Drug Interactions

Drug Interactions
“I beseech you, in the bowels of Christ, think it possible you may be mistaken.”
Oliver Cromwell, Lord protector of England, 1599-1658
“I don’t think this is related to my medicine,” you hear yourself telling your patient. Never dismiss a patient’s complaint about a side effect, but consider the possibility that you are wrong and the patient is right, possibly because of a hitherto unrecognized drug interaction (Cromwell puts the patient’s complaint in more dramatic language).
In this chapter, I focus mostly on drug metabolism, particularly the all-important CYP450 enzyme system that does the bulk of metabolism for psychotropics, including antipsychotics, and how it relates to serum drug levels. Renal excretion and plasma binding are generally not a clinical issue with antipsychotics.
ANTIPSYCHOTIC DRUG METABOLISM
Antipsychotics are mainly metabolized by the hepatic CYP450 enzyme system, but other systems, like the phase II glucuronidation enzyme system (uridine glucuronosyl transferase, or UGT), contribute to the deactivation of antipsychotics. For antipsychotic metabolism, the most important cytochrome isoenzymes are 3A4, 2D6, and 1A2. Consult Table 16.1 for the main metabolic pathways for commonly used antipsychotics.
TABLE 16.1. Antipsychotic Metabolic Pathways

Relevant Metabolite

CYP450 Metabolism

Alternative Metabolism

First-generation antipsychotics

Haloperidol

HP+a

3A4, 2D6

Glucuronidation

Fluphenazine

7-OH-FLUb

2D6

Perphenazine

None known

2D6

Second-generation antipsychotics

Aripiprazole

None active

3A4, 2D6

Clozapine

nor-CLZc

1A2, 3A4, 2C19, (2D6)

Olanzapine

None active

1A2, (2D6, 2C19?)

Glucuronidation

Quetiapine

None relevant

3A4, (2D6)

Risperidone

9-OH-RSPd

2D6, 3A4

Ziprasidone

None relevant

3A4 (33%)

Aldehyde oxidase (66%)

Main metabolizing enzymes in bold.

a HP+ is likely a neurotoxic metabolite.b 7-Hydroxyfluphenazine.c Norclozapine or N-desmethylclozapine; possibly responsible for hematologic toxicity.d 9-Hydroxyrisperidone (paliperidone); active moiety is risperidone plus 9-hydroxyrisperidone;9-hydroxyrisperidone is equipotent with risperidone.

Based on Freudenreich O, Goff DC. Antipsychotics. In: Ciraulo DA, Shader RI, Greenblatt DJ, et al. eds. Drug interactions in psychiatry. 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2006:177-241.

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Sep 12, 2016 | Posted by in PSYCHIATRY | Comments Off on Drug Interactions

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