Psychotropic Agents
Anxiolytics, Sedatives, and Hypnotics

NOTE: Midazolam is a schedule C-IV controlled substance.

Description: Midazolam first received FDA approval in December 1985. An oral formulation was FDA approved in October 1998. Roche has discontinued manufacture of the Versed® product line; however, generic midazolam products remain available.

Mechanism of Action: Benzodiazepines act at the level of the limbic, thalamic, and hypothalamic regions of the CNS and can produce any level of CNS depression required including sedation, hypnosis, skeletal muscle relaxation, and anticonvulsant activity. Recent evidence indicates that benzodiazepines exert their effects through enhancement of the gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex. GABA is an inhibitory neurotransmitter that exerts its effects at specific receptor subtypes designated GABA-A and GABA-B. GABA-A is the primary receptor subtype in the CNS and is thought to be involved in the actions of anxiolytics and sedatives.

Specific benzodiazepine receptor subtypes are thought to be coupled to GABA-A receptors. Three types of BNZ receptors are located in the CNS and other tissues; the BNZ1 receptors are located in the cerebellum and cerebral cortex, the BNZ2 receptors in the cerebral cortex and spinal cord, and the BNZ3 receptors in peripheral tissues. Activation of the BNZ1 receptor is thought to mediate sleep while the BNZ2 receptor affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. Benzodiazepines bind nonspecifically to BNZ1 and BNZ2 which ultimately enhances the effects of GABA. Midazolam has twice the affinity for benzodiazepine receptors than does diazepam. Unlike barbiturates which augment GABA responses by increasing the length of time that chloride channels are open, benzodiazepines enhance the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of GABA to the site opens the chloride channel resulting in a hyperpolarized cell membrane that prevents further excitation of the cell.

The antianxiety action of benzodiazepines may be a result of their ability to block cortical and limbic arousal following stimulation of the reticular pathways while muscle relaxation properties are mediated by inhibiting both mono- and polysynaptic pathways. Benzodiazepine can also depress muscle and motor nerve function directly. Animal studies of the anticonvulsant actions suggest that benzodiazepines augment presynaptic inhibition of neurons, thereby limiting the spread of electrical activity, although they do not actually inhibit the abnormally discharging focus. Benzodiazepines alleviate insomnia by decreasing the latency to sleep and increasing sleep continuity and total sleep time through their effects on GABA.

Pharmacokinetics: In the US, midazolam is approved only for oral or parenteral administration, although it has also been administered intranasally or rectally. Following intramuscular administration, absorption is rapid, with a mean bioavailability greater than 90%. Onset of action following IM and IV administration occurs in 5—15 minutes and 1.5—5 minutes, respectively. Maximum effects are seen in 20—60 minutes, with a recovery time of 2—6 hours. After oral administration, midazolam undergoes extensive first pass metabolism. Oral midazolam bioavailability is roughly 36%, and is independent of age or weight. Onset of anxiolytic and sedative effects usually occur within 10—30 minutes of oral administration, with the degree of sedation dependent on the dose administered and the presence or absence of other medications. Food does not appear to affect the extent of absorption, but the indications for oral midazolam often preclude feeding. Recovery times are similar to intravenous administration of a single dose. Midazolam is widely distributed, crossing both the blood-brain and placental barriers. It is unknown if distribution into breast milk occurs. Midazolam is 94—97% protein-bound and has a half-life of 1—5 hours. Extensive hydroxylation occurs in the liver. The primary metabolite is alpha-hydroxymidazolam, which is equipotent to midazolam. Up to 80% of midazolam is recovered in the urine as alpha-hydroxymidazolam glucuronide. Roughly 4% of the dose is metabolized to 1-hydroxymidazolam and 1,4-hydroxylmidazolam; these minor metabolites have less pharmacologic activity than midazolam, and are conjugated by the liver with subsequent renal excretion. Less than 0.03% of a dose is excreted unchanged in the urine.

Ariano RE, Kassum DA, Aronson KJ. Comparison of sedative recovery time after midazolam versus diazepam administration. Crit Care Med 1994;22:1492—6.