Amitriptyline

General characteristics. Structure:

Active ingredient: 25 mg of amitriptyline (in the form of a hydrochloride) in 1 tablet.

Pharmacological properties:

Pharmacodynamics. Amitriptyline - antidepressive means (tricyclic antidepressant). Renders also some analgeziruyushchy (the central genesis), 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. Has properties of the antiarrhytmic IA medicine (M) of a class, 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 and/or serotonin in the central nervous system (CNS) (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 render sedative and   m-holinoblokiruyushchee action.

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 arterial pressure (AP) and body temperature. Does not inhibit monoamine oxidase (MAO).

Antidepressive action develops within 2-3 weeks after the beginning of use.

Pharmacokinetics. Absorption - high. Bioavailability of amitriptyline of 30-60%, its active metabolite of a nortriptilin — 46-70%. Time of achievement of the maximum concentration (Tmax) after intake of 2,0-7,7 h. The volume of distribution is 5-10 l/kg. Effective therapeutic concentration in blood for amitriptyline – 50-250 ng/ml, for a nortriptilin of 50-150 ng/ml. The maximum concentration in a blood plasma (Cmax) of 0,04-0,16 mkg/ml. Passes (including нортриптилин) through gistogematichesky barriers, including a blood-brain barrier, the placental barrier, gets into breast milk. Communication with proteins of plasma - 96%.

It is metabolized in a liver with participation of isoenzymes of CYP2C19, CYP2D6, has effect of "the first passing" (by demethylation, a hydroxylation) with formation of active metabolites - a nortriptilina, 10-hydroxy-amitriptyline, and inactive metabolites. Plasma elimination half-life of blood (T1/2) - 10-26 hours for amitriptyline and 18-44 hours for a nortriptilin. It is removed by kidneys (mainly in the form of metabolites) - 80% in 2 weeks, partially with bile.

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).

As a part of complex therapy it is applied at the mixed emotional frustration, psychoses at schizophrenia, alcoholic abstinence, behavior disorders (activity and attention), night enuresis at children (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, migraines (prevention), a peptic ulcer of a stomach and a 12-perstny gut.

Route of administration and doses:

Appoint inside, without chewing, right after food (for reduction of irritation of a mucous membrane of a stomach).

Adults. The adult at a depression an initial dose - 25-50 mg for the night, then gradually the dose can be increased taking into account efficiency and portability of drug to the maximum 300 mg/days in 3 receptions (the greatest part of a dose is accepted for the night). At achievement of therapeutic effect the dose can be reduced to the minimum patient, effective depending on a state, gradually. Duration of a course of treatment is defined by a condition of the patient, efficiency and portability of the carried-out therapy and can make from several months to 1 year, and if necessary and more.

At advanced age at easy disturbances, and also at nervous bulimia, as a part of complex therapy at the mixed emotional frustration and behavior disorders, psychoses at schizophrenia and alcoholic abstinence appoint in a dose 25-100 mg/days (to night), after achievement of therapeutic effect pass to minimal effective doses - 10-50 mg/days.

For prevention of migraine, at a chronic pain syndrome of neurogenic character (including long headaches), and also in complex therapy of a peptic ulcer of a stomach and a 12-perstny gut - from 10-12,5-25 to 100 mg/days (the maximum part of a dose is accepted for the night).

Children. To children as antidepressant: from 6 to 12 years - 10-30 mg/days or 1-5 mg/kg/days are fractional, at teenage age - to 100 mg/days. The main part of a dose is accepted for the night.

At night enuresis at children of 6-10 years - 10-20 mg/days for the night, 11-16 years – to 50 mg/days.

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 the heart rate (HR), 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).

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 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 children, teenagers and young people (24 years are younger) with a depression, etc. mental disturbances antidepressants, in comparison with placebo, increase risk of emergence of suicide thoughts and suicide behavior. Therefore at purpose of amitriptyline or any other antidepressants at this category of patients it is necessary to correlate risk of a suicide and advantage of their use. In short-term researches at people 24 years are more senior the risk of a suicide did not increase, and at people 65 years are more senior decreased a little. During treatment by antidepressants for all patients observation for the purpose of early identification of suicide bents has to be established.

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 slezootdeleniye 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, increase or decrease in the ABP, a tremor or the spastic phenomena) reception of amitriptyline is gradually cancelled at least in 7 weeks prior to 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.

Side effects:

Connected with holinoblokiruyushchy effect of drug: 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.

From TsNS: drowsiness, unconscious states, fatigue, irritability, concern, a disorientation, hallucinations (especially at patients of advanced age and at patients with Parkinson's disease), uneasiness, excitement psychomotor, a mania, a hypomania, memory disturbance, decline in the ability to concentration of attention, sleeplessness, "dreadful" dreams, an adynamy; headache; dysarthtia, tremor of small muscles, especially hands, brushes, head and language, peripheral neuropathy (paresthesias), myasthenia, myoclonus; ataxy, extrapyramidal syndrome, increase and strengthening of epileptic seizures; changes on the electroencephalogram (EEG).

From CCC: tachycardia, a heart consciousness, dizziness, orthostatic hypotension, nonspecific changes on the electrocardiogram (ECG) (an interval of S-T or a tooth of T) at patients without 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 a GIT: nausea, heartburn, a gastralgia, hepatitis (including an abnormal liver function and cholestatic jaundice), vomiting, 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 antidiuretic hormone (ADG).

Allergic reactions: skin rash, itch, photosensitization, Quincke's disease, small tortoiseshell.

Others: hair loss, sonitus, hypostases, hyper pyrexia, hyperadenosis, ischuria, pollakiuria.

At prolonged treatment, especially in high doses, at its sharp termination development of a withdrawal is possible: nausea, vomiting, diarrhea, headache, indisposition, sleep disorders, unusual dreams, unusual excitement; at gradual cancellation after prolonged treatment - irritability, motive concern, sleep disorders, unusual dreams.

Connection with administration of drug is not established: volchanochnopodobny syndrome (palindromic rheumatism, emergence of antinuclear antibodies and positive rhematoid factor), abnormal liver function, ageusia.

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, derivatives of a 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 holinoblokator, derivatives of a fenotiazin 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); derivatives of a fenotiazin, besides, can increase risk of emergence of an antipsychotic malignant syndrome.

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.

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 glucocorticosteroids (GKS).

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.

Combined use with Disulfiramum, etc. inhibitors of an atsetaldegidrogenaza provokes a delirium.

Fluoxetine and флувоксамин increase concentration of amitriptyline in plasma (the amitriptyline dose decline for 50% can be required).

Estrogensoderzhashchy peroral contraceptive HP and estrogen can increase bioavailability of amitriptyline.

At simultaneous use of an amitriptiliin with a clonidine, guanetidiny, betanidiny, Reserpinum and metildopy - decrease in hypotensive effect of the last; with cocaine - risk of development of arrhythmias of heart.

Antiarrhytmic HP (like quinidine) strengthen risk of development of disturbances of a rhythm (possibly amitriptyline metabolism delay).

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 adrenomimetikami 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.

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).

Contraindications:

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

Due to the content of lactose of monohydrate (milk sugar) patients with rare hereditary diseases, such as intolerance of a galactose, deficit of lactase or glyukozo-galaktozny malabsorption should not accept drug.

Amitriptyline should be applied with care at persons with alcoholism, at bronchial asthma, schizophrenia (activation of psychosis), bipolar disorder, epilepsy is possible, at oppression of a marrowy hemopoiesis, diseases of cardiovascular system (CCC) (stenocardia, arrhythmia, heart blocks, chronic heart failure, a myocardial infarction, arterial hypertension), intraocular hypertensia, a stroke, decrease in motor function of the digestive tract (DT) (risk of emergence of paralytic intestinal impassability), a liver and/or renal failure, a thyrotoxicosis, a prostate hyperplasia, an ischuria, bladder hypotonia, at pregnancy (especially the I trimester), at advanced age.

Overdose:

Symptoms: 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, heart failure; 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, reception 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, the artificial ventilation of the lungs (AVL), etc. resuscitation actions are shown. The hemodialysis and an artificial diuresis are inefficient.

Storage conditions:

In the dry, protected from light place at a temperature not above 25 °C. A period of validity - 2 years.

Issue conditions:

According to the recipe

Packaging:

On 50 tablets in strip packagings and cardboard packs.