Thiopentone Tautomerism — FRCA Primary MCQ

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HardPharmacology - Intravenous AnaestheticsThiopentone TautomerismFRCA Primary

An intravenous induction agent is a weak acid whose heterocyclic ring can interconvert between lactam (keto) and lactim (enol) tautomers. It is supplied as a sodium salt with sodium carbonate in a strongly alkaline formulation, and acidification can precipitate the poorly water-soluble free acid. Which agent is described?

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Correct answer: D — Thiopentone

Explanation lettering: E = shown as B · B = shown as C · C = shown as E

D is thiopentone (thiopental). Its thiobarbiturate ring can undergo lactam–lactim, conventionally described as keto–enol, tautomerism. This should be distinguished from ionisation. Clinically, thiopental is supplied as its sodium salt with sodium carbonate; the reconstituted solution is strongly alkaline (pH 10–11), and lowering its pH promotes formation and precipitation of poorly water-soluble thiopental acid. The original explanation incorrectly reversed or oversimplified the relationship between pH and the tautomeric forms. Rapid brain entry is better attributed to thiopental's high intrinsic lipid solubility and substantial unionised fraction, rather than to the enol form becoming more lipid-soluble at physiological pH. Midazolam undergoes pH-dependent diazepine-ring opening and closure, not this barbiturate tautomerism. Ketamine, etomidate and propofol do not possess the characteristic thiobarbiturate ring.

Reference: Chierotti MR et al. The richest collection of tautomeric polymorphs: the case of 2-thiobarbituric acid. Chemistry. 2010;16:4347–4358. https://pubmed.ncbi.nlm.nih.gov/20183832/; UK formulation corroborated by Thiopental powder for solution for injection SmPC, section 6.2, revised 2023: https://www.medicines.org.uk/emc/product/665/smpc