Ziprasidone

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Ziprasidone
Ziprasidone.svg
Ziprasidone ball-and-stick model.png
Systematic (IUPAC) name
5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl}-6-chloro-1,3-dihydro-2H-indol-2-one
Clinical data
Trade names Geodon, Zeldox, Zipwell
AHFS/Drugs.com Monograph
MedlinePlus a699062
License data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration
Oral (capsules), IM
Legal status
Legal status
Pharmacokinetic data
Bioavailability 60% (oral)
100% (IM)
Metabolism Hepatic (aldehyde reductase)
Biological half-life 7 hours
Excretion Urine and feces
Identifiers
CAS Number 146939-27-7 YesY
ATC code N05AE04 (WHO)
PubChem CID 60854
IUPHAR/BPS 59
DrugBank DB00246 YesY
ChemSpider 54841 YesY
UNII 6UKA5VEJ6X YesY
KEGG D08687 YesY
ChEBI CHEBI:10119 YesY
ChEMBL CHEMBL708 YesY
Chemical data
Formula C21H21ClN4OS
Molar mass 412.936 g/mol
  (verify)

Ziprasidone (marketed as Geodon, Zeldox by Pfizer and Zipwell by Actavis) was the fifth atypical antipsychotic to gain approval (February 2001) in the United States. It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia, and acute mania and mixed states associated with bipolar disorder.[1] Its intramuscular injection form is approved for acute agitation in schizophrenic patients for whom treatment with just ziprasidone is appropriate. Ziprasidone is also used off-label for depression, bipolar maintenance, and PTSD.[2]

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.

Medical uses[edit]

Ziprazidone is approved by the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia, and acute mania and mixed states associated with bipolar disorder. Its intramuscular injection form is approved for acute agitation in schizophrenic patients for whom treatment with just ziprasidone is appropriate.[3]

Schizophrenia[edit]

Ziprasidone is effective in the treatment of schizophrenia, though evidence from the CATIE trials suggests it is less effective than olanzapine and of around equal effectiveness to quetiapine. Doses of around 120 mg daily and higher are usually required.[4]

Pharmacology[edit]

Binding profile[edit]

Ziprasidone acts as an antagonist/inverse agonist (unless otherwise noted) of the following receptors and transporters:[5][6][7][8][9]

Correspondence to clinical effects[edit]

Ziprasidone's affinities for most of the dopamine and serotonin receptors and the α1-adrenergic receptor are high and its affinity for the histamine H1 receptor is moderate.[5][14] It also displays some inhibition of synaptic reuptake of serotonin and norepinephrine, though not dopamine.[5][15]

Ziprasidone's efficacy in treating the positive symptoms of schizophrenia is believed to be mediated primarily via antagonism of the dopamine receptors, specifically D2. Blockade of the 5-HT2A receptor may also play a role in its effectiveness against positive symptoms, though the significance of this property in antipsychotic drugs is still debated among researchers.[16] Blockade of 5-HT2A and 5-HT2C and activation of 5-HT1A as well as inhibition of the reuptake of serotonin and norepinephrine may all contribute to its ability to alleviate negative symptoms.[17] The relatively weak antagonistic actions of ziprasidone on the α1-adrenergic receptor likely in part explains some of its side effects, such as orthostatic hypotension. Unlike many other antipsychotics, ziprasidone has no significant affinity for the mACh receptors, and as such lacks any anticholinergic side effects. Like most other antipsychotics, ziprasidone is sedating due primarily to serotonin and dopamine blockade.[18][19]

Pharmacokinetics[edit]

The systemic bioavailability of ziprasidone is 100% when administered intramuscularly and 60% when 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.[20] Steady state plasma concentrations are achieved within one to three days. Exposure increases in a dose-related manner and following three days of intramuscular dosing, little accumulation is observed.

Ziprasidone absorption is optimally achieved when administered with food. Without a meal preceding dose, the bioavailability of the drug is reduced by approximately 50%.[21][22]

Ziprasidone is hepatically metabolized by aldehyde oxidase; minor metabolism occurs via cytochrome P450 3A4 (CYP3A4).[23] Medications that induce (e.g. carbamazepine) or inhibit (e.g. ketoconazole) CYP3A4 have been shown to decrease and increase, respectively, blood levels of ziprasidone.[24][25]

Adverse effects[edit]

Ziprasidone received a black box warning due to increased mortality in elderly patients with dementia-related psychosis.[21]

Sources for the following lists of adverse effects[26][27][28][29][30]

Note: The percentages given are incidences of respective adverse effects.

Very common adverse effects (>10%)
Common adverse effects (1-10%)
- Tremor
- Dystonia
- Akathisia
- Parkinsonism
- Muscle rigidity
Uncommon (0.1-1%) adverse effects
Rare (<0.1%) side effects


Ziprasidone is known to cause activation into mania in some bipolar patients.[33][34][35]

This medication can cause birth defects, according to animal studies, although this side effect has not been confirmed in humans.[21]

Recently, the FDA required the manufacturers of some atypical antipsychotics to include a warning about the risk of hyperglycemia and Type II diabetes with atypical antipsychotics. Some evidence suggests that ziprasidone does not cause insulin resistance to the degree of other atypical antipsychotics, such as Zyprexa. Weight gain is also less of a concern with Ziprasidone compared to other atypical antipsychotics)[36][37][38][39] In fact, in a trial of long term therapy with ziprasidone, overweight patients (BMI > 27) actually had a mean weight loss overall;[21] According to the manufacturer insert, ziprasidone caused an average weight gain of 2.2 kg (4.8 lbs), which is significantly lower than other atypical antipsychotics, making this medication better for patients that are concerned about their weight. In December 2014, the FDA warned that ziprasidone could cause a potentially fatal skin reaction, Drug Reaction with Eosinophilia and Systemic Symptoms, although this was believed to occur only rarely.[40]

Discontinuation[edit]

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[41]

Lawsuit[edit]

In September 2009, the U.S. Justice Department announced that Pfizer had been ordered to pay an historic fine of $2.3 billion as a penalty for fraudulent marketing of several drugs, including Geodon.[42] Pfizer had illegally promoted Geodon and caused false claims to be submitted to government health care programs for uses that were not medically accepted indications. The civil settlement also resolves allegations that Pfizer paid kickbacks to health care providers to induce them to prescribe Geodon, as well as other, drugs. This was the largest civil fraud settlement in history against a pharmaceutical company.

References[edit]

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  32. ^ http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3619b1a.pdf)
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  41. ^ Group, BMJ, ed. (March 2009). "4.2.1". British National Formulary (57 ed.). United Kingdom: Royal Pharmaceutical Society of Great Britain. p. 192. ISSN 0260-535X. Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse. 
  42. ^ https://www.justice.gov/opa/pr/justice-department-announces-largest-health-care-fraud-settlement-its-history

Further reading[edit]

External links[edit]