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Pharmacokinetic Factors in the Adverse Cardiovascular Effects of Antipsychotic Drugs

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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 β-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.

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Acknowledgements

We thank Rebecca C. Scruggs, PharmD, for providing drug information services and David L. Armbruster, PhD, for providing editorial assistance from the University of Tennessee Health Science Center. There were no sources of funding or conflicts of interest directly relevant to the content of this review.

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Authors and Affiliations

  1. Departments of Pharmacy and Obstetrics/Gynecology, University of Tennessee Health Sciences Center, 9685 US Highway 70, Lakeland, Tennessee, 38002, USA

    Candace S. Brown

  2. Department of Psychiatry, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA

    Richard G. Farmer

  3. Department of Medicine (Cardiology), University of Tennessee Health Sciences Center, Memphis, Tennessee, USA

    Judith E. Soberman

  4. Department of Pharmacy (Drug Information Center), University of Tennessee Health Sciences Center, Memphis, Tennessee, USA

    Samantha F. Eichner

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  1. Candace S. Brown
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  2. Richard G. Farmer
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  4. Samantha F. Eichner
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Correspondence to Candace S. Brown.

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Brown, C.S., Farmer, R.G., Soberman, J.E. et al. Pharmacokinetic Factors in the Adverse Cardiovascular Effects of Antipsychotic Drugs. Clin Pharmacokinet 43, 33–56 (2004). https://doi.org/10.2165/00003088-200443010-00003

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