Benzodiazepines (Diazepam, Lorazepam, and Midazolam)
Pharmacology
Benzodiazepines potentiate inhibitory gamma-aminobutyric acid (GABA) neuronal activity in the CNS. Pharmacologic effects include reduction of anxiety, suppression of seizure activity, CNS depression (possible respiratory arrest when benzodiazepines are given rapidly intravenously), and inhibition of spinal afferent pathways to produce skeletal muscle relaxation.
Benzodiazepines interact with other receptors outside the CNS, especially in the heart. Diazepam has been reported to antagonize the cardiotoxic effect of chloroquine (the mechanism is unknown, but diazepam may compete with chloroquine for fixation sites on cardiac cells).
Benzodiazepines generally have little effect on the autonomic nervous system or cardiovascular system. However, enhancement of GABA neurotransmission may blunt sympathetic discharge (and lower blood pressure elevation associated with sympathomimetic intoxications). Additionally, diazepam may have an effect on choline transport and acetylcholine turnover in the CNS, which may be part of the basis for its beneficial effect in victims of nerve agent poisoning (eg, sarin, VX).
Pharmacokinetics. All these agents are well absorbed orally, but diazepam is not well absorbed intramuscularly. The drugs are eliminated by hepatic metabolism, with serum elimination half-lives of 1–50 hours. The duration of CNS effects is determined by the rate of drug redistribution from the brain to peripheral tissues. Active metabolites further extend the duration of effect of diazepam.
Diazepam. Onset of action is fast after intravenous injection but slow to intermediate after oral or rectal administration. The half-life is longer than 24 hours, although anticonvulsant effects and sedation are often shorter as a result of redistribution from the CNS.
Lorazepam. Onset is intermediate after intramuscular dosing. The elimination half-life is 10–20 hours, and owing to slower CNS redistribution, its anticonvulsant effects are generally longer than those of diazepam.
Midazolam. Onset is rapid after intramuscular or intravenous injection and intermediate after nasal application or ingestion. The half-life is 1.5–3 hours, and the duration of effects is very short owing to rapid redistribution from the brain. However, sedation may persist for 10 hours or longer after prolonged infusions as a result of saturation of peripheral sites and slowed redistribution.
Indications
Anxiety and agitation. Benzodiazepines often are used for the treatment of anxiety or agitation (eg, caused by sympathomimetic or hallucinogenic drug intoxication).
Convulsions. All three drugs can be used for the treatment of acute seizure activity or status epilepticus resulting from idiopathic epilepsy or convulsant drug overdose. Midazolam and lorazepam have the advantage of rapid absorption after intramuscular injection. Also, the duration of anticonvulsant action of lorazepam is longer than that of the other two agents.
Hypertension. These drugs can be used for the initial treatment of sympathomimetically induced hypertension.
Muscle relaxant. These drugs can be used for relaxation of excessive muscle rigidity and contractions (eg, as in strychnine poisoning or black widow spider envenomation, or in rigidity syndromes with hyperthermia, dyskinesias, or tetanus).
Chloroquine poisoning. Diazepam may antagonize cardiotoxicity.
Alcohol or sedative-hypnotic withdrawal. Diazepam and lorazepam are used to abate symptoms and signs of alcohol and hypnotic-sedative withdrawal (eg, anxiety, tremor, and seizures).
Conscious sedation. Midazolam is used to induce sedation and amnesia during brief procedures and in conjunction with neuromuscular paralysis for endotracheal intubation.
Nerve agents. These drugs can be used for the treatment of agitation, muscle fasciculations, and seizures associated with nerve agent poisoning (See Warfare Agents–Chemical). They may have an additive or synergistic effect with other nerve agent antidotes (2-PAM, atropine).
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