Ziprasidone
Encyclopedia
Ziprasidone 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 four drugs which Pfizer pleaded guilty to misbranding "with the intent to defraud or mislead" in 2009. 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.
Ziprasidone has a high affinity
for dopamine
, serotonin, and alpha-adrenergic receptors and a moderate affinity for histamine receptor
s, where it is believed to act as an antagonist
. Ziprasidone also displays some inhibition of synaptic reuptake of serotonin
and norepinephrine
, although the clinical significance of this is unknown. The mechanism of action of ziprasidone is unknown. However it has been theorized that its antipsychotic activity is mediated primarily by antagonism
at dopamine receptors, specifically D2. Serotonin antagonism may also play a role in the effectiveness of ziprasidone, but the significance of 5-HT2A
antagonism is debated among researchers. Ziprasidone has perhaps the most selective affinity for 5-HT2A receptors relative to D2 and 5-HT2C receptors of any neuroleptic. Antagonism at histaminic and alpha adrenergic receptors likely explains some of the side effects of ziprasidone, such as sedation
and orthostasis.
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%.
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.
due to increased mortality in elderly patients with dementia
-related psychosis
. 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.
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.
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. In fact, in a trial of long term therapy with ziprasidone, overweight patients (BMI
> 27) actually had a mean weight loss overall. 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. 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).
The British National Formulary
recommends a gradual withdrawal when discontinuing anti-psychotic treatment to avoid acute withdrawal syndrome or rapid relapse. 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. 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
. The present evidence suggests that these symptoms affect a small number of susceptible individuals treated with antipsychotics. Complicated and long-lasting rebound insomnia symptoms can also occur after withdrawing from antipsychotics.
Atypical antipsychotic
The atypical antipsychotics are a group of antipsychotic tranquilizing drugs used to treat psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia...
to gain FDA approval (February 2001). In the United States, Ziprasidone is Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) approved for the treatment of schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
, 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
Mania
Mania, the presence of which is a criterion for certain psychiatric diagnoses, is a state of abnormally elevated or irritable mood, arousal, and/ or energy levels. In a sense, it is the opposite of depression...
and mixed states associated with bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
. The brand name Geodon has been suggested to bring to mind the phrase 'down (don) to earth (geo
Geography
Geography is the science that studies the lands, features, inhabitants, and phenomena of Earth. A literal translation would be "to describe or write about the Earth". The first person to use the word "geography" was Eratosthenes...
)' 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
Mesylate
In chemistry, a mesylate is any salt or ester of methanesulfonic acid . In salts, the mesylate is present as the CH3SO3− anion. When modifying the International Nonproprietary Name of a pharmaceutical substance containing the group or anion, the correct spelling is mesilate .Mesylate esters are a...
salt, ziprasidone mesylate trihydrate, and is provided as a lyophilized powder.
Geodon was one of four drugs which Pfizer pleaded guilty to misbranding "with the intent to defraud or mislead" in 2009. 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.
Pharmacology
Ziprasidone possesses affinity for and acts at the following receptors and transporters:- D2 Antagonist (Ki = 4.8 nM)
- D3 Antagonist (Ki = 7.2 nM)
- 5-HT1A Agonist (Ki = 3.4 nM)
- 5-HT1D Antagonist (Ki = 2.3 nM)
- 5-HT2A Antagonist/Inverse Agonist (Ki = 0.4 nM)
- 5-HT2C (Ki = 1.3 nM)
- NET
- SERT
- H1 Antagonist (Ki = 47 nM)
- α1-adrenergic Antagonist (Ki = 10 nM)
- mACh (IC50 >1000 nM) [negligible affinity]
Ziprasidone has a high affinity
Dissociation constant
In chemistry, biochemistry, and pharmacology, a dissociation constant is a specific type of equilibrium constant that measures the propensity of a larger object to separate reversibly into smaller components, as when a complex falls apart into its component molecules, or when a salt splits up into...
for dopamine
Dopamine receptor
Dopamine receptors are a class of metabotropic G protein-coupled receptors that are prominent in the vertebrate central nervous system . The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors....
, serotonin, and alpha-adrenergic receptors and a moderate affinity for histamine receptor
Histamine receptor
The histamine receptors are a class of G protein-coupled receptors with histamine as their endogenous ligand.There are four known histamine receptors:*H1 receptor*H2 receptor*H3 receptor*H4 receptor-Comparison:...
s, where it is believed to act as an antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
. Ziprasidone also displays some inhibition of synaptic reuptake of serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
and norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
, although the clinical significance of this is unknown. The mechanism of action of ziprasidone is unknown. However it has been theorized that its antipsychotic activity is mediated primarily by antagonism
Antagonism
Antagonism is hostility that results in active resistance, opposition, or contentiousness.Additionally, it may refer to:*Antagonism , where the involvement of multiple agents reduces their overall effect...
at dopamine receptors, specifically D2. Serotonin antagonism may also play a role in the effectiveness of ziprasidone, but the significance of 5-HT2A
5-HT2A receptor
The mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor . This is the main excitatory receptor subtype among the GPCRs for serotonin , although 5-HT2A may also have an inhibitory effect on certain areas such...
antagonism is debated among researchers. Ziprasidone has perhaps the most selective affinity for 5-HT2A receptors relative to D2 and 5-HT2C receptors of any neuroleptic. Antagonism at histaminic and alpha adrenergic receptors likely explains some of the side effects of ziprasidone, such as sedation
Sedation
Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
and orthostasis.
Pharmacokinetics
The systemic bioavailabilityBioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
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%.
Ziprasidone is hepatically metabolized by aldehyde oxidase
Aldehyde oxidase
Aldehyde oxidase is an enzyme which generates carboxylic acids from aldehydes. It catalyzes the conversion of an aldehyde in the presence of oxygen and water to an acid and hydrogen peroxide.* an aldehyde + H2O + O2 a carboxylate + H2O2 + H+...
; minor metabolism occurs via cytochrome P450 3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
(CYP3A4). Medications that induce (e.g. carbamazepine
Carbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
) or inhibit (e.g. ketoconazole
Ketoconazole
Ketoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
) CYP3A4 have been shown to decrease and increase, respectively, blood levels of ziprasidone.
Adverse effects
Ziprasidone received a black box warningBlack box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
due to increased mortality in elderly patients with dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
-related psychosis
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
. It also slightly increases the QTc interval
QT interval
In cardiology, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In general, the QT interval represents electrical depolarization and repolarization of the left and right ventricles...
in some patients and increases the risk of a potentially lethal type of heart arrhythmia known as torsades de pointes
Torsades de pointes
Torsades de pointes, or simply torsades, is a French term that literally means "twisting of the points". It was first described by Dessertenne in 1966 and refers to a specific, rare variety of ventricular tachycardia that exhibits distinct characteristics on the electrocardiogram .- Presentation...
. Ziprasidone should be used cautiously in patients taking other medications likely to interact with ziprasidone or increase the QTc interval.
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.
Adverse events reported for ziprasidone include severe chest pains, impaired erectile function and stimulation, sedation
Sedation
Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
, insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, orthostasis, life-threatening neuroleptic malignant syndrome
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome is a life- threatening neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs...
, akathisia
Akathisia
Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...
, and the development of permanent neurological disorder
Neurological disorder
A neurological disorder is a disorder of the body's nervous system. Structural, biochemical or electrical abnormalities in the brain, spinal cord, or in the nerves leading to or from them, can result in symptoms such as paralysis, muscle weakness, poor coordination, loss of sensation, seizures,...
tardive dyskinesia
Tardive dyskinesia
Tardive dyskinesia is a difficult-to-treat form of dyskinesia that can be tardive...
. 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
Hyperglycemia
Hyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...
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
Olanzapine
Olanzapine is an atypical antipsychotic, approved by the FDA for the treatment of schizophrenia and bipolar disorder...
(Zyprexa)) at causing insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
and weight gain. In fact, in a trial of long term therapy with ziprasidone, overweight patients (BMI
Body mass index
The body mass index , or Quetelet index, is a heuristic proxy for human body fat based on an individual's weight and height. BMI does not actually measure the percentage of body fat. It was invented between 1830 and 1850 by the Belgian polymath Adolphe Quetelet during the course of developing...
> 27) actually had a mean weight loss overall. 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. 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
Clozapine
Clozapine is an antipsychotic medication used in the treatment of schizophrenia, and is also used off-label in the treatment of bipolar disorder. Wyatt. R and Chew...
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.The British National Formulary
British National Formulary
The British National Formulary is a medical and pharmaceutical reference book that contains a wide spectrum of information and advice on prescribing and pharmacology, along with specific facts and details about all medicines available on the National Health Service , including indication,...
recommends a gradual withdrawal when discontinuing anti-psychotic treatment to avoid acute withdrawal syndrome or rapid relapse. 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. Withdrawal symptoms reported to occur after discontinuation of antipsychotics include nausea, emesis, lightheadedness, diaphoresis
Diaphoresis
Diaphoresis is excessive sweating commonly associated with shock and other medical emergency conditions.Diaphoretic is the state of perspiring profusely, or something that has the power to cause increased perspiration....
, dyskinesia
Dyskinesia
Dyskinesia is a movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements, similar to tics or choreia. Dyskinesia can be anything from a slight tremor of the hands to uncontrollable movement of, most commonly, the upper body but...
, orthostasis, tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
, nervousness, dizziness, headache, excessive non-stop crying, and anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
. The present evidence suggests that these symptoms affect a small number of susceptible individuals treated with antipsychotics. Complicated and long-lasting rebound insomnia symptoms can also occur after withdrawing from antipsychotics.