Pharmacological action of Clozaril

Antipsychotic agent (neuroleptic), derivative of dibenzodiazepine. It has a pronounced antipsychotic and sedative effect. Practically does not cause extrapyramidal disturbances; in this regard, clozapine belongs to the group of so-called "atypical" antipsychotics.

The antipsychotic effect is due to the blockade of dopamine D2receptors in the mesolimbic and mesocortical structures of the brain.

The sedative effect is due to the blockade of α-adrenergic receptors of the reticular formation of the brain stem; antiemetic action - blockade of dopamine D2-receptors of the trigger zone of the vomiting center; hypothermic action - blockade of dopamine receptors of the hypothalamus. It has a peripheral and central m-anticholinergic, α-adrenergic blocking effect. Does not affect the concentration of prolactin in the blood.

The antipsychotic action is close to that of aliphatic phenothiazines, but without a "submelancholic shade" and unpleasant subjective sensations, does not have a cataleptogenic effect, and reduces the threshold of convulsive readiness.

Does not affect higher intellectual functions.

The development of the therapeutic effect is characterized by stages: the rapid onset of hypnotic and sedative action; relief of anxiety, psychomotor agitation and aggressiveness (after 3-6 days); antipsychotic action (after 1-2 weeks); action on negativism symptoms (after 20-40 days).

Pharmacokinetics

When taken orally, it is absorbed from the gastrointestinal tract quickly and almost completely. Cmax in plasma is achieved on average within 2.5 hours. Css is achieved after 8-10 days of admission. Undergoes intensive metabolism during the "first pass" through the liver with the formation of metabolites of low activity or inactive. Metabolized with the participation of the CYP1A2 isoenzyme. The distribution is intense and fast, penetrates the BBB. Protein binding - 95%.

T1/2 is characterized by variability and after taking a single dose of 75 mg is 8 hours (4-12 hours), after taking 100 mg 2 times / day - 12 hours (4-66 hours).

It is excreted by the kidneys - 50% and through the intestines - 30%.

Indications for the active substances of the drug Clozapine

Acute and chronic forms of schizophrenia, manic states, manic-depressive psychosis, psychomotor agitation in psychopathies, emotional and behavioral disorders (including in children), sleep disorders.

Dosage regimen

Set individually. For oral administration, a single dose is 50-200 mg, the daily dose is 200-400 mg. Treatment is usually started with a dose of 25-50 mg, then gradually increased by 25-50 mg per day to 200-300 mg / day for 7-14 days. The daily dose can be used once before bedtime or 2-3 times / day after meals. If treatment is discontinued, the dose should be gradually reduced over 1 to 2 weeks. After achieving a therapeutic effect, they switch to a maintenance course.

If necessary, clozapine can be administered IM.

The maximumdose oralis 600 mg / day.

In milder forms of the disease, for maintenance therapy, as well as in patients with hepatic and / or renal failure, chronic heart failure, cerebrovascular disorders, it is prescribed in lower daily doses (25-200 mg).

Contraindications to the use

Granulocytopenia or agranulocytosis in anamnesis (with the exception of the development of granulocytopenia or agranulocytosis due to previously used chemotherapy), inhibition of bone marrow hematopoiesis, myasthenia gravis, coma, toxic psychosis (including alcoholic), childhood, lactation period years, hypersensitivity to clozapine.

Application during pregnancy and lactation

Clozapine is contraindicated in pregnancy and lactation (breastfeeding).

Application for violations of liver function

Use with caution in severe liver failure. In patients with hepatic insufficiency, the drug is prescribed in a lower daily dose (25-200 mg).

Application for impaired renal function

Use with caution in severe renal failure. In patients with renal insufficiency, the drug is prescribed in a lower daily dose (25-200 mg).

Use in children

Contraindicated in children under 5 years of age. The safety and efficacy of clozapine in children and adolescents under the age of 16 has not been established.

Special instructions

Use with caution in severe diseases of the cardiovascular system, severe renal and / or liver failure, angle-closure glaucoma, with prostatic hyperplasia, intestinal atony, epilepsy, intercurrent diseases with febrile syndrome.

During the treatment period, systematic monitoring of the peripheral blood picture is necessary.

When using clozapine, alcohol should be avoided.

The safety and efficacy of clozapine in children and adolescents under the age of 16 has not been established.

Influence on the ability to drive vehicles and control mechanisms

Patients taking clozapine should refrain from potentially hazardous activities associated with the need for concentration and increased speed of psychomotor reactions.

Drug interaction

With simultaneous use with drugs that have a depressing effect on the central nervous system (including benzodiazepine derivatives), ethanol-containing drugs, ethanol, the severity and frequency of manifestations of a depressive effect on the central nervous system, increased depression of the respiratory center.

With simultaneous use with drugs that cause arterial hypotension, an additive hypotensive effect is possible.

With simultaneous use with drugs that cause myelodepression, it is possible to increase the inhibitory effect on bone marrow hematopoiesis; with anticholinergics - an increase in anticholinergic action is possible.

With simultaneous use with digoxin or with drugs characterized by high binding to proteins (including heparin, warfarin, phenytoin), their concentrations in blood plasma may increase, and clozapine may also be displaced from the sites of its binding to proteins by these drugs.

With simultaneous use with valproic acid, it is possible to change the concentration of clozapine in the blood plasma, while the clinical manifestations of the interaction were practically absent.

With simultaneous use with carbamazepine, the concentration of clozapine in the blood plasma decreases. Cases of severe pancytopenia and neuroleptic malignant syndrome have been described.

With simultaneous use with caffeine, the concentration of clozapine in the blood plasma increases and the incidence of side effects may increase.

With simultaneous use with lithium carbonate, myoclonus, convulsions, neuroleptic malignant syndrome, delirium, psychosis are possible.

With simultaneous use with risperidone, an increase in the concentration of clozapine in the blood plasma is possible, apparently due to a competitive effect on the CYP2D6 isoenzyme, which leads to inhibition of clozapine metabolism. With the rapid replacement of clozapine with risperidone, dystonia may develop.

Rifampicin can increase the metabolic rate of clozapine by inducing the isoenzymes CYP1A2 and CYP3A.

With simultaneous use with phenytoin, it is possible to reduce the concentration of clozapine in the blood plasma; with fluoxetine, paroxetine, sertraline, fluvoxamine, an increase in the concentration of clozapine in the blood plasma is possible, which in some patients is accompanied by manifestations of toxicity. This effect is especially pronounced with the simultaneous use of clozapine with fluvoxamine.

With simultaneous use with ciprofloxacin, an increase in the concentration of clozapine in blood plasma is possible.

Side effect

From the side of the central nervous system: drowsiness, headache, rarely - agitation, akathisia, confusion, extrapyramidal disorders (akinesia, hypokinesia, muscle stiffness, tremor), insomnia, restless sleep, depression, NNS, epileptic seizures, tardive dyskinesia, fever central genesis.

From the side of the cardiovascular system: tachycardia, arterial hypotension, orthostatic hypotension, accompanied by dizziness; rarely - flattening of the T wave on the ECG, arterial hypertension.

From the digestive system: hypersalivation, nausea, vomiting, dry mouth, heartburn.

From the side of metabolism: an increase in body weight, increased sweating.

From the hematopoietic system: rarely - eosinophilia, granulocytopenia up to agranulocytosis, leukopenia, thrombocytopenia.

Effects due to anticholinergic activity: dry mouth, accommodation disturbances, constipation, urinary disturbances.

Others: myasthenia gravis, decreased potency, violation of accommodation.