ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

Recent clinical investigations and reports of theoretical models have provided considerable insight into mechanisms of hepatic drug elimination and into derangements that may occur in drug absorption and disposition in patients with hepatic disease. Carefully conducted and well controlled clinical studies have demonstrated that hepatic disease may alter substantially one or more pharmacokinetic parameters of drug absorption and disposition. Phvsiological models of hepatic drug elimination have emphasised the importance of physiological variables such as hepatic blood flow, protein binding and intrinsic clearance of the liver on hepatic drug elimination. Both clinical investigations and theoretical considerations have indicated that the influence of hepatic disease on the pharmacokinetics of a drug may be complex and may result in either unchanged, retarded or even accelerated drug elimination. Changes in response to drugs in patients with hepatic impairment add to this complexity.Although general guidelines may be formulated now to assist clinicians in constructing dosage regimens of several important drug classes (notably the benzodiazepines and burbiturates) in hepatic disease. it is not now possible to predict in an individual the influence of a specific hepatic disease on the disposition of a drug, with the exception that the oral availability of drugs with high hepatic extraction ratios is increased in patients with cirrhosis and portacaval shunting of blood. Attempts to correlate concentrations of endogenous substances (such as bilirubin). or the pharmacokinetics of model drugs (such as antipyrine), with the pharmacokinetics of drugs that are useful in patients with hepatic impairment have not resulted in clinically useful tests of hepatic drug elimination. Following the administration of a drug to a patient with hepatic impairment, careful monitoring of the patient and also monitoring of plasma or blood drug concentrations remain important considerations.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

Thermal trauma reportedly induces a spectrum of intricate physiological alterations that often involve cardiovascular, hepatic, renal, and dermatological functions. Individual responses to varying degrees of burn and secondary complications may produce unpredictable changes in the pharmacokinetics of drugs.A number of reports describing the disposition of aminoglycoside antibiotics in burn patients have demonstrated clinically significant alterations in the pharmacokinetics of this class of drugs. Several authors have found significantly reduced serum half-lives in burn patients as compared with average values in non-burned subjects. Increased aminoglycoside clearances in some burn patients have been anributed to increased glomerular filtration secondary to elevated cardiac oulput, prostaglandin formation, and glucagon secretion: others anribute this to enhanced elimination of drug across damaged skin tissue. Monitoring of serum aminoglycoside concentrations is recommended because of the low therapeutic index of these agents and the variable course of renal function following burn injury.Topical application of mafenide acetate. povidone iodine, and gentamicin to burn wounds has resulted in varying amounts of systemic absorption. Various systemic toxicities have been attributed to these topical therapies, especially in patients with compromised renal function. The extent and area of the burn, degree of hydration, and the amount of drug applied are factors influencing transcutaneous absorption. Sulphonamide derivatives are excreted in the urine subsequent to the application of silver sulphadiazine cream, but silver ions appear to be localised on surface tissue and are thus unavailable to the subeschar space.Additional studies are needed to characterise the pharmacokinetics of medications commonly administered to burn patients. Unfortunately, the marked variability and fluctuations in pathophysiological status following burn trauma often confound the interpretation of such kinetic investigations.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

Metoprolol is absorbed over a large part of the intestine and over 95% of an oral therapeutic dose is generally recovered in the urine as unchanged drug and metabolites. Presystemic elimination accounts for about 50% degradation of acutely administered oral doses. The fraction of the dose available systemically may increase up to 70 to 80% with long term treatment. Since food may enhance the bioavailability of metoprolol the drug should preferably be taken in a standardised way in relation to meals.The drug distributes very rapidly between the blood and various extravascular sites, and only 1 to 2% of the total amount of drug in the body is localised in the blood at apparent distribution equilibrium. The binding to serum proteins is only about 10%. The drug diffuses readily across the placenta and the concentration in the umbilical and maternal venous blood is approximately the same. Despite a 3-to 4-fold accumulation in breast milk, adverse reactions in the breast-fed child seem unlikely, unless the child's hepatic function is severely underdeveloped.The drug is extensively metabolised and only about 5% of an oral dose and 10% of an intravenous dose is excreted in unchanged formviathe kidneys. Although 2 of the metabolites possess selective &bgr;1-adrenoceptor blocking activity, none of them contributes to the &bgr;-blocking effect of metoprolol.Impaired renal function has negligible influence on the disposition and bioavailability of metoprolol, but affects the elimination of the renally excreted metabolites. However, the metabolites are dialysable and approximately 50% of the metabolites are removed in anephric patients during a 5-hour dialysis period. Cirrhosis of the liver increases the bioavailability and reduces the total body clearance of metoprolol, and patients with portacaval anastomoses and those with signs of severely compromised liver function should initially be treated with reduced dosage. Hyperthyroid patients have enhanced metabolism of metoprolol and dose titration has to be carried out accordingly.The &bgr;-blocking effect is linearly related to the logarithm of the dose and the plasma concentration of the drug. The effect declines according to zero-order kinetics. The rate of decline of the effect can be retarded by administration of the drug in controlled release preparations which maintain significam &bgr;-blockade over a period of 24 hours.The antihypertensive effect increases with increasing dosage up to 200 to 300mg daily. The duration of the blood pressure lowering effect is longer than the &bgr;-blocking effect in terms of reduction of exercise-induced tachycardia, and the arterial blood pressure can be adequately controlled in most patients on a once daily dose regimen. The individual antihypertensive effect has been reported to be unrelated to the plasma concentrations of unchanged metoprolol. A significant and dose-dependent antianginal effect is achieved for acute doses of 50mg and more, corresponding to about 50ng/ml (approx. 200nmol/L). Determination of plasma levels in routine therapy is of limited value because of poor correlation between therapeutic effect and the plasma concentration of metoprolol in the individual patient.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

Frusemide 80mg was administered intravenously to 10 patients with alcoholic liver disease (fatty liver and Laennec's cirrhosis).Protein binding was correlated with serum albumin concentrations (r = 0.860, p < 0.001). The apparent volume of distribution ranged between 180 and 1206ml/kg body weight and correlated with the serum albumin concentration (r = 0.710, p. < 0.05) and the fraction of unbound drug (r = 0.758, p < 0.05). This fraction was 1.9 ± 0.2% in controls and 3.1 ± 0.9% in patients with cirrhosis (p < 0.01). Plasma half-life of frusemide varied 7-fold, between 0.60 and 4.27h, and was prolonged substantially in some patients compared with values in normal subjects. There was a highly significant correlation between the apparent volume of distribution and plasma half-life of frusemide (r = 0.938, p < 0.001).Frusemide was eliminated via both renal and non-renal mechanisms in all but 2 patients, who had advanced cirrhosis and eliminated the drug almost exclusively through the kidneys. The apparent volume of distribution was increased proportionally more than the decrease in protein binding explaining in part why higher doses of frusemide are needed in patients with liver disease to obtain the same response as in healthy subjects.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

The effect of progressive dose increments on the steady-state serum concentration of carbamazepine has been investigated prospectively in 20 adult institutionalised epileptic patients receiving long term therapy with the drug. In all but 1 subject. a strong positive correlation between the serum carbamazepine concentration and the prescribed daily dose was found. The relationship appeared to be linear over the dose range examined (600 to 1400mg in most patients). In some patients. a trend was observed for the extrapolated regression lines to yield positive y-axis intercepts. The latter were significamly different from zero in 3 patients. Although these findings suggest that the relationship between serum carbamazepine concentration and dose may be curvilinear over the lower range of doses, further studies are required to clarify this point.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

A method for measuring plasma prazosin concentrations is reported. This method, which involves high pressure liquid chromatography (HPLC) combined with fluorescence detection, has a sensitivity 20 times that of previous conventional fluorimetric techniques and twice that of other HPLC methods, and can be used to study the pharmacokinetics of prazosin at very low doses.Plasma prazosin concentrations were measured in 5 normal volunteers for 24 hours after single oral doses of 0.5 and 1.5mg of prazosin. On average, the lag time was 0.650 and 0.448 hours, and the elimination half-life 2.3 and 2.5 hours, for the 0.5 and 1.5mg doses, respectively. Peak prazosin concentrations occurred between 1.1 and 3.6 hours after dosing, and after the 1.5mg doses were associated with symptoms of faintness.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS