Relationship between plasma anxiolytic concentrations and the therapeutic response

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While the individual drugs in the benzodiazepine group differ in potency, all benzodiazepines in common use have anxiolytic, sedative-hypnotic, anticonvulsant and muscle-relaxant activity in ascending order of dose. The main clinical difference between the individual drugs lies in the time of onset of their therapeutic effect, and the intensity and duration of their clinical activity.

All benzodiazepines are derived from weak organic acids and some, such as midazolam, form water-soluble salts at a low pH. However, at normal physiological pHs, all benzodiazepines are lipophilic, the lipid solubility varying from highly lipophilic in the case of drugs like midazolam, flurazepam, diazepam and triazolam to slightly lipophilic for drugs such as clonazepam, bromazepam and lormetazepam. The benzodiazepines are also highly protein bound, so that at the plasma pH the proportion of the drug in the free form will vary from only 2% in the case of diazepam to about 30% with alprazolam. However, for most benzodiazepines the percentage of the drug in the pharmacologically active free form is independent of the total plasma concentration over a wide therapeutic range.

Transport of the benzodiazepines into the brain is rapid, the rate of uptake being determined by the physicochemical properties of the drug. Absorption from the gastrointestinal tract, or from an injection site, is the rate-limiting step governing the speed of onset of the therapeutic response. Oral absorption is more rapid when the drug is taken on an empty stomach.

The activity of benzodiazepines may be terminated when the drug is removed from the benzodiazepine receptor site and diffuses into peripheral adipose tissue sites and then metabolized in the liver, or when there is a decrease in the sensitivity of the benzodiazepine receptors following chronic exposure to the drug (termed acute tolerance). The rate of development of acute tolerance appears to vary with the different benzodiazepines, making it difficult to relate the changes in therapeutic response to the changes in plasma concentration.

Pharmacokinetic factors do play a role in terminating the pharmacological effects of these drugs however. It would appear that the distribution of the drug rather than its clearance is the most important factor governing the termination of action. The extent of peripheral distribution of a benzodiazepine increases according to the lipophilicity of the drug. This phase is usually rapid and leads to the termination of the therapeutic effects of the drug; the apparent elimination t1/2 of the drug is usually much slower and is not necessarily related to the time course of the pharmacological effects. This means that drugs with apparently long half-lives may have very short durations of action due to their extensive distribution throughout the body, whereas those drugs that are less lipophilic have a smaller Vd and therefore a longer duration of action, particularly after a single dose. Midazolam is an unusual benzodiazepine in that it is very lipophilic, has a large Vd and is rapidly metabolized and excreted. Both clearance and distribution therefore contribute to the cessation of its therapeutic effect.

The extent of accumulation of an anxiolytic will depend on the elimination half-life in relation to the dosing interval. Thus drugs with long half-lives will have cumulative sedative effects, and may impair cognition, following repeated administration. However, despite increasing blood and presumably brain concentrations of the drug, central depression does not increase in parallel because of the development of tolerance to the non-specific depressant actions of the drug. Long half-life anxiolytics are slowly eliminated whereas short half-life drugs tend to be eliminated rapidly. This means that the dose of the latter type of drug must be tapered slowly to avoid withdrawal effects at the end of a period of treatment.

Oxidation and conjugation are the principal mechanisms whereby the benzodiazepines are metabolized. Nitroreduction is an additional pathway that is involved in the metabolism of nitrazepam, flunitrazepam and clonazepam. Aliphatic hydroxylation and N-dealkylation are the main oxidative routes and often lead to active metabolites (e.g. diazepam gives rise to desmethyldiazepam, oxazepam and temazepam as active metabolites). The second main mechanism is hepatic conjugation to glucuronic acid. Drugs such as oxazepam, lorazepam, temazepam and lormetazepam are inactivated in this way. The main oxidative pathways are influenced by physiological factors such as age, by pathological factors such as hepatitis and by drugs such as the oestrogens and cimetidine which affect hepatic oxidative metabolism.

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.

Of the non-benzodiazepines that have been introduced recently for the treatment of anxiety and insomnia, buspirone and zopiclone have been the most extensively investigated so far. The pharmacokinetic characteristics of zopiclone have been studied in healthy subjects, in the elderly and in patients with renal and hepatic malfunction. It would appear that the kinetics of this drug only alter appreciably in patients in the terminal stages of renal or hepatic disease; in the elderly only a slight increase in the halflife of the drug was observed. Zopiclone is a short (approximately 5 hours) half-life hypnotic which is converted to another short half-life active metabolite, zopiclone N-oxide. The kinetics of the drug are not apparently altered by repeated daily dosing. Buspirone and its close analogue gepirone form the active metabolite 1-piperazine (1-PP). There is also extensive metabolism of the parent compound by hydroxylation and oxidation. The 1-PP metabolite is lipophilic and rapidly enters the brain, where it has an apparent t1/2 of about 2.5 hours. This metabolite also accumulates in the brain after chronic dosing, thereby suggesting that it contributes to the anxiolytic action of the parent compound.

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