Pharmacological properties
Clozapine (8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo-[b, e][1,4]-diazepine) belongs to the group of atypical neuroleptics. It has a pronounced antipsychotic and sedative effect, practically does not cause extrapyramidal disorders. The mechanism of antipsychotic action of clozapine has not been definitively established. The highest activity is noted in relation to dopamine receptors of the limbic region of the brain, where clozapine prevents the binding of dopamine to d1- and d2-dopamine receptors. This effect is less pronounced than in "typical" neuroleptics. Clozapine binds mainly in non-dopaminergic areas (with alpha-adrenergic receptors, serotonin, histamine and cholinergic receptors). Clozapine has little or no effect on the concentration of prolactin in the blood plasma, since it does not bind to dopamine receptors in the tuberoinfundibular tract. The characteristic pharmacological features of clozapine are the inhibition of the activation response to electrical stimulation of the reticular formation of the midbrain, recorded on the EEG, pronounced central and peripheral anticholinergic, as well as peripheral adrenolytic action. The drug does not have a cataleptogenic effect, inhibits the release of dopamine by presynaptic nerve endings.
Clinically, it is distinguished by a strong antipsychotic effect in combination with a sedative component in the absence of extrapyramidal side effects characteristic of other neuroleptics (which is possibly due to the central anticholinergic effect of the drug). It does not cause significant CNS depression, like aminazine and other aliphatic phenothiazines.
When taken orally, it is absorbed quickly and almost completely. The maximum concentration in the blood plasma is reached on average within 2.5 hours. The equilibrium concentration is reached after 8-10 days of administration. It is subjected to intensive metabolism during the first pass through the liver with the formation of metabolites of low activity or inactive. Distribution is intensive and rapid. Penetrates the blood-brain barrier. Binding to blood plasma proteins is 95%; half-life is 8 hours. Excreted by the kidneys - 50% and through the intestines - 30%.
Indication
It is used for hallucinatory-delusional, catatonic-hebephrenic, catatonic-hallucinatory states and states of psychomotor agitation in schizophrenia, for manic syndrome within the framework of manic-depressive psychosis, for affective tension and mood disorders, for psychopathy in disturbed patients. In some cases, the drug is effective in cases of resistance to treatment with other neuroleptics.
Application
The dose is set individually. It is prescribed orally (after meals) 2-3 times a day. A single dose for adults is usually 50-200 mg, a daily dose is 200-400 mg. Treatment is usually started with a dose of 25-50 mg, then gradually increased by 25-50 mg/day to 200-300 mg/day for 7-14 days. For maintenance therapy and outpatients, 25-200 mg/day is prescribed (can be given once in the evening). In low doses (25-50 mg), the drug can be used for sleep disorders of various genesis. When the drug is discontinued, the dose should be gradually reduced over 1-2 weeks. The maximum daily dose is 600 mg.
Contraindication
Contraindicated in patients with changes in blood composition, alcoholic and other toxic psychoses, spasmophilia, epilepsy, severe diseases of the liver, kidneys, cardiovascular system, hematopoietic disorders, angle-closure glaucoma, prostatic hypertrophy, intestinal atony, comatose states, and during pregnancy.
Side effects
The risk of occurrence and/or increased severity of side effects increases when clozapine is prescribed in a daily dose exceeding 450 mg.
From the blood system: granulocytopenia, agranulocytosis (usually develops within the first 18 weeks of treatment), eosinophilia and/or leukocytosis (especially during the first weeks of treatment).
From the side of the central nervous system: most often - drowsiness, increased fatigue, dizziness, headache, relatively rarely - extrapyramidal symptoms, usually mild in severity. There are reports of the development of rigidity, tremor, akathisia, as well as very rare reports of the development of neuroleptic malignant syndrome.
From the autonomic nervous system: feeling of dry mouth, impaired accommodation, sweating and thermoregulation, hyperthermia, excessive salivation.
Cardiovascular system: tachycardia, orthostatic hypotension, less often - fainting (especially in the first weeks of treatment), relatively rarely - arterial hypertension. In rare cases, collapse has been reported, which was accompanied by respiratory depression or arrest. There are isolated reports of changes in the ECG, the development of arrhythmias, myocarditis.
From the digestive tract and liver: nausea, vomiting, constipation are possible. Increased activity of liver enzymes has been reported, in rare cases - the development of cholestasis.
Urinary system: there are reports of cases of urinary incontinence and urinary retention.
Other: weight gain; there are isolated reports of skin reactions. Cases of sudden death have been described, which occur with equal frequency both among patients with mental disorders receiving antipsychotic drugs and among patients not receiving these drugs.
Special instructions
Like other neuroleptics, the drug should not be prescribed to outpatients if they perform work that requires rapid mental and physical reactions (transport drivers, etc.).
It is used with extreme caution in cases of suspected angle-closure glaucoma, prostatic hypertrophy, epilepsy (including a history), as well as in patients with diseases of the cardiovascular system, gastrointestinal tract, and impaired renal function.
During treatment, systematic monitoring of peripheral blood composition is necessary.
When using clozapine, alcohol consumption should be avoided.
Interactions
Clozapine may potentiate the central effects of ethanol, MAO inhibitors and CNS depressants (narcotic analgesics, antihistamines, benzodiazepine derivatives). With the simultaneous appointment of clozapine and benzodiazepines, as well as in the case of recent treatment with benzodiazepines, the risk of developing hypotensive reactions, collapse, as well as respiratory depression and arrest is increased. Mutual enhancement of effects is possible with the simultaneous appointment of clozapine and drugs with anticholinergic, hypotensive properties, as well as drugs that depress the respiratory center. With the simultaneous appointment of clozapine and drugs with a high degree of binding to blood plasma proteins (for example, warfarin), an increase in the content of the free fraction of any of the active substances in the blood is possible, which can lead to the occurrence of side effects.
Overdose
Drowsiness, coma, areflexia, confusion, agitation, delirium, increased reflexes, convulsions, increased salivation, mydriasis, impaired visual acuity, change in body temperature, tachycardia, hypotension, collapse, arrhythmia, impaired myocardial conduction, respiratory depression.
Treatment: gastric lavage, if necessary, prescribe activated charcoal. Symptomatic treatment is carried out under conditions of monitoring the function of the cardiovascular and respiratory systems, control of water-electrolyte balance and acid-base balance. In case of hypertension, the appointment of adrenaline and its derivatives should be avoided. For at least 4 days, a doctor's observation is necessary due to the possibility of developing late reactions. Peritoneal dialysis and hemodialysis are ineffective.
Storage conditions
In a dry place, protected from light.
