ISSN:0312-5963    

出版商:ADIS    

年代:1992

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1992

数据来源: ADIS

摘要:

The pharmacokinetics of drugs may be altered following an overdose. The degree of absorption depends on the physical characteristics of the drug; the rate of dissolution may delay or broaden peak serum concentrations. The pathophysiological effects of a drug may also limit or augment absorption. Altered distribution of drugs in overdose results from changes in the extent of protein binding and size of the volume of distribution. Saturation of hepatic enzyme systems in overdose is manifested by delayed metabolism or elimination of many drugs; renal elimination of unchanged drug may take on greater importance in this instance.Familiarity with the toxicokinetic profile of a given drug enables the physician to exploit these principles in order to limit toxicity. Delayed or prolonged absorption allows for late decomtamination. Multiple doses of activated charcoal are effective in interrupting both enteroenteric and enterohepatic recirculation. Alkalinisation-induced ion trapping enhances renal elimination of unchanged drugs which normally undergo hepatic transformation.For several drugs, chronic overdose due to altered distribution is associated with a greater severity of toxic manifestations despite relatively low serum drug concentrations. Conversely, with some drugs, induction of metabolic pathways may lead to more rapid drug elimination in chronic overdose. Knowledge of the pharmacokinetic alterations which occur in drug overdose enables the physician to predict toxicity with greater accuracy and to institute optimum therapy in a timely manner.

ISSN:0312-5963    

出版商:ADIS    

年代:1992

数据来源: ADIS

摘要:

The macrolide antibiotics include natural members, prodrugs and semisynthetic derivatives. These drugs are indicated in a variety of infections and are often combined with other drug therapies, thus creating the potential for pharmacokinetic interactions.Macrolides can both inhibit drug metabolism in the liver by complex formation and inactivation of microsomal drug oxidising enzymes and also interfere with microorganisms of the enteric flora through their antibiotic effects. Over the past 20 years, a number of reports have incriminated macrolides as a potential source of clinically severe drug interactions. However, differences have been found between the various macrolides in this regard and not all macrolides are responsible for drug interactions. With the recent advent of many semisynthetic macrolide antibiotics it is now evident that they may be classified into 3 different groups in causing drug interactions. The first group (e.g. troleandomycin, erythromycins) are those prone to forming nitrosoalkanes and the consequent formation of inactive cytochrome P450-metabolite complexes. The second group (e.g. josamycin, flurithromycin, roxithromycin, clarithromycin, miocamycin and midecamycin) form complexes to a lesser extent and rarely produce drug interactions. The last group (e.g. spiramycin, rokitamycin, dirithromycin and azithromycin) do not inactivate cytochrome P450 and are unable to modify the pharmacokinetics of other compounds.It appears that 2 structural factors are important for a macrolide antibiotic to lead to the induction of cytochrome P450 and the formationin vivoorin vitroof an inhibitory cytochrome P450-iron-nitrosoalkane metabolite complex: the presence in the macrolide molecules of a nonhindered readily accessibleN-dimethylamino group and the hydrophobic character of the drug.Troleandomycin ranks first as a potent inhibitor of microsomal liver enzymes, causing a significant decrease of the metabolism of methylprednisolone, theophylline, carbamazepine, phenazone (antipyrine) and triazolam. Troleandomycin can cause ergotism in patients receiving ergot alkaloids and cholestatic jaundice in those taking oral contraceptives.Erythromycin and its different prodrugs appear to be less potent inhibitors of drug metabolism. Case reports and controlled studies have, however, shown that erythromycins may interact with theophylline, carbamazepine, methylprednisolone, warfarin, cyclosporin, triazolam, midazolam, alfentanil, disopyramide and bromocriptine, decreasing drug clearance. The bioavailability of digoxin appears also to be increased by erythromycin in patients excreting high amounts of reduced digoxin metabolites, probably due to destruction of enteric flora responsible for the formation of these compounds. These incriminated macrolide antibiotics should not be administered concomitantly with other drugs known to be affected metabolically by them, or at the very least, combined administration should be carried out only with careful patient monitoring.Josamycin, midecamycin and probably also the related compounds miocamycin, clarithromycin and flurithromycin, may have a clinically significant interaction with carbamazepine and cyclosporin, requiring close monitoring. Roxithromycin interaction with drugs such as theophylline or cyclosporin does not seem to justify a dosage reduction. No pharmacokinetic interactions have yet been described for spiramycin, rokitamycin, dirithromycin and azithromycin.

ISSN:0312-5963    

出版商:ADIS    

年代:1992

数据来源: ADIS

摘要:

Multiple hepatic P450 enzymes play an important role in the oxidative biotransformation of a vast number of structurally diverse drugs. As such, these enzymes are a major determinant of the pharmacokinetic behaviour of most therapeutic agents. There are several factors that influence P450 activity, either directly or at the level of enzyme regulation.Drug elimination is decreased and the incidence of drug interactions is increased when there is competition between 2 or more drugs for oxidation by the same P450 enzyme. The available knowledge concerning the relationship between the presence of certain functional groups within the drug structure and inhibition of P450 activity is increasing. In many instances, it is possible to associate inhibition with certain drug classes, e.g. antimycotic imidazoles and macrolide antibiotics.Disease states, especially those with hepatic involvement, and the genetic makeup of the individual are conditions in which some P450s may be downregulated (that is, the enzyme concentrations in liver are decreased), with associated slower rates of drug elimination. In these individuals, dosages of drugs that are substrates for downregulated P450s should be decreased.Exposure to environmental pollutants as well as a large number of lipophilic drugs can result in induction (upregulation) of P450 enzyme activity. This raises the issue of previous approaches to the study of P450 inductionin vivo.The use of human hepatocyte preparations in culture is a promising new direction that could assist the determination of modifications to drug therapy necessitated by exposure to inducing agents. Until such information is obtained, however, the use of drugs known to increase the microsomal expression of particular P450s, and increase associated drug oxidation capacity in humans, should be used with caution.

ISSN:0312-5963    

出版商:ADIS    

年代:1992

数据来源: ADIS

摘要:

Antiemetic drugs are used to treat nausea and vomiting due to a variety of causes and have a wide range of pharmacological properties. The choice of drug will, therefore, depend in part on the condition being treated. The drugs can be classified as dopamine antagonists (including phenothiazines and nonphenothiazines). corticosteroids, cannabinoids, benzodiazepines, serotonin antagonists, antihistamines and anticholinergics.There is very little evidence of a relationship between plasma drug contentrations and either their efficacy or the incidence of adverse effects with most antiemetic drugs. With drugs for which concentration-effect studies have been performed, e.g. the benzodiazepines and antihistamines, the effects monitored have not been directly relevant to their use as antiemetics.Antiemetics are used widely, for example, in cancer chemotherapy. Nonetheless, apart from metoclopramide, little work has been done on the influence of indicators of systemic disease on the pharmacokinetics of antiemetic drugs.

ISSN:0312-5963    

出版商:ADIS    

年代:1992

数据来源: ADIS

摘要:

A pharmacokinetic study of&agr;1-antitrypsin (ATT) was performed in 2 groups of homozygous PiZ-deficient patients (treated and untreated) and 1 group of healthy volunteers. The distribution of the131I-labelled protein corresponds to a 3-compartment model. The intravenously administered protein diffused quickly to the extravascular compartment where some retention occurred. No significant difference in AAT metabolism was observed between the 3 groups.The half-life of the injected protein is slightly longer than 2.5 days. The AAT protein was not stored. These results confirm the observations collected during the clinical trials. That is, a weekly infusion is necessary to obtain stable serum AAT concentrations. Monthly infusions are unable to maintain a ‘plateau’ phase. The periodicity may be limited to every 2 weeks.

ISSN:0312-5963    

出版商:ADIS    

年代:1992

数据来源: ADIS