摘要:

A number of examples of altered drug disposition in patients with respiratory disease have been reported. These reports have been analysed in terms of absorption, distribution and elimination. The changes have been examined mechanistically in light of the pathophysiology of respiratory disease and the known influence of these physiological parameters on drug disposition. Our analysis has includedin vivoandin vitrodata from laboratory animals in addition to appropriate data from humans.Acute hypoxaemia appears to decrease intrinsic hepatic clearance while chronic hypoxia appears to increase intrinsic clearance. The free fraction of some bases isdecreasedin plasma taken from patients with chronic hypoxaemia and this change can interact with changes in intrinsic metabolic activity. Blood gas disturbances also can affect drug disposition by decreasing hepatic and renal perfusion.Cor pulmonale has not been linked to altered drug disposition, except in the case of theophylline. However, this pathophysiological condition may be equivalent to congestive cardiac failure through diminished hepatic and renal perfusion.The marked reduction (approximately 50%) in theophylline clearance documented in some asthmatic patients may reflect protein binding changes, a paradoxical response of metabolic pathways to hypoxaemia, or other as yet unidentified processes.It is apparent that respiratory disease significantly changes drug disposition through a number of interacting mechanisms. These have not been adequately studied to provide a basis for clinical dosage adjustment, however, general principles are emerging: Drugs showing flowdependent hepatic clearance (e.g. lignocaine/lidocaine, pethidine/meperidine, propoxyphene) and those drugs showing predominant renal clearance (aminoglycosides, digoxin) should be used with caution. Theophylline doses must be reduced on an empirical basis, as the mechanisms causing reduced clearance cannot be convincingly explained in terms of the pathophysiology of respiratory disease.The lungs must be added to the existing list of organs (liver, kidney, heart) whose dysfunction significantly affects drug disposition.

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS

摘要:

Knowledge acquired of the kinetic disposition and effects of theophylline over the past 8 years has increased the clinical utility of the drug in the treatment of cardiorespiratory disorders. Although the anhydrous theophylline content varies greatly between products, there is similar excellent oral bioavailability. An average 96% (range 75 to 105%) of an uncoated theophylline tablet is absorbed, with peak concentrations occurring from 0.5 to 2.0h. Enteric coated and many sustained release preparations have poor bioavailability. Intravenous preparations of aminophylline contain from 75 to 85% theophylline by weight. Other routes of administration are not to be recommended.In plasma, some 53 to 65% of theophylline is reversibly bound to protein. Premature neonates and adults with hepatic cirrhosis have reduced binding. The apparent volume of distribution in the steady state averages 0.5L/kg body weight regardless of sex, age (1 to 87 years), history of cigarette smoking, asthma, or acute pulmonary oedema. Premature neonates and adults with acidaemia, hepatic cirrhosis or obesity tend to have larger volumes of distribution for theophylline.Theophylline is eliminated by biotransformation in the liver and urinary excretion of its metabolites. Approximately 7 to 13% is excreted unchanged in the urine by a first order process. One of the metabolites, 3-methylxanthine, which is pharmacologically active but less potent than theophylline, is eliminated by Michaelis-Menten kinetics. Removal of dietary methylxanthines can increase the rate of elimination of a single dose of theophylline. Dose dependent elimination kinetics has been suggested but not conclusively demonstrated.The plasma theophylline concentration time curve after intravenous administration fits a 2 compartment open kinetic model with a rapid &agr; distribution phase completed within 30 to 45 minutes after an intravenous dose. The &bgr; elimination phase (t1/2&bgr;) is quite variable and in healthy adults ranges from 3 to 13h. As the apparent volume of distribution is little altered under most conditions, variations in theophylline elimination half-life reflect alterations in plasma theophylline clearance. The predominant factors which alter theophylline clearance are age, body weight, diet, smoking habits, other drugs and cardiorespiratory or hepatic disease.The elimination of theophylline is markedly decreased in premature infants and increased in childhood. The rapid clearance in childhood decreases toward adult values in the late teens. Some authors believe old ageper sedecreases an individual's capacity to eliminate theophylline. However, this may be a reflection of the inability of hepatic enzymes in the elderly to respond to factors in the diet or environment which usually stimulate theophylline clearance.The elimination half-life of theophylline is prolonged in obese subjects and maintenance doses must be calculated from ideal body weight. Theophylline clearance can be decreased by a high carbohydrate-low protein diet, as well as the ingestion of other methylxanthines such as caffeine. In contrast, a low carbohydrate-high protein diet, especially charcoal broiled meat, may enhance theophylline clearance.Theophylline clearance is markedly increased by tobacco or marihuana smoke. The rate of recovery from the stimulated state on cessation of smoking is unknown. Although there is some evidence that phenobarbitone treatment can slightly induce the hepatic metabolism of theophyllinein vitro,the evidence in man for such an effect is inconclusive. The macrolide antibiotics, troleandomycin and erythromycin, are potent inhibitors of theophylline elimination.There is no evidence that uncomplicated asthma or chronic bronchitis alters theophylline clearance but, as chronic obstructive lung disease ensues with complications such as pneumonia or cor pulmonale, theophylline clearance can be markedly impaired. The elimination of theophylline is also reduced by congestive heart failure or acute pulmonary oedema. The mechanism responsible for reduced theophylline clearance in patients with cardiorespiratory disease is unclear. Reduced hepatocellular function is apparently responsible for the most marked decrease in theophylline clearance in patients with hepatic cirrhosis. It is not clear if one or several biochemical tests of liver function will allow prediction of the degree of impairment of theophylline elimination in individual patients. Reduced theophylline clearance has been observed in febrile children with acute viral exanthems.The bronchodilator effect of theophylline is related to plasma theophylline concentrations in the post-distribution period, indicating that the site of its bronchodilator activity is outside of the central kinetic compartment. Continuous improvement in forced expiratory volumes can be observed over the plasma theophylline concentration range of 5 to 20mg/L. These concentrations can reduce the frequency of asthmatic attacks, abolish exercise induced bronchospasm and increase the ventilatory response to hypoxaemia.Plasma theophylline concentrations of 5 to 20mg/L can produce concentration related increases in forearm blood flow and reductions in cerebral blood flow. The mechanism responsible for the reduction in cerebral blood flow is not clear. Peripheral venous distensibility is maximally increased at 10mg/L. Cardiac output and heart rate are variably increased. Although myocardial oxygen consumption increases, there appears to be a greater increase in oxygen delivery by increased coronary blood flow, suggesting a direct reduction of coronary vascular resistance. Pulmonary vascular resistance is reduced with increased ventilation/perfusion abnormalities. Arterial oxygen tension may decrease in asthmatic patients even though airway obstruction is relieved.Serious adverse effects are rare at plasma theophylline concentrations below 20mg/L. The most frequent adverse effects involve the gastrointestinal system (anorexia, nausea, vomiting, abdominal discomfort) and the nervous system (headache, nervousness, anxiety), which usually occur with concentrations over 15mg/L. Between 20 and 40mg/L, sinus tachycardia and atrial or ventricular arrhythmias occur with increasing frequency. Above 40mg/L, focal or generalised seizures, or cardiorespiratory arrest can occur.For rapid attainment of therapeutic plasma theophylline concentrations, a loading dose of aminophylline 5.6mg/kg can be given over 20 minutes via a peripheral vein. Although this dose is relatively safe and almost universally applicable, caution must be exercised if the patient has received theophylline in the previous 12 to 24 hour period. Maintenance doses of theophylline for intravenous or oral use should be calculated based on ideal body weight and modified for the presence of factors which alter theophylline clearance.Dose guidelines are approximations only and the wide variability in theophylline clearance between individuals and with disease makes their indiscriminant application hazardous. It is rational to begin with smaller than recommended doses and increase at intervals as tolerated until the recommended amounts are administered. In adult patients, one may limit theophylline doses to 16mg/kg daily unless a plasma theophylline concentration is obtained as a guide for further adjustment. With the proper resources, interpretive skills, and timing of plasma samples, theophylline concentrations can give the clinician sufficient information to prescribe ideal theophylline doses for an individual patient, provided the clinician searches for and recognises factors which alter theophylline clearance in that patient.

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS

摘要:

Recent definition of the pharmacodynamics and pharmacokinetics of theophylline have increased the safety and efficacy of the drug for acute bronchodilator therapy and have greatly expanded its potential as a prophylactic agent in the management of chronic asthmatic symptoms. Specifically, benefit and risk from theophylline have been demonstrated to relate directly to serum theophylline concentration, which is itself a function of not only the dose but also the elimination characteristics of the drug in the individual patient.When used to treat acute symptoms, an initial loading dose of theophylline based on a volume of distribution of 0.5L/kg (range - 0.3 to 0.7L/kg) is required to rapidly attain maximum bronchodilator effect. There are wide interpatient differences in elimination rate. Dosage for continued therapy must be matched to the rate of elimination in the individual patient, which can be expressed as clearance. Under normal circumstances, this can only be done empirically by monitoring serum theophylline concentration at intervals and adjusting dosage until a steady state is reached with the serum theophylline concentration within the 10 to 20μg/ml therapeutic range.During long term therapy, product formulation must be carefully considered; sustained release preparations, if completely and reliably absorbed, offer therapeutic advantage, particularly for children. The most acceptable way to determine final dosage for long term therapy is to begin with doses sufficiently low to allow virtually universal acceptance of the medication, although optimum benefit will be obtained in very few. Gradual increases in dose at 3 day intervals until average doses are reached, if tolerated, minimises the frequency with which serum theophylline concentrations need to be measured. These doses should then, however, not be maintained or increased further without measurement of serum theophylline concentration. Final dosage adjustment can then be made. Serum theophylline measurement is therefore essential for optimum management of chronic asthma and, when rapidly available, increases the utility of theophylline for acute therapy.Six different basic methods for measuring theophylline in serum or plasma have been developed and multiple modifications of many of these have been utilised in various laboratories. Of greatest relevance are: (1) modifications of the traditional extraction methodology and measurement of ultraviolet absorbance first reported by Schack and Waxler in 1949; (2) high pressure liquid chromatography of which the reverse phase technology has become the most popular because of its commercial availability; and (3) the enzyme immunoassay which has recently been released and appears to have distinct advantage for the average clinical laboratory with regard to cost, specificity, ease of operation, speed of the assay and potential application of the equipment for assaying drugs other than theophylline.

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS

摘要:

The majority of migraine attacks are associated with gastrointestinal symptoms which add considerably to the distress and inconvenience caused by the headache. When salicylate absorption from effervescent aspirin tablets was studied during migraine, the rate of absorption was found to be reduced relative to that found in non-migrainous volunteers and in the same patients when headache-free. There is evidence that this reduced rate of absorption is caused by gastrointestinal stasis and reduced rate of gastric emptying. Patients in whom aspirin absorption was delayed were more likely to take longer to respond and to require additional treatment. Metoclopramide, which increases gastric emptying rate, has been shown to improve the rate of absorption of aspirin during migraine and also increase the rate of recovery from the attack and avoid the need for additional treatment; effects which were not shown by thiethylperazine.It is likely that delayed absorption during migraine affects some drugs other than aspirin, such as ergotamine, and it is therefore recommended that the most rapidly absorbable formulation should be used. If such treatment is ineffective, metoclopramide may be a useful addition and should be tried before resorting to other routes of administration.

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS

摘要:

A high performance liquid chromatography method for the determination of sulphamethoxazole and its metabolite N4-acetylsulphamethoxazole is described. The renal excretion rate and cumulative renal excretion of sulphamethoxazole is markedly influenced by urinary pH. With constant urinary pH, the renal excretion rate and the renal clearance of sulphamethoxazole is dependent on the urine flow. The renal clearance of the metabolite N4-acetylsulphamethoxazole is not influenced by urinary pH or urine flow.No clear acetylator phenotype could be detected in the group of volunteers studied. The extent of acetylation depends on the amount of sulphamethoxazole available for acetylation, thus indirectly on the urine pH and flow.

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS

摘要:

The pharmacokinetics of fluorouracil after oral, intravenous and rectal administration were compared in 12 patients with colorectal cancers.Oral administration of 10 to 15mg/kg gave variable plasma levels (0 to 10.5 &mgr;g/ml) and bioavailability (0 to 74%; mean 28%). Bioavailability increased markedly with increases in dose, suggesting saturation of the ‘first pass’ hepatic metabolism of the drug. Differences in bioavailability could not be related to standard liver function tests or the presence of metastatic deposits in the liver.Plasma levels were not detectable after rectal administration in the 4 patients studied and were very low (0 to 8&mgr;g/ml) during high dose (20 to 30mg/kg/24h) slow intravenous infusion in 6 patients.These findings indicate that different dose schedules and routes of administration produce markedly different plasma levels. They suggest that the rate of degradation of fluorouracil by the liver is quite variable and may become saturated with increasing dose. For these reasons monitoring of plasma levels of the drug in individual patients may be useful.

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS