2016-01-11 acem primary pharmacology - acem primary pharmacology (1) Flashcards
What is potency?
the amount of drug required to produce an effect of given intensity.
Potency is measured by the ed50 which is the amount (dose) of drug required to produce 50% of the drug’s maximal effect
What is efficacy?
measure of the maximum clinical respose to the drug regardless of dose
What is the ec50?
the dose at which 50% of people exhibit a quantified effect.
What is td 50?
The dose required to produce a toxic response in 50% of subjects (LD 50 has same definition but the toxic response is death)
What is the therapeutic index?
TD50/EC50 ratio
Give examples of lipid soluble ligands that cross the membrane and act on intracellular receltors?
steroids such as corticosteriods, sex steroids and vitamin D
These bind to the nucleus to stimulate transcription of genes and make new proteins- therefore the lag is 30 minutes to hours while the proteins are being made.
They persist in their effect over days when the agonist concentration goes to zero due to slow turnover of most enzymes and proteins
Give examples of substances that trigger ligand gated ion channels?
How does this work?
acetylcholine, gaba, excitatory amino acids
Receptor alters transmembrane conductance of ions and thereby alters electrical potential across the memebrane
Describe the nicotinic acetylcholine receptor?
pentamer made up of 5 polypeptide units (2 alpha, 2 beta, 1 gamma) which each cross the lipid bilayer 4 times and form a cylindrical structure. Binding of ach causes structural change that opens sodium channel. Occurs in milliseconds.
Give examples of substances that bind to a transmembrane receptor that stimulates a tyrosine kinase.
Insulin, PDGF, ANF
How do tyrosine kinase receptors work in general?
Receptor polypeptide consists of a hormone binding domain (extracellular) and an enzyme domain (cytoplasmic) which are connected through the membrane. Hormone binds with extracellular receptor, resulting conformational change that brings together the protein tyrosine kinase domains that become enzymatically active.
What are the three mechanisms by which a drug/ligand binding to a transmembrane protein can cause change?
- The transmembrane receptor contains an ion channel which changes shape e.g. gaba, ach
- The transmembrane receptor has a tyrosine kinase on the insidene.g. insulin, pdgf, anf
- Transmembrane receptor stimulates a g-protein- the activated g-protein changes the activity of a receptor element (usually an enzyme or an ion channel)
What is the advantage of signalling via g-proteins?
Signalling via G proteins allows effect to persist long after the extracellular receptor has dissociated from its agonist molecule
What do Gs G-proteins do?
increase adenylyl cyclase, causing increased cAMP
Give example of Gs G-proteins?
Beta adrenergic amines, glucagons, histamine, serotonin.
What do Gi G-proteins do?
Give examples of these?
decrease adenylyl cyclase, causing decreased cAMP Open cardiac potassium channels causing decreased heart rate
Alpha2 adrenergic amines, acetylcholine (muscarinic only), opioids, serotonin
What do Gold g-proteins do
Stimulate adenylyl cyclase causing increased cAMP.
stimulated by odourants
What do Gq G-proteins do?
Give examples of these?
Increase adenylyl cyclase causing increased cAMP Increase phopholipase C resulting in increased IP3, diacylglycerol and cytoplasmic calcium.
Acetylcholine (muscarinic), serotonin
What is the structure of g-protein coupled receptors?
serpentine receptors- polypetide chains which cross the membrane 7 times.
How does cAMP work?
G protein stimulates membrane adenylyl cyclase that converts ATP to cAMP. cAMP exerts most effects by stimulating cAMP dependent protein kinases.
How does calcium and phospholipase second messaging work?
G protein stimulates membrane enzyme phospholipase that hydrolyses PIP2 to DAG and IP3. DAG is confined to the membrane and activates protein kinase C.
IP3 diffuses through the cytoplasm to trigger release of calcium from internal stores. Calcium binds to calmodulin, which regulates calcium dependent protein kinases.
How are DAG and IP3 inactivated?
DAG inactivated by phosphorylation back to phospholipid.
IP3 rapidly inactivated by dephophorylation.
How does cGMP work?
small role -mainly intestinal mucosa and vascular smooth muscle. G protein stimulates membrane guanylyl cyclase which converts GTP to cGMP. cGMP exerts most effects by stimulating cAMP dependent protein kinases.
What is the volume of distribution?
What are the units?
It relates the amount of drug in the body to its concentration in blood or plasma- depends what it is soluble in/binds to.
Vd=Amount of drug in body /concentration. Most commonly expressed in units of litres per kilogram
Give an example of a drug that is distributed in the total body water?
What is the volume of distribution?
ethanol and other small water soluble molecules
0.61L/kg (42L)
Give an example if a drug that is distributed in the extracellular water?
What is the volume of distribution?
Mannitol, gentamycin
larger water soluble molecules
0.2l/kg
14 L
What is the volume of distribution of blood?
0.08l/kg= 5.6L
Give an example if a drug that is distributed in plasma? (and explain why it is largely confined to plasma)
What is the volume of distribution?
Heparin
0.04l/kg
Bound to a plasma protein
Give an example if a drug that is distributed in fat?
What is the volume of distribution?
DDT (insecticide)
0.2-.35l/kg (14-24l)
Give an example if a drug that is distributed in bone?
What is the volume of distribution?
0.07l/kg
(4.9L)
lead and flouride
What drugs cannot be removed by dialysis?
drugs with large volumes of distribution
Give examples of drugs with large volumes of distribution? (5-10L/kg)
Antidepressants
Phenothiazines
Propanolol
Verapamil
Give examples of drugs with small volumes of distribution? (
Theophylline Salicylate Phenobarbitone Lithium Phenytoin Heparin Warfarin
What is the half life of a drug?
Time required to change the amount of drug in the body by 1/2 during elimination or during a constant infusion
T1/2=0.7xVd / CL
Half life can refer to the drug itself or the active metabolites of the drug
What is allosteric action?
drugs that bind to the same receptor but do not prevent binding of the receptor molecule, may enhance or inhibit action
How is the action of transmembrane receptors terminated?
ligand binding often causes acellerated endoscytosis of reception followed by the degradation of the receptors and their bound ligands
Why are volumes of distribution greater than actual volumes found in the human body?
because it is the volume apparently necessary to contain the concentration found in blood, plasma or water
Drugs with very high volumes of distribution have much higher concentrations in the extravascular compartment then in the vascular compartment- i.e. not homogenously distributed.
Drugs that are completely retained within the vascular compartment have a minimum volume of distrubution
What is drug clearance?
Rate of elimination/concentration, this is additive when more than one organ clears it
i.e. CL(liver)= rate of elimination by liver/C
kidney generally excretes unchanged drug while liver metabolises
What is the rate of elimination?
CLx C when clearance is first order
calculated using the area under the time concentration curve (dose/AUC)
When is rate of elimination not first order?
capacity limited elimination e.g. phenytoin and ethanol, aspirin
also known as dose/concentration and saturatable elimination
cannot use auc to measure rate of elimination
rate of elimination = vmax x c/ km x c
What is flow-dependent elimination?
relevant for drugs that are cleared mainly on the first pass and therefore elimination depends on blood flow to the organ
What is bioavailability?
The fraction of the drug reaching the systemic circulation following administration by any route- IV has greatest bioavailability because it avoids first pass metabolism, extent of absorption (liphophilicity, reverse transporter associated with p glycoprotein)
How do your calculate the dosing rate for a drug?
CL x target concentration (TC)
How do you calculate the maintenance dose?
Drugs are usually administered in order to achieve a steady state where dosing equals elimination.
Dosing rate=CL X target concentration (TC)
Maintenance dose=dosing rate x dosing interval
When is a loading dose needed?
How does one calculate the loading dose?
Loading doses are required if the half-life of a drug is prolonged and the time taken to reach steady state would otherwise be prolonged
If the target concentration is known the clearance will determine the dosing rate
Loading dose=Vd X TC(target concentration)
Give a formula for systemic clearance of a drug?
Clearance can pertain to each organ and is additive in effect CLrenal+CLliver+CLother=CLsystemic.
What is another work for capacity limited clearance?
zero order kinetics
Describe how zero order kinetics works?
Drug elimination pathway becomes saturated at high concentration of drug. Elimination is proportional to concentration of the drug at low concentrations but at high concentrations elimination is constant.
e.g. Aspirin, Phenytoin, Ethanol
What is first order clearance?
First order clearance = clearance proportional to concentration
What are some drugs that exhibit flow dependent elimination? Give 3 examples?
Extraction is chiefly dependent on blood flow through the organ and the drug is almost completely extracted by the organ on first pass
Morphine Lignocaine Propanolol
What are some limitations to drug absorption in the gut?
Lipophilic (acyclovir) versus hydrophilic (atenolol) drugs
Bacterial metabolism within the gut (digoxin) Absorption abnormalities in small bowel.
What is the extraction ratio?
Extraction ratio defines the degree of first pass metabolism.
ER=CL liver /Q
(Q is hepatic blood flow = 90l/h)
Where does first pass elimination occur?
Can occur in gut wall, portal blood, or by excretion in bile. Most important is metabolism by liver.
What is the formula for systemic bioavailability?
Systemic bioavailability (F) =extent of absorption (f) X (1-ER)
How do you avoid hepatic first pass metabolism?
Hepatic first pass metabolism can be avoided by sublingual, transdermal and to a lesser extent, rectal administration
What is biotransformation?
Biotransformation is the metabolism of drugs that allows for the renal excretion of lipophilic, un-ionised or partially ionised drugs that would otherwise fail to be effectively excreted and have a prolonged duration of action.
Biotransformation transforms a lipophilic molecule into a more polar and therefore more readily excretable product.
Where does biotranformation occur
Biotransformation can occur in GIT (eg clonazepam, penicillin), lungs, skin, kidneys, but most important site is liver.
What are the two phases of biotransformation reactions?
Phase 1 reactions Convert the parent drug to a more polar metabolite by introducing or unmasking a functional group such as OH, NH2, SH.
Phase 2 reactions The introduced functional group combines with an endogenous substrate to form a highly polar conjugate. Enzymes for phase 2 reactions may be located in microsomes or in the cytosol. Phase 2 reactions can sometimes precede phase 1 reactions.
How do phase 1 reactions work?
Phase 1 reactions utilise mixed function oxidases located on the ER of liver cells and other tissues.
Require oxygen and NADPH to function. Mixed function oxidases include NADPH-cytochrome P450 reductase and cytochrome P450.
How many major CYP450 isoforms are there? What is the most important one?
Different P450 isoforms are responsible for metabolism of different drugs. 7 main isoforms account for most metabolism. CYP3A4 is the largest component, responsible for 60% of clinically prescribed drugs metabolised by the liver.
Where do phase 1 and 2 reactions occur?
Whase 1 occur on the ER, Phase 2 occur in microsomes and the cytosol
What are some genetic factors that affect biotransformation?
Suxamethonium - genetic defect in
pseudocholinesterase, causes suxamethonium to remain active for prolonged periods. Other examples - oxidation of ethanol, acetylation of isoniazid
What are some environmental factors that affect biotransformation?
Enzymes may be induced or inhibited by environmental factors.
Charcoal - induction
grapefruit juice -inhibition of CYP3A4 (responsible for 60% of drug metabolism)
What dies phenytoin do to digoxin metabolism?
Phenytoin enhances digoxin metabolism
What do barbituates do to warfarin metabolism?
Barbiturates enhance warfarin metabolism
The metabolism of what drugs does cimetidine affect?
Cimetidine inhibits warfarin and diazepam metabolism
The metabolism of what drugs is affected by cardiac disease?
Cardiac disease can affect drugs that are flow-limited
e.g. Morphine, Verapamil
What are the physical barriers to drug distribution? list 4
- Aqueous diffusion -generally determined by fixed law though if a drug is charged its flux will be influenced by electrical fields.
- Lipid diffusion - most important limiting factor for drug permeation. Lipid:aqueous partition coefficient determines how readily the molecule moves between acid aqueous and lipid media. The abililty of weak acids and bases to move between aqueous and lipid mediums depends on pH.
- Special carriers (active transport/facilitated diffusion) - for molecules that are too large or too insoluble - eg peptides, amino acids, glucose
- Endocytosis and exocytosis for very large molecules -eg vit B12, iron
What is fick’s law of diffusion
Passive flux of molecules down a concentration gradient equals the difference in concentration across the membrane (C1- C2) multiplied by the area of the membrane and the permeability coefficient, divided by the thickness of the membrane
conc grad x sa x perm coeff /thickness
Define weak acid?
a neutral molecule that can readily dissociate into an anion and a proton
Define weak base?
A neutral molecule that can combine with a proton and form a cation
What is the pKa?
pKa =the pH at which the concentrations of ionized and and inionized forms are equal
When are weak acids and bases more likely to be in a lipid soluble form?
More of a weak acid will be in a lipid soluble from at an acid pH.
More of a weak base will be in a lipid soluble form at an alkaline pH
This is important for excretion of drugs by the kidney.
What is the henderson hasselbach equation?
pH = pKa + log [base]/[acid]
What is the general structure of local anaesthetics?
Consist of a lipophilic group, ester or amide chain and ionisable group (usually a tertiary amine)
What are the two types of local anaesthetics?
Esters: Cocaine (procaine) (benzocaine)
Amides: Lignocaine Bupivicaine Prilocaine (etidocaine)
Define local anaesthetics?
Agents which reversibly block impulse conduction along nerve axons, thereby reducing pain sensation- usually do this by blocking voltage gated sodium channels
Where do local anaesthetics act on the sodium channel?
Blockade occurs at the intracellular end of the sodium channel
What are the pharmacodynamics of local anaesthetics?
Activated channels have higher affinity for drug therefore drug effect is more marked in rapidly firing fibres.
Progressive increase in drug concentration causes increased threshold, reduced action potential amplitude, then failure to produce an action potential.
What ion concentration changes increase and decrease the effects of local anaesthetics?
Local anaesthetic effect is increased by hyperkalaemia and decreased by hypercalcaemia
How does fibre type (size and myelination) affect how local anaesthetics work on the nerves?
Large diameter fibres less sensitive than small diameter fibres. (3 successive nodes required for blockade, nodes are further apart in large fibres).
Myelinated fibres of the same diameter as unmyelinated fibres tend to become blocked first.
Why are sensory nerves more sensitive to local anaesthetics?
Sensory fibres tend to have a fast firing rate and long action potential therefore are more sensitive to blockade.
How does the position of a nerve in the bundle affect how sensitive it is to local anaesthetics?
Peripheral nerves exposed first -motor nerves tend to be peripheral in large trunks.
What are the safe doses for lignocaine with/without adrenaline?
2mg/kg IV, 3mg/kg SC, 5mg/kg with adrenaline.
What is 1% solution of drug?
10mg/ml
What is the safe dose of bipivicaine and prilocaine?
Bupivacaine 2mg/kg SC
Prilocaine 3-5mg/kg IVRA
What are the relative potencies of the local anaesthetics, say lignocaine = 4
(if procaine = 1) Cocaine =2 Lignocaine =4 Bupivacaine = 16 Prilocaine = 3
What is the CNS toxicity of local anaesthetics?
Drowsiness, visual and auditory disturbance, restlessness, nystagmus, shivering, convulsions, CNS depression.
How do you manage convulsions caused by local anaesthetics?
If convulsion occurs, the patient should be hyperventilated to induce respiratory alkalosis as this lowers extracellular potassium and favours rested, low affinity sodium channels
Which local anaesthetics cause the most CNS and CVS toxicity?
Bupivacaine>lignocaine> prilocaine
Bipivicaine is most cardiotoxic -Although all local anesthetics potentially shorten the myocardial refractory period, bupivacaine avidly blocks the cardiac sodium channels, thereby making it most likely to precipitate malignant arrhythmias.
What are the cardiovascular effects of local anaesthetics?
Depression of cardiac pacemaker activity, excitability and conduction. Negative inotropic effect and decreased peripheral resistance.
How is cocaine different from other local anaesthetics in its cardiovascular effect?
noradrenaline uptake blockade and subsequent vasoconstriction and hypertension.
What haemotological toxicity do local anaesthetics have?
Prilocaine in high doses liberates the 0-toluidine metabolite that causes methaemoglobinaemia.
Which drug interract with local anaesthetics?
Fentanyl and midazolam utilise same microsomal enzymes in liver
Halothane, cimetidine and beta blockers decrease hepatic blood flow and therefore reduce metabolism
Enzyme inducers such as phenytoin may increase metabolism
Are local anaesthetics acid or base?
most are weak bases, potency depends on how liphophilic it is and therefore depends on the pH of the tissue
What is the active form of local anaesthetics? Is this the form that gets into the tissues?
Most are in a charged, cationic form and this is the active form at the receptor site, but the uncharged form is required for penetration - hence poor penetration in acidic (infected) tissue
How protein bound are local anaesthetics?
bupivicaine 95%, prilocaine 50%
What affects systemic absorption of local anaesthetics?
What does local effect depend on?
dose, vascularity of site of injection, drug-tissue binding, presence of vasoconstrictors (more effective for short acting highly lipid soluble drugs), chemical properties of the drug.
Local effect is proportional to the amount of drug that penetrates the nerve fibre
What is the comparative duration of action of the common local anaesthetics?
Cocaine -medium
Lignocaine -medium
Bupivacaine - long (up to 12 hours for peripheral nerve blocks)
Prilocaine - medium.
Why do ester local anaesthetics have a very short plasma half life?
Rapidly metabolised by pseudo- cholinesterase therefore half life less than 1 minute.
How are amide local anaesthetics metabolised?
Slowly hydrolysed by liver enzymes and excreted by kidney: Dosage reduction required in liver disease and reduced hepatic blood flow
Prilocaine metabolised most rapidly, lignocaine intermediate, bupivacaine slowest: Prilocaine metabolism produces O- toluidine
What are guedel’s stages of anaesthesia?
Stage of analgesia
Stage of excitement
Stage of surgical anaesthesia
Stage of medullary depression
What are the 5 factors that affect the brain uptake of an inhaled anaesthetic?
- Partial pressure of inspired anaesthetic agent
- Solubility (blood:gas partition coefficient)
The more soluble an agent the longer it takes for its partial pressure in blood to rise therefore the slower the onset of anaesthesia. - Pulmonary ventilation Increases the rate of induction of anaesthesia for drugs with high solubility - little effect on drugs with low solubility
- Pulmonary blood flow
Increased flow decreases the rate of induction with
soluble agents, little effect with poorly soluble agents. - Arteriovenous concentration gradient (tissue:blood solubility coefficient)
Gradient between arterial and mixed venous blood determined by uptake of agent by highly perfused organs such as brain, heart, liver, kidneys and gut. Drugs with high tissue:blood solubility coefficient take longer to reach equilibrium.
Define the MAC (minimal alveolar concentration).
Give an example of a drug with a high MAC?
What are the limits to using MAC?
The partial pressure (% concentration) of an agent which results in immobility of 50% of patients undergoing a surgical incision.
For nitrous oxide, MAC>100% means that even if the partial pressure of nitrous oxide is 760mmHg, incomplete anaesthesia is achieved.
There may be vast individual differences and the MAC gives no indication where the other 50% lie on the curve.
Why is steady state alveolar concentration a useful measure of potency?
When steady state is achieved, the partial pressure of an inhaled anaesthetic in the brain equals that in the lung, therefore measurement of steady state alveolar concentration gives a measure of potency
How do inhaled general anaesthetic agents work?
Increase in cellular threshold to firing with subsequent decreased spontaneous and evoked neuronal activity.
Ionic basis of effect includes activation of potassium currents to cause hyperpolarisation and opening of cation channels to decrease synaptic transmission.
Research suggests that agents interact with lipid membranes to cause distortion of ion channels.
What are the cardiovascular effects of general anaesthetic agents?
Dose related variable reduction in mean arterial pressure and myocardial oxygen demand. Effects may be masked by nitrous oxide which causes sympathetic stimulation
Nitrous oxide causes minimal depressant effects
Halothane sensitises the myocardium to catecholamines and is arrhythmogenic.
What are the respiratory effects of general anaesthetics? List 5
- Respiratory depression due to reduced TV and inadequate increased rate. (except nitrous oxide)
- Increase apneic threshold to pCO2.
- Decrease ventilatory response to hypoxia.
- Decrease mucociliary function leading to atelectasis.
- Most have bronchodilator action.
What are the CNS effects of general anaesthetics?
Increase metabolic rate and blood flow to brain due to reduced cerebrovascular resistance. Hyperventilation reduces this effect.
What are the GI and GU effects of general anaesthetics?
GUS
Reduced renal blood flow and GFR. Uterine relaxation (minimal with nitrous oxide)
GIT
Reduced hepatic blood flow.
Describe the acute and chronic toxicity of general anaesthetic agents?
Halothane -1 in 35000 cases of fatal hepatic necrosis.
Methoxyflurane -fluoride related nephrotoxicity.
Malignant hyperthermia -tachycardia, hypertension, acidosis, hyperkalaemia, muscle rigidity, hyperthermia ,more common if suxamethonium also used -treated with dantrolene.
Chronic exposure to Nitrous oxide is associated with megaloblastic anaemia
What is the MAC of the common anaesthetic agents?
Nitrous oxide >100
Isoflurane - 1.4
Halothane - 0.75
Methoxyfluorane - 0.16
What are the solubilities and the brain:blood partition coefficients of the common anaesthetic agents?
Solubility (blood:gas partition coefficient) : Nitrous oxide - 0.47 Isoflurane -1.4 Halothane - 2.3 Methoxyfluorane - 12
Brain:blood partition coefficient Nitrous oxide ␣ 1.1 Isoflurane - 2.6
Halothane - 2.9
Methoxyfluorane - 2.0
Give some examples of IV general anaesthetics?
Barbiturates Benzodiazepines Opioids Propofol Ketamine
Give examples of barbituate general anaesthetics?
Phenobarbitone
Thiopentone -ultra short acting barbiturate intravenous anaesthetic
How do barbituates work? (3 mechanisms)
- Barbiturates bind to components of the GABA receptor and facilitate its action by increasing the duration of chloride channel opening.
- At high concentrations GABA may directly stimulate the receptor.
- Also depress actions of other excitatory neurotransmitters and have non-synaptic membrane effects.
What is the structure of the GABA receptor in the CNS?
GABA receptor consists of 5 alpha, beta and gamma membrane-spanning proteins which can form different pentameric combinations.
What are the indications for barbiturates in humans?
What is the dose of thiopentone?
Phenobarbitone - neonatal seizures.
Thiopentone -anaesthesia
Dose Thiopentone 3-5mg/kg
What are the adverse effects of thiopentone?
Toxicity CVS Depression at high doses.
Dose dependent decreased blood pressure, stroke volume and cardiac output.
Respiratory depression.
Decreased cerebral metabolism and blood flow. Nystagmus.
Reduces hepatic and renal blood flow.
Dizziness, fatigue, amnesia, blurred vision. Tolerance. Dependence.
What interactions do barbituates have with other drugs?
Effects are potentiated by other sedatives such as alcohol or other sedatives-may cause fatal CVS depression.
Induction of liver enzymes - decreases effect of warfarin, anticonvulsants, digoxin.
What are the contraindications for barbiturates?
Precaution with liver failure. Readily crosses placenta and enters breast milk. Porphyrias
What is the absorption and distribution of thiopentone and phenobarbitone?
Phenobarbitone -Orally active, rapidly absorbed. 50% protein bound.
Thiopentone - intravenous
Highly lipid soluble and rapidly distributed to brain, then redistributed to other tissues. Redistribution from CNS to skeletal muscle and adipose tissue is important process that contributes to termination of CNS effects.
Initial redistribution to brain and viscera, then to lean tissues and then to fat
Metabolised slowly in liver to water- soluble inactive metabolites that are excreted in urine.
What are the half lives of thiopentone and phenobarbitone?
Phenobarbitone plasma half life 4 hours, excretion half life 4-5 days (therefore has a tendency to accumulate)
Thiopentone Produces hypnosis in one circulation time. Plasma:brain equilibrium occurs rapidly (
How much of thiopentone and phenobarbitone is excreted unchanged?
Phenobarbitone 20% excreted unchanged.
Thiopentone - 1% excreted unchanged, metabolised at 12- 16% per hour.
What is propofol?
Phenol derivative.
Short acting intravenous anaesthetic agent.
Presented as an oil in water emulsion.
How does propofol work?
Potentiates the action of inhibitory neurotransmitters including GABA and glycine.
What is the dosage of propofol?
Sedation 0.5-1mg/kg Usually given in 20mg increments
Induction of anaesthesia 2-2.5mg/kg Usually given in 40mg increments.
Dose can be repeated as required.
What are the adverse effects and contraindications of propofol?
- Marked hypotension (15- 25%) due to reduced peripheral vascular resistance (direct effect of propofol). Potent negative inotropic effects. No compensatory increase in heart rate.
- Potent respiratory depression. Brief apnoea common. Infusion produces decreased tidal volume. Some bronchodilation due to direct effect on smooth muscle.
- Rapid, smooth induction and clear headed recovery. Cerebral blood flow and ICP decrease slightly.
- General Pain in injection in 25%.
Contraindications: Acidosis and possible neurological sequelae in children therefore contraindicated under 3 years.
Given as an intravenous fat emulsion - previous vehicle cause hypersensitivity reactions.
Onset, distribution and elimination of propofol?
What is the volume of distribution and why?
Rapid onset (30 seconds) and recovery
Distribution half life (t1/2 alpha) : 2-8 minutes,
Elimination half life (t1/2 beta): 30- 60 minutes.
90% protein bound. Small volume of distribution.
Where and how quickly is propofol metabolised?
What determines the distribution of effect of propofol?
Rapidly metabolised in liver (10 times faster than thiopentone) and excreted in urine.
Duration of effect largely determined by redistribution.
Less than 1% excreted unchanged.
What is ketamine and how does it work?
Short acting non-barbiturate intravenous anaesthetic agent. Chemically related to PCP
Action may involve blockade of glutamic acid (NMDA) receptors.
Mechanism of action largely unknown
What kind of anaesthesia does ketamine produce?
Characteristic
dissociative anaesthesia :amnesia, profound analgesia, normal or slightly increased muscle tone without loss of consciousness or loss of protective reflexes.
What is the IV dose of ketamine?
1-4mg/kg Administer slowly over 60 seconds to avoid respiratory depression and pressor response
What is the onset and offset of ketamine?
Onset 30 seconds, duration of action 5- 10 minutes. Additional doses can be given without accumulation
(Intramuscular 6.5-13mg/kg
Onset 2 minutes, duration 20 minutes)
What are the organ effects and toxicity of ketamine?
- CVS: Increased heart rate, blood pressure and cardiac output via inhibition of noradrenaline reuptake -peaks 2-4 minutes after injection, declines after 20 minutes.
- RS: May increase or decrease respiratory rate for several minutes. Upper airway tone is maintained.
- CNS Marked increase in cerebral blood flow and intracranial pressure. Nystagmus
- Emergence phenomena in 12% -disorientation, sensory and perceptual illusions and vivid dreams. Less incidence in children and elderly.
Reduced by minimising verbal, tactile and visual stimuli during recovery Interactions
Avoid hypertensive agents
Contraindications Uncontrolled hypertension, severe cardiovascular disease
Where does ketamine distrubute to and how is the effect of ketamine terminated?
Distribution Highly lipid soluble.
Rapid distribution to all tissues.
Termination of effect due to redistribution from brain to peripheral tissues
What is the metabolism of ketamine?
Metabolised by liver to 4 different metabolites including norketamine which has one sixth the potency of ketamine
Metabolites excreted in urine.
What is the structure of muscle relaxants?
What are the 2 types of muscle relaxants?
Structure: All bear a structural resemblance to acetylcholine
Depolarising Suxamethonium= 2 acetylcholine molecules linked end-to-end.
Non- depolarising (NDPMRs) Isoquinolone, tubocurarine, atracurium.
Steroid: pancuronium, vecuronium, rocuronium.
How do depolarising muscle relaxants work?
- Binds with the nicotinic receptor at the neuromuscular junction to cause the sodium channel to open and the end plate to depolarise. This results in generalised disorganised contraction. Suxamethonium is not metabolised effectively at the synapse, therefore depolarised membranes remain depolarised and unresponsive to subsequent impulses.
- Phase 2 block (Desensitising): depolarisation gradually decreases and the membrane becomes repolarised. Membrane cannot become repolarised while suxamethonium is present- essentially this is the same as non-depolarising blockade.
How do non-depolarising muscle relaxants work?
Reversible blockade, act predominantly at nicotinic receptors. Prevents opening of the sodium channel, may also enter ion pore at higher does and cause blockade.
What are the doses of suxamethonium and verocuronium?
Suxamethonium 1-1.5mg/kg (children relatively resistant) May be given IM
Vecuronium 0.1mg/kg
What are the adverse effects of depolarising and non-depolarising muscle relaxants?
- CVS: Pancuronium causes a moderate increase in heart rate and cardiac output due to vagolytic action.
Vecuronium, rocuronium (and most others) have little or no cardiovascular effects - Suxamethonium stimulates all autonomic cholinoceptors to some extent.
Bradycardia and negative inotropic effects at low doses and especially after a second dose.
Prevented by premedication with atropine and by giving a minimum dose. - Hyperkalaemia Due to exaggerated release of potassium from extra- junctional nicotinic receptors. There is an exaggerated release with burns, renal failure.
- Raised intraocular pressure Raised intragastric pressure Raised intracranial pressure
- Muscle pain This is the most common side effect
Malignant hyperthermia: Tachycardia, tachypnoea, rigidity
Contraindications to muscle relaxants?
Personal or family history of malignant hyperthermia Muscular dystrophy
Absorption and distribution of muscle relaxants?
All are highly polar and inactive orally.
Non-depolarising : Rapid initial distribution, small volume of distribution.
Metabolism and excretion of depolarising muscle relaxants?
What defects in excretion are there and what effect can this cause? Is there a test for this?
Onset of action 30s, duration of action 5-10 minutes due to rapid hydrolysis by pseudo- cholinesterase.
This limits the amount of drug reaching the synaptic cleft. Very little plasma cholinesterase at end plate neuromuscular blockade is terminated by diffusion away from the endplate into extracellular fluid.
95% of the population will have a normal pseudo- cholinesterase response. 5% will have prolonged apnoea up to 10 minutes.
Metabolism and excretion of non depolarising muscle relaxants?
Onset of action 2-3 minutes Route of elimination correlates with duration of action.
Renal excretion is slow, hepatic excretion fast.
Steroid -metabolised to 3 hydroxy, 17 hydroxy and 3,17 hydroxy metabolites that also have clinical effect and may persist.
Vecuronium - duration of action 20-35 minutes, minimal cardiovascular effects, hepatic elimination - 85% eliminated into bile.
Pancuronium -duration of action 35minutes - 1 hour, mainly excreted by kidney.
Rocuronium - very rapid onset of action.
What is the fastest onset non-depolarising muscle relaxant?
rocuronium
Mechanism of action of dantrolene?
Acts on the sarcoplasmic reticulum of skeletal muscle
Causes reduced release of calcium from the sarcoplasmic reticulum
What is malignant hyperthermia?
Malignant hyperthermia can be triggered by general anaesthesia and neuromuscular blockade and is a hereditary impairment of the ability to sequester calcium in the sarcoplasmic reticulum
Trigger results in massive release of calcium with prolonged muscle contraction, lactic acidosis and hyperthermia
What are the classes of antipychotics?
- Phenothiazine derivatives: Chlorpromazine
- Thioxanthene: Thiothixene
- Butyrophenone derivatives : Haloperidol
- Miscellaneous: Clozapine, Rispiradone, Olanzapine
Mechanism of action of antipsychotics?
Dopamine antagonist ␣ antipsychotic action related to dopamine receptor blockade in mesolimbic and mesofrontal systems.
Chlorpromazine Alpha1=5H T2>D2>D1 Haloperidol D2>D1=D4>Alpha1> 5H T2 Clozapine Alpha1 =D4 >5HT2> D2=D1 Rispiridone D2=5HT2 Olanzapine 5HT2>D2=D1=Alpha1> H1
Potency of various antipsychotics?
Chlorpromazine -low Thiothixene - high Haloperidol - high Clozapine - medium Rispiradone - high Olanzapine - high
Dosing of antipsychotics?
Haloperidol Oral 1-15mg/day in divided doses. IM - 2-30mg IV - 1-5mg
Chlorpromazine PO/IM 25-50mg tds
Olanzapine 10mg PO/IM
CNS Toxicity of antipsychotics?
Toxicity CNS Extrapyramidal effects Extrapyramidal toxicity related to high D2 affinity; manifest as parkinsonism, akathisia, acute dystonic reactions, tardive dyskinesia.
Chlorpromazine -high Thiothixene - medium Haloperidol - very high Clozapine - very low Rispiradone - low Olanzapine - very low
Sedation: esp chlorpromazine
Clozapine -2% incidence of seizures (can also occur with other antipsychotics)
ANS Toxicity of antipsychotics?
Autonomic effects Antimuscarinic actions. Loss of accommodation, dry mouth, difficulty urinating, constipation : Alpha1 antagonist actions.
CVS Toxicity of antipsychotics?
Tachycardia, reduced stroke volume, decreased peripheral resistance, orthostatic hypotension
Thioridazine causes T wave abnormalities and is associated with prolonged QT, ventricular arrhythmias and sudden death
most- chlorpromazine, least: olanzapine and haloperidol
What is NMS and how is it treated?
Neuroleptic malignant syndrome Muscle rigidity, reduced sweating, fever, autonomic instability, leukocytosis
Marked increases in CK may result in renal failure -use bromocriptine
Endo, haem effects of antipsychotics?
Amenorrhoea, galactorrhoea, increased or decreased libido, impotence -secondary to blockade of dopamine induced tonic inhibition of prolactin secretion.
Clozapine, chlorpromazine may cause agranulocytosis
Chlorpromazine - corneal and lens deposits
Absorption and distribution of antipsychotics?
Orally active. Readily but incompletely absorbed.
Chlorpromazine Significant first pass metabolism :bioavailability 30%. Half life 30 hours.
Others- Moderate first pass metabolism : bioavailability 65%
95% protein bound, lipid soluble, high distribution volumes
Presentation of antipsychotic overdose?
Drowsiness, coma, neuromuscular excitability, convulsions. Miosis and loss of deep tendon reflexes. Hypotension and hypothermia.
Activated charcoal effective.
Supportive therapy.
Avoid adrenaline and lignocaine.
Mechanism of action of lithium? 3 broad effects
- Closely related to sodium -inhibits sodium exchange across membranes but no effect on sodium/potassium or sodium/calcium exchange.
- Effects on neurotransmitters Enhances the action of serotonin. Decreases noradrenaline and dopamine turnover. Augments the synthesis of acetylcholine.
- Effects on second messengers. Inhibits enzymes responsible for recycling of inositol compounds, resulting in depletion of PIP2, IP3 and DAG.
Usual maintenance dose of lithium
dose 500mg-1g/day
Interractions of lithium?
Renal clearance reduced by diuretics and some NSAIDs.
Increased extrapyramidal effects when used with antipsychotics (except newer drugs) May increase the duration of muscle relaxnants.
Lithium toxicity?
Tremor (alleviated by propanolol), choreoathetosis, motor hyperactivity, ataxia, dysarthria, aphasia.
Mental confusion, drowsiness and seizures at higher levels.
Endocrine: Reversible reduction in thyroid function.
GUS: Nephrogenic diabetes insipidus, chronic interstitial nephritis, minimal change glomerulonephritis.
CVS: Nodal depression and T wave flattening.
General Oedema and weight gain.
Lithium in pregnancy?
Clearance increases during pregnancy and falls following delivery.
??dysmorphogenesis - unsettled.
Lithium toxicity in newborns characterised by lethargy, cyanosis, poor suck and reflexes
Absorption and distribution of lithium?
Orally active, completely absorbed in 6-8 hours, peak levels 30 minutes. 100% bioavailability.
Distribution Total body water, slow entry into intracellular compartment. Some sequestration into bone.
Excretion of lithium?
Not metabolised. Excreted into urine at 20% of the rate of creatinine clearance.
Elimination half- life 20 hours.
Presentation and management of lithium overdose?
anorexia, nausea, vomiting, diarrhoea, muscle weakness, lack of cooordination
No specific antidote.
Clearance increased by osmotic diuresis and urinary alkalinisation. Readily removed by haemodialysis.
Give four examples of antidepressant classes?
tricyclincs- amytriptilline, imipramine
Heterocyclics:
SSRI:
MAOI’s
Tricyclics Imipramine
Amitriptyline
Heterocyclics
Second generation: Maprotiline (tetracyclic) ,Buproprion
Third generation: venlafaxine
SSRIs
fluoxetine
MAOs: Phenelzine, Moclobamide
How do tricyclic antidepressants work?
Adverse effects?
Blockade of amine (serotonin»_space;noradrenaline) reuptake pumps.
Antimuscarinic actions Alpha1, H1, H2 antagonist
> 1000mg toxic
CNS Sedation, seizures, psychosis, coma Antimuscarinic effects very common Tremor, insomnia
CVS Orthostatic hypotension Tachycardia and minor T/ST changes very common Conduction defects (long PR, wide QRS>0.1s, long QT and ST) and arrhythmias also common.
GIS Nausea, raised liver enzymes
How do heterocyclic antidepressants work?
Adverse effects?
Buproprion alters noradrenaline neurotransmission by an unknown mechanism. Third generation heterocyclics have additional antagonist of 5HT receptors.
Same as TCAs though less pronounced.
How do MAOI’s work?
Adverse effects?
Blockade of MAO mediated amine degradation. MAO-A metabolises noradrenaline and serotonin, MAO-B metabolises dopamine.
Initial increase in amine leads to down-regulation of receptors.
Adverse effects of SSRI?
Anxiety, insomnia, tremor, nausea, rash (may lead to severe vasculitis), decreased libido. SSRI use in combination with MAO may lead to toxic build up of serotonin and serotonin syndrome
What is serotonin syndrome?
TCAs and SSRIs Serotonin syndrome if characterised by hyperthermia, muscle rigidity, myoclonus.
Antidepressant interactions with other drugs?
Phenothiazines displace TCAs from protein binding site and potentiate action.
Nefazodone can inhibit P450-3A4 and block the metabolism of terfenadine and cisapride.
F luoxetine and paroxetine are potent inhibitors of P450-2D6 -desipramine, nortriptiline and flecainide are dependent on same enzyme system for clearance.
MAOs : Accumulation of tyramine (fermented foods and drinks) results in hypertension. Moclobamide is relatively short acting compared with older drugs therefore this effect is rare
Absorption and distribution of tricyclics?
Incompletely absorbed. Slow gastric emptying due to antimuscarinic effect. Significant first pass metabolism (bioavailability 30- 70%)
80-90% protein bound. High lipid solubility. Large Vd
Absorption and distribution of tetracyclics?
Incompletely absorbed. Significant first pass metabolism (bioavailability 30- 70%)
80% protein bound. High lipid solubility. Large Vd
Absorption and distribution of SSRI’s?
Well absorbed orally. Moderate first pass metabolism (bioavailability 50- 70%) 95% protein bound.
High lipid solubility. Large Vd
Absorption and distribution of MAOI’s?
Well absorbed orally.
Metabolism of tricyclics, tetracyclics, MAOI’s?
Tricyclics: Metabolised in liver to active metabolites. Half life 10-40 hours
Heterocyclics: Metabolised in liver to active metabolite. Half life 10-40 hours
SSRIs Metabolised in liver. Fluoxetine forms an active metabolite, nil with paroxetine. Half life 24-96 hours.
MAOs: Metabolised in liver. Acetylation of phenelzine varies between individuals and may persist for several weeks.
Antidepressant overdose?
Severe antimuscarinic response is common Extension of toxic effects listed plus respiratory depression, metabolic acidosis, heart failure, cardiac arrest
Give 4 examples of anticonvulsants that are sodium channel blockers/membrane stabilisers?
Phenytoin
Carbamazepine Sodium valproate Lamotrigine
Give 4 examples of anticonvulsants that are GABA modulators?
Benzodiazepines Gabapentin Vigabatrine Phenobarbitone
What kind of antiarrhythmic is phenytoin?
class 1b
Mechanisms of phenytoin?
Membrane stabiliser - preferentially binds to inactivated sodium channel and maintains inactivated state and therefore blocks sustained high frequency repetitive firing of action potentials.
Reduces calcium permeability therefore inhibits calcium related secretory processes.
May potentiate the effects of GABA
Inhibits release of serotonin and noradrenaline, promotes uptake of dopamine.
Inhibits monoamine oxidases.
Uses of phenytoin?
Prophylaxis and treatment of partial seizures and generalised tonic clonic seizures.
Fast atrial and ventricular arrhythmias resulting from digoxin toxicity.
Trigeminal neuralgia.
Dosing of phenytoin?
10-15mg/kg not exceeding 50mg/minute then 100mg orally every 8 hours
(slow administration due to propylene glycol diluent which may induce cardiac arrhythmias
Toxicity of phenytoin?
Dose related CNS: Nystagmus and loss of smooth ocular pursuit. Diplopia and ataxia. Sedation.
CVS: Cardiovascular collapse (diluent effect if rapid administration)
Idiosyncratic: Chronic use frequently leads to gingival hyperplasia and hirsutism, coarsening of facial features, diminished tendon reflexes and osteomalacia.
Rash, fever, rare agranulocytosis.
Interractions of phenytoin with other drugs?
Protein binding : Phenytoin is displaced by highly protein bound drugs such as sulphonamides, calcium channel blockers. Hypoproteinaemia causes increased free drug.
May confuse thyroid function tests due to affinity for TBG.
Enzyme inducers: Phenytoin induces liver enzymes and affects the metabolism of other drugs such as warfarin, opioids, neuromuscular blockers, beta blockers
Other inducers may reduce phenytoin levels - anticonvulsants, rifampicin, ciprofloxacin
Enzyme inhibitors Erythromycin, cimetidine
Absorption and distribution of phenytoin?
Orally active. Intramuscular absorption unpredictable. 90% bound to plasma proteins.
Maximal effect after IV dose occurs after 30-60 minutes and may persist for 24 hours
Accumulates in endoplasmic reticulum of brain, liver, muscle and fat.
Therapeutic concentration 10- 20ug/l
Where is phenytoin metabolised and what kind of kinetics does it display?
Metabolised by liver, excreted in bile, reabsorbed and excreted in urine.
Variable order kinetics: Elimination rate is dose dependent - at low doses there is first order kinetics but metabolism is saturated at therapeutic concentrations and small increases in dose quickly lead to toxicity.
Half life and steady state of phenytoin?
Half life 12-36 hours -much higher at high concentrations.
5-7 days to reach steady state.
Overdose of phenytoin
Overdose Toxicity varies between individuals CNS effects predominate though bradycardia and heart block can also occur
Mechanism of carbamazepine?
Membrane stabiliser - preferentially binds to inactivated sodium channel and maintains inactivated state and therefore blocks sustained high frequency repetitive firing of action potentials.
Also acts pre-synaptically to decrease synaptic transmission.
Inhibits reuptake and release of noradrenaline.
Interacts with adenosine receptors - ?significance
Toxicity of carbamazepine?
Skin rash common.
Diplopia, ataxia - often mild and reversible.
Drowsiness at high concentration.
Hyponatraemia and water intoxication rarely.
Rare agranulocytosis , leukopenia is common and just requires monitoring.
Interractions of carbamazepine?
Induces liver enzymes and affects own metabolism : half-life is typically halved from 40 to 20 hours with continuous therapy.
Phenytoin, carbamazepine, barbiturates and lamotrigine induce liver enzymes and reduce levels of each other.
Reduces effectiveness of benzodiazepines, pethidine, and warfarin.
Pharmacokinetics of carbamazepine?
Orally active
Rate of absorption variable but complete
Slow distribution. 70% protein bound.
Metabolised in liver -metabolite may have some clinical activity.
What is the active constituent of sodium valproate?
Fully ionised at body pH therefore active constituent is the valproate ion.
Mechanism of sodium valproate?
Membrane stabiliser - preferentially binds to inactivated sodium channel and maintains inactivated state and therefore blocks sustained high frequency repetitive firing of action potentials.
Increases levels of GABA - likely insignificant
Increases membrane potassium conductance
