摘要:

Since hypolipidaemic drugs are widely used, despite the still unanswered question whether lowering of plasma lipids has a protective effect on the development of atherosclerosis, discussion of the clinical pharmacokinetics of the main representatives of this group of drugs is warranted.Clofibrate is quantitatively transformed to its active metabolite, chlorophenoxyisobutyric acid (CPIB), immediately after oral administration. Absorption of CPIB is complete, but relatively slow with peak concentrations being attained 2 to 6 hours after the dose. The apparent volume of distribution is between 6 and 12 litres; plasma protein binding is higher than 90%, but is reduced in the nephrotic syndrome, in renal failure, and in cirrhosis. The elimination half-life of CPIB ranges between 10 and 25 hours, is shorter in patients with the nephrotic syndrome, but is prolonged in renal failure in close correlation with the degree of renal impairment. The plasma clearance of the total drug (mean of 7ml/min) appears to be increased in the nephrotic syndrome, but is decreased in renal failure and is unchanged in liver cirrhosis. Clearance of the unbound drug (mean of 240ml/min) is markedly reduced in renal failure, but is also reduced in liver cirrhosis. No pharmacokinetic changes are observed in acute hepatitis. Urinary excretion of CPIB is normally 10 to 15% of the dose; excretion is reduced in renal failure, but is unaffected in the nephrotic syndrome and in liver cirrhosis.Nicotinic acid is rapidly absorbed with peak concentrations being attained after 45 minutes. The systemic availability is about 90%. Accumulation of the drug is reported in red blood cells, but no information is available on its distribution and on its plasma protein binding. The plasma elimination half-life is about 45 minutes. One third of an oral dose is excreted in urine unchanged. With pharmacological doses the major metabolite is nicotinuric acid; other metabolites being N-methyl-nicotinamide, 2-pyridone, and 4-pyridone, respectively. A measurable pharmacological effect is achieved with plasma concentrations of 0.1 to 0.2&mgr;g/ml, while a therapeutic range of 0.5 to 1.0&mgr;g/ml is suggested. Flushing of the skin is reported to-occur only at the beginning of treatment when the plasma concentration of nicotinic acid increases. Several analogues of nicotinic acid have been developed with the intention of achieving a sustained effect by a gradualin vivoliberation of nicotinic acid.Cholestyramine is not absorbed from the gastrointestinal tract. As it is an anion exchange resin it may interfere with the absorption of a number of drugs by binding them to the resin.&bgr;-Sitosterol absorption is normally less than 5%, but has been 25% in 2 sisters, so that a genetically determined influence on absorption is assumed.Dextrothyroxine possesses only a small fraction of the hypermetabolic activity of its levoisomer. Absorption is between 40 and 50%, but is decreased in malabsorption syndromes and in some patients with liver cirrhosis. Plasma protein binding is higher than 99%. The elimination half-life is 6 to 7 days, but is decreased in hyperthyroidism and increased in hypothyroidism. Thyroxine is completely metabolised after oral dosing, one metabolite with pharmacological activity being triiodothyronine.

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS

摘要:

Acute and chronic ethanol ingestion can alter both the pharmacodynamics and pharmacokinetics of other drugs. For psychotherapeutic drugs, modification of drug action by alcohol is much more important than kinetic interaction, such as ethanol induced drug metabolism. In contrast, the importance of the effects of alcohol on the kinetics of other classes of drug is incomplete. The probability and mechanism of alcohol kinetic interactions with other drugs can nevertheless be anticipated, in part, on the basis of the extent of binding of the drug to plasma proteins, the capacity of the liver for extracting the drug from blood passing through the liver and the true distribution space of the drug. Highly bound drugs with low intrinsic hepatic clearance are among the most commonly reported to have their kinetics altered by ethanol (e.g. benzodiazepines, phenytoin, tolbutamide and warfarin). Less highly bound drugs are less consistently affected (e.g. meprobamate, glutethimide, pentobarbitone and phenobarbitone).Acute administration of ethanol to laboratory animals or incubation of microsomal preparations with ethanol inhibits the mixed function oxidase activity. In the human, the elimination half-life of meprobamate, pentobarbitone and tolbutamide is increased by acute ethanol administration. Chronic administration of ethanol to rats and humans causes proliferation of the smooth endoplasmic reticulum, increase in microsomal protein content and cytochrome P450and results in an augmentation in drug metabolising ability of the microsomesin vitro.Even though the plasma half-life of some drugs is decreased by chronic ethanol ingestion, the clinical determination of the mechanism is incomplete because few studies have measured drug metabolite levels. In addition, alcohol effects on drug distribution have not been studied very extensively.The effects of chronic alcohol ingestion on drugs with low and high hepatic extraction, high and low binding, important tissue localisation and microsomal and non-microsomal metabolism will be quite different. Systematic studies of the mechanism of alcohol kinetic interactions are needed. Such kinetic studies should be combined with pharmacodynamic measures in order to establish the clinical importance of changes in drug kinetics.

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS

摘要:

Opinion about dosage of digoxin in paediatric patients is divided. Difficulties in assessing the effect and toxicity of the glycoside in this age group could lead to administration of unnecessarily high doses. Current dosage schedules were therefore re-evaluated by use of recent pharmacokinetic information.Dose calculations were made on the basis that therapeutic serum concentrations of digoxin are similar in young and adult patients. Such a concept is supported by observations of the effect of digoxin in paediatric patients at comparatively small doses of the glycoside and by reported relationships between myocardial and serum digoxin concentrations at different ages. It was considered appropriate to achieve an average serum concentration of 2nmol/L. A loading dose by oral administration of 0.025mg/kg to full term neonates (<1 month) and 0.035mg/kg to infants [1 month to 1 (2) years] was calculated to achieve saturation of body stores. This should be followed by a maintenance dose 12h later. On average. oral maintenance treatment in full term neonates would be with a dose of 0.010mg/kg/day and in infants with a dose of 0.015 to 0.025mg/kg/day. Infants appear to be non-homogeneous with regard to body clearance capacity, hence the range in dose recommendation.A comparison of current dose recommendations and literature reports with the above calculations shows that the computed loading doses mean a considerable reduction. The calculated maintenance dose to neonates is also substantially decreased compared with existing regimens, whereas there is good agreement between current practice and calculations concerning maintenance digoxin treatment in infants.The calculated dosage schedule for neonates was applied in a clinical study of 5 patients. The efficacy was judged satisfactory, and serum concentrations were in the upper range of those predicted.We suggest that routinely recommended doses of digoxin to paediatric patients, particularly to neonates, are usually unnecessarily high.

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS

摘要:

Many factors influence the metabolism of drugs in man. Besides genetic factors, environmental factors may play a significant role in explaining the variation observed in the rates of drug metabolism between different individuals. Intentional or unintentional exposure to environmental chemicals could enhance or inhibit the activity of hepatic mixed function oxidases that metabolise drugs and other foreign chemicals, as well as endogenous substrates such as steroid hormones. A major source of such exposure may be occupational. Exposure to the heavy metal, lead, has been shown to inhibit drug metabolism; whereas intensive exposure to chlorinated insecticides, and other halogenated hydrocarbons such as polychlorinated biphenyls, has been shown to enhance the metabolism of test drugs such as antipyrine and phenylbutazone.An intentional source of exposure to foreign chemicals is cigarette smoke. Cigarette smoke contains polycyclic hydrocarbons, which are known inducers of hepatic mixed function oxidases. A number of studies have shown that cigarette smoking can alter the pharmacological action and/or the metabolism of some drugs. Pharmacokinetic studies have shown that cigarette smoking decreases the bioavailability of phenacetin and increases dosage requirements of theophylline by enhancing their rate of metabolism. Data, which are not very conclusive, indicate that heavy marijuana use may have an inhibitory effect on metabolism of some drugs and an inducing effect on others such as theophylline.Dietary factors may also play a significant role in the regulation of drug metabolism. Charcoal broiling which introduces polycyclic hydrocarbons into foods has been shown to enhance the metabolism of the test drug, antipyrine, and of such commonly used drugs as phenacetin and theophylline. Such intentional or unintentional exposure to environmental chemicals which may alter the rates of drug metabolism in man indicates the importance of individualisation of drug therapy.

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS

摘要:

The disposition of propranolol in blood has been investigated in 9 normal subjects and 7 patients with biopsy proven, well compensated cirrhosis using a protocol which allowed the estimation of the steady-state systemic availability of propranolol after oral administration. In addition, the systemic clearances of both antipyrine and indocyanine green (ICG) have been measured.The mean steady-state free (unbound) propranolol concentration in patients with cirrhosis was increased 3-fold in comparison with controls. This augmentation was due to an increase in systemic availability from 38 ± 3 % in controls to 54 ± 6%, a decrease in systemic clearance from 860 ± 90ml/min to 580 ± 140ml/min and an increase in free fraction of drug in blood from 0.06 ± 0.04 to 0.102 ± 0.65. The increase in the free fraction of drug also led to the volume of distribution increasing from 290 ± 17L to 380 ± 41L. As a consequence of both clearance and distribution changes, propranolol half-life increased from 4.0 ± 0.3h to 11.2 ± 3.2h.It is concluded that the reduced intrinsic clearance and/or portasystemic vascular shunts in cirrhosis, permits more of the absorbed drug to reach the circulation and that elimination of the drug from the systemic blood is also impaired. Furthermore, more of the drug in the systemic circulation is in the unbound form and potentially available to exert an increased pharmacological response.

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS