摘要:

Lignocaine is widely used as a local anaesthetic and antiarrhythmic drug. It is commonly administered to patients with acute myocardial infarction as prophylaxis for ventricular fibrillation, although its efficacy in preventing primary ventricular fibrillation is still debated. Toxicity, sometimes with serious clinical consequence, is not uncommon and is usually related to overdosage. Blood lignocaine concentrations correlate roughly with antiarrhythmic and toxic effects and might be useful as an end point for monitoring prophylactic therapy.Administration of lignocaine as a local anaesthetic may result in blood lignocaine concentration in the antiarrhythmic or even toxic ranges. Expected peak levels for various routes of local anaesthesia are tabulated so that ‘safe’ total doses can be calculated. Intramuscular injection of high doses results in sustained therapeutic levels but is often associated with early minor toxicity.Lignocaine is eliminated primarily by hepatic metabolism, which appears to be limited by liver perfusion. Active metabolites may contribute to therapeutic and/or toxic effects. Disease states such as cardiac failure or drugs that alter hepatic blood flow may significantly affect lignocaine clearance.Pharmacokinetic studies in man show wide variability in drug disposition between patients, even when cardiac and hepatic status is considered, making specific dosing recommendations a problem. With intravenous injection, multicompartment kinetics is observed, with an initial rapid decline phase and initial decline in antiarrhythmic activity due to redistribution. With constant infusion, steady state concentrations of lignocaine are seen after 3 to 4 hours in normal subjects and after 8 to 10 hours in patients with myocardial infarction without circulatory insufficiency. In patients with cardiac failure, blood lignocaine concentration may continue to rise for 24 to 48 hours. In the presence of cardiac failure, decreased volumes of distribution and clearance require reduction in loading and maintenance doses. Lignocaine clearance is reduced in patients with liver disease and appears to be a sensitive index of liver dysfunction. A dosing algorithm for treatment of patients with myocardial infarction is presented.

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS

摘要:

Although it is widely recommended that serum levels of aminoglycoside antibiotics be monitored by assay, the justification for this approach has not been clearly presented. A number of studies indicate that serum levels of these agents cannot be predicted reliably on the basis of simple dosage formulae; the major confounding factors being abnormalities of renal function and of extracellular fluid volume in addition to less well defined variables such as fever and anaemia. The influence of haemodialysis and concomitant administration of carbenicillin further complicate dosage estimations in patients with renal insufficiency.On the basis of currently available data, it is reasonable to suggest an optimum range of 5 to 8&mgr;g/ml for peak serum levels of gentamicin. There are no reliable studies from which to derive a comparable value for trough (pre-dose) concentrations. The relative importance of peak and trough values for nephrotoxicity and ototoxicity is an unresolved subject of controversy. However, it seems possible that neither of these individual values, but rather the ‘area under the time-concentration curve’ is the major risk factor for toxicity.In view of the unpredictability of serum levels, especially in seriously ill patients in a fluctuating physiological state, periodical serum gentamicin assays should be performed. The main objective of these assays is to ensure that the peak serum levels attained are adequate, but not unnecessarily high.

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS

摘要:

Malnutrition is usually complex, many deficiencies occurring simultaneously. Changes occur in almost every organ of the body. Apart from the pathophysiological changes which occur in protein-calorie malnutrition, vitamin, mineral and trace element deficiency is accompanied by diverse metabolic changes in tissues. As a consequence there is large potential for alteration of drug response in malnutrition, not only because of possible changes in drug kinetics but also because of changes in tissue uptake and localisation of drugs and potential alteration in drugreceptor interactions. The risk of susceptibility to drug-induced damage may also be increased.The functional status of the gastrointestinal tract is markedly altered in malnourished individuals and as a consequence the rate and extent of drug absorption is likely to be altered. First pass metabolism (intestinal and hepatic) is also likely to be altered. The profile of plasma proteins is considerably changed in malnourished individuals. In most cases, there is hypoalbuminaemia, the degree varying with the severity of malnutrition. Globulins however, are elevated, particularly in cases of infection. Lipoproteins are also reduced in states of malnutrition but there is no information on &agr;1-acid glycoproteins, which bind basic drugs. Malnutrition, by altering the total body water, body composition and drug binding can lead to changes in the volume of distribution of a drug, depending on its physicochemical properties and its ability to bind to macromolecules.Although electronmicroscopc studies indicate changes in endoplasmic reticulum, liver function in malnutrition seems to be generally well preserved. However, biotransformation of drugs may be altered due to changes in drug metabolising hepatic enzyme activity, alteration in drug binding characteristics of proteins and the significant metabolic and hormonal changes in malnutrition. There may be abnormalities in biliary excretion which may affect drug elimination, at least in severe forms of protein-calorie malnutrition. Severe malnutrition can lead to changes in cardiac and renal function. These changes may be indirectly responsible for alterations in excretion mechanisms.Malnutrition can lead to changes in renal function, although this may not be a uniform change and there are very little data on renal excretion mechanisms and their relationship to drug elimination in malnutrition. Cardiac function also seems to be affected in malnutrition, particularly in children. There is reduction in cardiac output and prolonged circulation time; changes which may indirectly be responsible for decreased renal and hepatic blood flow.Animal studies reveal that a number of macro- and micronutrient deficiencies can result in alteration in the rate of drug metabolism. Deficiencies in proteins, dietary fat, minerals and vitamins have all been shown to influence the activity of the mixed function oxidases. However, nutritional-pharmacological interactions in human populations are not as simple as observed under experimental conditions where most of the procedures are standardised and the number of variables minimised. A wide variety of environmental factors and complex multiple nutritional deficiencies react and modify nutritional-pharmacological inter-relationships in a human population.There are very few systematic studies of drug kinetics and drug response in malnutrition states in human populations. There is some evidence that absorption of oral tetracycline might be defective, but intramuscular penicillin and streptomycin seem to be absorbed adequately. The volume of distribution of tetracycline is markedly reduced in undernourished individuals. Although plasma albumin binding of a number of drugs has been shown to be reduced in malnourished individuals, with drugs such as tetracycline, phenylbutazone and sulphadiazine there is an increased rate of elimination. This is most probably due to increased amounts of free drug being available for metabolism. Studies of drug biotransformation in malnourished individuals are also as yet inadequate, but there have been a few reports of decreased rates of metabolism with drugs such as chloroquine, tetrachlorethylene and chloramphenicol. Observations on antipyrine pharmacokinetics in protein calorie malnutrition, anaemia, mineral deficiency and on experimental manipulation of proteins and carbohydrates in the diet, indicate that mixed function oxidases can be altered. However, the clinical significance of such findings are yet to be evaluated. The role of nutritional factors in development of cancer has attracted considerable attention. Some studies suggest that nutrition, cancer and drug metabolism (rate of hydroxylation) may be closely interlinked.Evaluation of drug kinetics and drug response in malnutrition must be studied systematically with a range of drugs of different physicochemical and pharmacokinetic properties. The relationship of drug kinetics, particularly drug metabolism, in various deficiency disorders to other environmental factors should also be established.

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS

摘要:

The elimination half-time and renal clearance of lithium was measured in 12 schizophrenic patients. Minimum plasma lithium concentrations during alternate dosage intervals in 5 patients increased rapidly during the first 2 to 3 days of treatment and reached a steady state level after 5 to 6 days. After the establishment of the remaining 7 patients on lithium the decline in plasma lithium concentration when treatment was stopped was monoexponential. Elimination half-times ranged from 19.3 to 41.3 hours (mean ± SD = 28.9 ± 7.9h) and were significantly correlated with renal creatinine clearance (p < 0.01). Renal lithium clearances ranged from 13.5 to 36.8ml/min (mean ± SD = 24.4 ± 8.0ml/min) and the apparent volumes of distribution ranged from 0.39 to 1.39L/kg (mean ± SD = 0.79 ± 0.34L/kg). There was no evidence that the elimination parameters of lithium in schizophrenic patients were significantly different from those in healthy individuals or manic-depressive patients.

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS

摘要:

The fate of an oral 100mg dose of35S-acetylcysteine, a mucolytic agent, was studied in 10 patients with respiratory disorders, 5 of whom underwent pneumonectomy or lobectomy a few hours after administration of the drug. In the 5 nonoperated patients, plasma radioactivity concentrations were maximal after 2 to 3 hours and remained high after 24 hours; about 22% of radioactivity was excreted in urine after 24 hours. In the 5 operated patients, plasma radioactivity concentrations were comparable with those in the nonoperated patients. Lung tissue radioactivity concentrations after 5 hours were comparable with those in plasma, while the presence of small amounts of radioactivity in the bronchial secretions indicates that acetylcysteine passes into the mucus.Total radioactivity after 5 hours consisted of free, unchanged drug and metabolites (about 22% of total in plasma, 48% in lung tissue), unchanged drug bound to protein by means of labile disulphide bridges (about 14% in plasma, 47% in lung tissue), and drug firmly bound to protein (about 64% in plasma, 5% in lung tissue).Oral acetylcysteine is rapidly absorbed and slowly excreted and is available in the lung in an active form for at least 5 hours at high concentrations.

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