Page 400 - Basic _ Clinical Pharmacology ( PDFDrive )

386 SECTION V Drugs That Act in the Central Nervous System

2. Barbiturates—With the exception of phenobarbital, only The activity of hepatic microsomal drug-metabolizing enzymes
insignificant quantities of the barbiturates are excreted unchanged. may be increased in patients exposed to certain older sedative-
The major metabolic pathways involve oxidation by hepatic hypnotics on a long-term basis (enzyme induction; see Chapter 4).
enzymes to form alcohols, acids, and ketones, which appear in Barbiturates (especially phenobarbital) and meprobamate are
the urine as glucuronide conjugates. The overall rate of hepatic most likely to cause this effect, which may result in an increase in
metabolism in humans depends on the individual drug but (with their hepatic metabolism as well as that of other drugs. Increased
the exception of the thiobarbiturates) is usually slow. The elimi- biotransformation of other pharmacologic agents as a result
nation half-lives of secobarbital and pentobarbital range from 18 of enzyme induction by barbiturates is a potential mechanism
to 48 hours in different individuals. The elimination half-life of underlying drug interactions (see Chapter 66). In contrast, benzo-
phenobarbital in humans is 4–5 days. Multiple dosing with these diazepines and the newer hypnotics do not change hepatic drug-
agents can lead to cumulative effects. metabolizing enzyme activity with continuous use.

3. Newer hypnotics—After oral administration of the standard Pharmacodynamics of Benzodiazepines,
formulation, zolpidem reaches peak plasma levels in 1–3 hours Barbiturates, & Newer Hypnotics
(Table 22–1). Sublingual and oral spray formulations of zolpidem
are also available. Zolpidem is rapidly metabolized to inactive A. Molecular Pharmacology of the GABA Receptor
A
metabolites via oxidation and hydroxylation by hepatic CYP3A4. The benzodiazepines, the barbiturates, zolpidem, zaleplon, eszopi-
The elimination half-life of the drug is greater in women and is clone, and many other drugs bind to molecular components of the
increased significantly in the elderly. A biphasic extended-release GABA receptor in neuronal membranes in the CNS. This recep-
A
formulation extends plasma levels by approximately 2 hours. tor, which functions as a chloride ion channel, is activated by the
Zaleplon is metabolized to inactive metabolites mainly by hepatic inhibitory neurotransmitter GABA (see Chapter 21).
aldehyde oxidase and partly by the cytochrome P450 isoform The GABA receptor has a pentameric structure assembled
A
CYP3A4. Dosage should be reduced in patients with hepatic from five subunits (each with four membrane-spanning domains)
impairment and in the elderly. Cimetidine, which inhibits both selected from multiple polypeptide classes (α, β, γ, δ, ε, π, ρ,
aldehyde dehydrogenase and CYP3A4, markedly increases the etc). Multiple subunits of several of these classes have been char-
peak plasma level of zaleplon. Eszopiclone is metabolized by acterized, eg, six different α, four β, and three γ. A model of the
hepatic cytochromes P450 (especially CYP3A4) to form the GABA receptor-chloride ion channel macromolecular complex is
A
inactive N-oxide derivative and weakly active desmethyleszopi- shown in Figure 22–6.
clone. The elimination half-life of eszopiclone is prolonged in A major isoform of the GABA receptor that is found in
A
the elderly and in the presence of inhibitors of CYP3A4 (eg, many regions of the brain consists of two α1 subunits, two β2
ketoconazole). Inducers of CYP3A4 (eg, rifampin) increase the subunits, and one γ2 subunit. In this isoform, the two binding
hepatic metabolism of eszopiclone. The orexin receptor antago- sites for GABA are located between adjacent α1 and β2 subunits,
nist suvorexant is also a substrate of CYP3A4, and its half-life is and the binding pocket for benzodiazepines (the BZ site of the
prolonged by inhibitors of the enzyme including azole antifungal GABA receptor) is between an α1 and the γ2 subunit. However,
A
drugs, clarithromycin, and verapamil. GABA receptors in different areas of the CNS consist of various
A
combinations of the essential subunits, and the benzodiazepines
C. Excretion bind to many of these, including receptor isoforms containing
The water-soluble metabolites of sedative-hypnotics, mostly α2, α3, and α5 subunits. Barbiturates also bind to multiple
formed via the phase II conjugation of phase I metabolites, are isoforms of the GABA receptor but at different sites from those
A
excreted mainly via the kidney. In most cases, changes in renal with which benzodiazepines interact. In contrast to benzodiaz-
function do not have a marked effect on the elimination of parent epines, zolpidem, zaleplon, and eszopiclone bind more selectively
drugs. Phenobarbital is excreted unchanged in the urine to a cer- because these drugs interact only with GABA -receptor isoforms
A
tain extent (20–30% in humans), and its elimination rate can be that contain α1 subunits. The heterogeneity of GABA A receptors
increased significantly by alkalinization of the urine. This is partly may constitute the molecular basis for the varied pharmacologic
due to increased ionization at alkaline pH, since phenobarbital is actions of benzodiazepines and related drugs (see Box: GABA
a weak acid with a pK of 7.4. Receptor Heterogeneity & Pharmacologic Selectivity).
a
In contrast to GABA itself, benzodiazepines and other sedative-
D. Factors Affecting Biodisposition hypnotics have a low affinity for GABA receptors, which are acti-
B
The biodisposition of sedative-hypnotics can be influenced by sev- vated by the spasmolytic drug baclofen (see Chapters 21 and 27).
eral factors, particularly alterations in hepatic function resulting
from disease or drug-induced increases or decreases in microsomal B. Neuropharmacology
enzyme activities (see Chapter 4). GABA (γ-aminobutyric acid) is a major inhibitory neurotransmit-
In very old patients and in patients with severe liver disease, ter in the CNS (see Chapter 21). Electrophysiologic studies have
the elimination half-lives of these drugs are often increased sig- shown that benzodiazepines potentiate GABAergic inhibition at all
nificantly. In such cases, multiple normal doses of these sedative- levels of the neuraxis, including the spinal cord, hypothalamus, hip-
hypnotics can result in excessive CNS effects. pocampus, substantia nigra, cerebellar cortex, and cerebral cortex.