Chapter 30). The latter are currently used widely in management of chronic anxiety disorders. Certain antihistaminic agents including hydroxyzine and promethazine (see Chapter 16) are also sedating. These agents commonly also exert marked effects on the peripheral autonomic nervous system. Other antihistaminic drugs with hypnotic effects, eg, diphenhydramine and doxylamine, are available in over-the-counter sleep aids.
A. Absorption and Distribution
The rates of oral absorption of sedative-hypnotics differ depending on a number of factors, including lipophilicity. For example, the absorption of triazolam is extremely rapid, and that of diaz epam and the active metabolite of clorazepate is more rapid than other commonly used benzodiazepines. Clorazepate, a prodrug, is converted to its active form, desmethyldiazepam (nordiazepam), by acid hydrolysis in the stomach. Most of the barbiturates and other older sedative-hypnotics, as well as the newer hypnotics (eszopiclone, zaleplon, zolpidem), are absorbed rapidly into the blood following oral administration.
Lipid solubility plays a major role in determining the rate at which a particular sedative-hypnotic enters the CNS. This property is responsible for the rapid onset of the effects of triazolam, thiopental (see Chapter 25), and the newer hypnotics.
All sedative-hypnotics cross the placental barrier during pregnancy. If sedative-hypnotics are given during the predelivery period, they may contribute to the depression of neonatal vital functions. Sedative-hypnotics are also detectable in breast milk and may exert depressant effects in the nursing infant.
B. Biotransformation
Metabolic transformation to more water-soluble metabolites is necessary for clearance of sedative-hypnotics from the body.
The microsomal drug-metabolizing enzyme systems of the liver are most important in this regard, so elimination half-life of these drugs depends mainly on the rate of their metabolic FIGURE 22–4 Chemical structures of newer hypnotics. transformation.
Melatonin receptors are thought to be involved in maintaining circadian rhythms underlying the sleep-wake cycle (see Chapter 16). Ramelteon, a novel hypnotic drug prescribed specifically for patients who have difficulty in falling asleep, is an agonist at MT1 and MT2 melatonin receptors located in the suprachiasmatic nuclei of the brain. Tasimelteon is similar and is approved for non-24-hour sleep-wake disorder. These drugs have no direct effects on GABAergic neurotransmission in the central nervous system. In polysomnography studies of patients with chronic insomnia, ramelteon reduced the latency of persistent sleep with no effects on sleep architecture and no rebound insomnia or significant withdrawal symptoms. The drug is rapidly absorbed after oral administration and undergoes extensive first-pass metabolism, forming an active metabolite with longer half-life (2–5 hours) than the parent drug. The CYP1A2 isoform of cytochrome P450 is mainly responsible for the metabolism of ramelteon, but the CYP2C9 isoform is also involved. Ramelteon should not be used in combination with inhibitors of CYP1A2 (eg, ciprofloxacin, flu-voxamine, tacrine, zileuton) or CYP2C9 (eg, fluconazole). Concur-rent use with the antidepressant fluvoxamine increases the peak plasma concentration of ramelteon over 50-fold! Ramelteon should be used with caution in patients with liver dysfunction. The CYP inducer rifampin markedly reduces the plasma levels of both ramelteon and its active metabolite. Adverse effects of ramelteon include dizziness, somnolence, fatigue, and endocrine changes.