Ziprasidone
Clinical data | |
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Trade names | Geodon, Zeldox, Zipwell, other |
AHFS/Drugs.com | Monograph |
MedlinePlus | a699062 |
License data |
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Pregnancy category |
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Routes of administration | By mouth, intramuscular injection (IM) |
Drug class | Atypical antipsychotic |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | 60% (oral)[3]
100% (IM) |
aldehyde reductase) | |
Elimination half-life | 7 to 10 hours[4] |
Excretion | Urine and feces |
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Ziprasidone, sold under the brand name Geodon among others, is an
Common side effects include
Ziprasidone was approved for medical use in the United States in 2001.
Medical uses
Ziprasidone is approved by the U.S.
In a 2013 study in a comparison of 15 antipsychotic drugs in effectiveness in treating schizophrenic symptoms, ziprasidone demonstrated mild-standard effectiveness. Ziprasidone was 15% more effective than lurasidone and iloperidone, approximately as effective as chlorpromazine and asenapine, and 9–13% less effective than haloperidol, quetiapine, and aripiprazole.[12] 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.[13]
Adverse effects
Ziprasidone (and all other second generation antipsychotics (SGAs)) received a
Sleepiness and headache are very common adverse effects (>10%).[6][7]
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[8]), rashes, fast heart beats, blood pressure falling when standing up quickly, muscle pain, weakness, twitches, dizziness, and anxiety.[6][7] 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 trigger 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.[14]
Recently, the FDA required the manufacturers of some atypical antipsychotics to include a warning about the risk of
Discontinuation
The
There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[26] It may also result in reoccurrence of the condition that is being treated.[27] Rarely tardive dyskinesia can occur when the medication is stopped.[25]
Pharmacology
Pharmacodynamics
Site | Ki (nM) | Action | Ref | |
---|---|---|---|---|
SERT | 112 | Blocker | [28] | |
NET | 44 | Blocker | [28] | |
DAT | >10,000 | ND | [28] | |
5-HT1A | 2.5–76 | Partial agonist | [29][30][31] | |
5-HT1B | 0.99–4.0 | Partial agonist | [30][28] | |
5-HT1D | 5.1–9.0 | Partial agonist | [30][28] | |
5-HT1E | 360–1,279 | ND | [30][28] | |
5-HT2A | 0.08–1.4 | Antagonist | [32][29][30] | |
5-HT2B | 27.2 | Antagonist | [28] | |
5-HT2C | 0.72–13 | Antagonist | [29] | |
5-HT3 | >10,000 | ND | [28] | |
5-HT5A | 291 | ND | [28] | |
5-HT6 | 61–76 | Antagonist | [31][29] | |
5-HT7 | 6.0–9.3 | Antagonist | [28][31][29] | |
α1A | 18 | Antagonist | [28][31] | |
α1B | 9.0 | Antagonist | [28] | |
α2A | 160 | Antagonist | [28][30][31] | |
α2B | 48 | Antagonist | [28][30][31] | |
α2C | 59–77 | Antagonist | [28][30][31] | |
β1 | ≥2,570 | ND | [30][28] | |
β2 | >10,000 | ND | [30][28] | |
D1 |
30–130 | ND | [28][29] | |
D2 |
4.8 | Antagonist | [33][29][31] | |
D2L |
4.6 | Antagonist | [30][34] | |
D2S |
4.2 | Antagonist | [30] | |
D3 |
7.2 | Antagonist | [33][29][30] | |
D4 |
0.8–105 | Antagonist | [33][29][28] | |
D4.2 |
28–39 | Antagonist | [34] | |
D4.4 |
14.9 | Antagonist | [35] | |
D5 |
152 | ND | [28] | |
H1 | 15–130 | Antagonist | [30][29][28] | |
H2 | 3,500 | ND | [28] | |
H3 | >10,000 | ND | [28] | |
H4 | >10,000 | ND | [28] | |
M1 | ≥300 | ND | [36][28][29] | |
M2 | ≥3,000 | ND | [36][28] | |
M3 | ≥1,300 | ND | [36][31][28] | |
M4 | ≥1,600 | ND | [36][28] | |
M5 | ≥1,600 | ND | [36][28] | |
σ1 | 110 | ND | [30] | |
σ2 | ND | ND | ND | |
Opioid | >1,000 | ND | [30] | |
nACh | >10,000 | ND | [28] | |
NMDA (PCP) |
>10,000 | ND | [28] | |
VDCC |
>10,000 | ND | [28][30] | |
VGSC | 2,620 | ND | [30] | |
hERG |
169 | Blocker | [37] | |
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. All data are for human cloned proteins, except H3 (guinea pig), σ1 (guinea pig), opioid (rodent), NMDA/PCP (rat), VDCC, and VGSC.[28] |
Correspondence to clinical effects
Ziprasidone mostly
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.[43] 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.[44]; however, its effects on the 5-HT1A receptor may be limited as a study[45] found ziprasidone would likely "produce detectable occupancy [of 5-HT1A receptors] only at higher doses that would produce unacceptable levels of side effects in man, although lower doses are sufficient to produce pharmacological effects." 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.[46][47]
Pharmacokinetics
The systemic bioavailability of ziprasidone is 100% when administered intramuscularly and 60% when administered orally without food.[3]
After a single dose intramuscular administration, the peak serum concentration typically occurs at about 60 minutes after the dose is administered, or earlier.[48] 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.
The bioavailability of the drug is reduced by approximately 50% if a meal is not eaten before Ziprasidone ingestion.[14][49]
Ziprasidone is hepatically metabolized by aldehyde oxidase; minor metabolism occurs via cytochrome P450 3A4 (CYP3A4).[50] Medications that induce (e.g. carbamazepine) or inhibit (e.g. ketoconazole) CYP3A4 have been shown to decrease and increase, respectively, blood levels of ziprasidone.[51][52]
Its biological half-life time is 10 hours at doses of 80–120 milligrams.[4]
History
Ziprasidone is chemically similar to
Phase I trials started in 1995.[56] In 1998 ziprasidone was approved in Sweden.[57][58] 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.[56][59][60]
Society and culture
Lawsuit
In September 2009, the U.S. Justice Department announced that Pfizer had been ordered to pay a historic fine of $2.3 billion as a penalty for fraudulent marketing of several drugs, including Geodon.[61] Pfizer had illegally promoted Geodon and submitted false claims 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.[citation needed]
References
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- ^ a b c "Product Information: Zeldox (ziprasidone hydrochloride)". Australia Therapeutic Goods Administration. February 24, 2016.
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- ^ "The Top 300 of 2020". ClinCalc. Retrieved October 7, 2022.
- ^ "Ziprasidone - Drug Usage Statistics". ClinCalc. Retrieved October 7, 2022.
- ^ "Pfizer to pay $2.3 billion to resolve criminal and civil health care liability relating to fraudulent marketing and the payment of kickbacks". Stop Medicare Fraud, US Dept of Health & Human Svc, and of US Dept of Justice. Archived from the original on August 30, 2012. Retrieved July 4, 2012.
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Further reading
- Taylor D (2006). Schizophrenia in Focus. Pharmaceutical Press. p. 123. ISBN 978-0-85369-607-0. Retrieved May 13, 2012.