[Chemical and pharmacologic aspects of benzodiazepines]

Benzodiazepines (BZ) discovered by chance by the American chemist Sternbach have been indispensable drugs not only in treatment of psychic disorders but also as antiepileptics and myorelaxants. Their heterocyclic structure is essential for the spectrum of activities. Pharmacokinetic studies have unveiled that many BZ are prodrugs of active metabolites. Nearly all BZ are lipophilic amides which are rapidly and efficiently resorbed after oral administration. Some BZ are subjected to a first-pass effect. Protein binding varies from 80-90%. Distribution is rapid but plasmatic levels are often not well correlated with biologic action. Hepatic metabolism is important whereby oxidative pathways prevail. BZ act through amplification of the effects of the neurotransmitter y-aminobutyric acid (GABA). The extent of action is thus limited within narrow margins. Subtypes of BZ-receptors found experimentally might indicate that certain actions i.e. anxiolysis arise via subtype specific binding. The development of more selective drugs, free of side effects, could therefore become possible. Newly developed BZ-antagonists counteract most BZ-effects efficiently. A practical classification of BZ uses plasmatic elimination-halflife (t 1/2): 1. Long-acting substances (t 1/2: up to 100 hrs): Diazepam, Nitrazepam, Flurazepam, Bromazepam (most with active metabolites) 2. Substances of intermediate action (t 1/2: up to 30 hrs): Oxazepam, Lorazepam, Flunitrazepam, Temazepam (few active metabolites) 3. Short-acting substances (t 1/2 up to 8 hrs): Triazolam, Nidazolam (few active metabolites)