Show the model answerAttempt it first — that is what makes it stick
What earns the marks10 marks
| Analgesic, in all four parts | The instruction governs the whole question. Answers written about ketamine as an induction agent attained less score |
|---|---|
| (a i) The three concentrations | 1 mark, and this is what earns it: 10, 50 and 100 mg/mL, with the isomer potencies |
| (a i) No opening statement | Long introductions were specifically recorded as irrelevant. One mark buys about three lines |
| (a ii) Several mechanisms, not one | 3 marks. Candidates failed to appreciate the various mechanisms by which ketamine acts as an analgesic |
| (a ii) The concentration switch | Sub-anaesthetic doses act on the closed channel allosterically; higher concentrations block open and closed channels |
| (a iii) A dose for every route | 3 marks. Many named the routes and gave the analgesic dose for none of them |
| (a iii) Norketamine | Active at about 30% of the parent, and it is why the analgesia outlasts the dose |
| (b) Advantages only | 3 marks. Disadvantages were irrelevant to the question and carried no mark |
| (b) Reversal of opioid tolerance | Named in the critique with its dose, 0.3 mg/kg/h |
| (b) Somatic more than visceral | An explicit qualification, and a cheap discriminating clause |
(a) i · 1 mark
Physicochemical properties
One mark, and the critique says exactly which facts carry it. Everything else here is the introduction that earned nothing.
Commonly lost: Many candidates wasted time giving a long opening introductory statement which is not relevant. A one-mark part is three or four lines. Structure, molecular weight, pKa, protein binding and lipid solubility are all real physicochemistry and none of them was what this mark was for, so the time spent on them came out of the nine marks that follow.
(a) ii · 3 marks
Mechanisms of action
Plural, and that is the whole point. Three marks will not be paid for the NMDA receptor described three times.
The NMDA action, and why the dose decides what it does
The binding
A non-competitive antagonist at the NMDA receptor. Glutamate continues to bind its own site; what is inhibited is the receptor’s activation by it. Presynaptic glutamate release falls as well.
And then the concentration decides which of two things happens
Sub-anaesthetic · analgesia
Ketamine binds the closed receptor and reduces the frequency of channel opening by an allosteric mechanism. Excitatory transmission is damped, not abolished, and the patient stays awake.
Higher concentration · dissociation
Both open and closed channels are blocked, which is what produces dissociative anaesthesia. Same receptor, same drug, a different mode of block.
Where the analgesia is interpreted
The analgesic effects are likely due to activity in the thalamic and limbic systems, which are responsible for the interpretation of the pain signal.
| Target | Action | Weight |
|---|---|---|
| NMDA receptor | Non-competitive block at the phencyclidine site inside the open channel; inhibits glutamate activation and reduces presynaptic glutamate release | primary |
| μ and κ opioid receptors | Antagonist at μ, agonist at κ; the S(+) isomer carries some μ activity, and part of the analgesia comes from here | secondary |
| Monoaminergic | Inhibits reuptake of catecholamines into postganglionic sympathetic nerve endings — a cocaine-like effect, and part of the sympathomimetic picture | secondary |
| Muscarinic receptors | Antagonist. Accounts for the anticholinergic picture: emergence delirium, bronchodilation, and the dry-mouth-that-is-not | high concentration only |
| Voltage-gated sodium channels | Inhibited, sharing a binding site with local anaesthetics | high concentration only |
| σ opioid receptors | Affected only at high concentration | high concentration only |
Commonly lost: Candidates failed to appreciate the various mechanisms of action of ketamine acting as an analgesic. Three marks, and the NMDA receptor is one of them. Naming the opioid, monoaminergic, sodium-channel and anti-inflammatory contributions costs a sentence each and is what the plural in “mechanisms” was asking for.
(a) iii · 3 marks
Pharmacokinetics
The part with the sharpest recorded failure: many answered on the routes of administration and gave the analgesic dose for none of them.
Commonly lost: Many candidates answered on the various routes of administration but did not mention the analgesic dose for each route. A route without a dose is half a point in a part where the doses are the content. Write them as a table and the omission becomes structurally difficult.
| Route or use | Analgesic dose | Where it comes from |
|---|---|---|
| Sedation and analgesia, intravenous | 0.2–0.8 mg/kg over 2–3 min | Standard reference dose |
| Sedation and analgesia, intramuscular | 2–4 mg/kg | Standard reference dose |
| Pre-emptive analgesia | 0.15–0.25 mg/kg | Standard reference dose |
| Analgesic bolus, intravenous | 0.2–0.5 mg/kg | Named in this critique |
| Analgesic bolus, intramuscular | 0.5–1.0 mg/kg | Named in this critique |
| Analgesic bolus, subcutaneous | 10–25 mg, or 0.2–0.5 mg/kg, intermittently as needed | Named in this critique |
| Analgesic infusion | 0.1–0.2 mg/kg/h, or 0.06–0.12 mg/kg/h | Named in this critique |
| Reversal of opioid tolerance | 0.3 mg/kg/h | Named in this critique |
| Point | Detail, and why it belongs here |
|---|---|
| Bioavailability decides the route | 93% parenterally, but only 20–30% orally because of extensive first-pass metabolism, and about 40–50% intranasally. This is why an oral analgesic dose is several times the intravenous one, and why the intranasal route exists at all |
| Norketamine is active and less potent | The principal metabolite, at about 30% of the potency of the parent, or one-third to one-fifth as potent. The active metabolites may contribute to prolonged effects of analgesia, which is the mechanism by which analgesia outlasts a single bolus |
| Onset and offset suit rescue analgesia | High lipid solubility and a small degree of protein binding give a rapid onset after an intravenous bolus, and termination of a single small dose is by redistribution, so an analgesic bolus can be titrated and repeated |
| Clearance is high and flow-dependent | Hepatic metabolism with a clearance approximating liver blood flow, so an infusion in a patient with a low cardiac output will accumulate. Relevant to the infusion rows above rather than to a single bolus |
(b) · 3 marks
Pharmacodynamic advantages as an analgesic
Advantages only. Some candidates answered with disadvantages, which were irrelevant to the question and carried no mark.
| Advantage | What it means for a patient in pain |
|---|---|
| Reversal of opioid tolerance | Named with its dose, 0.3 mg/kg/h. In a patient whose opioid requirement has escalated, ketamine restores the response rather than adding to the dose |
| Opioid sparing | A ketamine and opioid combination can result in decreased opioid consumption and extended analgesia. That is two claims, not one: less opioid, and for longer |
| Prevention of hyperalgesia | Ketamine prevents hyperalgesia, including the opioid-induced kind, which follows directly from NMDA antagonism and the prevention of central sensitisation |
| Useful in chronic pain, with an opioid | Named for anti-allodynia in particular, so the benefit extends beyond the acute perioperative setting |
| Cardiac output preserved | Analgesia without the fall in output that other agents impose, which is why it is chosen where the circulation is already marginal |
| Increased mean arterial pressure in the hypotensive patient | The one analgesic that supports the pressure while it relieves the pain, rather than trading one against the other |
| Laryngeal reflexes preserved | Analgesia can be given without taking over the airway, which is what makes it usable outside theatre and in the field |
| Less respiratory depression | Explicitly attributed by the critique to the lower effective dose used for analgesia rather than to an inherent respiratory safety |
| Bronchodilatation | Bronchial tone falls, so the analgesic is also an advantage in the patient with airflow obstruction |
Commonly lost: Some candidates mentioned pharmacodynamic disadvantages, which were irrelevant to the question and carried no mark. Emergence phenomena, hypersalivation, the rise in intraocular and intracranial pressure and the direct myocardial depression in the catecholamine-depleted patient are all real and none of them was asked for. If the balance feels one-sided, a single closing subordinate clause is enough, and it should not be more.