摘要:

Life-threatening increased intracranial pressure can be reversed by a variety of drugs. These compounds all have some disadvantages, producing rebound effects, severe coma or cardiovascular depression and electrolyte imbalance. However, reduction of intracranial pressure is a prerequisite for recovery and the benefits of treatment outweigh the risks.Dexamethasone is rapidly eliminated, the short half-life (about 3 hours) indicating that dosage intervals should be kept small. As yet, however, its therapeutic efficacy has not been clearly demonstrated. Therefore, an association between pharmacokinetics and pharmacodynamics cannot be established.Osmotic diuretics are the most widely used agents for reduction of intracranial pressure. Pharmacokinetics show a very close relationship to changes in serum osmolality, but there are large variations in the clearance. For the use of osmotics, the blood-brain barrier must be intact. Osmotic diuretics may lead to intracerebral oedema or to acute renal failure as serum osmolality increases. Considering the pharmacokinetics of each drug, and the dynamics of intracerebral pressure and osmolality, an intermittent, individually titrated dosage should be administered, with simultaneous monitoring of intracranial pressure.Frusemide (furosemide) can be used as an adjunct, to enhance the effect of osmotic diuretics. Its pharmacokinetics are limited by renal function, depending on age as well as on the extent of renal impairment. Altered renal elimination of concomitantly administered drugs, and electrolyte imbalances should be anticipated when diuretics are used.Barbiturates are certain to decrease intracranial pressure in humans by an as yet unknown mechanism. Their administration is recommended for patients that do not respond to conventional therapy.As barbiturates can result in deep coma, knowledge of their pharmacokinetics is of great importance for recovery. Following single doses, pentobarbitone has a relatively long elimination half-life (about 22 hours). However, after repeated administration for several days, its elimination may be enhanced due to autoinduction. Thiopentone kinetics are characterised by distribution and redistribution into deep peripheral compartments. Administration of high and frequent doses leads to considerably delayed recovery. This is not true for methohexitone, which shows comparable pharmacokinetics after single and multiple dose administration. Elimination depends on liver blood flow. Thus, recovery from methohexitone-coma is rapid. Rapid elimination is also an important characteristic of etomidate and alphaxolone/alphadolone, two non-barbiturate hypnotics.Patients requiring intracranial pressure-lowering medication are usually critically ill and on multiple drug therapy, leading to great variations in pharmacokinetics and pharmacodynamics. Drug interactions based on changes in plasma protein binding, drug metabolism activity and renal function have to be considered. Monitoring of plasma concentrations is therefore necessary to prevent side effects and to differentiate symptoms caused by intracranial pressure-reducing medication from those induced by coma due to brain damage.

ISSN:0312-5963    

出版商:ADIS    

年代:1987

数据来源: ADIS

摘要:

Kernicterus, the primary manifestation of neonatal bilirubin toxicity, remains an important complication of unconjugated hyperbilirubinaemia despite advances made with phototherapy and exchange transfusions. It results from the penetration of bilirubin into neuronal tissues of the CNS with subsequent damage to the mitochondrion. A number of factors may modify or potentiate bilirubin toxicity, including drugs administered to the infant. The importance of drug-bilirubin interactions in the pathogenesis of kernicterus was first realised quite inadvertently in the 1950s, and the potential risk for significant drug-bilirubin interactions has since become an important consideration in neonatal drug therapy. All drugs intended for use in newborn infants should be evaluated for their capacity to displace bilirubin. A number of techniques have been developed which have facilitated investigation of the mechanisms mediating the bilirubin-displacing effects of drugs and the pharmacokinetics of drug-bilirubin interactions. Further, the clinical risk for inducing kernicterus has been investigated for many of the drugs to which neonates may be exposed by direct administration, transplacentally, or through breast milk. This review summarises the available knowledge concerning the physicochemical properties and toxicities of bilirubin, reviews the methodologies used in evaluating drug-bilirubin interactions, and focuses on the mechanisms, pharmacokinetics and clinical significance of the bilirubin displacing effects of antibiotics, anticonvulsants, diuretics, and other important drug classes used in the treatment of neonates.

ISSN:0312-5963    

出版商:ADIS    

年代:1987

数据来源: ADIS

摘要:

&bgr;-Adrenoceptor antagonists are among the most commonly prescribed classes of drugs. They are indicated for the treatment of diseases such as hypertension and angina pectoris, in which long term therapy is often required. Since many &bgr;-adrenoceptor antagonists have short plasma elimination half-lives, divided daily dosing has often been necessary in order to provide continuous &bgr;-blockade throughout the day. However, such multiple-dose schedules may promote patient non-compliance and failure of the prescribed regimen. Long acting propranolol is a sustained release formulation of propranolol which has been developed to maintain therapeutic plasma propranolol concentrations throughout a 24-hour period while allowing once-daily dosing. Compared with conventionally formulated propranolol, long acting propranolol has a prolonged terminal half-life (8 to 11 hours), due to slower absorption from the gut. Systemic bioavailability of long acting propranolol is 30 to 50% less than that of the conventional formulation. This difference may result from increased hepatic metabolism. Peak drug concentrations are significantly lower than following identical doses of conventional propranolol, and the time to peak drug concentrations following administration is delayed. Relatively constant plasma concentrations and clinically significant inhibition of exercise-induced tachycardia are maintained throughout a 24-hour dosing interval following once-daily long acting propranolol. Once-daily long acting propranolol is as effective as divided doses of conventional propranolol for the treatment of hypertension and angina pectoris. Efficacy also appears comparable with once-daily administration of long acting conventional &bgr;-adrenoceptor antagonists such as atenolol and nadolol. Once-daily long acting propranolol provides clinically significant sustained &bgr;-adrenoceptor blockade and offers the potential for improved patient compliance due to once-daily dosing. Since provision of sustained &bgr;-adrenoceptor blockade appears to be particularly important in the treatment of angina, this may be the principal indication for which long acting propranolol has a therapeutic advantage independent of its potential to improve compliance.

ISSN:0312-5963    

出版商:ADIS    

年代:1987

数据来源: ADIS