihistamines is to decrease bronchial secretions
D. False. Histamine is produced from histidine via histidine decarboxylase, therefore it is decarboxylated not carboxylated. As we can see from A above, histamine contains an imidazole ring and amino acid side chain, there is no carboxylic acid group attached
E. True.
Histamine is an organic nitrogen compound (Fig 1a) made up of:
An imidazole ring (Fig 1b)
An amino acid chain (Fig 1c)
Each part of the molecule has a potentially unprotonated nitrogen atom and thus histamine is a base.
The two sites have a different pKa; that of the imidazole ring is 5.8 and of the amino acid chain is 9.4 (Fig 1d). Therefore, at physiologic pH, histamine is partially protonated.
Endogenous histamine is produced mainly in mast cells and basophils.
Histidine, an amino acid, is decarboxylated to histamine under the influence of histidine decarboxylase. The histamine so produced is stored in granules within mast cells and basophils.
These cells are found in large numbers at sites within the body that are subject to invasion by foreign material and injury, notably the respiratory tract, the gut, blood vessels and skin.
Non-mast cell histamine is also found in the brain and in enterochromaffin cells within the stomach.
Histamine can also be produced by bacteria found in perishable foods, particularly dark-meat fish. Consumption of contaminated products results in a condition known as scombroid poisoning. This is frequently confused for a seafood allergy as symptoms include rapid facial flushing, urticaria, diarrhoea and in severe cases bronchospasm, airway oedema and distributive shock.
Certain foods and drinks naturally contain histamine due to the fermentation process of bacteria or yeast, examples include fermented cabbage and radish, soybean paste, yogurt, cheese, ketchup, wine, and beer.
Histamine release from mast cells occurs mainly through immunologic mechanisms.
IgE antibodies result from prior exposure to an antigen. Antigens can then bind to existing IgE antibodies that are attached to the mast cell membrane (Fig 1a).
Antigen binding leads to mast cell degranulation and the release of histamine (Fig 1b).
Some substances, e.g. morphine, can cause direct release of histamine from mast cells.
The histamine released then exerts its effects by binding to histamine (H) receptors.
Four subtypes of H receptor have been identified: H1, H2, H3 and H4. This session focuses on the effects mediated via the H1 receptor and their treatment, however the effects of the other receptors are summarised in Table 1.
H2 receptors
These are primarily involved with gastric acid secretion and gastrointestinal motility.
H3 receptors
These are mainly located in the CNS and act to modulate the activity of other neurotransmitters.
H4 receptors
These are thought to play a role within the immune system by influencing the activity of eosinophils and mast cell recruitment to form part of an inflammatory response.
Regarding antihistamine pharmacokinetics:
A. Chlorphenamine is 70% protein bound in plasma
B. Cyclizine has an oral bioavailability of 33%
C. Promethazine is poorly absorbed orally therefore is usually administered intravenously
D. Loratadine undergoes hepatic metabolism predominantly via CYP2B6 and CYP2C9
E. Fexofenadine is mostly excreted unchanged in faecesGi
A. True.
B. False. This value is much higher at 75 - 80%. Cyclizine is absorbed well orally with a high bioavailability and can also be administered intramuscularly and intravenously.
C. False. Promethazine is well absorbed orally, however it has a high first pass metabolism giving an oral bioavailability of 25%. It is often administered orally for sedation, and can also be given intramuscularly or intravenously.
D. False. The main enzymes responsible for the metabolism of loratadine are CYP3A and CYP2D6.
E. True. 80% is excreted unchanged in the faeces and 12% unchanged in urine.
Give an overview of antihistamines, and the relevance to anaesthetics.
Explain the role of histamine within the body as well as its specific biochemistry, manufacture, storage and mechanisms of release
Describe the location, mechanism of activation, signalling and effects of stimulation of the H1 histamine receptor as well as the H2 H3 and H4 histamine receptors
List the indications for the use of antihistamines as well as their side-effects
Give examples of commonly-used antihistamine medications and describe the classification system
Describe the mechanism of action of commonly used antihistamines and their pharmacokinetics
List the advantages of the newer generations of antihistamines over first-generation antihistamines
Histamine binds to histamine receptors causing a wide range of effects depending on the type and location of the receptors
H1 histamine receptors are one of four subtypes of histamine receptor. They are predominantly found in vascular endothelium along with smooth muscle cells of the respiratory and gastrointestinal tracts
H1 histamine receptors show constitutive activity. They are able to activate the intracellular signalling pathway in the absence of a histamine ligand
Antihistamine drugs are inverse agonists. They are mainly indicated for the treatment of IgE-mediated type-1 hypersensitivity reactions
First-generation antihistamines are subdivided into five groups. They all cross the blood-brain barrier and can cause drowsiness
Second-generation antihistamines are more specific for peripheral H1 receptors. They generally do not enter the CNS to a significant level to cause the unwanted side-effects associated with the first-generation agents
Regarding histamine receptors:
A. H1 receptors are absent from the CNS
B. The H1 receptor is a Gs-protein-linked receptor
C. The effects of H1 receptor activation are mediated by the phospholipase C and phosphatidyl-inositol (PIP2) pathway
D. In the absence of ligand binding, H1 receptors are present in both active and inactive states
E. The overall effects of H1 receptor activation by histamine are due to resulting activation of Protein Kinase A
A. False. H1 are found in many systems within the body including in the CNS, thus accounting for their sedative side-effects.
B. False. The H2 receptor is a Gs-protein-linked receptor whereas the H1 receptor is a Gq-protein-linked.
C. True.
D. True. This is termed constitutive activity. Histamine binding favours the active state and antihistamine binding favours the inactive state.
E. False. This would be true of the H2 receptor however as discussed in question c above, H1 receptors activate phospholipase C and PIP2, this pathway overall results in an increase in intra-cellular calcium and protein kinase C (not A).
H1 receptors are found in many organs within the body.
They are expressed by endothelial cells and smooth muscle cells, as well as being found within the central nervous system (CNS).
There are large numbers in the respiratory tract, notably in the upper airways, on vascular endothelium and in the ileum of the gut.
Histamine binds to the H1 histamine receptor. Activation of these receptors causes effects dependant on the organ in which the receptors are located.
The H1 receptor is a Gq-protein-linked receptor (Fig 1a).
Its effects are mediated via the phospholipase C and phosphatidyl-inositol (PIP2) pathway (Fig 1b).
PIP2 is broken down to inositol triphosphate (IP3) and diacylglycerol (DAG) (Fig 1c).
In turn, the IP3 leads to calcium release from the endoplasmic reticulum and the DAG leads to activation of protein kinase C (Fig 1d).
Generally, activation of the H1 receptor leads to an increase in intracellular calcium with the effects being dependent on the cell type expressing the H1 receptor.
The two states of the H1 receptor, active and inactive, are in equilibrium.
Activity in the absence of histamine is known as constitutive activity.
The presence of histamine alters the equilibrium in favour of receptor activation.
All H1 antihistamines that have been examined to date are not antagonists but are inverse agonists (Fig 1), i.e. they bind to the H1 receptor and induce a change that increases the stability of the inactive form.
Therefore, all H1 antihistamines reduce the constitutive activity and decrease activation by histamine.
Activation of these receptors causes effects dependant on the organ in which the receptors are located.
These effects include vasodilatation, capillary leakage and oedema, bronchoconstriction, nausea and vomiting as well as alteration of sleep pattern, itching and pain.
These effects are all part of the body’s normal defence mechanism. When they become exaggerated in hypersensitivity they lead to a variety of pathological states, including anaphylaxis.
Clinical expression of H1 receptor activation depends on which receptors are affected and to what extent.
Clinical pictures cover a wide spectrum. At one end is allergic rhinitis, in which vasodilatation and capillary leakage leads to a blocked or runny nose and histamine receptors in the conjunctiva and on nerve endings in nasal passages cause itchy eyes and sneezing.
At the other end of the spectrum widespread receptor activation leads to profound vasodilatation, tachycardia and bronchospasm, all of which are characteristic of anaphylaxis.
Each of these drugs act via different mechanisms, but have the same end-point, which is to relax smooth muscle in the walls of bronchi. Can you identify the site of action of each class of drug?
β2 agonists act at a membrane receptor to increase the activity of adenylyl cyclase, which breaks down ATP to cAMP. This second messenger pathway leads to bronchodilation.
Acetylcholine acts at a membrane receptor to inhibit adenylyl cyclase (via a Gi protein), as well as bronchoconstricts via a Gq protein. Blocking muscarinic receptors therefore results in bronchodilation.
Phosphodiesterase breaks down cAMP. Drugs that inhibit this enzyme will therefore increase levels of cAMP and cause bronchodilation.
Give an overview of drugs that act on the respiratory system, and the relevance to anaesthetics.
Identify how drugs target the respiratory system based on a functional classification
Describe the molecular mechanisms of drug actions on the respiratory system
List the commonly used drugs and indications for their use
Drugs can affect the respiratory system in a number of ways. Useful therapeutic targets include airways, pulmonary blood vessels, respiratory control mechanisms and inflammatory mediators
Besides the treatment of acute asthma, anaesthetists may use these drugs to improve oxygenation and ventilation in the seriously ill patient
An understanding of the molecular mechanisms of the drugs allows a rational approach to their use, and a knowledge of predictable side-effects
The lungs’ unique position of receiving the entire cardiac output causes them to be exposed to a host of cellular and humoral mediators that are released into the bloodstream. Many of the inflammatory mediators have the common effects of bronchoconstriction, airway oedema and excess mucus production, which are central to common conditions such as asthma, sinusitis and allergic rhinitis.
Question: Can you name some classes of drug that may modify these diseases by their action of blocking production and/or effect of these mediators (there are at least four)?
Leukotriene receptor antagonists (LTAs)
Cromoglicate
Antihistamines
IgE monoclonal antibodies
Drag the drugs to the diseases that they are used to treat, then select Submit.
At which ‘functional level’ do the following drugs act?
Give an overview of the pharmacology of Drugs used in the treatment of acute asthma, and the relevance to anaesthetics.
Classify the severity of acute asthma according to the British Thoracic Society Guidelines
Describe a structured approach in the management of acute asthma
Describe the pharmacological mechanism of action of the most common drugs used in the management of acute asthma
Describe the alternative drug therapies that can be instituted in the critical care environment
Acute asthma must be assessed early, and risk stratified early
Acute asthma requires early and aggressive treatment with early review by critical care specialists
Pharmacological management aims to provide bronchodilatation and must be instigated in a stepwise protocolised manner
Constant reassessment is required to identify and treat any deterioration
The autonomic nervous system (ANS) is key to understanding why certain drugs are used in asthma. This is explored further in this session. However, try to answer these questions to check your current knowledge.
Regarding the autonomic nervous system:
A. It is made up of the parasympathetic and sympathetic nervous system
B. The sympathetic nervous system is responsible for bronchoconstriction
C. The parasympathetic nervous system is responsible for digestion
D. The parasympathetic nervous system neurotransmitters are exclusively noradrenaline and acetyl choline
E. The sympathetic nervous system acts upon nicotinic and muscarinic acetyl choline receptors exclusively
A. True.
B. False. The sympathetic nervous system is responsible for bronchodilatation.
C. True.
D. False. The parasympathetic nervous system does not use noradrenaline as a neurotransmitter.
E. False. The sympathetic nervous system acts upon nicotinic, muscarinic and adrenergic receptors.
The sympathetic nervous system has both paravertebral and prevertebral ganglia where the preganglionic nerves synapse.
The postganglionic neurones leave the ganglia to synapse with the target organ using noradrenaline as their neurotransmitter at the adrenoceptor.
Adrenoceptors can be classified as either alpha or beta adrenoceptors. Each adrenoceptor has a different function depending on its site and subtype
The parasympathetic nervous system originates from cranial nerves III, VII, IX and X and with nerves from spinal origin of S2-S4.
The preganglionic neurones are much longer compared to the sympathetic nervous system and synapse within ganglia that are situated close to their target organs.
The postganglionic neurones synapse with the target organ, onto muscarinic acetylcholine receptors using acetylcholine as the neurotransmitter
The effects of the parasympathetic and sympathetic receptors are summarised in 11:
Alpha receptors:
α1
Vascular smooth muscle
Vasoconstriction
α2
Central nervous system
Sedation
Analgesia
Beta receptors:
β1
Platelets
Heart
Platelet aggregation
Increased heart rate and contractility
β2
Bronchi
Vascular smooth muscle
Uterus
Relaxation of smooth muscle resulting in bronchodilatation and uterine relaxation
β3
Adipose tissue
Lipolysis
Muscarinic receptors:
Muscarinic 1 receptors
Brain
Secretory glands
Increased secretion of secretory organs
Muscarinic 2 receptors
Mainly in the heart
Modulates pacemaker activity
Reduces inotropy
Vasodilatation
Muscarinic 3 receptors
Smooth muscles of the bronchioles and arterioles
Mediates coronary artery vasodilatation
Regulates heart rate
Bronchoconstriction
Muscarinic 4 receptors
Mainly in the central nervous system
Regulate actions on potassium and calcium channels in CNS
Muscarinic 5 receptors
Mainly in the central nervous system
Regulate dopamine release
You have been asked to review a Stephen, a 37-year-old gentleman in the Emergency Department (ED), who has presented with acute onset shortness of breath.
Stephen has asthma and is known to the respiratory physicians in your hospital. When you arrive, Stephen is sat forward in the tripod position and appears anxious and very tachypnoeic. He is struggling to complete sentences in one breath.
Stephen’s observations are as follows:
Respiratory rate (RR) 30 breaths/minute
Peripheral oxygen saturations (SpO2) on room air 94%
Heart rate (HR) 105 beats/minute
Blood pressure (BP) 135/70
Temperature 36.7°C
Based on the above observations, what severity is Stephen’s acute asthma attack?
A. Moderate acute asthma
B. Acute severe asthma
C. Life-threatening asthma
D. Near fatal asthma
A. Incorrect. He is clearly more severe than this.
B. Correct. Based on a respiratory rate >25 breaths/minute and inability to complete sentences in one breath.
C. Incorrect. He does not have any features of acute severe asthma at this stage.
D. Incorrect. He does not have any features of acute severe asthma at this stage.
Give an overview of drugs that act on the GI tract, and the relevance to anaesthetics.
Classify the commonly used drugs that affect the GI tract
List the common use of such commonly-used drugs in daily clinical practice
List the advantages and contraindications of using these drugs in certain group of patients
Explain how to safely prescribe/administer these drugs in daily clinical practice
Proton pump inhibitors irreversibly block the proton pump and can achieve complete achlorohydria
Ranitidine is contraindicated in porphyria
Domperidone does not cross the blood-brain barrier and hence does not cause extra pyramidal side-effects
Sucralfate has no systemic effects but can reduce absorption of certain drugs by direct binding
Misoprostil is a uretrotonic and is also used in treatment of NSAID-induced ulcers
Which of these can be safely given to a patient with porphyria?
A. Ranitidine
B. Metoclopramide
C. Omeprazole
D. Cimetidine
A. Incorrect.
B. Incorrect.
C. Correct.
D. Incorrect.
All except omeprazole have potential to precipitate an acute porphyria attack.
Proton pump inhibitors (PPIs) are used for similar indications to that of H2 receptor antagonists but also in cases where H2 blockade may be insufficient. PPIs irreversibly block proton pump (K+/H+ ATPase) which mediates the gastric acid secretion in the parietal cell
Omeprazole irreversibly blocks the proton pump and hence achieves complete achlorohydria.
It is available as oral and IV formulation.
Table 1 lists its effects.
Omeprazole is a prodrug which becomes active within the parietal cell. It undergoes complete hepatic metabolism by cytochrome P450 to inactive metabolites, which are excreted in the urine (80%) and bile (20%).
It inhibits CYP2C19 which converts clopidogrel to its active form thereby reducing the anti-platelet effect of clopidogrel.
Oral dose is 20 mg once daily or IV 40 mg if oral contraindicated.
Lansoprazole is used as an alternative to omeprazole.
Dose is 15-30 mg OD.
Lansoprazole does not accumulate and its pharmacokinetics are unaltered by multiple dosing. The absorption of lansoprazole is rapid, with mean Cmax (peak serum concentration) occurring approximately 1.7 hours after oral dosing, and relatively complete with absolute bioavailability over 80%.
It is useful in treatment of severe oesophagitis due to its faster relief of symptoms than omeprazole.
It is cost-effective as compared to other PPIs.
It is prepared as gastro-resistant capsules or oro-dispersible tablets. This formulation is particularly useful in NG/PEG fed patients especially in critical care.
Try to match the neurotransmitters to their receptor sites.
Vagal afferents
5HT3, NK1
VN
mACh, H1, NK1
AP/CTZ
nACH, D2, 5HT3, NK1
NTS and VC
mACH, H1, D2, 5HT3, NK1
Vagal efferents
mACH
There are different pathways to vomiting. Please complete the pathways below.
PONV may act via multiple pathways:
Opioids and volatile anaesthetics cause PONV via stimulation of the CTZ.
GIT stimulation will act via the vagus nerve.
Patient anxiety will act via the higher cortex centres.
What are the pathways that involved in vomiting?
Vomiting is controlled by the vomiting centre, which is stimulated through different pathways acting in isolation or together. A number of different neurotransmitters are involved in each pathway. These include:
acetylcholine:
muscarinic (mACh)
nicotinic (nACh)
histamine 1 (H1)
dopamine 2 (D2)
serotonin (5-HT3)
neurokinin-1 (NK1)
The different pathways are the:
chemoreceptor trigger zone
The chemoreceptor trigger zone (CTZ), which is located within the area postrema at the base of the fourth ventricle, lies outside of the blood-brain barrier, and is therefore able to detect toxins, metabolites and drugs circulating in the blood and cerebrospinal fluid (CSF). The CTZ also receives input from vagal afferents in the GI tract. It projects into the nucleus tractus solitarius and vomiting centre.
nucleus tractus solitarius
The nucleus tractus solitarius (NTS), which is located within the area postrema and lower pons, receives inputs from the CTZ, vestibular and limbic systems.
vomiting centre
The vomiting centre controls a number of coordinated processes via efferent fibres leading to vasomotor, respiratory and salivary nuclei.
higher centres
It is poorly understood how the higher centres trigger vomiting.
First, assess baseline risk. The strategy for management of PONV will include non-pharmacological and pharmacological options.
Non-pharmacological management
Non-pharmacological management includes care with bag-mask ventilation to avoid gastric distension, minimising movement of patient, and ensuring adequate hydration.
Pharmacological management
Pharmacological management can be thought of in terms of which drugs to minimise patient exposure to (opioids and volatile anaesthetics), and which drugs to give (antiemetics).
Regional anaesthesia and/or TIVA
Regional anaesthesia and/or TIVA are options for management of patients with high risk of PONV, allowing for minimal opioids and potentially avoiding volatile anaesthetics and N2O.
Prophylaxis or acute treatment
Antiemetics may be used in the prophylaxis or acute treatment of PONV. A number of antiemetic agents can be used in combination for patients with higher risk of PONV.
Joan is a 28-year-old woman who is listed for a laparascopic cholecystectomy. She had a general anaesthetic 4 years previously for a laparoscopic appendicectomy and reports PONV following her anaesthetic, which delayed her discharge from recovery. She is a non-smoker and has type 1 diabetes mellitus with reasonable control, and no established end organ damage.
Question: What is Joan’s risk of PONV?
Question: How might you consider managing her PONV?
Joan has a number of risk factors for PONV:
Female
Non-smoker
History of PONV
She has a 60% chance of experiencing PONV, increased to 80% if you choose to use opioids for analgesia
Given her high risk for PONV, prophylaxis should be considered, and a number of antiemetics given in combination should be used.
As she is a diabetic, caution should be exercised when considering using dexamethasone. Dexamethasone has been shown to raise the blood glucose level in both diabetics and non-diabetics, with a greater increase seen in the former.
Avoiding volatile anaesthetic agents by using TIVA may be an option.
Risk factors for PONV can be thought of as falling into one of three categories: patient-related, anaesthesia-related, or surgery-related (Table 1).
Incidence of PONV reduces with age in the adult population; in the paediatric population children over 3 have a higher incidence of PONV than those under 3 years of age.
Multivariable analysis has allowed for the development of tools to predict a patient’s risk of PONV, and thus guide the anaesthetist’s choice of strategy for managing PONV. The Apfel simplified score uses only 4 factors to predict a 10%, 20%, 40%, 60% or 80% risk of PONV, depending on the presence of 0, 1, 2, 3 or 4 factors respectively (Table 2).
In children, the risk of postoperative vomiting (POV) is predicted using the score to predict POV in children (POVOC)
You are anaesthetising Samuel, a 5-year-old boy, for a tonsillectomy. He has never had an anaesthetic before, but his mother tells you she had PONV following an anaesthetic for appendectomy a few years ago.
Question: What risk factors for PONV does Samuel have?
Question: Which antiemetics could you consider using in this case?
POVOC is a simplified risk score used to predict the likelihood of PONV in children. Risk factors include:
duration of surgery >30 min
age >3 years
strabismus surgery
history of PONV in the child
history of PONV in the child’s relatives
Incidence of PONV is 9%, 10%, 30%, 55% or 70% with 0, 1, 2, 3 or 4 risk factors present respectively.
While not an independent risk factor for PONV according to POVOC, the Association of Paediatric Anaesthetisits of Great Britain and Ireland advise adenotonsillectomy is associated with increased PONV. They also include use of volatile agents as a risk factor in children.
Answer: Ondansetron should be considered as first-line treatment in children with high risk of PONV.
Dose: 0.1mg/kg up to 4mg maximum.
Given orally or IV: oral dispersible preparation of ondansetron has been found to be well tolerated and efficacious in children.
Dexamethasone is an effective antiemetic in children, and is more efficacious when given in combination with ondansetron.
Dose: 150μg/kg.
Metoclopramide, prochlorperazine and cyclizine are not recommended for the prevention of PONV in children.
Give an overview of the pharmacology of diuretics, and the relevance to anaesthetics.
Classify the diuretics in use
Explain their mechanism and sites of action
List their indications and side-effects
Describe their use in critical care
Diuretics are commonly used in patients after the age of 65 to treat hypertension, liver cirrhosis and heart failure
The main classes of diuretic are: carbonic anhydrase inhibitors, loop, osmotic, thiazide, epithelial sodium channel blockers and aldosterone antagonists
Side-effects pertain mainly to electrolyte disturbances, namely hypokalaemia, hypo- and hypercalcaemia, dysrhythmias and intravascular volume depletion
Acetazolamide is a sulfonamide derivative and a reversible inhibitor of carbonic anhydrase (CA).
Question: What other characteristics do you think acetazolamide may have?
Acetazolamide has demonstrable anticonvulsant properties.
It decreases the intraocular pressure and the pressure in the cerebrospinal fluid (CSF) by decreasing the rate of formation of CSF and aqueous humour by 50-60%.
Acetazolamide causes hyperchloraemic metabolic acidosis because it promotes excretion of alkaline urine. It also decreases the renal excretion of uric acid.
Acetazolamide is a sulfonamide derivative and a reversible inhibitor of carbonic anhydrase (CA) which is present within the cell cytosol and on the brush border of the proximal convoluted tubule (PCT) (Fig 1).
The cells of the proximal (and distal) tubules secrete H+ ions via Na+ -H+ exchange. Extrusion of sodium ions from the cells into the interstitium by Na+ -K+-ATPase lowers intracellular Na+ causing Na+ to enter the cell from the tubular lumen with coupled extrusion of H+. These H+ ions come from intracellular dissociation of carbonic acid (H2CO3) and the HCO3- formed diffuses into interstitial fluid. Hence for each H+ secreted, one Na+ and one HCO3- ion enter the interstitial fluid 1.
Carbonic anhydrase is an enzyme that catalyses the formation of carbonic acid and drugs like acetazolamide, which inhibit this enzyme, depress the secretion of H+ ions into tubular lumen and increase the secretion of HCO3- , Na+ and K+ ions causing alkaline urine. This fall in plasma HCO3- rapidly stimulates CA activity which then leads to tolerance to the action of acetazolamide 2. Its use as a diuretic is therefore now obsolete.
Side-effects
These can include:
metabolic acidosis
nephrolithiasis
paraesthesia
nausea and vomiting
anorexia
taste disturbances
hypokalaemia
Kinetics
Acetazolamide is secreted into the proximal tubule by organic acid transporters (OAT) and works at the luminal surface of the tubule. It has a half-life of 6-9 hours and is eliminated unchanged in the urine
Acetazolamide is well absorbed from the GI tract, reaching nearly 100% bioavailability via this route. It is 70-90% protein-bound in plasma.
Special points
Use is contraindicated in the presence of hepatic and renal failure because it worsens metabolic acidosis and promotes urolithiasis.
It is removed by haemodialysis and has been successfully used in critically-ill patients to correct metabolic alkalosis.
Other uses
Other uses for acetazolamide include:
glaucoma
prophylaxis and treatment of altitude sickness
Ménière’s disease
periodic paralysis
certain forms of epilepsy
Furosemide is a sulphonamide derivative that inhibits the Na+/K+/2Cl- co-transporter (NKCC2) in the thick part of the ascending loop of Henle by attaching to its Cl- binding site. It is safe to use in patients with allergies to sulphonamide antibiotics.
Question: What is caused by this inhibition?
It causes reduction of the tonicity of the renal medulla and production of hypotonic or isotonic urine. The renal blood flow (RBF) is increased and corticomedullary flow improved with blood being diverted from the juxtaglomerular region to the outer cortex. At a cellular level this is exerted via inhibition of Na+/K+/ATPase or by inhibition of glycolysis.
Loop diuretics
These are powerful diuretics that inhibit the reabsorption of as much as 25% of glomerular filtrate. They act on the thick ascending loop of Henle, inhibiting the Na+/K+/2Cl- carrier (NKCC2) in the luminal membrane by combining with the Cl- binding site (Fig 1). In the normal situation, one molecule of K+ and two molecules of Cl- are reabsorbed along with each molecule of Na+ via the NKCC2 carrier.
This causes reduction in:
the efficiency of the counter-current multiplier system
the hypertonicity of the medulla
tubuloglomerular feedback
the reabsorption of water in the collecting system
Other characteristics include that:
it is used in the treatment of salt and water overload associated with:
acute pulmonary oedema
chronic heart failure
liver cirrhosis complicated by ascites
nephrotic syndrome
renal failure
treatment of hypercalcaemia after correction of plasma volume
For reasons not fully understood, furosemide causes a therapeutically useful reduction in systemic and pulmonary vascular resistance before the onset of its diuretic action (hence its use in pulmonary oedema). After IV administration, diuresis occurs within a few minutes and lasts for about 2 hours. After oral administration, diuresis occurs within 1 hour and lasts 4-6 hours.
Side-effects
These include:
hypokalaemia (this may increase the toxicity of drugs like digoxin and Type 3 antiarrhythmic medications)
hypocalcaemia
hypomagnesaemia
hyponatraemia (sodium loss exceeding water loss)
hypochloraemic metabolic alkalosis
hyperuricaemia (which may precipitate acute gout)
dose-related hearing loss (especially when combined with an aminoglycoside). This is because it inhibits NKCC2 (as well as other enzymes) in the stria vascularis of the inner ear
Kinetics
Furosemide is highly protein-bound (96%), metabolised in the kidney to glucuronide and excreted either unchanged (80%) or as glucuronidated furosemide. Its elimination half-life is 45-90 minutes. It is not removed by dialysis.
In nephrotic syndrome, loop diuretics become bound to albumin in the tubular fluid and may not be able to act on NKCC2 and so this is a cause of diuretic resistance.
Mannitol is a low molecular weight sugar alcohol, typically made from fructose and hydrogen, containing one hydroxyl group (-OH) attached to each carbon atom. It acts as an osmotic diuretic, antioxidant and free radical scavenger. It does not cross an intact blood brain barrier.
Question: How does mannitol act?
It acts by increasing the osmolality of the glomerular filtrate and tubular fluid, thereby increasing urinary volume. Its main action is to reduce the CSF volume and pressure, by decreasing the rate of CSF formation, and by withdrawing the brain’s extracellular water across the blood-brain barrier. Because it increases circulatory volume, it is contraindicated in congestive cardiac failure and pulmonary oedema.
Osmotic diuretics are pharmacologically inert substances that are freely filtered at the glomerulus but not reabsorbed, leading to an increase in the osmolarity of the filtrate (Fig 1). To maintain osmotic balance, water is retained in the urine. Thus they have an intraluminal site of action.
The most well-known example is mannitol.
Mannitol causes a small increase in cardiac output and systolic blood pressure by expansion of plasma volume. Renal blood flow is increased with diuresis occurring within 1-3 hours after administration. Serum Na and K may decrease.
Kinetics
Mannitol is not metabolised in humans. It is excreted unchanged in urine with elimination half-life of 70 minutes.
Absorption from the small bowel is 17.5%
Special points
Blood products should not be administered with mannitol.
A total adult dose of over 3g/kg/day may produce a serum osmolality greater than 320mOsm/L.
Rebound increase in intracranial pressure (ICP) may occur after discontinuation of therapy.
Other Uses
Other uses for mannitol include:
reduction of pressure and volume of cerebrospinal fluid
acute glaucoma
treatment of rhabdomyolysis
to improve diuresis in transplanted kidneys
bowel preparation prior to lower GI surgery
Bendroflumethiazide exhibits its diuretic and antihypertensive action by inhibiting sodium chloride co-transport in the DCT.
Question: What does this inhibition result in?
Inhibition of Na+ reabsorption results in increased urinary excretion of Na+, K+ and H2O. The increased Na+ load in the DCT tends to stimulate the exchange with K+ and H+ causing hypokalaemic, hypochloraemic metabolic alkalosis.
Structurally similar to sulphonamides, thiazides are a class of organic molecules that contain adjacent sulphur and nitrogen atoms on one ring (benzothiadiazine). They act on the early segment of the distal convoluted tubule where it inhibits the Na+/Cl- co-transporter, thus preventing Na+ and Cl- from entering the tubular cell (Fig 1). Thiazides have a lower efficacy than loop diuretics, achieving a maximum natriuresis of about 8% of filtered sodium load 2. Thiazide diuretics reduce preload and also cause vasodilatation via an unknown mechanism and thus they are used in the management of essential hypertension.
Examples of thiazide diuretics include Bendroflumethiazide and hydrochlorothiazide. Thiazide-like diuretics do not have a benzothiadiazine structure but they nevertheless act on the Na+/Cl- co-transporter such as chlortalidone, indapamide and metolazone.
Bendroflumethiazide causes a decrease in plasma volume and also acts as a vasodilator. In toxic doses it can act as a central nervous system depressor. It decreases renal blood flow and can cause reduction in the glomerular filtration rate. It decreases the excretion of Ca2+ and increases excretion of Na+, K+, and Mg2+.
These drugs can cause an increase in blood sugar concentration by promoting glycogenolysis and reducing the rate of glycogenesis and insulin secretion.
Bendroflumethiazide and uric acid are secreted by the same mechanism in the renal tubules, which is why this competition leads to reduced uric acid excretion and, by increasing plasma levels of uric acid, may precipitate gout. Bendroflumethiazide increases plasma triglyceride and cholesterol concentrations.
Side-effects
These can include:
hyponatraemia (prolonged action of thiazides on DCT, where water cannot be reabsorbed, impairs free water clearance) 2
impotence (in up to 10% of cases)
acute pancreatitis
hyperglycaemia (dose-related effect due to hypokalemia and consequent reduced intracellular K+ inhibiting insulin release)
hypercalcaemia (due to reduced urinary excretion by inhibition of Ca2+ transport in PCT and DCT)
hypokalaemia
Kinetics
Bendroflumethiazide is highly protein-bound (94%) in plasma and is completely absorbed after oral administration. Onset of diuresis is slow but it has longer duration of action than loop diuretics. The natriuretic effect of bendroflumethiazide lasts up to 16-24 hours whereas that of chlortalidone lasts for 72 hours.
Special points
Bendroflumethiazide can cause hypercalcaemia and hypokalaemia and by this mechanism may potentiate the effect of non-depolarising muscle relaxants, predispose to dysrhythmias or precipitate digoxin toxicity.
Hypotension after administration of opioids, barbiturates and halothane can be exaggerated in patients on thiazide diuretics.
NSAIDs antagonise the effects of thiazides.
Other uses
Other uses for bendroflumethiazide include:
hypertension
oedema due to heart failure or nephrotic syndrome
diabetes insipidus
renal tubular acidosis
hypercalciuria
inhibition of lactation
Amiloride is a pyrazinoylguanidine which directly blocks the epithelial Na+ channel at the luminal surface of the DCT.
Question: What is the result of this inhibition?
As a result of the inhibition of the Na+ ion transport, the electrical potential across the tubular epithelium decreases and potassium ion excretion is inhibited. The net result is a slight increase in renal sodium ion excretion and a decrease in K+ ion excretion. Amiloride also decreases the enhanced excretion of magnesium which occurs when a thiazide or a loop diuretic is used alone.
Potassium sparing diuretics
These drugs produce a diuresis without urinary loss of K+. All such drugs act at the late DCT and collecting duct (Fig 1).
Within this category can be found:
epithelial sodium channel blockers such as amiloride and triamterene
aldosterone antagonists such as spironolactone, eplerenone
Amiloride causes a decrease in systolic and diastolic BP, probably by reducing the systemic vascular resistance postulated to occur by reducing the Na+ ion content of arteriolar smooth muscle.
Side-effects
These may include:
hyperkalaemia
alkaline urine and metabolic acidosis due to inhibition of H+ excretion
hyperuricaemia
Kinetics
Bioavailability is 50% with no active drug metabolism in humans.
50% is excreted in urine and 50% in faeces with a half-life of 18-24 hours.
Special points
Amiloride inhibits excretion of co-administered digoxin.
Concurrent NSAID therapy obtunds the diuretic and antihypertensive effect of the drug.
Give an overview of the pharmacology of the drugs acting on the uterus, and the relevance to anaesthesia.
Describe the physiology of the myometrium during labour
List the drugs used to aid uterine contraction and the management of postpartum haemorrhage
List the drugs used to inhibit uterine contraction and the indications for their use
Pregnancy and parturition are controlled by a complex balance of counteracting hormones
Obstetric anaesthetists are required to use uterotonics on a daily basis and must have a good understanding of the pharmacology and the potential adverse effects
Although tocolytics are used much less frequently than uterotonics, they are required in emergency situations. Anaesthetists should therefore be familiar with their use
Can you label the uterine anatomy?
Parturition can be divided into four physiological stage. Describe each of them.
Phase 1 - Functional Quiescence
For the majority of pregnancy, the myometrium is in a state of functional quiescence. This is maintained by the actions of various inhibitors such as:
Progesterone
Prostacyclin
Relaxin
Nitric oxide
Vasoactive intestinal peptide
Parathyroid hormone-related peptide
These inhibitors act by increasing levels of cAMP and cGMP. These inhibit intracellular calcium release, reducing myosin light chain kinase (MLCK) activity which is essential to muscle contraction.
BackgroundPhysiology of Parturition
Parturition can be divided into four physiological stages 1 2.
Select each of the four columns to learn more.
Phase 2 - Myometrial Activation
Myometrial activation occurs during the last 6-8 weeks of pregnancy in response to oestrogen. This involves the upregulation of contraction associated proteins such as:
Prostaglandin and oxytocin receptors
Connexin 43 (a gap junction protein)
Phase 3 - Stimulatory Phase
The stimulatory phase occurs with the onset of labour. Coordinated contractions can now be stimulated in the activated myometrium by:
Uterotonics
Oxytocin
Prostaglandins E2 and F2α
Corticotrophin-releasing hormone (CRH)
Phase 4 - Uterine Involution
Immediately after delivery the uterus has two main aims:
To control bleeding
To revert back to the pre-pregnancy state
Involution of the uterus occurs predominantly in response to the withdrawal of oestrogen and progesterone after delivery of the placenta and the actions of oxytocin (secreted by the posterior pituitary gland) on oxytocin receptors which causes myometrial contraction.
Regarding uterotonics:
A. Ergometrine is contraindicated in asthmatics
B. Misoprostol is a prostaglandin E2α analogue
C. Oxytocin is chemically similar to vasopressin
D. Ergometrine antagonises α2 adrenergic receptors
E. Carboprost is a third line uterotonic in the management of PPH
A. False. Although there have been case reports of ergometrine inducing wheeze, it is not contraindicated, whereas carboprost is contraindicated in asthmatics.
B. True. Misoprostol is a synthetic prostaglandin E2⍺ analogue.
C. True. Vasopressin and oxytocin are chemically similar peptide hormones secreted by the posterior pituitary gland.
D. False. Ergometrine causes hypertension by the agonism of ⍺2 receptors.
E. True. Carboprost should be used third line after oxytocin and Ergometrine (unless ergometrine is contraindicated).
Regarding tocolytics:
A. Sevoflurane has a stronger effect on uterine relaxation than isoflurane
B. Magnesium sulphate should be used to rapidly relax the uterus in an emergency
C. Indomethacin has been associated with causing persistent patent ductus arteriosus in the newborn
D. β agonists work via a G protein-coupled receptor to cause tocolysis
E. Atosiban is an oxytocin receptor antagonist used as a second-line agent for tocolysis in preterm labour
A. True. Sevoflurane and desflurane have a greater uterine relaxation effect than isoflurane.
B. False. Rapid bolus administration of magnesium sulphate is not safe. Volatile anaesthetics and GTN are used in these circumstances.
C. False. NSAIDs have been found to cause premature closure of the ductus arteriosus.
D. True. β2 receptor agonism increases cAMP via G protein-coupled receptor, this leads to inactivation of MLCK via phosphokinase which causes muscle relaxation.
E. True. This is recommended by NICE guidelines (NG 25).
Give an overview of the Principles of Actions of Antimicrobial Drugs, and the relevance to anaesthetics.
Identify differences between human and bacterial cells
Recognize how the different metabolic pathways of human and bacterial cells leads to selective toxicity of antibiotics
Understand the mechanisms of action of different classes of antibiotic drugs
Unique features of microbes, such as the bacterial cell wall, make the best targets for antimicrobial therapy with minimal toxicity
Many processes shared by microbes and humans nonetheless use significantly different enzymes that allow selective inhibition
Of these processes, DNA and protein synthesis are most important for antimicrobial therapy
Antimicrobial resistance is an increasing problem
Identify the differences between human and bacterial cells.
Regarding the selective toxicity of antibiotics:
A. Human cells derive folic acid from their diet
B. Humans have 50S/30S ribosomes so are not affected by antibiotics
C. Bacterial cells use peptidoglycan in their cell walls and human cells do not
D. DNA gyrase is present in human and bacterial cells
A. True.
B. False. Human ribosomes have 40S and 60S subunits whereas bacteria have 30S and 50S subunits.
C. True.
D. False. Human cells, unlike bacteria, do not have DNA gyrase.
How do antibiotics work?
The two methods of antibacterial action are:
- To attack targets present in bacteria but not in human cells (Fig 1b):
Inhibitors of bacterial cell wall synthesis
Inhibitors of folate metabolism
- To attack bacterial physiological and metabolic systems that differ from those in human cells (Fig 1c):
Inhibitors of ribosome function
Inhibitors of nucleic acid synthesis
Give an overview of the pharmacology of antibiotics, and the relevance to anaesthetics.
List the principles of antimicrobial therapy
Describe the mechanism of action of different classes of antibiotics
List which antibiotics are suitable for different sources of infection
List the commonly used antibiotics in anaesthesia and critical care with their mode of action, indication, side-effects and interactions
Explain the principles of antimicrobial stewardship
Basic microbiological knowledge can help identify likely sources of infection and appropriate empirical treatments
Antibiotics may have key drug-drug interactions that should be reviewed when prescribing
Antimicrobial stewardship is everyone’s job and still of vital importance when managing critically-ill patients
Describe each of the following penicillins that are used in critical care.
Amoxicillin
Amoxicillin may be used in combination with gentamicin and metronidazole in either sepsis of unknown origin protocols or intra-abdominal infection.
Benzylpenicillin
Benzylpenicillin is a good choice for pneumococcal pneumonia. It also has meningococcal activity but is not usually first line.
Ampicillin
High-dose ampicillin should be added to cover listeria meningitis in patients with risk factors, e.g. age >50, alcohol use, immunosuppression.
Flucloxacillin
Flucloxacillin is the treatment of choice for S. aureus, although usually teicoplanin or vancomycin will be used until drug sensitivities are known given the risk of MRSA.
The penicillins contain a β-lactam ring that prevents cross-linking of the peptidoglycan cell wall, leading to cell rupture, and are therefore bactericidal.
They are widely used to treat various infections, predominantly pneumonias, skin and soft tissue infections and intra-abdominal infections (either in combination or with a β-lactamase inhibitor such as clavulanic acid or tazobactam).
They are mostly renally excreted but only need dose adjustment at the extremes of renal function.
Their most important adverse event is anaphylaxis. It is important to interrogate a penicillin allergy history given the potential crossover of severe allergy to other antibiotic classes and the limits it can place on the choice of antibiotic therapies.
Other adverse events include GI upset (including C. Diff infection) and cholestatic jaundice.
Regarding different bacterial classifications:
A. Gram-positive cocci in chains are likely to be staphylococci
B. Pseudomonas is a Gram-positive rod
C. Gram-negative bacilli are a common cause of intra-abdominal infection
D. Patients with Gram-negative cocci in blood cultures are likely to require ceftriaxone
E. Patients on critical care with a clinical infection and Gram-positive cocci in blood cultures should receive a glycopeptide
A. False. Staph grow in clusters, streptococci grow in chains.
B. False. It is a Gram-negative rod.
C. True.
D. True. They may have a meningococcal infection.
E. True. They may have an invasive line infection and should be treated with vancomycin or teicoplanin until further microbiological information is known.
Regarding different antimicrobials:
A. Penicillins prevent cross-linking of the peptidoglycan cell wall leading to cell rupture and are therefore bacteriostatic
B. Cefuroxime and meropenem both contain a β-lactam ring
C. Ciprofloxacin acts by preventing DNA replication
D. Macrolides act on folate metabolism pathway
E. A clarithromycin allergy implies a clindamycin allergy
A. False. They are bactericidal.
B. True.
C. True.
D. False. They act on the bacterial ribosome, sulfonamides and trimethoprim act on the folate metabolism pathway.
E. False. They are in different antibiotic classes.
Discuss antibiotics that act on the cell wall
- Penicillins
The penicillins contain a β-lactam ring that prevents cross-linking of the peptidoglycan cell wall, leading to cell rupture, and are therefore bactericidal.
They are widely used to treat various infections, predominantly pneumonias, skin and soft tissue infections and intra-abdominal infections (either in combination or with a β-lactamase inhibitor such as clavulanic acid or tazobactam).
They are mostly renally excreted but only need dose adjustment at the extremes of renal function.
Their most important adverse event is anaphylaxis. It is important to interrogate a penicillin allergy history given the potential crossover of severe allergy to other antibiotic classes and the limits it can place on the choice of antibiotic therapies.
Other adverse events include GI upset (including C. Diff infection) and cholestatic jaundice.
- Cephalosporins
Cephalosporins are similar in structure to penicillins, as they too contain a β-lactam ring and prevent cross-linking of the cell wall leading to rupture.
They are usually renally cleared, except ceftriaxone which has around 50% biliary excretion.
There are 5 current generations of cephalosporins (Table 1).
Examples:
1st gen - Cefalexin, Cephradine
2nd gen - Cefaclor, Cefuroxime
3rd gen - Cefotaxime, Ceftriaxone, Ceftazidime
4th gen - Cefepime
With successive generations:
Gram-positive cover is generally reduced
Gram-negative cover is generally improved
Some third-generation drugs also have anti-pseudomonal activity and moderate anaerobic coverage
Commonly used cephalosporins in critical care are:
Cefuroxime, for pneumonia and UTIs
Ceftriaxone, generally reserved for CNS infections such as meningitis
Ceftazidime/avibactam is a new option for antibiotic resistant infection, particularly intra-abdominal, urinary and pneumonias.
Extended-spectrum β-lactamases (ESBLs) are β-lactamases that hydrolyse third-generation cephalosporins and monobactam antibiotics. ESBLs are most often produced by enterobacteria, such as E. coli.
- Carbapenems
Carbapenems also contain a β-lactam ring. They have a broader spectrum than penicillins and cephalosporins having activity against both Gram-positive and Gram-negative bacteria.
Typically they are not susceptible to β-lactamase enzymes and are hence useful in resistant infection.
They are most commonly used in:
Pneumonia
UTIs
Hospital-acquired intra-abdominal infection
CNS infection as they cross the blood-brain barrier
Meropenem and sodium valproate is an important drug interaction in critical care. Valproate levels can drop precipitously and lead to seizures.
Carbapenemase Producing Enterobacteriaceae (CPE) are becoming more prevalent and proactive infection control is essential given the lack of reliable treatment options.
Again, there may be reticence giving carbapenems to patients with severe penicillin allergy, but the evidence doesn’t seem to warrant this
- Glycopeptides
Glycopeptides are so called because of their composition of glycosylated cyclic non ribosomal peptides. They also inhibit cell wall synthesis but do not contain a β-lactam ring.
They are usually added for MRSA cover clinically and will often be started for Gram-positive cocci whilst awaiting speciation and sensitivity or when a line-infection is suspected.
The most commonly used agents in this class are:
Vancomycin
Vancomycin can be given either as a bolus with a loading dose or as a 24-hourly infusion in critical care. Oral vancomycin is not absorbed and is used in the treatment of C. Diff.
Levels must be monitored, especially in renal dysfunction.
Vancomycin’s main adverse effects are nephrotoxicity, phlebitis and ‘Red Man syndrome’ caused by histamine release (but is not a true allergic reaction and treatment may be restarted at a slower rate after anti-histamine administration if not severe).
Vancomycin resistant enterococci (VRE) is a common multi-drug resistant organism in critical care. It requires strict infection control as treatment is limited to antibiotics such as daptomycin and tigecycline.
Teicoplanin
Teicoplanin has a comparatively high risk of severe allergy (around 1 in 2000) and can be a common cause of post-induction anaphylaxis when used in theatres 4. It must be loaded BD for 4 doses, then given OD.
Discuss smaller classes of antibiotics and their action, as shown in the figure.
Metronidazole
Metronidazole, a nitroimidazole, is added for anaerobic cover for abscesses and aspiration pneumonias. Anaerobes are notoriously difficult to grow in the lab so initiation is on clinical history. Occasionally used against C. Diff infection. It produces a disulfiram type reaction with alcohol.
Clindamycin
Clindamycin, a lincosamide, is usually used in critical care for skin and soft tissue infection. It is particularly useful in necrotising fasciitis and invasive Group A strep infection due to its anti-toxin property. It also has anti-anaerobic properties. It may potentiate the effect of neuromuscular blockade.
Linezolid
Linezolid, an oxazolidone, is used against Gram-positive bacteria including MRSA and VRE. It has good lung penetration and is therefore a good option in staphylococcal pneumonias.
However, linezolid does have many drug-drug interactions and may cause a serotonin-syndrome with drugs such anti-depressants. It can also cause thrombocytopenia after prolonged use (>2 weeks).
Co-trimoxazole
Co-trimoxazole (sulfamethoxazole and trimethoprim) may be used in a number of infections, such as UTIs, but is most often used in Critical Care in PCP/PJP pneumonia in the immunosuppressed.
Diluted in 5% glucose and given QDS, it often requires >1.5 L of IV fluid for treatment doses. This can be avoided by using undiluted down a central line. It is prone to causing serious dermatological reactions including Stevens-Johnson syndrome.
As co-trimoxazole works by inhibiting folic acid metabolism, it must not be prescribed with other folate antagonists such as methotrexate. This interaction risks serious pancytopenia and mucositis.
Daptomycin
Daptomycin, a lipopeptide, is used against resistant Gram-positive bacteria. CK must be monitored throughout treatment as it can cause a rhabdomyolysis and statins therefore must be held.
Fosfomycin
Fosfomycin is a unique antibiotic and is not related to any others. It is currently mostly used as an oral agent for UTIs in the UK but has good Gram-positive and Gram-negative coverage, crosses the blood-brain barrier and has activity against multi-drug resistant organisms. It may be used in its intravenous form more as resistance patterns change.
Colistin
Colistin is often the last resort for resistant bacteria, especially Pseudomonas, Klebsiella and Acinetobacter. It is dosed in units (millions of them).
What are the principles of antimicrobial stewardship?
Stewardship in critical care has several facets including:
Improving diagnostics such as pre-antibiotic culture (including BAL) or rapid pathogen identification using PCR, potentially even as a point-of-care test
Ensuring rapid source control of infections when applicable to supplement antibiotic use
De-escalating antibiotics quickly based on culture results or if infection is deemed unlikely by clinical course, imaging or biomarkers (including procalcitonin)
Reducing infection by limiting invasive-line use, days of mechanical ventilation and cross-contamination between patients
Routine use of antimicrobial stewardship teams consisting of microbiologists, intensivists and pharmacists
Give an overview of antifungal and antiviral drugs, and the relevance to anaesthesia.
Describe the mechanism of action of the different classes of antiviral and antifungal drugs
Understand the principles of prescribing antiviral and antifungal drugs
Describe common side-effects of antiviral and antifungal medication, and be aware of monitoring requirements
Suggest empirical therapy based on likely pathogens
Fungal and viral infections are associated with high morbidity and mortality rates in the critical care setting
Systemic antifungal and antiviral drug use is effective. However, both classes of drug have narrow therapeutic indexes, thus close monitoring is required
Appropriate cultures should be sent prior to systemic antiviral and antifungal use. However, empirical therapy should not be delayed in high-risk groups
Prompt recognition and early MDT involvement is imperative to guide treatment of viral and fungal infections and subsequently improve outcomes
Discuss fungal infections.
Fungal infections are becoming increasingly common amongst immunocompromised, critically-ill patients. Fungi are eukaryotes. However, their cell membrane differs from that of animal cells as it contains ergosterol, as opposed to cholesterol in animals (Fig 1).
Fungi can be subclassified into two main subgroups:
Moulds (aspergillus)
Yeasts (candida)
Symptoms of fungal infections can be non-specific; therefore, a high index of suspicion is necessary in order to identify and successfully treat fungal infections.
Risk factors for invasive fungal infections in patients with weakened immunity include broad-spectrum antibiotic use, neutropenia and the use of intravascular catheters
- Candidas
Candida is responsible for the majority of fungal infections in critically-ill patients. While candida albicans is responsible for most infections, non-albicans infections are becoming increasingly common.
Most candida infections can be treated with fluconazole. However, resistance is increasing, e.g. candida krusei has natural resistance to fluconazole.
Candida infections are usually mucocutaneous. However, invasive candidiasis occurs when candida enters the blood stream, and is associated with high mortality rates.
Invasive candidiasis is defined as an infection in at least one extravascular site that is usually regarded as sterile; including the eye, central nervous system, liver, spleen, heart or lung.
The two most recognised sequelae of invasive candidiasis are:
Ocular involvement
Endocarditis
- Aspergillus
There are many aspergillus species, but only a few are responsible for causing human infection. Aspergillus fumigatus is the most common.
Invasive aspergillosis most commonly affects the respiratory tract, but in immunocompromised patients it can affect other organs.
Symptoms of aspergillus pneumonia are often non-specific, most commonly:
Pyrexia
Cough
Haemoptysis
Dyspnoea
Broncho-pulmonary lavage/lung tissue sampling can indicate the presence of aspergillus. However, clinical context must be used to distinguish between colonisation and true aspergillus infection.
Voriconazole is first-line treatment for invasive aspergillosis.
- Cryptococcus
Cryptococcus is uncommon, but infection can be life-threatening in immunocompromised patients, e.g. those with HIV disease. Cryptococcal meningitis is the most common form of fungal meningitis.
The treatment of choice is amphotericin/flucytosine, followed by oral fluconazole. Following successful treatment, fluconazole can be used for prophylaxis against cryptococcus relapse until immunity recovers.
- Histoplasmosis
Discuss antifungal agents.
Many fungal infections are superficial, and many antifungal agents are too toxic for systemic use. Systemic antifungal use, when necessary, is not without risk, and patients on these medications need close monitoring and early MDT involvement.
There are three major sub-classes of antifungal drugs:
Azoles
Polyenes
Echinocandins
The mechanism of action of antifungal drugs is largely based on interference with ergosterol synthesis or membrane function, leading to cell death (Fig 1)
- Azoles
Azole compounds inhibit lanosterol 14 α-demethylase, an enzyme involved in the final step of ergosterol synthesis. The lack of ergosterol causes abnormal fungal cell membrane function and its subsequent breakdown 6.
Some examples are:
Triazoles: fluconazole, itraconazole, voriconazole, posaconazole
Imidazoles: ketoconazole, miconazole, clotrimazole
Fluconazole is the first-line treatment against candida infection in the stable patient.
Voriconazole is the first-line treatment for invasive aspergillosis and fluconazole-resistant candida species.
Posaconazole is licenced for the treatment of invasive fungal infections unresponsive to conventional treatment. It is also used as prophylaxis in immunocompromised patients.
Adverse effects include:
Deranged liver function tests (LFTs)/hepatotoxicity
Drug-drug interactions
Nausea/vomiting/diarrhoea
Hypersensitivity
Rash/pruritus
- Polyenes
Amphotericin (Fig 1)
Intravenous amphotericin can be used for the treatment of systemic fungal infections. It is a polyene antifungal derived from streptomyces bacteria, and binds to ergosterol. This process creates pores within the cell membrane, disrupting the electrochemical gradient, leading to fungal cell death. Although amphotericin B is an extremely broad-spectrum and effective antifungal agent, its significant toxicities and side-effect profile limit its use. Resistance to amphotericin is uncommon 6, 7.
AmBisome (Fig 2)
AmBisome is lipid-base formulation of amphotericin B, consisting of amphotericin encapsulated in liposomes. This reduces drug toxicity, and improves its tolerability.
Uses include:
Severe invasive fungal infections
Adverse effects include:
Nephrotoxicity
Infusion reaction
Hypokalaemia
Hypomagnesemia
Phlebitis
Reversible normocytic anaemia
Nystatin is another example of a polyene antifungal. It is chemically very similar to amphotericin. However, it is even more toxic when given intravenously. For this reason, nystatin is only licensed as a topical agent, used commonly for treatment of superficial and mucocutaneous fungal infections
- Echinocandins
Echinocandins inhibit B-1,3-glucan synthase, which is an enzyme for synthesis of B-1, 3-glucans and a necessary component for fungal cell wall integrity. Drugs in this class include micafungin (Fig 1), caspofungin (Fig 2) and anidulafungin (Fig 3), all of which are structurally similar.
Although this class of drug have minimal known side-effects, costs limit their use and hence their use is reserved for invasive candidiasis in the clinically unstable patient 9.
Echinocandins are only active against aspergillus and candida species. However, anidulafungin and micafungin are not used for treatment of aspergillosis. Echinocandins are not effective against fungal infections of the CNS, because they have limited penetration of the blood-brain barrier
Uses 6:
Treatment for azole resistant fungal infections
Empirical therapy in suspected invasive candida infections in which azoles are contraindicated (unstable patient or recent azole use)
Second line agent invasive aspergillosis (caspofungin)
Adverse effects 6:
Deranged LFTs
Infusion-related reaction
Thrombophlebitis
Headache
Flushing/rash/pruritus
Discuss viral infection classifications i.e. human RNA and DNA viruses.
Viral illnesses are recognised as a cause of major mortality, especially in the critical care setting.
Viruses are obligate intracellular parasites. They are small organisms and include genetic material (DNA or RNA) contained within a capsid. The type of genetic material forms the basis of their classification.
Mortality rates from viral illnesses can be high
Discuss antiviral agents.
Antiviral drugs work by inhibiting pathogen development, as opposed to destroying the target pathogen itself. This process is done by interfering with a certain stage of the virus life cycle, thus preventing further viral replication (Fig 1). Because viruses are intracellular organisms, developing antiviral agents that target the virus without damaging host cells is difficult 14.
Creating novel antiviral drugs requires identifying viral proteins that can be targeted and thus disabled, inhibiting further viral replication.
Mechanism of action of antiviral drugs are largely based on interfering with one of the following processes 14:
Inhibition of viral attachment to host cell
Prevent genetic copying of virus
Prevent viral protein production
- Aciclovir
Aciclovir is a guanine analogue. It interferes with herpes virus DNA polymerase, inhibiting viral DNA replication. It is used against HSV and VZV infections. HSV is particularly responsive to treatment with aciclovir due to the presence of HSV thymidine kinase in infected cells, which, after intracellular uptake, converts aciclovir to aciclovir monophosphate. This is a process that host cell thymidine kinase cannot activate, therefore allowing the drug to specifically target infected cells 11.
Aciclovir is not effective against CMV or EBV. Aciclovir can cause obstructive crystalline nephropathy and is therefore given by slow intravenous infusion to avoid precipitation in the renal tubule.
Uses include:
Herpes simplex virus infections:
HSV encephalitis, genital, labial, peri-anal and rectal infections
Varicella zoster virus infections:
In immunocompromised patients if given within 72 hours of symptom onset
In non-immunocompromised patients if ophthalmic branch trigeminal nerve is involved
Adverse effects include:
Reversible acute kidney injury
Deranged LFTs
Phlebitis
CNS toxicity (tremor/confusion/fits)
Neuropsychiatric effects
Obstructive crystalline nephropathy
- Oseltamivir
Oseltamivir (Tamiflu®) and zanamivir are neuraminidase inhibitors and work by reducing the replication of influenza types A and B.
These drugs are only proven to be effective within 48 hours of symptom onset, otherwise they do not shorten course of the disease
Uses include 6:
Treatment of influenza A and B
Adverse effects include:
Abdominal pain
Headache
Nausea and vomiting
Altered consciousness
- Ganciclovir
Ganciclovir is a prodrug that is structurally similar to aciclovir, but is active against cytomegalovirus (CMV). It is also more toxic than aciclovir
Uses include:
Treatment of CMV
Prevention of CMV infection during immunosuppression post organ transplantation
Adverse effects include:
Leukopenia
Thrombocytopenia
Anaemia
Fever
Rash
Abnormal LFTs
- Forscarnet
Foscarnet, known by the brand name Foscavir®, is a pyrophosphate analogue. It inhibits viral DNA polymerase and therefore stops viral DNA replication
Uses include:
CMV disease (mucocutaneous HSV is unresponsive to aciclovir in immunocompromised patients)
Adverse effects include:
Nephrotoxicity
Nausea and vomiting
Electrolyte disturbances
Headache
Diarrhoea
Dizziness
- Remdesivir
Remdesivir, a nucleoside analogue prodrug, is a broad-spectrum antiviral drug. It was originally developed to treat hepatitis C and subsequently Ebola virus infection. However, clinical trials did not show clinical effectiveness.
Initial studies discovered antiviral properties against SARS and MERS coronavirus, although is not licensed for use for these indications. As of late 2020, remdesivir is being tested for the treatment of COVID-19 (SARS-CoV-2) and has been granted a licence for emergency use in some countries.
Preliminary data published in the New England Journal of Medicine suggested that remdesivir may be effective in reducing the recovery time in people hospitalised with COVID-19 who require supplemental oxygen, with a reduction of recovery time from 15 to 10 days, compared to the placebo group.
High mortality rates were seen despite remdesivir use, therefore further research is necessary to evaluate the efficiency of other therapies in conjunction with antiviral use.
Give an overview of the pharmacology of antiepiletic drugs, and the relevance to anaesthetics.
Describe the pharmacological principles of antiepileptic drugs
Classify antiepileptic drugs according to their mechanism of action
AEDs have multiple drug interactions, which need to be considered in the perioperative period
Perioperative care of patients with epilepsy should focus on minimisation of interference in normal AED regimes and avoiding physiological or pharmacological disturbances that may lower the seizure threshold
The AED treatment strategy should be individualised according to:
Seizure description, type, and aetiology
Epilepsy syndrome
Co-medications
Comorbidities
Patient’s lifestyle
Patient’s preference (families and/or carers as appropriate)
Valproate poses a significant risk of birth defects and developmental disorders in children born to pregnant women who take valproate during pregnancy
Status epilepticus is a common medical emergency with significant morbidity and mortality
Regarding phenytoin:
A. Both phenytoin and amiodarone can increase the risk of peripheral neuropathy
B. Phenytoin increases the concentration of carbamazepine
C. Phenytoin is predicted to decrease the efficacy of combined hormonal contraceptives
D. Phenytoin is predicted to decrease the exposure to dabigatran
E. Phenytoin should not be used for patients with acute porphyria
A. True.
B. False. Phenytoin decreases the concentration of carbamazepine.
C. True.
D. True. P-glycoprotein (P-gp) inhibitors, e.g. phenytoin, can increase the absorption of dabigatran etexilate, ultimately increasing both AUC and Cmax of dabigatran, the active drug. Conversely, P-gp inducers can reduce the absorption of dabigatran etexilate, ultimately decreasing AUC and Cmax of dabigatran, the active drug.
E. True.
The most common and best-characterised mechanism of AEDs is the pre- and post-synaptic blockade of voltage-gated sodium channels of axons.
Examples are Phenytoin
Carbamazepine
Lamotrigine
Regarding treating convulsive status epilepticus in adults:
A. Administer glucose (50 ml of 50% solution) and/or intravenous thiamine (250 mg) as high potency intravenous pabrinex if any suggestion of alcohol abuse or impaired nutrition
B. Securing the airway, administering oxygen and obtaining IV access is crucial in the first stage (Early Status, 0-10 minutes)
C. Emergency AED therapy should be administered in the 3rd stage, i.e. Established Status 0-60 mins
D. Consider the possibility of Non-epileptic Status in the 2nd stage (0-30 mins)
E. In the 4th stage (aka Refractory Status, 30-90 mins), it is advised to initiate intracranial pressure (ICP) monitoring where appropriate
A. True.
B. True.
C. False. Emergency AED therapy should be administered in the 2nd stage (0-30 mins).
D. True.
E. True.
A seizure is a transient occurrence of symptoms and/or signs due to abnormal excessive or synchronous neuronal activity in the brain.
Epilepsy is a disease of the brain defined by any of the following conditions:
At least two unprovoked, or reflex, seizures occurring more than 24 hours apart
One unprovoked, or reflex, seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years
Diagnosis of an epilepsy syndrome
Epilepsies are classified as (Fig 1):
Generalised epilepsy
Focal epilepsy
Combined generalised and focal epilepsy
Unknown epilepsy
Epilepsies are now described more precisely by their specific underlying etiologies (Fig 1).
Epilepsies may also be organised, by reliably identified common clinical and electrical characteristics, into epilepsy syndromes.
Epilepsy imitators are a range of conditions associated with recurrent paroxysmal events that may imitate and be misdiagnosed as epilepsies.
Examples of epilepsy imitators are:
Syncope and anoxic seizures, e.g. vasovagal syncope
Behavioural, psychological and psychiatric disorders, e.g. daydreaming
Sleep-related conditions, e.g. parasomnias
Paroxysmal movement disorders, e.g. stereotypies
Migraine-associated symptoms
Disorders, e.g. migraine with visual aura
Miscellaneous events, e.g. spinal myoclonus
Regarding the newer anticonvulsant drugs and their actions:
The most important inhibitory neurotransmitter in the brain is gamma-aminobutyric acid (GABA).
The GABA receptor has multiple binding sites for benzodiazepines, barbiturates and other substances (Fig 1). Activation allows an influx of chloride ions, causing hyperpolarisation of the neuronal membrane, which leads to the inhibition of neurotransmission (inhibitory post-synaptic potential).
Examples of GABA receptor agonists include:
Benzodiazepines (lorazepam, diazepam, clonazepam and clobazam)
Barbiturates (phenobarbital and primidone)
Reuptake of GABA is facilitated by GABA-transporters (GAT). These carry GABA from the synaptic space into neurons and glial cells, where GABA is metabolised.
GABA reuptake inhibitors (GRIs) cause increased amounts of GABA to be available in the synaptic cleft. GABA prolongs inhibitory post-synaptic potentials (IPSPs).
Tiagabine is an example of a GABA reuptake inhibitor.
GABA is metabolised by transamination in the extracellular compartment by GABA-transaminase (GABA-T). GABA transaminase inhibitors inhibit GABA-T. This causes a widespread increase in GABA concentrations in the brain, which leads to inhibition of excitatory processes that can initiate seizure activity.
Vigabatrin is an example of a GABA transaminase inhibitor.
Gabapentin, pregabalin and valproate are examples of AEDs with potential GABA mechanism of action. They affect glutamic acid decarboxylase (GAD) enzyme, which converts glutamate into GABA, thus enhancing the synthesis of GABA. Valproate also blocks the neuronal sodium channel.
Gabapentin and pregabalin are designed to mimic the neurotransmitter GABA. They do not, however, bind to GABA receptors.
Their mechanism of action involves the inhibition of alpha 2-delta (α2–δ) subunit of voltage-gated calcium channels (VGCC), reducing synaptic release of excitatory neurotransmitters.
Glutamate is an important excitatory neurotransmitter in the brain. Its receptor system is complex, and is classified into four main classes:
Alpha-Amino-3-Hydroxy-5-Methyl-Isoxazolepropionic Acid (AMPA) (ionotropic receptors; site of action for topiramate)
N-Methyl-D-Aspartate (NMDA) (ionotropic receptors; site of action for felbamate and ketamine)
Kainate (ionotropic receptors)
Metabotropic glutamate receptors
AMPA, NMDA and kainate receptors permit the entry of sodium and calcium ions.
Both ionotropic and metabotropic receptors are ligand-gated transmembrane proteins (Fig 1), but each type has a different mechanism of action.
Some AEDs have other mechanisms of action.
Levetiracetam binds to brain-specific synaptic vesicle protein 2A (SV2A), which is important for neurotransmitter vesicles ready to release their content. Lack of SV2A decreases action potential-dependent neurotransmission and inhibits presynaptic voltage-dependent calcium channels. Negative modulators impede impulse conduction across synapses.
Other examples of AEDS with other mechanisms of action include:
Brivaracetam
Rufinamide
Cannabidiol
Stiripentol
Match the antidepressant drugs to their site of action.
SSRIs
Selective Serotonin Re-uptake Inhibitors (SSRIs) are the most commonly used first-line antidepressant. They act specifically to prevent re-uptake of serotonin (or noradrenaline in the case of SNRIs) in the synaptic cleft. They are indicated in the treatment of depression and some anxiety disorders. They are well absorbed orally and have a half-life of 18-96 hours depending on the drug in question.
Some examples are:
sertraline
citalopram
fluoxetine
SSRIs block the active transport mechanism of serotonin back into the pre-synaptic nerve ending (Fig 1).
This increases the concentration of serotonin in the synaptic cleft.
As SSRIs are specific to serotonin re-uptake they have an improved side-effect profile compared to other antidepressants and importantly are less toxic in overdose. Important side-effects include:
GI side-effects, such as nausea or constipation
malaise, dry mouth, myalgia, arthralgia
an increase in anxiety and suicidal ideation particularly at the beginning of treatment or following dose alteration
QTc prolongation
serotonin syndrome
Tricyclic antidepressants (TCAs) classically consist of a 3 ring structure which competitively prevents re-uptake of serotonin and noradrenaline. Their actions are less specific than those of SSRIs and this is responsible for their broad side-effect profile. As well as 5-HT and NA re-uptake they block muscarinic, histaminergic and alpha-adrenoceptors.
They are indicated in the treatment of depressive illness, chronic pain and nocturnal enuresis.
TCAs are well absorbed from the gut due to their high lipid solubility. They have a high volume of distribution and are highly protein-bound. There is significant interpatient variability in their metabolism which occurs in the liver and often produces active metabolites.
TCAs often have long half-lives and can be dosed daily.
Some examples are:
amitriptyline
nortriptyline
imipramine
dothiepin
TCAs competitively inhibit the reuptake of noradrenaline and serotonin (Fig 1). This again increases the concentration of free neurotransmitter in the synaptic cleft.
TCAs have a broad side-effect profile secondary to the lack of selectivity of their action. This along with significant toxicity in overdose limits their use in patients with mood disorders. Important side-effects include:
CNS - sedation, seizures
anticholinergic - dry mouth, constipation, urinary retention and blurred vision
cardiovascular - prolonged QTc, postural hypotension especially in the elderly
toxic in overdose
Which antipsychotic agent is known to cause agranulocytosis?
A. Haloperidol
B. Olanzapine
C. Risperidone
D. Clozapine
E. Flupentixol
A. False. Haloperidol does not cause agranulocytosis.
B. False. Olanzapine does not cause agranulocytosis.
C. False. Risperidone does not cause agranulocytosis.
D. True. Clozapine causes serious agranulocytosis in 1% of patients and as such is only used when other atypical agents have been ineffective.
E. False. Flupentixol does not cause agranulocytosis.
Antipsychotic agents are dopamine D2 receptor antagonists and have varying degrees of action on other dopamine receptor subtypes. This accounts for their wide-ranging side-effects.
Antipsychotic agents can be broadly classified into typical (first generation) and atypical (second generation) agents.
Typical antipsychotics are referred to by their chemical structure:
phenothiazines, for example chlorpromazine
butyrophenone, for example haloperidol
thioxanthene, for example flupentixol
Typical antipsychotics share a strong tendency to produce extrapyramidal side-effects and have little effect on negative symptoms of schizophrenia.
Atypical agents (such as olanzapine, risperidone and clozapine) produce less extrapyramidal side-effects and can be more effective in the treatment of negative symptoms. This is due to their reduced activity at D2 receptors and increased antagonistic activity at 5-HT1A receptors.
Most antipsychotics have a half-life of 15-30 hours and are administered orally. There is considerable individual variation between the plasma concentration achieved per specific dose and the clinical response to each concentration. Dosage therefore needs to be adjusted on an individual basis.
Some antipsychotics, for example haloperidol (Haldol), can be esterified with long chain fatty acids. This enables IM depot injection effective for 28 days and particularly useful in patients with unreliable compliance with medication.
Side-effects of antipsychotic drugs can be broadly classified into neurological and non-neurological.
Neurological side-effects are largely extrapyramidal side-effects caused by D2 antagonism in the striatum.
These cause a Parkinsonian-like syndrome comprising rigidity, dystonias, akathisia (motor restlessness) and tardive dyskinesias.
Non-neurological effects include increased prolactin secretion, galactorrhoea, amenorrhoea, anti-muscarinic effects and weight gain.
Clozapine causes serious agranulocytosis in 1% of patients and as such is only used when other atypical agents have been ineffective.
Which of these antipsychotic agents is a phenothiazine?
A. Haloperidol
B. Chlorpromazine
C. Olanzapine
D. Flupentixol
E. Risperidone
A. False. Haloperidol is a typical antipsychotic of the butyrophenone class.
B. True. Chlorpromazine is a typical antipsychotic of the phenothiazine class.
C. False. Olanzapine is an atypical antipsychotic.
D. False. Flupentixol is a typical antipsychotic of the thioxanthene class.
E. False. Risperidone is an atypical antipsychotic.
Antipsychotic agents are dopamine D2 receptor antagonists and have varying degrees of action on other dopamine receptor subtypes. This accounts for their wide-ranging side-effects.
Antipsychotic agents can be broadly classified into typical (first generation) and atypical (second generation) agents.
Typical antipsychotics are referred to by their chemical structure:
phenothiazines, for example chlorpromazine
butyrophenone, for example haloperidol
thioxanthene, for example flupentixol
Typical antipsychotics share a strong tendency to produce extrapyramidal side-effects and have little effect on negative symptoms of schizophrenia.
Atypical agents (such as olanzapine, risperidone and clozapine) produce less extrapyramidal side-effects and can be more effective in the treatment of negative symptoms. This is due to their reduced activity at D2 receptors and increased antagonistic activity at 5-HT1A receptors.
Most antipsychotics have a half-life of 15-30 hours and are administered orally. There is considerable individual variation between the plasma concentration achieved per specific dose and the clinical response to each concentration. Dosage therefore needs to be adjusted on an individual basis.
Some antipsychotics, for example haloperidol (Haldol), can be esterified with long chain fatty acids. This enables IM depot injection effective for 28 days and particularly useful in patients with unreliable compliance with medication.
Side-effects of antipsychotic drugs can be broadly classified into neurological and non-neurological.
Neurological side-effects are largely extrapyramidal side-effects caused by D2 antagonism in the striatum.
These cause a Parkinsonian-like syndrome comprising rigidity, dystonias, akathisia (motor restlessness) and tardive dyskinesias.
Non-neurological effects include increased prolactin secretion, galactorrhoea, amenorrhoea, anti-muscarinic effects and weight gain.
Clozapine causes serious agranulocytosis in 1% of patients and as such is only used when other atypical agents have been ineffective.
Give an overview of the pharmacology of Anti-Diabetic Therapy: NIDDM and Insulin Therapy in Diabetes Mellitus, and the relevance to anaesthetics.
List the main classes of oral hypoglycaemic drugs
Explain the mechanism of action of oral hypoglycaemic drugs
Describe the main side-effects of oral hypoglycaemic drugs
Describe the different types of insulin and their uses
There is more choice of drugs than ever before
Sulphonylureas and metformin are still useful agents
There are ongoing concerns about glitazones
Incretins show promise, but it is too early to determine their ultimate role
Insulin therapy is being used as a therapeutic tool for earlier use in achieving glycaemic targets. However, there remain questions about its long-term safety and the possible risk of carcinogenesis
Drag each pharmacological class of anti-diabetic agent into the correct category
Oral hypoglycaemic drugs are only effective in patients who have NIDDM and who have residual insulin secretion.
Fig 1 summarises the eight different pharmacological classes of anti-diabetic agents that are currently in use.
These include agents which:
Increase insulin secretion (secretagogues)
Improve insulin action (sensitizers)
Delay glucose absorption (inhibitors)
Newer treatments, such as incretin therapy, have multiple glucoregulatory effects.
Sulphonylureas (Fig 1a) have been used since the 1950s and have been developed in two distinct generations:
First generation: tolbutamide and chlorpropamide (Fig 1b)
Second generation: glibenclamide and gliclazide (Fig 2)
These drugs reduce glycosylated haemoglobin (HbA1c) by 1-2%. HbA1c is a marker of the adequacy of glycaemic control over the preceding 3 months and is normally <7%.
Although safety is well established, there are some risks.
Question: What do you think are the risks of sulphonylureas?
Some of the risks of sulphonylureas are:
Hypoglycaemia may occur, especially with agents that have active metabolites
Some agents, e.g. glibenclamide, are metabolised to an active metabolite with significant renal excretion. Therefore, these agents should be avoided in the elderly and those with renal disease
Increased appetite may cause weight gain
Although there were early concerns that sulphonylureas increase the risk of cardiovascular events, it has now been found that they may reduce the risk to the cardiovascular system (CVS)
Regarding insulin:
A. Insulin is a steroid hormone
B. Insulin is available as short-term, medium-term and long-term acting formulations
C. Intermediate acting insulin is complexed with protamine or zinc
D. Long-acting insulins have up to 24 h duration of action
E. There are some concerns over links to carcinogenesis
A. False. Insulin is a polypeptide hormone consisting of an A and B chain linked by disulphide bridges.
B. True. Insulin is available in different formulations that act over a the full range from short-term to long-term.
C. True. Intermediate acting insulin is complexed with protamine, i.e. neutral protamine Hagedorn (NPH), or zinc.
D. True. Longer acting agents have a duration of action of up to 24 h.
E. True. Concerns have been raised over the long-term safety of insulin particularly with respect to an increased incidence of certain forms of cancer.
The blood-glucose lowering potency of individual agents is limited, but insulin therapy is the most effective at lowering blood glucose.
Insulin is no longer seen as a therapeutic ‘last resort’ after long-term oral agent combinations have failed. Starting insulin therapy with low doses in combination with oral agents is effective at achieving glycaemic targets and maintaining HbA1c values.
Insulin therapy can improve insulin resistance and may have potential cardiovascular benefits.
The goal for insulin therapy is to mimic as closely as possible the normal physiological pattern of insulin secretion seen in non-diabetic patients.
To meet the needs of both basal and postprandial insulin requirements, the ‘basal-bolus’ concept requires:
Basal insulin to suppress glucose production between meals and overnight and
Bolus insulin to limit postprandial hyperglycaemia
Newer fast-acting and basal insulin formulations have been developed to meet these requirements.
Insulin is a polypeptide that has two chains of amino-acids (A and B) that are linked by disulphide bridges (Fig 1).
Insulin is secreted by B/β-cells of the islets of Langerhans in the pancreas and is synthesised as a pre-cursor hormone.
Its half-life is 5 min and it is 80% degraded in the liver and the kidneys.
Physiological Effects
Insulin:
Increases cellular uptake of glucose
Increases glycogen synthesis
Reduces gluconeogenesis hypoglycaemia
Increases fatty acid synthesis
Increases amino acid uptake and protein synthesis
Increases K+ into cells
Increases anabolism
Give an overview of the pharmacology of Corticosteroids, Thyroxine and Drugs Used in Thyroid Disorders, and the relevance to anaesthesia.
Describe the indications for the use of corticosteroids in chronic and acute disease states and their relevant clinical effects
Identify measures that can be taken by the anaesthetist to mitigate complications from long-term steroid use
Explain how thyroid hormones are synthesised and released
List treatments used in hyperthyroidism and hypothyroidism and their complications relevant to anaesthetists
Corticosteroids are commonly used drugs with extensive effects on patient physiology that are relevant to the anaesthetist
Appropriate steroid supplementation is important for those patients who have recently been subject to supplementary exogenous steroid exposure in order to prevent cardiovascular collapse under the stress of surgery or major illness
Thyroid disease is common and it is important to understand its systemic features as both hypo and hyperthyroid states can be potentially dangerous for patients who are critically ill or undergoing surgery
Pharmacological treatment of thyroid disease is the now the most common management strategy for hypo and hyperthyroidism but drug treatment comes with potentially serious side-effects that are important to recognise
The effects of corticosteroids on the body include catabolic, cardiovascular and anti-inflammatory responses. Regarding these responses:
A. Glucocorticoids stimulate gluconeogenesis by the liver, antagonise the effects of insulin and lead to increased blood glucose concentrations
B. Glucocorticoids lead to an increase in protein synthesis and decrease catabolism of protein already in all body cells
C. Glucocorticoids promote mobilisation of fatty acids from adipose tissue and enhance oxidation of fatty acids in cells
D. Fluid and electrolyte homeostasis leads to sodium reabsorption, H2O retention and K+ and H+ excretion
E. Glucocorticoids cause a mild decrease in the number of red blood cells, neutrophils and platelets
A. True. Glucocorticoids stimulate gluconeogenesis by the liver, antagonise the effects of insulin and lead to increased blood glucose concentrations as part of carbohydrate, protein and lipid metabolism.
B. False. Glucocorticoids lead to a decrease in protein synthesis and increased catabolism of protein already in all body cells as part of carbohydrate, protein and lipid metabolism.
C. True. Glucocorticoids promote mobilisation of fatty acids from adipose tissue and enhance oxidation of fatty acids in cells as part of carbohydrate, protein and lipid metabolism.
D. True. Fluid and electrolyte homeostasis leads to sodium reabsorption, H2O retention and K+ and H+ excretion.
E. False. Glucocorticoids cause a mild increase in the number of red blood cells, neutrophils and platelets in the immune and haematological system.
The adrenal cortex secretes two broad groups of corticosteroids:
Mineralocorticoids, which have electrolyte-regulating activity
Glucocorticoids, which have metabolic-regulating activity
The adrenal cortex has three zones (Fig 1):
Zona glomerulosa, the outermost layer, which is the site of aldosterone production (mineralocorticoid)
Zona fasiculata, the middle layer, which is the site of cortisol and corticosterone production (glucocorticoids)
Zona reticularis, the innermost layer, which is the site of androgen production
In health, approximately 90% of cortisol is bound in the plasma, 75% of cortisol is bound to cortisol-binding globulin (CBG) and 15% is bound to plasma albumin. The 10% of cortisol that is unbound is the metabolically active steroid that has a plasma half-life of 60-90 minutes
Also regarding the responses of the body to corticosteroids:
A. The anti-inflammatory effects of glucocorticoids lead to immune suppression
B. Glucocorticoids reduce the release of antibodies and interleukins from white cells
C. Glucocorticoids decrease blood pressure through actions on the kidneys and vasculature
D. Glucocorticoids suppress the thyroid axis, inhibit pulsatile release of luteinizing hormone and follicle-stimulating hormone and lead to decreased secretion of growth hormone
E. An excess or deficiency of glucocorticoid has no effect on mood
A. True. The anti-inflammatory effects of glucocorticoids lead to immune suppression due to the inhibition of formation of pro-inflammatory mediators, suppression of the complement pathway and subsequent reduction in the number of circulating lymphocytes, monocytes and basophils.
B. True. Glucocorticoids reduce the release of antibodies and interleukins from white cells within the immune and haematological systems 2.
C. False. Within the cardiovascular system, glucocorticoids increase blood pressure through actions on the kidneys and vasculature. In vascular smooth muscle, they increase the reactivity of peripheral blood vessels to catecholamines.
D. True. Glucocorticoids suppress the thyroid axis, inhibit pulsatile release of luteinizing hormone and follicle-stimulating hormone and lead to decreased secretion of growth hormone.
E. False. Glucocorticoid excess or deficiency can manifest itself as depression, euphoria, psychosis or lethargy.
Adrenocorticotropic hormone (ACTH) and, therefore, cortisol secretion are under control of three broad mechanisms (Fig 1) 3:
Diurnal variation. Cortisol is secreted in an episodic manner from the adrenal gland and follows a circadian rhythm. Levels are highest in the morning on waking and lowest in the middle of the night
Negative feedback. Corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) from the hypothalamus cause the release of ACTH, which is the major stimulus for secretion of cortisol. Circulating cortisol has a negative feedback on the hypothalamus and anterior pituitary to decrease release of CRH and ACTH respectively and, therefore, decrease cortisol secretion
Stress. Physical, psychological and physiological stress can override the negative feedback mechanism and diurnal variation. Cortisol rises immediately and dramatically during stress in an attempt to limit potentially damaging inflammatory responses
Ingested iodine is absorbed from the gut as iodide and taken up into the thyroid follicular cells, where it is an essential component in the synthesis of thyroid hormones.
- Iodide trapping
Iodide in the blood is actively taken up using active cotransporters through the basolateral membrane of the thyroid follicular cells. This process is stimulated by thyroid stimulating hormone/thyrotopin (TSH) and inhibited by perchlorate and thiocyanate ions.
- Thyroglobulin
Thyroglobulin is synthesised within the cells and drifts to the apical membrane in vacuoles.
- Oxidation of iodide
Thyroid peroxidase, located in the apical membrane, oxidizes iodide to iodine.
- Iodination reaction
Iodinase binds iodine to the tyrosine components of thyroglobulin, forming monoiodotyrosine and diiodotyrosine.
- Oxidative condensation
Oxidative condensation of two diiodotyrosine residues forms T4 and condensation of monoiodotyrosine and diiodotyrosine forms T3, these reactions are catalysed by peroxidase enzymes.
- Storage
T3 and T4 are stored within the follicular colloid on thyroglobulin and can last several months.
- Fully iodinated thyroglobulin
Fully iodinated thyroglobulin is taken back into the cells by pinocytosis.
- Thyroglobulin digestion
Enzymes digest the thyroglobulin molecule. T3 and T4 pass out of the cell into the bloodstream. Incomplete but iodinated fragments of thyroglobulin remain within the cell and are recycled.
- Secretion
Thyroglobulin in vesicles is broken down by lysosomes to release T3 and T4 into the blood in the ratio 1:13.
- Transport
Total blood concentrations of T3 and T4 are 2 and 100 nmol/L respectively, but they are both >99% bound to the plasma proteins albumin and thyroid-binding globulin. T4 has a half-life of several days, being slowly metabolised to T3 and reverse T3. T3 itself has a half-life of about 24 hours.
The rate of secretion of thyroid hormones is regulated by specific feedback-loop mechanisms involving the hypothalamic-hypophyseal-thyroid axis. Thyroxine is released in response to TSH from the anterior pituitary whose release is inhibited by circulating unbound T3 and T4 and stimulated by thyrotropin-releasing hormone (TRH) from the hypothalamus (Fig 1).
The effect of thyroid hormones is to increase gene transcription in virtually all cells, increasing cellular enzyme and structural protein production. T4 becomes deiodinated to T3. This binds to intracellular receptors and initiates gene transcription in the nucleus and increased messenger ribonucleic acid (mRNA) production leading to increased protein synthesis by the cell.
At a cellular level, T3 and T4 cause an increase in the size and number of mitochondria and increase the action of the Na-K ATPase pump, perhaps by increasing cell permeability to Na.
Thyroid hormones increase gene transcription in all cells increasing the amount of cellular enzymes, transport proteins and structural proteins produced. They are essential for the normal function of cells and homeostasis.
Neurological system
Thyroid hormones are essential for the normal function of the central and peripheral nervous system.
Normal development
Thyroid hormones are required for normal growth and mental development.
A congenital lack of thyroxine leads to poor growth and severe mental retardation. This is checked for at birth in the UK using a neonatal heel-prick test.
Respiratory system
There is a rise in minute volume ventilation due to an increased rate and depth of respiration.
This is driven by the increased metabolic demands leading to increased oxygen consumption and carbon dioxide production.
Cardiovascular system
Thyroid hormones have a direct chronotropic and inotropic effect on the myocardium but the mean arterial blood pressure is unchanged due to vasodilatation and drop in diastolic pressure with an associated rise in pulse pressure.
Tachycardia is common with hyperthyroidism.
Gastrointestinal system
An increase in thyroid hormone levels leads to an increased appetite, GI motility and secretions.
Reproductive system
An imbalance in thyroid hormones can lead to infertility in both men and women.
Match the causes of hypothyroidism and hyperthyroidism that are listed to the correct condition.
The diagram highlights the signs and symptoms of hypothyroidism and hyperthyroidism in different physiologiucal systems.
Central Nervous System
Hypothyroidism:
Signs:
Nervousness
Slow thinking
Sluggish movement
Symptoms:
Poor memory, ‘brain fog’
Depression and mood swings
Psychosis
Mental slowness
Dementia
Poverty of movement
Ataxia
Slow-relaxing reflexes and myotonia
Deafness
Insomnia
Tingling and numbness in extremities
Hyperthyroidism
Signs:
Trembling hands
Symptoms:
Irritability
Anxiety
Hyperkinesia
Tremor
Cardiovascular system
Hypothyroidism
Signs:
Oedema
Pericardial and pleural effusions
Anaemia
Hypertension
Cardiac failure
Bradycardia
Cool peripheries
Symptoms:
Non-pitting oedema of the ankles
Slow pulse rate
Rapid heart rate with weak force of concentration
Pounding heartbeat
Hyperthyroidism
Signs:
High blood pressure
Fast heart rate
Pounding pulse
Symptoms:
Palpitations
Angina
Breathlessness
Hypertension
Cardiac failure
Tachycardia
Tachyarrhythmia
Atrial fibrillation
Vasodilatation
Gastrointestinal system
Hypothyroidism
Signs:
Unexplained weight gain
Symptoms:
Obesity
Constipation
Hyperthyroidism
Signs:
Nausea and vomiting
Symptoms:
Increased appetite
Vomiting
Diarrhoea
Genitourinary system
Hypothyroidism
Symptoms:
Menorrhagia and pre-menstrual tension in females
Loss of libido
Hyperthyroidism
Signs:
Breast development in men
Symptoms:
Oligomenorrhoea
Loss of libido
General signs and symptoms of hypothyroidism
Signs:
Low basal-activity level temperature
Cold, dry, sore, scaly skin
Sparse eyebrows especially at outer ends
Dry, course, brittle hair or hair loss
Brittle nails
Facial swelling especially around the eyes
Wasting of the tongue
Listless dull look to the eyes
Hoarse voice
Changes at the fundus oculi
Symptoms:
Malaise
Extreme tiredness, lethargy, lack of stamina and motivation, also 3 pm crash
Hypothermia
Intolerance to temperature changes, sweating and low body temperature
Arthralgia and myalgia
Dry coarse skin
‘Peaches and cream’ complexion
Loss of eyebrows and hair
Carpal tunnel syndrome
Brittle and ridged nails
General signs and symptoms of hyperthyroidism
Signs:
Weight loss
Muscle weakness
Skin flushing/blushing
Hair loss
Warm moist skin
Goitre
In Grave’s disease only:
Protruding eyes
Staring gaze
Symptoms:
Malaise
Weight loss and cachexia
Muscle weakness and proximal muscle wasting
Heat intolerance
Palmar erythema
Pretibial myxoedema (Grave’s disease)
In Grave’s disease only:
Blurred or double vision
Exophthalmos
Lid lag
Conjunctival oedema
Evidence-based indications for the use of steroids in anaesthesia and critical care include:
A. The prevention of PONV in day surgery
B. Cerebral oedema in closed-head injury
C. Anaphylaxis
D. Cardiac arrest
E. Hypotension in septic patient unresponsive to vasopressors
A. True. Corticosteroids such as dexamethasone reduce PONV.
B. False. Steroids are used to reduce and prevent cerebral oedema associated with intracerebral neoplasms.
C. True. Corticosteroids decrease airway swelling and reduce the occurrence of biphasic reactions in anaphylaxis.
D. False. Steroids currently have no role in cardiac arrest unless related to anaphylaxis.
E. True. In 2002, the Annane study showed patients with early septic shock who were non-responders to a cosyntrophin stimulation test and who received hydrocortisone therapy had improved 28-day survival.
Corticosteroid supplementation should be considered for patients being treated with steroids for hypoadrenalism or other diseases.
These patients are more prone to cardiovascular collapse in response to surgical stress, as they may display suppression of the pituitary adrenal axis and not secrete additional endogenous cortisol in response to surgical stress.
The specific duration and dose of steroid that can produce hypothalamic pituitary axis (HPA) depression varies from 2 days to 12 months after discontinuation of steroid therapy, but the ability to respond to stress is thought to return at around 2 months after discontinuation of supplementary steroids
Recent studies have found a poor correlation between HPA function and cumulative dose or duration of therapy
Any patient who has received the equivalent of 15 mg of prednisolone for >3 weeks should be suspected as having clinically significant HPA suppression.
The following tables outline corticosteroid replacement regimens for those undergoing surgery:
Patient currently taking high-dose immunosuppressive steroids – Give usual immunosuppressive dose during the perioperative period
Patient stopped taking steroids <3 months – Treat as if on steroids
Patient stopped taking steroids >3 months – No perioperative steroids necessary
Patients with early septic shock, who were non-responders to a cosyntrophin stimulation test and who received hydrocortisone 50 mg IV and 6-hourly fludrocortisone 50 mcg oral administration (PO) daily for 7 days had an improved 28-day survival. Steroids reduced the duration of vasopressor therapy regardless of the result of the stimulation test
Corticosteroids can decrease the incidence of treatment failure and decrease the length of hospital stay in patients with exacerbations of their chronic obstructive pulmonary disease (COPD). However, one study showed a trend towards more non-COPD hospital readmissions. There was no difference between 2-week and 8-week corticosteroid regimen
Prolonged low-dose methylprednisolone in early acute respiratory distress syndrome (ARDS) improved lung function, shortened ICU stay and improved ICU survival
Methylprednisolone given in ARDS persisting for longer than 7 days did not improve 60-day mortality but did improve ventilator and ICU-free days
The side-effects of glucocorticoid administration include:
A. Hypertension
B. Fluid retention, hypokalaemia and metabolic alkalosis
C. Gastroduodenal ulceration and GI bleeding
D. Decreased susceptibility to infection
A. True.
B. True.
C. True.
D. False. The anti-inflammatory effects of glucocorticoids lead to immune suppression due to the inhibition of formation of pro-inflammatory mediators, suppression of the complement pathway and subsequent reduction in the number of circulating lymphocytes, monocytes and basophils.
The risks of short-term, perioperative administration of steroids include:
Hypertension
Fluid retention, hypokalaemia and metabolic alkalosis
Gastroduodenal ulceration and GI bleeding
Psychiatric disturbances
Delayed wound healing
Hyperglycaemia
Immune suppression and increased susceptibility to infection
In the longer term, the effects of more prolonged steroid administration include Cushing’s disease
Regarding the synthesis and release of thyroid hormones:
A. Ingested iodine is absorbed from the gut as iodide
B. Iodine binds to position 3 of tyrosine in the thyroglobulin molecule and in the presence of iodinase enzyme forms mono-iodotyrosine and di-iodotyrosine
C. T3 is the more abundant and metabolically active form of thyroid hormone secreted by follicular cells
D. Peroxidase enzymes are crucial to the formation of T3 and T4
A. True. Iodine ingested in the diet is absorbed from the gut as iodide and stored in thyroid follicular cells in an energy dependent process stimulated by TSH.
B. True. Inside the follicular cells, thyroid peroxidase located in the apical membrane oxidizes iodide to iodine prior to the iodination reaction.
C. False. T3 is the more metabolically active form of thyroid hormone and initiates gene transcription however it is mostly converted from T4, which is secreted more abundantly by the thyroid gland.
D. True. Oxidative condensation of two diiodotyrosine residues forms T4 and condensation of monoiodotyrosine and diiodotyrosine forms T3, these reactions are catalysed by peroxidase enzymes.
The thyroid gland is the site of synthesis, storage and release of thyroid hormones. The thyroid gland is situated in the anterior neck extending from the level of the fifth cervical to first thoracic vertebra (Fig 1).
It can vary in weight but averages between 25-30 g in adults and its blood supply comes from the superior and inferior thyroid arteries at a rate of 500 ml/min/100 g.
The thyroid gland secretes two hormones from its functional units called follicles (acini):
Fig 1: thyroxine also known as T4 (93%)
Fig 2: tri-iodothyronine also known as T3 (7%)
Reverse T3 is a biologically inactive thyroid hormone formed from peripheral conversion of T4 by 5-deiodinase
Give an overview of the Effects of Drugs on the Eye and Vision; includes Intra-ocular Pressure, and the relevance to anaesthetics.
Explain the effects of the autonomic nervous system on the eye
Describe the control of intraocular pressure
Explain how anaesthetists can influence intraocular pressure
Describe common ophthalmology drugs and their systemic effects
Susceptible patients need attention to intraocular pressure intraoperatively. This means monitoring pressure areas, controlling CVP where possible and careful selection of drugs
The rise in IOP associated with laryngoscopy can be modified with opioids
Pupil size can influence intraocular pressure, especially in patients with acute angle-closure glaucoma
Topical ophthalmic drugs may not be entirely benign and autonomically-active drugs can have systemic effects in children or the elderly
The eye contains a complex variety of autonomic receptors, on both pre-synaptic and post-synaptic cell membranes. The receptors are distributed liberally throughout the various structures in the eye.
As the prevalence of glaucoma rises, so has interest in developing drugs that act on the autonomic supply to the eye. In general, parasympathomimetic agents decrease IOP and sympathomimetic agents increase IOP, apart from α2 agonists.
Parasympathetic muscarinic-3 (M3) receptors dominate in the ciliary muscle and iris sphincter, but receptors M1-M5 are present throughout 1. In theory, an M3 agonist should decrease elevated IOP. Cevimeline is such an M3 agonist, but it is used only in Sjögren’s syndrome and is actually contraindicated in acute angle closure glaucoma (AACG). Conversely, pilocarpine is a non-selective muscarinic agonist, and is indicated in glaucoma. This example illustrates the complexity of ocular autonomic supply.
Identify which of the neurotransmitters and receptors listed below sit in the diagram of the parasympathetic nervous system.
Identify which of the neurotransmitters and receptors listed below sit in the diagram of the sympathetic nervous system.
Arrange the following muscles and actions under the appropriate headings.
The eye is innervated in a number of ways:
Cranial nerve II, relaying visual sensory information to the brain
Cranial nerves III, IV and VI, supplying the extraocular muscles
Cranial nerve V, the ophthalmic branch of the trigeminal nerve, supplying sensation to the eye
Parasympathetic supply to the sphincter pupillae and ciliary muscles
Sympathetic supply via the superior cervical ganglion to the dilator pupillae
Autonomic nerves not only have an effect on pupil size and accommodation, they also have a direct effect on intraocular pressure (IOP). The relative effects of the sympathetic and parasympathetic systems can be complex.
Therefore, an understanding of autonomic pharmacology is important in managing IOP.
Control of IOP depends on intraglobal factors and extraglobal factors. Sort the factors listed below into the appropriate category.
Other external compression such as blinking can increase IOP by 10 mmHg, as measured by direct recording
Resorption of aqueous humour is governed by the pressure gradient between IOP and central venous pressure (CVP). This means that:
A. A rise in IOP normally can be compensated for by an increased rate of IVC drainage
B. A rise in CVP decreases IOP via the episcleral vessels
C. Damage to the canal of Schlemm increases IOP
A. True.
B. False. A rise in CVP increases IOP via the episcleral vessels.
C. True.
The aqueous humour refers to fluid within the anterior and posterior chambers of the eye, as distinct from the vitreous humour that occupies the space between lens and retina (Fig 1a).
IOP is influenced by the production and resorption of the aqueous humour, which follows a well-established route starting with production in the ciliary bodies. This is thought to be under adrenergic control, and studies show a preponderance of β2 adrenergic receptors in the ciliary body 2.
The aqueous humour then flows over the lens and iris into the anterior chamber, and from here it is reabsorbed via the canal of Schlemm, ultimately draining into episcleral vessels.
In which of the following patients might anaesthetists want to actively reduce IOP?
A. Patients with glaucoma
B. Patients with facial fractures
C. Patients with penetrating eye trauma
D. Patients with diabetic eye disease
A. Correct. Patients with angle closure glaucoma are at risk of retinal damage from sudden rises in IOP.
B. Incorrect. Patients with facial fractures are not necessarily at risk from elevated IOP, unless there is an extraglobal haematoma associated.
C. Correct. Patients with penetrating eye trauma are at risk of orbital contents expulsion if IOP rises.
D. Incorrect. Patients with diabetic eye disease are normally not at risk from elevated IOP.
The term ‘glaucoma’ is used to cover a collection of pathologies that results in optic nerve damage, not necessarily with elevated IOP.
Glaucoma is often categorised as ‘open-angle’ or ‘closed-angle’. The ‘angle’ is the angle between the cornea and the iris, called the iridocorneal angle.
The management of POAG and AACG is similar, with the primary aim of decreasing IOP. This can be done by:
- Decreasing the production of aqueous humour
A decrease in the production of aqueous humour is achieved by:
β-blockers such as timolol, which decrease aqueous humour production by antagonising the β2 receptors
α agonists such as brimonidine, which decrease aqueous humour production and increase outflow
Acetazolamide, a carbonic anhydrase inhibitor (CAI) that is given systemically, which decreases aqueous humour production in the ciliary body. It is used acutely in AACG. Topical CAIs are available for use in POAG
- Increasing the outflow of aqueous humour
Increasing the outflow of aqueous humour is achieved through:
Muscarinic agonists such as pilocarpine, which cause miosis, i.e. the pulling away of iris tissue from the trabecular meshwork so increasing the drainage of aqueous humour
Prostaglandin analogues, e.g. latanoprost, which are thought to break extracellular matrix, decreasing resistance to outflow
Using hyperosmolar agents
Mannitol is used intravenously in AACG to reduce IOP that is refractory to other agents.
All of these agents can be used alone or in combination. Systemic agents, e.g. acetazolamide and mannitol, are reserved for refractory or sight-threatening increased IOP.
Research into IOP changes caused by specific drugs is often complicated by the timing of the study drug with other drugs, laryngoscopy and intubation. The evidence for the effect of specific drugs is often mixed.
- Benzodiazepines
Intravenous diazepam seems to lower IOP 8.
Midazolam is generally quoted as having no effect
- Antiemetics
Metoclopramide is generally quoted as increasing IOP, but studies exist that find a decrease in IOP after administration.
Cyclizine’s antimuscarininc action mildly increases IOP .
Ondansetron has no effect on IOP
- Induction agents
Ketamine increases IOP, probably by increasing choroidal blood volume. However, the effect is not always consistent. Studies of children undergoing procedural sedation show a fall in IOP with ketamine
Propofol and thiopentone cause a dose-dependent decrease in IOP, which is more pronounced with propofol
Etomidate can cause myoclonus, and so is unsuitable for penetrating eye injuries
- Maintenance agents
Volatile agents all decrease IOP.
Nitrous oxide has no effect, but it should be avoided in the therapeutic injection of intravitreal gas because it quickly diffuses into this gas, increasing IOP.
- Neuromuscular blocking drugs
Suxamethonium increases IOP, and like ketamine it is probably because of increased choroidal blood volume. This has been thought to be due to muscle fasciculation, but a similar increase in IOP is seen in patients with detached extra-ocular muscles.
There is a case report of vitreous humour expulsion following suxamethonium administration.
The remaining non-depolarizing muscle relaxants cause a small decrease in IOP.
- Opioids
Opioids reduce IOP by causing miosis, thereby increasing aqueous outflow, and reducing arterial pressure.
Opioids can usefully mitigate the rise in IOP seen with laryngoscopy.
- Autonomically-active drugs
Topical atropine causes pupillary dilatation and potentially close the iridocorneal angle. This decreases aqueous outflow, potentially increasing IOP. Systemic atropine does not have the same effect.
In theory, sympathomimetics have the same effect, but only topically; systemic drugs tend not to increase IOP.
Topical ophthalmic drugs of interest can be divided into drugs that work on the sympathetic and parasympathetic nervous systems and local anaesthetics.
Sympathomimetics
Phenylephrine and adrenaline are commonly used perioperatively and systemic absorption can result in hypertension, arrhythmias and vasospasm.
This is mediated by α1 receptors (phenylephrine) and β and α1 receptors (adrenaline).
Parasympatholytics
Mydratics such as atropine are absorbed especially well.
The expected anticholinergic syndrome results with a dry mouth, flushing and tachycardia.
β-adrenoreceptor blockers
Used as treatment for chronic OAG, excessive use can cause bronchospasm, hypotension and bradycardia.
Patients on rate-limiting calcium channel blockers may be more vulnerable.
Local anaesthetics
Usually benign, but occasionally cocaine solutions are used that can have an arrhythmogenic effect.
Parasympathomimetics
Parasympathomimetics, usually pilocarpine are used to manage intraocular hypertension. They cause bronchospasm, bradycardia and hypotension in high-serum concentrations.
Systemic drugs
Aside from simple analgesics and some antibiotics, the only systemic drugs of interest in ophthalmology are acetazolamide and mannitol.
Both are diuretics.
Mannitol can dry the mouth, increase thirst and, occasionally, cause seizures.
What are the symptoms associated with early and severe alcohol withdrawal?
In the CNS, alcohol:
Stimulates inhibitory GABA pathways
Antagonises excitatory glutamate pathways
Chronic alcohol exposure:
Induces insensitivity to GABA because only alcohol maintains inhibitory tone
Increases sensitivity to glutamate
Normal function of these pathways can only be maintained with the constant presence of alcohol. If alcohol is withdrawn, GABAergic inhibitory tone is lost and glutamic excitatory tone is increased. The net result is alcohol withdrawal syndrome.
Rob is a 55-year-old man who is listed for an urgent para-umbilical hernia repair. Since leaving the army aged 35, he has been mostly out of work aside from a few casual jobs. He has been in and out of social housing and occasionally sleeps rough.
He started drinking heavily a few years after leaving the army, and is under follow-up for alcoholic liver disease. He has had numerous inpatient stays for drainage of ascites and alcohol withdrawal syndrome.
He has been struggling with a transiently obstructing para-umbilical hernia for the last year. It has now become irreducible and he has had symptoms of intestinal obstruction for 24 hours. The surgeons wish to take him to theatre urgently.
Question: What immediate concerns do you have?
Question: You see the patient and conclude that he is at high risk. He has a large incarcerated hernia and is tachycardic and hypotensive. You commence fluid resuscitation on the ward. What investigations would you ensure are done?
The patient’s results are as follows:
ABG (Fig 1)
ECG (Fig 2)
Question: What do you conclude from these investigations?
Your immediate concerns are threefold:
Emergency presentation with intestinal obstruction:
Aspiration
Fluid depletion
Acid-base disturbance
Chronic alcoholism:
Alcohol withdrawal syndrome
CNS complications
Cardiovascular disease and dysrhythmias
Hepatic disease
Tendency to reflux
Anaesthetic and surgical concerns:
He will need a rapid sequence induction
Metabolic liver function, especially of anaesthetic drugs
Synthetic liver function, especially of clotting factors and albumin
Surgical stress response
Postoperative care
FBC, U&E and liver function tests (LFTs)
Clotting
An arterial or venous blood gas
A thromboelastograph (TEG)
ECG
Your conclusions are shown below:
ABG
A partially compensated metabolic acidosis
Anaemia
Mild hyponatraemia
ECG
Sinus tachycardia
Left ventricular hypertrophy
Left axis deviation
Mild left ventricular strain (flat T waves laterally)
The remainder of the investigations show a macrocytic anaemia, leucocytosis, deranged LFTs and normal urea and creatinine.
The INR is 2.1.
After knife-to-skin, his ECG changes (Fig 1). Your opinion about this situation is:
A. This is atrial flutter
B. This is atrial fibrillation with a fast ventricular response
C. The changes are temporary and need no intervention
D. You need to address the cause of the change, which may fluid depletion, electrolyte abnormalities or inadequate analgesia
E. You should consider slowing or cardioverting the rhythm
A. False.
B. True.
C. False.
D. True.
E. True.
The atrial fibrillation slows and then cardioverts to sinus tachycardia with a fluid bolus. He goes in and out of AF throughout the rest of the procedure.
The surgeons then tell you that they are struggling with haemostasis, and you order a thromboelastography (TEG) while administering 4 cross-matched units of blood.
Question: What should you do to optimise clotting while the TEG is analysing?
Question: What abnormalities are shown in his TEG results (Fig 1a)?
Question: How can this be managed?
You should:
Keep the patient warm
Attempt to normalise pH
Give tranexamic acid
The prolonged R time shows that there is a problem with clot initiation (Fig 1b).
This can be managed by giving clotting factors in the form of fresh frozen plasma (FFP).
Regarding alcohol pharmacology:
A. 80% of ingested alcohol is absorbed in the stomach
B. Alcohol is subject to first order kinetics
C. The liver enzyme CYP 2E1 is induced in chronic alcohol use
D. Alcohol binds to GABAA receptors at the GABA binding site
E. Gastro-oesophageal reflux can give a false positive alcohol breath test
F. One unit of alcohol is 15 ml of pure ethanol
A. False. 20% of ingested alcohol is absorbed in the stomach and 80% in the duodenum.
B. False. Alcohol is subject to zero order kinetics.
C. True.
D. False. Alcohol binds to its own site at GABAA receptors, not at GABA or benzodiazepine sites.
E. True.
F. False. One unit of alcohol is 10 ml of pure ethanol. The similar American standard, one ‘drink’ is 15 ml of pure ethanol.
Alcohol is a small molecule with both hydrophilic and lipophilic properties, i.e. amphipathic. It can cross cell membranes and it is absorbed directly from the stomach (20%) and small intestine (80%). This absorption depends on:
Gastric emptying, especially as the majority of alcohol is absorbed in the small intestine
Intestinal transit time
Portal blood flow
Drinks with alcohol content of 20-30% (vol/vol) irritate the gastric mucosa, decreasing gastric motility. This means that an alcoholic beverage such as a gin and tonic causes a faster rise in blood alcohol concentration (BAC) than neat gin.
Alcohol is vulnerable to first-pass metabolism via alcohol dehydrogenase (ADH), primarily in liver hepatocytes but also in the gastric mucosa. Following first-pass metabolism, the remaining alcohol achieves equilibrium with surrounding tissues within 1-2 hours. Alcohol has a low volume of distribution of around 0.6 L/kg, consistent with its hydrophilic nature. BAC correlates well with alveolar concentrations, forming the basis of the breathalyser test.
Alcohol is metabolised by ADH to acetaldehyde. At least four different ADH isoenzymes exist, which can account for the differing rates in metabolism in different individuals.
ADH metabolism of alcohol follows zero-order kinetics (Fig 1). There are alternative routes of metabolism:
Cytochrome P450 enzymes CYP 2E1, which accounts for around 10% of clearance at low BAC, but this increases in chronic heavy drinkers as the enzyme is induced
Heme-enzyme catalase pathway, which converts a small proportion of alcohol (0-2%) to acetaldehyde and water
ADH metabolism of alcohol produces the toxic metabolite acetaldehyde. This is in turn metabolised to carbon dioxide. Approximately 50% of Japanese individuals are missing one aldehyde dehydrogenase isoenzyme and are vulnerable to the toxic effects of acetaldehyde. This is analogous to taking disulfiram, an aldehyde dehydrogenase inhibitor used to treat alcoholism.
Alcohol acts over a number of central nervous system (CNS) transmitter pathways to give the familiar effects listed in Table 1.
The best-characterised mechanism of action involves inhibitory gamma-aminobutyric acid type A (GABAA) receptors, also the site of action for thiopentone. Alcohol interacts at the receptor at a site different to both the GABA and benzodiazepine binding sites.
Additional sites of action for alcohol include augmenting inhibitory glycine pathways, and inhibiting excitatory N-methyl-D-aspartate (NMDA) and dopaminergic pathways. There may well also be crossover with opioid pathways, evidenced by the use of μ-receptor antagonists naloxone and naltrexone to block alcohol cravings.
Acute intoxication has the multisystemic effects listed in Table 2.
Outside the acute effects, there are a host of organ-specific effects related to chronic alcohol use that are relevant to the anaesthetist.
Chronic alcohol use should be approached as a multisystemic disease analogous to diabetes. A similar set of preoperative considerations arise.
The consequences of acute amphetamine use can potentially be encountered in patients presenting for emergency surgery. The management is the same, with a risk-benefit analysis of urgency of surgery.
The goals of anaesthesia include:
A. Cardiac stability
B. Avoiding inducing arrhythmias
C. Avoiding further sympathetic triggers
D. Avoiding the use of serotonergic drugs
E. Thermoregulation
A. True.
B. True.
C. True.
D. True.
The goals of anaesthesia are broadly similar to those in cocaine intoxication, i.e. cardiac stability, avoiding inducing arrhythmias, avoiding further sympathetic triggers and avoiding the use of serotonergic drugs such as tramadol, pethidine and other phenylpiperidines.
E. True. Thermoregulation is an additional problem, and paralysis may be the only way to arrest heat generation. Malignant hyperthermia, serotonin syndrome and MDMA hyperpyrexia exist on the same spectrum and have similar treatments. Therefore, it is reasonable to avoid malignant hyperthermia triggers in patients that have had MDMA hyperpyrexia in the past.
Amphetamines are active through a wide range of paracrine and endocrine communication systems (Fig 1). They:
Promote monoamine signalling pathways, including dopamine, serotonin, noradrenaline and histamine, by indirect agonism and monoamine oxidase inhibition
Influence hormonal signalling by increasing adrenocorticotrophic hormone (ACTH), antidiuretic hormone (ADH) and prolactin secretion
May have direct activity at a number of receptor types including serotonin receptors, muscarinic acetylcholine receptors and histamine receptors
Amphetamines bind to trace amine-associated receptor 1 (TAAR1), a G protein-coupled receptor, which is colocalised on the presynaptic membrane with monoamine transporters noradrenaline (NET), dopamine (DAT) and serotonin (SERT). Activation on TAAR1 results in inhibition of the monoamine transporters, possibly leading to their phosphorylation and internalisation, and reversal of the vesicular monoamine transporter (VMAT) pump in the storage vesicles. The net result is an increase of the monoamine in the synaptic cleft. In greater doses, amphetamines also inhibit monoamine oxidase (Fig 1).
Amphetamines are metabolised hepatically through conventional enzyme pathways, including CYP2D6. These enzymes have well known inducers and inhibitors (Table 1). There is an element of genetic variability in this metabolism. This does not tend to affect drug removal, but rather the production of active metabolites that stimulate ADH production.
Hyperpyrexia, serotonin syndrome and rhabdomyolysis
There is a lot of overlap between sympathetically driven hyperpyrexia, serotonin syndrome and the effects of dancing energetically in a hot crowded club.
Similarly, rhabdomyolysis may be driven by hyperpyrexia, a direct effect of amphetamines on muscle, or a combination of the two.
Treating hyperpyrexia and serotonin syndrome
Ultimately, treatment of hyperpyrexia and serotonin syndrome is supportive and can extend to full multi-organ support in the intensive care unit (ICU).
Case studies have found dantrolene to be effective for both. It is thought to decrease the heat-generating excitation-contraction coupling.
Dantrolene is indicated if a temperature of 39°C does not respond to cooling measures.
Treating rhabdomyolysis
Rhabdomyolysis in amphetamine toxicity can be very severe, heralding disseminated intravascular coagulation (DIC) and multi-organ failure.
There is no specific treatment for rhabdomyolysis. Supportive care is the mainstay of treatment.
Hyponatraemia and cerebral oedema
Warnings of fatal hyperpyrexia have led ecstasy users to habitually drink large amounts of fluid. A consequent syndrome of hyponatraemia and cerebral oedema is well recognised. This is augmented by:
Ecstasy-induced release of ADH
Ecstasy-induced xerostomia
Hyponatraemia presents as:
Confusion
Coma
Seizures
Delirium
Management is usually conservative with the patient self-correcting with a diuresis. Fluid restriction is indicated in more severe cases and hypertonic saline in the most severe. Loss of sodium is rapid and so its correction can be equally rapid.
Liver failure
Liver failure can present in the context of multi-organ failure or as an isolated choleostatic hepatitis in chronic ecstasy exposure.
It resolves with supportive management, but ecstasy-induced hepatic failure has required treatment with liver transplant.
