ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Zolpidem is an imidazopyridine which differs in structure from the benzodiazepines and zopiclone. It is a strong sedative with only minor anxiolytic, myorelaxant and anticonvulsant properties, and has been shown to be effective in inducing and maintaining sleep in adults. The available evidence suggests that zolpidem produces no rebound or withdrawal effects, and patients have experienced good daytime alertness. Zolpidem 10mg in non-elderly and a reduced dose of 5mg in elderly individuals are clinically effective.In humans, the major metabolic routes include oxidation and hydroxylation; none of the metabolites appears to be pharmacologically active. The pharmacological activity of zolpidem results from selective binding to the central benzodiazepine receptors of the &ohgr;1subtype.Zolpidem is approximately 92% bound to plasma proteins; absolute bioavailability of zolpidem is about 70%. After single 20mg oral doses, typical values of pharmacokinetic variables for zolpidem in humans are: a peak plasma concentration of 192 to 324 μg/L occurring 0.75 to 2.6 hours postdose; a terminal elimination half-life of 1.5 to 3.2 hours; and total clearance of 0.24 to 0.27 ml/min/kg. Zolpidem pharmacokinetics are unchanged during multiple-dose treatment.Zolpidem pharmacokinetics are not significantly influenced by gender. Clearance of zolpidem in children is 3 times higher than in young adults, and is lower in very elderly people. There are no significant differences in the pharmacokinetic parameters between various racial groups. Dosage reduction appears to be prudent in patients with renal disease, and caution should be exercised when prescribing zolpidem to elderly patients with hepatic impairment.Coadministration of haloperidol, cimetidine, ranitidine, chlorpromazine, warfarin, digoxin or flumazenil do not alter the pharmacokinetics of zolpidem; flumazenil predictably antagonises the hypnotic effects of zolpidem. Alertness tends to be reduced when cimetidine is combined with zolpidem. Volunteers treated with imipramine plus zolpidem developed anterograde amnesia.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Antidepressant drugs are among the most commonly encountered causes of self-poisoning. These drugs include tricyclics, tetracyclics, bicyclics and monocyclics, as well as monoamine oxidase (MAO) inhibitors and selective serotonin reuptake inhibitors (SSRIs). Of these, the tricyclic antidepressants (TCAs) are generally more toxic in overdose, with major toxicity usually manifesting within the first 6 hours after overdose.Various studies indicate that patients at risk of toxicity from TCA overdose may be identified by neurological, cardiovascular and electrocardiography status, together with a quantitative estimate of the plasma drug concentration. While there are various methods available for such chemical estimations, the most satisfactory appears to be fluorescence polarisation immunoassay which gives rapid quantitative results for a variety of TCAs.The selective MAO-A inhibitor antidepressants and the SSRIs are relatively nontoxic when taken alone. However, overdoses of combinations of MAO inhibitors and either SSRIs or TCAs with serotonin reuptake blocking activity may result in a serotonin syndrome with a severe or fatal outcome. Features of this syndrome include hyperpyrexia, disseminated intravascular coagulation, convulsions, coma and muscle rigidity, which may not develop until 6 to 12 hours after overdose. While qualitative chemical identification of these drugs following overdose is helpful in confirming the diagnosis, it is not mandatory. The increasing use of MAO-A inhibitors and SSRIs in the treatment of depression suggests that careful clinical observation is required when combination overdoses are suspected.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Although lithium continues to be regarded as the treatment of choice for bipolar disorders, the clinical use of this mood stabiliser is associated with an extremely narrow therapeutic range. Relatively minor increases in serum concentrations may induce serious adverse sequelae, and concentrations within the therapeutic range may result in toxic reactions. The safety of combining lithium with other medications, therefore, is a major concern, and extensive clinical experience has served to identify several significant drug interactions.Lithium removal from the body is achieved almost exclusively via renal means. As a result, any medication that alters glomerular filtration rates or affects electrolyte exchange in the nephron may influence the pharmacokinetic disposition of lithium. Concomitant use of diuretics has long been associated with the development of lithium toxicity, but the risk of significant interactions varies with the site of pharmacological action of the diuretic in the renal tubule. Thiazide diuretics have demonstrated the greatest potential to increase lithium concentrations, with a 25 to 40% increase in concentrations often evident after initiation of therapy. Osmotic diuretics and methyl xanthines appear to have the opposite effect on lithium clearance and have been advocated historically as antidotes for lithium toxicity. Loop diuretics and potassium-sparing agents have minor variable effects.Nonsteroidal anti-inflammatory drugs (NSAIDs) have also been associated with lithium toxicity, although the relative interactive potential of specific NSAIDs is difficult to determine. Small prospective studies have demonstrated large interindividual differences in lithium clearance values associated with different NSAIDs. A growing body of evidence also suggests that ACE inhibitors may impair lithium elimination, but further investigations are needed to identify patients at risk.Anecdotal reports have linked numerous medications with the development of neurotoxicity without an apparent effect on the pharmacokinetic disposition of lithium. Antipsychotics, anticonvulsants and calcium antagonists have all been implicated in a sufficient number of case reports to warrant concern. As these medications have all been commonly coadministered with lithium, the relative risk of serious interactions appears to be quite low, but caution is advised.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

The isoenzymes which catalyse the polymorphic hydroxylations of debrisoquine/sparteine andS-mephenytoin are cytochromes P450 2D6 and P450 2C19 (CYP2D6 and CYP2C19), respectively. CYP2D6 is involved in the stereospecific metabolism of several important groups of drugs, for example antiarrhythmics, antidepressants and neuroleptics.About 7% of Caucasians but only 1% of Orientals are poor metabolisers (PMs) of debrisoquine. The most common mutated alleleCYP2D6Bin Caucasian PMs is almost absent from their Oriental counterparts. On the other hand, the mean activity of CYP2D6 in Oriental extensive metabolisers (EMs) is lower than that in Caucasian EMs. This is due to the frequent distribution of a partially deficientCYP2D6allele causing a Pro34→ Ser amino acid exchange in as many as 50% of Oriental alleles. This is the molecular genetic basis for the slower metabolism of antidepressants and neuroleptics observed in Oriental compared with Caucasian people, and consequently for the lower dosages of these drugs used.While CYP2D6 catalyses the metabolism of lipophilic bases only, CYP2C19 is involved in the metabolism of acids (e.g.S-mephenytoin), bases (e.g. imipramine and omeprazole) and neutral drugs (e.g. diazepam). About 3% of Caucasians and 12 to 22% of Orientals are PMs ofS-mephenytoin. Polymerase chain reactionbased genotyping techniques recently became available for the twoCYP2C19mutated alleles m1and m2, which cause no enzyme to be expressed. m1accounts for about 80% of the mutations responsible for the PM phenotypes in Caucasian, Oriental and Black people.Diazepam is partially demethylated by CYP2C19, and the high frequency of mutated alleles in Orientals is probably the reason why such populations have a slower metabolism and are treated with lower doses of diazepam than Caucasians. Omeprazole is to a major extent hydroxylated by CYP2C19, and there is an approximately 10-fold difference in oral clearance between EMs and PMs ofS-mephenytoin.The separation of Caucasians from Orientals is fairly recent in the evolutionary process (40 000 to 60 000 years ago); the separation of Black from Caucasian/Oriental people occurred much earlier, about 150 000 years ago. As pronounced differences have been found between Caucasians and Orientals in the CYP2D6 and CYP2C19 enzymes, it might be expected that Black people will show even greater differences in this respect. Some studies have been performed with Black participants, but the picture is not clear. The mean CYP2D6 activity in Black EMs seems to be lower than that in Caucasian EMs and similar to that of Oriental EMs. The incidence of poor metabolism ofS-mephenytoin in Black people is 4 to 7%, i.e. between that of Caucasians and Orientals. The major mutation m1which causes the PM phenotype is the same in these 3 races, and is thus a very ancient one.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS