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Ziprasidone; Indications/Uses, Dosage, Side effects, Drug Interaction, Pregnancy

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.

Ziprasidone is the fifth atypical antipsychotic which is used for the treatment of schizophrenia as well as acute mania and mixed states associated with bipolar disorder. 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. Its immediate release intramuscular injection form is approved for acute agitation in people with schizophrenia. Ziprasidone is also used off-label for depression, bipolar maintenance, and post-traumatic stress disorder (PTSD).

Mechanism of Action of Ziprasidone

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. 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. 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.

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Indications of Ziprasidone

Autism
Bipolar Disorder
Body Dysmorphic Disorder
Obsessive Compulsive Disorder
Paranoid Disorder
Schizoaffective Disorder
Schizophrenia
Acute Agitation
Bipolar 1 Disorder
Mixed manic depressive episode
Treatment Resistant Major Depressive Disorder
Acute Manic episode

Contra Indications of Ziprasidone

Diabetes
Excessive fat in the blood
Low amount of magnesium in the blood
Extreme Loss of Body Water
Low amount of potassium in the blood
Overweight
Decreased Function of Bone Marrow
Deficiency of granulocytes a type of white blood Cell
Increased eosinophils in the Blood
Abnormal movements of face muscles and tongue
Neuroleptic malignant syndrome
Lower seizure threshold
Closed angle glaucoma
Very Rapid Heartbeat – Torsades de Pointes
Slow Heartbeat
Stroke
Disorder of the Blood Vessels of the Brain
blood clot in a deep vein of the extremities
Blood Pressure Drop Upon Standing
Abnormally low blood pressure
Paralysis of the Intestines
Constipation
Liver problems
Acute Inflammation of the Pancreas
Enlarged Prostate
Seizures
Cannot Empty Bladder
High Blood Sugar
abnormal liver function tests
Susceptible to Breathing Fluid Into Lungs
a mother who is producing milk and breastfeeding
Metabolic Syndrome X
Dementia in an Elderly Person
Decreased Motility Function of Stomach or Intestines

Dosage of Ziprasidone

Strengths: 40 mg; 20 mg; 60 mg; 80 mg

Schizophrenia

Oral

Initial dose: 20 mg orally twice a day
Maintenance dose: Adjust as clinically indicated at intervals of not less than 2 days
Maximum dose: 100 mg twice a day
A dose greater than 80 mg twice a day is generally not recommended.

Intramuscular

Recommended dose: 10 to 20 mg IM; may repeat 10 mg IM every 2 hours or 20 mg IM every 4 hours up to the maximum daily dose
Maximum dose: 40 mg IM per day
Duration of therapy: Use beyond 3 consecutive days has not been studied

Bipolar Disorder

Acute Treatment of Manic or Mixed Episodes

Initial dose: 40 mg orally twice daily
Increase dose to 60 mg or 80 mg twice daily on the second day; subsequently adjust dose based on tolerance and efficacy within the dose range of 40 to 80 mg orally twice a day.

Maintenance Treatment (as the adjunct to lithium or valproate)

Once stabilized, continue on the same dose within the range of 40 to 80 mg orally twice daily.

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Side Effects of Ziprasidone

The most common

Blurred vision
Aggressive behavior
agitation
anxiety
changes in vision, including blurred vision
difficulty concentrating
difficulty speaking or swallowing
dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
Chest pain or tightness
dry mouth
trembling or shaking of the hands or feet
stomach pain or cramping
diarrhea
a headache
stomach pain;
back pain, joint or muscle pain.
problems with your vision (including color vision);
sudden chest pain or trouble breathing;
pain or swelling in one or both legs;
a migraine headache;
pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating; or
feeling like you might pass out.

More common

Abdominal or stomach pain, discomfort, or tenderness
chills or fever
difficulty with moving
headache, severe and throbbing
joint or back pain
muscle aching or cramping
muscle pains or stiffness
chest pressure or squeezing pain in chest
discomfort in arms, shoulders, neck or upper back
excessive sweating
feeling of heaviness, pain, warmth and/or swelling in a leg or in the pelvis
sudden tingling or coldness in an arm or leg
sudden slow or difficult speech
sudden drowsiness or need to sleep
fast breathing
sharp pain when taking a deep breath
fast or slow heartbeat
coughing up blood
rust colored urine
decreased amount of urine

Rare

Anxiety
change in vision
chest pain or tightness
confusion
cough
Agitation
arm, back, or jaw pain
blurred vision
chest pain or discomfort
convulsions
extra heartbeats
fainting
hallucinations
headache
irritability
lightheadedness
mood or mental changes
muscle pain or cramps
muscle spasm or jerking of all extremities
nervousness

Drug Interactions of Ziprasidone

Ziprasidone may interact with following drug, supplements, & may change the efficacy of the drug

antihistamines (e.g,. cetirizine, doxylamine, diphenhydramine, hydroxyzine,loratadine)
anti-Parkinsons medications (e.g., amantadine, apomorphine, bromocriptine, levodopa,pramipexole, ropinirole)
antipsychotics (e.g., chlorpromazine, , haloperidol, quetiapine, risperidone)
antiseizure medications (e.g., clobazam, ethosuximide, felbamate, levetiracetam, phenobarbital, phenytoin, topiramate, valproic acid, zonisamide)
aripiprazole
“azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
baclofen
barbiturates (e.g., butalbital, pentobarbital, phenobarbital)
benzodiazepines (e.g., alprazolam, diazepam, lorazepam)
beta-adrenergic blockers (e.g., atenolol, propranolol, sotalol)
bupropion
calcitriol
calcium channel blockers (e.g., amlodipine, diltiazem, nifedipine, verapamil)
captopril
celecoxib
chloroquine
cholecalciferol
cyclosporine
dantrolene
domperidone
“gliptin” diabetes medications (e.g., linagliptin, saxagliptin, sitagliptin)
gabapentin
H2 antagonists (e.g., famotidine, ranitidine)
ipratropium
macrolide antibiotics (e.g., clarithromycin, erythromycin)
mirabegron
mirtazapine
monoamine oxidase inhibitors (MAOIs; moclobemide, phenelzine, rasagiline, selegiline, tranylcypromine)
non-steroidal anti-inflammatory medications (NSAIDs; e.g., diclofenac, ibuprofen, naproxen)
phosphodiesterase 5 inhibitors (e.g., sildenafil, vardenafil)tadalafil,
proton pump inhibitors (e.g., lansoprazole, omeprazole)
quinolone antibiotics (e.g., levofloxacin, norfloxacin, moxifloxacin)
selective serotonin reuptake inhibitors (SSRIs; e.g., paroxetine, fluoxetine,citalopram)
serotonin antagonists (anti-emetic medications; e.g., granisetron, ondansetron)
tapentadol
theophylline
thiazide diuretics (water pills; e.g., hydrochlorothiazide, indapamide, metolazone)
tramadol
tricyclic antidepressants (e.g., amitriptyline, clomipramine, desipramine, trimipramine)
tyrosine kinase inhibitors (e.g., dasatinib, imatinib, nilotinib, sunitinib)
“triptan” migraine medications (e.g., eletriptan, sumatriptan)

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Pregnancy Catagory of Ziprasidone

FDA Pregnancy Category C

Pregnancy

This medication should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while taking this medication, contact your doctor immediately.

Lactation

It is not known if ziprasidone passes into breast milk. If you are a breast-feeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breast-feeding.The safety and effectiveness of using this medication have not been established for children less than 18 years of age.