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Ketilept (Quetiapinum, Quetiapine) - has antipsychotic effects.
Mechanism of action. Quetiapine is an atypical antipsychotic, which exhibits higher affinity for serotonin receptors (5HT2) receptors than for dopamine D1 and D2 brain. Quetiapine also has a higher affinity for histamine and α1-adrenoceptors and smaller towards α2-adrenoceptors. There were no appreciable affinity for cholinergic muscarinic to quetiapine and benzodiazepine receptors. The standard tests shows quetiapine antipsychotic activity.
The results of the study of extrapyramidal symptoms (EPS) in animals revealed that quetiapine is weak catalepsy in a dose effective blocking dopamine D2-receptors. Quetiapine is a selective decrease in the activity of mesolimbic A10 dopaminergic neurones versus the A9 nigrostriatal neurones involved in motor function.
In clinical trials, there were no differences between the use of quetiapine (at a dose of 75-750 mg / day) and placebo in the incidence of cases of extrapyramidal symptoms and concomitant use of anticholinergics. Quetiapine does not cause long-term increase prolactin concentration in blood plasma. Numerous studies fixed dose there were no differences in the level of prolactin using quetiapine or placebo.
In clinical trials, quetiapine demonstrated efficacy in treating both positive and negative symptoms of schizophrenia.
Effects of quetiapine on 5HT2 and D2 receptors lasts up to 12 hours after ingestion.
When taken orally, quetiapine is well absorbed from the gastrointestinal tract and extensively metabolised in the liver. The major metabolites found in the plasma does not possess a pronounced pharmacological activity.
Food intake did not significantly affect the bioavailability of quetiapine. T1 / 2 is about 7 hours. Approximately 83% of quetiapine is bound to plasma proteins. The pharmacokinetics of quetiapine linear, differences in pharmacokinetic parameters in men and women is not observed.
The average clearance of quetiapine in elderly patients is 30-50% less than in patients aged 18 to 65 years.
The average plasma clearance of quetiapine is less than approximately 25% in patients with severe renal insufficiency (Cl kreatinina2) and in patients with liver disease (stable alcoholic cirrhosis), but the individual clearance figures are in the range corresponding to that of healthy people.
Approximately 73% of quetiapine is excreted in urine and 21% - with the feces. Less than 5% of quetiapine is not metabolized and is excreted unchanged by the kidneys, or the faeces. It is found that CYP3A4 metabolism is a key enzyme quetiapine mediated by cytochrome P450.
The pharmacokinetics of quetiapine study in varying dosage is shown in appointing quetiapine before receiving ketoconazole or concurrently with ketoconazole, occurs Cmax increase and AUC quetiapine, on average 235 and 522%, respectively, as well as a decrease in clearance quetiapine, on average, 84% . T1 / 2 of quetiapine was increased, but the average Tmax was not changed.
Quetiapine and its metabolites have some weak inhibitory activity towards cytochrome P450 enzymes 1A2, 2C9, 2C19, 2D6 and 3A4, but only at concentrations exceeding 10-50 times the concentration observed with commonly used effective dosage of 300-450 mg / day .
Based on the results of in vitro, should not be expected that co-administration of quetiapine with other drugs will result in clinically significant inhibition of the metabolism of other drugs mediated by cytochrome P450.
Ketilept should be used with caution in patients with diagnosed cardiovascular disease, cerebrovascular disease, or other conditions predisposing to hypotension.
Ketilept can cause orthostatic hypotension, particularly in the initial period of a dose of refinement; This often occurs in the elderly than in younger patients.
There was no relationship between quetiapine and QTc prolongation. However, the appointment of quetiapine in conjunction with drugs that prolong the interval QTs, care must be taken, especially in the elderly.
There were no differences in the incidence of seizures in patients taking Ketilept or placebo. However, as well as in the treatment of other antipsychotics, it is recommended to use caution when treating patients with the presence of seizures in history.
Ketilept as other antipsychotic drugs, with long-term use may cause tardive dyskinesia. In case of signs and symptoms of tardive dyskinesia should consider dose reduction or withdrawal of the drug.
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome may be associated with antipsychotic treatment conducted. The clinical manifestations of the syndrome include hyperthermia, altered mental status, muscular rigidity, instability of the autonomic nervous system, increased CPK levels. In such cases Ketilept should be repealed and treated appropriately.
Reactions sudden cancellation
Symptoms of acute cancellation (including nausea, vomiting, insomnia) are described in very rare cases, after abrupt cessation of antipsychotic drugs in high doses. Possible recurrence of symptoms of psychosis and the emergence of disorders associated with involuntary movements (akathisia, dystonia, dyskinesia). Therefore, if necessary, discontinuation is recommended a gradual reduction in dose.
In drawing up the diet for patients with lactose intolerance should be noted that the tablet film-coated 100 mg, 200 mg and 300 mg contain lactose, respectively, 17.05 mg, 34.1 mg and 50.94 mg. This drug should not be administered to patients with rare hereditary disorders galactose intolerance, lapp lactase hereditary deficiency or malabsorption syndrome glucose-galactose. Considering that quetiapine primarily affect the central nervous system, the drug should be used with caution in combination with other drugs having inhibitory effect on the CNS, or alcohol.
In controlled clinical trials quetiapine no cases of sustained severe neutropenia or agranulocytosis. The observation period after the registration of the drug leukopenia and / or neutropenia were after cessation of quetiapine. Possible risk factors for leucopenia and / or neutropenia include pre-existing reduction in the number of white blood cells and the presence of drug leukopenia and / or neutropenia in history.
As with other antipsychotics with alpha1-adrenoblokiruyuschey activity Ketilept may cause orthostatic hypotension with dizziness, tachycardia, and (in some patients), syncope, especially during the initial dose-titration period.
In very rare cases during quetiapine marked hyperglycemia, and worsening of pre-existing diabetes.
The connection of quetiapine with reduced levels of thyroid hormone (T4 and free T4) caused by his reception in small doses. The maximum decrease occurred during the first two to four weeks of quetiapine, but long-term course of treatment further decline did not occur. Less than significant decrease Ts and Ts reverse was observed only when taking quetiapine at higher doses. TSH and TSH levels (thyroxine-binding globulin) remained unchanged. In almost all cases, termination of quetiapine led to recovery of T4 and free T4 levels regardless of the duration of treatment. Symptomatic hypothyroidism is not detected.
Use in Pediatrics
Efficacy and safety of quetiapine in children and adolescents has not been established.
Effects on ability to drive vehicles and mechanisms
Due to the effect on the central nervous system Ketilept can cause drowsiness. Therefore, in the early stages of treatment, for individually defined period of time, the patient should not be allowed to drive motor vehicles or dangerous machinery. In the future, the degree of limitation is set individually.
Ketilept Inside, regardless of meals, 2 times a day.
Adults. The total daily dose for the first 4 days of therapy is 50 mg (Day 1), 100 mg (in Day 2), 200 mg (Day 3) and 300 mg (Day 4).
Starting from the 4th day of ordinary Ketilept effective daily dose is 300 mg of the drug. Depending on the clinical response and tolerability in each patient, the dose can be specified in the range of 150 to 750 mg / day.
Safety of daily doses above 800 mg in clinical studies has not been evaluated.
Children and adolescents. Efficacy and safety of quetiapine in children and adolescents has not been established.
Renal and hepatic insufficiency. It is recommended to begin treatment with 25 mg / day, then increase the daily dose of 25-50 mg to achieve an effective dose, depending on the clinical response of the patient and individual tolerability.
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