Aripiprazole

MECHANISMOF ACTION

Aripiprazole is a quinolinone-derived antipsychotic that functions as a partial agonist at D2 and 5HT-1A receptors while acting as an antagonist at 5HT-2A receptors. It exhibits high affinity for D2, D3, 5HT-1A, and 5HT-2A receptors and moderate affinity for D4, 5HT-2C, 5HT-7, alpha-1 adrenergic, and H1 receptors. Notably, it lacks affinity for muscarinic receptors at therapeutic doses. By stabilizing dopamine and serotonin levels in the nucleus accumbens, ventral tegmental area, and frontal cortex, aripiprazole helps manage the positive, negative, and cognitive symptoms of schizophrenia. Its functional selectivity in intracellular signaling requires over 90% D2 receptor occupancy for clinical efficacy, minimizing the risk of extrapyramidal symptoms.

Aripiprazole functions as a dopamine stabilizer, acting as a functional antagonist in regions with excessive dopamine, such as the mesolimbic pathway, while remaining largely inactive in areas with normal dopamine levels, such as the nigrostriatal and tuberoinfundibular pathways. Its partial agonism at D2 receptors is thought to contribute to its effectiveness in managing the positive, negative, and cognitive symptoms of schizophrenia. 

PHARMACOKINETICS

Absorption:

For tablets: Aripiprazole is readily absorbed after oral administration, with peak plasma levels achieved within 3 to 5 hours. Its tablet formulation has a high oral bioavailability of 87%, allowing for effective drug absorption and systemic distribution.

For oral solutions: Aripiprazole is effectively absorbed when taken orally as a solution, with higher plasma concentrations compared to the tablet form at equivalent doses. A relative bioavailability study in healthy individuals comparing 30 mg of aripiprazole solution to 30 mg of the tablet formulation found that the solution had 122% of the tablet's geometric mean Cmax and 114% of its AUC. Additionally, the single-dose pharmacokinetics of aripiprazole demonstrates linearity and dose proportionality within the 5 mg to 30 mg range.

Distribution:

Aripiprazole has a large steady-state volume of distribution (404 L or 4.9 L/kg) after intravenous administration.  At therapeutic levels, aripiprazole and its primary metabolite exhibit strong protein binding, with more than 99% bound to serum proteins, mainly albumin

Metabolism:

Aripiprazole undergoes metabolism through three primary pathways: dehydrogenation, hydroxylation, and N-dealkylation. In vitro studies indicate that CYP3A4 and CYP2D6 enzymes mediate dehydrogenation and hydroxylation, while CYP3A4 catalyzes N-dealkylation. Aripiprazole remains the dominant circulating drug in the body, and at steady state, its active metabolite, dehydro-aripiprazole, and accounts for approximately 40% of the drug’s plasma AUC.

Elimination:

After a single oral dose of [14C]-labeled aripiprazole, about 25% of the total radioactivity was eliminated through urine, while approximately 55% was excreted in feces. The average elimination half-lives for aripiprazole and its major metabolite, dehydro-aripiprazole, are approximately 75 hours and 94 hours, respectively. This indicates that both the drug and its metabolite stay in the body for a prolonged period before being eliminated.

PHARMACODYNAMICS

Aripiprazole demonstrates strong binding to dopamine D2 and D3 receptors, as well as serotonin 5-HT1a and 5-HT2a receptors, with Ki values of 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively. It shows moderate affinity for dopamine D4, serotonin 5-HT2c and 5-HT7 receptors, alpha1-adrenergic, and histamine H1 receptors, with Ki values of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively. Additionally, it has moderate affinity for the serotonin reuptake site. Aripiprazole does not significantly bind to cholinergic muscarinic receptors.

DOSAGE AND ADMINISTRATION

Aripiprazole can be taken with or without food and is offered in various forms, including oral tablets, disintegrating tablets (10 mg and 15 mg), oral solution, and both acute and long-acting intramuscular (IM) injections. However, the immediate-release IM injection (9.75 mg/1.3 mL) has been discontinued in the United States. Oral dosages range from 5 mg to 30 mg per day, with available tablet strengths of 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg. Both oral and IM administrations result in similar steady-state serum levels and effective symptom control. The half-life of oral aripiprazole is about 75 hours.

CONTRAINDICATIONS

Aripiprazole is contraindicated in individuals who have a known hypersensitivity to the drug or any of its ingredients.

DRUG INTERACTIONS

• Ketoconazole, itraconazole (Sporanox, Tolsura), posaconazole (Noxafil), and voriconazole (Vfend) are antifungal medications.

• Clarithromycin is an antibiotic used to treat bacterial infections.

• Paroxetine and fluoxetine are medications typically used to manage anxiety and depression.

• Carbamazepine (Tegretol, Carbatrol, and others) and phenytoin (Dilantin, Phenytek, and others) are commonly prescribed for treating seizures or nerve pain.

• Rifampin (Rifadin) is an antibiotic used to treat tuberculosis.

ADVERSE EFFECTS

Common side effects may include:

• Restlessness (akathisia)

• Movement issues, tremors, or muscle stiffness

• Sleepiness or fatigue

• Difficulty sleeping

• Nausea or vomiting

• Blurred vision

• Excessive salivation or drooling

• Dizziness

• Constipation

TOXICITY

According to FDA reports, there have been 76 cases of aripiprazole overdose, including both intentional and accidental overdoses, sometimes involving other substances. At present, there is no known antidote for aripiprazole overdose. However, administering activated charcoal early can help reduce the absorption of the drug if it was taken orally, such as in tablet form. The treatment for aripiprazole overdose primarily focuses on supportive care.