Pharmacokinetics of Benzodiazepines

All benzodiazepines exert their actions at specific receptors (p. 226). The choice between different agents is dictated by their speed, intensity, and duration of action. These, in turn, reflect physico-chemical and pharmacokinetic properties. Individual benzodiazepines remain in the body for very different lengths of time and are chiefly eliminated through biotransformation. Inactivation may entail a single chemical reaction or several steps (e.g., diazepam) before an inactive metabolite suitable for renal elimination is formed. Since the intermediary products may, in part, be pharmacologically active and, in part, be excreted more slowly than the parent substance, metabolites will accumulate with continued regular dosing and contribute significantly to the final effect.

Biotransformation begins either at substituents on the diazepine ring (diazepam: N-dealkylation at position 1; midazolam: hydroxylation of the methyl group on the imidazole ring) or at the diazepine ring itself. Hydroxylated midazolam is quickly eliminated following glucuronidation (ti/2 ~ 2 h). N-de-methyldiazepam (nordazepam) is biologically active and undergoes hydroxy-lation at position 3 on the diazepine ring. The hydroxylated product (oxaze-pam) again is pharmacologically active. By virtue of their long half-lives, diaze-pam (t1/2 ~ 32 h) and, still more so, its metabolite, nordazepam (t1/2 50-90 h), are eliminated slowly and accumulate during repeated intake. Oxazepam undergoes conjugation to glucuronic acid via its hydroxyl group (t1/2 = 8 h) and renal excretion (A).

The range of elimination half-lives for different benzodiazepines or their active metabolites is represented by the shaded areas (B). Substances with a short half-life that are not converted to active metabolites can be used for induction or maintenance of sleep (light blue area in B). Substances with a long half-life are preferable for long-term anxiolytic treatment (light green area)

because they permit maintenance of steady plasma levels with single daily dosing. Midazolam enjoys use by the i.v. route in preanesthetic medication and anesthetic combination regimens.

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