摘要:

The angiotensin converting enzyme inhibitors are an important therapeutic advance in the treatment of patients with hypertension and congestive heart failure. In addition, they are useful pharmacological probes to assess the contribution of the renin-angiotensin system to circulatory homeostasis.Captopril was the first angiotensin converting enzyme inhibitor approved for use in patients with hypertension and congestive heart failure. It is rapidly absorbed from the gastrointestinal tract, with detectable plasma concentrations apparent as early as 15 minutes. The extent of absorption is between 60 and 75% of an oral dose and peak plasma concentrations occur after approximately one hour. Captopril is primarily excreted by the kidneys via renal tubular secretion. Renal excretion is rapid, with 90% completed in the first 4 hours. The elimination half-life for unchanged captopril is about 1.7 hours and is markedly increased in the presence of renal insufficiency. Once absorbed, captopril is extensively metabolised to several forms, including a disulphide dimer of captopril, a captopril-cysteine disulphide, and other mixed disulphides with endogenous thiol compounds. It is probable that captopril and its pool of metabolites undergo reversible interconversions.Pharmacokinetic properties of captopril in patients with uncomplicated hypertension appear to be the same as in healthy subjects. However, long term administration of captopril leads to increased concentrations of total captopril, probably from the accumulation of captopril metabolites. Despite the number of potential influences on pharmacokinetic properties in patients with congestive heart failure, due to the many abnormalities in gastrointestinal tract oedema and reductions in splanchnic and renal blood flow, the available data suggest that its pharmacokinetic properties in patients with congestive heart failure resemble those in healthy subjects. However, additional data are necessary to confirm this.Enalapril is the second angiotensin converting enzyme inhibitor to become available. Enalapril is a prodrug that is well absorbed from the gastrointestinal tract, with 60 to 70% of an oral dose being absorbed. However, enalapril must be converted by hepatic esterases to the active form, enalaprilat. After the oral administration of enalapril, the tmaxfor enalapril is one hour, but for enalaprilat it is 4 hours. There is a prolonged terminal elimination phase with enalaprilat being detectable as late as 96 hours after dosing. Thus, enalapril has a much longer duration of action than captopril. Like captopril, enalapril is primarily excreted by the kidneys. The de-esterification of enalapril to enalaprilat probably occurs in the liver by hepatic esterases. There does not appear to be any other metabolite of enalapril other than enalaprilat.Like captopril, the pharmacokinetic properties of enalapril in patients with uncomplicated hypertension appear similar to those in healthy subjects. The pharmacokinetics of enalapril in patients with congestive heart failure have not been adequately assessed. Enalaprilat, the active form of enalapril, is available for intravenous injection. It appears to be useful as a probe of the renin-angiotensin system and can rapidly lower blood pressure in hypertensive crises. It will also rapidly reduce systemic vascular resistance and increase cardiac output in patients with congestive heart failure.

ISSN:0312-5963    

出版商:ADIS    

年代:1985

数据来源: ADIS

摘要:

Esterases, hydrolases which split ester bonds, hydrolyse a number of compounds used as drugs in humans. The enzymes involved are classified broadly as cholinesterases (including acetylcholinesterase), carboxylesterases, and arylesterases, but apart from acetylcholinesterase, their biological function is unknown. The acetylcholinesterase present in nerve endings involved in neurotransmission is inhibited by anticholinesterase drugs, e.g. neostigmine, and by organophosphorous compounds (mainly insecticides). Cholinesterases are primarily involved in drug hydrolysis in the plasma, arylesterases in the plasma and red blood cells, and carboxylesterases in the liver, gut and other tissues.The esterases exhibit specificities for certain substrates and inhibitors but a drug is often hydrolysed by more than one esterase at different sites. Aspirin (acetylsalicylic acid), for example, is hydrolysed to salicylate by carboxylesterases in the liver during the firstpass. Only 60% of an oral dose reaches the systemic circulation where it is hydrolysed by plasma cholinesterases and albumin and red blood cell arylesterases. Thus, the concentration of aspirin relative to salicylate in the circulation may be affected by individual variation in esterase levels and the relative roles of the different esterases, and this may influence the overall pharmacological effect. Other drugs have been less extensively investigated than aspirin and these include heroin (diacetylmorphine), suxamethonium (succinylcholine), clofibrate, carbimazole, procaine and other local anaesthetics. Ester prodrugs are widely used to improve absorption of drugs and in depot preparations. The active drug is released by hydrolysis by tissue carboxylesterases.Individual differences in esterase activity may be genetically determined, as is the case with atypical cholinesterases and the polymorphic distribution of serum paraoxonase and red blood cell esterase D. Disease states may also alter esterase activity.

ISSN:0312-5963    

出版商:ADIS    

年代:1985

数据来源: ADIS

摘要:

Peritoneal dialysis has become an accepted treatment modality for end-stage renal disease. The introduction of continuous ambulatory peritoneal dialysis (CAPD) has further popularised this technique. The need for adjustment of drug dosage in patients with endstage renal disease and the need for supplemental dosages following haemodialysis are well recognised. Little documentation exists concerning the need for supplemental drug dosage in patients on peritoneal dialysis. Knowledge of the influence of peritoneal dialysis on the elimination of specific drugs is essential to the rational design of dosage regimens in patients undergoing this dialysis technique.This review addresses the clinical pharmacokinetic aspects of drug therapy in patients undergoing peritoneal dialysis and considers: (1) the efficiency of the peritoneal membrane as a dialysing membrane; (2) the effects of peritoneal dialysis on the pharmacokinetics of drugs; (3) the pharmacokinetic models and estimation methods for peritoneal dialysis clearance and the effects of peritoneal dialysis on drug elimination; (4) the influence of the pharmacokinetic parameters of drugs on drug dialysability; and (5) the application of pharmacokinetic principles to the adjustment of drug dosage regimens in peritoneal dialysis patients. Data on drugs which have been studied in peritoneal dialysis are tabulated with inclusion of pharmacokinetic and dialysability information.

ISSN:0312-5963    

出版商:ADIS    

年代:1985

数据来源: ADIS

摘要:

Recent research indicates that physical exercise and fitness are new host factors with impact on hepatic drug metabolism, contributing to the intra- and interindividual variation in drug response.Moderate to heavy physical exercise for a few hours reduces liver blood flow as assessed by indocyanine green clearance, leading to a decreased elimination of drugs exhibiting flow-limited metabolism (high clearance drugs) such as lignocaine (lidocaine). However, hepatic elimination of drugs exhibiting capacity-limited metabolism (low clearance drugs) such as antipyrine (phenazone), diazepam and amylobarbitone (amobarbital) is not affected by acute physical exercise.Improved physical fitness as expressed by the maximum oxygen uptake seems to increase the elimination rate of the low clearance drug antipyrine and possibly also aminopyrine, while investigations of the biotransformation of high clearance drugs are contradictory.The sum of research in this recent field is rather limited and the mechanism whereby changes in physical fitness influence hepatic drug metabolism needs to be established. It is not known if other liver functions are changed. If the findings also apply for drugs with a low therapeutic index, there may be a risk of exercise-induced changes in drug efficacy and toxicity.It is suggested that future studies on host factors influencing drug metabolism should include information on physical activity.

ISSN:0312-5963    

出版商:ADIS    

年代:1985

数据来源: ADIS

摘要:

The literature on theophylline is confusing since in the same dose range one article will report linear kinetics while another will report non-linear kinetics. Single dose clearances and lower steady-state clearances of theophylline, recently reported in the literature, were used to estimate pooled Vmaxand Km values of the Michaelis-Menten equation for 10 normal subjects. The mean Vmaxwas 1960 mg/day and the mean Km was 24.1 mg/L. These values were then utilised to: (1) explain another set of different oral clearances following doses of 2 and 6 mg/kg reported in the literature; (2) estimate relative effects of dose rate and type of input on absolute bioavailability; (3) estimate AUC (0-∞) as a function of single dose over the range 0 to 1500mg; (4) estimate the average steady-state serum concentration of theophylline (Cssavand steady-state oral clearance (CLsspo) as a function of dose rate in mg/day; (5) illustrate how Michaelis-Menten kinetics alters the apparent first-order elimination rate constant and the half-life estimated from terminal log-linear plots at concentrations appreciably lower than the Km value; and (6) illustrate how Michaelis-Menten kinetics affects the estimation of a zero-order absorption rate constant using the Wagner-Nelson method.

ISSN:0312-5963    

出版商:ADIS    

年代:1985

数据来源: ADIS

摘要:

The pharmacokinetics of methimazole following therapeutic doses were studied in healthy subjects, in thyrotoxic and hypothyroid patients before and after treatment to euthyroidism, and in patients with renal or hepatic insufficiency, using a highly sensitive gas chromatographic-mass spectrometric assay. Following intravenous administration of 10mg to healthy subjects, methimazole had an initial distribution half-life (t1/2&agr;) of 0.10 to 0.23 hours and an elimination half-life (t1/2&bgr;) of 4.9 to 5.7 hours. The absolute bioavailability after oral administration of 10mg methimazole in the fasting state was high, with a mean of 93%.The pharmacokinetic profiles showed small interindividual variations, although one of the hypothyroid patients had a rapid elimination half-life, in both the hypothyroid and euthyroid state (2.6 and 2.4 hours, respectively). The elimination rate was not enhanced in the thyrotoxic patients but was slightly prolonged in the hypothyroid patients. There was no influence of renal insufficiency, but a prolonged elimination half-life was observed in patients with hepatic failure, the prolongation being proportional to the degree of impairment.Thus, the pharmacokinetics of methimazole are relatively simple with small interindividual variations. In general, there are no pharmacokinetic reasons to adjust dosage in the treatment of thyrotoxicosis, except in the rare case of concomitant advanced hepatic insufficiency.

ISSN:0312-5963    

出版商:ADIS    

年代:1985

数据来源: ADIS

摘要:

The possible development of a displacement interaction involving tolbutamide, in epileptic patients, has been explored by studying the serum protein binding of this drugin vitroin 199 samples of sera from patients treated with antiepileptic agents included in a programme of therapeutic drug monitoring. 82 of the samples were from patients receiving a single drug, 86 from patients treated with 2 drugs, and 31 from patients treated with 3 drugs. The free fraction of tolbutamide was higher in serum from patients treated with antiepileptic drugs than in serum from untreated ‘normal’ volunteers. The increase was more marked the greater the number of antiepileptic drugs administered. Valproate appeared to be the most powerful displacing agent.

ISSN:0312-5963    

出版商:ADIS    

年代:1985

数据来源: ADIS