Aripiprazole- A Brief Overview

Overview

Aripiprazole is an antipsychotic agent that acts as a partial agonist for dopamine type 2 and serotonin 1a receptors and an antagonist of serotonin 2a receptors. It is indicated for treating schizophrenia, bipolar and major depressive disorder, irritability associated with autism, and Tourette's syndrome. Aripiprazole exerts its effects through the agonism of dopamine and 5-HT1A receptors and the antagonism of alpha-adrenergic and 5-HT2A receptors. Aripiprazole was approved by the FDA on November 15, 2002.

Dosage Form:

• Tablets - 2, 5, 10, 15, 20, and 30 milligrams.

• Orally Disintegrating Tablets- 10 and 15 milligrams.

• Oral Solution- 1 milligram per milliliters.

• Injection- 9.75 milligrams per 1.3 milliliters single-dose vial.

Dosage and Administration:

Aripiprazole Injection Dosing Recommendations:

What Is the Clinical Use of Aripiprazole?

1. Psychosis- It can relieve both positive and negative symptoms.

2. Bipolar Depression- The patient’s mood swings from mania to depression; in such cases, Aripiprazole can be effective.

3. Tourette Syndrome- It includes involuntary movements as well as the production of unusual voices, which are blocked by Aripiprazole.

4. Autism- It includes reduced social interaction and communication; in such cases, Aripiprazole is used to treat autism.

Contraindications and Precautions:

1. Older Adults- Aripiprazole may be associated with increased mortality in older adults with dementia-related psychosis. Aripiprazole is not approved by the food and drug administration (FDA) for the treatment of behavior problems in older adults with dementia.

2. Cerebrovascular Event- Aripiprazole may increase the risk of cerebrovascular adverse events in patients, such as stroke.

3. Suicidal Ideations- Avoid using Aripiprazole in patients with suicidal ideations, as it may increase suicidal thoughts.

4. Breastfeeding- Aripiprazole is not recommended in women who are breastfeeding.

5. Caution- Caution should be taken in patients with cardiovascular, renal, or hepatic disease. Caution can also be exercised in patients with severe central nervous system depression and uncontrolled seizure disorders.

Use in Specific Population:

• Pregnancy- Neonates exposed to antipsychotic drugs like Aripiprazole are at risk for extrapyramidal and withdrawal symptoms during the third trimester of pregnancy.

• Nursing Mothers- Aripiprazole is present in human breast milk, so it is not recommended while breastfeeding.

• Pediatric Use- In pediatric patients with major depressive disorder and agitation associated with schizophrenia or bipolar mania, the safety and effectiveness of the drug should be considered before administration.

• Geriatric Use- Aripiprazole is not approved for treating patients with psychosis associated with Alzheimer’s disease.

• CYP2D6 Poor Metabolizers- Dosage adjustment is recommended in CYP2D6 poor metabolizers due to high Aripiprazole concentrations.

• Hepatic and Renal Impairment- No dosage adjustment for Aripiprazole is required.

Drug Interactions:

There are some medications that may interact with Aripiprazole, such as

• Carbamazepine- Carbamazepine speeds up one of the enzymes that break down Aripiprazole. This interaction can cause Aripiprazole to be less effective.

• St. John’s Wort- It can speed up one of the enzymes that break down Aripiprazole and cause it to leave the body faster, which makes Aripiprazole less effective.

• Parkinson’s Disease Medication- Taking Parkinson's disease medication and Aripiprazole together can make them both less effective.

• Clarithromycin- It can slow down the enzyme that breaks down Aripiprazole which means there will be too much Aripiprazole in the body, So the risk of side effects can increase.

• Antidepressants- Some antidepressants, like Fluoxetine and Paroxetine, can interact with Aripiprazole and slow down one of the enzymes that break it down and may make Aripiprazole cause side effects.

• Antifungals- Some antifungal medications, such as Ketoconazole and Fluconazole, can slow the enzyme that breaks down Aripiprazole, and this interaction can increase the risk of Aripiprazole side effects.

• Benzodiazepines- Combining Benzodiazepines and Aripiprazole can raise the risk of certain side effects.

• Blood Pressure Medications- The combination of Aripiprazole and blood pressure medications can suddenly cause blood pressure to drop too low.

• Opioids- They carry the risk of serious side effects, including slowed breathing and severe drowsiness. When taken with other medications, like Aripiprazole, that have the same side effects, the risk of experiencing them also increases.

For Patients:

What Is Schizophrenia?

Schizophrenia is considered a serious mental health condition that often develops in early adulthood through the mid-30s. While schizophrenia can be a lifelong severe mental illness, treatment can manage symptoms. Every person with schizophrenia has slightly different symptoms, and the first signs can be seen as subtle personality changes, irritability, or gradual encroachment of unusual thoughts. Patients are usually diagnosed after the onset of psychosis, which typically occurs in the late teens or early 20s for men and late 20s or early 30s for women. A first psychotic episode can feature delusions, hallucinations, and disordered speech and behavior.

Why Is Aripiprazole Prescribed?

Aripiprazole falls under a class of medications called atypical antipsychotics, and it functions by changing the activity of certain natural substances in the brain.

• Aripiprazole is used for the treatment of the symptoms of schizophrenia.

• It can be used alone or with other medications to treat the episodes of mania or mixed episodes in patients with bipolar disorder.

• Aripiprazole can be used with an antidepressant to treat depression when symptoms cannot be controlled by the antidepressant alone.

• Aripiprazole is also used to treat children who have autistic disorders. It may help control these children's irritable behavior, such as temper tantrums, aggression, and frequent mood changes.

• Aripiprazole is also used to treat children who have Tourette's disorder.

How Should Aripiprazole Be Used?

Aripiprazole comes in tablet, a solution, and in orally disintegrating tablet form and is usually taken once daily with or without food. Aripiprazole also comes in a tablet form that contains a sensor device to be taken by mouth. It is used in adults to provide information about how the medication is taken. Some important instructions while taking this medication are as follows-

• A doctor may start the medication with a low dose and then gradually increase or decrease the dose depending on how well the medication works for the patient and the side effects they might experience.

• Take Aripiprazole every day at around the same time.

• Follow the directions on the prescription label carefully and ask the doctor or pharmacist to explain any part that is not understandable.

• Take Aripiprazole exactly as directed. Do not take more or less or more often than the doctor prescribes.

• Do not stop taking Aripiprazole without consulting a doctor.

What Special Precautions Should Be Taken?

• Allergies- The patient should inform the doctor or the pharmacist if they are allergic to Aripiprazole or any of the ingredients present in Aripiprazole preparations or any other medications they are taking.

• Drug History- The doctor should be informed about the prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products the patient is taking or plans to take. Be sure to mention drugs such as antidepressants, antifungals, antihistamines, anxiety medications, and medications for high blood pressure, mental illness, irritable bowel syndrome, motion sickness, Parkinson's disease, ulcers, and urinary problems. Sedatives, seizures, and tranquilizers should also be informed. The doctor may need to change the doses of medications or monitor the patient carefully for side effects. Other medications can also interact with Aripiprazole, be sure to inform the doctor about all the medications.

• Medical History- The doctor should be informed about the patient’s medical conditions such as heart disease, history of heart failure or heart attack, high or low blood pressure, stroke, seizures, a low number of white blood cells, high cholesterol levels, trouble keeping balance, and swallowing difficulty.

• Pregnancy and Breastfeeding- The doctor should be informed if the patient is pregnant, especially if they are in the last few months of their pregnancy. One should also inform the doctor if the patient is planning for pregnancy or they are breastfeeding. If the patient becomes pregnant while taking Aripiprazole, consult a doctor immediately. Aripiprazole may cause problems in newborns post-delivery if it is taken during the last months of pregnancy.

• Surgery- If the patient is undergoing any surgery, including dental surgery, then that must be informed to the doctor.

Other Considerations:

• It is important to take the prescribed dose daily without regard to meals but take it with food if there is stomach acidity.

• Report to the healthcare provider if any adverse symptoms occur, such as high fever, sweating, anxiety, rapid pulse, nausea, vomiting, rash, etc.

• Do not take any over-the-counter drugs.

• Do not consume the drug with any dietary supplements unless advised by a physician.

• As the drug is known to cause drowsiness, take caution while driving or while performing any other task that requires mental alertness.

• Avoid sudden body change to avoid postural hypotension.

• Avoid alcohol during the course of medication.

What Are the Side Effects of Aripiprazole?

• Headache.

• Lightheadedness.

• Dizziness.

• Excess salivation.

• Constipation.

• Blurred vision.

• Nausea and vomiting.

• Allergic reactions.

• Weight gain.

• Raised body temperature.

• Muscle rigidity.

• Mental retardation.

• Tachycardia.

Storage and Disposal:

The tablets, solution, and orally disintegrating tablets are stored at room temperature and away from excess heat and moisture. Unused Aripiprazole solution should be disposed of six months after the bottle has been opened or when the expiration date is marked on the bottle has passed.

What Should Be Done in Case of an Overdose?

In case of an overdose, the poison control helpline number should be contacted immediately.

Symptoms of overdose:

• Drowsiness.

• Loss of consciousness.

• Seizures.

• Confusion.

• Widened pupils.

• Movements that cannot be controlled.

• Change in a heartbeat.

Other Information:

It is important to keep a written list of all the prescription and nonprescription (over-the-counter) medicines the patient takes and any products such as vitamins, minerals, or other dietary supplements. The list should be brought up when each person visits a doctor or is admitted to a hospital. It is also important information to carry the list in case of emergencies. The doctor may order laboratory tests before and during the treatment with Aripiprazole.

For Doctors:

Indications:

• Aripiprazole is FDA approved and is predominantly used for the symptomatic management of psychosis in patients with schizophrenia. It is also used as monotherapy or adjunctive therapy for acute manic episodes associated with bipolar disorder.

• The oral tablet and solution (liquid) are also approved by FDA for treating autism spectrum disorder.

• Aripiprazole also serves as an adjunctive treatment for major depressive disorder and Tourette syndrome.

Mechanism of Action:

Aripiprazole is an atypical antipsychotic that acts as a partial agonist at the D2 and the 5HT-1a receptors and an antagonist at the 5HT-2a receptor. It has a high affinity for the following receptors, D2, D3, 5HT-1a, and 5HT2. It has moderate affinity for D4, 5HT-2c, 5-HT7, alpha-1 adrenergic, and H1 receptors and no affinity for muscarinic receptors at recommended doses. It also stabilizes dopamine and serotonin within the nucleus accumbens, ventral tegmental area, and frontal cortex, which results in the management of positive, negative, and cognitive symptoms of schizophrenia. Aripiprazole can demonstrate functional selectivity in the intracellular signaling pathways by requiring a greater than 90 % occupancy rate at D2 receptors that need to be clinically active; thus, it does not produce several extrapyramidal symptoms. Aripiprazole works as a functional antagonist in areas of high dopamine, such as the mesolimbic pathway, while it remains inactive in areas with normal dopamine, such as the nigrostriatal and tuberoinfundibular pathways. The partial agonism of Aripiprazole at D2 receptors may be responsible for effectively managing the positive, negative, and cognitive symptoms of schizophrenia.

Pharmacokinetics:

Aripiprazole exhibits a high affinity for dopamine D2 and D3, serotonin 5-HT1A and 5- HT2A, serotonin 5-HT2C, and 5-HT7, alpha1-adrenergic and histamine H1 receptors and moderate affinity for the serotonin reuptake site. Aripiprazole has no affinity for cholinergic muscarinic receptors. Aripiprazole acts as a partial agonist at the dopamine D2 and the serotonin 5-HT1A receptors and also works as an antagonist at the serotonin 5-HT2A receptor. The efficacy of Aripiprazole is mediated through a combination of partial agonist activity at D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors. Actions at receptors other than D2, 5-HT1A, and 5-HT2A may explain some of the other clinical effects of Aripiprazole; for example, the postural hypotension observed with Aripiprazole can be explained by its antagonist activity at adrenergic alpha-1 receptors.

Pharmacodynamics:

• Absorption- Aripiprazole is well absorbed after administration of the tablet, with peak plasma concentrations occurring within three to five hours, and the absolute oral bioavailability of the tablet formulation is 87 %.

• Distribution- The steady-state volume of distribution of Aripiprazole following intravenous administration is 404 liters or 4.9 liters per kilogram of body weight.

• Metabolism and Elimination- Aripiprazole is metabolized mainly by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. The mean elimination half-lives for Aripiprazole are about 75 hours for extensive metabolizers and 146 hours for poor metabolizers. Following a single oral dose of Aripiprazole, approximately 25 % of the administered radioactivity was recovered in the urine and 55 % in feces. Less than one percent of unchanged Aripiprazole was excreted in the urine, and approximately 18 % of the oral dose was excreted unchanged in the feces.

Administration:

• Aripiprazole can be administered with or without any food and is available in oral tablets, disintegrating tablets, oral solutions, and intramuscular (IM) injections.

• Oral dosage ranges from 5 milligrams to 30 milligrams per day and is available in 2, 5, 10, 15, 20, and 30 milligrams tablets.

• The long-acting injectable formulation is available in 300 milligrams or 400 milligrams prefilled syringes, and they are administered once a month in patients with the potential for poor medication adherence.

• The doctor must consider the patient's oral tolerability for Aripiprazole before beginning the intramuscular medication.

• It is important to first continue oral Aripiprazole for 14 days, and then the long-acting intramuscular therapy should be initiated.

Adverse Effects:

• Akathisia.

• Resting tremor.

• Shuffling gait.

• Acute dystonic reactions.

• Oculogyric crises.

• Opisthotonos.

• Tardive dyskinesia.

• Weight gain.

• Hypercholesterolemia.

• Glucose dysregulation.

• Cardiovascular abnormalities.

• Hyperprolactinemia.

• Neuroleptic malignant syndrome.

• Liver function abnormalities.

• Jaundice.

• Seizures.

• Agranulocytosis.

Dose-Related Adverse Reactions:

• Schizophrenia- Adverse reaction to 30 milligrams dose is somnolence. In pediatric patients with schizophrenia, three common adverse reactions appeared: extrapyramidal disorder (10 mg, 30 mg), somnolence (10 mg, 30 mg), and tremor (10 mg, 30 mg).

• Bipolar Mania- In pediatric patients with bipolar mania, four common adverse reactions had a possible dose-response relationship at four weeks such as extrapyramidal disorder (10 mg, 30 mg), somnolence (10 mg, 30 mg); akathisia (10 mg, 30 mg); and salivary hypersecretion (10 mg, 30 mg).

• Autistic Disorder- In pediatric patients with autistic disorder, one common adverse reaction had a possible dose-response relationship: fatigue (5 mg,10 mg,15 mg).

Contraindication:

Aripiprazole is contraindicated in patients with hypersensitivity to the drug or any component of the dosage form.

Monitoring:

• Patients require close monitoring for any signs of side effects.

• Establishing baseline measurements of blood pressure, weight, height, body mass index (BMI), and waist circumference are important. It is essential to keep track of certain things such as electrolytes, liver function, fasting plasma glucose concentration, lipid panel, abnormal involuntary movement scale, and ocular exam findings.

• The doctor should consider switching antipsychotic medications if the patient’s weight gain is greater than or equal to five percent of the initial body weight.

• Monitoring the complete blood count frequently during the first few months in patients with preexisting leukopenia or neutropenia is important.

Toxicity-

There are no known antidotes for Aripiprazole overdose currently. However, the administration of early charcoal partially prevents the absorption of the drug if it is ingested orally. The management of Aripiprazole overdose should be focused on supportive therapy. The doctor must obtain an electrocardiogram to identify any cardiac arrhythmias.