摘要:

Phenytoin is a relatively insoluble weak acid, usually administered as the sodium salt. Bioavailability is dependent upon particle size and problems of generic inequivalence have therefore arisen, particularly in Scandinavia. The drug has a moderately large volume of distribution and is approximately 90% bound to plasma proteins. Clinically important displacement can be caused by bilirubin and several drugs, particularly sodium valproate, which is often combined with phenytoin. Displacement will lower the total serum concentration but will little affect the free drug concentration.The metabolism of phenytoin to the major metabolite, 5-(p-hydroxyphenyl)-5-(phenylhydantoin, is saturable, giving rise to a non linear dose-serum concentration relationship. Therefore, the dose range compatible with a therapeutic serum concentration is narrow within subjects, and monitoring serum concentrations is of particular value in dosage tailoring. In renal failure, the binding of phenytoin to plasma proteins is reduced and therefore a lower range of serum drug concentrations is compatible with therapeutic control. In liver disease, binding may also be impaired but delayed metabolism may occur in addition. During pregnancy the serum concentration may fall progressively as pregnancy advances, probably due to an increased rate of metabolism. Phenytoin readily crosses the placenta, and is metabolised rapidly by the neonate exposed in utero.

ISSN:0312-5963    

出版商:ADIS    

年代:1979

数据来源: ADIS

摘要:

The pharmacokinetics of widely used and of investigated aminoglycosides, namely kanamycin, gentamicin, tobramycin, amikacin, sisomicin and netilmicin, in normal volunteers and in patients with physiological states and disturbances known to alter their disposition are critically examined in view of recent developments. Analytical methods for the assay of aminoglycosides in biological fluids are briefly but critically described. Emphasis is placed on multicompartmental characterisation of aminoglycoside kinetics, especially as it relates to certain heretofore unexplained observations such as tissue accumulation and delayed elimination. Other components of the kinetic profile of aminoglycosides are reviewed. For practical purposes, aminoglycosides are neither protein bound nor biotransformed. The major route of elimination is glomerular filtration, and aminoglycosides undergo some tubular reabsorption. Relevant pharmacokinetic parameters from significant studies have been tabulated. Some practical aspects of distribution kinetics are then presented. All aspects considered, and even though therapeutic concentrations can be obtained in some patients, the penetration of aminoglycoside into the cerebrospinal fluid, bronchial secretions and biliary tract remains somewhat unpredictable, depending in particular on the underlying diseases. When feasible, local treatment such as aerosols, intrathecal or intraventricular supplementation of parenteral administration are to be recommended.Due to the almost exclusive excretion from the body by glomerular filtration, the elimination rate of aminoglycoside antibiotics is greatly affected by impairment of renal function. The mathematical relationships between pharmacokinetic parameters and renal function indicators are tabulated and discussed. The predictive potential of nomograms can be greatly improved by taking into consideration some physiological parameters such as sex, age, lean body mass, haematocrit and characterisation of disposition kinetics by multicompartmental models. However, actual serial monitoring of aminoglycoside concentrations in serum appears to be the most reliable method for therapeutic monitoring. Half-lives in patients with minimal renal function during haemodialysis, during peritoneal dialysis and during interdialysis periods are tabulated and the practical implications of these data discussed.In the neonatal period, the absorption rate after intramuscular injection appears to be faster than reported in adults and the volume of distribution is significantly larger. The major pharmacokinetic difference between neonates, infants and adults is the slower elimination: for instance, half-lives which average around 2 hours in adults with normal renal function can reach and sometimes exceed 5 to 6 hours during the very first days of life.The volume of distribution per kilogram of body weight is relatively smaller in obese subjects and in dehydrated patients than in normal subjects and can lead to overdosing when dosages are calculated on a body weight basis. Anaemia, fever, hypoxaemia and major burns are other pathological states which significantly influence pharmacokinetics of aminoglycosides. Inactivation by heparin, carbenicillin and ticarcillin is reviewed.The methods of administration currently favoured are briefly examined and a procedure which may be more applicable to the kinetics of aminoglycosides is suggested so that further comparative clinical trials may be undertaken of the assessment of the relative merits of different modes of administration.

ISSN:0312-5963    

出版商:ADIS    

年代:1979

数据来源: ADIS

摘要:

Serum creatinine concentrations are widely used clinically as an index of renal function. In stable normal or reduced renal function they are determined by the rate of creatinine production and the endogenous creatinine clearance, and, during changing renal function, also by the apparent volume of distribution of creatinine. These determinants of serum creatinine concentrations, however, are affected by age, sex and body weight. The rate of creatinine production is proportional to body weight, and it decreases with age and is slower in females than in males. The endogenous creatinine clearance decreases with age and is lower in females than in males. The apparent volume of distribution of creatinine is equal to the total body water, which is proportional to body weight, and it decreases with age and is lower in females than in males.The individual relationships between the determinants of serum creatinine concentrations and age, sex, and body weight have been established using data from published reports. The effects of age, sex, and body weight on the relationship between normal and reduced renal function and serum creatinine concentrations are illustrated by simulations. Equations are derived to predict endogenous creatinine clearance from serum creatinine concentrations, and a nomogram is presented for determining relative renal function from serum creatinine concentrations, which take into account the age, sex and body weight of the individual patient. It is recommended for rapid clinical evaluation of stable normal or reduced renal function. When rapid changes are expected clinically, however, it is recommended to use a mid urine collection period serum creatinine sample for creatinine clearance determination.

ISSN:0312-5963    

出版商:ADIS    

年代:1979

数据来源: ADIS

摘要:

Gilbert's syndrome is an inherited disorder which is characterised by unconjugated hyperbilirubinaemia. In patients with Gilbert's syndrome, both bilirubin clearance andin vitrohepatic microsomal uridine diphosphoglucuronyl transferase (UDPGT) activity are reduced. In addition, there is evidence suggesting impaired hepatic uptake of bilirubin in Gilbert's syndrome.Glucuronidation of a number of substrates appears to be impaired in Gilbert's syndrome, but the significance of the reported changes in oxidation and acetylation are less clear.

ISSN:0312-5963    

出版商:ADIS    

年代:1979

数据来源: ADIS

摘要:

Among the corticosteroids, prednisone is the most commonly used in the treatment of chronic active liver disease. However, its pharmacokinetics have only recently been investigated. Prednisone is effectively absorbed and converted to its active therapeutic derivative, prednisolone, in healthy volunteers and in patients with liver disease; the bioavailability of oral prednisone approximates 100% of an intravenous dose and is comparable after administration of either prednisone or prednisolone. Patients with liver disease and hypoalbuminaemia are more likely to suffer major side effects of prednisone as a consequence of decreased protein binding and delayed clearance of prednisolone. Dosage in such patients should be reduced in accordance with serum albumin concentration.

ISSN:0312-5963    

出版商:ADIS    

年代:1979

数据来源: ADIS