摘要:

About 70 to 80% of an oral dose of digoxin is absorbed, mainly in the proximal part of the small intestine. The degree of binding to serum albumin is 20 to 30%. Digoxin is extensively distributed in the tissues, as reflected by the large volume of distribution. High concentrations are found in the heart and kidneys, but the skeletal muscles form the largest digoxin storage. The half-life of elimination in healthy persons varies between 26 and 45 hours.The main route of elimination is renal excretion of digoxin, which is closely correlated with the glomerular filtration rate. In addition, some tubular secretion and perhaps tubular reabsorption occurs. Nearly all of the digoxin in the urine is excreted unchanged, with a small part as active metabolites. The clinical significance of dihydrodigoxin as a metabolite remains to be resolved. About 25 to 28% of digoxin is eliminated by nonrenal routes. Biliary excretion may rise up to 30% of a given dose, but the enterohepatic cycle seems to be of minor importance.The pharmacodynamic effects of digoxin, including toxic symptoms, are correlated with the uptake of digoxin in the heart after a single dose and with the steady state serum digoxin concentration during maintenance therapy.Impaired kidney function is the most important condition with an influence on the pharmacokinetics of digoxin. In addition to the renal clearance of creatinine, the bioavailability of the digoxin formulation used, the volume of distribution, the amount of extrarenal clearance, body weight and serum albumin concentration, are other factors which may modify the serum level of digoxin. Certain drug interactions may also occur during the absorptive phase. Exact prediction of serum digoxin concentrations by various dosage calculations has not succeeded. Since many factors may influence the sensitivity of the myocardium to digoxin, measurement of serum digoxin levels is only one, but a useful criterion, when making clinical decisions about adjustment of digoxin dosage.

ISSN:0312-5963    

出版商:ADIS    

年代:1977

数据来源: ADIS

摘要:

Based on clinical experience, infants with congestive heart failure are given larger doses of digoxin than adults, whether calculated on the basis of body weight or surface area. The reasons for this difference in dosage are not clear. The myocardium of the infants might be more resistant to the effects of digoxin than that of adults, and/or differences might exist between infants and adults concerning the absorption, distribution and elimination of the glycoside.Infants have been found to absorb digoxin in solution at the same rate and to the same extent as adults. The relative distribution of the glycoside to different tissues is also similar in the two age-groups. However, the binding of digoxin to several tissues seems to be more extensive in infants than in adults. In agreement with this, the apparent volume of distribution of the glycoside is larger in infants than in adults. In infants (except neonates), the elimination half-life of digoxin is shorter than in adults. As no enhanced urinary excretion has been found in infants there might be a non-renal elimination of the glycoside.With most prevailing dose schedules for digoxin, serum concentrations higher than those considered optimum for adults are often obtained in infants. It is known that infants tolerate higher serum digoxin concentrations than adults without developing signs of toxicity. However, it is not known whether such high concentrations are necessary for obtaining an adequate inotropic effect on the myocardium of the infants. If the relation between serum concentration and effect is the same in infants and adults, the loading (digitalising) dose generally given to infants is unnecessarily high.

ISSN:0312-5963    

出版商:ADIS    

年代:1977

数据来源: ADIS

摘要:

Although the liver is the major site for drug biotransformation, the effect of hepatic dysfunction on drug disposition has not been consistent or predictable. Most early studies of drug kinetics in liver disease measured only half-life. Only in the past few years has it been realised that liver diseases can affect drug absorption, hepatic metabolism, tissue distribution, and protein binding, which complicate interpretation of any change, or lack of change in drug half-life. Furthermore, it is now apparent that the efficiency with which a drug is metabolised by the liver, the extent of binding to blood constituents, and the aetiology and stage of the hepatic disorder are each important in determining whether significant alterations in drug disposition will occur.A pharmacokinetic perfusion model which takes into account many of the above factors has been proposed, and appears to be useful for predicting changes in the disposition of rapidly metabolised compounds. Nevertheless, the state of knowledge about those factors which limit the rate of metabolism of individual drugs or classes of drugs is inadequate, and no general model or guidelines which are useful clinically have been developed.Patients with hepatic disorders may show increases or decreases in sensitivity independent of alterations in drug disposition. The clinician caring for such patients must be cautious about the use of any drugs, and rely heavily on careful patient observation to determine efficacy or toxicity.

ISSN:0312-5963    

出版商:ADIS    

年代:1977

数据来源: ADIS

摘要:

There is a considerable range in the dose of many drugs that is required to produce a given pharmacological effect in an individual patient. This individual variation in dose requirement is sometimes reflected in the wide scatter in the steady state plasma concentration that follows the same oral dose of a drug given to any group of subjects. Such individual differences are largely due to variation in the rate of elimination of drugs.Gastrointestinal disease may also alter oral dose requirements by producing variation in both theamountandrateof drug absorption. These changes may be reflected in the plasma concentration/time curve that follows an oral dose.The amount of drug absorbed is simultaneously affected by many factors. These include the physicochemical properties of the drug and the physiological factors that operate within the gut, as well as the presence of other substances such as food, or interaction with other drugs in the gut. The availability of the drug within the intestinal lumen is largely governed by its dissolution characteristics, particularly factors which can interfere with dissolution of the drug product in the gut.Physiological factors within the gut that affect oral drug absorption include gastric emptying rate and intestinal motility, the pH of the gastrointestinal fluids, the activity of gastrointestinal drug metabolising enzymes (e.g. monoamine oxidase and dopa decarboxylase) or drug metabolising bacteria and the surface area of the gut.Many factors affect gastric emptying. These include disease, surgery and other drugs. A change in the rate of gastric emptying alters the rate of drug delivery from the stomach to the duodenum and upper small intestine. This may profoundly alter the plasma concentration/time curve that follows oral administration of many drugs.For some drugs, proximal jejunal disease may reduce, delay or increase the apparent amount of drug absorbed. Reduced absorption of an antibiotic leads to a fall in the peak plasma concentration. If the peak falls below the minimum inhibitory concentration for a particular organism then therapeutic failure may occur, if it is assumed that the peak plasma concentration is all important for antimicrobial activity. Excessive drug absorption may lead to drug toxicity.Abnormal drug absorption is a feature of lower small intestinal conditions such as Crohn's disease. This suggests that drug absorption is not confined to the jejunum but continues throughout the small intestine.It is not always possible to predict the pattern of drug malabsorption from a knowledge of the physicochemical and pharmacokinetic properties of the drug and the pathophysiology of the disease. The rate and amount of drug absorbed by one patient may differ from that in another patient with the same condition. Although these differences reflect normal individual variation, they are also related to the extent and activity of disease at the time of study.The similar abnormal plasma concentration/time curve that follows oral administration of clindamycin, sulphamethoxazole and trimethoprim in coeliac disease, small bowel diverticulosis and Crohn's disease suggests that a similar underlying mechanism in these conditions is responsible for the abnormal absorption of these three physicochemically unrelated drugs.

ISSN:0312-5963    

出版商:ADIS    

年代:1977

数据来源: ADIS

摘要:

Rifampicin, a potent antituberculosis agent, is frequently combined with other antituberculosis drugs, or with drugs belonging to entirely different classes which may be required during a long period of antituberculous treatment, and therefore has a potential for drug interactions of practical clinical importance.The absorption of rifampicin is markedly decreased when it is simultaneously administered with para-aminosalicylic acid granules, due to adsorption by an excipient, bentonite. Several clinical observations and investigations have indicated that rifampicin itself accelerates the metabolism of various other compounds, including oral anticoagulants, the contraceptive pill, oral hypoglycaemic agents and digitoxin.Rifampicin seems to be a potent inducer of drug metabolism in humans and it causes a proliferation of the smooth endoplasmatic reticulum and an increase of cytochrome P450content in the liver. It also increases its own rate of desacetylation. However, of the test compounds hexobarbitone and tolbutamide, the metabolic clearance increased 2 - to 3-fold following rifampicin treatment, whereas antipyrine clearance was unaltered. This indicates that there is a certain selectivity in the enzyme induction effect of rifampicin, although it remains unclear which compound will and which will not be affected.Rifampicin may also possibly interfere with hepatic uptake of other compounds, but the clinical significance of this type of interaction has not been clearly demonstrated. On the other hand, oral probenecid significantly increases the serum level of rifampicin, probably due to a similar depression of hepatic uptake.

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