Question 1

Describe the pharmacology of midazolam.

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College Answer

Most candidates had a broad understanding of the indications, mechanism of action and the broad pharmacodynamic effects of midazolam. Those candidates who scored poorly demonstrated a lack of clarity and detail around the pharmacokinetics which are critical to its use and side effect profile. The examiners noted the details surrounding its bioavailability, protein binding was either almost universally
absent or were generic statements that don’t score marks. Better candidates   mentioned the changes in ring structure and lipophilicity associated with changes in pH and showed good understanding of clinically relevant facts regarding lipid solubility and active metabolites.


Class Sedative
Chemistry Benzodiazepine
Routes of administration IV, IM, subcutaneously, intranasally buccaly and orally (though the oral dose required is about doubled)
Absorption 44% bioavailability; well absorbed, but also undergoes significant first-pass metabolism
Solubility pKa 6.7; good water solubility at pH <4 (as a hydrochloride salt) - when injected, it becomes lipid-soluble at physiologic pH
Distribution VOD = 0.8 to 1.5 L/kg; 96% protein bound
Target receptor GABA-A channel (a separate binding site from GABA)
Metabolism Hepatic metabolism to α-hydroxymidazolam (which is active), and then an inactive renally excreted glucouronide. α-hydroxymidazolam can accumulate in renal failure
Elimination Both the active metabolite and the inactive glucouronide are renally excreted
Time course of action Redistribution half-life is 15 minutes; elimination half-life is 1.5-3.5 hours
Mechanism of action Allosteric modulator of the GABA-A receptor: acts on GABA-A chloride channels, where it binds to a site distinct from the GABA binding site, and potentiates the effects of GABA, this increasing the chloride current and hyperpolarising the cell membrane of the neuron
Clinical effects Sedation, amnesia, anticonvulsant effect, mild decrease in cerebral oxygen demand, no effect on ICP.
Haemodynamic effects (decreased blood pressure and heart rate) are related to its suppression of the sympathetic nervous system. These are less pronounced than those of propofol.
Single best reference for further information Okkola & Ahonen (2008)


Dundee, J. W., et al. "Midazolam." Drugs 28.6 (1984): 519-543.

Olkkola, Klaus Tapio, and Jouni Ahonen. "Midazolam and other benzodiazepines." Modern anesthetics (2008): 335-360.

Gerecke, M. "Chemical structure and properties of midazolam compared with other benzodiazepines." British journal of clinical pharmacology 16.S1 (1983): 11S-16S.