摘要:

Serum concentration measurements of antibacterial agents are increasingly used to optimise drug dosage regimens. However, this approach is only justified for drugs with a low therapeutic index and poor predictability of serum concentrations, such as the aminoglycosides, chloramphenicol and vancomycin, whereas the penicillins and cephalosporins can safely be applied well above their minimum inhibitory concentrations.Wide interpatient variation in distribution and elimination are the main reasons for the unpredictability of aminoglycoside serum concentrations. It has been shown that in patients with normal creatinine clearance, the apparent elimination half-life of gentamicin varies from 0.4 to 7.6 hours. The pharmacokinetics of the aminoglycosides are most adequately described by a 3-compartment open model where the slow terminal half-life reflects elimination from the deep tissue compartment. The accumulation of the aminoglycosides in this compartment, which includes the kidneys and inner ear, is probably an important factor in their potential toxicity in these organs. Careful serum level monitoring may reduce, but cannot totally avoid, the risk of side effects. However, maintenance of effective drug levels appears to be at least an equally important goal of aminoglycoside serum level monitoring.Chloramphenicol is also a potentially toxic antibacterial agent. Its therapeutic range is usually considered to be 15 to 25 mg/L. The most important side effects are the ‘grey baby syndrome’ and bone marrow toxicity. Chloramphenicol is metabolised to several microbiologically inactive products. It also shows wide interpatient variability of its pharmacokinetics, especially in young children, and serum levels should therefore be followed in these patients.Vancomycin, a highly effective agent for staphylococcal and enterococcal infections, may also exhibit nephrotoxic and ototoxic side effects. A well-defined therapeutic range has not yet been established but in view of its minimum inhibitory concentrations it seems reasonable to maintain vancomycin serum concentrations between 15 and 50 mg/L. Since this drug is excreted unchanged in the urine, serum levels should particularly be monitored in patients with impaired renal function.The advances in routine therapeutic drug monitoring are directly related to rapid developments in technologies associated with the quantification of these agents. Microbiological plate diffusion assays are now often replaced by more specific immunoassays (radioimmunoassay, enzyme immunoassay, and fluorescence immunoassay) and chromatographic techniques.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

At present, there are two H2-receptor antagonists available for the treatment of peptic ulcer disease - cimetidine and ranitidine. Cimetidine is well known to interact with a number of concurrently administered drugs. Like cimetidine, ranitidine binds to cytochrome P-450 in the liver where it appears to exert an inhibitory effect, but to a lesser extent than cimetidine. Both H2-receptor antagonists may also reduce hepatic blood flow.Several drugs which are known to interact with cimetidine have been found not to interact significantly with ranitidine, including propranolol, lignocaine, phenytoin and diazepam. However, significant pharmacokinetic interactions between ranitidine and several other drugs have been established. These interactions may be attributed variously to an effect of ranitidine on hepatic metabolism or to an effect on the absorption of concomitantly administered drugs. For example, the bioavailability of midazolam is significantly increased due to the influence of ranitidine on gastric pH and thus on absorption of midazolam, leading to an increased soporific effect of this benzodiazepine; an effect of ranitidine on oxidative liver metabolism also appears to be a contributory factor in this interaction. Conversely, ranitidine distinctly reduced protein-bound cobalamin absorption from a mean of 7.66% prior to ranitidine administration to 0.84% during treatment with ranitidine 300mg daily.A significant pharmacokinetic interaction has also been demonstrated between ranitidine and procainamide: the AUC of procainamide increased and the renal clearance fell significantly from a mean of 378 to 309 ml/min with ranitidine co-administration. However, this interaction is due to a different mechanism. In this case, ranitidine appears to compete with procainamide for the common renal proximal tubular secretion site.The reported interactions of ranitidine with warfarin, metoprolol, nifedipine, theophylline and fentanyl appear to be due to inhibition of cytochrome P-450. In a clinical study, warfarin clearance was significantly reduced from 66.7 to 48.7 ml/min by ranitidine, and by cimetidine to 42.9 ml/min. Similarly, the elimination half-lives of metoprolol and nifedipine were distinctly prolonged and the AUCs significantly increased by ranitidine. However, the latter pharmacokinetic interactions appear unlikely to be of clinical significance since the clinical effects of metoprolol and nifedipine were unaffected by ranitidine treatment. In therapeutic concentrations, ranitidine inhibited the disappearance of fentanyl from anin vitromicrosomal preparation, indicating that it inhibits microsomal drug metabolism. In rat experiments, ranitidine also significantly reduced alcohol elimination by 19% (p < 0.01).The bioavailability of ranitidine itself was decreased by 33% due to concurrent administration of an aluminium-magnesium hydroxide antacid preparation (p < 0.05), and increased by propantheline (p < 0.05). The anticholinergic drug pirenzepine also produced a pharmacodynamic interaction with ranitidine, potentiating the inhibitory effect of the latter on gastric acid secretion.Thus present data show that ranitidine is involved in drug interactions which may be of clinical relevance. Adverse drug interactions can be avoided by careful monitoring of treated patients and adjustment of the dosage where appropriate.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

The quantitative aspects of the disposition in man of 12 antituberculosis drugs [isoniazid, rifampicin, (rifampin), ethambutol, para-aminosalicylic acid, pyrazinamide, streptomycin, kanamycin, ethionamide, cycloserine, capreomycin, viomycin and thiacetazone] are reviewed. Isoniazid appears to be the only agent for which plasma concentrations and clearance are related to hereditary differences in acetylator status and for which there is an appreciable ‘first-pass’ effect. Recent data cast doubt on the suggestion that isoniazid may be more hepatotoxic for rapid as opposed to slow acetylators. Continuous administration of rifampicin leads to induction of enzymes in the liver with a concomitant decrease in maximum plasma concentrations, the time required to achieve this level, elimination half-life, and area under the plasma concentration-time curve (AUC). Coadministration of para-aminosalicylic acid leads to increases in the serum concentrations and elimination half-life of isoniazid.With a few exceptions, the metabolites of the antituberculosis drugs are devoid of antimicrobial activity; the exceptions are 25-desacetylrifampicin which accounts for approximately 80% of the drug's antimicrobial activity in human bile, the acetylated and glycylated metabolites of para-aminosalicylic acid, and the sulphoxide metabolites of ethionamide.The effect of renal impairment is relatively unimportant for the excretion of isoniazid, rifampicin and para-aminosalicylic acid, but the elimination half-life of streptomycin increases to 100 hours when the blood urea nitrogen level is greater than 100mg/100ml, and ototoxicity is strikingly more frequent. In states of malnutrition, such as kwashiorkor, the protein binding of para-aminosalicylic acid decreases from 15% to essentially zero and in the case of ethionamide and streptomycin binding decreases by 6% and 16% respectively. Of the data concerning age-related effects, most notable are the prolonged elimination half-life of isoniazid in neonates (up to 19.8 hours), and the lower peak serum concentrations of rifampicin in children of one-third to one-tenth those of adults following a similar dose on a weight basis. For kanamycin, the maximum plasma concentration varies inversely with age but is not influenced by birthweight; however, the clearance is directly dependent upon birthweight and postnatal age. For the elderly, age is an insignificant factor for the elimination of isoniazid when compared with young adults of similar acetylator status, and the metabolism of rifampicin may be considered globally unaltered in this age group. The elimination half-life of kanamycin increases from 107 minutes in younger individuals to 282 minutes in elderly populations.Recent data indicate that isoniazid, rifampicin, ethambutol, para-aminosalicylic acid, pyrazinamide, streptomycin, kanamycin and cycloserine appear in measurable quantities in breast milk, with isoniazid having the highest recorded level of 2.3% of a daily administered dose.Pharmacokinetic drug interactions and techniques for therapeutic drug monitoring of each of these agents (and some of their metabolites) are also briefly reviewed. Consideration of the pharmacokinetics of these drugs in planning treatment regimens could lead to more rational, safer and possibly more efficacious use.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

Routine clinical pharmacokinetic data collected from patients receiving procainamide were analysed to estimate population pharmacokinetic parameters. 116 plasma concentration determinations for procainamide and 14 timed urine collections for the drug and its major metabolite N-acetylprocainamide (NAPA) were obtained from 39 patients, mostly males. The data were analysed using NONMEM, a computer program designed for population pharmacokinetic analysis that allows pooling of data from many individuals. Estimates of the influence of weight, height, renal function, and the presence of congestive heart failure (CHF) on the renal clearance (CLR), acetylation clearance (CLA), miscellaneous metabolic clearance (CLO), and volume of distribution (Vd) of procainamide were obtained.The mean (SE) CLR, CLA, CLOand Vd for procainamide in a 70kg patient with normal renal function were estimated to be 14.4 (2.3) L/h, 10.1 (1.7) L/h, 1.2 (1.3) L/h, and 136.0 (20.0) L, respectively. These pharmacokinetic parameters vary linearly with bodyweight; height adds no information if weight is known. The presence of CHF has no significant effect on either CLOor Vd, but reduces CLAand CLRby 11% (p < 0.01). Even after adjustments for CHF, renal function and weight, the total clearance and Vd of procainamide vary unpredictably among individuals, with a coefficient of variation between 30 and 40%, and < 50%, respectively.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS