Amitriptyline

General characteristics. Structure:

Active agent: Amitriptylini hydrochloridum of 28.3 mg (экв. 25 mg of amitriptyline).

Pharmacological properties:

Pharmacodynamics. Antidepressive means (tricyclic an_idepressant). Renders also some analgeziruyushchy (the central genesis), H2-gistaminoblokiruyushchee and antiserotoninovy action, promotes elimination of bed wetting and reduces appetite. Possesses the strong peripheral and central anticholinergic action caused by high affinity to m-holinoretseptoram; the strong sedation connected with affinity to H1 - to histamine receptors, and alpha and adrenoceptor blocking action. The HP of subgroup of Ia has properties antiarrhytmic, like quinidine in therapeutic doses slows down ventricular conductivity (at overdose can cause heavy intra ventricular blockade). The mechanism of antidepressive action is connected with increase in concentration of noradrenaline in synapses and/or serotonin in TsNS (decrease in their return absorption). Accumulation of these neurotransmitters results from inhibition of their return capture by membranes of presynaptic neurons. At prolonged use reduces functional activity of beta and adrenergic and serotoninovy receptors of a brain, normalizes adrenergic and serotonergic transfer, recovers the balance of these systems broken at depressions. At alarming depressions reduces alarm, agitation and depressive manifestations. The mechanism of antiulcerous action is caused by ability to block H2 - histamine receptors in covering cells of a stomach, and also to render sedative and m-holinoblokiruyushchee action (at a peptic ulcer of a stomach and a 12-perstny gut weakens pain, promotes acceleration of healing of an ulcer). Efficiency at bed wetting is caused, apparently, by the anticholinergic activity leading to increase in ability of a bladder to stretching, direct beta and adrenergic stimulation, the activity of alpha and adrenergic agonists which is followed by increase in a tone of a sphincter, and the central blockade of serotonin reuptake. Has the central analgeziruyushchy effect which as believe, can be connected with changes of concentration of monoamines in TsNS, especially serotonin, and influence on endogenous opioid systems. The action mechanism at nervous bulimia is not clear (can be similar to that at a depression). The clear effect of drug at bulimia at patients is shown both without depression, and at its existence, at the same time decrease in bulimia can be noted without the accompanying easing of the depression. When carrying out the general anesthesia reduces the ABP and body temperature. Does not inhibit MAO. Antidepressive action develops during 2-3 weeks after the beginning of use.

Pharmacokinetics. Absorption - high. Bioavailability of amitriptyline at various ways of introduction - 30-60%, its metabolite - a nortriptilin - 46-70%. Communication with proteins of plasma - 96%. Cmax - 0.04-0.16 mkg/ml. TCmax after intake is 2-7.7 h. At equal concentration of Cmax at reception of capsules below that causes smaller cardiotoxic effect. Distribution volume - 5-10 l/kg. Therapeutic concentration in blood for amitriptyline - 50-250 ng/ml, for a nortriptilin - 50-150 ng/ml. Easily passes (including нортриптилин) through gistogematichesky barriers, including GEB, the placental barrier, gets into breast milk. It is metabolized in a liver with participation of the fermental CYP2C19, CYP2D6 system, has effect of "the first passing" (by demethylation, a hydroxylation, N-oxidation) with formation of active metabolites - a nortriptilina, 10-hydroxy-amitriptyline - and inactive metabolites. It is removed by kidneys (mainly in the form of metabolites) - 80% for 2 weeks and partially with a fecal masses. T1/2 of amitriptyline is 10-26 h, a nortriptilina - 18-44 h.

Indications to use:

Depressions (especially with alarm, agitation and sleep disorders, including at children's age, endogenous, involutional, reactive, neurotic, medicinal, at organic lesions of a brain, alcoholic abstinence), schizophrenic psychoses, the mixed emotional frustration, behavior disorders (activity and attention), night enuresis (except for patients with bladder hypotonia), nervous bulimia, a chronic pain syndrome (chronic pains at oncological patients, migraine, rheumatic diseases, atypical pains in a face, post-herpetic neuralgia, a posttraumatic neuropathy, diabetic or other peripheral neuropathy), a headache, migraine (prevention), a peptic ulcer of a stomach and a 12-perstny gut.

Route of administration and doses:

Inside, without chewing, right after food (for reduction of irritation of a mucous membrane of a stomach). An initial dose adult - 25-50 mg for the night, then increase a dose within 5-6 days to 150-200 mg/days in 3 receptions (the maximum part of a dose is accepted for the night). If during 2 weeks there did not occur improvement, the daily dose is increased to 300 mg. At disappearance of symptoms of a depression the dose is reduced to 50-100 mg/days and not less than 3 months continue therapy. At advanced age at easy disturbances appoint in a dose 30-100 mg/days (to night), after achievement of therapeutic effect pass to minimal effective doses - 25-50 mg/days. In oil or in/in (to enter slowly) in a dose of 20-40 mg 4 times a day, gradually replacing with intake. Treatment duration - no more than 6-8 months. At night enuresis at children of 6-10 years - 10-20 mg/days for the night, 11-16 years - 25-50 mg/days. To children as antidepressant: from 6 to 12 years - 10-30 mg or 1-5 mg/kg/days are fractional, at teenage age - on 10 mg 3 times a day (if necessary to 100 mg/days). For prevention of migraine, at chronic pains of neurogenic character (including long headaches) - from 12.5-25 to 100 mg/days (the maximum part of a dose is accepted for the night).

Features of use:

Before an initiation of treatment control of the ABP (at patients with the lowered or labile ABP it can decrease still more) is necessary; during treatment - control of peripheral blood (the agranulocytosis in this connection it is recommended to watch a blood picture in some cases can develop, especially at fervescence, development of grippopodobny symptoms and quinsies), at long therapy - control of functions CCC and a liver. At elderly and patients with diseases of CCC control of ChSS, the ABP, an ECG is shown. On an ECG emergence of clinically insignificant changes is possible (smoothing of a tooth T, S-T segment depression, expansion of the QRS complex). Parenteral use is possible only in the conditions of a hospital, under observation of the doctor, with observance of a bed rest in the first days of therapy. Care is necessary upon sharp transition to vertical position from situation "lying" or "sitting". During treatment it is necessary to exclude the ethanol use. Appoint not earlier than whose in 14 days after cancellation of MAO inhibitors, since small doses. At the sudden termination of reception after prolonged treatment development of a syndrome of "cancellation" is possible. Amitriptyline in doses higher than 150 mg/days reduces a threshold of convulsive activity (it is necessary to consider risk of emergence of epileptic attacks at predisposed patients, and also in the presence of the factors contributing to emergence of other convulsive syndrome, for example injuries of a brain of any etiology, simultaneous use of antipsychotic HP (neuroleptics), during refusal of ethanol or cancellation of the HP having anticonvulsant properties, for example benzodiazepines). To the expressed depressions свойствен risk of suicide actions which can remain up to achievement of essential remission. In this regard in an initiation of treatment the combination with HP from group of benzodiazepines or antipsychotic HP and constant medical control can be shown (to charge to authorized representatives storage and delivery of HP). At patients with cyclic affective frustration in the period of a depressive phase against the background of therapy maniacal or hypomaniacal states can develop (the HP needs a dose decline or drug withdrawal and appointment antipsychotic). After stopping of the specified states if there are indications, treatment in low doses can be resumed. Because of possible cardiotoxic effects it is required to be careful at treatment of patients with a thyrotoxicosis or the patients receiving drugs of hormones of a thyroid gland. In combination with electroconvulsive therapy it is appointed only on condition of careful medical observation. At predisposed patients and patients of advanced age can provoke development of medicinal psychoses, preferential at night (after drug withdrawal pass within several days). Can cause paralytic intestinal impassability, it is preferential at patients with a chronic lock, advanced age or at the patients forced to observe a bed rest. Before carrying out the general or local anesthesia it is necessary to warn the anesthesiologist that the patient accepts amitriptyline. Owing to anticholinergic action decrease in a slyzootdeleniye and relative increase in amount of slime as a part of the lacrimal liquid is possible that can lead to damage of an epithelium of a cornea at the patients using contact lenses. At prolonged use increase in frequency of developing of caries of teeth is observed. The need for Riboflavinum can be increased. Studying of a reproduction on animals revealed adverse action on a fruit, and adequate and strictly controlled researches at pregnant women is not conducted. At pregnant women it is necessary to use drug only if the estimated advantage for mother exceeds potential risk for a fruit. Gets into breast milk and can cause drowsiness in babies. In order to avoid development of a syndrome of "cancellation" in newborns (it is shown by the asthma, drowsiness, intestinal gripes increased by nervous irritability, hypotension or hypertensia, a tremor or the spastic phenomena) reception of amitriptyline is gradually cancelled at least for 7 weeks before the expected childbirth. Children are more sensitive to acute overdose which should be considered dangerous and potentially deadly to them. During treatment it is necessary to be careful during the driving of motor transport and occupation other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions. With care. Alcoholism, bronchial asthma, maniac-depressive psychosis, oppression of a marrowy hemopoiesis, disease of CCC (stenocardia, arrhythmia, heart blocks, HSN, myocardial infarction, arterial hypertension), stroke, decrease in the GIT motor function (risk of emergence of paralytic intestinal impassability), intraocular hypertensia, liver and/or renal failure, thyrotoxicosis, prostate hyperplasia, ischuria, bladder hypotonia, schizophrenia (activation of psychosis), epilepsy, pregnancy (especially the I trimester is possible), advanced age.

Side effects:

Anticholinergic effects: a sight illegibility, accommodation paralysis, a mydriasis, increase in intraocular pressure (only at persons with local anatomic predisposition - a narrow corner of an anterior chamber), tachycardia, dryness in a mouth, confusion of consciousness, a delirium or hallucinations, locks, paralytic intestinal impassability, difficulty of an urination, decrease in sweating.

From a nervous system: drowsiness, an adynamy, unconscious states, concern, a disorientation, hallucinations (especially at patients of advanced age and at patients with Parkinson's disease), uneasiness, excitement, motive concern, a maniacal state, a hypomaniacal state, aggression, memory disturbance, depersonalization, strengthening of a depression, decline in the ability to concentration of attention, sleeplessness, "dreadful" dreams, yawning, an adynamy; activation of symptoms of psychosis; headache, myoclonus; dysarthtia, tremor of small muscles, especially hands, brushes, head and language, peripheral neuropathy (paresthesias), myasthenia, myoclonus; ataxy, extrapyramidal syndrome, increase and usilyny epileptic seizures; changes on EEG.

From CCC: tachycardia, heartbeat, dizziness, orthostatic hypotension, nonspecific changes on an ECG, (an interval of S-T or a tooth of T) at the patients who do not have heart diseases; arrhythmia, lability of the ABP (decrease or increase in the ABP), disturbance of intra ventricular conductivity (expansion of the QRS complex, change of an interval of P-Q, blockade of legs of a ventriculonector).

From the alimentary system: nausea, it is rare - hepatitis (including an abnormal liver function and cholestatic jaundice), heartburn, vomiting, a gastralgia, increase in appetite and body weight or a loss of appetite and body weights, stomatitis, taste change, diarrhea, darkening of language.

From endocrine system: increase in sizes (hypostasis) of testicles, a gynecomastia; increase in the sizes of mammary glands, galactorrhoea; decrease or increase in a libido, decrease in a potentiality, hypo - or a hyperglycemia, a hyponatremia (decrease in production of vasopressin), a syndrome of inadequate secretion of ADG.

From bodies of a hemopoiesis: agranulocytosis, leukopenia, thrombocytopenia, purpura, eosinophilia.

Interaction with other medicines:

At combined use of ethanol and HP, the oppressing TsNS (including other antidepressants, barbiturates, benzodiazepines and the general anesthetics), perhaps considerable strengthening of the oppressing action on TsNS, respiratory depression and hypotensive effect. Increases sensitivity to the drinks containing ethanol. Increases anticholinergic action of HP with anticholinergic activity (for example fenotiazin, protivoparkinsonichesky HP, an amantadin, atropine, Biperidinum, antihistaminic HP) that increases risk of emergence of side effects (from TsNS, sight, intestines and a bladder). At combined use with antihistaminic HP, a clonidine - strengthening of the oppressing action on TsNS; with atropine - increases risk of emergence of paralytic intestinal impassability; with the HP causing extrapyramidal reactions - increase in weight and frequency of extrapyramidal effects. At simultaneous use of amitriptyline and indirect anticoagulants (derivative coumarin or an indadion) increase in anticoagulating activity of the last is possible. Amitriptyline can strengthen the depression caused by GKS. At combined use with anticonvulsant HP strengthening of the oppressing action on TsNS, reduction of the threshold of convulsive activity (is possible when using in high doses) and decrease in efficiency of the last. HP for treatment of a thyrotoxicosis increase risk of development of an agranulocytosis. Reduces efficiency of Phenytoinum and alpha adrenoblockers. Inhibitors of a microsomal oxidation (Cimetidinum) extend T1/2, increase risk of development of toxic effects of amitriptyline (the dose decline for 20-30% can be required), inductors of microsomal enzymes of a liver (barbiturates, carbamazepine, Phenytoinum, nicotine and oral contraceptives) reduce concentration in plasma and reduce efficiency of amitriptyline. Fluoxetine and флувоксамин increase concentration of amitriptyline in plasma (the amitriptyline dose decline for 50% can be required). At combined use with holinoblokator, fenotiazina and benzodiazepines - mutual strengthening sedative and central holinoblokiruyushchy effects and increase in risk of developing of epileptic seizures (reduction of the threshold of convulsive activity); fenotiazina, besides, can increase risk of emergence of an antipsychotic malignant syndrome. At simultaneous use of amitriptyline with a clonidine, guanetidiny, betanidiny, Reserpinum and metildopy - decrease in hypotensive effect of the last; with cocaine - risk of development of arrhythmias of heart. Estrogensoderzhashchy peroral contraceptive HP and estrogen can increase bioavailability of amitriptyline; antiarrhytmic HP (like quinidine) strengthen risk of development of disturbances of a rhythm (possibly delay of metabolism of an amytriptilin). Combined use with Disulfiramum, etc. inhibitors of an atsetaldegidrogenaza provokes a delirium. It is incompatible with MAO inhibitors (increase in frequency of the periods of a hyper pyrexia, heavy spasms, hypertensive crises and the death of the patient are possible). Pimozidum and probucol can strengthen heart arrhythmias that is shown in lengthening of an interval of Q-T on an ECG. Strengthens action on CCC Epinephrinum, Norepinephrinum, the izoprenalina, ephedrine and Phenylephrinum (including and when these HP are a part of local anesthetics) and increases risk of development of disturbances of a cordial rhythm, tachycardia, heavy arterial hypertension. At joint appointment with an alpha adrenostimulyatorami for intranasal introduction or for use in ophthalmology (at considerable system absorption) vasoconstrictive action of the last can amplify. At joint reception with hormones of a thyroid gland - mutual strengthening of therapeutic effect and toxic action (include arrhythmias of heart and a promoting effect on TsNS). M-holinoblokatory and antipsychotic HP (neuroleptics) increase risk of development of a hyper pyrexia (especially at hot weather). At joint appointment with other gematotoksichny HP strengthening of a gematotoksichnost is possible.

Contraindications:

Hypersensitivity, use together with MAO inhibitors and for 2 weeks before an initiation of treatment, a myocardial infarction (the acute and subacute periods), an acute drunkenness, acute intoxication in somnolent, analgeziruyushchy and psychoactive HP, closed-angle glaucoma, heavy disturbances of AV and intra ventricular conductivity (blockade of legs of a ventriculonector, AV blockade of the II Art.), the lactation period, children's age (up to 6 years - peroral forms, up to 12 years at in oil and in introduction).

Overdose:

From TsNS: drowsiness, a stupor, a coma, an ataxy, hallucinations, concern, psychomotor excitement, decline in the ability to concentration of attention, a disorientation, confusion of consciousness, a dysarthtia, a hyperreflexia, muscle tension, a choreoathetosis, an epileptic syndrome.

From CCC: decrease in the ABP, tachycardia, arrhythmia, disturbance of endocardiac conductivity characteristic of intoxication tricyclic antidepressants of change of an ECG (especially QRS), shock, SN; seldom or never - a cardiac standstill.

Others: respiratory depression, short wind, cyanosis, vomiting, a hyperthermia, a mydriasis, the increased sweating, an oliguria or an anury. Symptoms develop in 4 h after overdose, reach a maximum in 24 h and 4-6 days last. At suspicion on overdose, especially at children, the patient should be hospitalized.

Treatment: at oral administration: gastric lavage, purpose of absorbent carbon; symptomatic and maintenance therapy; at heavy anticholinergic effects (decrease in the ABP, arrhythmia, a coma, myoclonic epileptic seizures) - administration of inhibitors of cholinesterase (use of physostigmine is not recommended because of the increased risk of developing of spasms); maintenance of the ABP and water and electrolytic balance. Control of functions CCC (including an ECG) within 5 days (the recurrence can come in 48 h and later), anticonvulsant therapy, IVL, etc. resuscitation actions are shown. The hemodialysis and an artificial diuresis are inefficient.

Storage conditions:

List B. In the dry, protected from light place, at a temperature not above 25 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets of 25 mg (planimetric strip packagings).