摘要:

In the drug therapy of cardiac emergencies, it is necessary to rapidly achieve therapeutic drug concentrations and adjust drug dose as the patient's clinical status changes. Cardiac dysfunction is often present and may alter drug pharmacokinetics. Circulatory failure causes sympathetically mediated vasoconstriction in most tissues, with relative sparing of the brain and heart due to autoregulation. Blood flow to vasoconstricted tissues is reduced, and the available cardiac output is redistributed so that the heart and brain receive a greater fraction. Drug distribution to tissues is therefore slowed, and the initial concentration of drug in blood is higher when circulatory failure is present than when it is absent. This higher blood concentration is reflected by higher concentrations of drug in the brain and heart, which are relatively well perfused. Initial doses of many drugs need to be reduced in patients with circulatory failure to prevent cardiac or central nervous system toxicity.Cardiac output is markedly diminished during cardiopulmonary resuscitation (CPR), but blood flow distribution is qualitatively similar to that of circulatory failure with spontaneous circulation. Pneumatic trousers increase lower extremity vascular resistance and may produce a similar redistribution of blood flow. Drug distribution during the use of CPR or pneumatic trousers should be similar to that of circulatory failure with spontaneous circulation, but few data are available to guide drug dosing during the use of these interventions. Animal data suggest that the central volume of distribution of some drugs during CPR may be as small as one-tenth of normal.Drug metabolism in circulatory failure may be impaired by reduced hepatic blood flow resulting in decreased clearance of highly extracted drugs, or by hepatocellular dysfunction resulting in decreased clearance of poorly extracted drugs. Drug excretion may be impaired by reduced renal blood flow resulting in decreased filtration or secretion and increased reabsorption. The maintenance dose of many drugs must therefore be reduced in the presence of circulatory failure.Intravenous drug administration is preferred in patients with circulatory failure. The central intravenous route is often convenient but must be used cautiously when administering potentially cardiotoxic drugs. Intratracheal administration appears to be a promising alternative for some drugs, such as adrenaline (epinephrine). Intracardiac injections are hazardous and offer no demonstrated advantage over other routes.Interpretation of drug concentrations in blood during cardiac emergencies must take account of the degree of protein binding of drug. Increases in the acute phase reactant &agr;1-acid glycoprotein may decrease the unbound concentration of highly extracted drugs or increase the total concentration of poorly extracted drugs. Heparin can displace drugs from albumin by increasing free fatty acid concentrations, but this appears to be an in vitro artefact. The site of drug sampling may also be important: arterial concentrations of drug may greatly exceed venous concentrations during the distribution phase due to tissue uptake of drug.Most antiarrhythmic drugs have half-lives of at least several hours and require many hours to reach a steady-state blood concentration when administered as a constant rate intravenous infusion. Therapeutic blood concentrations of such drugs can be achieved more rapidly by administering a loading dose consisting of 1 or more intravenous bolus doses or rapid infusions. Catecholamines have half-lives of several minutes, so a loading dose is not required. The application of pharmacokinetic and pharmacodynamic considerations to drug dosing in cardiac emergencies is illustrated by considering the use of several antiarrhythmic agents [lignocaine (lidocaine), procainamide, verapamil, propranolol, bretylium], inotropic and vasopressor agents [noradrenaline (norepinephrine), adrenaline, dopamine, dobutamine, isoprenaline (isoproterenol)], and atropine.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

Since up to 90% of a theophylline dose is biotransformed, drugs influencing microsomal enzyme systems in the liver may affect the elimination of theophylline. Other integrated mechanisms (e.g. hepatic uptake) may also be altered by concurrent administration of other drugs. Whatever the mechanism, the interaction may be sufficient to necessitate adjustment of the theophylline dosage, preferably guided by plasma theophylline determinations.Comedication with phenobarbitone may require an increase of the theophylline dose by about 30% due to increased clearance resulting from enzyme induction. Similarly, with phenytoin and carbamazepine a dose increase of about 40 to 50% may be required. In the case of rifampicin, isoniazid or sulphinpyrazone comedication, an increase of the theophylline dose by about 20 to 25% may be needed.On the other hand, other drugs decrease theophylline clearance, making a reduction in the dose of concurrent theophylline advisable: with usual doses of erythromycin, propranolol and isoprenaline (isoproterenol), a reduction of about 25% is needed; with cimetidine and oral contraceptives by about 30% or more; and with triacetyloleandomycin (troleandomycin) by about 50%. In high doses, the xanthine oxidase inhibitor allopurinol can also retard theophylline elimination, and a reduction of the theophylline dose by about 20% may be advisable.Conflicting results have been reported on the influence of frusemide (furosemide) and influenza vaccines, while data regarding the effect of corticosteroids, benzodiazepines and verapamil on theophylline kinetics are not yet conclusive.Many drugs, however, appear not to significantly affect theophylline clearance. Some are from the same therapeutic group as the drugs mentioned above and offer clinical alternatives for coadministration with theophylline. Examples of drugs not found to have a significant effect on theophylline pharmacokinetics are ranitidine, josamycin, midecamycin, amoxycillin, tetracycline, cephalexin, cefaclor, orciprenaline, metoprolol, antacids, medroxyprogesterone acetate, metoclopramide and metronidazole.Most of the drugs discussed in this review appear not to affect the volume of distribution of theophylline significantly.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

Among the few antineoplastic agents investigated pharmacologically in children and adults, methotrexate has been clearly demonstrated to be handled differently in the two age groups. Age has in fact proved to be a major determinant, exerting an effect on both the pharmacokinetics and pharmacodynamics of methotrexate. Its pharmacokinetics, in turn, determine the drug toxicity. The &bgr;-phase of methotrexate clearance, represented by the plasma drug concentration 48 hours from the start of a 6-hour infusion in a high dose treatment regimen, appears to be constant with age. In children, an increasing plasma drug concentration is apparent with increasing age, but whether this trend reflects a potential increase in the area under the plasma concentration-time curve of methotrexate has yet to be defined.Recent investigations have suggested that the drug is more completely distributed in the tissues of children than adults at the same infused dosage. This may explain the increased tissue toxicity caused by methotrexate. However, other observations suggest a faster drug turnover rate in the tissues of children. This may prevent the drug from concentrating in vital organs. Whether the metabolism of methotrexate, particularly the biosynthesis of methotrexate polyglutamates, plays a role in the biological effect of the drug is worthy of further investigation.The high brain tissue concentration after systemic methotrexate infusion and the slower efflux of methotrexate from brain tissues and cerebrospinal fluid make these tissues vulnerable to methotrexate toxicity.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

The renal clearance of lithium will decrease, and hence the risk of acute lithium toxicity will increase, in any situation leading to dehydration and sodium depletion. Patients on long term lithium therapy with progressively declining urinary concentrating ability may be at special risk in this regard.Chronic histological changes in the kidney attributed to lithium therapy correlate with age rather than with the duration of lithium therapy. Age-related renal histological changes are associated with decreased glomerular filtration rate and therefore reduced renal lithium clearance. Thus, the dose of lithium should be reduced with advancing age.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

The mean and standard deviation of lignocaine (lidocaine) pharmacokinetic parameters in a patient population were determined on the basis of 327 serum concentration measurements obtained in 42 patients treated for ventricular arrhythmias. The application of a Bayesian forecasting method, which uses the estimates of the population parameters and 1 or 2 serum concentration measurements as feedback information, was tested retrospectively in 17 of the 42 patients (group I, 32 levels), and prospectively in 10 additional patients (group II, 20 levels). With I individual feedback concentration, sampled 2 to 4 hours after the start of lignocaine infusion, serum concentrations at 12 and 24 hours could be accurately predicted. The prediction error (measured minus predicted concentration) ranged between −1.2 and +1.6 (mean −0.03) mg/L in group I, and from −0.7 to +1.5 mg/L (mean +0.13) mg/L in group II; the correlation coefficient of measured and predicted levels were 0.92 and 0.86, respectively.In contrast, a prediction of lignocaine concentrations in these patients using only population parameters without feedback was poor: range of the prediction error = −3.1 to +3.0 mg/L (mean = +0.001 mg/L, r = 0.63, groups I and II, n = 52).The results demonstrate that with the Bayesian forecasting technique, accurate assessment of individual dosage requirements can be obtained within a few hours after starting lignocaine therapy.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

Mecillinam (amdinocillin) serum concentrations and urinary excretion of the drug and its degradation products were determined in 9 subjects: 1 with normal renal function, 4 with varying degrees of renal failure, and 4 on haemodialysis for end-stage renal failure. The results conform to first-order elimination kinetics. With decreasing glomerular filtration, renal clearance decreases sharply, and in severe renal failure approaches the value of creatinine clearance. However, elimination of the drug also takes place by non-renal clearance, which was found to be 48.8 ± 9.1 (SD) ml/min. Concentrations of mecillinam and its degradation products were also determined in haemodialysis ultrafiltrate. From these data and other evidence, it is concluded that degradation of the drug is the chief mechanism of non-renal elimination.Based on the relationship between creatinine clearance and plasma clearance of mecillinam, and considering that the drug is a relatively non-toxic bactericidal antibiotic, the following dosage adjustment scheme is proposed: glomerular filtration rate over 30 ml/min: normal dosage; 10-30 ml/min: 50% of normal dosage; under 10 ml/min: 25% of normal dosage. Even when dosage is adjusted, therapeutic concentrations of the drug will appear in urine in most cases. During haemodialysis, which increases clearance of the drug by 100%, the dosage should, in principle, be doubled. Alternatively the treatment schedule may be modified by giving the dose just after each dialysis.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS