摘要:

Cardiac failure is often associated with disturbances in cardiac output, autonomic nervous system activity, central and systemic venous pressures, and sodium and water metabolism. These disturbances influence the extent and pattern of tissue perfusion, may lead to tissue hypoxia and visceral congestion, and may alter gastrointestinal motility. By these mechanisms, cardiac failure potentially affects absorption and disposition characteristics of drugs, which may necessitate adjustment in dosage regimen for optimum therapy.Lignocaine is the drug which has been studied most extensively in cardiac failure. Volumes of distribution and clearance are decreased. As a drug whose metabolism is largely limited by liver blood flow, decreased blood flow to the liver accounts for some of the change in clearance, but impaired hepatic metabolism appears also to play a role in some patients. Accumulation of active metabolites of lignocaine and procainamide in patients with cardiac failure can influence therapeutic and toxic effects. Theophylline metabolism, which is largely independent of blood flow, appears to be reduced significantly in patients with severe cardiac failure and necessitates reduction of dosage. In the presence of severe cardiac failure, digoxin clearance may be less than anticipated on the basis of estimates of renal function. Quinidine plasma levels may be higher after single doses due to reduced volume of distribution. Quinidine metabolites are believed not to be pharmacologically active but may create confusion with nonspecific assays. Specific assays are recommended in cardiac failure, especially complicated by renal insufficiency.Data are lacking relating pharmacokinetic alterations to haemodynamic measurements in patients with cardiac failure. Whereas the direction of change in pharmacokinetic parameters may be predicted, variability in the magnitude of change is so great that determination of drug concentration in blood remains an essential adjunct to therapy.

ISSN:0312-5963    

出版商:ADIS    

年代:1976

数据来源: ADIS

摘要:

Sulphasalazine consists of 5-aminosalicylic acid and sulphapyridine both linked together by an azo bond. Sulphasalazine is clearly useful in long-term management of ulcerative colitis and may be useful in Crohn's disease. The absorption, metabolism and excretion of sulphasalazine is similar in volunteers and patients with ulcerative colitis or Crohn's disease. Sulphasalazine serves as a vehicle to deliver its possible active components, 5-aminosalicylic acid and sulphapyridine, to the colon in higher concentrations than could be achieved by oral administration of either one alone. Sulphasalazine reaches the colon mostly unchanged and is split by gut bacteria at the azo linkage, releasing 5-aminosalicylic acid and sulphapyridine.5-Aminosalicylic acid may act locally and is not absorbed to any great extent. On the contrary, sulphapyridine is mostly absorbed from the colon and may act both locally, during mucosal absorption, and systemically. A positive correlation exists between serum total sulphapyridine concentration and both therapeutic efficacy and toxicity. Sulphapyridine metabolism is largely determined by inherited acetylator phenotype, either slow or fast. Slow acetylators have higher levels of free sulphapyridine and lower levels of acetylated sulphapyridine than fast acetylators, and are likely to have more toxic symptoms on equivalent doses of sulphasalazine. Therapeutic effects of sulphasalazine in ulcerative colitis and Crohn's disease correlate with serum concentrations of total sulphapyridine (20 to 50&mgr;/ml), and toxicity with total sulphapyridine concentrations > 50&mgr;g/ml. Side-effects are mostly observed among slow acetylators. In long-term therapy of ulcerative colitis doses of 2 to 3g/day of sulphasalazine are most likely to sustain remissions and avoid toxicity. During therapy with sulphasalazine, determination of acetylator phenotype and total sulphapyridine concentration can guide effective dosage and avoid side-effects. A single serum sample for free and acetylated sulphapyridine concentrations is sufficient for this purpose.

ISSN:0312-5963    

出版商:ADIS    

年代:1976

数据来源: ADIS

摘要:

Drugs that are administered to man may be biotransformed to yield metabolites that are pharmacologically active. The therapeutic and toxic activities of drug metabolites and the species in which this activity was demonstrated are compiled for the metabolites of 58 drugs. The metabolite to parent drug ratio in the plasma of non-uraemic man and the percentage urinary excretion of the metabolite in non-uraemic man are also tabulated. Those active metabolites with significant pharmacological activity and high plasma levels, both relative to that of the parent drug, will probably contribute substantially to the pharmacological effect ascribed to the parent drug. Active metabolites may accumulate in patients with end stage renal disease if renal excretion is a major elimination pathway for the metabolite. This is true even if the active metabolite is a minor metabolite of the parent drug, as long as the minor metabolite is not further biotransformed and is mainly excreted in the urine. Minor metabolite accumulation may also occur if it is further biotransformed by a pathway inhibited in uraemia. Some clinical examples of the accumulation of active drug metabolites in patients with renal failure are: (a) The abolition of premature ventricular contractions and prevention of paroxysmal atrial tachycardia in some cardiac patients with poor renal function treated with procainamide are associated with high levels of N-acetylprocainamide. (b) The severe irritability and twitching seen in a uraemic patient treated with pethidine (meperidine) are associated with high levels of norpethidine. (c) The severe muscle weakness and tenderness seen in patients with renal failure receiving clofibrate are associated with excessive accumulation of the free acid metabolite of clofibrate. (d) Patients with severe renal insufficiency taking allopurinol appear to experience a higher incidence of side reactions, possibly due to the accumulation of oxipurinol. (e) Accumulation of free and acetylated sulphonamides in patients with renal failure is associated with an increase in toxic side-effects (severe nausea and vomiting, evanescent macular rash). (f) Peripheral neuritis seen after nitrofurantoin therapy in patients with impaired renal function is thought to be due to accumulation of a toxic metabolite.The high incidence of adverse drug reactions seen in patients with renal failure may for some drugs be explained in part, as the above examples illustrate, by the accumulation of active drug metabolites.Monitoring plasma levels of drugs can be an important guide to therapy. However, if a drug has an active metabolite, determination of parent drug alone may cause misleading interpretations of blood level measurements. The plasma level of the active metabolite should also be determined and its time-action characteristics taken into account in any clinical decisions based on drug level monitoring.

ISSN:0312-5963    

出版商:ADIS    

年代:1976

数据来源: ADIS

摘要:

Plasma protein binding of phenytoin (diphenylhydantoin) in 63 epileptic patients was investigated with an ultrafiltration technique at room temperature using14C-labelled phenytoin. A strong correlation was found between the total and the unbound drug concentration (r = 0.97, p < 0.001). The unbound phenytoin fraction was 7.1 ± 1.0% with a range of 4.9 to 10.2%. This variation is considerably less than that reported recently by different authors. Individual phenytoin binding was reproducible when the determination was repeated several weeks later. Salivary phenytoin concentrations in 33 epileptic patients were significantly correlated to the unbound (r = 0.83) and total concentrations (r = 0.82) of phenytoin in plasma. This study confirms that the clinical practice of monitoring total phenytoin plasma concentrations is sufficient, since the unbound phenytoin fraction has only a 2-fold interindividual variation in epileptic patients, provided that they do not suffer from renal or hepatic disease.

ISSN:0312-5963    

出版商:ADIS    

年代:1976

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1976

数据来源: ADIS