Benzodiazepines

The basic chemical structure of the benzodiazepines consists of a benzene ring coupled to a seven-member heterocyclic structure containing two nitrogens (diazepine) at positions 1 and 4. Of the 2,000 benzodiazepines that have been synthesized, approximately 15 clinically useful compounds are on the market in the United States.

Benzodiazepines also possess muscle relaxant activity. Their pharmacology is discussed in Chapter 30. Diazepam (Valium) has been used for control of flexor and extensor spasms, spinal spasticity, and multiple sclerosis. The muscle relaxant effect of the benzodiazepines may be mediated by an action on the primary afferents in the spinal cord, resulting in an increased level of presynaptic inhibition of muscle tone. Polysynaptic reflexes are inhibited.The most troublesome side effect is drowsiness, which is dose dependent. Tolerance to both the therapeutic effects and the side effects develops.

For details of the chemistry and SARs of the BZDs, see thediscussion of anxiolytic sedative–hypnotic drugs. Amongthe current clinically useful drugs, the structural features associatedwith anticonvulsant activity are identical with thoseassociated with anxiolytic sedative–hypnotic activity.

Although it is widely claimed that the benzodiazepine drugs have a specific calming or anxiolytic effect, their most prominent and easily quantifiable action is central nervous system depression. In very low therapeutic doses, this depression manifests as relief of anxiety that is often accompanied by a feeling of sluggishness or drowsiness. As the dose is increased, the degree of depression is intensified such that muscle relaxation, hypnosis and a more intense central nervous system depression occur. This depression is related to the ability of these drugs to facilitate the inhibitory actions of GABA.
A significant advantage of the benzodiazepines over other central nervous system depressants (e.g., the barbiturates) is that they possess a much greater separation between the dose that produces sleep and the dose that produces death. This increased margin of safety has been one of the major reasons benzodiazepines have largely replaced the barbiturates and other types of sedative– hypnotics in the treatment of anxiety and insomnia. In addition, benzodiazepine administration is associated with few side effects.

Midazolam (Versed), diazepam (Valium), and lorazepam (Ativan) are benzodiazepine derivatives that are useful in anesthesia. Midazolam is the most popular of these agents for the induction of anesthesia. Its popularity is related to its aqueous solubility and to its short duration of action, which permits a prompt return of psychomotor competence. Unlike midazolam, lorazepam and diazepam are not water soluble and must be formulated in propylene glycol; the latter is irritating to the vasculature on parenteral administration.
Benzodiazepines are useful as orally administered premedications. They are also used intravenously in doses that produce conscious sedation rather than hypnosis. Sedated patients tolerate unpleasant procedures (e.g., wound repair, bronchoscopy, angiography) while maintaining cardiorespiratory function and the ability to respond to tactile stimulation or verbal commands.
Midazolam has a shorter half-life (t_1/2β = 1.3–2.2 hours) than either diazepam (t_1/2β = 30 hours) or lorazepam and is not converted in the liver to active metabolites, as is diazepam. Thus, use of midazolam results in a more rapid return to psychomotor competence. Doses may need to be lowered by at least 30% in older patients and in those premedicated with opioids or other sedative drugs.

When used with other sedative–hypnotics or alcohol, the benzodiazepines will produce additive central nervous system depression.
Many benzodiazepines are metabolized by the cytochrome P450 (CYP) enzyme designated CYP3A4. CYP3A4 is inhibited by grapefruit juice and by drugs such as ketoconazole, itraconazole, nefazodone, erythromycin, and ritonavir. Coadministration of these substances along with a benzodiazepine may result in intensification and prolongation of the benzodiazepine effect. Conversely, rifampin, carbamazepine, and phenytoin can induce the CYP3A4 enzyme, and therefore their coadministration can reduce the therapeutic effect of the benzodiazepines.