Pharmacodynamics
Antidepressant (tricyclic antidepressant). It also has some analgesic (central genesis), antiserotonin effect, helps to eliminate bedwetting and reduces appetite.
It has a strong peripheral and central anticholinergic effect due to a high affinity for m-cholinergic receptors; strong sedative effect associated with an affinity for H1-histamine receptors, and alpha-adrenergic blocking action.
It has the properties of a class IA antiarrhythmic drug, like quinidine in therapeutic doses, it slows down ventricular conduction (in case of overdose, it can cause severe intraventricular blockade).
The mechanism of antidepressant action is associated with an increase in the concentration of norepinephrine and / or serotonin in the central nervous system (CNS) (a decrease in their reabsorption).
The accumulation of these neurotransmitters occurs as a result of inhibition of their reuptake by the membranes of presynaptic neurons. With prolonged use, it reduces the functional activity of beta-adrenergic and serotonin receptors in the brain, normalizes adrenergic and serotonergic transmission, restores the balance of these systems, disturbed in depressive conditions. In anxiety-depressive states, it reduces anxiety, agitation and depressive manifestations.
The mechanism of antiulcer action is due to the ability to provide sedative and m-anticholinergic action. Efficacy for bedwetting is apparently due to anticholinergic activity, leading to an increase in the ability of the bladder to stretch, direct beta-adrenergic stimulation, alpha-adrenergic agonist activity, accompanied by an increase in sphincter tone, and central blockade of serotonin uptake. Has a central analgesic effect, which is believed to be associated with changes in the concentration of monoamines in the central nervous system, especially serotonin, and the effect on the endogenous opioid system.
The mechanism of action for bulimia nervosa is unclear (may be similar to that for depression). A clear effect of the drug has been shown in bulimia in patients both without depression, and in its presence, while a decrease in bulimia can be noted without a concomitant weakening of depression itself.
During general anesthesia, it lowers blood pressure and body temperature. Does not inhibit monoamine oxidase (MAO).
The antidepressant effect develops within 2-3 weeks after the start of use.
Pharmacokinetics
Absorption is high.
The bioavailability of amitriptyline is 30-60%, its active metabolite nortriptyline is 46-70%. The time to reach Cmax after ingestion is 2.0-7.7 hours. Vd is 5-10 l / kg. Effective therapeutic blood concentrations for amitriptyline are 50-250 ng / ml, for nortriptyline 50-150 ng / ml.
Cmax 0.04-0.16 μg / ml. Passes (including nortriptyline) through the histohematological barriers, including the blood-brain barrier, placental barrier, enters breast milk. Communication with plasma proteins - 96%.
It is metabolized in the liver with the participation of isoenzymes CYP2C19, CYP2D6, has a "first pass" effect (by demethylation, hydroxylation) with the formation of active metabolites - nortriptyline, 10-hydroxy-amitriptyline, and inactive metabolites. T1 / 2 from blood plasma - 10-26 hours for amitriptyline and 18-44 hours for nortriptyline. It is excreted by the kidneys (mainly in the form of metabolites) - 80% in 2 weeks, partly with bile.
Contraindications
Hypersensitivity, the use together with MAO inhibitors and 2 weeks before starting treatment, myocardial infarction (acute and subacute periods), acute alcohol intoxication, acute intoxication with hypnotics, analgesic and psychoactive drugs, angle-closure glaucoma, severe AV and intraventricular conduction block ( bundle of His, AV block II degree), lactation period, children's age up to 6 years. Due to the content of lactose monohydrate (milk sugar) in tablets, the drug should not be taken by patients with rare hereditary diseases, such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption. Carefully. Amitriptyline should be used with caution in persons with alcoholism, bronchial asthma, schizophrenia (possible activation of psychosis), bipolar disorder, epilepsy, inhibition of bone marrow hematopoiesis, diseases of the cardiovascular system (CVS) (angina pectoris, arrhythmia, heart block, chronic heart failure, myocardial infarction, arterial hypertension), intraocular hypertension, stroke, decreased motor function of the gastrointestinal tract (GIT) (risk of paralytic intestinal obstruction), hepatic and / or renal failure, thyrotoxicosis, prostatic hyperplasia, urinary retention, hypotension of the bladder, during pregnancy (especially the first trimester) , in old age.
Pregnancy and lactation
In pregnant women, the drug should be used only if the intended benefit to the mother outweighs the potential risk to the fetus.
It passes into breast milk and may cause drowsiness in infants. To avoid the development of withdrawal syndrome in newborns (manifested by shortness of breath, drowsiness, intestinal colic, increased nervous excitability, increase or decrease in blood pressure, tremors or spastic phenomena), amitriptyline is gradually canceled at least 7 weeks before the expected birth.
Side effects
Associated with the anticholinergic action of the drug: blurred vision, accommodation paralysis, mydriasis, increased intraocular pressure (only in individuals with a local anatomical predisposition - a narrow angle of the anterior chamber), tachycardia, dry mouth, confusion (delirium or hallucinations), constipation, paralytic intestinal obstruction, difficulty urinating. From the side of the central nervous system: drowsiness, fainting, fatigue, irritability, anxiety, disorientation, hallucinations (especially in elderly patients and in patients with Parkinson's disease), anxiety, psychomotor agitation, mania, hypomania, memory impairment, decreased ability to concentrate, insomnia, "nightmares", asthenia; headache; dysarthria, tremor of small muscles, especially arms, hands, head and tongue, peripheral neuropathy (paresthesia), myasthenia gravis, myoclonus; ataxia, extrapyramidal syndrome, increased frequency and intensification of epileptic seizures; changes in the electroencephalogram (EEG). From the CVS: tachycardia, palpitations, dizziness, orthostatic hypotension, nonspecific changes in the electrocardiogram (ECG) (S-T interval or T wave) in patients without heart disease; arrhythmia, lability of blood pressure (decrease or increase in blood pressure), violation of intraventricular conduction (expansion of the QRS complex, changes in the P-Q interval, bundle branch block). From the gastrointestinal tract: nausea, heartburn, gastralgia, hepatitis (including impaired liver function and cholestatic jaundice), vomiting, increased appetite and body weight or decreased appetite and body weight, stomatitis, taste changes, diarrhea, darkening of the tongue. From the endocrine system: an increase in size (edema) of the testicles, gynecomastia; an increase in the size of the mammary glands, galactorrhea; decreased or increased libido, decreased potency, hypo- or hyperglycemia, hyponatremia (decreased production of vasopressin), syndrome of inappropriate secretion of antidiuretic hormone (ADH). Allergic reactions: skin rash, itching, photosensitivity, angioedema, urticaria. Others: hair loss, tinnitus, edema, hyperpyrexia, swollen lymph nodes, urinary retention, pollakiuria.
With long-term treatment, especially in high doses, with its abrupt termination, the development of withdrawal syndrome is possible: nausea, vomiting, diarrhea, headache, malaise, sleep disturbances, unusual dreams, unusual agitation; with gradual withdrawal after long-term treatment - irritability, motor restlessness, sleep disturbances, unusual dreams.
The relationship with taking the drug has not been established: lupus-like syndrome (migratory arthritis, the appearance of antinuclear antibodies and positive rheumatoid factor), liver dysfunction, ageusia.
Interaction
With the combined use of ethanol and drugs that depress the central nervous system (including other antidepressants, barbiturates, benzadiazepines and general anesthetics), a significant increase in the inhibitory effect on the central nervous system, respiratory depression and hypotensive effect is possible. Increases sensitivity to ethanol-containing drinks. Increases the anticholinergic effect of drugs with anticholinergic activity (for example, phenothiazine derivatives, antiparkinsonian drugs, amantadine, atropine, biperiden, antihistamines), which increases the risk of side effects (from the central nervous system, vision, intestines and bladder). When used together with anticholinergics, phenothiazine derivatives and benzodiazepines - mutual enhancement of sedative and central anticholinergic effects and an increased risk of epileptic seizures (lowering the threshold of seizure activity); derivatives of phenothiazine, in addition, may increase the risk of neuroleptic malignant syndrome. When combined with anticonvulsant drugs, it is possible to increase the inhibitory effect on the central nervous system, reduce the threshold of seizure activity (when used in high doses) and reduce the effectiveness of the latter. When used together with antihistamines, clonidine - an increase in the inhibitory effect on the central nervous system; with atropine - increases the risk of paralytic intestinal obstruction; with drugs that cause extrapyramidal reactions - an increase in the severity and frequency of extrapyramidal effects. With the simultaneous use of amitriptyline and indirect anticoagulants (coumarin or indadione derivatives), an increase in the anticoagulant activity of the latter is possible. Amitriptyline can increase depression induced by glucocorticosteroids (GCS). Medicines for the treatment of thyrotoxicosis increase the risk of agranulocytosis. Reduces the effectiveness of phenytoin and alpha-blockers. Inhibitors of microsomal oxidation (cimetidine) lengthen T1 / 2, increase the risk of developing the toxic effects of amitriptyline (a dose reduction of 20-30% may be required), inducers of microsomal liver enzymes (barbiturates, carbamazepine, phenytoin, nicotine and oral contraceptives) reduce plasma concentrations and reduce the effectiveness of amitriptyline. 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. With the simultaneous use of amitriptyline with clonidine, guanethidine, betanidine, reserpine and methyldopa - a decrease in the hypotensive effect of the latter; with cocaine - the risk of developing cardiac arrhythmias. Antiarrhythmic drugs (such as quinidine) increase the risk of rhythm disturbances (possibly slowing down the metabolism of amitriptyline).
Pimozide and probucol can increase cardiac arrhythmias, which is manifested in the prolongation of the Q-T interval on the ECG. Enhances the effect on CVS of epinephrine, norepinephrine, isoprenaline, ephedrine and phenylephrine (including when these drugs are part of local anesthetics) and increases the risk of developing cardiac arrhythmias, tachycardia, and severe arterial hypertension. When administered together with alpha-adrenergic agonists for intranasal administration or for use in ophthalmology (with significant systemic absorption), the vasoconstrictor effect of the latter may increase. When taken together with thyroid hormones - mutual enhancement of the therapeutic effect and toxic effect (including cardiac arrhythmias and a stimulating effect on the central nervous system). M-anticholinergics and antipsychotic drugs (neuroleptics) increase the risk of developing hyperpyrexia (especially in hot weather). When administered together with other hematotoxic drugs, an increase in hematotoxicity is possible. Incompatible with MAO inhibitors (there may be an increase in the frequency of periods of hyperpyrexia, severe convulsions, hypertensive crises and patient death).
Dosage and administration
Assign orally, without chewing, immediately after eating (to reduce irritation of the gastric mucosa).
For 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, up to a maximum of 300 mg / day. in 3 divided doses (most of the dose is taken at night). When a therapeutic effect is achieved, the dose can 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 effectiveness and tolerance of the therapy and can range from several months to 1 year, and if necessary, even more. In old age, with mild disorders, as well as with bulimia nervosa, as part of complex therapy for mixed emotional disorders and behavioral disorders, psychosis with schizophrenia and alcohol withdrawal, it is prescribed at a dose of 25-100 mg / day. (at night), after reaching the therapeutic effect, they switch to the minimum effective dose - 10-50 mg / day. For the prevention of migraine, with chronic pain syndrome of a neurogenic nature (including prolonged headaches), as well as in the complex therapy of gastric ulcer and 12 duodenal ulcer - from 10-12.5-25 to 100 mg / day. (the maximum part of the dose is taken at night). Children as an antidepressant: from 6 to 12 years old - 10-30 mg / day. or 1-5 mg / kg / day. fractionally, in adolescence - up to 100 mg / day.
With nocturnal enuresis in children 6-10 years old - 10-20 mg / day. at night, 11-16 years old - up to 50 mg / day.
Overdose
Symptoms
From the side of the central nervous system: drowsiness, stupor, coma, ataxia, hallucinations, anxiety, psychomotor agitation, decreased ability to concentrate, disorientation, confusion, dysarthria, hyperreflexia, muscle rigidity, choreoathetosis, epileptic syndrome.
On the part of the CVS: decreased blood pressure, tachycardia, arrhythmia, impaired intracardiac conduction, ECG changes characteristic of intoxication with tricyclic antidepressants (especially QRS), shock, heart failure; in very rare cases, cardiac arrest.
Others: respiratory depression, shortness of breath, cyanosis, vomiting, pyrexia, mydriasis, increased sweating, oliguria or anuria.
Symptoms develop 4 hours after an overdose, reach a maximum after 24 hours and last 4-6 days. If an overdose is suspected, especially in children, the patient should be hospitalized.
Treatment: for oral administration: gastric lavage, intake of activated carbon; symptomatic and supportive therapy; with severe anticholinergic effects (lowering blood pressure, arrhythmias, coma, myoclonic epileptic seizures) - the introduction of cholinesterase inhibitors (the use of physostigmine is not recommended due to the increased risk of seizures); maintaining blood pressure and water and electrolyte balance. Shown monitoring of the functions of the CVS (including ECG) for 5 days (relapse can occur after 48 hours and later), anticonvulsant therapy, artificial ventilation (ALV) and other resuscitation measures. Hemodialysis and forced diuresis are ineffective.
Special instructions
Before starting treatment, blood pressure control is necessary (in patients with low or labile blood pressure, it may decrease even more); during the period of treatment - control of peripheral blood (in some cases, agranulocytosis may develop, and therefore it is recommended to monitor the blood picture, especially with an increase in body temperature, the development of flu-like symptoms and tonsillitis), with prolonged therapy - control of the functions of the CVS and liver. In the elderly and patients with CVD diseases, monitoring of heart rate, blood pressure, ECG is shown. On the ECG, clinically insignificant changes may appear (smoothing of the T wave, depression of the S-T segment, expansion of the QRS complex).
Care must be taken when moving abruptly to an upright position from a "lying" or "sitting" position.
During the treatment period, the use of ethanol should be excluded.
Assign no earlier than 14 days after the abolition of MAO inhibitors, starting with small doses.
With a sudden cessation of admission after long-term treatment, the development of a withdrawal syndrome is possible.
Amitriptyline at doses above 150 mg / day. reduces the threshold of seizure activity (you should take into account the risk of epileptic seizures in predisposed patients, as well as in the presence of other factors predisposing to the occurrence of seizure syndrome, for example, brain damage of any etiology, the simultaneous use of antipsychotic drugs (neuroleptics), during the period of refusal from ethanol or discontinuation of drugs with anticonvulsant properties, such as benzodiazepines). Severe depression is characterized by the risk of suicidal actions, which can persist until significant remission is achieved. In this regard, at the beginning of treatment, a combination with drugs from the benzodiazepine group or antipsychotic drugs and constant medical supervision (entrusting authorized persons with the storage and delivery of drugs) may be indicated.In children, adolescents and young people (under 24 years of age) 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 benefits of their use should be correlated. In short-term studies, the risk of suicide did not increase in people over 24 years old, and in people over 65 years old it decreased slightly.During treatment with antidepressants, all patients should be monitored for early detection of suicidal tendencies.In patients with cyclic affective disorders during the depressive phase during therapy, manic or hypomanic states may develop (it is necessary to reduce the dose or discontinue the drug and prescribe an antipsychotic drug). After the relief of these conditions, if there are indications, treatment in low doses can be resumed. Due to the possible cardiotoxic effects, care must be taken when treating patients with thyrotoxicosis or patients receiving thyroid hormone preparations.
In combination with electroconvulsive therapy, it is prescribed only with careful medical supervision.
In predisposed patients and elderly patients, it can provoke the development of drug psychoses, mainly at night (after discontinuation of the drug, they disappear within a few days).
May cause paralytic intestinal obstruction, mainly in patients with chronic constipation, the elderly, or in patients who have to comply with bed rest.
Before performing general or local anesthesia, the anesthesiologist should be warned that the patient is taking amitriptyline.
Due to the anticholinergic effect, it is possible to reduce tearing and a relative increase in the amount of mucus in the tear fluid, which can lead to damage to the corneal epithelium in patients using contact lenses. With prolonged use, there is an increase in the incidence of dental caries. The need for riboflavin may be increased.
The study of reproduction in animals has revealed an adverse effect on the fetus, and adequate and strictly controlled studies in pregnant women have not been carried out. In pregnant women, the drug should be used only if the intended benefit to the mother outweighs the potential risk to the fetus.
It passes into breast milk and may cause drowsiness in infants. To avoid the development of withdrawal syndrome in newborns (manifested by shortness of breath, drowsiness, intestinal colic, increased nervous excitability, increase or decrease in blood pressure, tremors or spastic phenomena), amitriptyline is gradually canceled at least 7 weeks before the expected birth.
Children are more sensitive to acute overdose, which should be considered dangerous and potentially fatal for them.
During the period of treatment, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration of attention and speed of psychomotor reactions.
