Amitriptyline increases. Amitriptyline - emergency or last resort
Dosage form: tablets Composition:1 tablet contains:
active substance: Amitriptyline hydrochloride 0.0283 g (in terms of amitriptyline 0.0250 g);
Excipients: corn starch 0.078 g, lactose monohydrate 0.185815 g, colloidal silicon dioxide 0.001 g, medical gelatin 0.000885 g, magnesium stearate 0.003 g, talc 0.003 g.
Description: Tablets are white to off-white with a creamy tint, round, biconvex in shape. Pharmacotherapeutic group: Antidepressant ATX:N.06.A.A.09 Amitriptyline
Pharmacodynamics:Amitriptyline is a tricyclic antidepressant from the group of non-selective inhibitors of neuronal monoamine uptake. It has a pronounced thymoanalytic and sedative effect.
PharmacodynamicsThe mechanism of the antidepressant action of amitriptyline is associated with inhibition of the reverse neuronal uptake of catecholamines (norepinephrine, dopamine) and serotonin into the central nervous system.
Amitriptyline is an antagonist of muscarinic cholinergic receptors in the central nervous system and in the periphery, and also has peripheral antihistamine (III) and antiadrenergic properties.
The antidepressant effect develops within 2-4 weeks after the start of use.
Pharmacokinetics:Absorption is high. Amitriptyline is quickly and well absorbed from the gastrointestinal tract after oral administration. Time to reach maximum concentration (T
m ah) after oral administration 2-7.7 hours. The bioavailability of amitriptyline is from 33 to 62%, its active metabolite nortriptyline is 46-70%. Volume of distribution 5-10 l/kg. Effective therapeutic concentrations in the blood of amitriptyline are 50-250 ng/ml, for nortriptyline (its active metabolite) 50-150 ng/ml. Maximum concentration in blood plasma (C m ah) - 0.04-0.16 μg/ml. Passes through histohematic barriers, including the blood-brain barrier (including nortriptyline). Amitriptyline concentrations in tissues are higher than in plasma. Communication with plasma proteins 92 - 96%.Metabolism
Metabolized in the liver by demethylation (isoenzymes CYP2D19, CYP3A) and hydroxylation (isoenzyme CYP2D6) with the formation of active metabolites - nortriptyline, 10-hydroxyamitriptyline, 10-hydroxynortriptyline and inactive metabolites. The main active metabolite is the secondary amine - nortriptyline. Metabolites 10-hydroxyamitriptylip and 10-hydroxynortriptyline are also active, but their effect is much less pronounced.
Amitriptyline and nortriptyline are conjugated with glucuronic acid, but these conjugates are inactive.
Demythylnortriptyline and amitriptyline-N-oxide are present in blood plasma in low concentrations and are practically devoid of pharmacological activity. Compared to amitriptyline, all metabolites have a significantly less pronounced m-cholithiasis-blocking effect.
Removal
The plasma half-life ranges from 9 to 46 hours for amitriptyline and from 18 to 95 hours for nortriptyline. The average total creatinine clearance is 39.2 ± 10.18 l/h. It is excreted mainly at night - 80%, partly with bile. Complete elimination within 7-14 days. Amitriptyline penetrates the placental barrier and is excreted into breast milk. The breast milk/plasma concentration ratio is 0.4-1.5. When breastfeeding while taking amitriptyline, an average of 2% of the dose taken by the mother, calculated by body weight (in mg/kg), enters the child's body. Equilibrium plasma concentrations of amitriptyline and nortriptyline are achieved in most patients within a week.
Elderly patients
In elderly patients, there is an increase in the half-life and a decrease in clearance of amitriptyline due to a decrease in metabolic rate.
Patients with liver dysfunction
Impaired liver function may lead to a slower metabolism of amitriptyline and an increase in its plasma concentrations.
Patients with impaired renal function
Renal failure does not affect the kinetics of the drug. Indications:Endogenous depression and other depressive disorders.
Contraindications:Hypersensitivity to amitriptyline or the excipients of the drug, lactose intolerance, lactase deficiency, glucose-galactose malabsorption.
Concomitant treatment with monoamine oxidase inhibitors (MAOIs) and two weeks before starting treatment (see section "Interaction with other drugs"),
Heart failure in the stage of decompensation.
Insufficiency of coronary circulation.
Acute and recovery periods of myocardial infarction.
Impaired conduction of the heart muscle.
Severe liver and kidney diseases with severe dysfunction.
Peptic ulcer of the stomach and duodenum in the acute stage.
Prostatic hyperplasia.
Urinary retention, including with prostatic hyperplasia.
Atony of the bladder.
Pyloric stenosis, paralytic ileus.
Pregnancy, breastfeeding period.
Children's age up to 18 years old.
Acute poisoning with alcohol, barbiturates or opioids.
Angle-closure glaucoma.
Carefully:Amitriptyline should be used with caution in persons suffering from alcoholism, with bronchial asthma, manic-depressive psychosis (MDP) and epilepsy (see Special Instructions), in elderly patients, with suppression of bone marrow hematopoiesis, hyperthyroidism, diseases of the cardiovascular system (angina pectoris, arterial hypertension), bipolar affective disorder (after recovery from the depressive phase), intraocular hypertension, decreased motor function of the gastrointestinal tract (risk of paralytic ileus), concomitant use with selective serotonin reuptake inhibitors (SSRIs), schizophrenia (possible activation of psychosis) .
Pregnancy and lactation:The use of the drug during pregnancy and breastfeeding is contraindicated. During pregnancy, amitriptyline should be used only in cases where the expected benefit to the mother outweighs the potential risk to the fetus. The drug should not be used in III trimester of pregnancy unless absolutely necessary. If the drug is used during pregnancy, the patient should be warned about the high risk of such use for the fetus, especially in the third trimester of pregnancy. During breastfeeding, it is necessary to either stop taking the drug or stop breastfeeding. If this is not done, the baby’s condition should be monitored, especially during the first four weeks after birth. To avoid the development of “withdrawal” syndrome in newborns (manifested by shortness of breath, sniffling, intestinal colic, increased nervous excitability, increased or decreased blood pressure, tremor or spasticity), amitriptyline should be discontinued gradually, starting a dose reduction at least 7 weeks before the expected birth. Directions for use and dosage:Prescribed orally (during or after meals).
The initial daily dose when taken orally is 50-75 mg (25 mg in 2-3 doses), then the dose is gradually increased by 25-50 mg until the desired antidepressant effect is obtained. The optimal daily therapeutic dose is 150-200 mg (the maximum dose is taken at night). For severe depression that is resistant to therapy, the dose is increased to 300 mg or more, to the maximum tolerated dose (the maximum dose for outpatients is 150 mg/day). In these cases, it is advisable to begin treatment with intramuscular or intravenous administration of the drug, using higher initial doses, accelerating the increase in dosage under the control of the somatic condition.
After obtaining a stable antidepressant effect after 2-4 weeks, the dose is gradually and slowly reduced. If signs of depression appear when reducing doses, you should return to the previous dose.
If the patient's condition does not improve within 3-4 weeks of treatment, then further therapy is not advisable.
In elderly patients with mild disorders, in outpatient practice, doses are 25-50-100 mg maximum, in divided doses or 1 time per day at night.
Withdrawal syndrome
With long-term treatment, especially in high doses, if the drug is abruptly stopped, undesirable reactions such as headache,
nausea, vomiting, diarrhea, irritability, malaise, insomnia, sleep disturbance with vivid unusual dreams, increased excitability. Side effects:Mainly associated with the anticholinergic effect of the drug: accommodation paresis, blurred vision, increased intraocular pressure, dry mouth, constipation, intestinal obstruction, urinary retention, increased body temperature. All these phenomena usually disappear after adaptation to the drug or dose reduction. Some of the side effects listed below, such as headache, difficulty concentrating. Sleep disturbances, anxiety, tremors, and decreased libido can be symptoms of depression and usually decrease as the depressive state improves.
The incidence of side effects is listed as: very common (>1/10): common (>1/100 to<1/10); нечасто (от >1/1000 to<1/100); редко (от >1/10000 to<1/1000); очень редко (<1/10000); частота неизвестна (частоту встречаемости побочного эффекта невозможно оценить на основании имеющихся данных).
From the side of the system: very often headaches, drowsiness, tremor, dizziness; often - impaired concentration, increased fatigue, weakness, irritability, tinnitus, dysarthria, polyneuropathy, dysgeusia (impaired sense of taste), paresthesia, ataxia, agitation, extrapyramidal disorders, increased frequency of epileptic seizures, peripheral neuropathy, infrequently - insomnia, convulsions, anxiety; rarely akathisia.
From the side of mental activity: very often - confusion, disorientation, decreased libido; infrequently - decreased cognitive function, hypomania, mania, anxiety, night “nightmares”; rarely - aggressiveness, delirium (in the elderly), hallucinations, in women - delayed orgasm, loss of the ability to achieve orgasm; frequency unknown suicidal thoughts, suicidal behavior.
From the cardiovascular system: very often - palpitations, tachycardia, orthostatic hypotension, cardiac arrhythmia, extrasystole; often atrioventricular block, bundle branch block, symptoms of heart failure, fainting; infrequently - increased blood pressure, nonspecific changes on the ECG in patients not suffering from heart disease; rarely - myocardial infarction; very rarely - atrial fibrillation, ventricular fibrillation, cardiomyopathy.
From the digestive system: very often - dry mouth, constipation, nausea, heartburn, anorexia, darkening of the tongue, discomfort in the epigastrium, gastralgia; often - inflammation of the oral mucosa, gum disease, irreversible dental caries, a burning sensation in the mouth, intestinal obstruction; uncommon - cholestatic jaundice, diarrhea, vomiting, swelling of the tongue, stomatitis; rarely - enlarged salivary glands, paralytic intestinal obstruction, liver dysfunction, hepatitis.
From the urinary system: often - urinary retention.
From the reproductive system: often - change in potency.
From the endocrine system: infrequently - galactorrhea; rarely - swelling of the testicles; frequency unknown - gynecomastia.
From the hematopoietic organs: rarely - suppression of bone marrow hematopoiesis, purpura.
From the immune system: infrequently, skin rash, itching, urticaria; rarely - photosensitivity, angioedema; very rarely - allergic inflammation of the alveoli and lung tissue (pneumonia, Loeffler's syndrome);
From the skin and subcutaneous tissue: very often hyperhidrosis; infrequently - swelling of the face.
From the body as a whole: very often increased appetite; often - fatigue, change in body weight with prolonged use, nasal congestion; rarely - hair loss, enlarged lymph nodes, hyperpyrexia, impaired liver function tests, increased alkaline phosphatase in the blood, pollakiuria, decreased appetite; very rarely - allergic vasculitis.
From the organs of vision: often - blurred vision, impaired accommodation, dilated pupils, increased intraocular pressure; rarely - accommodation paresis. From the hearing organs: rarely - tinnitus, auditory hallucinations.
From laboratory and instrumental data: very often - increased intraocular pressure; often changes in the EEG, intraventricular conduction disturbances (prolongation of the QT interval, widening of the QRS complex on the ECG), “jumping” blood pressure, decreased production of antidiuretic hormone, hyponatremia; rarely - hypoglycemia or hyperglycemia, glucosuria. impaired glucose tolerance, agranulocytosis, leukopenia, eosinophilia. thrombocytopenia, increased activity of liver transaminases.
Overdose:Symptoms
Reactions to overdose can vary significantly between patients.
Symptoms may develop slowly and unnoticeably, or sharply and suddenly. During the first hours, drowsiness or agitation, disorientation, and confusion are observed. dilated pupils, increased body temperature, shortness of breath, dysarthria, agitation and hallucinations.
Anticholinergic symptoms (mydriasis, tachycardia, urinary retention, dry mucous membranes, slowed intestinal motility), convulsions, seizures, muscle rigidity, fever, sudden depression of the central nervous system, depression of consciousness up to coma, respiratory depression. Symptoms of the cardiovascular system: arrhythmias (ventricular tachyarrhythmia, cardiac arrhythmias such as torsade des pointes, ventricular fibrillation). The ECG is characterized by prolongation of the PR interval, widening of the QRS complex, prolongation of the QT interval, flattening or inversion of the T wave, ST segment depression and varying degrees of intracardiac conduction block, which can progress to cardiac arrest. QRS widening usually correlates with the severity of toxic effects due to acute overdose. Heart failure, low blood pressure, cardiogenic shock. Metabolic disorders: metabolic acidosis, hypokalemia. After awakening, confusion, agitation, hallucinations, and ataxia are again possible.
Treatment
Discontinuation of amitriptyline therapy, hospitalization (intensive care unit).
Treatment is symptomatic and supportive. Probing and gastric lavage, even if a long time has passed after taking the drug orally, with the preliminary administration of activated charcoal. Careful observation, even if the case seems uncomplicated. Monitoring level of consciousness, pulse, blood pressure and respiration. Frequent monitoring of serum electrolytes and blood gases. Airway control, if necessary, should be carried out using intubation. To prevent possible respiratory arrest, it is recommended to use a ventilator. Continuous ECG monitoring and control of cardiac function are indicated for 3-5 days. because relapse may occur within 48 hours or later. For widened QRS intervals, heart failure and ventricular arrhythmias, a positive effect can be achieved by shifting the pH to the alkaline side (by administering bicarbonate or moderate hyperventilation) and by rapid infusion of hypertonic sodium chloride solution (100-200 mmol Na+). It is possible to use appropriate antiarrhythmics, for example, lidocaine for ventricular arrhythmias at a dose of 50-100 mg IV (1-1.5 mg/kg), then 1-3 mg/min by IV infusion. If necessary, cardioversion and defibrillation are performed. To treat circulatory failure, plasma expanders should be used, and in severe cases, dobutamine infusions at an initial rate of 2-3 mcg/kt per minute with dose increases depending on the response. For agitation and convulsions, diazepam can be used. Hemodialysis and forced diuresis are not very effective. Interaction:Amitriptyline enhances the inhibitory effect on the central nervous system of the following drugs: antipsychotics, sedatives and hypnotics, anticonvulsants, analgesics, anesthetics, alcohol; exhibits synergism when interacting with other antidepressants. Tricyclic antidepressants, including amitriptyline, are metabolized by the hepatic cytochrome P450 isoenzyme CYP2D6. The CYP2D6 isoenzyme in humans has several isoforms. CYP2D6 isoenzymes can inhibit various psychotropic drugs, for example, antipsychotics, selective serotonin reuptake inhibitors (SSRIs) with the exception of citalopram (a very weak inhibitor of the CYP2D6 isoenzyme),
