Ziprasidone

Ziprasidone

Clinical data
Trade names	Geodon, Zeldox, Zipwell
AHFS/Drugs.com	Monograph
MedlinePlus	a699062
License data	US FDA: Ziprasidone
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Routes of administration	Oral (capsules), IM
ATC code	N05AE04 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	60% (oral)[1] 100% (IM)
Metabolism	Hepatic (aldehyde reductase)
Biological half-life	7 to 10 hours[2]
Excretion	Urine and feces
Identifiers
IUPAC name 5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl}-6-chloro-1,3-dihydro-2H-indol-2-one
CAS Number	146939-27-7 Y
PubChem CID	60854
IUPHAR/BPS	59
DrugBank	DB00246 Y
ChemSpider	54841 Y
UNII	6UKA5VEJ6X
KEGG	D08687 Y
ChEBI	CHEBI:10119 Y
ChEMBL	CHEMBL708 Y
ECHA InfoCard	100.106.954
Chemical and physical data
Formula	C21H21ClN4OS
Molar mass	412.936 g/mol
3D model (JSmol)	Interactive image
SMILES O=C1Cc2c(N1)cc(Cl)c(c2)CCN3CCN(CC3)c4nsc5ccccc45
InChI InChI=1S/C21H21ClN4OS/c22-17-13-18-15(12-20(27)23-18)11-14(17)5-6-25-7-9-26(10-8-25)21-16-3-1-2-4-19(16)28-24-21/h1-4,11,13H,5-10,12H2,(H,23,27) Y Key:MVWVFYHBGMAFLY-UHFFFAOYSA-N Y
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Ziprasidone (marketed as Geodon among others) is a medication of the atypical antipsychotic type. It is used for the treatment of schizophrenia as well as acute mania and mixed states associated with bipolar disorder.^[3] Its intramuscular injection form is approved for acute agitation in people with schizophrenia. Ziprasidone is also used off-label for depression, bipolar maintenance, and posttraumatic stress disorder (PTSD).^[4]

The by mouth 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. Ziprasidone gained approval in the United States on February 5, 2001.^[5][6]

Medical uses

Ziprazidone is approved by the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia as well as 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.^[7]

In a 2013 study in a comparison of 15 antipsychotic drugs in effectivity in treating schizophrenic symptoms, ziprasidone demonstrated low-medium effectivity. Less effective than clozapine, slightly less effective than haloperidol, quetiapine, and aripiprazole, approximately as effective as chlorpromazine, and slightly more effective than lurasidone.^[8] Ziprasidone is effective in the treatment of schizophrenia, though evidence from the CATIE trials suggests it is less effective than olanzapine, and equally as effective compared to quetiapine. There are higher discontinuation rates for lower doses of Ziprasidone, which are also less effective than higher doses.^[9]

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.^[10]

Adverse effects

Ziprasidone received a black box warning due to increased mortality in elderly patients with dementia-related psychosis.^[11]

Sleepiness and headache are very common adverse effects (>10%).^[12][13]

Common adverse effects (1–10%), include producing too much saliva or having dry mouth, runny nose, respiratory disorders or coughing, nausea and vomiting, stomach aches, constipation or diarrhea, loss of appetite, weight gain (but the smallest risk for weight gain compared to other antipsychotics^[14]), rashes, fast heart beats, blood pressure falling when standing up quickly, muscle pain, weakness, twitches, dizziness, and anxiety.^[12][13] Extrapyramidal symptoms are also common and include tremor, dystonia (sustained or repetitive muscle contractions), akathisia (the feeling of a need to be in motion), parkinsonism, and muscle rigidity; in a 2013 meta-analysis of 15 antipsychotic drugs, ziprasidone ranked 8th for such side effects.^[15]

Ziprasidone is known to cause activation into mania in some bipolar patients.^[16][17][18]

This medication can cause birth defects, according to animal studies, although this side effect has not been confirmed in humans.^[11]

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.^{[19][20][21][22]} In fact, in a trial of long term therapy with ziprasidone, overweight patients (BMI > 27) actually had a mean weight loss overall.^[11] 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.^[23]

Pharmacology

Ziprasidone is a full antagonist of D2 receptors and of 5-HT_2A receptors and is a partial agonist of 5-HT_1A receptors and a partial antagonist of 5-HT_2C receptors and 5-HT_1D receptors.^[1]

Ziprasidone acts as an antagonist/inverse agonist (unless otherwise noted) of the following receptors and transporters:^{[24][25][26][27][28]}

• 5-HT_1A receptor (K_i = 12 nM) (partial agonist)^[29]
• 5-HT_1B receptor (K_i = 4.0 nM) (partial agonist)^[30]
• 5-HT_1D receptor (K_i = 2.3 nM)
• 5-HT_2A receptor (K_i = 0.6 nM)
• 5-HT_2C receptor (K_i = 13 nM)
• 5-HT₆ receptor (K_i = 61 nM)
• 5-HT₇ receptor (K_i = 6 nM)
• D₁ receptor (K_i = 30 nM)
• D₂ receptor (K_i = 6.8 nM)
• D₃ receptor (K_i = 7.2 nM)
• α_1A-adrenergic receptor (K_i = 18 nM)
• α_2A-adrenergic receptor (K_i = 160 nM)
• H₁ receptor (K_i = 63 nM)
• 5-HT transporter (K_i = 53 nM) (inhibitor)^[31]
• NE transporter (K_i = 48 nM) (inhibitor)^[31]

Correspondence to clinical effects

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.^[24][32] It also displays some inhibition of synaptic reuptake of serotonin and norepinephrine, though not dopamine.^[24][33]

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-HT_2A 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.^[34] Blockade of 5-HT_2A and 5-HT_2C and activation of 5-HT_1A as well as inhibition of the reuptake of serotonin and norepinephrine may all contribute to its ability to alleviate negative symptoms.^[35] 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.^[36][37]

Pharmacokinetics

The systemic bioavailability of ziprasidone is 100% when administered intramuscularly and 60% when administered orally without food.^[1]

After a single dose intramuscular administration, the peak serum concentration typically occurs at about 60 minutes after the dose is administered, or earlier.^[38] 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%.^[11][39]

Ziprasidone is hepatically metabolized by aldehyde oxidase; minor metabolism occurs via cytochrome P450 3A4 (CYP3A4).^[40] Medications that induce (e.g. carbamazepine) or inhibit (e.g. ketoconazole) CYP3A4 have been shown to decrease and increase, respectively, blood levels of ziprasidone.^[41][42]

Its biological half-life time is 10 hours at doses of 80-120 milligrams.^[2]

Society and culture

Lawsuit

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.^[43] 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.

History

Ziprasidone is a structural analogue of Risperidone.^[44] Ziprasidone is similar chemically to Risperidone.^[45] In 1987,^[46] Ziprasidone was first synthesized on the Pfizer central research campus in Groton, Connecticut.^[47]

Phase I trials started in 1995.^[48] In 1998 ziprasidone was approved in Sweden.^[49][50] After the FDA raised concerns about long QT syndrome, more clinical trials were conducted and submitted to the FDA, which approved the drug on February 5, 2001.^[48][51][52]

References

Further reading

• David Taylor (2006). Schizophrenia in Focus. Pharmaceutical Press. p. 123. ISBN 978-0-85369-607-0. Retrieved May 13, 2012.