Benzodiazepines with active metabolites

Table 1 Benzodiazepines with active metabolites that have long half-lives metabolism and predominant metabolite half-lives...

Compounds such as oxazepam and lorazepam, which possess inactive metabolites, are relatively short acting, whereas compounds such as prazepam, with several active metabolites, have longer disposition half-lives. Consequently, it may be necessary to reduce the doses of those benzodiazepines with active metabolites. 

In the elderly, secondary to a decreased capacity for oxidation and alterations in the volume of distribution, drug accumulation can result. Patients with hepatic disease also are at risk for drug accumulation and subsequent complications. Therefore, intermediate- or short-acting benzodiazepines without active metabolites are preferred for chronic use in the elderly and those with liver disorders. Elderly patients are also sensitive to the CNS adverse effects of benzodiazepines (regardless of half-life) and their use is associated with a high frequency of falls and hip fractures. 

The relative contribution of the active metabolites of the benzodiazepines to the overall therapeutic effect of the parent compound will depend on the concentration of the metabolite formed, its agonist potency at central benzodiazepine receptors and its lipophilicity. For example, after the chronic administration of diazepam, desmethyldiazepam accumulates in the brain. As this metabolite has potency at the benzodiazepine receptors equal to diazepam, the metabolite probably plays an important part in the overall action of diazepam. In the case of clobazam, however, even though the active metabolite desmethylclobazam is present in higher concentrations than the parent compound after chronic administration, it has a lower potency than clobazam and therefore is of less importance than the parent compound with regard to the anxiolytic effect. 

Zopiclone is widely used as a sedative-hypnotic. It is metabolized to an inactive N-desmethylated derivative and an active N-oxide compound, both of which contain chiral centres. S-Zopiclone has a 50-fold higher affinity for the benzodiazepine receptor site than the R-enantiomer. This could be therapeutically important, particularly if the formation and the urinary excretion of the active metabolite benefits the S-isomer, which appears to be the case. As the half-life of the R-enantiomer is longer than that of the S-form, it would seem advantageous to use the R-isomer in order to avoid the possibility of daytime sedation and hangover effects which commonly occur with long-acting benzodiazepine receptor agonists. 

The range of elimination half-lives for different benzodiazepines or their active metabolites is represented by the shaded areas (B). Substances with a short half-life that are not converted to active metabolites can be used for induction or maintenance of sleep (light blue area in B). Substances with a long half-life are preferable for long-term anxiolytic treatment (light green area)... 

Discontinuation of a hypnotic after a month of continued use can cause a rebound of REM (rapid eye movement) sleep. The duration of action of a hypnotic is determined not only by the half-life of the mother substance but especially by their biological half-life determined by the half-life of the mother substance and the biological active metabolites. On this basis the benzodiazepines can be divided in four different groups ultra short-acting with a half-life < 6 hours such as midazolam and triazolam, short-acting with half-lives between 6 and 12 hours like lormetazepam, loprazolam, oxazepam and temazepam. Alprazolam, bromazepam... 

Benzodiazepines—including diazepam, lorazepam, and midazolam—are used intravenously in anesthesia (see Chapter 25), often in combination with other agents. Not surprisingly, benzodiazepines given in large doses as adjuncts to general anesthetics may contribute to a persistent postanesthetic respiratory depression. This is probably related to their relatively long half-lives and the formation of active metabolites. However, such depressant actions of the benzodiazepines are usually reversible with flumazenil. 

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 relationship to the time course of pharmacologic effects. Those 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 shorter half-lives and are metabolized directly to inactive glucuronides. Some pharmacokinetic properties of selected benzodiazepines are listed in Table 22-1. 

The pharmacokinetic properties of the benzodiazepines in part determine their clinical use. In general, the drugs are well absorbed, widely distributed, and extensively metabolized, with many active metabolites. The rate of distribution of benzodiazepines within the body is different from that of other antiseizure drugs. Diazepam and lorazepam in particular are rapidly and extensively distributed to the tissues, with volumes of distribution between 1 L/kg and 3 L/kg. The onset of action is very rapid. Total body clearances of the parent drug and its metabolites are low, corresponding to half-lives of 20-40 hours. 

Diazepam is a benzodiazepine. Diazepam is more reliably absorbed following oral rather than intramuscular admininstration. This may be due to precipitation in the muscle. Diazepam appears to undergo enterohepatic recirculation with a second plasma peak occurring 4-6 hours after initial administration. This may be associated with re-sedation. Diazepam is oxidised in the liver to active metabolites including desmethyldiazepam (nordiazepam), which has a half-life of over 100 hours. Benzodiazepine oxidation may be impaired in patients with liver disease and in some elderly patients. Metabolism of benzodiazepines such as oxazepam and lorazepam is not impaired in the elderly and in those with liver dysfunction. 

Benzodiazepine (BZ) intoxication is manifested as slurred speech, poor coordination, swaying, drowsiness, hypotension, nystagmus, and confusion. Signs and symptoms of BZ withdrawal are similar to those of alcohol withdrawal, including muscle pain, anxiety, restlessness, confusion, irritability, haJlucinations, delirium, seizures, and cardiovascular collapse. Withdrawal from short-acting BZs (e.g., oxazepam, lorazepam, alprazolam) has an onset within 12 to 24 hours of the last dose. Diazepam, chlordiazep-oxide, and clorazepate have elimination half-lives (or active metabolites with elimination half-lives) of 24 to greater than 100 hours. So, withdrawal may be delayed for several days after their discontinuation. Sedative-hypnotic dependence is summarized in Table 73-2. 

Pharmacokinetics. Benzodiazepines are effective after administration by mouth but enter the circulation at very different rates that are reflected in the speed of onset of action, e.g. alprazolam is rapid, oxazepam is slow (Table 19.8). The liver metabolises them, usually to inactive metabolites but some compoimds produce active metabolites, some with long t) which greatly extends drug action, e.g. chlordiazepoxide, clorazepate and diazepam all form desmethyldiazepam (t/ 80 h). 

There are three new benzodiazepine derivatives being used as hypnotics (see figure 16-C). Estazolam (ProSom) is a triazolobenzodiazepine with a rapid onset of action, intermediate half-life, and no significant active metabolites thus it does not... 

Benzodiazepines, like most lipid-soluble drugs, undergo biotransformation to more water-soluble glucuronide compounds, which are eventually eliminated in the urine. The primary metabolites of diazepam (N-desmethyldiazepam) and midazolam (a-hydroxymidazolam) are pharmacologically active, with similar potency to their parent compounds. These active metabolites are probably of little clinical significance after i.v. administration, because of their rapid elimination and the significance of redistribution in the termination of the CNS effect. 

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