Ziprasidone 146939-27-7

Pharmacology

Ziprasidone has a high affinity for dopamine, serotonin, and alpha-adrenergic receptors and a moderate affinity for histamine receptors, where it is believed to act as an antagonist. 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-HT_2A receptors relative to D₂ and 5-HT_2C receptors of any neuroleptic. 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 reduced by approximately 50%. Ziprasidone is hepatically metabolized by aldehyde oxidase; minor metabolism occurs via cytochrome P450 3A4 (CYP3A4). Medications that induce (e. g. carbamazepine) or inhibit (e. g. ketoconazole) CYP3A4 have been shown to decrease and increase, respectively, blood levels of ziprasidone.

Adverse effects

Ziprasidone received a black box warning due to increased mortality in elderly patients with dementia-related psychosis. It also slightly increases the QTc interval in some patients and increases the risk of a potentially lethal type of heart arrhythmia 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. Ziprasidone is known to cause activation into mania in some bipolar patients. This medication can cause birth defects, according to animal studies, although this side effect has not been confirmed in humans. In fact, in a trial of long term therapy with ziprasidone, overweight patients (BMI > 27) actually had a mean weight loss overall. has supported the efficacy of this use.