摘要:

Organic antithyroid drugs used today include propylthiouracil and the mercaptoimidazolines, carbimazole and methimazole. They can be measured with accuracy and in small quantities in serum by gas-liquid chromatography, high performance liquid chromatography and radio-immunoassay. Bioavailability of these drugs varies from 80 to 95%. During absorption carbimazole, which itself is inactive, is completely converted to methimazole. The total volume of distribution is about 40L for methimazole and around 30L for propylthiouracil, which is about 80% protein-bound, while methimazole is virtually non-protein-bound. Drug transfer across the placenta and into breast milk is also higher for the more lipid-soluble methimazole than for propylthiouracil, which is excreted into breast milk only in small quantities so that no harmful effect to the suckling infant is to be expected. Both drugs are concentrated in the thyroid gland, exerting an effect on intrathyroidal iodine metabolism for periods exceeding those in which serum concentrations can be measured.Less than 10% of both drugs is excreted unchanged in the urine, but detailed metabolic pathways are unknown. The half-life of methimazole is 3 to 5 hours with a total clearance of about 200ml/minute. Propylthiouracil has a half-life of 1 to 2 hours with a clearance of around 120ml/min/m2. Some studies have shown an increased rate of metabolism of antithyroid drugs in hyperthyroidism, in particular for methimazole. No reliable information exists regarding pharmacokinetics of these agents in renal and hepatic failure or in children. The clearance of propylthiouracil is unchanged in the elderly. Several mechanisms for the inhibiting effect of these agents on intrathyroidal hormone metabolism have been suggested. In contrast to methimazole, propylthiouracil inhibits the peripheral conversion of thyroxine to tri-iodothyronine. Preliminary dose-response studies with propylthiouracil suggest a peak therapeutic serum concentration of above 4μg/ml in the treatment of thyrotoxicosis.The choice between the antithyroid drugs is based more upon personal preference and experience than on strict pharmacological principles, as no important differences exist between these drugs with regard to the rate of remission or frequency of occurrence of serious adverse reactions.

ISSN:0312-5963    

出版商:ADIS    

年代:1981

数据来源: ADIS

摘要:

It is a major goal of clinical pharmacology to understand the dose-effect relationship in therapeutics. Much progress towards this goal has been made in the last 2 decades through the development of pharmacokinetics as a discipline. The study of pharmacokinetics seeks to explain the time course of drug concentration in the body. Recognition of the crucial concepts of clearance and volume of distribution has provided an important link to the physiological determinants of drug disposition. Mathematical models of absorption, distribution, metabolism and elimination have been extensively applied, and generally their predictions agree remarkably well with actual observations. However, the time course of drug concentration cannot in itself predict the time course or magnitude of drug effect. When drug concentrations at the effect site have reached equilibrium and the response is constant, the concentration-effect relationship is known as pharmacodynamics. Mathematical models of pharmacodynamics have been used widely by pharmacologists to describe drug effects on isolated tissues. The crucial concepts of pharmacodynamics are potency — reflecting the sensitivity of the organ or tissue to a drug, and efficacy — describing the maximum response. These concepts have been embodied in a simple mathematical expression, the Emaxmodel, which provides a practical tool for predicting drug response analogous to the compartmental model in pharmacokinetics for predicting drug concentration.The application of pharmacodynamics to the study of drug actionin vivorequires the linking of pharmacokinetics and pharmacodynamics to predict firstly the dose-concentration, and then the concentration-effect relationship. This may be done directly by equating the concentration predicted by a pharmacokinetic model to the effect site concentration, but this simplistic approach is often not appropriate for various reasons, including delay in drug equilibrium with the receptor site, use of indirect measures of drug action, the presence of active metabolites, or homeostatic responses, thus often necessitating the use of more complex models.The relative pharmacodynamic bioavailability of different preparations of the same drug may be determined from the time course of a drug effect. Bioavailability determined in this way may differ markedly from bioavailability defined by measurements of drug concentration if active metabolites are formed or if effects are produced in the non-linear region of the concentration-effect relationship.The influence of changes in the extent of plasma protein binding may be important in the interpretation of drug concentration measurements since it is generally held that only the unbound fraction is pharmacologically active. Clear examples of this phenomenon are few, but this reflects the general paucity of adequate observations rather than casting doubt on the usual assumption.The design of rational dosing regimens for clinical therapeutics cannot be performed with a knowledge of pharmacokinetics alone. The time course of drug effect may be essentially independent of concentration when a dose produces near maximal effects throughout the dosing interval. If effects are between 20 and 80% of maximum, the response will decrease linearly even though concentrations are declining exponentially. Finally, at relatively small degrees of effect, the time course of drug effect and concentration will be in parallel. The usual ‘rule of thumb’ of dosing every half-life is a conservative strategy for limiting wide fluctuations in drug effect, but demands more from the patient in terms of dosing frequency than may be necessary to achieve consistent drug action. On the other hand, if therapeutic success is dependent more on cumulative response than moment to moment activity, the use of extended dosing intervals may markedly reduce the effectiveness of the same average dose. Considerations of these factors can be incorporated into a dosing scheme by combined application of the principles of pharmacokinetics and pharmacodynamics.

ISSN:0312-5963    

出版商:ADIS    

年代:1981

数据来源: ADIS

摘要:

Seven male inpatients suffering from acute schizophrenia were treated with chlorpromazine elixir 100mg 8-hourly for 9 weeks. Nortriptyline 50mg 8-hourly was added during weeks 4, 5 and 6. Plasma chlorpromazine concentrations, antipyrine plasma half-life, blood pressure, pulse rate, pupil size, salivation, handwriting and clinical state were measured at weekly intervals.Plasma chlorpromazine concentrations rose when nortriptyline was added, and the antipyrine plasma half-life was prolonged. Blood pressure dropped on institution of chlorpromazine and dropped further with the addition of nortriptyline. The pulse rate rose in a parallel fashion. Pupil size, salivation and handwriting were diminished by chlorpromazine, but hardly affected further by nortriptyline. The addition of nortriptyline dramatically reversed the therapeutic actions of chlorpromazine, mainly through pharmacodynamic interaction.It is concluded that this combination is potentially deleterious, and must be used with care.

ISSN:0312-5963    

出版商:ADIS    

年代:1981

数据来源: ADIS

摘要:

The pharmacokinetics of digoxin and metildigoxin were investigated in geriatric patients on maintenance treatment. Minimum serum glycoside concentrations were determined on 3 consecutive days, and the elimination rate over a withdrawal period of 4 to 6 days was studied.In patients with serum creatinine levels of ≤ 1.3mg/dl, the oral standard dose (D1) of digoxin necessary for a minimum serum concentration of 1.0ng/ml was 1.4 times higher than that of metildigoxin. There was no significant difference in the elimination rate of both glycosides.The pharmacokinetics of metildigoxin were further investigated in patients with elevated serum creatinine levels. The standard dose was best correlated with the creatinine clearance, calculated from the serum creatinine, age, weight and sex of the patients. The apparent volume of distribution of metildigoxin decreased with the drug's total body clearance.

ISSN:0312-5963    

出版商:ADIS    

年代:1981

数据来源: ADIS

摘要:

Theophylline total body clearance was calculated in 59 adult patients requiring intravenous aminophylline therapy. Group 1 consisted of 36 chronic obstructive pulmonary disease patients who were cigarette smokers without other conditions known to alter theophylline kinetics (age range: 22 to 79 years). Group 2 consisted of 23 chronic obstructive pulmonary disease patients who were cigarette smokers with a similar degree of congestive heart failure, but free of other characteristics or diseases that affect theophylline disposition (age range: 41 to 81 years). When individual theophylline total body clearance values were plotted against age in each group, poor correlation coefficients were found, indicating that age is not a good predictor of total body clearance of theophylline (group 1: r = 0.101; group 2: r = 0.276). Each group was also broken into ‘younger’ and ‘older’ patients. No significant differences in theophylline total body clearance values were found between the younger and older patients for either group 1 or 2, suggesting that a theophylline dosage reduction is not necessary in cigarette smoking patients over an arbitrary age limit.

ISSN:0312-5963    

出版商:ADIS    

年代:1981

数据来源: ADIS

摘要:

The penetration of mecillinam, a new &bgr;-lactam penicillin-like antibiotic, into cerebrospinal fluid (CSF) was investigated in 11 children in whom all but 1 was presumed to have non-inflamed meninges. 30 minutes after a single intravenous dose of 30mg/kg, a concentration of approximately 0.30μg/ml was achieved in the CSF (corresponding mean serum concentration 75μg/ml), and this level was maintained during the next 4 hours in spite of rapidly declining serum concentrations, indicating a slow equilibration of mecillinam over the blood-liquor barrier. I child with suspected inflamed meninges showed a much higher CSF level of 12.1 μg/ml. It is concluded that mecillinam, as is the case for other penicillins, apparently crosses non-inflamed meninges poorly.

ISSN:0312-5963    

出版商:ADIS    

年代:1981

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1981

数据来源: ADIS