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Ziprasidone - The Atypical Amongst Atypical Antipsychotics

Author: wikipedia, Posted on Tuesday, November 01 @ 05:58:39 IST by RxPG  

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Psychiatry

Ziprasidone was the fifth atypical antipsychotic to gain FDA approval. Ziprasidone is FDA approved for the treatment of schizophrenia, and the intramuscular injection form of Ziprasidone is approved for acute agitation in schizophrenic patients. "Unlabeled" uses include treatment of bipolar disorder.

Pharmacology

Ziprasidone has a high affinity for dopamine, serotonin, and alpha-adrenergic receptors and a medium affinity for histaminic receptors. Ziprasidone is somewhat unique among the "atypicals" in that it also displays some inhibition of synaptic reuptake of serotonin and norepinephrine, although the clinical significance of this is unknown. The mechanism of action of ziprasidone is unknown. However it is theorized that its antipsychotic activity is mediated primarily by antagonism at dopamine receptors, specifically D2. Serotonin antagonism may also play a role in the effectiveness of ziprasidone, but the significance of 5-HT2A antagonism is debated among researchers. Antagonism at histaminic and alpha adrenergic receptors likely explains some of the side effects of ziprasidone, such as sedation and orthostasis.

Pharmacokinetics

The systemic bioavailability of ziprasidone administered intramuscularly is 100%, or 60%, administered orally with food. After a single dose intramuscular administration, the peak serum concentration typically occurs at about 60 minutes after the dose is administered, or earlier. Steady state plasma concentrations are achieved within one to three days. The mean half-life (T 1/2) ranges from two to five hours. Exposure increases in a dose-related manner and following three days of intramuscular dosing, little accumulation is observed.

Metabolism

Ziprasidone is hepatically metabolized by aldehyde reductase. Minor metabolism occurs via cytochrome P450 3A4. Medication that induce (e.g carbamazepine) or inhibit (e.g. ketoconazole) CYP3A4 have been shown to decrease and increase, respectively, blood levels of ziprasidone. There are no known induces or inhibitors of aldehyde reductase.

Adverse Events

Ziprasidone may increase the QTc interval in some patients and may increase the risk of a type of heart arrythmia known as torsades de pointes. Ziprasidone should be used cautiously in patients taking other medications likely to interact with ziprasidone or increase the QTc interval.

Adverse events reported for ziprasidone include sedation, insomnia, orthostasis, akathisia and other permanent extrapyramidal side-effects such as tardive dyskinesia.

Recently, the FDA required the manufacturers of all atypical antipsychotics to include a warning about the risk of hyperglycemia and Type II diabetes with atypical antipsychotics. Some evidence suggests that ziprasidone may not be as bad as some of the other atypical antipsychotics at causing insulin resistance and weight gain. In fact, in a trial of long term therapy with ziprasidone, overweight patients (BMI>27) actually had a mean weight loss overall. Ziprasidone, though, is not a weight loss drug. The weight loss reflected in this study on ziprsidone was really reflective of patients who had gained weight on other antipsychotics who were now trending back toward their baseline.


Note: This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article Ziprasidone.



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