Pharmacology

Question 1

What is Nalorphine

Answer 1

Nalorphine is N-allylnormorphine which is a mixed opioid agonist-antagonist with opioid antagonist and analgesic properties. It is an antagonist at MOR (mu receptors) and a near full agonist at KOR (kappa receptors). It is equally potent with morphine as an analgesic but is not clinically useful due to a high incidence of dysphoria. It can displace opioid agonists from mu receptors, helping to reverse respiratory depression.

Question 2

Digoxin

Answer 2

Digoxin has indirect effects via the vagus nerve as well as its direct effects.

Inhibition of the cardiac sodium-potassium ATPase increases the intracellular sodium concentrations and this leads to a displacement of calcium, increasing its availability. This is responsible for the positive inotropic effect.

Fifty per cent to 70% of digoxin is excreted unchanged in the urine and doses need to be altered in renal failure.

Toxicity is increased in hypokalaemia, hypomagnesaemia and hypernatraemia.

Question 3

Thyroid hormone

Answer 3

Triiodothyronine (T3) and thyroxine (T4) are the principal thyroid hormones produced (THs), stored and secreted by the thyroid gland.

Thyroid stimulating hormone (TSH) from the anterior pituitary gland stimulates the release of T4 and T3 into the circulation. The ratio T4 to of secreted T3 is in the order of 200:1. Serum T4 is 40-fold higher than T3. However, only 0.03% of T4 is unbound to plasma proteins and therefore unavailable to diffuse into the target cells compared with 0.3% unbound T3. A majority of circulating T3 results from 5′-deiodination of the outer ring of T4 by deiodinases.

Type I deiodinase is found in peripheral tissues such as liver and kidney and is responsible for the conversion of the majority of T4 to T3 in circulation. Type II deiodinase is found in brain, pituitary, and brown adipose tissue and primarily converts T4 to T3 for intracellular use.

Reverse T3 (rT3) is an isomer of T3 and is inactive. It differs from T3 in that the missing deiodinated iodine is from the inner ring of the thyroxine molecule compared with outer ring on T3. In some conditions an excessive production of rT3 can lead to competition for the 5′-deiodinase enzyme system leading to less peripheral conversion of T4 to T3.

The T3 molecules are further processed by decarboxylation and deiodination for the production of iodothyronamine (T1a) and thyronamine (T0a) respectively. These are also inactive metabolites.

Question 4

Severinghaus electrode

Answer 4

The Severinghaus carbon dioxide electrode measures the partial pressure of carbon dioxide (PCO2) as the result of a pH change in an electrolyte solution. It measures the pH change associated with CO2 reacting with an electrolyte solution, which produces hydrogen ions and causes a pH change. It does not directly measure the PCO2. The glass electrode measures the pH change.

It is a modified pH electrode consisting of:

Measuring electrode: silver/silver chloride surrounded by buffer solution with hydrogen ion sensitive glass on the outside.

Reference (calomel) electrode: mercury/mercury chloride or silver/siver chloride surrounded by a solution of potassium chloride. A CO2 permeable membrane separates the sample from the electrolyte solution (not permeable to bicarbonate ions) and the integrity of this membrane is vital for accuracy.

The system should be maintained at 37°C (not 36°C) and requires regular calibration.

It has slow response times (not fast), because it takes several minutes for the CO2 to diffuse and reach equilibrium across the membrane.

Question 5

What effects do MAO-is have?

Answer 5

In general MAOIs:

Enhance the hypotensive effects of angiotensin-II receptor antagonists, clonidine and verapamil
Enhance the hypoglycaemic effect of metformin, insulin and sulphonylureas and
Antagonise the anticonvulsant effect of carbamazepine and barbiturates.

Question 6

pH of 0.9% Sodium Chloride

Answer 6

5.5

Question 7

pH of Hartmann’s

Answer 7

6.5

Question 8

pH of 5% Glucose

Answer 8

4.15

Question 9

pH of Gelofusine

Answer 9

7.4

Question 10

pH of 3% Hypertonic saline

Answer 10

5.0

Question 11

List the Amino Amide Local Anaesthetics

Answer 11

Bupivacaine
Lidocaine
Ropivacaine
Prilocaine
Levobupivacaine
Mepivacaine

Question 12

List the Amino Ester Local Anaesthetics

Answer 12

Chloroprocaine
Procaine
Tetracaine
Articaine

Question 13

Context sensitive half life of Remifentanil

Answer 13

5 minutes

Question 14

Context sensitive half life of Alfentinil

Answer 14

50 minutes

Question 15

Context sensitive half life of Fentanyl

Answer 15

450 minutes

Question 16

Context sensitive half life of Propofol

Answer 16

40 minutes

Question 17

Context sensitive half life of Thiopental

Answer 17

150 minutes

Question 18

Half life of Midazolam

Answer 18

1-3 hours

Question 19

Half life of Lorazepam

Answer 19

12 hours

Question 20

Half life of Temazepam

Answer 20

6-8 hours

Question 21

Half life of Diazepam

Answer 21

24 - 48 hours

Question 22

Affinity

Answer 22

Measure of strength with which a drug binds to a receptor at a given concentration

Question 23

Potency

Answer 23

Measure of the quantity (dose) of a drug needed to produce a maximal effect

Question 24

Efficacy

Answer 24

Measure of the magnitude of effect once the drug-receptor complex is formed

Question 25

Drug overdose

Answer 25

An overdose is a toxic reaction linked to an excess dose or to impaired excretion, or both. For example, the use of long-acting opioids in patients with renal failure, or a prescription resulting in an error in dosing of insulin.

Question 26

Drug side effect

Answer 26

A side-effect is an undesirable pharmacological effect that happens at recommended doses. For example, constipation with opioids or tachycardia with cyclizine.

Question 27

Drug interaction

Answer 27

Drug interaction is the action of a drug on the effectiveness or toxicity of another drug 2. Examples include flumazenil, a competitive antagonist, reversing the effect of benzodiazepines, or premedication with a benzodiazepine followed by propofol at induction. In the latter case, the dose of propofol required to achieve the same level of anaesthesia is lower.

Question 28

Drug intolerance

Answer 28

Drug intolerance is defined as a low threshold to the normal pharmacological action of a drug.

Question 29

Drug idiosyncrasy

Answer 29

Drug idiosyncrasy is a genetically determined, qualitatively abnormal reaction to a drug related to a metabolic or enzyme deficiency. An example is the prolonged action of suxamethonium (succinylcholine) in susceptible individuals (Fig 1).

Question 30

Drug allergy & pseudo-allergy

Answer 30

A drug allergy is an immunologically mediated reaction, characterised by specificity, transferability by antibodies or lymphocytes, and recurrence on re-exposure.

Pseudoallergic reactions have the same clinical manifestations as allergic reactions, due to histamine release, but are not immunologic reactions. Examples include an allergy to aspirin or NSAIDs in general (Fig 2).

Question 31

Drug tolerance

Answer 31

Drug tolerance may be thought of as a decrease in pharmacological response following repeated or prolonged drug administration. The process is usually reversible by means of periods without use of the drug (known as a drug holiday).

Question 32

Phase I metabolism includes

Answer 32

Oxidation (most common), Reduction and Hydrolysis

Question 33

Phase II metabolism includes

Answer 33

Glucuronidation (most common), Acetylation, Sulphation, Methylation, Glutathione conjugation

Question 34

Omeprazole

Answer 34

Omeprazole is a proton pump inhibitor (PPI) that is inactive at neutral pH.

In an acid environment it rearranges into two types of reactive molecule that react with sulphydryl groups in the hydrogen ion/potassium ion ATPase (not hydroxyl groups).

The enzyme is irreversibly inhibited and thus acid secretion resumes only after new enzyme is synthesised.

Omeprazole has an elimination half life of 40 minutes.

Proton pump inhibitors are associated with many drug interactions that include enhancing the effect of phenytoin and warfarin, and the possible inhibition of diazepam metabolism.

Question 35

Blood:gas coefficient at 37 for Desflurane

Answer 35

0.45

Question 36

Blood:gas coefficient at 37 for Nitrous Oxide

Answer 36

0.47

Question 37

Blood:gas coefficient at 37 for Sevoflurane

Answer 37

0.65

Question 38

Blood:gas coefficient at 37 for Isoflurane

Answer 38

1.4

Question 39

Blood:gas coefficient at 37 for Halothane

Answer 39

2.3

Question 40

MAC of Desflurane

Answer 40

6.6

Question 41

MAC of Sevoflurane

Answer 41

2.0

Question 42

MAC of Isoflurane

Answer 42

1.1

Question 43

MAC of Halothane

Answer 43

0.75

Question 44

MAC of Nitrous Oxide

Answer 44

104

Question 45

Ideal anaesthetic agent (pharmacological properties)

Answer 45

Pleasant smell
No respiratory irritation or depressant effect (avoiding coughing or breath holding on induction)
Low blood:gas partition coefficient (so fast onset/offset)
Potent, with a low MAC and high oil:gas coefficient (so no supplemental anaesthesia is required)
Minimal metabolism (avoiding toxic metabolites)
Excretion via the lungs
Cardiovascular stability
Analgesia properties
Non-epileptogenic
No increase in intracranial pressure

Question 46

Ideal anaesthetic agent (physical properties)

Answer 46

Liquid at room temperature (so easy to store and handle)
Stable at room temperature
Stable in light
Non-flammable
Inert when in contact with metal, rubber and soda lime
Inexpensive (can be used in low-income settings)
Environmentally safe
Low latent heat of vaporisation
High saturated vapour pressure (for easy vaporisation)

Question 47

Saturated Vapour Pressure

Answer 47

This is the pressure that exists above its liquid phase at equilibrium and is dependent on temperature, but independent of other gases present.

Question 48

Calculated Serum Osmolarity

Answer 48

Calculated osmolarity = 2 (Na + K) + Glucose + Urea (all in mmol/L).

Question 49

Drug tolerance

Answer 49

Tolerance is the decrease in effect seen despite maintaining a concentration of a drug.

This may involve downregulation of opioid receptors or reduced production of endogenous opioids.

Question 50

Drug dependence

Answer 50

Dependence exists when the sudden withdrawal of an opioid, after repeated use for a period of time, results in various physical and psychological signs.

Question 51

Addiction

Answer 51

Addiction is a long lasting disease that can cause major health, social and economic problems. It is characterised by a powerful, compulsive urge to use opioids even when they are no longer required for medical reasons.

Anaesthetists have a responsibility to ensure opioids prescribed around the perioperative period to do not become misused.

Question 52

CSHT of Remifentanil after 8 hours

Answer 52

5 mins

Question 53

CSHT of Propofol after 8 hours

Answer 53

40 minutes

Question 54

CSHT of Alfentanil after 8 hours

Answer 54

50 minutes

Question 55

CSHT of Fentanyl after 8 hours

Answer 55

250 minutes

Question 56

CSHT of Thiopental after 8 hours

Answer 56

150 minutes

Question 57

Adrenaline

Answer 57

Adrenaline is the archetypal adrenergic drug and the most important drug in real emergencies. It is out of favour in intensive care because it is associated with more acidosis and possibly worse outcomes. β2 activity potententiates the glycolytic pathway and increases lactate production. The tachycardia and inotropism increases myocardial oxygen consumption.

Receptors: α1, β1 and β2

Question 58

Noradrenaline

Answer 58

More than just a vasoconstrictor, noradrenaline is still the drug most commonly used to increase vascular tone, though fluid status must always be ascertained and corrected first.

It differs from adrenaline mainly at the β2 receptor, so it lacks vasodilatory properties and, in sicker hearts that rely on β2 agonism, it is a less effective inotrope.

Receptors: α1 and β1

Question 59

Isoprenaline

Answer 59

There is no vasoconstriction with this drug but it is a very powerful inotrope that results in unfettered tachycardia. Therefore, it is mostly used to treat bradycardia.

Receptors: β1 and β2

Question 60

Salbutamol

Answer 60

Salbutamol is used exclusively for its β2 selectivity and can relieve bronchospasm that is too severe for the inhaled drug to reach its site of action.

Receptor: β2

Question 61

Dopamine

Answer 61

Dopamine is a natural catecholamine and precursor of the others. There are still many who believe its effects on dopaminergic receptors gives it a special place in renal protection. Others believe that the associated hyperprolactinaemia and immune deficiency is responsible for increased mortality. It seems to be coming back into favour on mainland Europe.

Receptor: α1 and β1

Question 62

Dobutamine

Answer 62

Dobutamine is a relatively β1-selective agonist, used for cardiac stress testing. It causes less tachycardia than isoprenaline for a given degree of inotropy because of its α activity, which generates inotropy directly and causes bradycardia indirectly through the baroreflex. It is the first choice of inotrope in many general ICUs.

Receptors: α1 and β1

Question 63

Dopexamine

Answer 63

Dopexamine is favoured by some intensivists for its splanchnic vasodilation through β2 and dopaminergic receptors, but the evidence of its benefit in clinical practice is weak.

Receptors: β2

Question 64

Tell me about Sodium Nitroprusside:

Answer 64

(There is an open access review of this drug 2. Sodium nitroprusside (SNP) is a potent and short-acting drug so historically was a commonly-used IV medication. However, preparation and administration difficulties along with side-effects and concerns about cyanide toxicity have limited its use.)
This is presented as a lyophilised reddish-brown powder containing 50 mg of SNP. When reconstituted in 5% dextrose it makes a light orange solution with pH 4.5. If exposed to sunlight it will turn dark brown due to the liberation of cyanide (CN-) ions and so it must be protected with aluminium foil.

The rate of infusion should start at 0.3 μg/kg/min and increase to a maximum of 10 μg/kg/min, titrated to effect. Treatment must be limited to the shortest exposure necessary.

This is an inorganic complex which functions as a prodrug. It vasodilates the arteries and veins by the production of nitric oxide (NO). Nitroprusside reacts rapidly with oxyhaemoglobin and oxidises the haem ion to its ferric state (methaemoglobin) with the release of NO and cyanide (CN).

The NO diffuses rapidly through the endothelium and activates guanylate cyclase leading to increased cyclic GMP in cells by the conversion of guanosine triphosphate.

The influx of calcium ions into vascular smooth muscle is inhibited, however uptake into smooth endoplasmic reticulum is increased, so cytoplasmic levels fall, which results in vasodilation via smooth muscle relaxation.

Arterial vasodilation reduces the systemic vascular resistance and leads to a drop in blood pressure. Venous vasodilation reduces preload due to increased venous capacitance. Cardiac output is maintained by a reflex tachycardia. Some patients may develop tachyphylaxis.

SNP may inhibit pulmonary hypoxic vasoconstriction and so supplemental oxygen may be required. Plasma catecholamine and renin levels rise during infusion. Paralytic ileus has been reported. Nausea and vomiting, dizziness, abdominal pain and muscle twitching are examples of other unwanted side-effects, but these abate when the infusion is stopped.

Question 65

Tell me about GTN

Answer 65

Glyceryl trinitrate (GTN) an organic nitrate. It primarily dilates capacitance vessels (venules), arterial vasodilatation can occur at higher concentrations. It can be given as an infusion to control blood pressure.

The recommended concentration for infusion is 100 μg/ml.

GTN is adsorbed onto plastic bags and giving sets (polyvinyl chloride) and so should be infused from a glass bottle or from polyethylene syringes and infusion lines. Although the recommended concentration for infusion is 100 μg/ml diluted with either 0.9% sodium chloride (NaCl) or 5% glucose, it is acceptable to give the 1 mg/ml solution undiluted via a syringe driver.

The dose starts at 2 μg/kg/min (8.4 ml/h of a 1 mg/ml solution for a 70 kg patient) and is titrated up or down as needed. Onset time is very rapid and its maximum effect is seen in 90-120 seconds.

GTN vasodilates veins by the production of NO. GTN is converted to NO in the mitochondria through the action of mitochondrial aldehyde dehydrogenase 2 (mADH2) to produce glyceryl dinitrate (GDN) and NO.

GTN is similar to SNP in that they are both prodrugs working through the metabolite NO, which stimulates GC leading to an increase in cGMP and smooth muscle relaxation.

Despite a similar mechanism of action to SNP, GTN produces vasodilation mainly in the capacitance vessels (veins), although arteries are dilated to some extent. Thus, GTN reduces preload, venous return, ventricular end-diastolic pressure and wall tension. Myocardial oxygen demand is reduced and coronary blood flow is increased to subendocardial regions (hence the use in angina and cardiac failure).

Tachyphylaxis may be due to depletion of sulphydryl groups in the vascular smooth muscle.

Question 66

Tell me about Hydralazine

Answer 66

Hydralazine is principally an arteriodilator. It is most frequently used as an oral hypotensive agent in the treatment of pre-eclampsia. However, it can also be given IV and, unlike SNP, does not have any toxic metabolites.

Hydralazine is often given in repeated bolus doses, since its duration of action is longer than for the IV nitrates. It also has a slower onset of action, taking about five minutes before the peak effect is seen.

It is presented as 20 mg of dry powder in an ampoule and reconstituted with water to give the required dilution.

It may be given by IV injection in doses of 2-4 mg and repeated as necessary always bearing in mind the slow onset of action. It can also be given by infusion starting at a rate of 200-300 μg/min, decreasing to maintenance of 50-150 μg/min.

Pharmacogenetic variability affects the bioavailability of hydralazine when given orally, but is less important when used intravenously.

The mechanism of action is unknown, but is postulated to involve the activation of guanylate cyclase and increase in intracellular cGMP. This leads to a decrease in intracellular calcium and vasodilation.

The main effect of hydralazine is to reduce arteriolar tone and systemic vascular resistance.

Question 67

Tell me about Magnesium

Answer 67

Magnesium is the 4th most plentiful cation (after Na, K, Ca) in the body. The ionised fraction is physiologically active. An arteriolar vasodilator with minimal effects on the venous circulation.

Magnesium has proven particularly useful in the management of blood pressure during surgery for phaeochromocytoma (Fig 1).

2 ml, 5 ml and 10 ml ampoules of of 50% magnesium sulphate are available.

2 ml = 1 g = 4 mmol MgSO4.

A loading dose of 40-60 mg/kg of the sulphate followed by an infusion of 1-2 g/h, is designed to achieve serum magnesium concentrations between 2-4 mmol/L.

Magnesium is a physiological antagonist of calcium at the presynaptic adrenergic terminal and in vascular smooth muscle cells.

Magnesium exerts a direct depressant effect on myocardial and vascular smooth muscle. It inhibits the release of catecholamines from the adrenal medulla and peripheral adrenergic terminals, and directly blocks catecholamine receptors. As a result, cardiac output and vascular tone are reduced, resulting in hypotension and decreased pulmonary vascular resistance.

Other effects include antiarrhythmic activity, anticonvulsant activity, muscle weakness, bronchodilation, respiratory muscle weakness, reduced uterine tone and impaired platelet activity.

Question 68

Tell me about Phentolamine

Answer 68

The only IV α-adrenoceptor antagonist used for intraoperative hypotension is phentolamine. This imidazolone is a competitive non-selective ɑ-blocker, with an affinity for ɑ1-adrenoreceptors of three times that of ɑ2-adrenoreceptors.

Used in hypertensive crises due to excessive sympathomimetics, MAOI reactions with tyramine and pheochromocytoma, especially during tumour manipulation.

Noradrenaline binds to post-synaptic ɑ1 receptors and, via second messenger, intracellular calcium is increased leading to smooth muscle contraction and vasoconstriction. Phentolamine blocks these receptors causing a marked reduction in systemic vascular resistance.

Disadvantages: Reflex tachycardia
Possible cardiac ischaemia
Marked congestion of nasal mucosa

Question 69

Tell me about Esmolol

Answer 69

The effects of catecholamines are antagonised by β-blockers. These induce a bradycardia (by prolonging diastolic depolarisation in phase 4), reduce myocardial contractility and prolong AV conduction.

Esmolol is a relatively cardio-selective β-blocker with a rapid onset and offset. Esmolol may be given as a slow IV bolus of 0.5 mg/kg, repeated every 10-15 minutes or as an infusion of up to 300 μg/kg/min titrated to effect.

Esmolol is relatively selective for β1-adrenergic receptors, but β2 antagonism can be seen when large doses are used. It should be used with caution in asthmatics.

Esmolol has a short duration of action because it is an ester and is rapidly hydrolysed by red blood cell esterases. There are no toxic or active metabolites.

It is also important to know that esmolol solution contains propylene glycol, which may cause a metabolic acidosis during prolonged infusions.

Question 70

Tell me about Labetalol

Answer 70

Labetalol is a competitive antagonist at both β and α1 receptors in a ratio of about 7:1, so it is primarily a β antagonist. It has a slower onset and offset of effect than esmolol. Selective α1 blockade produces peripheral vasodilation while beta blockade prevents reflex tachycardia. The α1 effect of labetalol reduces systemic vascular resistance, which preserves renal blood flow.

Ampoules contain 20 ml of 5 mg/ml of labetalol. It can be given by intermittent bolus dose of 10-20 mg repeated every 5-10 minutes as required or as an infusion at 1-2 mg/kg/h.

Onset is variable, but usually within 5-10 minutes. Unlike esmolol, labetalol is not an ester and undergoes hepatic metabolism with a half-life of 4-6 hours.

Labetalol is the most commonly used hypotensive agent for use in pregnancy. Bronchospasm and Raynaud’s phenomenon may occur less frequently than with esmolol.

Severe hepatocellular damage has been reported after administration.

Question 71

Tell me about Clonidine

Answer 71

Dexmedetomidine and clonidine are imidazole compounds with agonist activity at central imidazole receptors and α-adrenoceptors.

Clonidine is an alpha-agonist with an affinity for α-2 receptors 200 times that for α1 receptors. It is a partial agonist.

It stimulates receptors in the lateral reticular nucleus resulting in reduced central sympathetic outflow, and in the spinal cord where they augment endogenous opioid release and modulate the descending noradrenergic pathways involved in spinal nociceptive processing.

Transmembrane signalling of α2 receptors is coupled to Gi, leading to reduced intracellular cAMP. Potassium channels are also activated.

Rebound hypertension may be seen when stopped abruptly, particular when high doses are used. It also has sedative and analgesia effects.

Elimination half-life is 9-18 hours. 50% is metabolised in the liver to inactive metabolites and 50% excreted unchanged in the urine. The dose should be reduced in renal impairment.

Question 72

Tell me about Ganglion Blockers

Answer 72

Ganglion blockers are no longer available in the UK but they have been used extensively in the past.

They are competitive antagonists at the nicotinic acetylcholine receptors in autonomic ganglia, both sympathetic and parasympathetic. Loss of sympathetic tone in arterioles results in hypotension with minimal reflex tachycardia as the parasympathetic cardiac ganglia are also blocked.

Pentolinium was usually given as multiple small boluses, each lasting 20-40 minutes. Trimetaphan, known as trimethaphan in the US, was given by infusion and the hypotensive effect was augmented by histamine release.

Prolonged use was associated with neuromuscular blockade.

Question 73

Side effects of Thiazides

Answer 73

Hypokalaemia
Impaired glucose tolerance
Hypercalcaemia
Hypomagnesaemia
Hypochloraemic alkalosis (due to renal loss of acid)
Gout
Photosensitivity
Rashes
Postural hypotension
Aplastic anaemia.

Question 74

Ketamine

Answer 74

Ketamine is a phencyclidine derivative that is an NMDA receptor antagonist. It causes a dose-dependent depression of the CNS and induces a dissociative anaesthetic state with profound analgesia and amnesia.

It has a chiral centre and is usually presented as a racemic mixture with two optical isomers, S (+) and R (-) forms in equal proportions. The S (+) isomer is two to three times more potent than the R (-) form and is less likely to cause emergence delirium and hallucinations.

Ketamine is extensively metabolised by hepatic microsomal cytochrome P450 enzymes. Its main metabolite is norketamine that has one third to one fifth as potent as its parent compound.
It is known to increase the CMRO2, cerebral blood flow and potentially increase intracranial pressure.

Question 75

Aprotinin

Answer 75

is an enzyme inhibitor acting on plasmin and kallikrein and is classed as an antifibrinolytic. It is indicated in patients with high risk of Blood Loss.

Question 78

Insulin

Answer 78

Is composed of two polypeptide chains (A and B) linked by disulphide bridges. The A chain contains 21 amino acids, the B chain contains 30 amino acids.

One physiological action of insulin is to increase the permeability of cell membranes to potassium, magnesium and phosphate ions. This forms the basis of treating life threatening hyperkalaemia with a glucose/insulin infusion.

During fasting, serum insulin and glucose levels fall whilst lipolysis increases.

Secretion is stimulated by:
- Beta adrenergic stimulation
- Vagal stimulation
- Stress
- Glucose, fructose, mannose and amino acids
- Glucagon and other gut hormones
- Sulphonylureas and
- Phosphodiesterase inhibitors.

Question 79

Acetazolamide

Answer 79

Is a Zinc containing enzyme that inhibits carbonic anhydrase. It is found in: Erythrocytes, the nephron, Pulmonary endothelium, gut, pancreas, cardiac and skeletal muscle.
There are 7 isoenzymes known.
Isoenzyme IV is found in the brush border of the proximal convoluted tubule.
Isoenzyme II is found in luminal cells.

Question 80

Tapentadol

Answer 80

Tapentadol is a relatively new synthetic analgesic that has been introduced for the treatment of moderate to severe acute and chronic pain. It is a centrally acting opioid with two mechanisms of action, including agonism at the μ-opioid receptor (MOP) and inhibition of norepinephrine reuptake (NRI), producing analgesia at spinal and supraspinal levels.

The principal metabolic pathway is conjugation with glucuronic acid to produce glucuronides. It is also metabolized into N-desmethyl tapentadol (2%) and hydroxy tapentadol (13%) by CYP2C9 and CYP 2C19 isoenzymes. All metabolites are inactive.

Question 81

Tell me about Sodium Nitroprusside

Answer 81

Sodium nitroprusside (SNP) is a vasodilator and is used as an antihypertensive drug.

It is presented as a powder (not solution) which is reconstituted to form a solution unstable in light. The solutions should be protected from light to prevent breakdown into coloured products.

It is active within 30 seconds of administration and initially dilates the venous system and as the dose increases the arterial smooth muscle is affected. Thus the systemic vascular resistance is reduced and a compensatory tachycardia is common.

Cardiac output is maintained and myocardial contractility often increases as afterload and preload are reduced, particularly in a failing heart

The cerebral blood flow is increased and the intracranial pressure may increase.

The pulmonary shunt may be increased due to the impairment of hypoxic pulmonary vasoconstriction.

The plasma half life is about two minutes (not 10).

Cyanide toxicity may occur as a side effect of its use, especially in vitamin B12 deficiency.

Question 82

Tell me about Amiodarone

Answer 82

Amiodarone is a benzofuran derivative and a class III antiarrhythmic drug that is unrelated chemically to other antiarrhythmics.

When administered orally, the bioavailability of amiodarone is quite variable, with rates ranging from 22% to 95%.

Amiodarone is extensively metabolised in the liver, and can affect the metabolism of numerous other drugs.

The major metabolite of amiodarone is desethylamiodarone (DEA), which also has antiarrhythmic properties.

The metabolism of amiodarone is inhibited by grapefruit juice, leading to elevated serum levels of amiodarone.

It contains 37.3% iodine by weight and following long term treatment there is significant accumulation of iodine. Consequently thyroid function disorders may occur.

Other side effects of amiodarone include the development of corneal microdeposits that are reversible on withdrawal of treatment.

Amiodarone inhibits the metabolism of warfarin and so potentiates the anticoagulant effect.

Question 83

What are the metabolites of Diazepam

Answer 83

Temazepam
Nordiazepam (120 hour half life)
Oxazepam
Desmethyldiazepam

Question 84

Tell me about Enoximone

Answer 84

Enoximone is a competitive and selective inhibitor of type III isoenzyme of phopshpodiesterase.

Consequenrtly, it casues increased intracellular cAMP - with vasodilatation and inotropic effects.

It is used in cardiac failure.

Side effects include arrhthymias, deranged LFTs and thrombocytopenia.

Question 85

Features of High Hepatic Extraction Ratio and Examples of Drugs:

Answer 85

Undergo extensive first-pass metabolism when given orally
Drug clearance that is dependent on liver blood flow, and
Much less sensitive to alterations in protein binding and intrinsic metabolism
Examples of such drugs include morphine, lidocaine, propranolol, and etomidate.

Question 86

Features of Low Hepatic Extraction Ratio and Examples of Drugs:

Answer 86

Drug clearance that is independent of liver blood flow
Is very sensitive to alterations in protein binding and intrinsic metabolism, and
Have no first-pass metabolism when given orally.
Examples of such drugs include warfarin and phenytoin.

Question 87

Tell me about the pharmacokinetic properties of Local Anaesthetics

Answer 87

Local anaesthetics are weak bases.

The potency is related to the lipid solubility. The onset of action is related to the pKa and the pH of the surrounding tissues. The lower the pKa of the local anaesthetic, the greater proportion of the drug is in its unionised form which penetrates the nerve cell membrane more readily.

The duration of action is proportional to the extent of protein binding.

Toxicity of local anaesthetics is related to raised systemic blood concentrations and is related to the site of administration as well as factors that reduce systemic absorption, such as the use of a vasoconstrictor. Highest systemic concentrations are found after intercostals, caudal and epidural administration.