Medokardil

Medocardil is a drug blocking the activity of α-, as well as β-adrenergic receptors.

Indications Medocardil

It is used to treat primary hypertension (both in combination with other antihypertensive drugs (especially diuretics of a thiazide type), and in the form of monotherapy).

Also appointed with a stable form of angina, which has a chronic character.

It is prescribed for stable CHF (as a supplement to the standard treatment with digoxin, diuretic drugs or ACE inhibitors) to prevent the progression of the disease in people with cardiac insufficiency of the 2nd-3rd class (according to the NYHA classification).

[1], [2]

Release form

The release of the medication is realized in tablets packed in 10 pieces inside the blister plate. The pack contains 3 or 10 such plates.

[3]

Pharmacodynamics

Carvedilol is an indiscriminate β-blocker with vasodilating properties. In addition, it has antiproliferative and antioxidant effects.

The active element is a racemate. Different enantiomers differ in their metabolic processes and drug effects. Enantiomer type S (-) is involved in blocking α1-, as well as β-adrenoreceptors, while enantiomer type R (+) is able to block only α1-adrenergic receptors.

Non-selective cardio blockade of β-adrenergic receptors, which develops under the influence of drugs, lowers the level of blood pressure, cardiac output and heart rate. Carvedilol weakens the pressure inside the pulmonary arteries, as well as the right atrium. Blocking the activity of α1-adrenergic receptors, the substance leads to the expansion of peripheral vessels and weakens systemic vascular resistance. These effects can ease the burden on the heart muscle and prevent the occurrence of angina attacks.

In people with heart failure, this effect leads to an increase in the left ventricular ejection fraction and a decrease in manifestations of pathology. This effect was observed in people with left ventricular dysfunction.

Carvedilol does not have BCA, similar to propranolol with membrane-stabilizing effect. The plasma activity of renin decreases, and the fluid inside the body is delayed rarely. The impact on the level of heart rate and blood pressure develops after 1-2 hours after the drug has been taken.

In individuals with elevated values of blood pressure on a background of healthy kidney work, the drug reduces the resistance of blood vessels inside the kidneys. At the same time, no noticeable changes in the processes of renal circulation, glomerular filtration and excretion of electrolytes are observed. Support for peripheral circulation helps to minimize the incidence of limb cooling, which is often observed with β-blocker therapy.

Medication usually does not affect the serum lipoprotein indices.

[4], [5]

Pharmacokinetics

When administered orally, carvedilol is absorbed almost completely and at high speed, almost completely synthesizing with the intraplasma protein. The distribution volumes are approximately 2 l / kg. Values of LS inside the plasma are proportional to the size of the dosage taken.

The significant metabolic disintegration observed after the 1st hepatic transit (mainly with the participation of liver enzymes CYP2D6, as well as CYP2C9), results in a bioavailability of the substance reaching only about 30%. In the process, 3 active metabolic products are formed, which exert a β-blocking effect. One of these components (the 4'-hydroxyphenyl derivative compound) has a higher (13-fold) β-blocking effect than carvedilol. In comparison with the active element, active metabolic products have a weaker vasodilating effect. In connection with the stereoselective metabolism, the plasma indices of R (+) carvedilol are twice or three times higher than the values of S (-) carvedilol.

The number of active metabolic products inside the plasma is approximately ten times lower than the values of carvedilol. The half-life is also very different - it is 5-9 hours for the substance R (+), and for 7-11 hours for the substance S (-).

In elderly people there is an increase in plasma indices of carvedilol by 50%. In individuals with hepatic cirrhosis, the bioavailability of drugs increases fourfold, and plasma Cmax five times the same in a healthy person.

In people with impaired liver function, the level of bioavailability increases to 80% due to a decrease in metabolic disintegration at the 1st pass.

Because the excretion of carvedilol mainly occurs with feces, people with problems in the kidneys will most likely not be marked by significant cumulation of the drug.

Eating food slows the absorption rate of LS inside the stomach, but it does not affect the bioavailability.

[6], [7], [8], [9]

Dosing and administration

To prevent the appearance of orthostatic symptoms and to slow the absorption, the medicine is taken with food in case of heart failure. The size of the portion is determined individually. It is necessary to drink Medocardilum with plain water. Begin therapy with small portions, gradually increasing them to obtain the optimal therapeutic effect.

The process of therapy is stopped gradually, reducing the portion for 1-2 weeks. In cases where therapy was interrupted for a period longer than 14 days, it is necessary to restore it, starting with a small dosage.

Primary hypertension.

At the initial stage it is necessary to take medicines in a dose of 12.5 mg (in the morning after breakfast) or in a dose of 6.25 mg with a 2-fold intake per day (in the morning and also in the evening). After 2 days of therapy, the portion is increased to 25 mg, with 1-fold intake in the morning (1 tablet, having a volume of 25 mg) or with a 2-fold intake of 12.5 mg per day. At the end of 2 weeks it is allowed to increase the dosage again before using 25 mg 2 times a day.

The size of the maximum allowable 1-fold dosage in the treatment of hypertension is 25 mg, and for a day in general - a maximum of 50 mg.

Initially, people with heart failure in the treatment of increased blood pressure should take 2-fold a day for 3,125 mg of the drug.

If a dose of 3.125 mg is required, it is necessary to use the medicament forms of carvedilol containing the appropriate amount of the active element.

Stable form of angina, which has a chronic character.

First for a day take 12.5 mg LS (2-fold intake, after eating food). After 2 days, the portion is allowed to be raised to 25 mg with a 2-time application per day.

The size of the maximum portion of Medocardil in the treatment of chronic form of angina is 25 mg with a 2-time application per day. When treating patients with cardiac insufficiency, it is first necessary to prescribe drugs in a dose of 3,125 mg, taken 2 times a day.

Stable form of cardiac insufficiency, which is chronic.

Medication is prescribed as an auxiliary in the therapy of stable heart failure, which is mild or moderate, as well as severe form of CHF (it is necessary to combine the drug with ACE inhibitors, diuretics, as well as with medicines of digitalis). It can also be used by people with intolerance to ACE inhibitors. The administration of carvedilol is possible only after equilibration of the portions of ACE inhibitor, diuretic and digitalis (if used).

Selection of dosages is carried out individually. During the first 2-3 hours from the first application or after the rationing, careful medical supervision should be performed to check the patient's tolerance of the drug. If he has a slowdown in heart rate to below 55 beats / minute, carvedilol should be reduced. With the development of signs of an increase in the indices of blood pressure, it is first necessary to consider the option with a lowering of the dose of ACE inhibitor or a diuretic agent, and if this measure is insufficient, already reduce the dose of Medocardil.

At the initial stage of therapy, or after increasing the dose, temporary potentiation of heart failure may develop. With such disorders, the diuretic dosage is increased. In some cases, a temporary lowering of a portion of carvedilol or even its withdrawal is required. Increase dosage or resume therapy is allowed after the normalization of the clinical condition.

The size of the initial dose is 3,125 mg with a 2-fold intake per day. With the normal tolerability of such a dosage, it is allowed to gradually increase it (at intervals of 14 days) until the optimal level is reached. Next, the drug is used in a dose of 6.25 mg (2 times per day), and later - 12.5 mg (2-fold) and 25 mg (2-fold). All these enhancements are carried out under the condition that the patient well tolerates the previously assigned portion. Take should be the highest possible dosage at which there is good tolerability. It is recommended to consume a maximum of 25 mg of the drug 2 times a day. For people weighing over 85 kg, the dose is allowed to be carefully raised to 50 mg with 2-times daily intake.

[19], [20]

Use Medocardil during pregnancy

Due to a lack of clinical information on the impact of Medocardil in its use during pregnancy, it is impossible to determine the potential risks for fetal development. In this case it is necessary to take into account that β-blockers have a dangerous medicinal effect on the fetus - they can provoke a bradycardia, hypotonia or hypoglycemia. Therefore, the medication can not be administered during pregnancy.

Because there is a possibility of carvedilol passing into the mother's milk, for the period of therapy it is necessary to refuse breastfeeding.

Contraindications

The main contraindications:

• presence of strong sensitivity to medicinal elements;
• having a severe degree of decrease in the values of blood pressure (the systolic blood pressure index is less than 85 mmHg);
• failure of cardiac function in decompensated or unstable form;
• heart failure, which requires the introduction of positive inotropic drugs or diuretics;
• bradycardia, which has a severe character (below 50 beats / minute in a calm state), as well as blockade of the 2nd or 3rd degree (except for people using permanent pacemakers);
• cardiogenic shock;
• spontaneous angina;
• Short's syndrome (this includes the sinoauric blockade);
• the obstructive pathologies affecting the respiratory ducts;
• spasms of bronchi or asthma present in the anamnesis;
• pulmonary heart disease or pulmonary hypertension;
• deficiency in the liver, which has a pronounced form;
• metabolic acidosis;
• pheochromocytoma (if not controlled by an α-blocker).

[10], [11], [12], [13], [14], [15]

Side effects Medocardil

The use of carvedilol drugs can trigger the appearance of such side effects:

• lesions that are infectious or invasive: pneumonia or bronchitis, as well as infections in the urinary tract or upper respiratory system;
• disorders of the immune function: hypersensitivity (signs of allergy), as well as anaphylactic manifestations;
• disorders in the central nervous system: dizziness, depression, sleep disorders, fatigue, headaches, loss of consciousness (usually at the initial stage of therapy) and paresthesia;
• manifestations affecting the activity of SSS: bradycardia, angina with tachycardia, orthostatic collapse, increased blood pressure, peripheral vascular disorders (peripheral vascular disease or cooling of extremities). In addition, Reynaud's syndrome or intermittent claudication, hypervolemia, progression of heart failure, swelling (including orthostatic, peripheral or generalized, as well as swelling in the legs and genitals) and blockade;
• problems with the work of the respiratory system: pulmonary edema, nasal congestion, dyspnea and asthma (in people with intolerance);
• disorders of the digestive function: vomiting, dyspeptic symptoms, constipation, melena and nausea, and in addition abdominal pain, diarrhea, periodontitis and dry mouth mucosa;
• lesions of the epidermis: itching, dermatitis, rashes, lichen planus, urticaria, and in addition hyperhidrosis, alopecia, exanthema of allergic origin, as well as psoriasis or its exacerbation;
• violations in the work of visual organs: weakening of tearing (dry eye mucous membranes), visual disturbance and eye irritation;
• disorders of metabolic processes: weight gain, problems with controlling blood sugar values (hyper- or hypoglycemia) in diabetics, as well as hypercholesterolemia;
• lesions affecting the function of ODA: arthralgia, pain in the limbs and convulsions;
• problems with the urogenital system: hematuria, urination disorder, renal function deficiency, albuminuria, impotence, kidney problems in people with diffuse disorders in the peripheral arteries, and hyperuricemia, urinary incontinence in women and glucosuria;
• laboratory data: an increase in GGT or transaminase in the blood serum, the development of leuko- or thrombocytopenia, hyponatremia, hyperkalemia, as well as hypertriglyceridemia or anemia, and in addition a decrease in prothrombin and an increase in the level of creatinine, alkaline phosphatase or urea;
• Other: pain, asthenia, influenza-like symptoms, increased temperature. In addition, the treatment may have symptoms of latent diabetes or exacerbate the manifestation of an existing one.

In addition to visual disorders, dizziness, as well as bradycardia, all other negative reactions mentioned above do not depend on the size of dosages. Headaches, loss of consciousness, asthenia and dizziness are often of an easy nature and usually occur at the initial stage of therapy.

In people with heart failure in stagnant form, even greater deterioration of this disease, as well as fluid retention, can develop as a result of an increase in the portion of drugs through titration.

[16], [17], [18]

Overdose

Signs of intoxication: a sharp decrease in blood pressure (systolic indicators are up to 80 mm), bradycardia (below 50 beats / minute), heart failure, respiratory function (bronchial spasms), cardiogenic shock, and in addition vomiting, feelings confusion and convulsions (this includes generalized patients); In addition, there is a lack of blood flow or cardiac arrest. Side effects may also be potentiated.

To eliminate the disturbances, during the first hours, induce vomiting and perform gastric lavage, and after that, on intensive care, monitor vital indicators and adjust them if necessary.

Supporting procedures:

• with a bradycardia having a pronounced form - use of 0.5-2 mg atropine;
• to maintain the work of the heart - 1-5 mg (up to 10 mg maximum) of glucagon is injected intravenously by a jet method, and then the administration of glucagon through continuous infusions in a dose of 2-5 mg / hour or adrenomimetics (such as isoprenaline or orciprenaline) in serving 0.5-1 mg;
• if a positive inotropic effect is required, it is necessary to decide on the use of PDE element inhibitors;
• if there is a predominant peripheral vasodilating effect, norepinephrine is used in repeated portions equal to 5-10 μg, or in an infusion of 5 μg / min, followed by titration, depending on the blood pressure values;
• to stop bronchial spasms - the use of β2-adrenomimetics in the form of an aerosol or, in the absence of effect, by an intravenous route. In addition, intravenous aminophylline may be administered via slow infusion or injection;
• in the case of convulsions - slow iv injection of clonazepam or diazepam;
• with severe poisoning and development of cardiogenic shock, the supporting procedures continue to be carried out until the patient's condition is normalized, taking into account the half-life of carvedilol;
• In the case of development of bradycardia, resistant to treatment, it is necessary to use a pacemaker.

[21]

Interactions with other drugs

Digoxin.

Combination with Medocardil leads to an increase in digoxin values by approximately 15%. Both of these drugs inhibit the rate of AB-conduction. It requires increased control of digoxin values at the initial stage of therapy, during the adjustment of portions or after the application of carvedilol.

Insulin or inwardly taken antidiabetic medications.

Medications that have a β-blocking effect are capable of potentiating the effect of lowering blood glucose values and the effect of insulin with antidiabetic medications used orally. Symptoms of hypoglycemia can be weakened or masked (especially tachycardia), which means that people who use oral antidiabetics drugs or insulin need to constantly monitor blood sugar values.

Substances that slow or stimulate the processes of hepatic metabolism.

Rifampicin reduces the plasma values of carvedilol by about 70%. An AUC increase of approximately 30% occurs with cimetidine, but no change in Cmax is observed.

With increased attention, it is necessary to treat people taking medications that stimulate oxidases that have a mixed function (rifampicin), because this can lower serum carvedilol levels. Also, agents that inhibit the above process (cimetidine) can not be used, because the serum level may increase. But, taking into account the weak effect of cimetidine on the drug indices, the possibility of any therapeutically significant interaction is minimal.

Medications that lower the values of catecholamines.

In people using drugs with β-blocking effect, and substances capable of lowering the values of catecholamines (in this list of methyldopa and gaunedin with reserpine and guanfacin, and in addition MAOI excluding MAOI-B), it is necessary to closely monitor the development of signs of hypotension or bradycardia of severe character.

Ciclosporin.

People with a kidney transplant who had vascular rejection of a chronic nature, after the initiation of therapy with Medocardil, there was a moderate increase in the mean minimum values of cyclosporine. Lowering the dose of cyclosporine to maintain its performance in the drug-effective range is needed in about 30% of patients, while other such adjustment is not required. In such people, a portion of cyclosporine on average was reduced by approximately 20%.

It is necessary to closely monitor the values of cyclosporine from the start of carvedilol treatment, because different patients have quite different clinical responses.

Diltiazem, verapamil or other antiarrhythmic drugs.

Combination with a drug may increase the likelihood of an AV conduction disorder. There are isolated reports of conduction disorder (occasionally complicated by hemodynamic disorder) with simultaneous use of carvedilol with diltiazem.

As with other drugs that have a β-blocking effect (for oral use of drugs in combination with the channel blockers Ca-diltiazem or verapamil), it is necessary to monitor the values of blood pressure and perform ECG procedures. Such drugs should not be injected through an IV injection.

It is necessary to closely monitor the patient's condition when using the medication together with amiodarone (orally) or anti-arrhythmic drugs of the first category. In people taking amiodarone, soon after the initiation of therapy with β-blockers, ventricular fibrillation, bradycardia, and cardiac arrest were noted. There is a possibility of occurrence of heart failure in treatment with intravenous administration of substances of category Ia or Ic.

Klonidin.

The combination of drugs with β-blocking activity and clonidine can lead to potentiation of hypotensive effects and effects on heart rate. At the end of concomitant therapy with beta-blockers and clonidine, the use of the β-blocker should be discontinued first. Further, after a few days, with the gradual reduction of the portion, the treatment with clonidine is also canceled.

Hypotensive drugs.

Like other drugs that have a β-blocking effect, carvedilol is able to potentiate the effect of other medicines applied with it with antihypertensive effects (eg antagonists of α1-terminal activity) or cause a decrease in blood pressure in accordance with its profile of negative reactions.

Anesthetics.

It is required to use with caution the medicine for anesthesia, because carvedilol with anesthetics develops a synergistic negative hypertensive and inotropic effect.

[22], [23], [24]

Storage conditions

Medocardilus is required to be kept in a place that is closed from access by young children. The temperature is not more than 25 ° C.

[25]

Shelf life

Medocardil can be used within 24 months from the date of manufacture of the drug.

Application for children

It is forbidden to use Medocardil in pediatrics, because for this group of patients there is no information on the drug effect and safety.

Analogues

Analogues of the drug are medicines Atram, Cardivas, Carvedigamma, dilator with Karvid and Carvedilol, and in addition Carvium, Cardilol, Corvazan with Carvetrend, Coriol with Karvideksom, Protekard, Cardoz and Talliton.

[26], [27], [28], [29], [30],

Reviews

Medocardil is receiving a large number of positive reviews in medical forums. Both patients and doctors say that the medicine perfectly copes with its therapeutic function - it treats diseases that affect CAS.