摘要:

Glyceryl trinitrate has been used for more than a century for the treatment of angina pectoris and, more recently, for the treatment of congestive heart failure. The introduction of transdermal delivery systems has renewed the controversy regarding the efficacy of the drug, mainly in the light of the development of tolerance.With concentrations of the order of 1 μg/L or less, the measurement of glyceryl trinitrate in plasma is not easy: gas chromatography with electron capture detection has been used widely but recently gas chromatography-mass spectrometry has provided satisfactory results. Assay problems are most likely to be responsible for some of the unexpected results reported. Further factors which may confound the results of the study of plasma concentrations are the rapid metabolism of glyceryl trinitrate in bloodin vitro,adsorption to containers and infusion sets, and the uptake and/or metabolism in vessel walls. From the intravenous infusion data, the large interindividual variability in plasma concentrations of glyceryl trinitrate is apparent. The plasma half-life is about 2 to 3 minutes; plasma clearance values reported vary from 216 to 3270 L/h, indicating extensive non-hepatic metabolism. With transdermal administration, mainly with the transdermal controlled delivery systems, plasma concentrations of glyceryl trinitrate appear to be maintained for up to 24 hours, with large interindividual variations.Despite the ability to maintain, for example with the transdermal delivery systems, relatively constant concentrations of glyceryl trinitrate, it has not been possible to find a relationship between plasma concentrations and pharmacological or clinical effects. This is in part due to the attenuation of the effects with time; from the available data it is clear that this attenuation occurs at a pharmacodynamic level (reflex adaptation and tolerance) and not at the pharmacokinetic level.

ISSN:0312-5963    

出版商:ADIS    

年代:1987

数据来源: ADIS

摘要:

The availability of specific chemical assays and the development of appropriate biological models have made it feasible to study the relationship between the pharmacokinetics and the pharmacodynamics of nifedipine, a relationship that is presumed to be sigmoidal for most effects. In healthy volunteers the haemodynamic effects of a single dose of nifedipine are markedly influenced by the pharmaceutical preparation and the rate of drug input. When the plasma concentration of nifedipine increases rapidly, such as after an intravenous bolus injection or rapidly disintegrating capsules, there is a marked increase in heart rate and little or even no effect on blood pressure. On the other hand, when the drug is given as a slow intravenous infusion or as a sustained release tablet and when the capsules are taken together with food, the decrease in blood pressure is accompanied by few or no changes in heart rate. Furthermore, it has been shown that not only haemodynamic effects of nifedipine, but also oesophageal motor function may be used as a quantifiable pharmacological effect. For patients with angina pectoris, a plasma concentration range that is associated with optimal treatment has not been defined, since large interindividual variations in the nifedipine plasma concentration were observed in effectively treated patients. For patients with hypertension, significant sigmoidally shaped correlations between blood pressure reduction and nifedipine plasma concentrations following single or multiple doses have been demonstrated. The concentration-effect parameters were very similar to those found for normotensive subjects. After 6 weeks of treatment the potency of the drug had decreased, which might indicate the development of some tolerance. In patients with severe renal impairment, the maximal effect of nifedipine on diastolic blood pressure was more than doubled, which cannot be explained by differences in pharmacokinetics; therefore these patients appear to be more sensitive at the pharmacodynamic level. In patients with liver cirrhosis, the pharmacokinetics of nifedipine were quite different due to reduced protein binding and reduced enzyme activity; in patients with a portacaval shunt, considerable increased bypassing of the liver during the first pass after oral administration was observed. When corrected for free drug concentrations, the concentration-effect relationship for these patients is essentially the same as that found for healthy subjects. &bgr;-Blocking agents administered together with nifedipine have been found to interact at both the kinetic and the dynamic levels, but the effects are highly dependent upon dose and route of administration. When 2 drugs are given together, the clearance of each may change, probably as a result of their transient opposite effects on hepatic blood flow. The effects on systolic and diastolic blood pressure were found to be increased by combined administration. H2-Receptor blocking agents have been shown to interfere with the kinetics of nifedipine. Cimetidine, and to a lesser extent ranitidine, inhibited its metabolism markedly, causing a more pronounced antihypertensive effect. Smoking interfered with the action of nifedipine in patients with angina pectoris. When these patients stopped smoking, they suffered fewer anginal attacks and could exercise longer; the nifedipine plasma concentrations, before and after discontinuation of smoking, were at the same level. It is concluded that it is feasible to study the influence of certain factors on the pharmacological response to nifedipine in a quantitative fashion by characterising the concentration-effect relationship in terms of well-defined parameters.

ISSN:0312-5963    

出版商:ADIS    

年代:1987

数据来源: ADIS

摘要:

Nicotine intake is considered to be a major factor in sustaining tobacco addiction. For this reason, nicotine gum has recently been introduced as an adjuvant to smoking cessation. The introduction of nicotine as a ‘therapeutic’ entity necessitates a careful examination of its clinical pharmacokinetics.Insufficient data exist to quantitatively assess the absorption of nicotine after oral administration. Based upon physicochemical and pharmacokinetic principles, the oral bioavailability of nicotine would be expected to be less than 20%. The limited data available in the literature appear to support this conclusion. Absorption from the oral mucosa is the principal site of nicotine absorption in subjects who chew tobacco or nicotine gum. Absorption by this route is highly pH dependent. Nicotine is also readily absorbed from the nasal mucosa, and after topical administration.Nicotine distributes extensively into body tissues with a volume of distribution ranging from 1.0 to 3.0 L/kg. Nicotine has been shown to transfer across the placenta and into breast milk in humans. Plasma protein binding is negligible, ranging from 4.9 to 20%.The predominant route of nicotine elimination is hepatic metabolism. Although a number of metabolites of nicotine have been identified, it is unclear whether any of these compounds contribute to the pharmacological effect of nicotine. Nicotine is also excreted unchanged in urine in a pH-dependent fashion. With urinary pH less than 5, an average 23% of the nicotine dose is excreted unchanged. When urinary pH is maintained above 7.0, unchanged nicotine urinary excretion drops to 2%.After intravenous administration, nicotine exhibits biexponential decline in plasma. Total plasma clearance ranges from 0.92 to 2.43 L/min. During urinary acidification, renal clearance averages 0.20 L/min. Non-renal blood clearance averages 1.2 L/min, indicating that nicotine elimination is dependent on hepatic blood flow.The literature is devoid of information regarding the effect of disease on the pharmacokinetics of nicotine. Based upon the drug's pharmacokinetics in healthy smokers, it would be anticipated that disease states which alter hepatic blood flow may have the greatest impact on nicotine pharmacokinetics. In addition, drugs which alter hepatic blood flow may cause significant alterations in the systemic clearance of nicotine.Dependence on smoking appears to be related, at least in part, to the achievement of a rapid rise in plasma nicotine concentrations. If this assessment is correct, the most desirable adjuvant for smoking cessation would be one that closely mimics this pattern of plasma nicotine concentrations. Thus, the slow rise in plasma concentrations after chewing nicotine gum may suggest a pharmacokinetic explanation for the relatively high failure rate with this method of smoking cessation. It appears that because the rate of nicotine absorption is even slower than with the gum formulation, transdermal preparations are unlikely to be a satisfactory alternative to smoking. Further investigations are, therefore, required to determine a formulation which gives the desired plasma nicotine concentration profile.One of the major effects of smoking on drug therapy is the induction of drug-metabolising enzymes. However, the effects on drug metabolising capacity when a subject changes from smoking to nicotine gum has not yet been studied. The effect nicotine itself has on drug metabolism in humans is also unknown.Considerable work remains to define adequately the clinical pharmacokinetics of nicotine. Determination of factors which influence the efficacy of nicotine as an adjuvant in smoking cessation may prove beneficial in reducing the number of tobacco consumers worldwide.

ISSN:0312-5963    

出版商:ADIS    

年代:1987

数据来源: ADIS

摘要:

Binding to plasma proteins can affect the pharmacokinetics and pharmacodynamics of drugs. Age is one of many factors which can affect plasma protein binding of drugs.Unfortunately, very few generalities can be drawn from the studies of the effect of age on protein binding. Whether age has an effect on protein binding is dependent not only on the drug, but also on the manner in which the study is conducted. Several studies involve patients with various disease states making assessment of the effect of age alone on protein binding difficult. Results of different studies on the same drug do not always agree - in one case finding no change in protein binding with age and in another, a significant increase or decrease in protein binding. Most drugs which exhibit increased binding (decreased free fraction) in elderly subjects are basic and tend to have a greater affinity for &agr;1-acid glycoprotein than for albumin. The list of drugs exhibiting decreased binding (increased free fraction) in the elderly is longer and includes both acidic and basic drugs.The impact of changes in protein binding with age is dependent on the magnitude of the change, on the pharmacokinetic characteristics of the drug and on its therapeutic index. Some changes, although statistically significant, are not likely to be of importance clinically. From the studies reviewed, the free fraction is changed by greater than 50% in the elderly for only a few drugs, e.g. acetazolamide, diflunisal, etomidate, naproxen, salicylate, valproate and zimeldine.1

ISSN:0312-5963    

出版商:ADIS    

年代:1987

数据来源: ADIS

摘要:

Plasma mianserin and desmethylmianserin concentrations were measured in 17 clinically depressed elderly patients after a single 30mg dose of mianserin. The patients then received mianserin 30mg daily for up to 6 weeks and the plasma concentrations were measured at weekly intervals. The relationship between concentrations of mianserin and desmethylmianserin at steady-state and at 16 and 24 hours after the single test dose was not good enough to be used for prediction of dosage requirements. Reasons for this finding are discussed.

ISSN:0312-5963    

出版商:ADIS    

年代:1987

数据来源: ADIS