Antipsychotic (antipsychotic). The therapeutic effect of aripiprazole in schizophrenia is believed to be due to a combination of partial agonistic activity against dopamine D2 and serotonin 5-HT1 receptors and antagonistic activity against serotonin 5-HT2 receptors.
Aripiprazole has high in vitro affinity for dopamine D2 and D3 receptors, serotonin 5-HT1a- and 5-HT2a receptors, and moderate affinity for dopamine D4, serotonin 5-HT2c and 5-HT7, α1-adrenergic receptors and histones H1 receptors. Aripiprazole is also characterized by moderate affinity for serotonin reuptake sites and lack of affinity for muscarinic receptors.
After oral administration, aripiprazole is rapidly absorbed from the digestive tract. Cmax in plasma is reached after 3-5 hours. Absolute bioavailability is 87%. Eating does not affect the bioavailability of aripiprazole.
Css is reached after 14 days. Cumulation of the drug with repeated administration is predictable. The pharmacokinetics of aripiprazole in equilibrium are dose proportional. No diurnal fluctuations in the distribution of aripiprazole and its metabolite dehydroaripiprazole were noted.
Aripiprazole is intensively distributed in tissues, Vd is 4.9 l / kg. At a therapeutic concentration of more than 99%, aripiprazole binds to serum proteins, mainly albumin.
It was found that dehydroaripiprazole, the main metabolite in human plasma, has the same affinity for dopamine D2 receptors as aripiprazole.
Aripiprazole undergoes a presystemic metabolism only to a minimal extent. Aripiprazole is metabolized in the liver in three ways: dehydrogenation, hydroxylation and N-dealkylation. In vitro dehydrogenation and hydroxylation of aripiprazole occurs under the action of isoenzymes CYP3A4 and CYP2D6, N-dealkylation - CYP3A4.
At equilibrium, the AUC of dehydroaripiprazole is about 39% of the plasma AUC of aripiprazole.
The average T1 / 2 of aripiprazole is about 75 hours.
After a single dose of 14C-labeled aripiprazole, approximately 27% and 60% of the radioactivity is determined in urine and feces, respectively. Less than 1% of unchanged aripiprazole is determined in the urine and approximately 18% of the dose taken is unchanged with feces. The total clearance of aripiprazole is 0.7 ml / min / kg, mainly due to excretion by the liver.
Senile dementia, lactation, childhood and adolescence up to 18 years, hypersensitivity to aripiprazole.
Pregnancy and lactation
Adequate and strictly controlled clinical studies of safety during pregnancy have not been conducted. Aripirazole can be used during pregnancy in cases where the potential benefit of therapy to the mother outweighs the potential risk to the fetus.
It is not known whether aripirazole with breast milk is excreted in humans. The use of aripiprazole during lactation (breastfeeding) is contraindicated.
In experimental studies, it was shown that aripiprazole is excreted in milk in lactating rats.
From the cardiovascular system: often - orthostatic hypotension, tachycardia; possibly - bradycardia, palpitations, myocardial infarction, QT interval prolongation, cardiac arrest, hemorrhage, atrial fibrillation, heart failure, AV block, myocardial ischemia, deep vein thrombosis, phlebitis, extrasystole; rarely - vasovagal syndrome, enlargement of the heart, atrial flutter, thrombophlebitis, intracranial bleeding, cerebral ischemia; very rarely - fainting. From the digestive system: very often - nausea, loss of appetite; often - dyspepsia, vomiting; constipation; possible - increased appetite, gastroenteritis, difficulty swallowing, flatulence, gastritis, dental caries, gingivitis, hemorrhoids, gastroesophageal reflux, gastrointestinal hemorrhage, periodontal abscess, swelling of the tongue, fecal incontinence, colitis, rectal hemorrhage, stomatitis, , cholecystitis, fecaloma, candidiasis of the oral mucosa, gallstone disease, belching, stomach ulcer; rarely - esophagitis, gum bleeding, tongue inflammation, bloody vomiting, intestinal bleeding, duodenal ulcer, cheilitis, hepatitis, enlarged liver, pancreatitis, intestinal perforation; very rarely - increased activity of ALT, AST, alkaline phosphatase.
Allergic reactions: very rarely - anaphylaxis, angioedema, pruritus and urticaria.
From the musculoskeletal system: often - myalgia, cramps; possibly - pain in joints and bones, myasthenia gravis, arthritis, arthrosis, muscle weakness, cramping, bursitis; very rarely - an increase in CPK activity, rhabdomyolysis, tendonitis, tenobursitis, rheumatoid arthritis, myopathy.
From the side of the central nervous system and peripheral nervous system: very often - insomnia, drowsiness, akathisia; often - dizziness, tremor, extrapyramidal syndrome, psychomotor agitation, depression, nervousness, increased salivation, hostility, suicidal thoughts, manic thoughts, unsteady gait, confusion, resistance to performing passive movements (gear syndrome); possibly dystonia, muscle twitching, impaired attention, paresthesia, tremor of the extremities, impotence, bradykinesia, decreased / increased libido, panic reactions, apathy, memory loss, stupor, amnesia, stroke, hyperactivity, depersonalization, dyskinesia, restless legs syndrome (akathisia), myoclonus, suppressed mood, increased reflexes, slowing of mental function, hypersensitivity to stimuli, hypotension, disturbance of the oculomotor reaction; rarely - delirium, euphoria, buccogloss syndrome, akinesia, depression of consciousness up to loss of consciousness, reduced reflexes, obsessive thoughts, ZNS.
From the respiratory system: often - shortness of breath, pneumonia; possibly asthma, nosebleeds, hiccups, laryngitis; rarely - hemoptysis, aspiration pneumonia, increased sputum production, dry nasal mucosa, pulmonary edema, pulmonary embolism, hypoxia, respiratory failure, apnea.
Dermatological reactions: often - dry skin, itching, excessive sweating, skin ulceration; possibly - acne, vesiculobular (vesicular) rash, eczema, alopecia, psoriasis, seborrhea; rarely - maculopapular rash, exfoliative dermatitis, urticaria.
From the sensory organs: often - conjunctivitis, earache; possibly dry eyes, eye pain, tinnitus, middle ear inflammation, cataracts, loss of taste, blepharitis; rarely - increased lacrimation, frequent blinking, otitis externa, amblyopia, deafness, diplopia, ocular hemorrhage, photophobia.
From the urinary system: often - urinary incontinence; possible - cystitis, frequent urination, leukorrhea, urinary retention, hematuria, dysuria, amenorrhea, premature ejaculation, vaginal bleeding, vaginal candidiasis, renal failure, uterine bleeding, menorrhagia, albuminuria, kidney stones, nocturia, urination; rarely - pain in the mammary gland, cervicitis, galactorrhea, anorgasmia, burning in the genitourinary system, glycosuria, gynecomastia (enlargement of the mammary glands in men), urolithiasis, painful erection.
On the part of the body as a whole: often - flu-like syndrome, peripheral edema, pain in the chest, in the neck; possible - pelvic pain, facial swelling, malaise, photosensitivity, jaw pain, chills, stiffness of the jaw, bloating, tension in the chest; rare - sore throat, stiffness in the back, heaviness in the head, candidiasis, stiffness in the throat, Mendelssohn syndrome, heat stroke.
From the side of metabolism: often - weight loss, increased levels of CPK; possible - dehydration, edema, hypercholesterolemia, hyperglycemia, hypokalemia, diabetes mellitus, hyperlipidemia, hypoglycemia, thirst, increased blood urea, hyponatremia, iron deficiency anemia, increased creatinine, bilirubinemia, increased LDH levels; rarely - hyperkalemia, gout, hypernatremia, cyanosis, urine acidification, hypoglycemic reaction.
There are various ways of aripiprazole metabolism, including involving enzymes CYP2D6 and CYP3A4. In studies in healthy people, powerful inhibitors of CYP2D6 (quinidine) and CYP3A4 (ketoconazole) reduced the clearance of aripiprazole by ingestion by 52% and 38%, respectively (the dose of aripiprazole should be reduced while it is used with CYP3A4 and CYP2D6 inhibitors).
The administration of aripiprazole in a dose of 30 mg simultaneously with carbamazepine, a powerful inducer of CYP3A4, was accompanied by a decrease in Cmax and AUC of aripiprazole by 68% and 73%, respectively, and a decrease in Cmax and AUC of its active metabolite of dehydroaripiprazole by 69% and 71%, respectively. Other powerful inducers of CYP3A4 and CYP2D6 can be expected to have a similar effect.
Dosage and administration
The method of application and the dosage regimen of a particular drug depends on its form of release and other factors. The optimal dosage regimen is determined by the doctor. The compliance of the dosage form of a particular preparation with the indications for use and the dosage regimen should be strictly observed.
Individual, depending on the indications, the course of the disease, tolerability of therapy. The dose is 10-30 mg 1 time / day.
Use with caution in patients with cardiovascular diseases (coronary heart disease, including myocardial infarction, chronic heart failure, impaired conduction), conditions predisposing to arterial hypotension (dehydration, hypovolemia and taking antihypertensive drugs) due to the possibility of development orthostatic hypotension;
in patients with cerebrovascular disease, with convulsive seizures or suffering from diseases in which convulsions are possible; in patients with an increased risk of hyperthermia (for example, with intense physical exertion, overheating, taking anticholinergics, with dehydration due to the ability of antipsychotics to disrupt thermoregulation); in patients with an increased risk of aspiration pneumonia due to the risk of impaired motor function of the esophagus and aspiration; in patients with obesity, with a history of diabetes; taking funds with m-anticholinergic activity.
The tendency to suicidal thoughts and attempts is characteristic of psychoses, therefore, when conducting drug therapy, careful medical supervision is necessary.
The risk of developing tardive dyskinesia increases with the duration of antipsychotic therapy, so if symptoms of tardive dyskinesia appear while taking aripiprazole, you should reduce the dose or cancel it. After discontinuation of therapy, these symptoms may temporarily intensify or even appear for the first time.
In the treatment of antipsychotics, including aripiprazole may develop ZNS, which is manifested by hyperpyrexia, muscle rigidity, mental disorders and instability of the autonomic nervous system (irregular heart rate and blood pressure, tachycardia, sweating and cardiac arrhythmias). In addition, sometimes there is an increase in CPK activity, myoglobinuria (rhabdomyolysis) and acute renal failure. In case of symptoms of CNS or unexplained fever, all antipsychotics, including aripirazole must be discontinued.
Hyperglycemia, in some cases severe and associated with ketoacidosis, which can lead to hyperosmolar coma and even death, has been observed in patients taking atypical antipsychotics. Although the relationship between taking atypical antipsychotics and hyperglycemic type disorders remains unclear, patients who are diagnosed with diabetes should regularly check their blood glucose levels when taking atypical antipsychotics. Patients who have risk factors for diabetes (obesity, the presence of diabetes in the family) when taking atypical antipsychotics should determine the level of glucose in the blood at the beginning of the course and periodically during the drug. Any patient taking atypical antipsychotics requires constant monitoring of symptoms of hyperglycemia, including increased thirst, increased urination, polyphagy, and weakness. Influence on the ability to drive vehicles and control mechanisms
As with the appointment of other antipsychotics, when prescribing aripiprazole, the patient should be warned about the dangers of working with moving mechanisms and driving.