Pharmacokinetics of benzodiazepines and their antagonists

Abstract

Summary Diazepam and midazolam are the most widely used parenteral benzodiazepines. Like other benzodiazepines, they act by enhancing the inhibitory effects of GABA on the postsynaptic neurone by binding to a specific receptor. There is a close relationship between the concentration of the benzodiazepines and their clinical effect. At low concentrations, anxiolysis and anticonvulsant effects dominate. However, with increasing concentrations, sedation and hypnosis become the principal clinical effects. Benzodiazepines are extensively bound to plasma proteins (80–98%), resulting in a small ‘free fraction’ which can cross the blood-brain barrier. Although benzodiazepines are well absorbed after oral administration, midazolam has the largest first-pass elimination by the liver. The parenteral preparations of both diazepam and midazolam can be given intramuscularly, but the absorption of diazepam is erratic and causes pain at the site of injection. Midazolam is rapidly absorbed with peak plasma concentrations occurring 20–30 min after injection. Diazepam and midazolam can also be given rectally, and midazolam has been administered via the nasal mucosa (i.e. intranasally). Due to their lipophilicity, benzodiazepines display a large volume of distribution (0.7–2l/kg). Metabolism takes place in the liver by oxidation or conjugation. The primary metabolite of diazepam is pharmacologically active, with a prolonged elimination half-life which may contribute to a prolongation in the duration of its clinical effects. The hepatic clearance rate for midazolam is approximately ten times higher than that for diazepam, and this is also reflected in its much shorter elimination half-life value. Thus, midazolam is the drug of choice when prolonged administration of a benzodiazepine is necessary (e.g. in intensive care settings). Flumazenil is a benzodiazepine compound with a high affinity for the benzodiazepine receptor but with almost no intrinsic activity. Hence, it acts as a highly selective competitive antagonist at the benzodiazepine receptor. Flumazenil has a smaller volume of distribution and a higher clearance rate than the benzodiazepine agonist drugs, resulting in a short elimination half-life of 60 min. This may have clinical consequences when flumazenil is used for antagonism of intense (deep) sedation following administration of long-acting benzodiazeptines. Initial recovery may be followed by relapse into the sedative state, i.e. resedation. Further studies are needed to define the role of flumazenil in clinical practice.