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Pharmacokinetic factors in the adverse cardiovascular effects of antipsychotic drugs.

Abstract：

:Antipsychotics may cause serious adverse cardiovascular effects, including prolonged QT interval and sudden death. This review considers antipsychotic-induced cardiovascular events from three perspectives: high-risk drugs, high-risk individuals and high-risk drug interactions. Pharmacokinetic drug interactions involving the cytochrome P450 (CYP) enzymatic pathway and pharmacodynamic interactions leading to direct cardiotoxic effects are discussed. Original reports on antipsychotic-induced drug interactions are reviewed, with consideration of management guidelines. The literature was reviewed from 1 January 1966 to 1 February 2002. The literature search revealed only 12 original articles published on antipsychotic drug interactions leading to cardiovascular adverse events. Only 4 of the 12 reports were prospective studies; the remainder were either retrospective or anecdotal.Although poor study designs preclude a definitive statement, it appears that pharmacokinetic interactions primarily involved the CYP2D6 and CYP3A4 enzymatic pathways. Those involving the CYP2D6 isozyme included interactions with tricyclic antidepressants, selective serotonergic reuptake inhibitors and beta-blockers. Among these drug interactions, tricyclic antidepressants were most likely to reach clinical significance because of their limited therapeutic index. Drug interactions related to the CYP3A4 pathway were generally less severe, and involved high-potency antipsychotics coadministered with inhibitors such as clarithromycin. Strategies are discussed for the management of adverse cardiovascular events related to antipsychotic drug interactions, including the use of an algorithm. Large, randomised, placebo-controlled studies with strict inclusion criteria are needed to determine the role that antipsychotics play in QT prolongation and sudden death.

journal_name

Clin Pharmacokinet

journal_title

Clinical pharmacokinetics

authors

Brown CS,Farmer RG,Soberman JE,Eichner SF

doi

10.2165/00003088-200443010-00003

keywords:

subject

Has Abstract

pub_date

2004-01-01 00:00:00

pages

33-56

issue

eissn

0312-5963

issn

1179-1926

pii

4313

journal_volume

pub_type

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Pharmacokinetic factors in the adverse cardiovascular effects of antipsychotic drugs.