Significations et usages de Ziprasidone

Ziprasidone

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
AHFS/Drugs.com	monograph
MedlinePlus	a699062
Licence data	US FDA:link
Pregnancy cat.	C (US)
Legal status	℞ Prescription only
Routes	Oral, IM
Pharmacokinetic data
Bioavailability	60% (oral) 100% (IM)
Metabolism	hepatic (aldehyde reductase)
Half-life	7 hours
Excretion	Urine and feces
Identifiers
CAS number	146939-27-7 Y
ATC code	N05AE04
PubChem	CID 60854
IUPHAR ligand	59
DrugBank	DB00246
ChemSpider	54841 Y
UNII	6UKA5VEJ6X Y
KEGG	D08687 Y
ChEBI	CHEBI:10119 Y
ChEMBL	CHEMBL708 Y
Chemical data
Formula	C21H21ClN4OS
Mol. mass	412.936 g/mol
SMILES O=C5Nc1c(cc(c(Cl)c1)CCN4CCN(c3nsc2ccccc23)CC4)C5
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
Y (what is this?)  (verify)

Ziprasidone (marketed as Geodon, Zeldox by Pfizer) was the fifth atypical antipsychotic to gain FDA approval (February 2001). In the United States, 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 and mixed states 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.

Geodon was one of five drugs which Pfizer pleaded guilty to misbranding "with the intent to defraud or mislead" in 2009 as a result of a qui tam lawsuit by Stefan P. Kruszewski. Pfizer agreed to pay $2.3 billion (£1.4 billion) in settlement, and entered a corporate integrity agreement. Pfizer was found to have illegally promoted four of its drugs for use in conditions that had not been approved by the FDA.^[1]

  Pharmacology

  Binding profile

Ziprasidone acts as an antagonist/inverse agonist (unless otherwise noted) of the following receptors and transporters:^[2][3][4][5]

  Correspondance 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.^[2][10] It also displays some inhibition of synaptic reuptake of serotonin and norepinephrine, though not dopamine.^[2][11]

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.^[12] 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.^[13] The relatively weak antagonistic actions of ziprasidone on the α₁-adrenergic and H₁ receptors likely in part explain some of its side effects, such as sedation and orthostatic hypotension. Unlike many other antipsychotics, ziprasidone has no significant affinity for the mACh receptors, and as such lacks any anticholinergic side effects.

  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 optimally achieved when administered with food. Without a meal preceding dose, the bioavailability of the drug is reduced by approximately 50%.^[14][15]

Ziprasidone is hepatically metabolized by aldehyde oxidase; minor metabolism occurs via cytochrome P450 3A4 (CYP3A4).^[16] Medications that induce (e.g. carbamazepine) or inhibit (e.g. ketoconazole) CYP3A4 have been shown to decrease and increase, respectively, blood levels of ziprasidone.^[17][18]

  Adverse effects

Ziprasidone received a black box warning due to increased mortality in elderly patients with dementia-related psychosis.^[14] 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.^[19]

Ziprasidone is known to cause activation into mania in some bipolar patients.^[20][21][22]

This medication can cause birth defects, according to animal studies, although this side effect has not been confirmed in humans.^[14]

Adverse events reported for ziprasidone include severe chest pains, impaired erectile function and stimulation, sedation, insomnia, orthostasis, life-threatening neuroleptic malignant syndrome, akathisia, and the development of permanent neurological disorder tardive dyskinesia. Rarely, temporary speech disorders may result.

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 may not be as bad as some of the other atypical antipsychotics (namely, olanzapine (Zyprexa)) at causing insulin resistance and weight gain.^{[23][24][25][26]} In fact, in a trial of long term therapy with ziprasidone, overweight patients (BMI > 27) actually had a mean weight loss overall.^[14] However, Ziprasidone 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.^{[citation needed]} According to the manufacturer insert , ziprasidone caused an average weight gain of 2.2 kg (4.8 lbs) (which is significantly lower than other atypicals–clozapine and olanzapine).

  Discontinuation

Ziprasidone should be discontinued gradually, with careful consideration from the prescribing doctor, to avoid withdrawal symptoms or relapse. Withdrawal may become even more difficult after failed attempts.^{[citation needed]}

The British National Formulary recommends a gradual withdrawal when discontinuing anti-psychotic treatment to avoid acute withdrawal syndrome or rapid relapse.^[27] Due to compensatory changes at dopamine, serotonin, adrenergic and histamine receptor sites in the central nervous system, withdrawal symptoms can occur during abrupt or over-rapid reduction in dosage.

However, despite increasing demand for safe and effective antipsychotic withdrawal protocols or dose-reduction schedules, no specific guidelines with proven safety and efficacy are currently available. Some have suggested using The Ashton Manual, originally developed for benzodiazapine withdrawal. Support groups such as The Icarus Project and other online forums provide resources and social support for those attempting to discontinue antipsychotics and other psychiatric medications.^[28] Withdrawal symptoms reported to occur after discontinuation of antipsychotics include nausea, emesis, lightheadedness, diaphoresis, dyskinesia, orthostasis, tachycardia, nervousness, dizziness, headache, excessive non-stop crying, and anxiety.^[29][30] Some have argued that additional somatic and psychiatric symptoms associated with dopaminergic super-sensitivity, including dyskinesia and acute psychosis, are common features of withdrawal in individuals treated with neuroleptics.^{[31][32][33][34]} This has led some to suggest that the withdrawal process might itself be schizo-mimetic, producing schizophrenia-like symptoms even in previously healthy patients, indicating a possible pharmacological origin of mental illness in a yet unknown percentage of patients currently and previously treated with antipsychotics. This question is unresolved, and remains a highly controversial issue among professionals in the medical and mental health communities, as well the public.^[35] Complicated and long-lasting rebound insomnia symptoms can also occur after withdrawing from antipsychotics.^[36]

  Overdose

Ziprasidone doses as large as 3,240 mg have been "survived without sequelae." The most common effects reported by Pfizer include extrapyramidal reactions, somnolence, tremor, and anxiety.

  References

  Further reading

• David Taylor (2006). Schizophrenia In Focus. Pharmaceutical Press. p. 123. ISBN 978-0-85369-607-0. http://books.google.com/books?id=CyEUUKDScOIC&pg=PA123. Retrieved 13 May 2012. 

  External links

• Geodon manufacturer's website
• Geodon Package Insert