Ziprasidone

Ziprasidone (marketed as Geodon, Zeldox) was the fifth atypical antipsychotic to gain FDA approval (February 2001). Ziprasidone is Food and Drug Administration (FDA) approved for the treatment of schizophrenia, and the intramuscular injection form of ziprasidone is approved for acute agitation in schizophrenic patients. Ziprasidone has also received approval for acute treatment of mania associated with bipolar disorder. The brand name Geodon has been suggested to bring to mind the phrase 'down (don) to earth (geo)' referring to the goals of the medication.

The oral form of ziprasidone is the hydrochloride salt, ziprasidone hydrochloride. The intramuscular form, on the other hand, is the mesylate salt, ziprasidone mesylate trihydrate, and is provided as a lyophilized powder.

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Pharmacology

Ziprasidone has a high affinity for dopamine, serotonin, and alpha-adrenergic receptors and a medium affinity for histaminic receptors. Ziprasidone 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 has been 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-HT_2A antagonism is debated among researchers. Ziprasidone has perhaps the most selective affinity for 5-HT2A receptors relative to D2 and 5-HT2C receptors of any neuroleptic, even greater than that of risperidone [1]. 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 ranges from two to five hours. Exposure increases in a dose-related manner and following three days of intramuscular dosing, little accumulation is observed.

Ziprasidone absorption is not optimally achieved when administered without food. Without a meal preceding dose, the bioavailability of the drug is approximately 50-60%. At lower doses Ziprasidone may have a higher affinity for the 5-HT and Norepinephrine transmitter systems, which might be a factor in the activation into mania that is possible with the drug in patients with bipolar disorder.

Metabolism

Ziprasidone is hepatically metabolized by aldehyde oxidase. 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 inducers or inhibitors of aldehyde reductase.

Adverse events

Ziprasidone received a (black box) due to the fact that Geodon slightly increases the QTc interval (see QT interval) in some patients and increases the risk of a potentially lethal 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. http://www.fda.gov/medWatch/safety/2002/geodon.htm

This medication can cause birth defects, according to animal studies, although this side effect has not been confirmed in humans.^[1]

Adverse events reported for ziprasidone include sedation, insomnia, orthostasis, life-threatening neuroleptic malignant syndrome, akathisia, and the development of permanent neurological disorder tardive dyskinesia. Rarely, temporary speech disorders may result. See the FDA label for more information.

Recently, the FDA required the manufacturers of some atypical antipsychotics 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 (namely, olanzapine (Zyprexa)) 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 ziprasidone was really reflective of patients who had gained weight on other antipsychotics who were now trending back toward their baseline. According to the manufacturer insert, ziprasidone caused an average weight gain of 2.2kg (4.8lbs) (which is significantly lower than other atypicals - quetiapine and aripiprazole)and olanzapine).

References