Azaleptol

Azaleptol has sedative and antipsychotic properties. It almost does not provoke the development of extrapyramidal disorders, which is why it is included in the category of "atypical" neuroleptic drugs.

Indications Azaleptol

The indication for prescribing the drug is schizophrenia (in the absence of results from therapy with standard neuroleptics or the patient’s hypersensitivity to them).

Release form

It is available in tablets of 25 or 100 mg. One blister contains 10 tablets, one package contains 5 blister strips. It can also be available in containers of 50 tablets (1 container per package).

Pharmacodynamics

The mechanism of the antipsychotic effect of the active substance of the drug has not yet been fully established. It is most active in relation to dopamine receptors located in the limbic region of the brain. Here, clozapine prevents the synthesis of dopamine with its receptors (type D1 and D2). This property is not as pronounced as in standard neuroleptics - this substance is synthesized mainly in non-dopaminergic areas (where histamine and serotonin receptors, cholinergic receptors, and α-adrenergic receptors are located).

Clozapine has little or no effect on plasma prolactin concentrations because it does not bind to dopamine receptors within the tuberoinfundibular tract.

Among the characteristic pharmacological properties of the active component is the suppression of the activation response due to electrical stimulation of the midbrain reticular formation, and in addition to this, a pronounced central cholinolytic effect, as well as peripheral action and peripheral adrenolytic effect. The drug does not have cataleptogenic properties. There is evidence that it can slow down the process of dopamine release from presynaptic nerve roots.

Clinical properties – a powerful antipsychotic effect, which is combined with sedative properties. At the same time, the drug does not have extrapyramidal side effects inherent in other neuroleptic drugs (it is possible that such a property is associated with the presence of a central anticholinergic effect in the drug). It does not have a strong general depressant effect on the central nervous system, unlike aminazine and other aliphatic phenothiazines.

Pharmacokinetics

The absorption rate of Azaleptol after oral administration is 90-95%. The degree of absorption and its rate do not depend on food intake. During the first pass, the drug is moderately metabolized. The bioavailability level figures are 50-60%.

In a steady state after 2-time use of the drug, the peak blood concentration occurs on average after 2.1 hours (within 0.4-4.2 hours). The distribution volume is 1.6 l/kg. Synthesis of the active component with plasma protein is approximately 95%.

Before the process of elimination of the active component, it is almost completely metabolized. At the same time, only one of the main breakdown products of the substance is pharmacologically active - desmethyl-clozapine. The properties of this metabolite are similar to the effects of clozapine, but they are weakly expressed and their effect is less long-lasting.

The active ingredient is eliminated in 2 stages (the average half-life is 12 hours (6-26 hours)). When using a single dose (75 mg), the half-life is 7.9 hours. This figure increases to 14.2 hours if the drug reaches a steady state after taking a single dose daily for at least 1 week. A small portion of the unchanged drug is determined in the feces with urine. About 50% of the dosage is excreted as decay products with urine, and another 30% with feces.

It is noted that during the equilibrium period of concentration, in the case of an increase in the dosage of the drug from 37.5 to 75/150 mg 2 times a day, there is a linear (dose-dependent) increase in the AUC level, and in addition to this, the minimum and maximum indicators in the blood plasma.

Dosing and administration

It should be taken orally after meals, 2-3 times a day. A single dose for an adult patient is 50-200 mg. It is allowed to take 200-400 mg of the drug per day. The treatment process usually begins with a dosage of 25-50 mg, and then it is gradually increased (25-50 mg every day) to a daily rate of 200-300 mg over 1-2 weeks.

For maintenance treatment, as well as for outpatients, 25-200 mg should be taken per day (a single dose is allowed in the evening).

In case of drug withdrawal, the dosage should be gradually reduced over 1-2 weeks. No more than 600 mg per day is allowed.

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Use Azaleptol during pregnancy

During pregnancy, the drug should be taken with caution. It is prescribed only in cases where the benefit from using the drug is higher than the development of negative effects from it for the fetus.

Neonatal exposure to antipsychotics (including clozapine) during the third trimester of pregnancy may increase the risk of adverse reactions (including extrapyramidal disorders or withdrawal syndrome) that develop after delivery and may vary in duration and severity. Symptoms of increased blood pressure, agitation, drowsiness, respiratory or feeding disorders have been observed. Therefore, the condition of newborns requires careful monitoring.

Contraindications

Among the contraindications:

• if there are changes in blood counts (development of agranulocytosis or granulocytopenia);
• alcoholic and other psychoses caused by toxins;
• infantile tetany;
• epilepsy;
• severe forms of cardiovascular diseases, as well as kidney or liver diseases;
• pathologies of the hematopoietic system;
• closed-angle glaucoma;
• prostate hypertrophy;
• intestinal atony;
• state of coma;
• vascular collapse or suppression of central nervous system function of any origin;
• paralytic form of intestinal obstruction.

Side effects Azaleptol

The possibility of developing or increasing side effects increases if the drug is prescribed in a dosage of more than 450 mg (per day). Among them:

• agranulocytosis or granulocytopenia, which mainly appear during the first 18 weeks of treatment;
• leukocytosis or eosinophilia of unknown origin may develop (especially during the first weeks of treatment);
• often develop severe fatigue or a feeling of drowsiness. Headaches, dizziness, epileptic seizures, and in addition convulsive twitching may occur. Extrapyramidal disorder develops quite rarely, usually in a mild form. There are also data on the appearance of tremor, rigidity, and in addition akathisia. A malignant form of neuroleptic syndrome develops isolated;
• dry mouth, disturbance of sweating, accommodation or thermoregulation processes. Also development of hyperthermia or ptyalism;
• tachycardia or orthostatic collapse may develop. In rarer cases, fainting (especially during the first weeks of therapy). An increase in blood pressure is rarely observed. Collapse occurs occasionally, which is accompanied by depression of the respiratory process or its cessation. Changes in ECG readings occur sporadically, myocarditis, arrhythmia, thromboembolism or pericarditis develop;
• constipation or vomiting with nausea may develop. The activity of liver enzymes increases occasionally. Pancreatitis, intrahepatic cholestasis or usual cholestasis, and dysphagia are rarely observed;
• there is information about the development of urinary incontinence or, on the contrary, its retention. Priapism, tubulointerstitial nephritis, and an increase in the level of creatine phosphokinase may be observed;
• weight gain. Skin allergies are occasionally observed.

There is information about sudden deaths of patients, which occur equally often both with patients suffering from mental disorders and treated with antipsychotics, and with patients who have not undergone treatment.

Among other reactions:

• development of diabetes and decreased glucose tolerance;
• development of delirium or the appearance of confusion;
• cardiomyopathy, anemia or thrombocytopenia;
• tardive dyskinesia;
• rapidly progressive liver necrosis;
• development of ketoacidosis, acute hyperglycemia, and in addition hypertriglyceridemia or hypercholesterolemia, as well as a state of non-ketonemic coma;
• depression of the respiratory process or its cessation.

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Overdose

Symptoms of overdose include:

• feeling drowsy, agitated, or confused;
• the appearance of hallucinations, convulsions, or dyspnea;
• development of tachycardia, mydriasis, arrhythmia, extrapyramidal disorders, collapse, aspiration pneumonia, and also ptyalism;
• a state of delirium, lethargy or coma;
• areflexia or, conversely, hyperreflexia;
• loss of visual acuity;
• lowering blood pressure;
• changes in body temperature;
• problems with conduction within the myocardium;
• depression of respiratory function or its cessation.

To eliminate such manifestations, gastric lavage should be performed, and if necessary, the patient should be given activated carbon. Symptomatic therapy is also performed with monitoring of the respiratory and cardiovascular systems; in addition, it is necessary to monitor the water-electrolyte and acid-base balance.

If blood pressure levels drop, the patient should not be prescribed adrenaline or its derivatives.

You should be monitored by a doctor for at least 4 days to exclude the risk of late reactions.

Hemodialysis with peritoneal dialysis does not provide the desired effect.

Interactions with other drugs

Clozapine can enhance the central effect of ethyl alcohol, drugs that depress the central nervous system (such as benzodiazepine derivatives, antihistamines, and opiates), and also MAO inhibitors. In case of combining the drug with benzodiazepines, and also when using Azaleptol shortly after benzodiazepine therapy, the possibility of hypotension reactions increases, as well as the development of collapse and depression of respiratory processes or its cessation.

When combined, the effect of Azaleptol and drugs with antihypertensive and anticholinergic effects, as well as drugs that suppress respiratory function, may be mutually enhanced.

Combination of clozapine with drugs that are effectively synthesized with plasma protein (for example, warfarin) may increase the free fraction of any of the active components in the blood, which may cause adverse reactions.

Combination of Azaleptol with drugs that suppress bone marrow function is prohibited.

As a result of the combined use of high doses of Azaleptol and erythromycin or cimetidine, the plasma concentration of clozapine increases, and side effects develop.

There are isolated reports of increased serum clozapine levels as a result of combination with fluvoxamine or other selective serotonin reuptake inhibitors (sertraline or fluoxetine, as well as paroxetine or citalopram).

Medicines that increase the activity of enzymes of the hemoprotein P450 system are capable of decreasing the plasma concentration of the active component of Azaleptol. Due to the withdrawal of carbamazepine used simultaneously, the plasma index of clozapine increased. The compound with phenytoin decreases the plasma index of clozapine, as a result of which the effectiveness of the drug is weakened.

Combination with lithium drugs, as well as drugs that affect the central nervous system, may increase the possibility of developing a malignant form of neuroleptic syndrome.

Since Azaleptol has adrenolytic properties, it is able to reduce the hypertensive effect of the substance norepinephrine, and in addition other drugs that have predominant α-adrenergic properties. It can also eliminate the pressor effect of adrenaline.

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Storage conditions

The medicine must be kept in normal conditions for medicines - out of reach of sunlight, children, and moisture. Temperature - maximum 25 degrees.

Shelf life

Azaleptol is suitable for use for 3 years from the date of manufacture of this medicine.