ACEM Pharm part 1 - acem primary pharmacology Flashcards
1
Q
What is potency?
How is it measured.
A
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
2
Q
What is efficacy?
A
measure of the maximum clinical respose to the drug regardless of dose
3
Q
What is the ec50?
A
the dose at which 50% of people exhibit a quantified effect.
4
Q
What is td 50?
A
The dose required to produce a toxic response in 50% of subjects (LD 50 has same definition but the toxic response is death)
5
Q
What is the therapeutic index?
A
TD50/EC50 ratio Quantitatively, it is the ratio given by the lethal (animal studies) or toxic dose (human studies) of a drug for 50% of the population (LD50 or TD50) divided by the minimum effective dose for 50% of the population (ED50). Remifentanyl 33,000:1; tetrahydrocannabinol 1000:1, while diazepam 100:1 and morphine 70:1
6
Q
Give examples of lipid soluble ligands that cross the membrane and act on intracellular receltors?
A
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
7
Q
Give examples of substances that trigger ligand gated ion channels? How does this work?
A
acetylcholine, gaba, excitatory amino acids Receptor alters transmembrane conductance of ions and thereby alters electrical potential across the memebrane
8
Q
Describe the nicotinic acetylcholine receptor?
A
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.
9
Q
Give examples of substances that bind to a transmembrane receptor that stimulates a tyrosine kinase.
A
Insulin, platelet derived growth factor (PDGF) & atrial natriuritic peptide (ANP)
10
Q
How do tyrosine kinase receptors work in general?
A
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.
11
Q
What are the three mechanisms by which a drug/ligand binding to a transmembrane protein can cause change?
A
- The transmembrane receptor contains an ion channel which changes shape e.g. gaba, ACh
- The transmembrane receptor has a tyrosine kinase on the in side e.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)
12
Q
What is the advantage of signalling via g-proteins?
A
Signalling via G proteins allows effect to persist long after the extracellular receptor has dissociated from its agonist molecule
13
Q
What do Gs G-proteins do?
A
increase adenylyl cyclase, causing increased cAMP
14
Q
Give example of Gs G-proteins?
A
Beta adrenergic amines, glucagons, histamine, serotonin.
15
Q
What do Gi G-proteins do? Give examples of these?
A
Decrease adenylyl cyclase, causing decreased cAMP
Alpha2 adrenergic amines, acetylcholine (muscarinic only), opioids, serotonin
The ACh M2 muscarinic receptors cause inhibition of voltage-gated Ca2+ channels, and increasing efflux of K+, in general, leading to inhibitory-type effects to decrease heart rate
16
Q
What do Golf g-proteins do
A
Stimulate adenylyl cyclase causing increased cAMP. They are stimulated by odourants
17
Q
What do Gq G-proteins do? Give examples of these?
A
Increase adenylyl cyclase causing increased cAMP Increase phopholipase C resulting in increased IP3, diacylglycerol and cytoplasmic calcium. Acetylcholine (muscarinic), serotonin or noradrenaline in alpha1 receptors within peripheral vasculature.
18
Q
What is the structure of g-protein coupled receptors?
A
serpentine receptors- polypetide chains which cross the membrane 7 times.
19
Q
How does cAMP work?
A
G protein stimulates membrane adenylyl cyclase that converts ATP to cAMP. cAMP exerts most effects by stimulating cAMP dependent protein kinases.
20
Q
How does calcium and phospholipase second messaging work?
A
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.
21
Q
How are DAG and IP3 inactivated?
A
DAG inactivated by phosphorylation back to phospholipid. IP3 rapidly inactivated by dephophorylation.
22
Q
How does cGMP work?
A
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.
23
Q
What is the volume of distribution? What are the units?
A
- It is a theoretical value used clinically when trying to determine the loading dose necessary for a desired blood concentration of a drug or for estimating a blood concentration in the treatment of overdose. - Vd is the volume of plasma that would be necessary to account for the total amount of drug in the patient’s body, if that drug were present throughout the body at the same concentration as found in the plasma. - This value is usually further divided by the patient’s body weight, and the result expressed in terms of litres per kilogram - Vd=Amount of drug in body /concentration.
24
Q
Give an example of a drug that is distributed in the total body water? What is the volume of distribution?
A
ethanol and other small water soluble molecules 0.61L/kg (42L)
25
Give an example of 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
26
What is the volume of distribution of blood?
0.08l/kg= 5.6L
27
Give an example of 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
28
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)
29
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
30
What drugs cannot be removed by dialysis?
drugs with large volumes of distribution
31
Give examples of drugs with large volumes of distribution? (5-10L/kg)
Antidepressants Phenothiazines Propanolol Verapamil
32
Give examples of drugs with small volumes of distribution? (\<1l/kg)
Theophylline Salicylate Phenobarbitone Lithium Phenytoin Heparin Warfarin
33
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
34
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
35
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
36
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
37
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
38
What is the rate of elimination?
CLx C when clearance is first order calculated using the area under the time concentration curve (dose/AUC)
39
When is rate of elimination not first order?
1. 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 2. Rate of elimination = vmax x c/ km x c
40
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
41
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)
42
How do your calculate the dosing rate for a drug?
CL x target concentration (TC)
43
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
44
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)
45
Give a formula for systemic clearance of a drug?
Clearance can pertain to each organ and is additive in effect CLrenal+CLliver+CLother=CLsystemic.
46
What is another word for capacity limited clearance?
zero order kinetics
47
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
48
What is first order clearance?
First order clearance = clearance proportional to concentration
49
What is flow dependent elimination? Give 3 examples of drugs efected by this principle?
* Extraction is chiefly dependent on blood flow through the organ and the drug is almost completely extracted by the liver on first pass
* Morphine Lignocaine Propanolol
50
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.
51
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)
52
Where does first pass elimination occur?
Can occur in gut wall, portal blood, or by excretion in bile. Most important is metabolism by liver.
53
What is the formula for systemic bioavailability?
Systemic bioavailability (F) =extent of absorption (f) X (1-ER) [extraction ratio]
54
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
55
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.
56
Where does biotranformation occur?
Biotransformation can occur in GIT (eg clonazepam, penicillin), lungs, skin, kidneys, but most important site is liver.
57
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.
58
What are four (4) key features of phase 1 biotransformation reactions?
1. Includes oxidative, reductive, and hydrolytic reactions.
2. In these type of reactions, a polar group is either introduced or unmasked, so the drug molecule becomes more water-soluble and can be excreted.
3. Reactions are non-synthetic in nature and in general produce a more water-soluble and less active metabolites.
4. The majority of metabolites are generated by a common hydroxylating enzyme system known as Cytochrome P450.
59
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.
60
What are the three (3) key features of phase 2 biotransformation reactions?
1. These reactions involve covalent attachment of small polar endogenous molecule such as glucuronic acid, sulfate, or glycine to form water-soluble compounds.
2. This is also known as a conjugation reaction.
3. The final compounds have a larger molecular weight.
61
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.
62
Where do phase 1 and 2 reactions occur?
Whase 1 occur on the ER, Phase 2 occur in microsomes and the cytosol
63
List some examples of genetic factors that affect biotransformation?
1. Suxamethonium - genetic defect in pseudocholinesterase causes suxamethonium to remain active for prolonged periods.
2. The "asian gene" where there is increased effectiveness of alcohol oxidase that metabolises ethanol (reducing the "buzz") but a reduced capacity of acetaldehyde dehydrogenase to metabolise the toxic acetaldehyde that produces the the "asian flush" and other associated symptoms
3. N-acetyltransferase a phase-II conjugating liver enzyme. The slow acetylator phenotype often experiences toxicity from drugs such as isoniazid, sulfonamides, procainamide, and hydralazine, whereas the fast acetylator phenotype may not respond to isoniazid and hydralazine in the management of tuberculosis and hypertension, respectively.
64
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)
65
What does phenytoin do to digoxin metabolism?
Phenytoin enhances digoxin metabolism
66
What cytochrome metabolises warfarin and list examples of drugs that inhibit or enhance this CyP.
Warfarin is a racemic mixture of S and R isomers. The S isomer is five times more potent than the R isomer.
The S isomer is metabolised CyP 2C9 enzyme whereas the R isomer is metabolised via CyP 3A4
* Inhibitors of CYP2C9 (eg. metronidazole,
trimethoprim/sulfamethoxazole (bactrim) may result in significant rise in the INR
* Dilitiazem and ciprofloxacin inhibits the metabolism of the R isomer and only has a modest effect
* Amiodarone can have a profounde increase because it interes with the clearance of both isomers
Enhance metabolism
* Barbiturates (i.e. phenobarbitol) enhance warfarin metabolism by inducing CyP3A4
67
Cimetidine (histamine H2 antagonist) effects the metabolism of what drugs?
Cimetidine inhibits warfarin and diazepam metabolism
68
The metabolism of what drugs is affected by cardiac disease?
Cardiac disease can affect drugs that are flow-limited e.g. Morphine, Verapamil
69
What are the four (4) physical barriers to drug distribution?
1. **Aqueous diffusion** - generally determined by fixed law though if a drug is charged its flux will be influenced by electrical fields.
2. **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.
3. **Special carriers** (active transport/facilitated diffusion) - for molecules that are too large or too insoluble - eg peptides, amino acids, glucose
4. **Endocytosis and exocytosis** for very large molecules -eg vit B12, iron
70
What is fick's law of diffusion
FICK'S LAW OF DIFFUSION STATES: "The rate of transfer of a gas through a sheet of tissue is proportional to the tissue area and the difference in gas partial pressure between the 2 sides and inversely proportional to the tissue thickness."
Volume of gas (per unit time)=Area/Thickness x Diffusion constant x (Partial Pressure 1 - Partial Pressure 2)
dV/dt = A/T \* D \* (P1 - P2)
71
Define weak acid?
a neutral molecule that can readily dissociate into an anion and a proton
72
Define weak base?
A neutral molecule that can combine with a proton and form a cation
73
What is the pKa?
pKa is the logarithmic constant where pKa is equal to −log10 Ka of the acid dissociation constant (Ka).
The larger the value of pKa, the smaller the extent of dissociation at any given pH —that is, the weaker the acid. pKa =the pH at which the concentrations of ionized and and inionized forms are equal
74
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.
75
What is the henderson hasselbach equation?
pH = pKa + log [base]/[acid]
76
What is the general structure of local anaesthetics?
Consist of a lipophilic group, ester or amide chain and ionisable group (usually a tertiary amine)
77
What are the two types of local anaesthetics?
1. **Esters**: Cocaine, procaine & benzocaine
2. **Amides**: Lignocaine, bupivicaine & prilocaine (etidocaine)
78
What are the three (3) key the clinical differences between and ester and an amide local anasesthetic?
1. The ester linkage is more easily broken than the amide bond so the ester drugs are less stable in solution and cannot be stored for as long as amides.
2. Amide anaesthetics are also heat-stable and can therefore be autoclaved; esters cannot.
3. The metabolism of most esters results in the production of para-aminobenzoate (PABA) which is associated with allergic reaction. Amides, in contrast, very rarely cause allergic phenomena.
For these reasons amides are now more commonly used than esters.
79
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
80
Where do local anaesthetics act on the sodium channel?
Blockade occurs at the intracellular end of the sodium channel
81
What are the pharmacodynamics of local anaesthetics?
* Activated channels have higher affinity for the drug, therefore drug effect is more marked in rapidly firing fibres.
* The progressive increase in drug concentration causes increased threshold, reduced action potential amplitude, then failure to produce an action potential.
82
What ion concentration changes increase and decrease the effects of local anaesthetics?
Local anaesthetic effect is increased by hyperkalaemia and decreased by hypercalcaemia
83
How does fibre type (size and myelination) affect how local anaesthetics work on the nerves?
* Large diameter fibres are less sensitive than small diameter fibres because three successive nodes required for blockade and nodes are further apart in large fibres.
* Myelinated fibres of the same diameter as unmyelinated fibres tend to become blocked first.
84
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.
85
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.
86
What are the safe doses for lignocaine with/without adrenaline?
2mg/kg IV, 3mg/kg SC, 5mg/kg with adrenaline.
87
What is 1% solution of drug?
10mg/ml
88
What is the safe dose of bipivicaine and prilocaine?
Bupivacaine 2mg/kg SC Prilocaine 3-5mg/kg IVRA
89
What are the relative potencies of the local anaesthetics, say lignocaine = 4
(if procaine = 1) Cocaine =2 Lignocaine =4 Bupivacaine = 16 Prilocaine = 3
90
What is the CNS toxicity of local anaesthetics?
Drowsiness, visual and auditory disturbance, restlessness, nystagmus, shivering, convulsions, CNS depression.
91
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
92
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.
93
What are the cardiovascular effects of local anaesthetics?
* Depression of cardiac pacemaker activity, excitability and conduction.
* Negative inotropic effect and decreased peripheral resistance.
94
How is cocaine different from other local anaesthetics in its cardiovascular effect?
Whilst it is a Na channel blocker like other local anasthetics it also blocks reuptake of catecholamines in the presynaptic neurons in the central and peripheral nervous system, resulting in increased sympathetic output and increased catecholamines.
* Acute doses of cocaine suppress myocardial contractility, reduce coronary caliber and coronary blood flow, induce electrical abnormalities in the heart, and in conscious preparations increase heart rate and blood pressure.
* These effects will decrease myocardial oxygen supply and may increase demand (if heart rate and blood pressure rise). Thus, myocardial ischemia and/or infarction may occur.
95
What haemotological toxicity do local anaesthetics have?
Prilocaine in high doses can cause methaemoglobinaemia which can result in an increased O2 binding, reduced ability of RBC to release oxygen to tissues, a leftward shift of the dissociation curve and subsequent tissue hypoxia.
96
What drugs 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
97
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
98
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
99
How protein bound are local anaesthetics?
bupivicaine 95%, prilocaine 50%
100
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
101
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.
102
Why do ester local anaesthetics have a very short plasma half life?
Rapidly metabolised by pseudo- cholinesterase therefore half life less than 1 minute.
103
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
104
What are guedel's stages of anaesthesia?
Stage of analgesia Stage of excitement Stage of surgical anaesthesia Stage of medullary depression
105
What are the 5 factors that affect the brain uptake of an inhaled anaesthetic?
1. Partial pressure of inspired anaesthetic agent 2. 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. 2. Pulmonary ventilation Increases the rate of induction of anaesthesia for drugs with high solubility - little effect on drugs with low solubility 3. Pulmonary blood flow Increased flow decreases the rate of induction with soluble agents, little effect with poorly soluble agents. 4. 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.
106
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.
107
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
108
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.
109
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.
110
What are the respiratory effects of general anaesthetics? List 5
1. Respiratory depression due to reduced TV and inadequate increased rate. (except nitrous oxide) 2. Increase apneic threshold to pCO2. 3. Decrease ventilatory response to hypoxia. 4. Decrease mucociliary function leading to atelectasis. 5. Most have bronchodilator action.
111
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.
112
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.
113
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
114
What is the MAC of the common anaesthetic agents?
Nitrous oxide \>100 Isoflurane - 1.4 Halothane - 0.75 Methoxyfluorane - 0.16
115
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
116
Give some examples of IV general anaesthetics?
Barbiturates Benzodiazepines Opioids Propofol Ketamine
117
Give examples of barbituate general anaesthetics?
Phenobarbitone Thiopentone -ultra short acting barbiturate intravenous anaesthetic
118
How do barbituates work? (3 mechanisms)
1. Barbiturates bind to components of the GABA receptor and facilitate its action by increasing the duration of chloride channel opening. 2. At high concentrations GABA may directly stimulate the receptor. 3. Also depress actions of other excitatory neurotransmitters and have non-synaptic membrane effects.
119
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.
120
What are the indications for barbiturates in humans? What is the dose of thiopentone?
Phenobarbitone - neonatal seizures. Thiopentone -anaesthesia Dose Thiopentone 3-5mg/kg
121
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.
122
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.
123
What are the contraindications for barbiturates?
Precaution with liver failure. Readily crosses placenta and enters breast milk. Porphyrias
124
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.
125
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 (\< 1 minute) due to high lipid solubility. Rapid redistribution is responsible for short acting effect of 20-30minutes
126
How much of thiopentone and phenobarbitone is excreted unchanged?
Phenobarbitone 20% excreted unchanged. Thiopentone - 1% excreted unchanged, metabolised at 12- 16% per hour.
127
What is propofol?
Phenol derivative. Short acting intravenous anaesthetic agent. Presented as an oil in water emulsion.
128
How does propofol work?
Potentiates the action of inhibitory neurotransmitters including GABA and glycine.
129
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.
130
What are the adverse effects and contraindications of propofol?
1. Marked hypotension (15- 25%) due to reduced peripheral vascular resistance (direct effect of propofol). Potent negative inotropic effects. No compensatory increase in heart rate. 2. Potent respiratory depression. Brief apnoea common. Infusion produces decreased tidal volume. Some bronchodilation due to direct effect on smooth muscle. 3. Rapid, smooth induction and clear headed recovery. Cerebral blood flow and ICP decrease slightly. 4. 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.
131
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.
132
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.
133
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
134
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.
135
What is the IV dose of ketamine?
1-4mg/kg Administer slowly over 60 seconds to avoid respiratory depression and pressor response
136
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)
137
What are the organ effects and toxicity of ketamine?
1. CVS: Increased heart rate, blood pressure and cardiac output via inhibition of noradrenaline reuptake -peaks 2-4 minutes after injection, declines after 20 minutes. 2. RS: May increase or decrease respiratory rate for several minutes. Upper airway tone is maintained. 3. CNS Marked increase in cerebral blood flow and intracranial pressure. Nystagmus 4. 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
138
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
139
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.
140
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.
141
How do depolarising muscle relaxants work?
1. 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. 2. 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.
142
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.
143
What are the doses of suxamethonium and verocuronium?
Suxamethonium 1-1.5mg/kg (children relatively resistant) May be given IM Vecuronium 0.1mg/kg
144
What are the adverse effects of depolarising and non-depolarising muscle relaxants?
1. 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 2. 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. 3. Hyperkalaemia Due to exaggerated release of potassium from extra- junctional nicotinic receptors. There is an exaggerated release with burns, renal failure. 4. Raised intraocular pressure Raised intragastric pressure Raised intracranial pressure 5. Muscle pain This is the most common side effect Malignant hyperthermia: Tachycardia, tachypnoea, rigidity
145
Contraindications to muscle relaxants?
Personal or family history of malignant hyperthermia Muscular dystrophy
146
Absorption and distribution of muscle relaxants?
All are highly polar and inactive orally. Non-depolarising : Rapid initial distribution, small volume of distribution.
147
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. \<\<1% have profound apnoea lasting several hours - this may be treated with fresh frozen plasma. Plasma cholinesterase may also be reduced in pregnancy, cardiac or renal failure, liver disease, hypoproteinaemia, and thyrotoxicosis -this will result in prolonged action.
148
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.
149
What is the fastest onset non-depolarising muscle relaxant?
rocuronium
150
Mechanism of action of dantrolene?
Acts on the sarcoplasmic reticulum of skeletal muscle Causes reduced release of calcium from the sarcoplasmic reticulum
151
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
152
What are the classes of antipychotics?
1. Phenothiazine derivatives: Chlorpromazine 2. Thioxanthene: Thiothixene 3. Butyrophenone derivatives : Haloperidol 4. Miscellaneous: Clozapine, Rispiradone, Olanzapine
153
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
154
Potency of various antipsychotics?
Chlorpromazine -low Thiothixene - high Haloperidol - high Clozapine - medium Rispiradone - high Olanzapine - high
155
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
156
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)
157
ANS Toxicity of antipsychotics?
Autonomic effects Antimuscarinic actions. Loss of accommodation, dry mouth, difficulty urinating, constipation : Alpha1 antagonist actions.
158
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
159
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
160
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
161
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
162
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.
163
Mechanism of action of lithium? 3 broad effects
1. Closely related to sodium -inhibits sodium exchange across membranes but no effect on sodium/potassium or sodium/calcium exchange. 2. Effects on neurotransmitters Enhances the action of serotonin. Decreases noradrenaline and dopamine turnover. Augments the synthesis of acetylcholine. 3. Effects on second messengers. Inhibits enzymes responsible for recycling of inositol compounds, resulting in depletion of PIP2, IP3 and DAG.
164
Usual maintenance dose of lithium
dose 500mg-1g/day
165
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.
166
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.
167
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
168
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.
169
Excretion of lithium?
Not metabolised. Excreted into urine at 20% of the rate of creatinine clearance. Elimination half- life 20 hours.
170
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.
171
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
172
How do tricyclic antidepressants work? Adverse effects?
Blockade of amine (serotonin \>\>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
173
What are three (3) key features of phase 2 biotransformation reactions?
1. These reactions involve covalent attachment of small polar endogenous molecule such as glucuronic acid, sulfate, or glycine to form water-soluble compounds. 2. This is also known as a conjugation reaction. 3. The final compounds have a larger molecular weight.
174
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.
175
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.
176
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
177
What is serotonin syndrome?
TCAs and SSRIs Serotonin syndrome if characterised by hyperthermia, muscle rigidity, myoclonus.
178
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
179
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
180
Absorption and distribution of tetracyclics?
Incompletely absorbed. Significant first pass metabolism (bioavailability 30- 70%) 80% protein bound. High lipid solubility. Large Vd
181
Absorption and distribution of SSRI's?
Well absorbed orally. Moderate first pass metabolism (bioavailability 50- 70%) 95% protein bound. High lipid solubility. Large Vd
182
Absorption and distribution of MAOI's?
Well absorbed orally.
183
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.
184
Antidepressant overdose?
Severe antimuscarinic response is common Extension of toxic effects listed plus respiratory depression, metabolic acidosis, heart failure, cardiac arrest
185
Give 4 examples of anticonvulsants that are sodium channel blockers/membrane stabilisers?
Phenytoin Carbamazepine Sodium valproate Lamotrigine
186
Give 4 examples of anticonvulsants that are GABA modulators?
Benzodiazepines Gabapentin Vigabatrine Phenobarbitone
187
What kind of antiarrhythmic is phenytoin?
class 1b
188
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.
189
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.
190
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
191
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.
192
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
193
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
194
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.
195
Half life and steady state of phenytoin?
Half life 12-36 hours -much higher at high concentrations. 5-7 days to reach steady state.
196
Overdose of phenytoin
Overdose Toxicity varies between individuals CNS effects predominate though bradycardia and heart block can also occur
197
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
198
Toxicity of carbamazepine produces what signs?
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.
199
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.
200
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.
201
What is the active constituent of sodium valproate?
Fully ionised at body pH therefore active constituent is the valproate ion.
202
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
203
Toxicity of sodium valproate?
Dose related nausea vomiting and abdominal pain. Sedation (particularly if used with phenobarbitone) Tremor, weight gain, hair loss. Idiosyncratic hepatotoxicity -may be fatal, more common in children under 2 years, usually occurs within 4 months of starting the drug.
204
Inerractions of sodium valproate?
Dose related nausea vomiting and abdominal pain. Sedation (particularly if used with phenobarbitone) Tremor, weight gain, hair loss. Idiosyncratic hepatotoxicity - may be fatal, more common in children under 2 years, usually occurs within 4 months of starting the drug.
205
Absorption and distribution of sodium valproate?
Orally active. 80% bioavailability. 90% plasma protein bound. Distribution confined to extracellular water due to ionised status and protein binding.
206
Metabolism and excretion of sodium valproate?
Clearance is dose dependant - it inhibits its own metabolism at low doses. At higher doses there is increased free valproate. 20% excreted as a direct conjugate of valproate. 80% metabolised in liver and excreted in urine. Half life 9-18 hours.
207
What does lamotrigine resemble in structure?
Phenytoin
208
Mechanism of lamortigine
Membrane stabiliser - preferentially binds to inactivated sodium channel and maintains inactivated state and therefore blocks sustained high frequency repetitive firing of action potentials.
209
Indication for lamictal
Partial seizures. Usually used in add- on therapy but increasingly used alone.
210
What is valproate best for?
Absence seizures. Generalised tonic- clonic seizures
211
Inerractons of lamortigine
`Phenytoin, carbamazepine, barbiturates and lamotrigine induce liver enzymes and reduce levels of each other. Reduces effectiveness of benzodiazepines, pethidine, warfarin.
212
Side effects of lamrtigine
rash- if rash then cease lamortigine as linked to SJS, aseptic meningitis, leukopaenia, dizzyness, headache diplopia
213
Absorption and excretion of lamotrigine?
Orally active. 50% protein bound. Linear kinetics. Metabolised by liver and excreted by urine. Half life 24 hours, reduced to 15 hours if taking enzyme inducing drugs.
214
Mechanism of vigabatrine? Absorption and excretion of vigabatrine?
Reversible inhibitor of GABA aminotransferase which degrades GABA. GABA levels are therefore increased. Indicated for partial seizures. Orally active. Renally excreted. Short (5-8 hour) half life)
215
Toxicity of vigabatrine?
Dizziness, drowsiness and weight gain. Agitation and confusion rare
216
Structure and action of gabapentin? Indications in epilepsy?
Amino acid analogue of GABA. Despite structural relationship to GABA, does not act on GABA receptors but may alter GABA metabolism. Partial seizures. Usually used in add- on therapy but increasingly used alone.
217
Interractions of gabapentin?
Does not induce liver enzymes. No significant interactions.
218
Absorption and excretion of gabapentin?
Orally active. Not protein bound. Renally excreted. Short (5-8 hour) half life)
219
Mechanism of action of benzodiazepines?
Bind to GABA receptor in CNS Benzodiazepines bind to the gamma subunit and in association with GABA, triggers chloride channel opening and subsequent hyperpolarisation. Benzodiaepines increase the efficacy of GABAergic synaptic transmission -they do not cause chloride channel opening alone.
220
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.
221
Dose of diazepam and midazolam used for sedation:
Diazepam Oral, IV or PR Adult 5-40mg Child 0.1-0.3mg/kg Midazolam IV/IM 0.03-0.2mg/kg (higher dose used for induction of anaesthesia)
222
Does tolerance occur to resp depression with benzo's?
no
223
Do benzodiazepine cross breast milk and placenta?
yes
224
What interracts with benzodiazepines?
Effects potentiated by other sedatives such as alcohol - may cause fatal CVS and respiratory depression.
225
What does benzo absorption depend on? Which benzodiazepines are best and worst absorbed?
Orally active. Absorption dependent on lipid solubility. Diazepam most lipid soluble. Oxazepam, lorazepam and temazepam least lipid soluble. They are highly protein bound and CNS uptake dependent is also dependent on lipid solubility.
226
What is the timeline of sedation by temazepam
Peak sedation 15 minutes after IM injection, 4 minutes after IV injection
227
How are benzodiazepine effects terminated?
Redistribution from CNS to skeletal muscle and adipose tissue is important process that contributes to termination of CNS effects.
228
How are benzodiazepines metabolised?
Metabolised in liver to water-soluble metabolites that are excreted in urine. Metabolites may be more active than parent drug (diazepam forms desmethyldiazepam which is transformed to oxazepam and temazepam)
229
What are the half lives of diazepam, temazepam and midazolam?
Diazepam -20-80 hours (metabolite persist much longer) Temazepam -10-40 hours. Midazolam 2-4 hours Elimination may increase up to 6 times in elderly patients in ICU
230
What is the action of flumazenil?
Reversal of benzodiazepine induced clinical effect. Reversal of respiratory depression is unpredictable.
231
Side effects of flumazenil?
Agitation, confusion, dizziness, nausea May precipitate severe withdrawal syndrome if existing physiological dependence. Very likely to induce convulsions if patient has a known seizure disorder or in TCA overdose.
232
Absorption of flumazenil?
Undergoes significant first pass metabolism if administered orally. Intravenous administration. Rapid onset. 50% protein bound. Small volume of distribution.
233
Metabolism of flumazenil?
Rapid hepatic metabolism to inert metabolites and excreted in urine. Short half life 0.7- 1.3 hours. Infusion may be necessary.
234
What are the spinal and supraspinal sites of pain transmission?
Spinal Dorsal horn pain transmission neurons of spinal cord. Pain transmission: Ventral caudal thalamus Diencephalon Pain modulation: Cortex Midbrain periaqueductal gray area Rostral ventral medulla
235
What is the mechanism of mu opioid receptors? What are the subtypes?
Receptor binding causes closure of voltage gated calcium channels on presynaptic neurons and decreased transmitter release. Also causes opening of potassium channels on post synaptic neurons resulting in hyperpolarisation and formation of IPSPs mu1, mu2
236
Action of mu opioid receptors?
Analgesia Euphoria Sedation Respiratory depression Tolerance and dependence
237
Agonists of mu opioid receptors
F ull: Morphine Pethidine Fentanyl Partial: Codeine
238
Delta opioid receptors types and mechanisms?
delta 1 delta 2 Receptor binding causes closure of voltage gated calcium channels on presynaptic neurons and decreased transmitter release. This causes spinal analgesia.
239
Agonists of delta opioid receptors?
morphine and codeine are partial agonists
240
Subtypes and action of kappa opioid receptors
kappa 1, kappa 2 , kappa 3 Receptor binding causes closure of voltage gated calcium channels on presynaptic neurons and decreased transmitter release.
241
What are morphine, codeine and heroin classified as?
Phenanthrenes
242
What are the Phenylheptylamines?
methadone
243
What are Phenylpiperidines?
pethidine, fentanyl, loperamide
244
Can endogenous opioids cause release of exogenous opioids?
yes
245
What receptors does morphine act on?
mu, delta, kappa
246
What is paperveretum?
mixture of 253 parts morphine, 23 parts papaverine, 20 parts codeine - sometimes used as a premedication. Essentially identical actions as morphine though greater sedation and relief of anxiety.
247
Endocrine effects of opioids?
stimulates ADH, prolactin and somatotropin, inhibits LH Histamine release- itching and urticaria
248
General effects of opioids on smooth muscles?
increase tone e.g.increased biliary smooth muscle contraction, increased GI smooth muscle contraction
249
Action of morphine in APO?
Reduced preload and afterload, reduced anxiety, reduced dyspnoea
250
Respiratory effects of opioids
respiratory depession truncal rigidity- reduces thoracic compliance and increases work of breathing- likely supraspinal effect
251
Withdrawal to opioids?
rhinorrhea, lacrimation, yawning, chills, piloerection, hyperventilation, hyperthermia, mydriasis, muscular aches, vomiting, diarrhoea, and anxiety. Onset 6-10 hours, Peak 36-48 hours, Lasts 5 days
252
Absorption of opioids?
Rapid absorption orally but high (and unpredictable) first pass metabolism therefore low bioavailability. Variable protein binding. Concentrates in highly perfused organs. Structure determines how readily the drug crosses the blood/brain barrier -codeine and fentanyl cross quite readily, morphine less so.
253
Excretion of opiates?
Metabolised in liver and excreted in urine. Morphine, codeine - metabolised in liver to active metabolites that may have greater activity than parent drug. Excreted in urine. Small amount excreted in bile. Metabolites may accumulate in renal failure.
254
Codeine mechanism?
Less efficacious - partial agonist at mu and delta receptors only. Few side effects due to low potency. Constipation is prominent.
255
Absorption and metabolism of codeine?
The structure of codeine protects it from first pass effects and increases ability to cross the blood brain barrier. 10% is metabolised to morphine
256
Potency of pethidine?
One tenth as potent as morphine.
257
Metabolism of pethidine? What interracts with this?
Metabolite 50% as active as parent drug - and is associated with seizures. Halothane and enflurane decrease clearance by 50%.
258
Mechanism of fentanyl
highly selective mu agonist only
259
Toxicity of fentanyl:
CNS toxicity: Little hypnosis or sedation Potent respiratory depression Truncal rigidity Marked muscle rigidity at high doses. Peripheral toxicity: Bradycardia with little effect on cardiac output or blood pressure. Obtunds the cardiovascular response to intubation. Minimal histamine release. Halothane and enflurane decrease clearance by 50%.
260
Fentanyl potency, onset of action, duration of action?
IV or transdermal 33% bioavailability given PO More lipid soluble than morphine therefore crosses the blood/brain barrier more readily. Rapid onset of action. 50-80 times more potent than morphine. Small dose has a shorter duration of action (1-1.5 hours) - larger doses 4-6 hours.
261
What is heroin metabolised to?
converted to morphine by tissue esterases
262
Tramadol mechanism?
Centrally acting analgesic with some opioid properties. Not structurally related to opioids Weak mu agonist actions Noradrenaline inhibition and serotonin reuptake inhibition.
263
Dose of tramadol:
Mild to moderate pain Dose PO/IV 50-100mg tds- rapidly orally absorbed
264
Side effects of tramadol?
Similar CNS and peripheral side effects No respiratory depression except at high doses No cardiac effects No histamine release Does not suppress opioid withdrawal symptoms Increased risk of seizures Avoid with SSRIs and MAOs due to actions on serotonin Increased tramadol metabolism with enzyme inducers such as tramadol
265
Methadone potency?
Orally active, equivalent potency, longer duration of action Tolerance and dependence develop and resolve more slowly and symptoms are milder.
266
Naloxone mechanism of action? How does it act at the organ level?
Antagonist action at opioid receptors. More potent action at mu receptors than delta or kappa. Inert if no agonist present. Antagonist action results in reversal of opioid induced effects in 1-3 minutes.
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Duration of action of naloxone vs naltrexone?
naloxone: Extensive first pass metabolism therefore IV only. Short half life 1-2 hours (duration of action usually 20 minutes) therefore frequent dosing required in overdose naltrexone: Longer half life than naloxone (10 hours) and will block the effects of injected heroin for 48 hours
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Mechanism of ethanol?
No specific receptor. Affects broad range of molecular processes including neurotransmission, enzyme action, electron transport chain, ion transport. Enhances the action of GABA Inhibits the action of glutamate
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Oran effects of ethanol?
Intoxication. Myocardial depression. Smooth muscle relaxation.
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Liver and GI toxicity of ethanol?
Increased alcohol metabolism leads to increased NADH/NAD+ ratio, resulting in reduced gluconeogenesis, hypoglycaemia, ketoacidosis and promotion of TG synthesis from FFA. Accumulation of acetaldehyde promotes inflammation. Nutritional deficiency is due to reduced intake and reduced absorption due to small bowel injury - reduces free radical scavengers such as glutathione Increased gastric and pancreatic secretion, alteration of mucosal barriers resulting in gastritis.
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Non-GI toxicity of ethanol?
CNS: Nystagmus. Generalised symmetrical peripheral neuropathy. Gait disturbance and ataxia. Dementia. Wernicke-Korsacoff syndrome - paralysis of external ocular muscles, ataxia, acute confusion, memory loss. CVS toxicity Dilated cardiomyopathy, ventricular hypertrophy, fibrosis. Atrial and ventricular arrhythmias. Hypertension. Blood: Mild anaemia due to folate deficiency. Immune system: Higher rates of infection Foetal alcohol syndrome: Poor growth, microcephaly, poor coordination, flattened facial features, minor joint abnormalities, congenital heart defects. Cancer: Mouth, pharynx, larynx, oesophagus, liver. Interactions: Additive effect with other sedatives. Acute use tends to inhibit enzymes, chronic use induces. Additive effect with hypoglycaemics and vasodilators.
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Absorption and distribution of ethanol?
Small, water soluble molecule rapidly absorbed from GIT. Vd approximates TBW. Concentration in CNS rises quickly due to large blood flow.
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Metabolism of ethanol?
90% metabolised by liver, 10% excreted by lungs and urine. Metabolism follows zero order kinetics at approximately 1 standard drink per hour. Ethanol converted to acetaldehyde by alcohol dehydrogenase in liver and stomach and by mixed function oxidase. MFO activity increases in alcoholism. Acetaldehyde converted to acetate by aldehyde dehydrogenase. Acetete converted to carbon dioxide and water.
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Mechanism of disulfram and the effect this causes with alcohol?
Inhibition of aldehyde dehydrogenase therefore aldehyde accumulates. Flushing, throbbing, headache, nausea, vomiting, sweating, hypotension, confusion within a few minutes of alcohol consumption.
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Interractions of disulfram with other drugs?
Interactions Inhibits the metabolism of phenytoin, warfarin, isoniazid. Other drugs including metronidazole, cephalosporins may have disulfiram like effects.
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Absorption and excretion of disulfram?
Orally active. Rapidly and completely absorbed Slow elimination
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How does methanol affect the human body?
No specific receptor. Affects broad range of molecular processes including neurotransmission, enzyme action, electron transport chain, ion transport. Enhances the action of GABA. Inhibits the action of glutamate.
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Symptoms of methanol consumption?
Visual disturbance predominates -may take 30 hours to be present. Formaldehyde may be detectable on breath.
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Treatment of methanol intake?
Charcoal ineffective Supportive Intravenous ethanol- higher affinity for alcohol dehydrogenase therefore less formate. Haemodialysis effective
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Toxicity of methanol
Toxicity is probably related to the formation of formate. Visual disturbances (snowstorm sensation) is typical. CVS and CNS depression, metabolic acidosis.
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Distribution of methanol?
Small, water- soluble molecule rapidly absorbed from GIT. Vd approximates TBW. Concentration in CNS rises quickly due to large blood flow.
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Treatment of ethylene glycol overdose?
Charcoal ineffective. Supportive. Intravenous ethanol -higher affinity for alcohol dehydrogenase. Consider alcohol dehydrogenase inhibitor - 4- methylpyrazole. Haemodialysis effective.
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Toxicity of ethylene glycol poisoning?
Transient excitation followed by CNS depression. Severe high anion gap metabolic acidosis after 4-12 hours. Renal insufficiency due to deposition of oxalate.
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Metacolism of ethylene glycol?
Converted to toxic aldehydes and oxalate by alcohol dehydrogenase.
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Mechanisms of sodium chromoglycate? Toxicity?
Alteration of function of chloride channels in cell membranes Inhibition of mast cell degranulation Likely inhibits mediator release from other cells Used for asthma prevention through MDI or inhaler toxicity: Reversible dermatitis, myositis or gastroenteritis in 2%
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Theophilline structure and mechanism
Inhibits phosphodiesterase at high concentrations resulting reduced degradation of cAMP and high intracellular cAMP. Increased intracellular cAMP leads to smooth muscle relaxation. Increased cAMP in the heart leads to calcium influx and positive chronotropic and inotropic action Inhibition of respiratory mucosal adenosine receptors which cause contraction of smooth muscle and histamine release Blockade of cardiac adenosine receptors leading to increased catecholamine release Possible anti-inflammatory action.
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Dosing of theophilline in asthma?
Loading dose should be given slowly as rapid loading results in transient toxic plasma levels. Dose Orally 3-4mg/kg tds Tends to be avoided IV due to toxicities but can be given as an intravenous loading dose followed by infusion
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Toxicity and interractions of theophilline?
Therapeutic and toxic effects closely related to blood level. Therapeutic range 5-20mg/l Anorexia, nausea, vomiting, headache at 15mg/l Seizures or arrhythmias at \>40mg/l Interactions : Clearance enhanced by liver enzyme inducers -phenytoin, phenobarbitone. Clearance reduced by propanolol, macrolides, cimetidine, OCP, calcium channel blockers.
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Absorption and distribution of theophilline?
Absorption Well absorbed orally. Distribution Volume of distribution is proportional to lean body weight. Rapid intravenous loading causes transient toxic plasma levels
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Metabolism of theophilline? What type of kinetics does it display?
Metabolised by liver (therefore reduced dose in liver disease, heart failure). 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. Children clear theophylline most rapidly -poor in neonates and young infants
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Mechanism of salbutamol at the molecular and cellular level?
B2 receptor agonists Stimulation of adenylyl cyclase results in increased cAMP Inhibits release of mediators Bronchodilation due to smooth muscle relaxation. Inhibition of mediator release from mast cells. Inhibition of microvascular leakage. Increase mucociliary transport.
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IV dosing of salbutamol?
Intravenous/SC Adults Loading dose 200ug then 5-20ug/min Children Loading dose 7.5ug/kg then 5ug/kg/hr
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Toxicity of salbutamol
Predictable beta agonist actions Tachycardia, palpitations, nausea, dizziness, tremor are common May cause an initial reduced pO2 due to ventilation/perfusion mismatch Hypokalaemia - especially high doses in combination with methylxanthines and diuretics Hyperglycaemia and possible ketoacidosis in diabetics Excessive use may result in tolerance
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Metabolism of salbutamol
Metabolised by liver. 28% excreted unchanged by kidney Half life 4 hours. Salmeterol has long duration of action due to high lipid solubility rather than long duration of action
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Mechanism of ipratropim
Muscarinic antagonist Comtetitively inhibits the action of acetylcholine at muscarinic receptors
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Toxicity of ipratropium
Predictable antimuscarinic effects though poor systemic absorption minimises this
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Absorption and excretion of ipratropium
Absorption Poor systemic absorption Quaternary ammonium structure leads to poor penetration into CNS. 10% of dose reaches airways, 90% swallowed. Onset 1-3 minutes. Peak effect 1-2 hours. 90% excreted unchanged in faeces Half life 3 hours.
