Amitriptyline, tablets 10 mg 50 pcs

Pharmacodynamics

Amitriptyline is an antidepressant (tricyclic antidepressant). It also has some analgesic (of central genesis), antiserotonin action, helps eliminate nocturnal urinary incontinence and reduces appetite.

It has strong peripheral and central anticholinergic action due to high affinity to m-cholinoreceptors; strong sedative effect associated with affinity to H1-histamine receptors and alpha-adrenoblocking action. It has the properties of an antiarrhythmic drug (drug of class IA); like quinidine, in therapeutic doses it slows ventricular conduction (in overdose it may cause severe intraventricular blockade).

The mechanism of antidepressant action is associated with an increase in the concentration of noradrenaline and/or serotonin in the central nervous system (reduction of their reverse absorption). Accumulation of these neurotransmitters occurs as a result of inhibition of their reuptake by membranes of presynaptic neurons. With long-term use it reduces the functional activity of beta-adrenergic and serotonin receptors of the brain, normalizes adrenergic and serotonergic transmission, restores the balance of these systems that are disturbed in depressive states. In anxiety-depressive states it reduces anxiety, agitation and depressive manifestations.

The mechanism of anti-ulcer action is due to the ability to have sedative and m-cholinoblocking effects.

The efficacy in nocturnal urinary incontinence appears to be due to anticholinergic activity resulting in increased bladder distension capacity, direct beta-adrenergic stimulation, alpha-adrenergic agonist activity accompanied by increased sphincter tone, and central serotonin takeover blockade.

It has a central analgesic effect, which is thought to be due to changes in CNS monoamine concentrations, particularly serotonin, and to effects on endogenous opioid systems.

The mechanism of action in bulimia nervosa is unclear (it may be similar to that in depression). The drug has been shown to have a distinct bulimia effect in patients both without and with depression, and a decrease in bulimia may be seen without concomitant relief of depression itself.

In general anesthesia, it reduces blood pressure (BP) and body temperature. It does not inhibit monoamine oxidase (MAO).

The antidepressant effect develops within 2-3 weeks after the start of use.

Pharmacokinetics

Absorption is high. Bioavailability of amitriptyline is 30-60%, its active metabolite nortriptyline is 46-70%. Time to reach maximum concentration (Tmax) after oral administration 2.0-7.7 hours. The volume of distribution is 5-10 l/kg. Effective therapeutic blood concentrations for amitriptyline are 50-250 ng/ml, for nortriptyline 50-150 ng/ml. Maximum plasma concentration (Cmax) is 0.04-0.16 µg/ml. Passes (including nortriptyline) through histohematic barriers, including the blood-brain barrier, placental barrier, penetrates into breast milk. Binding with plasma proteins is 96%.

It is metabolized in the liver with participation of CYP2C19, CYP2D6 isoenzymes, has “first pass” effect (by demethylation, hydroxylation) with the formation of active metabolites – nortriptyline, 10-hydroxy-amitriptyline, and inactive metabolites. The blood plasma elimination half-life (T1/2) is 10-26 hours for amitriptyline and 18-44 hours for nortriptyline. Excreted by the kidneys (mainly as metabolites) – 80% in 2 weeks, partially in the bile.

Indications

Depression (especially with anxiety, agitation and sleep disorders, including in childhood, endogenous, involutional, reactive, neurotic, medication, with organic brain lesions).

. As a part of complex therapy it is used for mixed emotional disorders, psychosis in schizophrenia, alcohol withdrawal, behavior disorders (activity and attention), nocturnal enuresis in children (except for patients with bladder hypotension), bulimia nervosa, chronic pain syndrome (chronic pain in cancer patients, migraine, rheumatic diseases, atypical pain in the face, postherpetic neuralgia, posttraumatic neuropathy, diabetic or others. peripheral neuropathy), headache, migraine (prevention), gastric and 12 duodenal ulcer.

Active ingredient

Composition

1 tablet contains:

the active ingredient:

amitriptyline hydrochloride – 11.32 mg, which corresponds to 10 mg of amitriptyline;

auxiliary substances:

Microcrystalline cellulose,

lactose monohydrate (milk sugar),

Pregelatinized starch,

Colloidal silicon dioxide (aerosil),

Talk,

Magnesium stearate.

How to take, the dosage

Prescribe orally, without chewing, immediately after meals (to reduce gastric mucosal irritation).

Adults

In adults with depression, the initial dose is 25-50 mg at night, then the dose can be gradually increased taking into account the effectiveness and tolerability of the drug to a maximum
300 mg/day in 3 doses (most of the dose is taken at night). When the therapeutic effect is achieved, the dose may be gradually reduced to the minimum effective, depending on the patient’s condition. The duration of the course of treatment is determined by the patient’s condition, the efficiency and tolerability of the therapy, and may vary from several months to one year, and more if necessary.

In elderly patients with mild disorders as well as in case of bulimia nervosa, as a part of complex therapy in mixed emotional and behavioral disorders, psychosis in schizophrenia and alcohol withdrawal are prescribed in dose of 25-100 mg/day (at night); after achieving therapeutic effect the minimum effective dose of 10-50 mg/day is used.

For migraine prophylaxis, in chronic pain syndrome of neurogenic character (including prolonged headache), and also in complex therapy of gastric and duodenal ulcer – from 10-12.5-25 to 100 mg/day (maximum dose is taken at night).

Children

Children as an antidepressant: 6 to 12 years – 10-30 mg/day or 1-5 mg/kg/day fractionally, in adolescents – up to 100 mg/day. The main part of the dose is taken at night.

In nocturnal enuresis in children 6-10 years – 10-20 mg/day at night, 11-16 years – up to 50 mg/day.

Interaction

When using ethanol and CNS depressant drugs (including other antidepressants, barbiturates, benzadiazepines and general anesthetics) together, a significant increase in CNS depressant effect, respiratory depression and hypotensive effect are possible.

It increases sensitivity to beverages containing ethanol.

Enhances the anticholinergic activity of drugs with anticholinergic activity (e.g., phenothiazine derivatives, anti-Parkinsonian drugs, amantadine, atropine, biperidine, antihistamine drugs), which increases the risk of side effects (CNS, vision, bowel and bladder). When co-administration with choline blockers, phenothiazine derivatives and benzodiazepines – mutual enhancement of sedative and central choline blocking effects and increased risk of epileptic seizures (lower threshold of seizure activity); phenothiazine derivatives may also increase the risk of neuroleptic malignant syndrome.

When used concomitantly with anticonvulsants, increased CNS depression, decreased seizure threshold (when used in high doses) and decreased effectiveness of the latter may occur.

When used concomitantly with antihistamines, clonidine – increased CNS depression; with atropine – increased risk of paralytic ileus; with drugs causing extrapyramidal reactions – increased severity and frequency of extrapyramidal effects.

In concomitant use of amitriptyline and indirect anticoagulants (coumarin derivatives or indadeon) the anticoagulant activity of the latter may increase.

Amitriptyline may increase depression caused by glucocorticosteroids (GCS).

The drugs for the treatment of thyrotoxicosis increase the risk of agranulocytosis.

Decreases the effectiveness of phenytoin and alpha-adrenoblockers.

Microsomal oxidation inhibitors (cimetidine) prolong T1/2, increase the risk of toxic effects of amitriptyline (a 20-30% dose reduction may be required), microsomal liver enzyme inducers (barbiturates, carbamazepine, phenytoin, nicotine and oral contraceptives) decrease the plasma concentration and decrease the effectiveness of amitriptyline.

The co-administration with disulfiram and other acetaldehydrogenase inhibitors provokes delirium.

Fluoxetine and fluvoxamine increase the plasma concentration of amitriptyline (it may be necessary to reduce the dose of amitriptyline by 50%).

Estrogen-containing oral contraceptive drugs and estrogens may increase the bioavailability of amitriptyline.

In concomitant use of amitriptyline with clonidine, guanethidine, betanidine, reserpine and methyldopa – decrease the hypotensive effect of the latter; with cocaine – risk of cardiac arrhythmias.

The antiarrhythmic drugs (such as quinidine) increase the risk of arrhythmias (the metabolism of amitriptyline may be slowed).

Pimozide and probucol may exacerbate cardiac arrhythmias, which is manifested by prolongation of the Q-T interval on the ECG.

The effects of epinephrine, norepinephrine, isoprenaline, ephedrine, and phenylephrine on the SCS (including when these drugs are part of local anesthetics) and increase the risk of cardiac rhythm disturbances, tachycardia, and severe arterial hypertension.

The vasoconstrictor effect of alpha-adrenomimetics for intranasal administration or for use in ophthalmology (with significant systemic absorption) may increase when co-administered.

In co-administration with thyroid hormones – mutual enhancement of therapeutic effects and toxic effects (include cardiac arrhythmias and stimulating effects on the CNS).

M-cholinoblockers and antipsychotic drugs (neuroleptics) increase the risk of hyperpyrexia (especially in hot weather).

The co-administration with other hematotoxic drugs may increase hematotoxicity.

Incompatible with MAO inhibitors (increased frequency of periods of hyperpyrexia, severe seizures, hypertensive crises and patient death are possible).

Special Instructions

Before treatment it is necessary to control BP (in patients with low or labile BP it may decrease even more); during treatment – control of peripheral blood (in some cases agranulocytosis may develop, therefore it is recommended to monitor the blood picture, especially with fever, flu-like symptoms and angina), during long-term therapy – control of CSS and liver functions. The elderly and patients with diseases of the cardiovascular system should have control of heart rate (HR), BP, ECG. ECG may show clinically insignificant changes (smoothed T wave, depressed S-T segment, widened QRS complex).

Precaution should be exercised when suddenly going upright from lying or sitting position.

Ethanol should be avoided during treatment.

Prescribe at least 14 days after withdrawal of MAOI inhibitors, starting with low doses.

The development of withdrawal syndrome may occur if the drug is stopped suddenly after long-term treatment.

Amitriptyline in doses above 150 mg/day lowers the seizure threshold (the risk of epileptic seizures in predisposed patients should be taken into account, as well as in the presence of other predisposing conditions. other factors predisposing to the development of a seizure syndrome, such as brain damage of any etiology, concurrent use of antipsychotic drugs (neuroleptics), withdrawal from ethanol, or withdrawal of drugs with anticonvulsant properties, such as benzodiazepines.)

The risk of suicidal behavior is inherent in severe depression and may persist until substantial remission is achieved. Because of this, a combination of benzodiazepine or neuroleptic medications may be indicated at the beginning of treatment and constant physician supervision (entrusting trusted persons to store and dispense medications).

In children, adolescents and young adults (younger than 24 years) with depression and other mental disorders, antidepressants, compared with placebo, increase the risk of suicidal thoughts and suicidal behavior. Therefore, when prescribing amitriptyline or any other antidepressants in this category of patients the risk of suicide and the benefit of their use should be correlated. In short-term studies, the risk of suicide did not increase in people over 24 years of age, and slightly decreased in people over 65 years of age. All patients should be monitored during antidepressant treatment for early detection of suicidal tendencies.

In patients with cyclic affective disorder during the depressive phase, manic or hypomanic states may develop during therapy (dose reduction or drug withdrawal and administration of antipsychotic medication is necessary). After these states have subsided, if indicated, treatment at low doses may be resumed.

Because of possible cardiotoxic effects, caution is required when treating patients with thyrotoxicosis or patients receiving thyroid hormone preparations.

In combination with electroconvulsive therapy, it is prescribed only with close medical supervision.

In predisposed patients and elderly patients, it may provoke the development of drug-induced psychosis, mainly at night (after withdrawal of the drug goes away within a few days).

May cause paralytic ileus, mainly in chronically constipated, elderly patients or in patients who are forced to remain in bed.

The anesthesiologist should be advised before general or local anesthesia that the patient is taking amitriptyline.

The anticholinergic effects may decrease tear production and increase the relative amount of mucus in the lacrimal fluid, which can lead to corneal epithelial damage in patients who wear contact lenses.

An increase in the incidence of dental caries has been observed with long-term use. There may be an increased need for riboflavin.

Animal reproduction studies have shown adverse effects on the fetus, and adequate and well-controlled studies in pregnant women have not been conducted. In pregnant women, the drug should be used only if the estimated benefit to the mother exceeds the potential risk to the fetus.

It penetrates into the breast milk and may cause somnolence in infants.

In order to avoid the development of “withdrawal” syndrome in newborns (manifested by shortness of breath, drowsiness, intestinal colic, increased nervous excitability, high or low blood pressure, tremor or spastic phenomena) amitriptyline administration should be gradually stopped at least 7 weeks before the expected delivery.

Children are more susceptible to acute overdose, which should be considered dangerous and potentially fatal for them.

During treatment, caution should be exercised when driving motor vehicles and engaging in other potentially hazardous activities that require increased concentration and quick psychomotor reactions.

Contraindications

Side effects

Choline-blocking-related effects of the drug: blurred vision, accommodation paralysis, mydriasis, increased intraocular pressure (only in persons with a local anatomical predisposition – narrow angle of the anterior chamber), tachycardia, dry mouth, confusion (delirium or hallucinations), constipation, paralytic bowel obstruction, difficulty in urination.

CNS side: drowsiness, fainting, fatigue, irritability, restlessness, disorientation, hallucinations (especially in elderly patients and patients with Parkinson’s disease), anxiety, psychomotor agitation, mania, hypomania, memory impairment, decreased ability to concentrate, insomnia, “nightmare” dreams, asthenia; headache; dysarthria, tremors of small muscles, especially hands, arms, head and tongue, peripheral neuropathy (paresthesias), myasthenia, myoclonus; ataxia, extrapyramidal syndrome, increased frequency and intensity of epileptic seizures; changes on electroencephalogram (EEG).

Particularly cardiac disorders: tachycardia, palpitations, dizziness, orthostatic hypotension, nonspecific electrocardiogram (ECG) changes (S-T interval or T wave) in patients without heart disease; arrhythmia, BP labile (decrease or increase of BP), intraventricular conduction disorders (QRS dilation, P-Q changes, Gis pedicle block).

Gastrointestinal disorders: nausea, heartburn, gastralgia, hepatitis (including liver dysfunction and cholestatic jaundice), vomiting, increased appetite and body weight or decreased appetite and body weight, stomatitis, change in taste, diarrhea, darkened tongue.

Endocrine system: increase in the size (swelling) of the testes, gynecomastia; increase in breast size, galactorrhea; decreased or increased libido, decreased potency, hypo- or hyperglycemia, hyponatremia (decreased production of vasopressin), syndrome of inadequate secretion of antidiuretic hormone (ADH).

Allergic reactions: skin rash, itching, photosensitization, angioedema, urticaria.

Others: hair loss, tinnitus, edema, hyperpyrexia, enlarged lymph nodes, urinary retention, pollakiuria.

In long-term treatment, especially in high doses, when it is stopped abruptly, withdrawal syndrome may develop: nausea, vomiting, diarrhea, headache, malaise, sleep disorders, unusual dreams, unusual agitation; in gradual withdrawal after long-term treatment, irritability, motor restlessness, sleep disorders, unusual dreams.

The association with taking the drug has not been established: lupus-like syndrome (arthritis migrans, appearance of antinuclear antibodies and positive rheumatoid factor), liver dysfunction, aguesia.

Overdose

Symptoms: CNS: somnolence, stupor, coma, ataxia, hallucinations, anxiety, psychomotor agitation, decreased ability to concentrate, disorientation, confusion, dysarthria, hyperreflexia, muscle rigidity, choreoathetosis, epileptic syndrome.

Particularly tricyclic antidepressants: decrease in blood pressure, tachycardia, arrhythmia, disturbance of intracardiac conduction, ECG changes (especially QRS) characteristic of intoxication, shock, heart failure; in very rare cases – cardiac arrest.

Others: respiratory depression, dyspnea, cyanosis, vomiting, hyperthermia, mydriasis, increased sweating, oliguria or anuria.

The symptoms develop 4 h after overdose, reach a maximum of 24 h and last for 4-6 days. If overdose is suspected, especially in children, the patient should be hospitalized.

Treatment: if administered orally: Gastric lavage, administration of activated charcoal; symptomatic and supportive therapy; in severe anticholinergic effects (decreased BP, arrhythmia, coma, myoclonic epileptic seizures) – administration of cholinesterase inhibitors (use of physostigmine is not recommended because of increased risk of convulsions); maintenance of BP and water-electrolyte balance. Control of cardiac function (including ECG) for 5 days (relapse may occur after 48 hours or later), anticonvulsant therapy, artificial lung ventilation (ALV) and other resuscitation measures are indicated. Hemodialysis and forced diuresis are ineffective.