Describe the pharmacology of midazolam.
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.