Sedative-Hypnotics Pharmacokinetics

Pharmacokinetics:

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 diazepam 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 central nervous system. This property is responsible for the rapid onset of central nervous system effects of triazolam, thiopental, 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.

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 transformation.

Benzodiazepines

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

 The formation of active metabolites has complicated studies on the pharmacokinetics of the benzodiazepines in humans because the elimination half-life of the parent drug may have little relation to the time course of pharmacologic effects. Benzodiazepines for which the parent drug or active metabolites have long half-lives are more likely to cause cumulative effects with multiple doses. Cumulative and residual effects such as excessive drowsiness appear to be less of a problem with such drugs as estazolam, oxazepam, and lorazepam, which have relatively short half-lives and are metabolized directly to inactive glucuronides.The metabolism of several commonly used benzodiazepines including diazepam, midazolam, and triazolam is affected by inhibitors and inducers of hepatic P450 isozyme.

Pharmacokinetic Properties of Some Benzodiazepines and Newer Hypnotics in Humans.

Drug Tmax1 (hours)   t1/22 (hours)   Comments Alprazolam 1–2 12–15 Rapid oral absorption Chlordiazepoxide 2–4 15–40 Active metabolites; erratic bioavailability from IM injection Clorazepate 1–2 (nordiazepam) 50–100 Prodrug; hydrolyzed to active form in stomach Diazepam 1–2 20–80 Active metabolites; erratic bioavailability from IM injection Eszopiclone 1 6 Minor active metabolites Flurazepam 1–2 40–100 Active metabolites with long half-lives Lorazepam 1–6 10–20 No active metabolites Oxazepam 2–4 10–20 No active metabolites Temazepam 2–3 10–40 Slow oral absorption Triazolam 1 2–3 Rapid onset; short duration of action Zaleplon < 1 1–2 Metabolized via aldehyde dehydrogenase Zolpidem 1–3 1.5–3.5 No active metabolites

¹Time to peak blood level.

²Includes half-lives of major metabolites.

Barbiturates

With the exception of phenobarbital, only insignificant quantities of the barbiturates are excreted unchanged. The major metabolic pathways involve oxidation by hepatic enzymes to form alcohols, acids, and ketones, which appear in the urine as glucuronide conjugates. The overall rate of hepatic metabolism in humans depends on the individual drug but (with the exception of the thiobarbiturates) is usually slow. The elimination half-lives of secobarbital and pentobarbital range from 18 to 48 hours in different individuals. The elimination half-life of phenobarbital in humans is 4–5 days. Multiple dosing with these agents can lead to cumulative effects.

Newer Hypnotics

After oral administration of the standard formulation, zolpidem reaches peak plasma levels in 1.6 hours. A biphasic release formulation extends plasma levels by approximately 2 hours. Zolpidem is rapidly metabolized to inactive metabolites via oxidation and hydroxylation by hepatic cytochromes P450 including the CYP3A4 isozyme. The elimination half-life of the drug is 1.5–3.5 hours, with clearance decreased in elderly patients. Zaleplon is metabolized to inactive metabolites mainly by hepatic aldehyde oxidase and partly by the cytochrome P450 isoform CYP3A4. The half-life of the drug is about 1 hour. Dosage should be reduced in patients with hepatic impairment and in the elderly. Cimetidine, which inhibits both aldehyde dehydrogenase and CYP3A4, markedly increases the peak plasma level of zaleplon. Eszopiclone is metabolized by hepatic cytochromes P450 (especially CYP3A4) to form the inactive N-oxide derivative and weakly active desmethyleszopiclone. The elimination half-life of eszopiclone is approximately 6 hours and is prolonged in the elderly and in the presence of inhibitors of CYP3A4 (eg, ketoconazole). Inducers of CYP3A4 (eg, rifampin) increase the hepatic metabolism of eszopiclone.

Excretion

The water-soluble metabolites of sedative-hypnotics, mostly formed via the conjugation of phase I metabolites, are excreted mainly via the kidney. In most cases, changes in renal function do not have a marked effect on the elimination of parent drugs. Phenobarbital is excreted unchanged in the urine to a certain extent (20–30% in humans), and its elimination rate can be increased significantly by alkalinization of the urine. This is partly due to increased ionization at alkaline pH, since phenobarbital is a weak acid with a pK_a of 7.4.

Factors Affecting Biodisposition

The biodisposition of sedative-hypnotics can be influenced by several factors, particularly alterations in hepatic function resulting from disease or drug-induced increases or decreases in microsomal enzyme activities.

In very old patients and in patients with severe liver disease, the elimination half-lives of these drugs are often increased significantly. In such cases, multiple normal doses of these sedative-hypnotics can result in excessive central nervous system effects.

The activity of hepatic microsomal drug-metabolizing enzymes may be increased in patients exposed to certain older sedative-hypnotics on a long-term basis. Barbiturates (especially phenobarbital) and meprobamate are most likely to cause this effect, which may result in an increase in their hepatic metabolism as well as that of other drugs. Increased biotransformation of other pharmacologic agents as a result of enzyme induction by barbiturates is a potential mechanism underlying drug interactions. In contrast, benzodiazepines and the newer hypnotics do not change hepatic drug-metabolizing enzyme activity with continuous use.

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