Page 398 - Basic _ Clinical Pharmacology ( PDFDrive )

384 SECTION V Drugs That Act in the Central Nervous System

Ramelteon and Tasimelteon

Melatonin receptors are thought to be involved in maintaining forming an active metabolite with longer half-life (2–5 hours)
circadian rhythms underlying the sleep-wake cycle (see Chapter than the parent drug. The CYP1A2 isoform of cytochrome P450
16). Ramelteon, a novel hypnotic drug prescribed specifically is mainly responsible for the metabolism of ramelteon, but the
for patients who have difficulty in falling asleep, is an agonist at CYP2C9 isoform is also involved. Ramelteon should not be used
MT 1 and MT 2 melatonin receptors located in the suprachiasmatic in combination with inhibitors of CYP1A2 (eg, ciprofloxacin, flu-
nuclei of the brain. Tasimelteon is similar and is approved for non- voxamine, tacrine, zileuton) or CYP2C9 (eg, fluconazole). Concur-
24-hour sleep-wake disorder. These drugs have no direct effects rent use with the antidepressant fluvoxamine increases the peak
on GABAergic neurotransmission in the central nervous system. plasma concentration of ramelteon over 50-fold!
In polysomnography studies of patients with chronic insomnia, Ramelteon should be used with caution in patients with
ramelteon reduced the latency of persistent sleep with no effects liver dysfunction. The CYP inducer rifampin markedly reduces
on sleep architecture and no rebound insomnia or significant the plasma levels of both ramelteon and its active metabolite.
withdrawal symptoms. The drug is rapidly absorbed after oral Adverse effects of ramelteon include dizziness, somnolence,
administration and undergoes extensive first-pass metabolism, fatigue, and endocrine changes.

1. Benzodiazepines—Hepatic metabolism accounts for the desmethyldiazepam, which has an elimination half-life of more
clearance of all benzodiazepines. The patterns and rates of than 40 hours, is an active metabolite of chlordiazepoxide,
metabolism depend on the individual drugs. Most benzodi- diazepam, prazepam, and clorazepate. Alprazolam and triazolam
azepines undergo microsomal oxidation (phase I reactions), undergo α-hydroxylation, and the resulting metabolites appear
including N-dealkylation and aliphatic hydroxylation catalyzed to exert short-lived pharmacologic effects because they are
by cytochrome P450 isozymes, especially CYP3A4. The metabo- rapidly conjugated to form inactive glucuronides. The short
lites are subsequently conjugated (phase II reactions) to form elimination half-life of triazolam (2–3 hours) favors its use as a
glucuronides that are excreted in the urine. However, many hypnotic rather than as a sedative drug.
phase I metabolites of benzodiazepines are pharmacologically The formation of active metabolites has complicated stud-
active, some with long half-lives (Figure 22–5). For example, ies on the pharmacokinetics of the benzodiazepines in humans

Chlordiazepoxide Diazepam Prazepam Clorazepate (inactive)

Desmethylchlordiazepoxide*

Demoxepam* Desmethyldiazepam* Alprazolam and triazolam

Oxazepam* Alpha-hydroxy metabolites*

Hydroxyethyl-
flurazepam*

Flurazepam CONJUGATION Lorazepam
Desalkyl-
flurazepam*

URINARY
EXCRETION

*
FIGURE 22–5 Biotransformation of benzodiazepines. Boldface, drugs available for clinical use in various countries; , active metabolite.