Close
4
pipeline-prospector-insert-v1
X

Overview

Client Email Product
CAS 146939-27-7
PharmaCompass
  • Chemistry
CAS 146939-27-7
Also known as: 146939-27-7, Geodon, Zeldox, Ziprasidone hydrochloride, Ziprazidone, Ziprasidone [inn:ban]
Molecular Formula
C21H21ClN4OS
Molecular Weight
412.936  g/mol
InChI Key
MVWVFYHBGMAFLY-UHFFFAOYSA-N
FDA UNII
6UKA5VEJ6X

Ziprasidone (marketed as Geodon, Zeldox) was the fifth atypical antipsychotic to gain FDA approval (February 2001). 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 associated with bipolar disorder. [Wikipedia]
Ziprasidone is an Atypical Antipsychotic.
1 2D Structure

CAS 146939-27-7

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
5-[2-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]ethyl]-6-chloro-1,3-dihydroindol-2-one
2.1.2 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)
2.1.3 InChI Key
MVWVFYHBGMAFLY-UHFFFAOYSA-N
2.1.4 Canonical SMILES
C1CN(CCN1CCC2=C(C=C3C(=C2)CC(=O)N3)Cl)C4=NSC5=CC=CC=C54
2.2 Other Identifiers
2.2.1 UNII
6UKA5VEJ6X
2.3 Synonyms
2.3.1 Depositor-Supplied Synonyms

1. 146939-27-7

2. Geodon

3. Zeldox

4. Ziprasidone Hydrochloride

5. Ziprazidone

6. Ziprasidone [inn:ban]

7. Ziprasidona

8. Ziprasidonum

9. Unii-6uka5vej6x

10. Cp 88059

11. Zipradon (tn)

12. Ziprasidone (inn)

13. Ziprasidone Mesylate Trihydrate

14. 6uka5vej6x

15. Chembl708

16. C21h21cln4os

17. Cp-88,059

18. Chebi:10119

19. Cp 88059-01

20. Cp-88,059-1

21. Cp-88,059-01

22. Geodon (tn)

23. Ziprasidone Mesilate

24. Ziprasidone Mesylate

25. Dsstox_cid_3753

26. 5-[2-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]ethyl]-6-chloro-1,3-dihydroindol-2-one

27. Dsstox_rid_77186

28. Dsstox_gsid_23753

29. 5-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)-6-chloroindolin-2-one

30. 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2h-indol-2-one

31. 5-{2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-yl]ethyl}-6-chloro-1,3-dihydro-2h-indol-2-one

32. 5-{2-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]ethyl}-6-chloro-1,3-dihydro-2h-indol-2-one

33. 2h-indol-2-one, 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-

34. 2h-indol-2-one, 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-

35. Cas-146939-27-7

36. Ncgc00186050-01

37. Cp-880591

38. Cp-88059-1

39. Cp-8805927

40. Cp-88059-27

41. Zaprasidone

42. Zipradon

43. Geodon Oral

44. Hsdb 7745

45. 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2h-indol-2-one

46. Zeldox (tn)

47. D0e0nj

48. D0r1jv

49. Gtpl59

50. C07568

51. Schembl28028

52. Mls000759435

53. Bidd:gt0042

54. Ac1l1u27

55. Dtxsid4023753

56. Ambap122883-93-6

57. Molport-003-850-885

58. Mvwvfyhbgmafly-uhfffaoysa-n

59. Zinc538550

60. Tox21_112194

61. Tox21_113525

62. 4169ah

63. Bdbm50048803

64. Cz0013

65. Akos015900383

66. Tox21_112194_1

67. Am90310

68. Api0004647

69. Cs-1071

70. Db00246

71. Tc-5280

72. Ncgc00263539-01

73. Ncgc00263539-03

74. Ac-23360

75. Aj-23401

76. An-16930

77. Bc643069

78. Cpd000466328

79. Hy-14542

80. Ls-83744

81. Sam001246607

82. Sc-22049

83. Smr000466328

84. Tl8000889

85. 138982-67-9 (hydrochloride Monohydrate)

86. Ft-0654208

87. Ft-0655916

88. Vu0286234-2

89. 4770-ep2272537a2

90. 4770-ep2272841a1

91. 4770-ep2275420a1

92. 4770-ep2280010a2

93. 4770-ep2298731a1

94. 4770-ep2298776a1

95. 4770-ep2301936a1

96. 4770-ep2308875a1

97. 4770-ep2316836a1

98. D08687

99. W-5149

100. Ab00639925-02

101. Ab00639925-04

102. Ab00639925_05

103. Ab00639925_06

104. 883z936

105. A808568

106. L000659

107. Cp 88059;cp-88059;cp88059

108. I14-0766

109. 122883-93-6,138982-67-9(clh.h2o),146939-27-7(freebase)

110. 5-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-6-chloro-1,3-dihydro-indol-2-one

111. 5-[2-[4-(1,2-benzothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydroindol-2-one

112. 5-[2-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]ethyl]-6-chloranyl-1,3-dihydroindol-2-one

113. 5-[2-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]ethyl]-6-chloro-indolin-2-one

114. 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-ethyl)-6-chloro-1,3-dihydro-2h-indol-2-one

115. 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2h-indole-2-one

116. 5-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-6-chloro-1,3-dihydro-indol-2-one (ziprasidone)

117. 5-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-6-chloro-1,3-dihydro-indol-2-one(norastemizole)

118. 5-{2-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]ethyl}-6-chloro-2,3-dihydro-1h-indol-2-one

119. 6-chloro-5-[2-[4-(7-thia-8-azabicyclo[4.3.0]nona-1,3,5,8-tetraen-9-yl)piperazin-1-yl]ethyl]-1,3-dihydroindol-2-one

120. Ziprasidone Solution, 1.0 Mg/ml In 1,2-dimethoxyethane, Ampule Of 1 Ml, Certified Reference Material

2.4 Create Date
2005-06-24
3 Chemical and Physical Properties
Molecular Weight 412.936 g/mol
Molecular Formula C21H21ClN4OS
Hydrogen Bond Donor Count1
Hydrogen Bond Acceptor Count5
Rotatable Bond Count4
Exact Mass412.112 g/mol
Monoisotopic Mass412.112 g/mol
Topological Polar Surface Area76.7 A^2
Heavy Atom Count28
Formal Charge0
Complexity573
Isotope Atom Count0
Defined Atom Stereocenter Count0
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Drug Information
1 of 3  
Drug NameGEODON
Active IngredientZIPRASIDONE MESYLATE
CompanyPFIZER (Application Number: N020919)

2 of 3  
Drug NameGEODON
Active IngredientZIPRASIDONE HYDROCHLORIDE
CompanyPFIZER (Application Number: N020825. Patents: 6150366, 6245766)

3 of 3  
Drug NameZIPRASIDONE HYDROCHLORIDE
Active IngredientZIPRASIDONE HYDROCHLORIDE
CompanyAPOTEX INC (Application Number: A077561); AUROBINDO PHARMA LTD (Application Number: A204117); DR REDDYS LABS INC (Application Number: A077565); LUPIN PHARMS (Application Number: A077560); MACLEODS PHARMS LTD (Application Number: A204375); MYLAN PHARMS INC (Application Number: A202395); SANDOZ INC (Application Number: A077562); WOCKHARDT LTD (Application Number: A090348); ZYDUS PHARMS USA INC (Application Number: A208988)

4.2 Therapeutic Uses

Antipsychotic Agents; Dopamine Antagonists; Serotonin Antagonists

National Library of Medicine's Medical Subject Headings. Ziprasidone. Online file (MeSH, 2015). Available from, as of Septmeber 2, 2015: http://www.nlm.nih.gov/mesh/MBrowser.html


Ziprasidone is indicated for the treatment of schizophrenia. The efficacy of oral ziprasidone was established in four short-term (4- and 6-week) controlled trials of adult schizophrenic inpatients and in one maintenance trial of stable adult schizophrenic inpatients. /Included in US product label/

NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of March 30, 2015: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a


Ziprasidone is indicated as monotherapy for the acute treatment of manic or mixed episodes associated with bipolar I disorder. Efficacy was established in two 3-week monotherapy studies in adult patients /Included in US product label/

NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of March 30, 2015: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a


Ziprasidone is indicated as an adjunct to lithium or valproate for the maintenance treatment of bipolar I disorder. Efficacy was established in a maintenance trial in adult patients. The efficacy of ziprasidone as monotherapy for the maintenance treatment of bipolar I disorder has not been systematically evaluated in controlled clinical trials /Included in US product label/

NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of March 30, 2015: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a


4.3 Drug Warning

/BOXED WARNING/ WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Ziprasidone is not approved for the treatment of patients with Dementia-Related Psychosis.

NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of March 30, 2015: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a


Contraindications /include/ known history of QT prolongation (including congenital long QT syndrome), recent acute myocardial infarction, or uncompensated heart failure. Concomitant therapy with other drugs that prolong the QT interval. Known hypersensitivity to ziprasidone.

American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2496


Geriatric patients with dementia-related psychosis treated with atypical antipsychotic drugs appear to be at an increased risk of death compared with that among patients receiving placebo. Analyses of seventeen placebo-controlled trials (average duration of 10 weeks) revealed an approximate 1.6 - to 1.7-fold increase in mortality among geriatric patients receiving atypical antipsychotic drugs (ie, aripiprazole, olanzapine, quetiapine, risperidone) compared with that in patients receiving placebo. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. The manufacturer states that ziprasidone is not approved for the treatment of patients with dementia-related psychosis.

American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2496


Prolongation of the QT interval can result in an occurrence of ventricular arrhythmias (eg, torsades de pointes) and/or sudden death. In one study, oral ziprasidone prolonged the QT interval on ECG by a mean of 9-14 msec more than that observed in patients receiving risperidone, olanzapine, quetiapine, or haloperidol, but approximately 14 msec less than that observed in patients receiving thioridazine. ... Patients at particular risk of torsades de pointes and/or sudden death include those with bradycardia, hypokalemia, or hypomagnesemia, those receiving concomitant therapy with other drugs that prolong the QTC interval, and those with congenital prolongation of QTC interval. The manufacturer states that ziprasidone should be avoided in patients with congenital prolongation of the QT interval or a history of cardiac arrhythmias and in those receiving concomitant therapy with other drugs that prolong the QTC interval.

American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2496


Baseline serum potassium and magnesium concentrations should be determined in patients at risk for substantial electrolyte (ie, potassium, magnesium) disturbances, particularly those receiving concomitant diuretic therapy, and hypokalemia or hypomagnesemia should be corrected prior to initiating ziprasidone. Clinical and ECG monitoring of cardiac function, including appropriate ambulatory ECG monitoring (eg, Holter monitoring), is recommended during ziprasidone therapy in patients with symptoms that could indicate torsades de pointes (eg, dizziness, palpitations, syncope). Ziprasidone therapy should be discontinued if the QTC interval exceeds 500 msec.

American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2496


Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported in patients receiving antipsychotic agents, including rare cases associated with ziprasidone therapy.

American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2496


Because use of antipsychotic agents, including ziprasidone, may be associated with tardive dyskinesia (a syndrome of potentially irreversible, involuntary, dyskinetic movements), ziprasidone should be prescribed in a manner that is most likely to minimize the occurrence of this syndrome. Chronic antipsychotic treatment generally should be reserved for patients with a chronic illness that is known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the lowest dosage and the shortest duration of treatment producing a satisfactory clinical response should be sought, and the need for continued treatment should be reassessed periodically. The American Psychiatric Association (APA) currently recommends that patients receiving atypical antipsychotic agents be assessed clinically for abnormal involuntary movements every 12 months and that patients considered to be at increased risk for tardive dyskinesia be assessed every 6 months. If signs and symptoms of tardive dyskinesia appear in a ziprasidone-treated patient, ziprasidone discontinuance should be considered; however, some patients may require continued treatment with the drug despite presence of the syndrome.

American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2496


Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients receiving atypical antipsychotic agents. While confounding factors such as an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population make it difficult to establish with certainty the relationship between use of agents in this drug class and glucose abnormalities, epidemiologic studies (which did not include ziprasidone) suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotic agents included in the studies (e.g., clozapine, olanzapine, quetiapine, risperidone); it remains to be determined whether ziprasidone also is associated with this increased risk. Although there have been few reports of hyperglycemia or diabetes in patients receiving ziprasidone, it is not known whether the paucity of such reports is due to relatively limited experience with the drug. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics currently are not available. While some evidence suggests that the risk for diabetes may be greater with some atypical antipsychotics (e.g., clozapine, olanzapine) than with others (e.g., aripiprazole, asenapine, iloperidone, lurasidone, quetiapine, risperidone, ziprasidone) in the class, available data are conflicting and insufficient to provide reliable estimates of relative risk associated with use of the various atypical antipsychotics. The manufacturers of atypical antipsychotic agents state that patients with preexisting diabetes mellitus in whom therapy with an atypical antipsychotic is initiated should be closely monitored for worsening of glucose control; those with risk factors for diabetes (e.g., obesity, family history of diabetes) should undergo fasting blood glucose testing upon therapy initiation and periodically throughout treatment. Any patient who develops manifestations of hyperglycemia (including polydipsia, polyuria, polyphagia, and weakness) during treatment with an atypical antipsychotic should undergo fasting blood glucose testing. In some cases, patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the suspect drug; in other cases, hyperglycemia resolved with discontinuance of the antipsychotic.

American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2497


Rash and/or urticaria, possibly related to dose and/or duration of therapy, occurred in about 5% of patients in clinical studies and have necessitated discontinuance of the drug in about 17% of these patients. Several ziprasidone-treated patients with rash had signs and symptoms of associated systemic illness (e.g., elevated leukocyte count). Adjunctive treatment with antihistamines or corticosteroids and/or drug discontinuance may be required. Ziprasidone should be discontinued if an alternative etiology of rash cannot be identified.

American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2496


Orthostatic hypotension and associated adverse effects (e.g., dizziness, tachycardia, syncope) may occur during ziprasidone therapy in some patients, particularly during the initial dosage titration period, because of the drug's alpha1-adrenergic blocking activity. Syncope was reported in 0.6% of ziprasidone-treated patients in clinical studies. Ziprasidone should be used with particular caution in patients with known cardiovascular disease (e.g., history of myocardial infarction or ischemic heart disease, heart failure, conduction abnormalities), cerebrovascular disease, and/or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy).

American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2497


Seizures occurred in 0.4% of patients receiving ziprasidone in clinical trials. Ziprasidone should be used with caution in patients with a history of seizures or with conditions that may lower the seizure threshold (e.g., dementia of the Alzheimer's type); conditions that lower the seizure threshold may be more prevalent in patients 65 years of age or older.

American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2497


Esophageal dysmotility and aspiration have been associated with the use of antipsychotic agents.1 Aspiration pneumonia is a common cause of morbidity and mortality in geriatric patients, particularly in those with advanced Alzheimer's dementia. Ziprasidone should be used with caution in patients at risk for aspiration pneumonia (e.g., geriatric patients, those with advanced Alzheimer's dementia).

American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2497


Suicide is an attendant risk with psychotic illness or bipolar disorder; high-risk patients should be closely supervised. Ziprasidone should be prescribed in the smallest quantity consistent with good patient management to reduce the risk of overdosage.

American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2497


Prolactin concentrations exceeding 22 ng/mL were reported in about 20% of patients receiving ziprasidone in phase II or III clinical studies compared with about 4, 46, or 89% of those receiving placebo, haloperidol, or risperidone, respectively.

American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2497


Median weight gain of 0.5 kg occurred in patients receiving ziprasidone compared with no median weight change in those receiving placebo. In clinical studies, ziprasidone reportedly caused less weight gain than clozapine, olanzapine, quetiapine, or risperidone.

American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2497


Somnolence was a commonly reported adverse event in patients treated with ziprasidone. In the 4- and 6-week placebo-controlled trials, somnolence was reported in 14% of patients on ziprasidone compared to 7% of placebo patients. Somnolence led to discontinuation in 0.3% of patients in short-term clinical trials. Since ziprasidone has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about performing activities requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating hazardous machinery until they are reasonably certain that ziprasidone therapy does not affect them adversely.

NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of March 30, 2015: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a


One case of priapism was reported in the premarketing database. While the relationship of the event to ziprasidone use has not been established, other drugs with alpha-adrenergic blocking effects have been reported to induce priapism, and it is possible that ziprasidone may share this capacity. Severe priapism may require surgical intervention.

NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of March 30, 2015: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a


Although not reported with ziprasidone in premarketing trials, disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing ziprasidone for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, eg, exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of March 30, 2015: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a


Pharmacokinetics of oral ziprasidone hydrochloride (20 mg twice daily for 8 days) were similar between individuals with varying degrees of renal impairment and those with normal renal function, suggesting that dosage adjustment based on the degree of renal impairment is generally not necessary. Ziprasidone is not removed by hemodialysis. Ziprasidone for IM injection has not been systematically evaluated in patients with renal impairment. However, commercially available ziprasidone for injection, when reconstituted, contains methanesulfonic acid solubilized to sulfobutylether beta-cyclodextrin sodium, an excipient that is cleared by renal filtration. Therefore, IM ziprasidone should be used with caution in patients with renal impairment.

American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2498


Adverse effects occurring in 5% or more of patients with schizophrenia receiving oral ziprasidone and at a frequency at least twice the that reported with placebo include somnolence and respiratory tract infection.

American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2498


Adverse effects occurring in 5% or more of patients with schizophrenia receiving IM ziprasidone 10 or 20 mg and at a frequency at least twice that reported among those receiving IM ziprasidone 2 mg include somnolence, headache, and nausea.

American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2498


Adverse effects occurring in 5% or more of patients with bipolar mania receiving oral ziprasidone and at a frequency at least twice that reported with placebo include somnolence, extrapyramidal symptoms, dizziness, akathisia, abnormal vision, asthenia, and vomiting.

American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2498


Adverse events /reported in post-marketing surveillance/ include rare occurrences of the following (no causal relationship with ziprasidone has been established): Cardiac Disorders: Tachycardia, torsade de pointes (in the presence of multiple confounding factors); Digestive System Disorders: Swollen tongue; Nervous System Disorders: Facial droop, neuroleptic malignant syndrome, serotonin syndrome (alone or in combination with serotonergic medicinal products), tardive dyskinesia; Psychiatric Disorders: Insomnia, mania/hypomania; Reproductive System and Breast Disorders: Galactorrhea, priapism; Skin and subcutaneous Tissue Disorders: Allergic reaction (such as allergic dermatitis, angioedema, orofacial edema, urticaria), rash; Urogenital System Disorders: Enuresis, urinary incontinence; Vascular Disorders: Postural hypotension, syncope.

NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of March 30, 2015: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a


As ziprasidone is cleared substantially by the liver, the presence of hepatic impairment would be expected to increase the AUC of ziprasidone; a multiple-dose study at 20 mg BID for 5 days in subjects (n=13) with clinically significant (Childs-Pugh Class A and B) cirrhosis revealed an increase in AUC 0-12 of 13% and 34% in Childs-Pugh Class A and B, respectively, compared to a matched control group (n=14). A half-life of 7.1 hours was observed in subjects with cirrhosis compared to 4.8 hours in the control group.

NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of March 30, 2015: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a


Not known whether ziprasidone is distributed into milk; use in nursing women is not recommended.

American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2496


FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./

NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of March 30, 2015: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a


According to premarketing studies, at least 1% of ziprasidone-treated patients exhibited hypertension; however, this figure is not necessarily attributable to the drug. A PubMed/MEDLINE search yielded no articles describing hypertension as a possible adverse event associated with oral ziprasidone therapy. We describe a 53-year-old African-American woman with hypertension and schizophrenia whose blood pressure increased during ziprasidone therapy. She experienced no similar blood pressure increases during therapy with four other atypical antipsychotics. Her mean systolic blood pressure during ziprasidone treatment (158 mm Hg) was significantly higher than before (141 mm Hg) and after (135 mm Hg) treatment. Also, her mean diastolic blood pressure during ziprasidone treatment (88 mm Hg) was significantly higher than after treatment (79 mm Hg). Linear regression analysis demonstrated that the patient's systolic blood pressure increased significantly with ziprasidone dose (regression coefficient [B] = 0.22 mm Hg x day/mg, 95% confidence interval 0.10-0.34, p=0.001). Thus, after adjusting for the effect of antihypertensive doses, an increase of 40 mg/day in ziprasidone yielded an increase of 8.8 mm Hg in systolic blood pressure. For unknown (perhaps genetic) reasons, this patient may have been particularly sensitive to ziprasidone. Clinicians prescribing ziprasidone in patients with hypertension should be aware that their hypertension could worsen with the addition of ziprasidone. If this occurs, replacement of ziprasidone with a different antipsychotic should be considered.

Villanueva N et al; Pharmacotherapy 26 (9): 1352-7 (2006)


... Psychiatric patients treated with atypical antipsychotic medications should be closely monitored for rhabdomyolysis during correction of hyponatremia, thus permitting prompt therapy to limit its complications.

Zaidi AN; Ann Pharmacother 39 (10): 1726-31 (2005)


4.4 Drug Indication

For the treatment of schizophrenia and related psychotic disorders.


FDA Label


5 Pharmacology and Biochemistry
5.1 Pharmacology

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.


Ziprasidone is a benzothiazolylpiperazine derivative and an atypical antipsychotic agent with an antischizophrenic property. Ziprasidone functions as an antagonist at the dopamine D2 and serotonin 5-HT2A and 5-HT1D receptors, and as an agonist at the 5-HT1A receptor. Ziprasidone also inhibits the synaptic reuptake of serotonin and norepinephrine. The mechanism of action by which ziprasidone exerts its antischizophrenic effect is unknown but is potentially mediated through a combination of dopamine D2 and serotonin 5-HT2 antagonism. This agent also has antagonistic activity against histamine H1 and alpha-1-adrenergic receptors.


Ziprasidone Mesylate is the mesylate salt form of ziprasidone, a benzothiazolylpiperazine derivative and an atypical antipsychotic agent with an antischizophrenic property. Ziprasidone mesylate functions as an antagonist at the dopamine D2 and serotonin 5-HT2A and 5-HT1D receptors, and as an agonist at the 5-HT1A receptor. Ziprasidone mesylate also inhibits the synaptic reuptake of serotonin and norepinephrine. The mechanism of action by which ziprasidone mesylate exerts its antischizophrenic effect is unknown but is potentially mediated through a combination of dopamine D2 and serotonin 5-HT2 antagonism. This agent also has antagonistic activity against histamine H1 and alpha-1-adrenergic receptors.


Ziprasidone Hydrochloride is the hydrochloride salt form of ziprasidone, a benzothiazolylpiperazine derivative and an atypical antipsychotic agent with an antischizophrenic property. Ziprasidone hydrochloride functions as an antagonist at the dopamine D2 and serotonin 5-HT2A and 5-HT1D receptors, and as an agonist at the 5-HT1A receptor. Ziprasidone hydrochloride also inhibits synaptic reuptake of serotonin and norepinephrine. The mechanism of action by which ziprasidone hydrochloride exerts its antischizophrenic effect is unknown but is potentially mediated through a combination of dopamine D2 and serotonin 5-HT2 antagonism. This agent also has antagonistic activity against histamine H1 and alpha-1-adrenergic receptors.


5.2 MeSH Pharmacological Classification

Dopamine Antagonists

Drugs that bind to but do not activate DOPAMINE RECEPTORS, thereby blocking the actions of dopamine or exogenous agonists. Many drugs used in the treatment of psychotic disorders (ANTIPSYCHOTIC AGENTS) are dopamine antagonists, although their therapeutic effects may be due to long-term adjustments of the brain rather than to the acute effects of blocking dopamine receptors. Dopamine antagonists have been used for several other clinical purposes including as ANTIEMETICS, in the treatment of Tourette syndrome, and for hiccup. Dopamine receptor blockade is associated with NEUROLEPTIC MALIGNANT SYNDROME.


Antipsychotic Agents

Agents that control agitated psychotic behavior, alleviate acute psychotic states, reduce psychotic symptoms, and exert a quieting effect. They are used in SCHIZOPHRENIA; senile dementia; transient psychosis following surgery; or MYOCARDIAL INFARCTION; etc. These drugs are often referred to as neuroleptics alluding to the tendency to produce neurological side effects, but not all antipsychotics are likely to produce such effects. Many of these drugs may also be effective against nausea, emesis, and pruritus.


Serotonin Antagonists

Drugs that bind to but do not activate serotonin receptors, thereby blocking the actions of serotonin or SEROTONIN RECEPTOR AGONISTS.


5.3 FDA Pharmacological Classification
5.3.1 Active Moiety

ZIPRASIDONE


5.3.2 FDA UNII

6UKA5VEJ6X


5.3.3 Pharmacological Classes

Established Pharmacologic Class [EPC]

Atypical Antipsychotic


5.4 ATC Code

N - Nervous system
N05 - Psycholeptics
N05A - Antipsychotics
N05AE - Indole derivatives
N05AE04 - Ziprasidone


5.5 Absorption, Distribution and Excretion

Absorption

~60%


Route of Elimination

Ziprasidone is extensively metabolized after oral administration with only a small amount excreted in the urine (<1%) or feces (<4%) as unchanged drug. Approximately 20% of the dose is excreted in the urine, with approximately 66% being eliminated in the feces.


Volume of Distribution

1.5 L/kg


Clearance

7.5 mL/min/kg


Ziprasidone is well absorbed after oral administration, reaching peak plasma concentrations in 6 to 8 hours. The absolute bioavailability of a 20 mg dose under fed conditions is approximately 60%. The absorption of ziprasidone is increased up to two-fold in the presence of food.

NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a


The bioavailability of ziprasidone administered intramuscularly is 100%. After intramuscular administration of single doses, peak serum concentrations typically occur at approximately 60 minutes post-dose or earlier ...

NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a


Steady-state concentrations are achieved within one to three days of dosing. The mean apparent systemic clearance is 7.5 mL/min/kg.

NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a


Ziprasidone has a mean apparent volume of distribution of 1.5 L/kg. It is greater than 99% bound to plasma proteins, binding primarily to albumin and alpha1-acid glycoprotein.

NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a


Ziprasidone's activity is primarily due to the parent drug. The multiple-dose pharmacokinetics of ziprasidone are dose-proportional within the proposed clinical dose range, and ziprasidone accumulation is predictable with multiple dosing.

NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a


Ziprasidone is extensively metabolized after oral administration with only a small amount excreted in the urine (<1%) or feces (<4%) as unchanged drug.

NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a


Approximately 20% of the dose is excreted in the urine, with approximately 66% being eliminated in the feces. Unchanged ziprasidone represents about 44% of total drug-related material in serum.

NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a


As ziprasidone is cleared substantially by the liver, the presence of hepatic impairment would be expected to increase the AUC of ziprasidone; a multiple-dose study at 20 mg BID for 5 days in subjects (n=13) with clinically significant (Childs-Pugh Class A and B) cirrhosis revealed an increase in AUC 0-12 of 13% and 34% in Childs-Pugh Class A and B, respectively, compared to a matched control group (n=14). A half-life of 7.1 hours was observed in subjects with cirrhosis compared to 4.8 hours in the control group.

NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a


To compare the pharmacokinetics of ziprasidone in healthy young (18-45 years) men and women, and healthy elderly (> or = 65 years) men and women. Eight young men, 11 young women, 8 elderly men and 8 elderly women were given oral ziprasidone 40 mg day(-1), in two evenly divided daily doses, for 7 days, followed by a single 20 mg dose on day 8. Serum samples were collected immediately before the morning dose on days 1-8, for up to 12 hr after dosing on day 1 and for up to 96 hr after dosing on day 8. The resulting data were used to derive pharmacokinetic parameters of ziprasidone in each age and gender group. Steady-state serum concentrations of ziprasidone were achieved within 2-3 days. The steady-state pharmacokinetics of ziprasidone, determined 8 days after the initiation of treatment, were similar in the young men, elderly men and young women. Assessment of gender effects by analysis of variance revealed statistically significant differences in Cmax (85 vs. 69 ng mL(-1) and tmax (3.19 vs. 4.81 hr) but no differences in AUC(0,12 hr) or lambda(z). Assessment of age effects by analysis of variance revealed statistically significant differences in AUC(0,12 hr) (560 vs. 465 ng mL(-1) hr), Cmax (85 vs. 69 ng mL(-1) and lambda(z) (0.126 vs. 0.197 L hr(-1) but no difference in tmax. Assessment of age and gender effects by analysis of covariance, with body weight as the covariate, did not reveal any significant differences. The mean t(1/2), z in the young men, young women, elderly men and elderly women were 3.1, 4.1, 5.7 and 5.3 hr, respectively. Standard deviations of the means for the pharmacokinetic parameters for the elderly women tended to be large.[Wilner KD et al; Br J Clin Pharmacol 49 (Suppl 1): 15S-20S (2000)] Full text: PMC2015054


The metabolism and excretion of ziprasidone (5-[2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-yl]ethyl]-6-+++chloroindolin-2-one hydrochloride hydrate) were studied in Long Evans rats after oral administration of a single dose of a mixture of 14C- and 3H-labeled ziprasidone. The radioactive dose was quantitatively recovered over 7 days in both male and female rats. The percentage of the dose excreted in urine, bile, and feces of rats was 21.6, 19.2, and 55.6%, respectively. The total excretion in urine and bile suggested that at least 41% of the drug was absorbed. Absorption of ziprasidone was rapid, and the mean plasma concentrations of the unchanged drug and metabolites were slightly higher in the female rats than in the males. The maximal plasma concentrations for ziprasidone and metabolites were reached at 1 hr in both male and female rats. Based on AUC (0-12 hr) values, approximately 59 and 52% of the circulating radioactivity (average of 14C and 3H) was attributable to metabolites in male and female rats, respectively. ...

Prakash C et al; Drug Metab Dispos 25 (2): 206-18 (1997)


... The pharmacokinetics of intramuscular ziprasidone include rapid attainment of therapeutic drug level (time to reach peak serum concentration [tmax]< or=60 minutes postdose), a mean terminal elimination half-life ranging from 2 to 5 hours, bioavailability of approximately 100%, exposure to drug that increases in a dose-related manner and little drug accumulation even after 3 days of repeated intramuscular administration.The metabolism and elimination of intramuscular ziprasidone have not been extensively evaluated. The principal difference between any oral versus intramuscular formulations of a drug is in first-pass metabolism. Oral ziprasidone is eliminated mainly via the hepatic route and <1% is eliminated in urine and <4% in feces as unchanged drug. That would not be expected to change with the intramuscular route of administration. Low concentrations of ziprasidone are seen 12-18 hours after the last intramuscular injection. The rapid clearance of ziprasidone from plasma after an intramuscular administration results in little to no persistence of plasma drug level when switching from intramuscular to oral drug administration. ...

Preskorn SH; Clin Pharmacokinet 44 (11): 1117-33 (2005)


5.6 Metabolism/Metabolites

Metabolism

Hepatic


Ziprasidone is extensively metabolized in the liver principally via reduction by aldehyde oxidase with minimal excretion of unchanged drug in urine or feces. About one-third of ziprasidone's metabolic clearance is mediated by the cytochrome P-450 (CYP) 3A4 isoenzyme.

American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2496


Ziprasidone is primarily cleared via three metabolic routes to yield four major circulating metabolites, benzisothiazole (BITP) sulphoxide, BITP-sulphone, ziprasidone sulphoxide, and S-methyl-dihydroziprasidone.

NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a


In vitro studies using human liver subcellular fractions indicate that S-methyl-dihydroziprasidone is generated in two steps. The data indicate that the reduction reaction is mediated by aldehyde oxidase and the subsequent methylation is mediated by thiol methyltransferase.

NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a


In vitro studies using human liver microsomes and recombinant enzymes indicate that CYP3A4 is the major CYP contributing to the oxidative metabolism of ziprasidone. CYP1A2 may contribute to a much lesser extent. Based on in vivo abundance of excretory metabolites, less than one-third of ziprasidone metabolic clearance is mediated by cytochrome P450 catalyzed oxidation and approximately two-thirds via reduction by aldehyde oxidase. There are no known clinically relevant inhibitors or inducers of aldehyde oxidase.

NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a


The metabolism and excretion of ziprasidone (5-[2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-yl]ethyl]-6-+++chloroindolin-2-one hydrochloride hydrate) were studied in Long Evans rats after oral administration of a single dose of a mixture of 14C- and 3H-labeled ziprasidone. ... Ziprasidone was extensively metabolized in rats, and only a small amount of ziprasidone was excreted as unchanged drug. Twelve metabolites were identified ... The structures of eight metabolites were unambiguously confirmed by coelution on HPLC with synthetic standards, and four additional metabolites were partially identified. There was a gender-related difference in the excretion of urinary metabolites in Long Evans rats. The major route of metabolism in male rats involved N-dealkylation. In female rats the major metabolites were due to oxidation at the benzisothiazole ring. Based on the structures of these metabolites, four major and two minor routes of metabolism of ziprasidone were identified. The major routes included 1) N-dealkylation of the ethyl side chain attached to the piperazinyl nitrogen, 2) oxidation at the sulfur, resulting in the formation of sulfoxide and sulfone, 3) oxidation on the benzisothiazole moiety (other than sulfur), and 4) hydration of the C==N bond and subsequent oxidation at the sulfur of the benzisothiazole moiety. The minor routes involved N-oxidation on the piperazine ring and hydrolysis of the oxindole moiety.

Prakash C et al; Drug Metab Dispos 25 (2): 206-18 (1997)


5.7 Biological Half-Life

7 hours


Elimination of ziprasidone is mainly via hepatic metabolism with a mean terminal half-life of about 7 hours within the proposed clinical dose range.

NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a


The mean t(1/2), z in the young men, young women, elderly men and elderly women were 3.1, 4.1, 5.7 and 5.3 hr, respectively.[Wilner KD et al; Br J Clin Pharmacol 49 (Suppl 1): 15S-20S (2000)] Full text: PMC2015054


5.8 Mechanism of Action

Ziprasidone's antipsychotic activity is likely due to a combination of its antagonistic function at D2 receptors in the mesolimbic pathways and at 5HT2A receptors in the frontal cortex. Alleviation of positive symptoms is due to antagonism at D2 receptors while relief of negative symptoms are due to 5HT2A antagonism.


Ziprasidone is a benzisothiazolyl piperazine-derivative antipsychotic agent that is chemically unrelated to other currently available antipsychotic agents (eg, butyrophenones, phenothiazines) and has been referred to as an atypical or second-generation antipsychotic agent. The exact mechanism of antipsychotic action of ziprasidone has not been fully elucidated but, like that of other atypical antipsychotic agents (eg, olanzapine, risperidone), may involve antagonism of central type 2 serotonergic (5-HT2) receptors and central dopamine D2 receptors. As with other drugs that are effective in bipolar disorder, the precise mechanism of antimanic action of ziprasidone has not been fully elucidated. Antagonism of various other receptors (eg, histamine H1 receptors, alpha1-adrenergic receptors) may contribute to other therapeutic and adverse effects (eg, orthostatic hypotension, somnolence) observed with ziprasidone.

American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 2507


Ziprasidone exhibited high in vitro binding affinity for the dopamine D2 and D3, the serotonin 5HT2A, 5HT2C, 5HT1A, 5HT1D, and alpha1-adrenergic receptors (Ki s of 4.8, 7.2, 0.4, 1.3, 3.4, 2, and 10 nM, respectively), and moderate affinity for the histamine H1 receptor (Ki=47 nM). Ziprasidone functioned as an antagonist at the D2, 5HT2A, and 5HT1D receptors, and as an agonist at the 5HT1A receptor. Ziprasidone inhibited synaptic reuptake of serotonin and norepinephrine. No appreciable affinity was exhibited for other receptor/binding sites tested, including the cholinergic muscarinic receptor (IC50 >1 uM).

NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a


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 histamine H1 receptors may explain the somnolence observed with this drug. Ziprasidone's antagonism of alpha1-adrenergic receptors may explain the orthostatic hypotension observed with this drug.

NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a


c-Fos immunohistochemistry was performed on paraformaldehyde-fixed cryosections of rat brains obtained, initially, from animals 2, 4, or 6 hr after oral administration of 10 mg/kg ziprasidone or vehicle and, subsequently, from animals 2 hr after oral administration of 1, 3, or 10 mg/kg ziprasidone or vehicle. The density of immunoreactive nuclei was assessed in pre-determined forebrain regions. Ziprasidone induced a time-dependent increase in the density of c-Fos-positive nuclei that was maximal at 2 hr. At the 2 hr time-point, c-Fos expression was significantly (p<0.05) elevated in the shell and core of the nucleus accumbens, lateral and medial caudate putamen, and lateral septum. At 4 hr post-dose, c-Fos expression was also significantly increased in the cingulate gyrus. Ziprasidone-induced c-Fos expression was dose-dependent with significant (p<0.05) c-Fos expression observed in the nucleus accumbens (shell and core) and caudate putamen (lateral and medial) at 3 and 10 mg/kg and in the lateral septum at 10 mg/kg. Increased c-Fos expression in the nucleus accumbens and lateral septum is considered to be predictive of activity against positive symptoms, in the caudate putamen of motor side effect liability, and in the cingulate gyrus of efficacy against negative symptoms. Thus, the observed pattern of c-Fos expression induced in rat brain by ziprasidone is consistent with its reported clinical effects...

Jennings CA et al; Psychopharmacology (Berl) 184 (1): 13-20 (2006)


... The mechanism of action for antipsychotics has not been fully elucidated, but the hypothermia induced by this class of medications is believed to be driven through the antagonism of the dopamine (D(1-4)) and 5-hydroxytryptamine-2 (5-HT2) receptors. It has been theorized that under normal conditions, there is a balance between dopamine acting to reduce the body temperature and 5-HT2 acting to elevate body temperature. Atypical antipsychotics, particularly ziprasidone, appear to have a higher affinity to antagonize the 5-HT2 receptor and less at the D(2) receptor, therefore creating an imbalance favoring the lowering of core body temperature. Other theories include the antagonism of alpha(1) receptors by these medications causing vasodilatation and shunting of blood to the skin causing profound heat loss. ...

Gibbons GM et al; Am J Emerg Med 26 (6): 737.e1-2 (2008)


Ask Us for Pharmaceutical Supplier and Partner
Ask Us, Find A Supplier / Partner
No Commissions, No Strings Attached, Get Connected for FREE

What are you looking for?

How can we help you?

The request can't be empty

Please read our Privacy Policy carefully

You must agree to the privacy policy

The name can't be empty
The company can't be empty.
The email can't be empty Please enter a valid email.
The mobile can't be empty

Advertise With Us

Advertise With Us