Amitriptyline

General characteristics. Structure:

Active ingredient: 10 mg of amitriptyline (in the form of a hydrochloride) in 1 ml of solution.

Excipients: Dextrosums monohydrate in terms of a dextrose, sodium chloride, a benzetoniya chloride, Acidum hydrochloricum or sodium hydroxide, water for injections.

Pharmacological properties:

Pharmacodynamics. Amitriptyline - tricyclic antidepressant with sedation. Amitriptyline equally inhibits the return capture of noradrenaline and seyorotonin in presynaptic nerve termination. The main metabolite of amitriptyline - нортриптилин - oppresses the return capture of a noradrenayolin than serotonin rather stronger. Has cholinolytic and H1-histamine activity. Renders powerful antidepressive, sedative and anxiolytic action.

Pharmacokinetics. Absorption. Amitriptyline possesses high absorption. Time of achievement of the maximum concentration (TCmax) after intake - 4-8 h, Cmax makes 0,04-0,16 mkg/ml. Equilibrium concentration is reached approximately in 1-2 weeks after the beginning of course treatment. Concentration of amitriptyline in fabrics are higher, than in plasma. Bioavailability of amitriptyline at various ways of introduction - 33-62%, its akyotivny metabolite of a nortriptilin - 46-70%. The volume of distribution (Vd) - 5-10 l/kg. Effective therapeutic concentration of amitriptyline in blood - 50-250 ng/ml, for a nortriptilin (its active metabolite) - 50-150 ng/ml. Communication with proteins of a plazyoma - 92-96%. Amitriptyline passes through gistogematologichesky barriers, including a blood-brain barrier (including нортриптилин), gets through a placental barrier, is emitted in breast milk in the concentration similar plasma.

Metabolism. Metabolism of amitriptyline is carried out preferential at the expense of a demetiliroyovaniye (isoenzymes of CYP2D6, CYP3A) and a hydroxylation (CYP2D6 isoenzyme) with the subsequent conjugation with glucuronic acid. Metabolism характеризует­ся considerable genetic polymorphism. The main active metabolite is secondary amine - нортриптилин. Metabolites cis-and trans-10-гидросиамитриптилин and cis-and trance-10-gidroksinortriptilin are characterized similar with nortriptiliny an activity profile though their action is expressed znayochitelno more weakly. Demetilnortriptilin and amitriptyline-N-oxide are present at a blood plasma in insignificant concentration; last metabolite practically ли­шен pharmacological activity. In comparison with amitriptyline all metaboliyota possess the action which was considerably less expressed to m-holinoblokiruyushchim. The major factor defining renal clearance, and, respectively, a kontsentrayotion in a blood plasma is hydroxylation speed. At a small share of people genetically caused slowed-down hydroxylation is observed.

Removal. An elimination half-life (T1/2) from a blood plasma - 10-28 h for amitriptyline, for a nortriptilin - 16-80 h. The average general clearance of amitriptyline makes 39,24±10,18 l/h. Amitriptyline preferential by kidneys and through intestines in the form of metaboyolit is removed. About 50% of the entered amitriptyline are removed with urine in a look 10-gidroksi-amitriptyline and its conjugate with glucuronic acid, about 27% are removed in the form of 10-hydroxy-nortriptilina and less than 5% of amitriptyline are removed in the form of initial substance and a nortriptilin. Full removal of amitriptyline from an organism happens within 7 days.

Elderly patients. At elderly patients increase in an elimination half-life and reduction of clearance of amitriptyline owing to reduction in the rate of metabolism is noted.

Patients with abnormal liver functions. Abnormal liver functions can lead to delay of metabolism of an amitriptiliyon and increase in its plasma concentration.

Patients with renal failures. Patients with disturbance of functions of kidneys have a removal of metabolites of amitriptyline and a noryotriptilin in a slowed-up way though metabolism per se does not change. Because of communication with blood belyoka amitriptyline is not removed from a blood plasma by dialysis.

Indications to use:

Endogenous depressions and other depressive frustration.

Route of administration and doses:

Appoint intramusculary and intravenously. Doses of drug select individually depending on age and a condition of the patient.

At depressions, resistant to therapy: intramusculary and intravenously (to enter slowly!) enter in a dose 10-20-30 mg to 4 times a day, increase in a dose should be carried out gradually, the maximum daily dose of 150 mg; 1-2 weeks later pereyokhodit on administration of drug inside.

To elderly people enter lower doses and raise them more slowly.

If the condition of the patient does not improve within 3-4 weeks of treatment, then dalneyyoshy therapy is inexpedient.

Cancellation. Drug should be cancelled gradually in order to avoid development of symptoms of "cancellation". Symptoms of "cancellation": after prolonged use at the sharp termination of reception there can be such undesirable reactions as nausea, vomiting, diarrhea, a headache, an indisposition, sleeplessness, unusual dreams, an unusual vozyobuzhdeniye, irritability; after prolonged use at the gradual otyomena - irritability, sleep disorders, unusual dreams. These symptoms do not demonstrate development of accustoming to drug.

Features of use:

Use during pregnancy is not recommended. If drug is used by pregnant women, it is necessary to warn about high risk of such reception for a fruit, especially in the III trimester of pregnancy. Use of high doses of tricyclic antidepressants in the III trimester of pregnancy can lead to neurologic frustration at the newborn. Sonliyovost cases at newborns whose mothers applied нортриптилин (an amitriptyline metabolite) during pregnancy are registered, urination delay cases are noted. Amitriptyline gets into breast milk. The relation of concentration makes chest milk / plasma 0,4-1,5 at the child who is on breastfeeding. At amitriptyline use breastfeeding should be stopped. If it is not made, it is necessary to watch a condition of the child, especially in techeyony the first four weeks after the birth. The child who is on breastfeeding can have nezhelatelyyony reactions (see the section "Side effect").

Should not appoint tricyclic antidepressants children and teenagers in a vozyorasta up to 18 years because of insufficiency of data on efficiency and a drug safety at this group of patients.

Amitriptyline in doses higher than 150 mg/days reduces a threshold of convulsive activity therefore it is necessary to consider possibility of convulsive frustration at patients with those in the anamnesis, and at injuries of a brain of any etioyologiya, simultaneous use of neuroleptics, during refusal of ethanol or cancellation of the medicines having anticonvulsant properties (benzodiazepines).

Any depressive frustration in itself increases risk of a suicide. Therefore during treatment observation for the purpose of early identification of disturbances or changes of behavior, and also suicide bents has to be antidepressants for all patients ustanovleyono.

Use of anesthetics during a course of treatment three - and tetracyclic antideyopressant can increase risk of developing of arrhythmia and decrease in the ABP. Sleduyoet whenever possible to stop use of amitriptyline some days before hiyorurgichesky intervention. In case of need urgent surgical intervention the anesthesiologist has to be warned about treatment of the patient by amitriptyline.

Amounts of slime as a part of the lacrimal liquid are possible dryness in a mouth and decrease in a slezoobrazovaniye with relative uvelicheyoniy that can lead to a cornea epithelium povrezhyodeniye at the patients using contact lenses.

Influence on ability to manage vehicles and mechanisms. During treatment it is necessary to be careful at management of transportyony means and occupation of other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reyoaktion.

Side effects:

The WHO classification of undesirable side reactions on development frequency: very frequent - 1/10 appointments (> 10%); frequent - 1/100 appointments (> 1%, but <10%); infrequent - 1/1000 appointments (> ODES of %, but <1%); rare - 1/10000 appointments (> 0,01%, but <0,1%); very rare - less than 1/10000 appointments (<0,01%).

Disturbances from blood and lymphatic system: seldom - oppression of a kostyonomozgovy hemopoiesis, an agranulocytosis, a leukopenia, thrombocytopenia, an eosinophilia.

Disturbances from a metabolism and food: very often - increase in weight; seldom - weight reduction, a loss of appetite.

Disturbances of mentality: often - confusion of consciousness, decrease in a libido; infrequently - a giyopomaniye, a mania, alarm, sleeplessness, "dreadful" dreams; seldom - deliyoriya (at elderly patients), hallucinations (at patients with schizophrenia).

Disturbances from a nervous system: very often - drowsiness, a tremor, a goloyovokruzheniya, headaches; often - disturbance of concentration of attention, a dysgeusia, paresthesias, an ataxy; infrequently - spasms.

Disturbances from an organ of sight: very often - accommodation disturbance; час­то - a mydriasis; infrequently - increase in intraocular pressure.

Disturbances from an acoustic organ and labyrinth disturbances: infrequently - a sonitus.

Disturbances from heart: very often - the strengthened heartbeat, tachycardia, orthostatic hypotension; often - an atrioventricular block (AV blockade), blockade of a leg of a ventriculonector, disturbance of endocardiac conductivity, registriruyeyomy only on an ECG, but not shown clinically (increase in QT of an interval, a QRS complex uveyolicheniye); infrequently - arterial hypertension; seldom - arrhythmia.

Disturbances from digestive tract: very often - dryness in a mouth, a lock, nausea; infrequently - diarrhea, vomiting, a paraglossa; seldom - increase in slyunyony glands, paralytic intestinal impassability.

Disturbances from a liver and biliary tract: seldom - jaundice, narusheyony indicators of a functional condition of a liver, increase in activity of the shchelochyony phosphatase (SP) of blood and transaminases.

Disturbances from skin and hypodermic fabrics: very often - a hyperhidrosis; не­часто - skin rash, a small tortoiseshell, a face edema; seldom - an alopecia, reactions of a fotosensiyobilization.

Disturbances from kidneys and urinary tract: infrequently - an ischuria.

Disturbances from generative organs and a mammary gland: often - erectile dysfunction; seldom - a gynecomastia.

The general frustration and disturbances in an injection site: often - fatigue; seldom - a pyrexia.

Cancellation symptoms: after prolonged use at the sharp termination of a priyomeneniye there can be such undesirable reactions as nausea, vomiting, diarrhea, a headache, an indisposition, sleeplessness, unusual dreams, an unusual vozyobuzhdeniye, irritability; after prolonged use at gradual cancellation - irritability, sleep disorders, unusual dreams. These symptoms do not demonstrate development of accustoming to drug.

Some of undesirable reactions, for example, the headache, a tremor, disturbance of concentration of attention, a lock and decrease in a libido can be displays of a depression and disappear in process of permission of a depression.

If any of the side effects specified in the instruction are aggravated, or you noticed any other side effects which are not specified in the instruction, report about it to the doctor.

Interaction with other medicines:

The concomitant use of amitriptyline and MAO inhibitors can cause a serotoninovy syndrome (agitation, confusion of consciousness, a tremor, a myoclonus, a hyperthermia are possible).

Amitriptyline can be appointed in 14 days after the treatment termination the MAO neyoobratimy inhibitors and at least in 1 day after the therapy termination by the MAO reversible inhibitor of A type - moklobemidy. MAO inhibitors can be appointed in 14 days after the end of reception of amitriptyline. Amitriptyline can strengthen effect of alcohol, barbiturates and other substances, the oppressing TsNS.

As tricyclic antidepressants, including amitriptyline, can strengthen effect of anticholinergic drugs on organs of sight, TsNS, a kiyoshechnik and a bladder, it is necessary to avoid their simultaneous use because of risk of development of paralytic intestinal impassability, a hyper pyrexia.

At reception of tricyclic antidepressants in combination with anticholinergic drugs or neuroleptics, especially in hot weather, perhaps razviyoty hyper pyrexias.

Amitriptyline can strengthen action of Epinephrinum, ephedrine, an izoprenalin, Norepinephrinum, Phenylephrinum and fenilpropanolamin on cardiovascular system; thereof it is not necessary to apply the anesthetics, antiedematouses and other drugs containing these substances along with amitriptyline.

Can reduce anti-hypertensive effect of a guanetidin, betanidin, Reserpinum, clonidine and Methyldopums. At a concomitant use of tricyclic antidepresyosant it is necessary to correct antihypertensive therapy.

At combined use with antihistaminic medicines strengthening of the oppressing action on TsNS is possible; with the medicines causing extrapyramidal reactions - increase in weight and frequency of extrapyramidal effects.

The concomitant use of amitriptyline and the drugs extending QT an interval (antiaritmik (quinidine), antihistaminic drugs (астемизол and терфенадин), some neuroleptics (a tsizaprid, a galofantrin and a sotalol, especially, of Pimozidum and a sertindol)), increases risk of development of ventricular arrhythmia. Antifungal drugs, for example, флуконазол, тербинафин - increase the level of concentration of tricyclic antidepressants in serum and, sootvetstyovenno, their toxicity. Faints and development of paroxysms of ventricular tachycardia (Torsade de Pointes) are possible.

Barbiturates and other inductors of enzymes, for example, rifampicin and carbamazepine, etc. can strengthen metabolism of tricyclic antidepressants, and in a rezulyyotata of what to lower concentration of tricyclic antidepressants in a blood plasma and to reduce their efficiency.

At simultaneous use with Cimetidinum, methylphenidate and blockers of calcium channels amitriptyline metabolism delay, increase in its concentration in a blood plasma and development of toxic effects is possible.

At joint appointment with neuroleptics it is necessary to consider that tritsiklicheyosky antidepressants and neuroleptics mutually inhibit metabolism of each other, reducing a threshold of convulsive readiness.

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 glucocorticoid means (GKS).

At combined use with anticonvulsant medicines 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 poyosledny.

The concomitant use with medicines for treatment of a thyrotoxicosis increases risk of development of an agranulocytosis.

Because of risk of development of arrhythmias patients need to observe extra care at an amitriptyline nayoznacheniya with hyperfunction of a thyroid gland or to the payotsiyenta receiving thyroid drugs.

Fluoxetine and флувоксамин can increase concentration of amitriptyline in a blood plazyoma (the amitriptyline dose decline can be required).

At combined use with holinoblokator, fenotiazina and benzodiazepines perhaps mutual strengthening sedative and central holinoblokiyoruyushchy effects and increase in risk of developing of epileptic seizures (reduction of the threshold of convulsive activity).

Estrogensoderzhashchy peroral contraceptive medicines and estrogen can increase bioavailability of amitriptyline. For recovery of efficiency or decrease in toxicity there can be necessary a reduction of a dose or is oestrogenic, or amitriptyline. However cancellation of a preyoparat can be required.

Combined use with Disulfiramum and other inhibitors of an atsetaldegidrogenaza can increase risk of development of psychotic states and confusion of consciousness.

At use of amitriptyline together with Phenytoinum metabolism of the last is oppressed, and the risk of its toxic action (an ataxy, a giperreflekyosiya, a nystagmus, a tremor) increases. At the beginning of use of amitriptyline for patients, poluyochayushchy Phenytoinum, it is necessary to control concentration of the last in a blood plasma because of increase in risk of oppression of his metabolism. At the same time it is necessary to control therapeutic effect of amitriptyline since increase in its dose can be required.

Drugs of the St. John's Wort which is made a hole reduce the maximum concentration of amitriptyline in a blood plasma approximately by 20% due to activation of hepatic metabolism of amitriptyline CYP3A4 isoenzyme. What increases risk of a vozniknoyoveniye of a serotoninovy syndrome. This combination can be applied with dose adjustment of amitriptyline depending on results of measurement of its concentration in a blood plasma.

At simultaneous use of valproic acid the clearance of an amityoriptilin from a blood plasma decreases that can lead to increase in concentration of amitriptyline and its metabolite - a nortriptilina. At combined use of amitriptyline and valproic acid it is necessary to control concentration of amitriptyline and a nortriptilin in blood serum. Can be required snizheyony doses of amitriptyline.

At simultaneous use of amitriptyline in a high dose and lithium drugs within more than half a year development of spasms, cardiovascular oslozhyoneniye is possible. Emergence of signs of neurotoxic effect in a viyoda of a tremor, disturbances of memory, an otvlekayemost, disorganization of thinking even is also possible at normal concentration of lithium in blood and average doses of amitriptyline.

Contraindications:

Hypersensitivity, myocardial infarction (the acute and subacute periods), arityomiya, heavy disturbances of an atrioventricular and intra ventricular provodimoyosta (blockade of legs of a ventriculonector, an atrioventricular block of the II degree), heart failure, an acute drunkenness, acute intoxication snotvoryony, analgeziruyushchy and psychoactive drugs, a closed-angle glauyokoma, an ischuria, including at a prostate hyperplasia, paraliyotichesky intestinal impassability, a pyloric stenosis, a hypopotassemia, soputstyovuyushchy use of the drugs extending QT interval or defiant a hypopotassemia, the lactation period, children's age up to 18 years.

Contraindicated simultaneous use with monoamine oxidase inhibitors (MAO) and their use within 14 days prior to the beginning of and after the end of treatment. If at you one of the listed diseases, before administration of drug surely consult with the doctor.

With care. Convulsive frustration, an alcoholism, a prostate hyperplasia, a serious illness of a liver and cardiovascular system, bronchial asthma, the maniac-depressive psychosis (MDP) and epilepsy (see the section "Special Instructions"), oppression of a marrowy hemopoiesis, a hyperthyroidism, a thyrotoxicosis, an urination delay, bladder hypotonia, stenocardia, the increased intraocular pressure, decrease in motor function of digestive tract (risk of emergence of paralytic intestinal impassability), schizophrenia (хо­тя at reception usually there is no aggravation of productive symptomatology), poyozhily age, pregnancy, the breastfeeding period.

If at you one of the listed diseases, before administration of drug obyazayotelno consult with the doctor.

Overdose:

Reactions to overdose at different patients significantly differ. Reception more than 500 mg cause moderately expressed or tyayozhely intoxication in adult patients. A lethal dose of amitriptyline - 1200 mg.

Symptoms. Symptoms can develop slowly and imperceptibly, or sharply and suddenly. In a teyocheniye of the first hours drowsiness or excitement, agitation and gallyuyotsination is observed.

Anticholinergic symptoms: mydriasis, tachycardia, urination delay, suyokhost of mucous membranes, temperature increase, delay of motility of intestines. Neuromental signs: spasms, sudden oppression of the central nervous system (CNS), decrease in level of consciousness up to a coma, breath suppression. Symptoms from heart: In process of increase of signs of overdose nayorastat changes from cardiovascular system. Arrhythmias (a zheludochyokovy tachyarrhythmia, disturbances of a cordial rhythm as Torsade de Pointes, a fibyorillyation of ventricles). On an ECG lengthening of an interval of PR, expansion of the QRS complex, lengthening of an interval of QT, flattening or inversion of a tooth of T, a depresyosiya of a segment of ST and blockade of endocardiac conductivity of various degree is characteristic, koyotory can progress up to a cardiac standstill, a lowering of arterial pressure, heart failure, intra ventricular blockade, frequent pulse.

Expansion of the QRS complex usually correlates with weight of toxic effects owing to acute overdose.

Heart failure, decrease in the ABP, cardiogenic shock. Metabolic acidosis, hypopotassemia.

After awakening confusion of consciousness, excitement, gallyutsiyonation, an ataxy is again possible.

Treatment: the therapy termination by amitriptyline, administration of physostigmine of 1 - 3 mg kayozhdy 1-2 hours in oil or in/in, liquid infusion, symptomatic therapy, podderyozhany the arterial pressure 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, a gastric lavage are ineffective.

Storage conditions:

To store in the place protected from light at a temperature not above 25 °C. To store in the places unavailable to children. A period of validity - 3 years. Not to use after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Solution for intravenous and intramuscular administration of 10 mg/ml in ampoules on 2 ml. Packaging: on 5 ampoules in a blister strip packaging from a film of polyvinyl chloride and printing aluminum foil varnished or the flexible packaging on the basis of a folyyoga aluminum, or without foil. On 1 or 2 blister strip packagings with the application instruction, a knife or the scarificator ampoule in a pack from a cardboard. On 20, 50 or 100 blister strip packagings with a foil with 10, 25 or 50 instyoruktion on use, knives or scarificators ampoule in boxes from a cardboard or in boxes from corrugated fibreboard (for a hospital). When packaging ampoules with notches, rings or points of a break ampoule or scarificators do not put knives.