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, Zeldox, Zipwell
AHFS/Drugs.com	monograph
MedlinePlus	a699062
Licence data	US FDA:link
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Legal status	AU: S4 (Prescription only) US: ℞-only
Routes of administration	Oral (capsules), IM
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 Y
ATC code	N05AE04 (WHO)
PubChem	CID: 60854
IUPHAR/BPS	59
DrugBank	DB00246 Y
ChemSpider	54841 Y
UNII	6UKA5VEJ6X Y
KEGG	D08687 Y
ChEBI	CHEBI:10119 Y
ChEMBL	CHEMBL708 Y
Chemical data
Formula	C21H21ClN4OS
Molecular 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
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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. 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.

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

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.

Schizophrenia

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.

Pharmacology

Binding profile

Ziprasidone acts as an antagonist/inverse agonist (unless otherwise noted) of the following receptors and transporters:

• 5-HT_1A receptor (K_i = 12 nM) (partial agonist)
• 5-HT_1B receptor (K_i = 4.0 nM) (partial agonist)
• 5-HT_1D receptor (K_i = 2.3 nM)
• 5-HT_1E receptor (K_i = 360 nM)
• 5-HT_1F receptor (K_i = >10,000 nM) (inactive)
• 5-HT_2A receptor (K_i = 0.6 nM)
• 5-HT_2B receptor (K_i = 27 nM)
• 5-HT_2C receptor (K_i = 13 nM)
• 5-HT₃ receptor (K_i = > 10,000 nM) (inactive)
• 5-HT₄ receptor (K_i = > 10,000 nM) (inactive)
• 5-HT_5A receptor (K_i = 291 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)
• D₄ receptor (K_i = 39 nM)
• D₅ receptor (K_i = 152 nM)
• α_1A-adrenergic receptor (K_i = 18 nM)
• α_2A-adrenergic receptor (K_i = 160 nM)
• H₁ receptor (K_i = 63 nM)
• mACh receptors (K_i = >10,000 nM) (inactive)
• 5-HT transporter (K_i = 53 nM) (inhibitor)
• NE transporter (K_i = 48 nM) (inhibitor)
• DA transporter (K_i = >10,000 nM) (inactive)

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. It also displays some inhibition of synaptic reuptake of serotonin and norepinephrine, though not dopamine.

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. 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. 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 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. 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%.

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

Adverse effects

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

Sources for the following lists of adverse effects

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

Very common adverse effects (>10%)

• Somnolence
• Headache

Common adverse effects (1-10%)

• Hypersalivation
• Respiratory disorders
• Nausea
• Vomiting
• Dry mouth
• Constipation
• Dyspepsia
• Dizziness
• Extrapyramidal symptoms (EPS) such as: (in a recent meta-analysis of 15 antipsychotic drugs it came 8th for extrapyramidal side effects)

- Tremor

- Dystonia

- Akathisia

- Parkinsonism

- Muscle rigidity

• Rash
• Tachycardia
• Orthostatic hypotension
• Diarrhea
• Anorexia
• Myalgia
• Rhinitis
• Cough
• Anxiety
• Abnormal vision
• Spasmodic movement
• Asthenia
• Weight gain (usually less prominent than with other atypical antipsychotics, as is supported by a recent meta-analysis in which it produced the 2nd least weight gain, after haloperidol)

Uncommon (0.1-1%) adverse effects

• Abnormal gait
• Thirst
• Palpitation
• Hyperprolactinaemia (according to a recent meta-analysis of 15 atypical antipsychotics it produces less prolactin elevation than risperidone, paliperidone, haloperidol, sertindole and lurasidone)
• Dysphagia
• Flatulence
• Gastritis
• Tinnitus
• Photophobia
• Hepatic enzyme increased
• Increased appetite
• Heart rate increased
• Rhinitis
• Joint stiffness
• Muscle cramps
• Pain in extremity
• Ataxia
• Bradykinesia
• Cogwheel rigidity
• Disturbance in attention
• Drooling
• Dysarthria
• Generalised tonic-clonic seizures
• Hypokinesia
• Hypersomnia
• Hypoaesthesia
• Lethargy
• Oculogyric crisis
• Paraesthesia
• Tardive dyskinesia
• Vertigo
• Throat tightness
• Nightmares
• Dyspnoea
• Sore throat
• Dysuria
• Urinary incontinence
• Acne
• Maculopapular rash
• Rash
• Urticaria

Rare (<0.1%) side effects

• Drug Reaction with Eosinophilia and Systemic Symptoms
• Chest pain
• Feeling hot
• Pyrexia
• Sluggishness
• Gastroesophageal reflux
• Loose stools
• Lymphopaenia
• Ear pain
• Positional vertigo
• Amblyopia
• Eye pruritus
• Visual disturbance
• Blood lactic dehydrogenase increased
• Body temperature increased
• QT interval prolongation
• Eosinophilia
• Hypocalcaemia
• Liver function test abnormal
• Increased pulse
• Arthropathy
• Musculoskeletal discomfort
• Trismus
• Akinesia
• Paresis
• Restless legs syndrome
• Torticollis
• Anorgasmia
• Bradyphrenia
• Flat affect
• Panic attack
• Sleep walking
• Hiccups
• Erectile dysfunction
• Galactorrhoea
• Gynaecomastia
• Priapism
• Alopecia
• Allergic dermatitis
• Erythema
• Psoriasis
• Skin irritation
• Swelling face
• Papular rash
• Neuroleptic malignant syndrome
• Tardive dyskinesia

Ziprasidone is known to cause activation into mania in some bipolar patients.

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

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. In fact, in a trial of long term therapy with ziprasidone, overweight patients (BMI > 27) actually had a mean weight loss overall; 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.

Discontinuation

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

External links

• Geodon manufacturer's website
• Geodon Package Insert