摘要:

All &bgr;-adrenoreceptor blocking drugs seem to be fairly rapidly and completely absorbed from the gastro-intestinal tract. The rate of absorption, however, appears to be lower in elderly patients and possibly also in patients with renal failure than in younger patients.The extent of bioavailability varies considerably between different &bgr;-blockers. Some of these drugs (e.g. alprenolol and propranolol) have a low extent of bioavailability due to a high first-pass elimination effect, while pindolol and practolol for example are influenced very little by this effect. However, as some &bgr;-blockers form active metabolites, the bioavailability calculated as the ratio between the area under the plasma concentration time curve of unchanged drug after oral and intravenous administration does not give an accurate estimation of the fraction of the biologically active dose reaching the systemic circulation.The &bgr;-blockers so far studied are rapidly distributed in the body. The t1/2 of distribution ranges between 5 to 30 minutes. The apparent volume of distribution varies 3-to 4-fold between the compounds but in all cases the apparent volume of distribution exceeds the physiological body space. In patients with impaired liver function an increase of the volume of distribution of propranolol has been found.The &bgr;-blockers are relatively rapidly eliminated from the body and most of them have an elimination half-life between 2 to 4 hours. For atenolol, practolol and sotalol higher values have been reported. The most lipophilic &bgr;-blockers are almost completely metabolised in the liver, whereas those of lower lipophilicity are mainly excreted via the kidneys. Impaired liver and kidney function have been found to significantly influence the rate of elimination of those &bgr;-blockers eliminated via the insufficient organ of elimination.Numerous investigators have shown that the &bgr;-blocking effect is linearly related to the logarithm of the plasma concentration. In spite of this relationship, it is difficult from mean data to predict the individual plasma concentration which is necessary for a certain degree of &bgr;-blockade. This might be due to variations in the quantitative formation of active metabolites, individual differences in the plasma protein binding and rather flat plasma level-response curves.Also with respect to the therapeutic effect, the plasma levels vary considerably between individuals. This limits the value of determination of plasma concentrations in order to adjust the therapeutic dose. Our recommendation is that these facilities should be utilised in selected patient groups, e.g. those who have a poor therapeutic response to a &bgr;-blocker although the dose is high, and those patients with impaired renal or liver function.The duration of &bgr;-blockade is dose-dependent since the pharmacological effect declines with a constant rate (zero-order kinetics) within relatively wide dosage intervals. The rate of decline is a function of the plasma half-life and the slope of the regression line for the effect versus plasma concentration. This implies that most of the &bgr;-blockers can be administered at substantially longer intervals than indicated by their half-lives.

ISSN:0312-5963    

出版商:ADIS    

年代:1976

数据来源: ADIS

摘要:

The pharmacokinetics of propranolol can be quantitatively explained on a physiological basis from a knowledge of the effects of four biological determinants: (1) the activity of the drug metabolising enzymes (intrinsic clearance); (2) hepatic blood flow; (3) drug binding, and (4) the anatomical arrangement of the hepatic circulation. Disturbances of all these determinants can occur in chronic liver disease and result in predictable changes in propranolol disposition. These changes, as well as those occurring with other drugs in chronic liver disease, may be explained by ‘intact hepatocyte theory’ which postulates that the major pathophysiological change occurring in compensated chronic liver disease is a reduction in relatively normally perfused and functioning cell mass with the development of intrahepatic portasystemic vascular shunts.

ISSN:0312-5963    

出版商:ADIS    

年代:1976

数据来源: ADIS

摘要:

The elderly are generally considered to be different from young people in terms of drug response and this applies particularly to quantitative differences. While altered drug handling is a major potential source of difference in responsiveness to drugs, the relative contribution of pharmacokinetics and pharmacodynamics to this difference is not clear. In the present review we have examined the available data on pharmacokinetics in the elderly.In the past, data pertaining to animal models have been extrapolated to man and in the absence of human experimentation these assumptions have tended to hold sway. This is best exemplified by studies on drug absorption. The absorption of actively transported substances may in fact be diminished in the elderly. However, most drugs are absorbed by passive diffusion and the recently available evidence in man indicates that there is no age-dependent change.While definitive data on the effect of old age on drug metabolising ability in animals is available, no direct assessments have been made in man. Many of the studies carried out using drug plasma half-life and clearance assessments are complicated by changes in distribution. This is best illustrated by a definitive study with diazepam, in which marked prolongation of plasma half-life was accompanied by an increase in apparent volume of distribution in the elderly. This latter change influences plasma drug clearance and, possibly, drug concentration at its site of action. Thus, the implications for drug effect of such changes in volume of distribution remain to be clarified.In theory, the rate of elimination of antipyrine should provide a good index of drug metabolising ability. Both plasma half-life and clearance values suggest a decrease in metabolism in the elderly. No other drug has been studied as intensively and the evidence for a diminished metabolism of other drugs in the elderly is less definite. Thus, while it is likely that the metabolism of some drugs is impaired in old age, it is not possible at this time to generalise with regard to the effect of age on drug metabolising ability in man.It is also difficult to generalise about age-related changes in plasma protein binding of drugs. With some drugs, binding to plasma protein does not appear to be altered and for two drugs - warfarin and phenytoin, the findings of different investigators conflict.Diminution of glomerular filtration rate, renal plasma flow and associated tubular function with age have been well documented. Drug clearance comparisons between old and young have been carried out for only three renally excreted drugs - digoxin, propicillin and sulphamethizole. With digoxin and sulphamethizole, the evidence is that renal excretion is diminished in the elderly. With propicillin, changes in volume of distribution predominate, resulting in higher plasma levels in the elderly but similar percent recovery in urine. In the remaining studies, drug plasma levels and/or plasma half-life values indicate that older patients are exposed to higher plasma concentrations of drugs and while the data is insufficient to explain the findings in kinetic terms, it is likely that diminished renal excretion is mainly responsible.In conclusion, with the exception of renally-excreted drugs, there is at present insufficient data on which to make recommendations with respect to doses of drugs in the elderly. The importance of changes in volume of distribution are not clear and data obtained from single dose studies are not necessarily pertinent to multiple dose continuous therapy. In addition, many elderly patients have multiple pathology and the findings from studies on healthy subjects may not be applicable. Future studies must combine pharmacokinetic and pharmacodynamic aspects in the relevant clinical setting so that the practical significance, if any, of altered kinetics emerges.

ISSN:0312-5963    

出版商:ADIS    

年代:1976

数据来源: ADIS

摘要:

The purpose of this article is to review and summarise those aspects of the pharmacokinetic behaviour of the penicillins that may be of particular interest to the clinician. While these antibiotics differ markedly in their acid stability and oral absorption, misleading inferences may be drawn from simple inspection of the maximal serum concentrations produced by a given dose administered orally. A more accurate picture emerges when serum protein binding and intrinsic activity of the drugs are taken into account. All of the penicillins are readily and actively secreted by the renal tubules and most are eliminated, almost completely unchanged, in the urine. The majority are excreted in small quantities in the bile, but this is a major route for elimination of nafcillin from the body.Distribution of the penicillins in ‘non-specialised’ sites is excellent. In contrast, penetration of the central nervous system and eye are poor, and of the prostate, minimal. Inflammation reduces the barriers to penetration of these areas. However, quantitative data related to this phenomenon in man are few. Probenecid actively competes with the ‘export’ pump of the meninges and renal tubular cells. This results in an increase in concentrations of the penicillins in the blood and cerebrospinal fluid. The effect of this agent on active secretion of these antibiotics from the eye and biliary tract is minimal.While elimination of the penicillins from the body takes place largely via renal excretion, penicillin V and oxacillin are extensively degraded as well. In contrast to the situation with respect to ‘natural’ and ‘broad-spectrum’ penicillins, the serum half-life of the isoxazolyl congeners and nafcillin is only minimally prolonged in the presence of renal failure. These agents are only weakly haemodialyzable, while the other penicillins are rapidly removed from the circulation by this procedure.

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