摘要:

Summary:Five commonly used antiarrhythmic agents are examined with regard to their pharmacokinetics, pharmacology, electrophysiology, and clinical utility. The effective, nontoxic plasma levels are noted, and important drug-drug interactions with these agents are noted. Monitoring plasma levels of these agents serves a useful function in that it identifies patients who are not compliant, who are taking too little drug, or who are taking too much drug. Current techniques do not allow rapid, reproducible, and inexpensive measurements of free (vs. bound) drug in the plasma, a quantity that is likely to be substantially more valuable in determining drug effect than total plasma concentration. Previous studies on drug effectiveness may not have taken into account natural fluctuations in arrhythmia frequencies that mimic drug effect.

ISSN:0163-4356    

出版商:OVID    

年代:1982

数据来源: OVID

ISSN:0163-4356    

出版商:OVID    

年代:1982

数据来源: OVID

摘要:

Summary:The gradual onset of action and pronounced pharmacokinetic variability provide a solid rationale for drug plasma level monitoring in psychopharmacology. For tricyclic antidepressants a well-established drug level therapeutic effect relationship is available for a few compounds (imipramine, nortiptyline, amitriptyline); and for these, plasma level monitoring can ensure more efficient and safe treatment. The relationship has been demonstrated only in endogenously depressed patients. Various pharmacokinetic problems such as dose-dependent kinetics (imipramine in elderly patients), autoinduction (chlorpromazine), drug interaction (inhibitory effect of neuroleptics on metabolism of tricyclic antidepressants), and changes in protein binding may be better controlled by monitoring the drug levels. In amitriptyline intoxications, a possible change in the elimination kinetics results in a very slow decline in plasma levels for several days; and plasma level measurements might help to identify those patients at prolonged risk of adverse reactions. Some side effects—in particular, orthostatic hypotension—occur at subtherapeutic drug levels and therefore cannot be prevented by drug level monitoring, and monitoring of other (physiological) variables is more important. Drug level monitoring of tricyclic antidepressants thus can be considered a valuable addition to the treatment program, but it cannot replace proper clinical practice in terms of diagnostic evaluation and control of patients.

ISSN:0163-4356    

出版商:OVID    

年代:1982

数据来源: OVID

摘要:

Summary:Inappropriate plasma drug concentrations may be one major reason why many patients fail to show a satisfactory clinical response or experience side-effects to treatment with tricyclic antidepressants. One way of improving the situation is to try to reduce the variability in plasma concentrations by individualising drug dosage regimens as early as possible in treatment. This could be done if it were possible to predict the steady-state plasma concentrations that would be achieved by patients on any given dosage regimen. Our own studies, as well as those of other groups, have demonstrated that it is possible to make such predictions from simple measurements of drug plasma concentrations after administration of a single test dose of antidepressant. The test is best carried out in addition to therapeutic monitoring and is a simple means of selecting the optimum starting dose. The clinical advantages of a simple tolerance test are (1) ensuring that an appropriate dosage is prescribed, (2) reducing the number of dosage alterations, (3) reducing the risk of toxicity, and (4) checking patient compliance when used in combination with routine therapeutic monitoring.

ISSN:0163-4356    

出版商:OVID    

年代:1982

数据来源: OVID

摘要:

Summary:Recent studies demonstrating a relationship between plasma levels and effects of haloperidol, thioridazine, chlorpromazine, butaperazine, fluphenazine, and perphenazine suggest that therapeutic plasma level monitoring of neuroleptics may be clinically useful. Chlorpromazine, thioridazine, levomepromazine, and loxapine have active metabolites which attain plasma levels within the same range as that of the parent compound after therapeutic doses of the drug. The metabolites often have pharmacological profiles which are different from that of the parent drug, and some metabolites apparently contribute to the side effects of the drug but do not possess any neuroleptic potency. The ratios between the plasma levels of metabolites and the parent compound show large interpatient variations, and the metabolites should, therefore, be measured together with the parent drug by therapeutic plasma level monitoring. Accordingly, the assay method should be carefully selected in order to include metabolites which may contribute to the therapeutic or side effects of the drug.

ISSN:0163-4356    

出版商:OVID    

年代:1982

数据来源: OVID

摘要:

Summary:Chlorpromazine (CPZ) therapeutic drug monitoring is beset by inconclusive and controversial evidence on the positive correlation of plasma CPZ concentration and psychiatric improvement. Failure to establish meaningful correlation between plasma concentration and clinical benefit may be explained by chemical assay problems; differences in the pharmacokinetic plasma CPZ and metabolite profile due to age, acuteness or chronicity of the disease; drug interactions; and duration of neuroleptic treatment. At the other end, measurement of clinical effects in psychiatry suffers such draw-backs as less distinct and specific clinical end points, the patient's subjectiveness of symptoms and the investigator's subjectiveness on clinical scoring, and the ethical consideration of placebo use. Our data showed the following: (1) Plasma levels of CPZ parent compound correlated better with improvement in thought disorders and paranoid delusion than with total Brief Psychiatric Rating Scale; there were no correlations with depression and withdrawal retardation. (2) Chronically treated patients achieved significantly lower plasma CPZ compared to acutely treated patients on oral CPZ dose but not those treated with an intramuscular dose. (3) Children, in comparison to adults, require higher doses to achieve similar plasma CPZ levels and have a lower response threshold, both for clinical improvement and toxicity. (4) The plasma concentration of CPZ can be diminished by concomitant use of anticholinergics. (5) A drug “holiday” increases peak plasma concentration of CPZ and may benefit the nonresponders.

ISSN:0163-4356    

出版商:OVID    

年代:1982

数据来源: OVID

摘要:

Summary:The available data on haloperidol pharmacokinetics and haloperidol plasma level monitoring in neuropsychiatric patients are reviewed and compared with authors' personal observations. It appears that although haloperidol disposition can be described by linear kinetics in volunteers, this is not the case in patients in whom a 7–10-fold variability in plasma levels is observed for the same dosage together with the possibility of saturation kinetics and/or first pass effect. Anticholinergics may interfere with haloperidol absorption, and significant differences in disposition rate and binding have been observed in children and cirrhotic patients. A clear correlation appears to exist between plasma concentrations and side effects or adverse reactions with threshold levels for extrapyramidal syndromes of 6–9 ng/ml. Threshold levels for therapeutic effects vary with syndromes and age. In Gilles de la Tourette syndrome, active levels are of the order of 1–3 ng/ml, whereas in psychotic syndromes levels of 10–15 ng/ml are requested. In mania, a good therapeutic effect has been observed with plasma levels of 2.5–4.5 ng/ml. In general, children require lower plasma levels for the same therapeutic effects. In chronic unresponsive schizophrenic patients, poor drug bioavailability is not the major factor for the lack of response, and the possibility that these patients constitute a nosological subgroup is suggested. Therapeutic drug monitoring of haloperidol appears justified because (a) no direct relationship exists between daily doses and haloperidol steady-state plasma levels; (b) there is a possibility of saturation kinetics at higher doses; (c) commonly associated drugs or diseases may alter the kinetic profile of the drug; (d) drug disposition is faster in children than in adults; (e) optimal plasma concentration appears to differ in various pathological syndromes and age groups; and (f) side-effects and adverse reactions are clearly related to haloperidol plasma levels.

ISSN:0163-4356    

出版商:OVID    

年代:1982

数据来源: OVID

摘要:

Summary:Preliminary studies with the radioreceptor assay for neuroleptics suggest several advantages of this technique. Consistent with results obtained with other techniques, it is obvious that there is variation among individuals in terms of the serum levels obtained on given oral doses of neuroleptics; in addition, total daily dose correlates poorly with serum levels. The radioreceptor assay technique, however, is relatively uncomplicated and inexpensive and relies on methods that are commonly used in general hospital laboratories. Unlike gas chromatography/mass spectrometry, gas-liquid chromatography, and even radioimmunoassay—which are highly discriminative—the radioreceptor assay detects both parent drugs and active metabolites of virtu-ally all classes of neuroleptics on the basis of their presumed physiologic mechanism of action.

ISSN:0163-4356    

出版商:OVID    

年代:1982

数据来源: OVID

摘要:

Summary:The pharmacokinetics and the ratio between salivary and serum concentrations of phenobarbital (PB) were determined in 10 women undergoing treatment in late pregnancy. An approximately 2.5-fold variation was measured in the apparent relative clearance rates of PB in the women studied. The means of the total clearance rate (0.255 L/h), the relative clearance rate (4.0 ml/h/kg of body weight), the elimination half-life (95 h), the elimination rate constant (0.0071/h), and the apparent volume of distribution (35.49 L) were within the ranges observed in nonpregnant subjects. The PB concentration in saliva was 34% of that in serum. Salivary and serum levels of PB correlated closely with each other. Serum γ-glutamyl transpeptidase activity increased, and total bilirubin concentrations decreased during PB treatment, both of which can be linked to the PB-caused hepatic microsomal enzyme induction phenomenon. The variation in clearance rate emphasizes the importance of close monitoring of PB treatment of pregnant women. The results suggest that salivary PB measurements can be used with sufficient accuracy to predict PB concentrations in the serum and to optimize PB treatment during pregnancy.

ISSN:0163-4356    

出版商:OVID    

年代:1982

数据来源: OVID

摘要:

Summary:The influences on theophylline metabolism are multifactorial, resulting in significant inter- and intrapatient variability in drug responsiveness. Clinical investigations with adult patients have demonstrated the influence of diet on theophylline metabolism following a single drug dose. We have undertaken this study to examine the effect of nutritional factors on theophylline pharmacokinetics in 14 asthmatic children receiving the drug on a chronic basis. For 12-day periods each patient received three separate diets with different proportions of protein and carbohydrate but with constant fat and caloric intake. Significant differences were detected for theophylline half-life, apparent volume of distribution, and metabolic clearance rate. The high-protein diet markedly shortened the drug-elimination half-life relative to a normal diet, and high carbohydrate significantly increased it (both p < 0.001). Other kinetic parameters confirmed this pattern. Our findings in children clearly establish that nutritional factors have a significant environmental influence on theophylline metabolism during the drug's steady-state pharmacokinetics.

ISSN:0163-4356    

出版商:OVID    

年代:1982

数据来源: OVID