Amitriptyline

General characteristics. Structure:

Active agent Amitriptylini hydrochloridum of 28,3 mg (in terms of amitriptyline of 25 mg).

Excipients: lactose (sugar milk) - 50 mg, potato starch - 8,5 mg, povidone of 25 - 1,25 mg, cellulose of microcrystallic-10,25 mg, magnesium stearate - 0,7 mg, talc of-1,0 mg.

Pharmacological properties:

Pharmacodynamics. The mechanism of antidepressive effect of amitriptyline is connected with oppression of the return neyronalny capture of catecholamines (noradrenaline, dopamine) and serotonin in TsNS. Amitriptyline is an antagonist of muskarinovy cholinergic receptors in TsNS and on the periphery, possesses peripheral anti-histamine (H1) and antiadrener-gichesky properties. Also causes antineuralgic (the central analgetic), antiulcerous and antibuli-michesky action, it is effective at bed wetting. Antidepressive action develops during 2-4 weeks after the beginning of use.

Pharmacokinetics. Absorption — high. Time of achievement of the maximum concentration (Ttakh) after intake of 4-8 hours. Bioavailability of amitriptyline from 33 to 62%, its active metabolite of a nortriptilin — 46-70%. The volume of distribution is 5-10 l/kg. Effective therapeutic concentration in amitriptyline blood — 50-250 ng/ml, for a nortriptilin (its active metabolite) of 50-150 ng/ml. The maximum concentration in a blood plasma (Stakh) — 0,04-0,16 mkg/ml. Passes through gistogematichesky barriers, including a blood-brain barrier (including нортриптилин). Concentration of amitriptyline in fabrics are higher, than in plasma. Communication with proteins of a pazma — 92-96%. It is metabolized in a liver (by demethylation, a hydroxylation) with formation of active metabolites — a nortriptilina, 10-hydroxy-amitriptyline, and inactive metabolites. The period of removal from a blood plasma from 10 to 28 hours for amitriptyline and from 16 to 80 hours for a nortriptilin. It is allocated with kidneys — 80%, partially with bile. Full removal within 7-14 days.
Amitriptyline gets through a placental barrier, is emitted in breast milk in the concentration similar plasma.

Indications to use:

To apply strictly on doctor's orders.
— Depressions of any etiology. It is especially effective at alarming depressions, owing to expressiveness of sedation. Does not cause an aggravation of productive symptomatology (nonsense, hallucinations) unlike antidepressants with a promoting effect.
— The mixed emotional frustration and disturbances in behavior; phobic frustration.
— Children's enuresis (except for children with a hypotonic bladder).
— Psychogenic anorexia, bulimic neurosis.
— Neurogenic pains of chronic character, for prevention of migraine.

Route of administration and doses:

Appoint inside (in time or after food). The initial daily dose at intake makes 50-75 mg (25 mg in 2-3 receptions), then the dose is gradually increased by 25-50 mg before obtaining desirable antidepressive effect. The optimum daily therapeutic dose makes 150-200 mg (the maximum part of a dose is accepted for the night). At heavy depressions, resistant to therapy, the dose is increased to 300 mg and more, to the most tolerable dose (the maximum dose for ambulatories — 150 mg/days). In these cases it is reasonable to begin treatment with intramuscular or intravenous administration of drug, applying at the same time higher initial doses, accelerating building of dosages under control of a somatic state. After obtaining lasting antidepressive effect in 2-4 weeks of a dose gradually and slowly reduce. In case of symptoms of a depression at decrease in doses it is necessary to return to a former dose. If the condition of the patient does not improve within 3-4 weeks of treatment, then further therapy is inexpedient. At patients of advanced age at easy disturbances, in out-patient practice, doses make 25-50-100 mg as much as possible, in the divided doses or 1 time a day for the night. At enuresis to children 6 years of 12,5-25 mg before going to bed are more senior (the dose should not exceed 2,5 mg/kg of body weight of the child). For prevention of migraine, chronic pains of neurogenic character (including long headaches) from 12,5-25 mg to 100 mg/days.

Features of use:

Amitriptyline in doses higher than 150 mg/days reduces a threshold of convulsive activity therefore it is necessary to consider possibility of convulsive attacks at patients with those in the anamnesis and at that category of patients who are predisposed to it because of age or injuries. Treatment by amitriptyline has to take place in advanced age under careful control, using the minimum doses of drug and their gradual increase, in order to avoid development of delirious frustration, a hypomania of other complications.
Patients with depressive phase MDP can pass into a maniacal stage.
During reception of amitriptyline driving of vehicles, service of mechanisms and other types of the works demanding the increased concentration of attention and also alcohol intake is forbidden.

Side effects:

Side effects are generally connected with holinoblokiruyu-shchy effect of drug: accommodation paresis, a sight illegibility, increase in intraocular pressure, dryness in a mouth, a lock, intestinal impassability, an urination delay, fervescence. All these phenomena usually pass after adaptation to drug or decrease in doses.
- From the central nervous system: a headache, an ataxy, increased fatigue, weakness, irritability, dizziness, a sonitus, drowsiness or sleeplessness, disturbance of concentration of attention, dreadful dreams, a dysarthtia, confusion of consciousness, a hallucination, motive excitement, a disorientation, a tremor, paresthesias, a peripheral neuropathy, changes on EEG. Seldom — extrapyramidal frustration, spasms, alarm.
- From cardiovascular system: tachycardia, arrhythmia, conductivity disturbance, lability of arterial pressure, expansion of the QRS complex on an ECG (disturbance of intra ventricular conductivity), symptoms of heart failure, a faint.
- From digestive tract: nausea, vomiting, heartburn, anorexia, stomatitis, taste disturbances, darkening of language, a sensation of discomfort in epigastriums, a gastralgia, increase in activity of "hepatic" transaminases, seldom cholestatic jaundice, diarrhea.
- From endocrine system: increase in the sizes of chest glands men and at women, a galactorrhoea, change have secretions of antidiuretic hormone (ADG), change of a libido, potentiality. - it is rare — hypo - or a hyperglycemia, a glucosuria, disturbance of tolerance to glucose, hypostasis of testicles.
- Allergic reactions: skin rash, itch, photosensitization, Quincke's disease, small tortoiseshell.
- Other: an agranulocytosis, a leukopenia, an eosinophilia, thrombocytopenia, a purpura and other changes of blood, a hair loss, a hyperadenosis, increase in body weight at prolonged use, perspiration, a pollakiuria.
- At prolonged treatment, especially in high doses, at the sharp termination of treatment, development of a withdrawal is possible: a headache, nausea, vomiting, diarrhea, and also irritability, a sleep disorder with bright, unusual dreams, a hyperexcitability.

Interaction with other medicines:

Amitriptyline strengthens the oppressing action on TsNS of the following drugs: neuroleptics, sedative and hypnagogues, anticonvulsant drugs, analgetics, anesthetics, alcohol; shows a synergism at interaction with other antidepressants.
At combined use of amitriptyline with neuroleptics, and/or anticholinergic drugs there can be a febrile temperature reaction, paralytic intestinal impassability.

Amitriptyline exponentiates hypertensive effects of catecholamines and other adrenostimulyator that increases risk of development of disturbances of a cordial rhythm, tachycardias, heavy arterial hypertension, but inhibits effects of the drugs influencing release of noradrenaline.
Amitriptyline can reduce anti-hypertensive action of a guanetidin and drugs with the similar mechanism of action, and also to weaken effect of anticonvulsants. At simultaneous use of amitriptyline and anticoagulants — coumarin derivatives increase in anticoagulating activity of the last.

At a concomitant use of amitriptyline and Cimetidinum increase in concentration in amitriptyline plasma with possible development of toxic effects is possible. Inductors of microsomal enzymes of a liver (barbiturates, carbamazepine) reduce plasma concentration of amitriptyline.

Amitriptyline strengthens action of the protivoparkinsonichesky means and other medicines causing extrapyramidal reactions.

Quinidine slows down amitriptyline metabolism. Combined use of amitriptyline with Disulfiramum and other inhibitors of an atsetaldegiddegidrogenaza can provoke a delirium.

Estrogensoderzhashchy peroral contraceptives can increase bioavailability of amitriptyline; Pimozidum and probucol can strengthen cardiac arrhythmias. Amitriptyline can strengthen the depression caused by glucocorticosteroids; combined use with medicines for treatment of a thyrotoxicosis increases risk of development of an agranulocytosis.

The concomitant use of amitriptyline with MAO inhibitors can lead to a lethal outcome. Having rummaged in treatment between reception of MAO inhibitors and tricyclic antidepressants has to make not less than 14 days!

Contraindications:

— Heart failure in a decompensation stage.
— Acute and recovery period of a myocardial infarction.
— Disturbances of conductivity of a cardiac muscle.
— The expressed arterial hypertension.
— Acute diseases of a liver and kidneys, with the expressed disturbance of functions.
— A peptic ulcer of a stomach and 12 gut humus in an aggravation stage.
— Prostate hypertrophy.
— Bladder atony.
— Pylorostenosis, paralytic impassability of intestines.
— Simultaneous or in the previous 2 weeks treatment by MAO inhibitors.
— Pregnancy, breastfeeding period.
— Children up to 6 years.
— Hypersensitivity to amitriptyline.

Amitriptyline should be applied With CARE at the persons having alcoholism at bronchial asthma, the maniac-depressive psychosis (MDP) and epilepsy, at oppression of a marrowy hemopoiesis, a hyperthyroidism, stenocardia and heart failure, closed-angle glaucoma, intraocular hypertensia, schizophrenia (though at its reception usually there is no aggravation of productive symptomatology).

Overdose:

Drowsiness, disorientation, confusion of consciousness, expansion of pupils, fervescence, asthma, dysarthtia, excitement, hallucinations, convulsive attacks, muscle tension, coma, vomiting, arrhythmia, arterial hypotension, heart failure, respiratory depression.

Help measures: therapy termination by amitriptyline, gastric lavage, liquid infusion, symptomatic therapy, maintenance of the ABP and water and electrolytic balance. Monitoring of cardiovascular activity (ECG) within 5 days since the recurrence can come in 48 hours and later is shown. The hemodialysis and an artificial diuresis are a little effective.

Storage conditions:

List B. To store 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.
On 10, 50 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished.
On 10, 20, 30, 40, 50 or 100 tablets in a container polymeric for medicines or a bottle from glass melt with the screwed plastic or aluminum covers.
One container (bottle) or 1,2,3,4,5,6,8 or 10 blister strip packagings together with the application instruction place in a pack from a cardboard.
On 5,10 or 20 containers (bottles) or on 20,40,60,80 and 100 blister strip packagings together with the corresponding number of application instructions place in a box from a cardboard (for hospitals).