Show the model answerAttempt it first — that is what makes it stick
What earns the marks10 marks
| (a) Three steps, in order | 2 marks. The enzyme's normal job, what happens when it is inhibited, and the competition that follows |
|---|---|
| (a) It is not a receptor drug | Some candidates thought the anticholinesterase acts at the receptor. It acts on an enzyme; acetylcholine does the rest |
| (b) Both receptor types | 8 marks. The majority wrote only the muscarinic effects. Nicotinic effects were available and largely unclaimed |
| (b) Detail, not headings | Most did not describe the muscarinic effects in enough detail to gain marks. "Bradycardia" alone is not the mark |
| (b) The mivacurium and suxamethonium interaction | Specifically credited. Neostigmine inhibits plasma cholinesterase as well |
| (b) Depolarising block from overdose | Specifically credited, and the reason the ceiling matters |
| (b) The antimuscarinic | Specifically credited. Say which one, and why it is given at the same time |
2 marks
How an anticholinesterase antagonises a neuromuscular block
Two marks for three sentences. The examination set out exactly what they were for, and the order matters because each step is the reason for the next.
The three steps the examination asked for
Step 1 — the enzyme's normal job
Acetylcholinesterase hydrolyses acetylcholine in the synaptic cleft, which is what normally terminates transmission and keeps junctional acetylcholine low between impulses.
Step 2 — what inhibition does
Neostigmine inhibits that enzyme, so acetylcholine is no longer broken down and accumulates in the cleft. Nothing has yet happened at any receptor.
Step 3 — the antagonism itself
The accumulated acetylcholine competes with the neuromuscular blocking drug for the nicotinic receptors and displaces it by mass action, restoring transmission.
Commonly lost: Some candidates held the wrong concept that the drug inhibits an action at a receptor. It does not. It inhibits an enzyme. Everything that follows is acetylcholine out-competing the antagonist, which is why the effect has a ceiling and why a drug that removes the relaxant instead does not.
8 marks — the section that decided the question
Adverse effects of an intravenous dose of neostigmine given postoperatively
Organise by receptor, because that is what the examination was checking. Then the three specific items it named, each of which is a mark on its own.
| System | Effect | Detail that earns the mark |
|---|---|---|
| Cardiovascular | Bradycardia and other bradyarrhythmias | Not bradycardia alone: sinus and nodal bradycardia, junctional rhythms, ventricular escape beats, complete heart block and asystole have all been reported. Reported in up to 50–60% of patients in some studies. The time course parallels the onset of the anticholinesterase given — fastest with edrophonium, slower with neostigmine, slowest with pyridostigmine |
| Respiratory | Bronchoconstriction and increased secretions | Increased airway resistance and bronchial secretions; may precipitate bronchospasm in an asthmatic. A specific hazard in a patient who has just been extubated |
| Gastrointestinal | Increased motility and secretion | Increased salivation, increased gastric fluid secretion, increased gastric and intestinal motility, and abdominal cramps. Given with atropine in smaller doses it decreases lower oesophageal sphincter tone. Increased motility has been raised as a concern for a fresh bowel anastomosis |
| Nausea and vomiting | Contested, and worth saying so | Neostigmine may cause nausea and vomiting through a central effect, and intrathecal neostigmine clearly increases it through a direct brainstem action. But a meta-analysis of eight trials in 1134 patients found no evidence of increased early or late nausea and vomiting with intravenous neostigmine. Stating that the association is not established reads better than asserting it |
| Ocular and other | Miosis, lacrimation, sweating, urinary urgency | The rest of the muscarinic picture, worth a line together |
Commonly lost: Most candidates did not describe the muscarinic effects in enough detail to gain marks. A list of one-word headings is not eight marks’ worth; each system needs the effect and its consequence.
| Site | Effect | Mechanism |
|---|---|---|
| Neuromuscular junction, in excess | Paradoxical muscle weakness | Too much acetylcholine at the junction is not benign. Proposed mechanisms are desensitisation of the acetylcholine receptor, a depolarising blockade, and open channel blockade — the same three ideas that explain a phase I block |
| Upper airway | Reduced dilator muscle tone and increased collapsibility | In volunteers given rocuronium, neostigmine administered after the train-of-four ratio had recovered to 1.0 produced genioglossus impairment and increased upper airway collapsibility; animal work shows reduced upper airway dilator tone, impaired diaphragmatic function and reduced minute ventilation. This is the argument against reversing a patient who does not need it |
| Autonomic ganglia | Stimulation | Ganglionic transmission is nicotinic, so the ganglia are exposed to the same rise in acetylcholine |
| Item | What to write |
|---|---|
| Interaction with mivacurium or suxamethonium | Neostigmine inhibits plasma cholinesterase as well as acetylcholinesterase. Both of those relaxants are destroyed by plasma cholinesterase, so neostigmine prolongs them rather than reversing them. Edrophonium, which does not inhibit the enzyme in the same way, is the more suitable agent after mivacurium |
| Depolarising blockade after an overdose | Beyond the point of maximal enzyme inhibition, more neostigmine adds no antagonism and the surplus acetylcholine can itself produce a depolarising block. Additional drug beyond about 60–80 µg/kg provides no further benefit, and a second dose of 70 µg/kg given during a deep block usually does not improve recovery. Note that maximal effective doses have not been firmly defined and vary with the depth of block and the relaxant used |
| Co-administration of an antimuscarinic | Because only the nicotinic effect is wanted, an antimuscarinic is given at the same time to block the rest. Glycopyrrolate is matched to neostigmine because their onsets are similar — glycopyrrolate 2–3 minutes against atropine's 1 minute — and because, being a quaternary amine, it does not cross the blood–brain barrier. Bradyarrhythmias still occur despite it |
The depth of block each reversal agent can reach
Depth of block runs from intense at the top to shallow at the bottom, which is the direction a block travels during a case. Sugammadex has a dose at every depth, including one given immediately after an intubating dose before any recovery at all, because it removes the drug from the plasma rather than competing with it at the receptor. Neostigmine cannot cross the line: it works by raising junctional acetylcholine, and once acetylcholinesterase is fully inhibited no further increase is available, so a deeper block simply does not respond. That is the ceiling effect, and it is why some spontaneous recovery must be present before neostigmine is given. The two mechanisms differ in kind: neostigmine acts indirectly as a competitive antagonist, and competition can always be overcome by more agonist — which is precisely why it has a ceiling. Sugammadex is non-competitive, and has none.
Writing it in the time you actually have
Two marks and eight, so write in a ratio of one to four
Part (a) is three sentences. Everything else belongs to part (b), and the fastest way to lose it is to spend five minutes proving you know how an enzyme works.
| Minutes | Part | What to write |
|---|---|---|
| 0–3 | (a) · 2 marks | The three steps in order: the enzyme hydrolyses acetylcholine, inhibition makes it accumulate, the accumulation out-competes the relaxant at the nicotinic receptor. Add the carbamylated complex only if it costs nothing |
| 3–4 | Plan (b) | Write two headings — muscarinic and nicotinic — plus a third for the three named items. This one minute is what prevents the failure mode |
| 4–11 | (b) · muscarinic | Five systems, each with the effect and its detail. Cardiovascular first and in most depth, because the arrhythmia list is where the detail marks are |
| 11–15 | (b) · nicotinic | Excess acetylcholine at the junction, its three proposed mechanisms, upper airway effects, and the ganglia |
| 15–18 | (b) · the named three | Mivacurium and suxamethonium prolonged, depolarising block from overdose, and the antimuscarinic with a reason |