Pharmacokinetics

Pharmacokinetic and pharmacodynamic issues are not generally a major concern with antipsychotic treatment; however, additive side effects may occur with combined treatment, and a few clinically significant drug interactions are notable (Table 37-9). All of the antipsychotics are highly protein-bound; however, protein-binding interactions are generally not clinically significant. Absorption of most antipsychotics is not affected by food, with the exception of ziprasidone, the absorption of which is increased by 60% to 70% when given with meals.

Table 37-9 Metabolism and Drug Interactions With Antipsychotics

Mjijor CVP450

Oth»rCVPJM

Drfira» dntipiyihotic

AnllpiythtKt

Mer-ali.ilji. En^yinL*

Mel«bulk P-atli wayi

Concentration}

Concentration!

CVirapine

lAi

FluvoMmne, cipnoflooodrx

Ciqarelle smoking

Risperidone

iDtl

3A3*

fluoxetine, paooeiine

Carbamate pine

[»anzapini*

1AJ

¿Oft

FluvcKtamne, ciptolVwadri

(Kjaufi n? ^mokiiii]

r^aioHrtine

Quettaplne

riu^oourinine, kecooonaTQl?

Qibaniazepkic

iAi/4

FlijAMrrwii,

tail» pint

Anpiprazofe

JSAi/1

306

FluraMrmmf, heUK-onarole

Garbjrwepive

llapft «Jone

JD4 3A4

KetaccmareXe, fluwetin^

paiojratine

Asenapme

1AJ

iFlu*>xarinine

Hiik^iiOil

iDG, 3K3/4

FIu'/t^^itj ne. (lLH?:<*tlnt,

ke1i>:orwiole

2D6

1A2

FliMMttfrtne

Q)HHtt smoking

PirpheJiiiine

FluvoxarrnTe, fluoxetine,

[JfliCTBtini

i YWith, i yti H I'fLirfr1 P-dfj{) ¡VjtflJyr i YWith, i yti H I'fLirfr1 P-dfj{) ¡VjtflJyr

All antipsychotics are, at least to some extent, metabolized by hepatic microsomal enzymes to water-soluble compounds that are excreted by the kidneys. Table 37-9 lists the primary metabolic enzymes and some potential drug interactions for the an-

tipsychotic medications. Clinicians should assess the clinical impact of the addition or discontinuation of these drugs in individual patients and should make appropriate adjustments when necessary. Unlike the other antipsychotics, ziprasidone is mostly metabolized by aldehyde oxidase, a metabolic system independent of the CYP450 system. Paliperidone, the 9-hydroxy metabolite of risperidone, is mostly excreted unchanged in the urine, although up to one-third may be metabolized. Another recent discovery in metabolism of antipsychotics and their distribution involves the transmembrane energy-dependent efflux transporter, P-glycoprotein. This may limit the ability of a number of drugs to penetrate the blood-brain barrier and therefore im-

pact pharmacologic activity in the brain. Antipsychotics currently known to use this pathway include perphenazine, haloperidol, fluphenazine, quetiapine, risperidone, 48

and olanzapine.

Due to its propensity to cause prolongation of the QTc interval, the use of ziprasidone with other agents that prolong the QTc interval should be avoided. These other agents include, but are not limited to, antiarrhythmic medications such as quin-idine and sotalol, certain FGAs (chlorpromazine, droperidol, mesoridazine, pimozide, and thioridazine), and certain antibiotics (e.g., gatifloxacin, halofantrine, mefloquine, moxifloxacin, and pentamidine). Ziprasidone has not been shown to have clinically significant drug interactions with the CYP4503A3/4 inhibitors regarding increasing the QTc; however, higher doses, especially given with inhibitors of CYP4503A3/4 (e.g., ketoconazole and erythromycin), should be used cautiously. Clinicians should also be vigilant to avoid pharmacodynamic interactions with any of the antipsychotics involving additive side effects from combination therapies. Side effects that may be worsened with combination therapies include sedation, hypotension, anticholinergic symptoms, and weight gain or metabolic abnormalities.

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