Pharmacodynamics and pharmacokinetics
Pharmacodynamics
Antipsychotic drug, refers to dibenzodiazepine . Has a strong sedative and antipsychotic effect. Almost does not provoke the appearance of extrapyramidal disorders , which is why clozapine is classified as an atypical type of antipsychotic.
The antipsychotic effect is caused by the blockade of D2-dopamine receptors in certain brain structures.
The sedative effect occurs due to blockade of alpha-adrenergic receptors in the brainstem ; the antiemetic effect is due to the blockade of D2-dopamine receptors of the vomiting center ; the hypothermic effect provokes inhibition of dopamine receptors in the hypothalamus region . The drug has central and peripheral m-anticholinergic, alpha-adrenergic blocking effects. Does not change plasma prolactin
The antipsychotic effect is not accompanied by subjective unpleasant sensations, does not have a cataleptogenic effect, but lowers the convulsive threshold. Does not change higher intellectual activity.
The therapeutic effect develops in stages: first, a hypnotic and sedative effect develops quickly; then after 3-6 days anxiety, aggressiveness and psychomotor agitation disappear; after another 1-2 weeks, the antipsychotic effect is recorded; a decrease in symptoms of negativism occurs after 25-40 days of treatment.
Pharmacokinetics
Well absorbed in the intestines. Bioavailability is 30-57%. The highest concentration is determined in the blood in most cases after 2.5-3 hours.
Reacts with plasma proteins by 96%. The active substance is quickly distributed throughout the tissues and accumulates in parenchymal organs (liver, lungs, kidneys).
Transformed in the liver under the action of the enzyme CYP1A2, the derivatives have weak pharmacological activity or are completely inactive.
It is excreted in the form of derivatives by the kidneys (half of the dose taken) and with bile (35% of the dose taken). The half-life is subject to strong fluctuations and can last from 4 hours to 2.5 days.
Pharmacological properties of the drug Clozapine
Tricyclic dibenzodiazepine derivative. Neuroleptic, has antipsychotic and sedative effects. Blocks dopamine receptors in the central nervous system, has peripheral and central anticholinergic, as well as adrenolytic, antihistamine and antiserotonin effects. A distinctive feature of clozapine is that it practically does not cause significant extrapyramidal disorders and does not have a pronounced inhibitory effect. Treatment with clozapine does not cause an increase in prolactin levels in the blood and, therefore, does not lead to the development of gynecomastia, amenorrhea, galactorrhea and impotence.
Contraindications
- suppression of bone marrow hematopoiesis;
- granulocytopenia, granulocytosis in the past (except in cases where these conditions developed as a result of chemotherapy );
- comatose states;
- myasthenia gravis;
- lactose intolerance lactase deficiency , glucose-galactose malabsorption syndrome;
- toxic psychosis;
- pregnancy and lactation;
- allergy to clozapine ;
- age less than 16 years.
The drug should be prescribed with caution for decompensated cardiovascular diseases, angle-closure glaucoma , severe renal and liver failure, prostate hyperplasia , epilepsy , intercurrent disorders with febrile syndrome , intestinal atony .
Side effects
- Reactions from the nervous system: drowsiness, dizziness, fever, headache, agitation, fainting, confusion, akathisia, hypokinesia, tremor , depression , muscle rigidity , sleep disturbances, epileptic seizures, insomnia , neuroleptic malignant syndrome (difficulty breathing, tachypnea, convulsions, arrhythmia , unstable blood pressure, fever, involuntary urination, muscle rigidity, fatigue, pale skin), tardive dyskinesia .
- From the genitourinary system: urinary retention, decreased potency.
- Metabolism: weight gain.
- From the skeletal system: myasthenia gravis .
- From the digestive system: dry mouth, nausea, hypersalivation , heartburn , vomiting, constipation .
- From the side of hematopoiesis: granulocytopenia, leukopenia, agranulocytosis (manifested by chills, sore throat, fever , inflammation of the gums and oral mucosa, furunculosis , deterioration of wound healing, exacerbation of chronic foci of infections - periostitis , tonsillitis , pyoderma ), thrombocytopenia .
- From the sensory organs: deterioration of accommodation.
- From the circulatory side: decrease or increase in blood pressure, tachycardia , decrease in the T wave on the ECG .
Side effects of the drug Clozapine
The risk of occurrence and/or intensification of side effects increases when clozapine is prescribed in a daily dose exceeding 450 mg. Hematological: granulocytopenia, agranulocytosis (usually develops during the first 18 weeks of treatment); the development of eosinophilia and/or leukocytosis of unknown etiology is possible (especially during the first weeks of treatment). From the side of the central nervous system: most often - drowsiness, increased fatigue; Possible dizziness, headache, relatively rarely - extrapyramidal symptoms, usually of mild 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: a feeling of dry mouth, disturbances of accommodation, sweating and thermoregulation, hyperthermia, excessive salivation. From the cardiovascular system: possible tachycardia, orthostatic hypotension, less often - fainting (especially in the first weeks of treatment), relatively rarely - hypertension (arterial hypertension). In rare cases, collapse has been reported, accompanied by depression or respiratory arrest. There are isolated reports of changes in the ECG, the development of arrhythmia, and myocarditis. From the digestive tract and liver: nausea, vomiting, constipation are possible. An increase in the activity of liver enzymes has been reported, and in rare cases, the development of cholestasis. From the urinary system: there are reports of cases of urinary incontinence and urinary retention. Other: weight gain; There are isolated reports of the development of skin reactions. Cases of sudden death have been described, occurring with equal frequency both among people with mental disorders receiving antipsychotic drugs and among patients who do not receive these drugs.
Clozasten, instructions for use (Method and dosage)
Clozasten tablets are taken orally, after meals, two to three times a day.
A single dose for persons over 16 years of age is 50-200 mg, the initial dose is 150-300 mg per day, the standard dose is 200-400 mg per day. The maximum dose is 600 mg per day.
The dosage is selected individually, first prescribing 25 mg of the drug per day, and then gradually increasing by 25-50 mg per day until the therapeutic effect is registered.
For diseases in mild forms for maintenance treatment, as well as in persons with insufficiency of the kidneys, liver or heart, with cerebrovascular diseases, the drug is prescribed in lower doses (25-200 mg per day).
It is necessary to take into account the stages of onset of the therapeutic effect (as indicated above: the rapid onset of a hypnotic and sedative effect; then, within 3-6 days, anxiety, aggressiveness and psychomotor agitation are relieved; after 2-3 weeks, registration of an antipsychopathic effect; after 20-40 days – disappearance of signs of negativism.
After achieving a therapeutic effect, they switch to a maintenance therapy regimen.
Overdose
Signs of overdose: drowsiness, stupor, respiratory depression, soporosis, delirious disorders , coma, anxiety, epileptic seizures, temperature lability, collapse , agitation, decreased blood pressure, tachycardia, arrhythmia, intestinal atony .
Overdose therapy: gastric lavage with enterosorbents , maintaining breathing and heart function, monitoring electrolyte and acid-base balance, symptomatic treatment. During the 4 days following the disappearance of signs of poisoning, the patient is monitored in case of late complications. Hemodialysis is ineffective.
Interaction
Stimulates the effect of antihypertensive, hypnotic and sedatives, opioid analgesics, drugs for general anesthesia, MAO inhibitors, ethanol. Suppresses the effect of Levodopa and other dopamine receptor stimulants.
Adsorption from the intestines worsens when taking antacids with a gel-like consistency and Cholestyramine.
In combination with benzodiazepines , disturbance of consciousness, excessive decrease in blood pressure, and respiratory arrest are possible.
Concomitant use of lithium-containing drugs increases the neurotoxicity of Clozasten ( convulsions , delirium, extrapyramidal disorders ).
Concomitant use of Pentetrazole increases the likelihood of seizures .
The drug should not be used together with antipsychotics, tricyclic antidepressants, gold preparations, hematotoxic agents, carbamazepine, antidepressants, antimalarials and thyreostatics .
Caution is recommended when prescribing anticoagulants, anticonvulsants, hypoglycemic and antimicrobial drugs .
Myelotoxic drugs enhance the hematotoxic effects of Clozasten.
Drug interactions Clozapine
Clozapine can potentiate the central effects of ethanol, MAO inhibitors and CNS depressants (narcotic analgesics, antihistamines, benzodiazepine derivatives). With the simultaneous administration 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 administration of clozapine and drugs that have anticholinergic, hypotensive properties, as well as drugs that depress respiration. With the simultaneous administration of clozapine and drugs that have a high degree of binding to plasma proteins (for example, warfarin), it is possible to increase the content of the free fraction of any of the active substances in the blood, which can lead to side effects.
special instructions
granulocytopenia occurs, treatment must be stopped immediately.
To relieve arterial hypotension after taking clozapine , it is allowed to use only norepinephrine or Angiotensin .
When using clozapine, it is recommended to abstain from drinking alcoholic beverages.
At the beginning of treatment, peripheral blood patterns should be monitored weekly and every 3 months. granulocytopenia develops, treatment is immediately stopped.
During treatment with this drug, use caution when driving due to a possible worsening of the reaction.
Special instructions for the use of Clozapine
Given the high risk of developing agranulocytosis during treatment with clozapine, it should be prescribed only to those patients with schizophrenia who have no effect from treatment with classical antipsychotics or in case of their intolerance. A prerequisite is also that the patient initially has a normal quantitative and qualitative composition (leukocyte formula) of leukocytes in the blood. During treatment with clozapine, systematic monitoring of the number of leukocytes and leukocyte formula is necessary: weekly for the first 18 weeks and at least once a month thereafter throughout the course of treatment. Caution should be exercised when prescribing clozapine to patients with prostatic hypertrophy and angle-closure glaucoma; diseases of the liver, kidneys, heart. In these patients, systematic monitoring of the function of the liver, kidneys, and cardiovascular system is necessary. Due to the ability of clozapine to cause sedation and lower the seizure threshold, patients should avoid driving vehicles or operating potentially dangerous machinery, especially during the first weeks of treatment. The safety of clozapine during pregnancy has not been established. If clozapine is prescribed during breastfeeding, breastfeeding should be interrupted.
Analogues of Clozasten
Level 4 ATX code matches:
Lakvel
Leponex
Zalasta
Quentiax
Ketilept
Zyprexa
Clozapine
Quetiapine
Seroquel
Azaleptin
Azaleptin, Azaleptol, Leponex, Hedonin, Clozapine, Quetixol, Quetipin, Quetirol, Ketilept, Nantharide, Seroquel.
