2020A Question 01
Outline the possible reasons for prolonged paralysis induced by an intravenous dose of 1 mg.kg-1 of suxamethonium.
Examiner Report
The domains assessed on this question were the pharmacology of suxamethonium in a normal individual (i.e. what is the normal dose, duration of action and why), the significance of butyrylcholinesterase (BChE), quantitative defects/deficiencies in BChE, qualitative defects in BChE and other non-metabolic factors affecting duration.
Common failures included lack of addressing all domains, especially insufficient knowledge of the genetics of BChE, or failure to mention anything other than genetic defects in BChE. Many candidates were keen to assume a drug error, even though the question specifically stated a dose of 1mg/kg given intravenously. Some candidates incorrectly stated that suxamethonium is metabolised at the NMJ by acetylcholinesterase.
This topic is covered in Stoelting 5th ed Ch.12, Hemmings & Egan 2nd ed Ch.22. A briefer summary is given here: Pharmacology of neuromuscular blocking drugs, Continuing Education in Anaesthesia Critical Care & Pain, Volume 4, Issue 1, February 2004, Pages 2–7 Jonas Appiah-Ankam, , Jennifer M Hunter.
Model Answer
Structure:
- Introduction
- Enzyme abnormality (suxamethonium apnoea)
- Enzyme deficiency (phys, path)
- Enzyme inhibition (drug)
Introduction
- Usual dose 1mg.kg-1
- Usual offset 5-10 mins due to high capacity butyrylchoineterase (BChE)
- Two stage metabolism to choline and succinic acid
BChE Abnormality (Suxamethonium Apnoea)
Genetics:
- Two copies
- Four alleles:
- Normal (N)
- Dibucaine-resistance (DR)
- Chloride-resistant (CR)
- Absent (A)
| Alleles | % Population | Dibucaine Number | Duration |
|---|---|---|---|
| N-N | 96% | 80 | 5-10mins |
| N-DR | ≤4% | 60 | 15-30mins |
| DR-DR | 0.03% | 20 | 8-12 hours |
| Action | Response |
|---|---|
| Test | - Patient’s plasma + dibucaine + 10-5 benzylcholine - Dibucaine number = % inhibition of benzylcholine metabolism - Normal-normal → 80% inhibition (as above) |
| Management | - If no reversal after 30 mins - Prolonged ventilation and sedation in ICU - Monitor with nerve stimulator - +/- FFP |
BChE Deficiency
Rarely significant.
| Cause | Mechanism |
|---|---|
| Physiological | - Neonate → ↓ Production - Pregnancy → ↑ ECF water → Same amount but ↓ concentration |
| Pathological | - Heart failure - Liver failure - Renal failure - Thyrotoxicosis - Cancer |
BChE Inhibition
Rarely significant
Mechanism:
- Acetylcholinesterase inhibitors e.g. Neostigmine
- Metoclopramide
- Ketamine
- Oral contraceptive
- Lithium
- Lignocaine
- Ester local anaesthetics
- Cyclophosphamide