Brands, Medical Use, Clinical Data
- Dopamine Antagonists
- Serotonin Antagonist
Brands / Synonyms
For the treatment of schizophrenia
Ziprasidone is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives and is indicated for the treatment of schizophrenia. Ziprasidone is a selective monoaminergic antagonist with high affinity for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), 1 and 2 adrenergic, and H1 histaminergic receptors. Ziprasidone acts as an antagonist at other receptors, but with lower potency. Antagonism at receptors other than dopamine and 5HT2 with similar receptor affinities may explain some of the other therapeutic and side effects of Ziprasidone. Ziprasidone's antagonism of muscarinic M1-5 receptors may explain its anticholinergic effects. Ziprasidone's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Ziprasidone's antagonism of adrenergic a1 receptors may explain the orthostatic hypotension observed with this drug. Ziprasidone functions as an antagonist at the Dopamine D2 , 5HT-2A , and 5HT-1D receptors, and as an agonist at the 5HT-1A receptor. Ziprasidone also inhibits synaptic reuptake of serotonin and norepinephrine.
Mechanism of Action
The mechanism of action of Ziprasidone, as with other drugs used to treat schizophrenia, is unknown. Ziprasidone exhibited high in vitro binding affinity for the dopamine D2 and D3, the serotonin 5HT2A, 5HT2C, 5HT1A, 5HT1D and alpha 1-adrenergic receptors, and moderate affinity for the histamine H1 receptor. However, it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptor antagonism.
Biotrnasformation / Drug Metabolism
Because of ziprasidoneís dose-related prolongation of the QT interval and the known association of fatal
arrhythmias with QT prolongation by some other drugs, ziprasidone is contraindicated in patients with a known history
of QT prolongation (including congenital long QT syndrome), with recent acute myocardial infarction, or with
uncompensated heart failure.
Pharmacokinetic/pharmacodynamic studies between ziprasidone and other drugs that prolong the QT interval have not
been performed. An additive effect of ziprasidone and other drugs that prolong the QT interval cannot be excluded.
Therefore, ziprasidone should not be given with dofetilide, sotalol, quinidine, other Class Ia and III
anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacin, gatifloxacin,
moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate,
probucol or tacrolimus. Ziprasidone is also contraindicated with drugs that have demonstrated QT prolongation as one
of their pharmacodynamic effects and have this effect described in the full prescribing information as a
contraindication or a boxed or bolded warning.
Ziprasidone is contraindicated in individuals with a known hypersensitivity to the product.
Drug-drug interactions can be pharmacodynamic (combined pharmacologic effects) or pharmacokinetic (alteration of
plasma levels). The risks of using ziprasidone in combination with other drugs have been evaluated as described
below. Based upon the pharmacodynamic and pharmacokinetic profile of ziprasidone, possible interactions could be
- Ziprasidone should not be used with any drug that prolongs the QT interval .
- Given the primary CNS effects of ziprasidone, caution should be used when it is taken in combination with other
centrally acting drugs.
- Because of its potential for inducing hypotension, ziprasidone may enhance the effects of certain
- Ziprasidone may antagonize the effects of levodopa and dopamine agonists.
The Effect of Other Drugs on Ziprasidone
Carbamazepine Carbamazepine is an inducer of CYP3A4; administration of 200 mg BID for 21 days resulted in a
decrease of approximately 35% in the AUC of ziprasidone. This effect may be greater when higher doses of
carbamazepine are administered.
Ketoconazole Ketoconazole, a potent inhibitor of CYP3A4, at a dose of 400 mg QD for 5 days, increased the
AUC and C max of ziprasidone by about 35-40%. Other inhibitors of CYP3A4 would be expected to have similar
Cimetidine Cimetidine at a dose of 800 mg QD for 2 days did not affect ziprasidone pharmacokinetics.
Antacid The coadministration of 30 mL of MAALOX with ziprasidone did not affect the pharmacokinetics of
In addition, population pharmacokinetic analysis of schizophrenic patients enrolled in controlled clinical trials
has not revealed evidence of any clinically significant pharmacokinetic interactions with benztropine, propranolol,
Effect of Ziprasidone on Other Drugs
In vitro studies revealed little potential for ziprasidone to interfere with the metabolism of drugs
cleared primarily by CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and little potential for drug interactions with
ziprasidone due to displacement.
Lithium Ziprasidone at a dose of 40 mg BID administered concomitantly with lithium at a dose of 450 mg BID
for 7 days did not affect the steady-state level or renal clearance of lithium.
Oral Contraceptives Ziprasidone at a dose of 20 mg BID did not affect the pharmacokinetics of concomitantly
administered oral contraceptives, ethinylestradiol (0.03 mg) and levonorgestrel (0.15 mg).
Dextromethorphan Consistent with in vitro results, a study in normal healthy volunteers showed that
ziprasidone did not alter the metabolism of dextromethorphan, a CYP2D6 model substrate, to its major metabolite,
dextrorphan. There was no statistically significant change in the urinary dextromethorphan/dextrorphan ratio.