Methyldopa (Methyldopa)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceMethyldopaMethyldopa
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  • Dopegit®
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    EGIS ZAO Pharmaceutical Plant     Hungary
  • Methyldopa
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    R-PHARM, CJSC     Russia
    • Dosage form: & nbsppills
    Composition:

    For one tablet:

    Active substance: methyldopa sesquihydrate - 282.00 mg in terms of methyldopa - 250.00 mg.

    Excipients: corn starch - 40.00 mg, copovidone - 10.50 mg, povidone K-5.25 mg, talc-5.25 mg, stearic acid - 3.50 mg, silicon dioxide colloid (Aerosil) - 1.75 mg, magnesium stearate - 1.75 mg.

    Description:

    Round, biconcave tablets from white to grayish white. Presence of marble is admissible.

    Pharmacotherapeutic group:Hypotensive central agent
    ATX: & nbsp

    C.02.A.B   Methyldopa

    Pharmacodynamics:

    Methyldopa is an antihypertensive agent of central action.

    The drug has an antihypertensive effect through its metabolite (alpha-methylnoradrenaline) through several mechanisms:

    - decrease in sympathetic tone by stimulation of central inhibitory presynaptic alpha-2 receptors:

    - replacement of endogenous dopamine on dopaminergic nerve endings - in as a false neurotransmitter;

    - a decrease in renin activity of blood plasma and peripheral vascular resistance;

    - suppression of the enzyme DOPA-decarboxylase, which reduces the synthesis of noradrenaline, dopamine, serotonin, and the concentration of noradrenaline and epinephrine in tissues.

    Methyldopa does not directly affect cardiac function, does not reduce cardiac output, does not cause reflex tachycardia, nor does it reduce the glomerular filtration rate (GFR), renal blood flow, or filtration fraction. In some cases, the heart rate decreases.

    Reduces blood pressure (BP) both in a prone position and standing, only rarely causes orthostatic hypotension.

    The maximum decrease in blood pressure occurs 4-6 hours after ingestion and lasts 12-24 hours. After repeated administration, the maximum hypotensive effect develops within 2-3 days.

    After the drug is stopped, the blood pressure returns to the baseline within 1-2 days.

    Pharmacokinetics:

    The degree of absorption of methyldopa during oral administration is variable, bioavailability averages 25%. The maximum concentration in blood plasma is achieved two to three hours after taking the drug. The drug is slightly (less than 20%) associated with plasma proteins.The place of the main and intensive metabolism of methyldopa is the liver. The active metabolite - alpha-methylnoradrenaline - comes from the central adrenergic neurons.

    Approximately 70% of methyldopa is excreted unchanged in urine, and the rest is excreted unchanged. With normal renal function, the elimination half-life is 1.7 hours. The active substance of the drug is completely eliminated from the body within 36 hours.

    Methyldopa is excreted by hemodialysis, 6-hour hemodialysis can withdraw 60% of the absorbed dose of methyldopa from the circulating blood, peritoneal dialysis - approximately 22-39% for 22-39 hours.

    Methyldopa penetrates the placental barrier and is excreted in breast milk.

    Special patient groups

    When renal failure the excretion of methyldopa slows down in accordance with the degree of impaired renal function. With severe renal dysfunction (without hemodialysis), the half-life of methyldopa is 10 times longer.

    Indications:

    Arterial hypertension.

    Contraindications:

    - Hypersensitivity to the drug;

    - acute hepatitis, cirrhosis;

    - liver disease in the history of methyldopa;

    - concomitant therapy with monoamine oxidase inhibitors (MAO);

    - depression;

    - hemolytic anemia;

    - acute myocardial infarction;

    - pheochromocytoma;

    - children up to three years;

    - hepatic porphyria.

    Carefully:

    Renal failure (dose adjustment required), elderly and children's age (over three years old), diencephalic syndrome; with special care - hepatic porphyria in the immediate family of the patient.

    Pregnancy and lactation:

    Pregnant women who receive methyldopu for the treatment of hypertension should be carefully monitored by a physician.

    Clinical studies indicate that after the use of methyldopa during the second and third trimester of pregnancy, no signs of damage to the fetus or newborn have been revealed. But since adequate, properly controlled studies in the third trimester of pregnancy are not carried out, the drug is recommended only after a careful comparison of all risks and benefits of admission.

    The study of children born to mothers who took methyldopa after the 26th week of pregnancy did not reveal any undesirable effects of the drug.In pregnant women who took the drug in the third trimester, the fetus was better than women who do not take the drug.

    Category B on the effect on pregnancy.

    Breastfeeding period

    Methyldopa is excreted in breast milk, so prescribe the drug nursing women are recommended after careful comparison of risk and benefit.

    Dosing and Administration:

    For oral administration. Tablets can be taken before or after meals.

    Dosage should be selected for each patient individually.

    The initial dose of methyldopa for adults is 250 mg 2-3 times a day for the first 2 days. After that, the daily dose can be increased or decreased, depending on the degree of BP reduction, stepwise at 250 mg with 2-day intervals.

    To reduce the severity of sedation, first increase the evening dose.

    The usual maintenance dose is 500-2000 mg per day for 2-4 admission. If there is no effective reduction in blood pressure, it is recommended to use a combination with other antihypertensive drugs (for example, with thiazide diuretics).

    The maximum daily dose is 3000 mg (12 tablets). It is inadmissible to exceed the maximum daily dose (12 tablets).

    48 hours after discontinuation of the drug, blood pressure returns to the original.With the withdrawal of the drug, the phenomenon of "recoil" is not observed.

    After 1-3 months of treatment, tolerance can develop. Effective control of blood pressure can be restored by adding a diuretic or increasing the dose of methyldopa.

    In elderly patients initiation of methyldopa therapy should be done using the lowest possible dose of the drug, as often fainting occurs. To prevent fainting, the initial daily dose should not exceed 250 mg, usually in 2 divided doses, with a slow increase in dose every 2 days if necessary. The maximum dose should not exceed 2000 mg (8 tablets) per day.

    Patients with impaired renal function: lower doses should be used. With mild renal failure, the glomerular filtration rate (GFR) is 60-89 ml / min / 1.73 m2 should maintain the interval between doses of 8 hours, with moderate failure (GFR - 30-59 ml / min / 1.73 m2) interval should be 8-12 hours, and with severe renal failure (GFR less than 30 ml / min / 1.73 m2) 12-24 hours.

    Methyldopa is removed during hemodialysis, after this procedure the patient should be given an additional dose of the drug 250 mg to avoid an increase in blood pressure.

    Children over three years old: the recommended initial dose of methyldopa is 10 mg / kg of body weight per day for 2-4 admission. If necessary, the daily dose can be gradually increased at intervals of not less than two days. The maximum daily dose should not exceed 3000 mg (12 tablets).

    Side effects:

    At the beginning of therapy with the drug, as well as increasing the dose of the drug, transient sedation, headache, general weakness and increased fatigue can be observed.

    Classification of adverse reactions depending on frequency: very often (≥1 / 10), often (from ≥ 1/100 to <1/10), infrequently (from ≥ 1/1000 to <1/100), rarely (from ≥ 1/10000 to <1/1000), very rarely (<1/1000), individual cases. In each of these categories, undesirable effects are presented in descending order of severity.

    Infections and parasitic diseases: isolated cases - inflammation of the salivary glands.

    Violations of the blood and lymphatic system: rarely - hemolytic anemia, leukopenia, agranulocytosis and granulocytopenia, thrombocytopenia; isolated cases - oppression of bone marrow function, eosinophilia.

    Immune system disorders: individual cases - vasculitis, lupus syndrome, drug fever.

    Disorders from the endocrine system: isolated cases - hyperprolactinaemia.

    Disorders of the psyche: very rarely - mental disorders (including nightmarish dreams, usually reversible, mild psychosis and depression), decreased libido.

    Disturbances from the nervous system: very rarely - parkinsonism; individual cases - peripheral paralysis of the facial nerve (Bell's paralysis), decreased intelligence, involuntary choreoathetotic motor activity, symptoms of cerebral circulatory insufficiency (possibly as a consequence of arterial hypotension), headache, sedation (usually transient), general weakness or fatigue, dizziness , paresthesia.

    Heart Disease: very rarely - the progression of angina pectoris, myocarditis, pericarditis; isolated cases - congestive heart failure, sinus bradycardia.

    Vascular disorders: prolonged hypersensitivity of the carotid sinus, orthostatic hypotension (a dose reduction is recommended).

    Disturbances from the respiratory system: isolated cases - nasal congestion.

    Disorders from the gastrointestinal tract: very rarely - pancreatitis; some cases - colitis, vomiting, diarrhea, pain or dark staining of the tongue, nausea, constipation, bloating, flatulence, dryness of the oral mucosa.

    Disturbances from the liver and bile ducts: isolated cases - hepatitis, necrotic hepatitis, cholestasis, jaundice.

    Disturbances from the skin and subcutaneous tissues: isolated cases - toxic epidermal necrolysis, eczema or skin rash, resembling lichen.

    Disturbances from musculoskeletal and connective tissue: individual cases - mild pain in the joints with or without edema, myalgia.

    Violations of the genitals and mammary gland: individual cases - gynecomastia, galactorrhea, amenorrhea, impotence, impaired ejaculation.

    General disorders and disorders at the site of administration: individual cases - peripheral edema, weight gain. Peripheral edema and weight gain usually regress with diuretic therapy. If swelling builds up or signs of heart failure appear, the drug should be discontinued.

    Laboratory and instrumental data: very rarely - a positive test of Coombs; isolated cases - positive results of tests for antinuclear antibodies, LE-cells and rheumatoid factor, increased activity of "liver" transaminases, increased urea concentration in the blood.

    Overdose:

    Symptoms: pronounced BP reduction, pronounced bradycardia, weakness, drowsiness, inhibition, tremor, dizziness, constipation, flatulence, diarrhea, nausea, vomiting, intestinal atony.

    Treatment: if necessary, symptomatic and supportive activities should be carried out. Soon after an overdose, gastric lavage and stimulation of vomiting can reduce the amount of absorbed drug, infusion therapy can accelerate renal excretion of the drug. It is necessary to control the heart rate and cardiac output, the volume of circulating blood, electrolyte balance, bowel and kidney function, as well as the brain. If necessary, you can enter sympathomimetics (for example, adrenaline). Methyldopa is removed by hemodialysis.

    Interaction:

    Methyldopa It is not possible to apply simultaneously with the following drugs:

    • MAO inhibitors.

    Simultaneous use with the following drugs requires special care:

    Preparations, reducing antihypertensive effect of methyldopa tablets:

    • sympathomimetics,
    • tricyclic antidepressants,
    • derivatives of phenothiazine,
    • oral iron preparations, including as part of multivitamin complexes and bioadditives (may reduce the bioavailability of methyldopa),
    • nonsteroidal anti-inflammatory drugs,
    • estrogenic preparations.
    Preparations, reinforcing antihypertensive effect of methyldopa:
    • other antihypertensive agents, beta-blockers. blockers of calcium channels, diuretics, etc.,
    • levodopa + carbidopa (orthostatic hypotension may develop, in this case, patients after taking drugs should be in a horizontal position for 1-2 hours),
    • general anesthetics (see "Special instructions"),
    • muscle relaxants (baclofen, tizanidine),
    • barbiturates,
    • anxiolytic drugs (tranquilizers),
    • ethanol,
    • alprostadil,
    • linezolid.

    Methyldopa and the following drugs may change the pharmacological effects of each other:

    • lithium (the danger of increasing lithium toxicity),
    • levodopa (a decrease in the anti-Parkinsonian effect and an increase in undesirable effects on the central nervous system);
    • verapamil (weighting of the bradycardia),
    • beta2-adrenomimetiki (development of severe arterial hypotension with simultaneous infusion of salbutamol),
    • Ethanol and other drugs that depress the central nervous system (increased depression).
    • anticoagulants (increased anticoagulant effect, risk of bleeding),
    • bromocriptine (possibly an undesirable effect on the concentration of prolactin),
    • haloperidol (possibly a violation of cognitive functions - disorientation and confused state of consciousness).

    Careful monitoring is required when combined with catechol O-methyltransferase inhibitors (tolcapone, entacapone), which can cause an increase in the heart rate and possibly heart rhythm disturbances and excessive changes in blood pressure.

    Effect on the results of laboratory methods

    Because the methyldopa fluoresces at the same wavelength as catecholamines, high concentrations of catecholamines (metanephrine) can be detected in the urine, which prevents the diagnosis of pheochromocytoma. but methyldopa does not affect the evaluation of the concentration of vanilli my mandelic acid in the urine.

    Drug therapy methyldopa can influence the determination of uric acid in blood and urine by the phosphotungstic method, serum creatinine by Popper's method (reaction with picric acid in alkaline medium) and ACT (colorimetric method) in the blood serum. On the effect of methyldopa on spectrophotometric analysis of the concentration ACT not reported.

    Special instructions:

    Due to the fact that when the drug was taken, cases of hemolytic anemia and severe liver damage, as well as positive Coombs tests, during treatment, liver function and peripheral blood picture monitoring are necessary.

    Before the start of the methyldopa treatment course, the number of blood cells, hemoglobin, hematocrit should be examined, followed by monitoring during therapy.

    During the first 6-10 weeks of therapy, perform a direct Coombs test, which should then be repeated every six months or a year. A positive Coombs test can be detected in 10-20% of patients receiving this drug, especially after taking more than 1 g of methyldopa daily for six months or one year. Less than 5% of these patients may develop hemolytic anemia.In this case, you must immediately stop taking methyldopa. After discontinuing the drug, hemolytic anemia should be resolved. If this does not happen, corticosteroids or an analysis of other possible causes of hemolytic anemia is required. If hemolytic anemia is caused by methyldopa, the patient should not continue to receive this drug.

    The positive Coombs test becomes negative after a few weeks or months after the drug is discontinued. In itself, the presence of a positive Coombs test or its appearance in a patient is not a contraindication to methyldopa therapy. If the Coombs test becomes positive on the background of methyldopa treatment, the presence of hemolytic anemia and the degree of clinical significance of the positive Coombs test should be checked. For example, in addition to a positive direct Coombs test, a positive indirect Coombs test is less likely to affect cross-compatibility of blood. If it is necessary to transfuse a patient receiving methyldopa, direct and indirect Coombs tests should be performed.In the absence of hemolytic anemia, only the direct Coombs test is usually positive. The Coombs direct test alone does not affect the typing or cross-matching of blood. If the indirect Coombs test is also positive, a specialist from a hematologist or transfusiologist should be consulted.

    During the first 6-12 weeks of treatment, as well as at any time in the occurrence of unexplained fever, it is necessary to determine the activity of "liver" transaminases and the leukocyte formula. When changing the activity of "liver" transaminases or the presence of jaundice, we should assume an increased sensitivity reaction in which there is cholestasis, damage to hepatic cells or hepatitis. In very rare cases, deadly necrosis of the liver can occur. Therefore, if the activity of "liver" transaminases changes or if symptoms of hepatic insufficiency arise, the course of treatment should be stopped immediately. Such patients can no longer be prescribed methyldopa. If this condition is caused by a hypersensitivity reaction, then the fever and liver function abnormalities occur after the drug is discontinued.Such patients can no longer be prescribed methyldopa.

    Patients with a history of liver disease or a history of liver function should be given this medication with extreme caution.

    During treatment, very rare cases of leukopenia, granulocytopenia and thrombocytopenia are possible. Usually they pass after the abolition of methyldopa.

    Some patients may develop visible swelling or weight gain during methyldopa; with these conditions, diuretics should be prescribed. Treatment with methyldopa can not continue with the growth of edema or the development of symptoms of heart failure.

    Methyldopa is excreted during dialysis, so after this procedure, blood pressure may increase (see "Method of administration and dose").

    Patients receiving methyldopa should reduce the doses of general anesthetics. If arterial hypotension occurs during general anesthesia, vasoconstrictive agents may be used to correct it. Adrenergic receptors retain sensitivity when taking methyldopa.

    In patients with severe bilateral lesions of cerebral vessels, in rare cases involuntary choreoathetoid movements may occur.Stop the use of the drug in the occurrence of choreoathetoid movements in patients with cerebral atherosclerosis.

    If liver porphyria is present in the immediate family of the patient, methyldopa should be used with extreme caution.

    When applying the drug, it is possible to change the color (darkening) of urine.

    When taking methyldopa, you should avoid drinking alcoholic beverages.

    Effect on the ability to drive transp. cf. and fur:

    In the initial period (the duration of which is determined individually), a prolonged course of treatment is prohibited from driving vehicles and performing work with an increased risk of accidents. In subsequent periods, the degree of restriction is set for each patient individually.

    Form release / dosage:Tablets, 250 mg.
    Packaging:

    For 50 tablets in a jar (bottle) a polymer (made of polyethylene or polypropylene) for drugs, sealed with a screw cap polymer (made of polyethylene or polypropylene).

    Free space in the jar (bottle) is filled with cotton absorbent medical cotton.

    Each jar (bottle), together with the instruction for use, is placed in a pack of cardboard box.

    Storage conditions:

    In the dark place at a temperature of no higher than 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    2 years.

    Do not use after expiry date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-003802
    Date of registration:22.08.2016
    Expiration Date:22.08.2021
    The owner of the registration certificate:R-PHARM, CJSC R-PHARM, CJSC Russia
    Manufacturer: & nbsp
    Information update date: & nbsp07.05.2018
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