Show the model answerAttempt it first — that is what makes it stick
What earns the marks10 marks
| (a) Non-competitive | 1 mark. The commonest single error was calling the antagonism competitive |
|---|---|
| (a) Two clinical features, explicitly | Some described the concept without stating two features as asked, and lost the mark for it |
| (b) Two DISTINCT pathways | 2 marks. Many detailed the NMDA receptor's cellular function instead of naming a second pathway |
| (b) Move beyond NMDA | Opioid receptors, monoamine reuptake inhibition, or voltage-gated ion channels |
| (c) Norketamine is LESS potent | 3 marks. A frequent misconception was that it is more potent than the parent compound |
| (c) Beyond the metabolite | Enzyme induction with chronic use, and tolerance and dependence, were universally omitted |
| (d) Justify each indication | 4 marks, and the highest scoring part. Justification, not a list |
| (d) Do not include contraindications | A few suggested induction in severe cardiac disease or uncontrolled raised ICP |
1 mark
The mechanism of dissociative anaesthesia, with two key clinical features
Mechanism, in the order it should be written
Commonly lost: A common point of confusion was describing the antagonism as competitive rather than the correct term, non-competitive. The distinction is not semantic: a competitive antagonist is by definition surmountable by more agonist, and this one is not, because its site is inside the channel rather than at the glutamate site.
2 marks
Two of the pathways by which ketamine produces analgesia
| Pathway | Mechanism | Consequence |
|---|---|---|
| NMDA receptor antagonism | Non-competitive block at the spinal dorsal horn inhibits wide-dynamic-range neuronal activity and prevents central sensitisation; supraspinally it acts in the thalamic and limbic systems responsible for interpreting the pain signal | Prevents wind-up and central sensitisation; prevents opioid-induced hyperalgesia and attenuates acute opioid tolerance |
| Opioid receptor interaction | Antagonist at μ and agonist at κ; the S(+) isomer carries some μ activity | A direct analgesic contribution independent of the NMDA action |
| Monoamine reuptake inhibition | Inhibits reuptake of noradrenaline and serotonin, and activates descending inhibitory monoaminergic pathways | Augments endogenous descending pain inhibition |
| Voltage-gated sodium channel inhibition | Shares a binding site with the local anaesthetics | A local-anaesthetic-like membrane-stabilising contribution |
| Anti-inflammatory action | Reduces tumour necrosis factor alpha, interleukin-6 and interleukin-8, and suppresses NF-κB expression | A contribution to analgesia in inflammatory pain states |
Commonly lost: Many candidates detailed the NMDA receptor’s cellular function at length rather than outlining a second distinct pathway. Stronger answers moved beyond the NMDA receptor to opioid receptors, monoamine reuptake inhibition, or effects on voltage-gated ion channels. Two marks, two pathways: name the second one in its own sentence.
3 marks
The metabolism of ketamine and its clinical significance
The metabolic pathway
| Point | Detail |
|---|---|
| Norketamine is active, and LESS potent than ketamine | Reported at 20–30%, or one-third to one-fifth, of the potency of the parent compound. It contributes to prolonged analgesia after a bolus or an infusion — which is why analgesia outlasts the anaesthetic |
| Clearance approximates liver blood flow | A high hepatic extraction ratio, so clearance is flow-limited. A fall in hepatic blood flow — or any drug that reduces cardiac output — prolongs the effect, whereas enzyme activity itself matters relatively little |
| Extensive first-pass metabolism | Bioavailability is 93% parenterally but only 20–30% orally, and about 40–50% intranasally. This is why the oral dose is several times the intravenous dose and why the intranasal route exists |
| Enzyme induction with chronic use | Universally omitted. Repeated administration induces the hepatic enzymes that metabolise it, contributing to tolerance |
| Tolerance and dependence | Also universally omitted. A consequence of both enzyme induction and receptor-level adaptation, and the reason chronic infusions lose effect |
| No dependence on plasma cholinesterase or renal function for the parent drug | The conjugates are renally excreted, but the offset of a single dose does not depend on the kidney |
Commonly lost: A frequent misconception was that norketamine is more potent than its parent compound; it is in fact less. And two significances were universally omitted: enzyme induction with chronic use, and the potential for tolerance and dependence. In a three-mark part, naming the metabolite is one mark — the other two are in what follows from it.
4 marks — the highest scoring part
The clinical indications of ketamine, with justification
| Indication | Justification |
|---|---|
| Induction in the shocked or hypovolaemic patient | Sympathetic stimulation through increased central sympathetic outflow and inhibition of catecholamine reuptake raises heart rate, cardiac output and blood pressure, where every other induction agent lowers them |
| Induction in severe asthma or bronchospasm | Bronchodilatation, consistent with its muscarinic antagonism and sympathomimetic action |
| Anaesthesia where the airway must keep working | Respiratory drive is largely preserved and laryngeal reflexes relatively so, so ventilation need not be taken over. Useful in the difficult airway and in field or resource-limited settings |
| Analgesia — acute, chronic and opioid-sparing | Intense analgesia at sub-anaesthetic concentrations; prevents opioid-induced hyperalgesia and attenuates opioid tolerance through NMDA antagonism. Reversal of opioid tolerance at 0.3 mg/kg/h |
| Procedural sedation and analgesia, particularly in children | A single agent providing analgesia, amnesia and immobility, with intramuscular, oral and intranasal routes available when no vein is |
| Burns dressing changes and repeated painful procedures | Profound analgesia without cardiovascular depression, and it can be repeated intramuscularly |
| Obstetric haemorrhage | Maintains maternal blood pressure where propofol and thiopentone would not |
| Treatment-resistant depression | An S(+)-ketamine nasal spray is approved for this indication — worth a clause, and outside the operating theatre |
Commonly lost: A minimal number of candidates suggested its use in contraindicated situations — induction in severe cardiac disease, or in uncontrolled raised intracranial pressure. Both turn a mark into a lost one. In ischaemic heart disease the tachycardia and hypertension raise myocardial oxygen demand while shortening diastole; in uncontrolled intracranial hypertension in a spontaneously breathing patient ketamine can raise intracranial pressure further.
The teaching behind this answer — ketamine and dissociative anaesthesia