Pharmacodynamic Drug Interactions with Ziprasidone

In prior columns, I focused on a number of potentially serious drug interactions that can produce adverse effects in your patients. Many of the drug-interaction mechanisms have been mediated by inhibition of induction of specific cytochrome P-450 (CYP-450) microsomal enzymes. Therefore, the mechanisms of these interactions can broadly be classified as pharmacokinetic drug interactions, which occur when a precipitant drug causes a change in the absorption, distribution, metabolism, or excretion of an object medication.

This month, I will examine a potentially serious pharmacodynamic drug interaction. Pharmacodynamic drug interactions occur when medications with additive or antagonistic pharmacologic effects are combined. The simplest examples of the extremes of this type of interaction mechanism are the combination of two medications with central nervous system (CNS) depressant effects (additive effects) and the combination of a beta₂ agonist and a nonspecific beta blocker (antagonistic effects).

Ziprasidone hydrochloride (Geo-don; Pfizer Pharmaceuticals) was approved by the FDA in February 2001. It is an antipsychotic agent indicated for the treatment of schizophrenia that is chemically unrelated to phenothiazine or butyrophenone antipsychotic agents. Ziprasidone?s mechanism of action is thought to be mediated through a combination of dopamine type 2 (D₂) and serotonin type 2 (5-HT₂) antagonism. Antagonism at receptors other than dopamine and 5-HT₂ (histamine₁ receptors and alpha₁ receptors) with similar receptor affinities may explain some of the other therapeutic and side effects of ziprasidone.

The QTc Interval

The pharmacodynamic interaction of interest with ziprasidone is its potential to prolong the QTc interval and its combination with other medications that can cause the same cardiac conduction effect. Prolongation of the QTc interval is associated in some drugs with the ability to cause torsades de pointes?type arrhythmia, a potentially fatal polymorphic ventricular tachycardia, and sudden death. Ziprasidone has a greater capacity to prolong the QT/QTc interval, compared with several other antipsychotic agents that could be employed to treat schizophrenia. Whether ziprasidone will cause torsades de pointes or increase the rate of sudden death is not yet definitively known.

The relationship of QT prolongation to torsades de pointes is clearest for larger increases in the QTc interval (?20 msec), but it is possible that smaller QTc prolongations may also increase risk, or increase it in susceptible individuals such as those with bradycardia, hypokalemia, hypomag-nesemia, or genetic predisposition. Although torsades de pointes has not been observed in association with the use of ziprasidone at recommended doses, experience is too limited to rule out an increased risk. Because of ziprasidone?s dose-related prolongation of the QT interval and the known association of fatal arrhythmias with QT prolongation by some other medications, this drug is contraindicated in patients with a known history of QT prolongation (including congenital long QT syndrome), as well as with recent acute myocardial infarction or with uncompensated heart failure.

Ziprasidone should not be used with other drugs that prolong the QT interval, including quinidine,

dofetilide, sotalol, other class 1A and class 3 antiar-rhythmic agents, mesoridazine, thiori-dazine, chlorpromazine, droperidol, pimozide, moxifloxacin, sparfloxacin, gatifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, lev-omethadyl acetate, dolasetron mesy-late, probucol, or tacrolimus (Table). Ziprasidone is also contraindicated with drugs that have demonstrated QT prolongation as one of their pharmacody-namic effects and have this effect described in the full prescribing information as a contraindication or a boxed or bold warning.

It is recommended that patients being considered for ziprasidone therapy who are at risk for significant electrolyte disturbances (hypokalemia in particular) have baseline serum potassium and magnesium measurements. Hypokalemia (and/or hypomagne-semia) may increase the risk of QT prolongation and arrhythmia. Hy-pokalemia may result from diuretic therapy, diarrhea, and other causes. Patients with low serum potassium and/or magnesium should be given those electrolytes before proceeding with treatment. It is essential to periodically monitor serum electrolytes in patients in whom diuretic therapy is introduced during ziprasidone treatment.

Persistently long QTc intervals may also increase the risk of further prolongation and arrhythmia, but it is not clear that routine screenings of electrocardiogram measures are effective in detecting such patients. Ziprasidone should be discontinued in patients who are found to have persistent QTc measurements >500 msec.

Patients receiving ziprasidone should be counseled to speak with a health care professional concerning their use of other medications, including nonprescription medications, supplements, and herbal products. Patients should be instructed to contact their health care professional immediately if they experience fainting or loss of consciousness or if they feel a change in palpitations. These symptoms indicate a potential cardiac adverse event.

Additional InteractionsAdditional pharmacodynamic interactions that can occur with the use of ziprasidone include sedation, hypotension, and dopamine antagonism. Given the primary CNS effects of ziprasidone, caution should be used when it is taken in combination with other centrally acting drugs because of the potential for additive sedation and CNS effects. Since ziprasidone?s potential for inducing hypotension is most likely due to its antagonism of alpha₁-adrenergic receptors, it may enhance the effects of certain antihypertensive medications. Ziprasidone may also antagonize the effects of levodopa and dopamine agonists because of its dopamine receptor antagonist properties.

OverviewBecause ziprasidone is a metabolic substrate for the CYP3A4 enzyme, medications that induce CYP3A4 (eg, carbamazepine) can decrease plasma levels of ziprasidone. Conversely, medications that inhibit CYP3A4 (eg, keto-conazole) can increase plasma levels of ziprasidone. Additional information concerning a variety of CYP3A4 inhibitors and inducers dosed chronically at therapeutic levels is needed to understand the full extent of these potentially serious drug interactions.

As always, I encourage you to submit to mmancano@pharmacytimes. com any drug interaction topics you would like to see discussed in future columns.

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. G. Henry, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to:

ghenry@mwc.com

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