Midazolam Ring Opening — FRCA Primary MCQ
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Correct answer: C — Acidic formulation favours an open-ring water-soluble species; physiological pH favours ring closure and increased lipid solubility.
Explanation lettering: D = shown as A · A = shown as B · B = shown as C · C = shown as D
Midazolam is an imidazobenzodiazepine with a pKa of approximately 6.0. In its acidic parenteral formulation, the protonated open-ring species predominates, providing aqueous solubility without an organic cosolvent. As the pH rises after injection, the ring closes; at physiological pH, the drug is largely unionised and lipid-soluble, facilitating rapid CNS penetration. Therefore, B is correct. A gives an incorrect pKa. C reverses the structural changes occurring with increasing pH. D is false because the unusual pH-dependent ring equilibrium provides water solubility. E is false because acid-induced ring opening is reversible and is not metabolic inactivation; midazolam is separately metabolised mainly by CYP3A enzymes to pharmacologically active 1'-hydroxymidazolam.
Reference: Royal College of Anaesthetists. Guide to the FRCA Examination: The Primary, Fourth Edition, MCQ answer 11(e), 2013. https://www.rcoa.ac.uk/media/49221