Trazodone

Structural formula

Trazodone

Chemical name

2- [3- [4- (3-Chlorophenyl) -1-piperazinyl] propyl] -1,2,4-triazolo [4,3-a] pyridin-3 (2H) -one (as hydrochloride)

Gross formula

19 H 22 ClN 5 O

CAS Code

19794-93-5

Characteristics of the substance Trazodone

Thiazolopyridine derivative; the chemical structure does not apply to tricyclic, tetracyclic or other groups of antidepressants. Trazodone hydrochloride is an odorless white crystalline powder, highly soluble in water. The molecular weight is 408.33.

Pharmacology

Pharmacological action – antidepressant .

The mechanism of action is not fully understood. Preclinical studies have shown that trazodone selectively inhibits serotonin reuptake by brain synaptosomes and acts as an antagonist of 5-HT 2A / 2C serotonin receptors. Does not inhibit MAO, does not stimulate the central nervous system. It is an antagonist of alpha 1 -adrenoreceptors.

It stops the mental (affective tension, fear, insomnia) and somatic (palpitations, headache, myalgia, frequent urination, increased sweating) manifestations of anxiety. Increases the depth and duration of sleep in patients with depression, restores the physiological structure of sleep.

It is well absorbed from the digestive tract. Reception of trazodone during or immediately after a meal slows down the absorption rate, reduces C max of trazodone in the blood and increases T max ( T max is 0.5–2 hours). Binding to plasma proteins 89–95%. It passes through the histohematological barriers, including the BBB . It is metabolized in the liver, mainly with the participation of the isoenzyme CYP3A4 of cytochrome P450, the active metabolite is m-chlorophenylpiperazine. T 1/2 biphasic: the duration of the early phase is 3–6 hours, late 5–9 hours; cumulation is possible in some patients. It is excreted in the bile (20%) and in the urine (75%, incl. 70% in the form of inactive metabolites) within 98 hours after administration.

There is evidence of the effectiveness of trazodone in bulimia, kleptomania, pain syndrome in diabetic neuropathy and other types of chronic pain, phobias, including agoraphobia, panic attacks, acute withdrawal syndrome with alcoholism and for the prevention of migraine.

Use of the substance Trazodone

Depressive states of various etiologies (endogenous, psychotic, neurotic, somatogenic, etc.) with severe anxiety, tension.

Contraindications

Hypersensitivity, alcohol intoxication, and intoxication of hypnotic drugs, the age of 6 years.

Application restrictions

Myocardial infarction (early recovery period), AV block, arterial hypertension (dose adjustment of antihypertensive drugs may be required), ventricular arrhythmia, a history of priapism, liver and / or renal failure, under 18 years of age.

Pregnancy and lactation

Should not be used by pregnant women. In animal experiments, it has been shown that trazodone at doses 30–50 times higher than the MPDF causes congenital malformations and increases the frequency of fetal resorption.

The FDA category of action for the fetus is C.

At the time of treatment should stop breastfeeding. Trazodone and its metabolites are found in the milk of lactating rats. It is not known whether trazodone is secreted into human milk.

Side effects of the substance Trazodone

From the nervous system and sensory organs: fatigue, weakness, headache, dizziness, insomnia, drowsiness, agitation, psychosis, hypomania, hallucinations, tremors, muscle twitches, large convulsive seizures (grand mal) , aphasia, ataxia, akathisia, dyskinesia, paresthesia, confusion, syncope, blurred vision, diplopia.

On the part of the cardiovascular system and blood (hematopoiesis, hemostasis): arterial hypotension, including orthostatic; atrial fibrillation, arrhythmias (including tachy and bradycardia, ectopic ventricular rhythms), congestive heart failure, leukocytosis or leukopenia, neutropenia (usually minor), hemolytic anemia, methemoglobinemia.

From the digestive tract: increased appetite, dryness and an unpleasant aftertaste in the mouth, hypersalivation, caries, diseases of the teeth, oral candidiasis, nausea, vomiting, flatulence, diarrhea, constipation, cholestasis, increased levels of bilirubin and amylase in blood plasma, jaundice.

From the genitourinary system: urinary retention, increased urination, hematuria, premature menstruation, hirsutism, increased libido, priapism, impotence, retrograde ejaculation.

Allergic reactions: skin rash, urticaria.

Other: myalgia, chest pain, alopecia, psoriasis, edema.

Interaction

Unlike typical antidepressants, it does not reduce the deprimative effects of reserpine, weakens the central effect of amphetamine and peripheral effect of norepinephrine. Potentiates the effect of drugs that depress the central nervous system ( including barbiturates, tricyclic antidepressants, antihistamines, clonidine, alcohol), anticholinergics and muscle relaxants. With concomitant use with antihypertensive drugs, the risk of orthostatic hypotension increases. It weakens the effect of psychostimulants. Increases the plasma concentration of digoxin and phenytoin. Do not use concomitantly with MAO inhibitors.

Interaction with inhibitors of the isoenzyme CYP3A4

In vitro studies of trazodone metabolism indicate the possibility of its interaction with inhibitors of the CYP3A4 isoenzymecytochrome P450, such as ketoconazole, ritonavir, indinavir sulfate and fluoxetine. CYP3A4 inhibitorscan lead to a significant increase in the concentration of trazodone in plasma, thereby increasing the likelihood of adverse events. Therefore, iftakenin combination with potent CYP3A4 inhibitors, thedose of trazodone should be reduced.

Interactions with ritonavir

The effect of short-term administration of ritonavir (200 mg 2 times a day for 2 days) on the pharmacokinetics of a single dose of trazodone (50 mg) was studied in 10 healthy subjects. It was shown that C max of trazodone increased by 34%, AUC – by 2.4 times, T 1/2  – by 2.2 times, clearance decreased by 52%. Side effects, including nausea, hypotension, fainting, were observed when ritonavir and trazodone were used together. With the simultaneous use of ritonavir and trazodone, a dose reduction of trazodone may be necessary.

Interactions with carbamazepine

After co-administration of the CYP3A4 inducer carbamazepine (at a dose of 400 mg / day) with trazodone (100-300 mg daily), carbamazepine reduced the plasma concentration of trazodone and m-chlorophenylpiperazine (active metabolite) by 60 and 76%, respectively. Patients taking trazodone and carbamazepine simultaneously should be closely monitored.

Overdose

Symptoms: nausea, vomiting, drowsiness, dizziness, decreased blood pressure , impaired coordination, priapism, epileptiform seizures, changes in the ECG , respiratory arrest, aggravation of adverse reactions.

Treatment: gastric lavage, forced diuresis, intake of activated charcoal, maintenance of vital functions, symptomatic therapy. There is no specific antidote.

Route of administration

Inside.

Precautions Trazodone

During treatment, a general blood test should be performed regularly (for the timely detection of leuko- and neutropenia), ECG monitoring in patients with cardiovascular diseases is desirable . Careful monitoring of patients with suicidal tendencies is required, especially in the first weeks of treatment. Treatment is immediately discontinued with the development of priapism, severe neutro- and leukopenia; in other cases, discontinuation of the drug should be carried out gradually. During treatment, alcohol should be avoided.

Use with caution while working for drivers of vehicles and people whose activities are associated with increased concentration of attention.

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