摘要:

The therapeutic effect of the tricyclic antidepressants is subject to marked interindividual differences in response. Only 50 to 70% of depressed patients usually benefit from treatment. The antidepressive effect is most clearly drug-related in endogenous depressions and less convincing in other types of depression. However, even within diagnostically homogenous groups of depressed patients, the antidepressive effect is variable. Some of this variability may be explained by the pronounced interindividual variation in pharmacokinetics of tricyclic antidepressants, in particular variation in steady state plasma levels.Studies with nortriptyline in endogenous depressions have indicated that a therapeutic effect is only achieved when the plasma level is above 50 and below 150 to 180&mgr;g/L, above which patients respond poorly. For imipramine, most patients respond well when plasma levels of imipramine + desipramine are above 200 to 240&mgr;g/L. Very high plasma levels do not appear to impair the antidepressive effect of imipramine. The present data on other antidepressants are less clear.For nortriptyline and imipramine, as well as other antidepressants, there is a need for more studies on larger patient populations comprising different diagnostic categories, and designed and conducted with careful consideration of the number of methodological problems involved in interpreting plasma level/effect relationships. The use of plasma level monitoring in cases of intoxication with tricyclic antidepressants is potentially useful, but studies in this area are limited.

ISSN:0312-5963    

出版商:ADIS    

年代:1977

数据来源: ADIS

摘要:

Binding of antimicrobial agents to serum proteins, and to extravascular tissues, affects their distribution, elimination, and pharmacological activity. The extent of binding of drugs to serum proteins is both drug concentration and protein concentration dependent. However, changes in drug concentrations within the therapeutic range have little effect.Drug-protein binding may be reduced by the presence of other drugs, and also by endogenous substances. The latter may be important in cases of impaired renal or hepatic function and in disease states associated with elevated free fatty acids. The greatest reductions in protein binding are observed with drugs that are normally highly bound.Equations are presented to describe the influence of the binding of drugs to serum proteins and tissues on the percentage of drug which is free in the body, the concentration of free and total drug in serum, and the apparent distribution volume of drug in the body. Changes in the percentage bound to serum proteins tend to produce curvilinear changes in the various values with the greatest changes occurring with highly bound drugs (greater than 80% binding). Changes in the percentage bound to tissues tend to produce linear changes in all values except the apparent drug distribution volume. Small changes in tissue binding of highly bound drugs cause marked changes in apparent distribution volumes.Although tissue and extravascular fluid drug levels are primarily influenced by the free drug levels in serum, calculation of actual tissue levels is complicated by variable binding characteristics of specific tissues and tissue fluids, and also by the lipophilic nature of the drug.Renal elimination of antimicrobial agents is markedly influenced by serum protein binding if the major elimination mechanism is glomerular filtration. Serum protein binding has little effect on drug elimination in cases of elimination by renal tubular secretion and hepatic extraction. As in the case of distribution, renal clearance and hepatic extraction may be a function of both protein binding and drug lipophilicity.A drug which is bound to serum proteins has no antibacterial activity in vitro. However, binding of drugs to serum proteins in vivo has major clinical significance only when levels of free drug are reduced to values below the minimum inhibitory concentrations of susceptible micro-organisms. In many cases, high protein binding may be compensated for by greater intrinsic antimicrobial activity of lipophilic drugs.

ISSN:0312-5963    

出版商:ADIS    

年代:1977

数据来源: ADIS

摘要:

Antacids are commonly used drugs which are considered inert and free of pharmacological effect by many patients and physicians. When administered with other drugs, antacids can alter absorption or excretion of these agents, at times reducing their plasma level and effect and in other cases causing toxicity.Although many antacid-drug interaction studies have been performed in animals orin vitroand others show only minor effects in man, several clinically important interactions and their mechanisms have been verified in man. Antacids which reduce drug dissolution or bind drugs in the gastrointestinal tract have been shown to inhibit absorption and reduce efficacy of tetracyclines, digoxin, phenytoin and certain psychotherapeutic agents. Aluminium hydroxide gel delays gastric emptying, delaying isoniazid absorption and lowering blood levels. By elevating urine pH, antacids cause accelerated excretion of acidic drugs like salicylate and per contra may cause retention of basic drugs like quinidine or amphetamine.While the efficacy of many drugs may not be affected by antacids, the absorption or excretion of other drugs which have not yet been studied are undoubtedly altered by antacid administration. It is therefore advisable, where possible, to administer other drugs at least a half to I hour before antacid ingestion to ensure consistent absorption and effect. Long-term antacid ingestion should be avoided when other drugs are taken, unless antacid use is clinically indicated and is of proven benefit.

ISSN:0312-5963    

出版商:ADIS    

年代:1977

数据来源: ADIS

摘要:

Successful withdrawal of digoxin in small highly selected groups of patients and in larger groups, in which many patients had no cardiac lesion, have led to speculation as to the value of maintenance digoxin following an episode of heart failure. Recent experience in general medical outpatients receiving maintenance digoxin, and also in many cases potent diuretics, suggests that such doubts are largely misplaced.Differences in bioavailability between formulations have hindered the prediction of dose requirements. Standardisation of dissolution rate has reduced this contribution to the measured variation in individual absorption, but substantial variation remains which is probably due to individual differences in gastrointestinal function.The best criterion by which to judge the appropriateness of a prescription would be the clinical response of the patient. Nevertheless, guidelines are required for initial treatment and even for long term treatment of those patients in whom there is no convenient indicator of therapeutic response. In both situations, renal function, measured by creatinine clearance, has been the best guide to the dose schedule required to achieve the desired mean steady state serum digoxin concentration. In adult patients with normal or only slightly impaired renal function, and normal atrio-ventricular conduction, the most practical procedure may be to start all patients on the same dose schedule.Symptoms of toxicity can occur at mean serum concentrations within the published therapeutic range. In these circumstances, reduction of the dose by small steps may abolish toxicity without loss of therapeutic response. Failure to reduce the dose encourages non-compliance. Further reduction during follow-up may be necessary because of deterioration of renal function or progression of cardiac disease.

ISSN:0312-5963    

出版商:ADIS    

年代:1977

数据来源: ADIS

摘要:

The disposition kinetics of digitoxin have not been as thoroughly examined as those of digoxin. Digitoxin appears to be rapidly and completely absorbed after oral or intramuscular administration although there have been no estimates of absolute bioavailability. There is only one study that has examined the relative bioavailability of two commercial digitoxin tablets (USA) and no differences were found other than in rates of absorption. The near identical responses produced by equal oral and intravenous doses of digitoxin support the suggestion of completeness of absorption.The digitoxin plasma concentration-time curve seems to be adequately described by a two compartment open model, although such data have not been rigorously analysed. Distribution is complete within 4 to 6 hours and response is not associated with plasma concentrations during the distributive phase, suggesting that the site of action resides in a tissue compartment of a multi-compartment pharmacokinetic model. Digitoxin is strongly bound (> 90%) to plasma protein (albumin) with an association constant of 9.62 × 104litre/mole. The volume of distribution of digitoxin is approximately 0.6 L/kg, although estimates vary considerably. This volume is much smaller than digoxin, consistent with the great plasma protein binding of digitoxin.As with the estimation of the other pharmacokinetic parameters of digitoxin, estimates of elimination vary greatly, primarily as a result of differences in assay methods. Digitoxin is eliminated by hepatic metabolism and as unchanged drug in the urine and faeces. Metabolism is considered to be the major route of elimination, accounting for about 70% of a dose. While most reports indicate that only 30% of a digitoxin dose is eliminated intact (in urine and faeces) this value may be as high as 48%. Digitoxin elimination appears to be independent of dose and route of administration, although there is substantial inter-patient variant in elimination half-life. Half-lives range from 2.4 to 16.4 days with a mean value of approximately 7.6 days. The shortest mean half-life (4.8 days) was observed with the most specific assay and the longest mean half-life (9.8 days) with the least specific method.Renal insufficiency has been reported to result in either decreased or increased digitoxin elimination. While elimination may be expected to increase if plasma protein binding is reduced, there are conflicting reports on the influence of renal insufficiency on digitoxin binding. Part of this conflict may be resolved with the observation that patients undergoing haemodialysis and who receive heparin have a greater fraction of free digitoxin in plasma soon after heparin administration. It appears that plasma free fatty acid concentrations increase in response to heparin which in turn competes with digitoxin for albumin binding sites. Digitoxin half-life is reported to be shortened and volume of distribution increased in nephrotic patients. The influence of hepatic impairment on digitoxin elimination has not been thoroughly examined and there is only one report suggesting reduced elimination in this situation.Cholestyramine has been shown to reduce digitoxin half-life by interfering with the enterohepatic recycling of the drug. There have been no reports to indicate that other drugs may displace digitoxin from plasma protein binding sites. Concurrent administration of phenylbutazone, phenobarbitone, and phenytoin decrease digitoxin plasma concentrations; presumably by inducing digitoxin metabolism. Phenobarbitone, rifampicin and spironolactone have been reported to decrease digitoxin half-life.Numerous studies have attempted to better define the therapeutic plasma concentration range of digitoxin. Plasma concentrations greater than 35 to 40ng/ml are generally considered to be associated with potential toxicity while concentrations from 15 to 25ng/ml are considered to be within the therapeutic range. As with digoxin there is considerable variation and overlap in plasma concentrations associated with toxicity and therapeutic response.

ISSN:0312-5963    

出版商:ADIS    

年代:1977

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1977

数据来源: ADIS