摘要:

This article reviews clinical pharmacokinetic data on 8 new antiarrhythmic agents. Some of these drugs have been studied extensively while others are relatively new, with incomplete data due to limited evaluation.Amiodarone is a class III antiarrhythmic drug which is effective in treating many atrial and ventricular arrhythmias that are refractory to other drugs. Amiodarone accumulates extensively in tissues and its disposition characteristics are best described by models with 3 and 4 compartments. Its apparent volume of distribution is very large (1300 to 11,000L) and its elimination half-life very long (53 days). A delay of up to 28 days from initiation of treatment to onset of antiarrhythmic effect may be observed, and the antiarrhythmic effect may persist for weeks to months following cessation of therapy. Clinically significant drug interactions have been observed with amiodarone and warfarin, digoxin, quinidine and procainamide.Encainide is a class Ic antiarrhythmic drug. Although it has a short elimination half-life (1 to 3h), 2 major metabolites with antiarrhythmic effects accumulate in the plasma of patients during long term therapy. Plasma concentrations of O-demethyl encainide appear to correlate with the antiarrhythmic effect.Flecainide, another class Ic antiarrhythmic agent, has an elimination half-life of 14 hours which makes it suitable for twice daily dosing. Flecainide elimination is prolonged in patients with low output heart failure. Significant drug interactions with digoxin and cimetidine have been reported.Lorcainide is also a class Ic antiarrhythmic drug, the bioavailability of which is non-linear. Clearance of the drug is reduced during long term therapy. A major active metabolite, norlorcainide, accumulates in the plasma of patients during long term therapy and its concentration exceeds that of lorcainide by a factor of 2. The elimination half-lives of lorcainide (9h) and norlorcainide (28h) allow for once or twice daily dosing.Mexiletine, a class 1b antiarrhythmic drug, is structurally similar to lignocaine (lidocaine). A sustained release formulation provides effective plasma concentrations when administered twice daily. The apparent volume of distribution of mexiletine is 5.0 to 6.6 L/kg, and the elimination half-life varies from 6 to 12 hours in normal subjects and from 11 to 17 hours in cardiac patients. Mexilitine is extensively metabolised but the metabolites are not pharmacologically active. Renal elimination of mexiletine is pH dependent. Drugs which induce hepatic metabolism significantly alter the pharmacokinetics of mexiletine.Pirmenol, a class 1a agent, is one of the newer antiarrhythmic agents undergoing clinical trials. Its apparent volume of distribution ranges from 0.76 to 2.3 L/kg; elimination half-life is 6 to 8 hours.Propafenone is a unique antiarrhythmic drug. In addition to blocking the fast sodium channel, it has some depressive effects on the calcium channel as well as mild sympatholytic activity. Bioavailability is dose-dependent and systemic clearance decreases during long term treatment. Propafenone is extensively metabolised and at least 1 active metabolite, 5-hydroxypropafenone, has been identified. The elimination half-life is 2 to 4 hours in normal subjects and 2 to 13 hours in cardiac arrhythmia patients.Tocainide, a class Ib antiarrhythmic drug, is a lignocaine congener which is suitable for oral use. Tocainide is extensively metabolised but the metabolites do not have cardiac effects. The apparent volume of distribution ranges from 1.6 to 2.9 L/kg; elimination half-life varies from 11 to 15 hours. Tocainide elimination is impaired in patients with renal insufficiency and hepatic cirrhosis.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

The influence of drug-drug and drug-food interactions affecting the absorption of orally administered medication is reviewed. Drug-drug interactions can be classified in terms of indirect effects by one drug on gastrointestinal tract physiology influencing the absorption of other drugs, or direct interactions involving altered pH, adsorption, absorption, or chelation. Most, but not all, drug-drug interactions result in reduced or delayed systemic drug availability.Drug-food interactions may result in reduced, delayed, or increased systemic drug availability. The absorption of only a small number of drugs is unaffected by concomitant food intake. The degree of interaction and whether it positively or negatively affects drug absorption depends on a number of factors including the physical and chemical nature of the drug, the formulation, the type of meal, and the time interval between eating and dosing.Mechanisms of drug-food interactions are not well characterised. They clearly involve both direct and indirect factors in a similar fashion to drug-drug interactions, but indirect factors probably predominate. Reduced or delayed drug absorption is generally attributed, at least in part, to delayed stomach-emptying due to food. Increased absorption may also result from delayed stomach-emptying facilitating greater drug dissolution before it passes from the stomach into the small intestine. Increased bioavailability of some drugs, e.g. propranolol, metoprolol and labetalol, may be related to reduced presystemic clearance.The potential clinical implications of drug-drug and drug-food interactions must be taken into account with oral medications in order to minimise variations in systemic drug availability and hence in clinical efficacy.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

The yield of a cigarette is determined by the tobacco blend, the length of the cigarette, the cigarette paper, the filter and air dilution. Cigarette yield has been defined by tradition and by law to be the yield of nicotine, tar and carbon monoxide obtained from a 35ml puff volume of 2-second duration taken every minute during the burning time of the cigarette.Normally smokers draw a puff into their mouth and then inhale. Mouth delivery is largely determined by personal smoking behaviour. The puff volume, number of puffs taken per cigarette, and number of cigarettes smoked per day determine both the volume and the mass of daily mouth delivery. There are marked differences in smoking behaviour, and the delivery is substantially altered from the yield values obtained with the standardised test procedure. Body uptake of smoke ingredients is determined by smoke chemical parameters, smoker inhalation behaviour, lung morphology, and physiological parameters. The physiological parameters include tidal volume, vital capacity, rate of breathing, and rate of clearance for the lung.Given these behavioural and physiological differences in individual delivery and uptake it is not surprising that differences in measured parameters occur within smokers of cigarettes with a particular yield. Biological differences among individuals, such as metabolic and size differences, cause additional variations in these values. Therefore, the estimates of nicotine and tar delivery can vary widely in studies of individual uptake when the estimates are based upon sample population data.The variables in both smoking behaviour and in chemical and physiological factors which alter uptake make it essential to have a crossover design for any study. The large standard error for the plasma concentration of cotinine (a major metabolite of nicotine) within a sample population, and the log linear nature of the plasma cotinine concentration curve, requires a very large sample size for any study of cigarette delivery or uptake. When comparisons of brands are made, average values are misleading in that the skew to the high values obscures frequency differences among the lower values within the samples. It is important to remember that smoker compliance with study design is very essential. It would be impossible to know that individual smokers failed to remain on the prescribed regimen during a study that attempted to have smokers of higher yield brands switch to lower yield brands.Epidemiology studies consistently find a higher incidence of both lung cancer and cardiovascular disease among smokers compared with non-smokers. There is evidence that the reduction in sales-weighted average tar yield of 30mg to 15mg has been accompanied by a decrease in the incidence of those diseases reported to be increased in the smoking population over non-smokers. Several studies have shown a dose-response relationship for the number of cigarettes smoked and lung cancer. The dose-response relationship for cardiovascular disease is less clear. A major part of the reduction in these disease states could be related to reduced numbers of smokers per 100,000 population. As cigarette yields decrease to tar values near 1mg, measurements of tar and nicotine uptake must be improved.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

10 psychiatric inpatients with a diagnosis of depression were entered into a prospective study to investigate the repeated one-point method as a method of predicting steady-state concentrations for nortriptyline. Four males and 4 females completed all requirements of the protocol.Single plasma concentrations obtained after the first and second daily doses were found to be accurate predictors of the steady-state minimum plasma concentrations. The difference between the measured and the predicted steady-state minimum values ranged from 2.10 to 32.7 &mgr;g/L with a standard deviation 10.4 and a mean of 10.5 &mgr;g/L, assuming a normal distribution. The correlation coefficient of predictedversusmeasured concentrations was 0.946 with 90% confidence limits, ranging from 0.800 to 0.990.The repeated one-point method was found to be an accurate predictor of steady-state minimum plasma concentrations in patients receiving nortriptyline. This method should allow for individual adjustment of dose while minimising the time required to achieve therapeutic, non-toxic plasma concentrations.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

Five clinical strategies for monitoring serum tobramycin concentrations were compared in a population of children and young adults with normal renal function receiving tobramycin for suspected sepsis. The drug monitoring strategies were evaluated on the basis of the ability of each to predict subsequent drug levels. The strategies included 3 methods requiring assessment of individual drug disposition: (a) measurement of peak drug concentrations after 2 separate doses; (b) a 3-point kinetic study to define distribution volume and elimination rate; (c) a 3-point kinetic study with adjustment of the value for elimination rate to account for deep compartment drug accumulation; and 2 strategies using a fixed-dose approach in which prediction of individual levels was made on the basis of mean population kinetic parameters.Although all methods were of similar accuracy, the fixed-dose strategy was the most precise in predicting subsequent serum tobramycin levels (95% tolerance limits = 84−135% of predicted). Poor performance of the other strategies was accounted for by interpatient variability of tobramycin disposition that was small relative to the intrapatient variability in these measurements.We conclude that these strategies for aminoglycoside serum level monitoring, which have proven beneficial in patients with impaired renal function, afford little benefit to children and young adults with normal renal function. Administration of these drugs on a fixed-dose schedule without serum concentration monitoring appears to be warranted in this select population. Alternatively, specific strategies for this population must be developed that consider the small interindividual differences in drug disposition and low incidence of toxicity.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

Physiological and temporal variation in the disposition of midazolam has been reported. In order to delineate the underlying mechanisms of these alterations, we infused in 5 healthy male volunteers for 26 hours midazolam at a rate of 0.025 mg/kg/h preceded by a bolus of 0.05 mg/kg. Thus, steady-state conditions were rapidly achieved. Plasma levels of midazolam were monitored on a 2-hourly basis during this period. In addition, the pharmacodynamic response to the new sedative/hypnotic benzodiazepine was characterised by a pencil tracking test, sedation index formed from visual analogue scales, and choice reaction time.In all subjects, small (4 to 16%) but clinically irrelevant fluctuations of steady-state plasma concentrations around 45 ng/ml were observed. During the night-time (11pm to 7am) plasma concentrations were slightly (p = 0.074) higher than during the daytime. Total plasma clearance varied from 563 to 823 ml/min. Plasma protein binding of midazolam was time independent.Since in only 1 of 5 subjects was a circadian rhythm observed, fluctuations in plasma midazolam concentrations under controlled and constant conditions are probably not of clinical significance.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS