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Pharmacology of Dormicum (midazolam) and Anexate (flumazenil)

Midazolam and flumazenil have some characteristics in common which make them suitable partners as benzodiazepine (BZD) agonist and antagonist. After intravenous (i.v.) administration, both drugs are rapidly distributed into similar distribution volumes, from which they are cleared with a comparable short climination half‐life (t1/2β) in the range of 1 h (flumazenil) to 3 h (midazolam). Both drugs undergo hepatic metabolisation with a relatively high hepatic extraction ratio of around 0.3 for midazolam and 0.6 for flumazenil. The metabolisation of midazolam and flumazenil may equally be affected by considerable loss of active liver cells or by temporarily reduced hepatic blood flow. In such a case, elimination of both drugs may be prolonged in the same way. Flumazenil has only an inactive metabolite. The main active α‐hydroxy‐metabolite of midazolam does not contribute much to the activity of midazolam after parenteral administration. Its potency is lower than that of midazolam and its shorter elimination half‐life (0.8 h) does not prolong the activity of the parent drug. As indicated by the therapeutic index, both drugs have a very high safety margin, which is considerably higher than that of thiopentone or propofol. Only low doses of both drugs are necessary to produce initial effects. Increasing doses intensify the drug activity and a ceiling effect is observed after maximal doses of midazolam and flumazenil. The onset of effect immediately follows the diffusion of the substances into the CNS and can be observed within the first minutes following flumazenil or midazolam administration. The rapid onset of effect allows both drugs to be administered in repeated small bolus doses under close observation of the patient's reaction. This titrated administration allows one to consider the individual requirements of the patient, his age, and physical condition. The titration method not only allows the optimisation of the drug's effect in each patient but also contributes to tolerability and minimisation of adverse events.