Pharmacological properties
Pharmacodynamics. Amitriptyline belongs to the group of tricyclic antidepressants. Amitriptyline is a tertiary amine and by its mechanism of action occupies a central place among tricyclic antidepressants, since it blocks the reuptake of serotonin and noradrenaline by presynaptic nerve endings to the same extent. The main metabolite of the compound, nortriptyline, is a more potent inhibitor of noradrenaline uptake, but also blocks serotonin uptake. Amitriptyline has a pronounced anticholinergic, antihistamine and sedative effect, and also potentiates the action of catecholamines.
Suppression of REM sleep (rapid eye movement) is a hallmark of antidepressant activity. Tricyclic antidepressants, as well as selective serotonin reuptake inhibitors and MAO inhibitors, suppress REM sleep and increase deep slow-wave sleep.
Amitriptyline increases pathologically low mood levels.
Due to its sedative effect, amitriptyline is particularly effective in anxiety-depressive states accompanied by agitation and sleep disturbances.
The antidepressant effect usually develops after 2-4 weeks of therapy, while the sedative effect does not decrease.
The analgesic effect of the drug is not related to the antidepressant effect, since analgesia occurs much earlier than any mood changes, and often as a result of taking the drug in a much smaller dose than is necessary to provide a mood change.
It is possible to effectively treat nocturnal enuresis.
Pharmacokinetics
Saroten tablets
Absorption. Oral administration of the drug in tablets leads to the achievement of maximum serum concentrations after approximately 4 h (Tmax = 3.89 ± 1.87 h; range 1.03-7.98 h). After oral administration of 50 mg, the mean Cmax value is 30.95 ± 9.61 ng/mL, range 10.85-45.70 ng/mL (111.57 ± 34.64 nmol/L; range 39.06-164 , 52 nmol/L). The mean absolute oral bioavailability is 53% (Fabs = 0.527 ± 0.123; range 0.219-0.756).
Distribution: Plasma protein binding is approximately 95%. Amitriptyline and its major metabolite, nortriptyline, cross the placental barrier.
Biotransformation. The metabolism of amitriptyline occurs mainly by demethylation (CYP 2C19, CYP 3A) and hydroxylation (CYP 2D6) with subsequent conjugation with glucuronic acid. In this case, the metabolism is characterized by genetically determined polymorphism. The main active metabolite is the secondary amine nortriptyline. Nortriptyline is a more potent inhibitor of norepinephrine uptake than serotonin, while amitriptyline inhibits the uptake of both neurotransmitters to the same extent. Further metabolites (cis- and trans-10-hydroxyamitriptyline, as well as cis- and trans-10-hydroxynortriptyline) are characterized by a profile identical to that of nortriptyline, having a significantly lower potency. Demethylnortriptyline and amitriptyline-N-oxide are detected in plasma only in small amounts, the latter being completely inactive. All metabolites have lower anticholinergic activity than amitriptyline and nortriptyline. The total content of 10-hydroxynortriptyline dominates in plasma, but most metabolites are in the conjugated state.
Elimination. Half-life. The T½ for amitriptyline after oral administration is approximately 25 h (24.65 ± 6.31 h, range 16.49-40.36 h). The mean systemic clearance is 39.24 ± 10.18 l/h, range 24.53-53.73 l/h.
Excretion occurs mainly in the urine. Renal excretion of unchanged amitriptyline is insignificant (approximately 2%).
Amitriptyline and nortriptyline pass into breast milk in small amounts. The ratio of breast milk to serum concentrations in women receiving treatment with the drug is 1: 2. The estimated daily amount (amitriptyline + nortriptyline) received by the infant is approximately 2% of the maternal amitriptyline dose based on the infant's body weight (mg/kg).
Steady-state total plasma levels of amitriptyline and nortriptyline are achieved in most patients within week 1. In this state, the plasma levels of the substance during the day are represented approximately equally by amitriptyline and nortriptyline during treatment with conventional tablets of the drug 3 times a day.
Elderly patients have been shown to have a longer half-life due to less intensive metabolism.
Liver dysfunction, depending on the severity, may limit hepatic absorption, resulting in higher plasma drug levels.
Impaired renal function does not affect the kinetics of the drug.
The metabolism of the drug depends on genetic polymorphism (CYP 2D6 and CYP 2C19 isoenzymes).
Pharmacokinetic/pharmacodynamic relationship. Therapeutic plasma concentrations in major depressive disorder are 100-250 ng/mL (≈370-925 nmol/L) (sum of amitriptyline and nortriptyline). Levels of 300-400 ng/mL are associated with an increased risk of cardiac conduction disturbances in the form of QRS complex widening or AV block.
After oral administration of Saroten Retard, a slow release and absorption of the active substance in the gastrointestinal tract is noted. In contrast to tablets, which are characterized by a pronounced initial peak of the serum concentration curve, when the drug is taken in the form of capsules, the serum concentration curve increases slowly with a plateau at lower concentration values than the peak of the curve for the tablet form; the maximum serum concentration is reached (T max) in 7.1 ± 1.9 h; range 2-10 h). After oral administration of 50 mg, the average C max value is 21.5 ± 9.0 ng / ml; range 13.2-35.8 ng / ml (77.5 ± 32.4 nmol / l). This eliminates the risk of complications from the cardiovascular system due to the high peak concentration of the drug.
When the capsules are taken in the evening, the concentration of amitriptyline is maximal later in the night, then decreases during the following day, while the concentration of nortriptyline remains stable throughout the day, thus prevailing during the day.
Indication
Severe depression, accompanied by anxiety, agitation, sleep disturbances; depressive states in patients with schizophrenia in combination with a neuroleptic to prevent exacerbation of hallucinations and paranoid delusions; chronic pain syndrome; nocturnal enuresis in the absence of organic pathology.
Application
Saroten tablets
Treatment should be initiated at low doses and titrated gradually with careful monitoring of clinical response and signs of drug sensitivity. Doses of 150 mg/day (up to 225 mg/day, and sometimes up to 300 mg/day) should be administered in a hospital setting.
depression
Adults: initially 25 mg 3 times a day with a gradual increase if necessary by 25 mg every other day until a dose of 150 mg/day is reached (rarely up to 225-300 mg/day in a hospital setting).
The maintenance dose corresponds to the optimal therapeutic dose.
Patients over 65 years of age: initially 10 mg 3 times a day with a gradual increase if necessary every other day to 100-150 mg/day. An additional dose is usually prescribed in the evening. The maintenance dose corresponds to the optimal therapeutic dose.
Chronic pain syndrome
Adults: 25 mg in the evening. The dose may be gradually increased depending on the effectiveness of therapy to a maximum of 100 mg in the evening.
Elderly patients: Treatment should be started with approximately 1/2 of the recommended dose.
Nocturnal enuresis
Children: aged 7-12 years - 25 mg, over 12 years - 50 mg 0.5-1 hour before bedtime.
The duration of therapy is no more than 3 months.
Renal impairment: Amitriptyline can be administered in normal doses to patients with renal impairment.
Hepatic impairment: Careful dose selection and, if possible, determination of serum levels is recommended.
Method of administration: increasing the dose is usually carried out by taking the drug in the evening or before bedtime. In maintenance therapy, the total daily dose can be taken once, preferably before bedtime. The tablets should be swallowed with water.
Saroten Retard capsules
depression
Adults: initially prescribed 50 mg in the evening with an increase if necessary at intervals of 1 week by 50 mg until a dose of 100-150 mg is reached in the evening. The maintenance dose corresponds to the optimal therapeutic dose.
Elderly patients: initially 25 mg in the evening, increasing if necessary at intervals of 1 week by 25 mg to a dose of 50-75 mg in the evening. The maintenance dose corresponds to the optimal therapeutic dose.
Chronic pain syndrome
Adults: Initially 25 mg in the evening. The dose may be gradually increased depending on the effectiveness of therapy to a maximum of 100 mg in the evening. In elderly patients, treatment should be started with half the recommended dose.
Nocturnal enuresis
Children aged 7-12 years are prescribed 25 mg, over 12 years - 50 mg 0.5-1 hour before bedtime. Duration of therapy - no more than 3 months.
Amitriptyline can be administered in normal doses to patients with impaired renal function.
In patients with impaired liver function, careful dose selection and, if possible, determination of serum levels of the drug are recommended.
Method of administration. Saroten Retard capsules are taken once a day in the evening.
The capsules should be swallowed with water.
It is permissible to open the capsules and swallow the granules of the drug, washing them down with a cool drink, such as yogurt. The granules should not be chewed.
Duration of therapy. The antidepressant effect usually develops within 2-4 weeks. Treatment with antidepressants is symptomatic and therefore should be carried out for an appropriate period of time, usually up to 6 months after recovery in order to prevent relapse. In patients with recurrent (unipolar) depression, maintenance therapy may be necessary for several years to prevent new episodes.
Discontinuation of treatment: If treatment is discontinued, the dose should be gradually reduced over several weeks.
Contraindication
Hypersensitivity to amitriptyline or any component of the drug.
Recent myocardial infarction. Any kind of blockage or heart rhythm disturbance, as well as coronary artery disease.
Concomitant treatment with MAO inhibitors is contraindicated (see Interactions with other drugs).
Amitriptyline can cause side effects that are similar to those seen with other tricyclic antidepressants. Some of the side effects listed below (headache, tremor, difficulty concentrating, constipation, and decreased libido) can also be symptoms of depression and usually improve as the depression improves.
organ system frequency of manifestation
| Blood and lymphatic system disorders | rarely | Bone marrow depression, agranulocytosis, leukopenia, eosinophilia, thrombocytopenia |
| metabolic disorders | rarely | decreased appetite |
| Mental disorders | often | Confusion, decreased libido |
| Not often | Hypomania, mania, anxiety, insomnia, nightmares |
| rarely | Delirium (in elderly patients), hallucinations (in patients with schizophrenia) |
| Nervous system disorders | Very often | Drowsiness, tremor, dizziness, headache |
| often | Disturbances in attention, dysgeusia, paraesthesia, ataxia |
| Not often | cramps |
| Visual impairment | Very often | accommodation disorder |
| often | mydriasis |
| Not often | Increased intraocular pressure |
| Hearing and vestibular disorders | Not often | Tinnitus |
| Cardiovascular system disorders | Very often | Increased heart rate, tachycardia, orthostatic hypotension |
| often | AV block, bundle branch block Change in ECG parameters: prolongation of the QT interval and QRS complex) |
| Not often | AG |
| rarely | arrhythmia |
| Gastrointestinal disorders | Very often | Dry mouth, constipation, nausea |
| Not often | Diarrhea, vomiting, swollen tongue |
| rarely | Salivary gland enlargement, paralytic ileus |
| Liver and biliary tract disorders | rarely | jaundice Impaired liver function tests, increased blood LF activity and transaminases |
| Skin and subcutaneous tissue disorders | Very often | hyperhidrosis |
| Not often | Skin rash, urticaria, facial edema |
| rarely | Alopecia, photosensitivity reactions |
| Urinary system disorders | Not often | urinary retention |
| Reproductive system and mammary gland disorders | often | erectile dysfunction |
| rarely | gynecomastia |
| general disorders | often | fatigue |
| rarely | pyrexia |
| other manifestations | Very often | Weight gain |
| rarely | Weight loss |
|
Special instructions
Amitriptyline should not be administered simultaneously with MAO inhibitors. Treatment with amitriptyline can be started 14 days after discontinuation of irreversible non-selective MAO inhibitors, as well as at least 1 day after discontinuation of reversible drugs - moclobemide and selegiline.
Treatment with MAO inhibitors can be started no earlier than 14 days after stopping amitriptyline.
The simultaneous use of these drugs may lead to the development of serotonin syndrome (a combination of symptoms including agitation, confusion, tremor, muscle rigidity, and hyperthermia).
When using the drug in high doses, the likelihood of developing heart rhythm disorders and severe hypotension increases. The development of such conditions is also possible when using normal doses in patients with existing heart disease.
Amitriptyline is prescribed with caution to patients with convulsive syndrome, urinary retention, prostatic hypertrophy, hyperthyroidism, paranoid conditions, severe liver dysfunction, or chronic diseases of the cardiovascular system.
In depressive states, the risk of suicide attempts remains. This risk may exist until the onset of stable remission and arise spontaneously during the course of therapy. Individuals with suicidal tendencies should not be prescribed the drug in high doses. Against the background of treatment with antidepressants, it is necessary to carefully monitor the condition of patients, especially at the beginning of therapy, for clinical deterioration and / or the appearance of suicidal thoughts and behavior.
Suicidal patients should not have access to large quantities of the drug.
Particular attention is required when prescribing amitriptyline to patients with hyperthyroidism or taking thyroid hormone preparations, as the development of cardiac arrhythmias is possible.
Elderly patients are particularly prone to developing postural hypotension during treatment with amitriptyline.
In patients with manic-depressive disorders, the disease may transition to a manic phase; from the moment of the onset of the manic phase of the disease, amitriptyline therapy must be discontinued.
Patients with decreased anterior chamber depth and narrowing of its angle may experience attacks of acute glaucoma due to pupil dilation.
The use of anesthetics in combination with tri-/tetracyclic antidepressant therapy may increase the risk of arrhythmias and hypotension. If possible, amitriptyline should be discontinued several days before surgery. If urgent surgery is required, the anesthesiologist should be informed of amitriptyline treatment.
Like other psychotropic drugs, amitriptyline can alter the body's tolerance to insulin and glucose, which requires correction of antidiabetic therapy in patients with diabetes; in addition, the depressive illness itself can manifest itself as changes in the patient's glucose balance.
Cases of hyperpyrexia have been reported with the use of tricyclic antidepressants when administered concomitantly with anticholinergic or neuroleptic drugs, especially during hot weather.
Abrupt discontinuation of therapy after long-term treatment may cause withdrawal symptoms such as headache, malaise, insomnia, and irritability. These symptoms are not signs of drug dependence.
Excipients: tablets drug
