Medocardil

Medocardil is a drug that blocks the activity of α- and β-adrenergic receptors.

Indications Medocardil

It is used to treat primary hypertension (both in combination with other antihypertensive drugs (especially thiazide diuretics) and as monotherapy).

It is also prescribed for stable angina pectoris, which is chronic in nature.

It is prescribed for stable CHF (as an addition to standard treatment using digoxin, diuretics or ACE inhibitors) to prevent disease progression in individuals with class 2-3 cardiac failure (according to the NYHA classification).

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Release form

The drug is released in tablets, packed in 10 pieces inside a blister plate. The pack contains 3 or 10 such plates.

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Pharmacodynamics

Carvedilol is a non-selective β-blocker with vasodilating properties. In addition, it has antiproliferative and antioxidant effects.

The active ingredient is a racemate. Different enantiomers differ in their metabolic processes and medicinal effects. The S(-) enantiomer is involved in blocking α1- and β-adrenoreceptors, while the R(+) enantiomer is capable of blocking only α1-adrenoreceptors.

Non-selective cardiac blockade of β-adrenoreceptors, developing under the influence of drugs, reduces the level of blood pressure, cardiac output and heart rate. Carvedilol reduces the pressure inside the pulmonary arteries, as well as the right atrium. By blocking the activity of α1-adrenoreceptors, the substance leads to the expansion of peripheral vessels and reduces systemic vascular resistance. These effects make it possible to reduce the load 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 the manifestations of pathology. This is the effect observed in people with left ventricular dysfunction.

Carvedilol does not have an ICA, similar to propranolol, having a membrane-stabilizing effect. Plasma renin activity decreases, and fluid is rarely retained in the body. The effect on the level of heart rate and blood pressure develops after 1-2 hours from the moment of taking the drug.

In people with elevated blood pressure values against the background of healthy kidney function, the drug reduces the resistance of blood vessels inside the kidneys. At the same time, no noticeable changes in the processes of renal blood circulation, glomerular filtration and electrolyte excretion are observed. Support of peripheral circulation helps to minimize cases of cooling of the extremities, which is often observed during therapy with β-blockers.

The drug usually does not affect serum lipoprotein levels.

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Pharmacokinetics

When taken orally, carvedilol is absorbed almost completely and at a high rate, while being almost completely synthesized with intraplasmic protein. Distribution volumes are approximately 2 l/kg. The values of the drug in plasma are proportional to the size of the dose taken.

The significant metabolic breakdown observed after the first liver passage (mainly with the participation of the liver enzymes CYP2D6 and CYP2C9) leads to the fact that the bioavailability of the substance reaches only approximately 30%. In the process, 3 active metabolic products are formed that have a β-blocking effect. One of these components (a 4'-hydroxyphenyl derivative compound) has a higher (13 times) β-blocking effect than carvedilol. In comparison with the active substance, the active metabolic products have a weaker vasodilatory effect. Due to stereoselective metabolism, the plasma values of R(+) carvedilol are two/three times higher than the values of S(-) carvedilol.

The amount of active metabolic products in 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 R(+) substance, and 7-11 hours for the S(-) substance.

In elderly people, plasma carvedilol levels increase by 50%. In people with liver cirrhosis, the bioavailability values of the drug increase fourfold, and plasma Cmax is five times higher than the same values in a healthy person.

In people with impaired liver function, the bioavailability level increases to 80% due to a decrease in first-pass metabolic breakdown.

Because excretion of carvedilol occurs primarily in the feces, individuals with kidney problems are unlikely to experience significant accumulation of the drug.

Eating food slows down the rate of absorption of the drug in the stomach, but does not affect its bioavailability values.

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Dosing and administration

To prevent orthostatic symptoms and slow absorption, the medicine is taken with food in case of heart failure. The portion size is determined individually. Medocardil should be washed down with plain water. Therapy should be started with small portions, gradually increasing them until the optimal therapeutic effect is achieved.

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

Primary hypertension.

At the initial stage, the drug should be taken in a dose of 12.5 mg (in the morning after breakfast) or in a dose of 6.25 mg with 2-time use per day (in the morning and in the evening). After 2 days of therapy, the dose is increased to 25 mg, with 1-time use in the morning (1 tablet with a volume of 25 mg) or with 2-time use of 12.5 mg per day. After 2 weeks, it is allowed to increase the dosage again to 25 mg 2 times per day.

The maximum permissible single dose for the treatment of hypertension is 25 mg, and the maximum per day in total is 50 mg.

Initially, people with heart failure, when treating high blood pressure, need to take 3.125 mg of the drug twice a day.

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

A stable form of angina pectoris that is chronic in nature.

At first, 12.5 mg of the drug is taken per day (2 times a day, after eating). After 2 days, the dose can be increased to 25 mg with 2 times a day use.

The maximum dose of Medocardil for the treatment of chronic angina is 25 mg, taken twice a day. When treating people with cardiac insufficiency, the drug should initially be prescribed in a dose of 3.125 mg, taken twice a day.

A stable form of cardiac failure that is chronic in nature.

The drug is prescribed as an adjunct in the treatment of stable heart failure, mild or moderate, as well as severe CHF (the drug should be combined with ACE inhibitors, diuretics, and digitalis drugs). It can also be used by people with intolerance to ACE inhibitors. Carvedilol can only be prescribed after balancing the doses of ACE inhibitors, diuretics, and digitalis (if used).

Dosage selection is carried out individually. During the first 2-3 hours from the moment of the first use or after increasing the dose, careful medical monitoring should be carried out to check the patient's tolerance of the drug. If he/she has a slowdown in heart rate to below 55 beats per minute, it is necessary to reduce the dose of carvedilol. If signs of increased blood pressure develop, it is necessary to first consider the option of reducing the dose of ACE inhibitor or diuretic, and if this measure is insufficient, then reduce the dose of Medocardil.

At the initial stage of therapy or after increasing the dose, temporary potentiation of cardiac insufficiency may develop. In such disorders, the dosage of the diuretic is increased. In some cases, a temporary reduction in the dose of carvedilol or even its cancellation is required. It is allowed to increase the dosage or resume therapy after the clinical condition has normalized.

The initial dosage is 3.125 mg, taken twice a day. If this dosage is well tolerated, it can be gradually increased (at intervals of 14 days) until the optimal level is reached. Then the medicine is taken in a dose of 6.25 mg (2 times a day), and later - 12.5 mg (2 times) and 25 mg (2 times). All these increases are carried out provided that the patient tolerates the previously prescribed dose well. The highest dosage should be taken, at which good tolerance is observed. It is recommended to take a maximum of 25 mg of the drug 2 times a day. People whose weight is over 85 kg, the dose is allowed to be carefully increased to 50 mg, taken 2 times a day.

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Use Medocardil during pregnancy

Due to the lack of clinical data on the effects of Medocardil when used during pregnancy, it is impossible to determine potential risks to fetal development. It should be noted that β-blockers have a dangerous medicinal effect on the fetus - they can provoke bradycardia, hypotension or hypoglycemia. Therefore, the drug should not be prescribed during pregnancy.

Because there is a possibility of carvedilol passing into breast milk, breastfeeding should be discontinued during therapy.

Contraindications

Main contraindications:

• presence of strong sensitivity to medicinal elements;
• a severe decrease in blood pressure (systolic blood pressure is less than 85 mm Hg);
• cardiac insufficiency in decompensated or unstable form;
• heart failure, which requires the administration of positive inotropic drugs or diuretics;
• bradycardia of a severe nature (below 50 beats/minute at rest), as well as 2nd or 3rd degree block (except for people using permanent pacemakers);
• cardiogenic shock;
• spontaneous angina;
• Short's syndrome (this includes sinoatrial block);
• obstructive pathologies affecting the respiratory tract;
• history of bronchospasms or asthma;
• pulmonary heart disease or pulmonary hypertension;
• severe liver failure;
• metabolic acidosis;
• pheochromocytoma (if not controlled with an α-blocker).

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Side effects Medocardil

The use of carvedilol may cause the following side effects:

• lesions of an infectious or invasive nature: pneumonia or bronchitis, as well as infections in the urinary tract or upper respiratory system;
• immune dysfunction: hypersensitivity (signs of allergy), as well as anaphylactic reactions;
• disorders of 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 the cardiovascular system: bradycardia, angina with tachycardia, orthostatic collapse, elevated blood pressure, peripheral blood flow disorders (peripheral vascular disease or cold extremities). In addition, Raynaud's syndrome or intermittent claudication, hypervolemia, progression of cardiac failure, edema (including orthostatic, peripheral or generalized, as well as edema in the legs and genitals) and blockade are noted;
• problems with the respiratory system: pulmonary edema, nasal congestion, dyspnea and asthma (in people with intolerance);
• digestive disorders: vomiting, dyspeptic symptoms, constipation, melena and nausea, as well as abdominal pain, diarrhea, periodontitis and dry mouth;
• lesions of the epidermis: itching, dermatitis, rashes, lichen planus, urticaria, as well as hyperhidrosis, alopecia, allergic exanthema, as well as psoriasis or its exacerbation;
• disturbances in the functioning of the visual organs: decreased lacrimation (dryness of the mucous membranes of the eye), visual impairment and eye irritation;
• metabolic disorders: weight gain, problems with blood sugar control (hyper- or hypoglycemia) in diabetics, as well as hypercholesterolemia;
• lesions affecting the function of the musculoskeletal system: arthralgia, pain in the limbs and cramps;
• problems with the urogenital system: hematuria, urinary disorder, renal failure, albuminuria, impotence, kidney problems in people with diffuse peripheral arterial disease, as well as hyperuricemia, urinary incontinence in women and glucosuria;
• laboratory test data: increased GGT or transaminase levels in the blood serum, development of leukopenia or thrombocytopenia, hyponatremia, hyperkalemia, as well as hypertriglyceridemia or anemia, and in addition, decreased prothrombin values and increased levels of creatinine, alkaline phosphatase or urea;
• other: pain, asthenia, flu-like symptoms, increased temperature. In addition, during treatment, symptoms of latent diabetes may arise or the manifestations of an existing one may increase.

Apart from visual disturbances, dizziness and bradycardia, all other adverse reactions listed above are independent of dosage. Headaches, loss of consciousness, asthenia and dizziness are often mild and usually occur early in the therapy.

In individuals with congestive heart failure, further worsening of the disease, as well as fluid retention, may develop as a result of increasing the dose of the drug through titration.

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Overdose

Signs of intoxication: a sharp decrease in blood pressure (systolic readings are up to 80 mm), development of bradycardia (below 50 beats/minute), heart failure, respiratory disorders (bronchial spasms), cardiogenic shock, as well as vomiting, confusion and convulsions (including generalized ones); in addition, there is insufficient blood flow or cardiac arrest. Side effects may also be potentiated.

To eliminate the disorders, it is necessary to induce vomiting and perform gastric lavage during the first hours, and then, in intensive care, monitor vital indicators and correct them if necessary.

Supportive procedures:

• in case of severe bradycardia – use 0.5-2 mg of atropine;
• to support the work of the heart - 1-5 mg (up to 10 mg maximum) of glucagon is administered intravenously using the jet method, and then glucagon is administered through prolonged infusions in portions of 2-5 mg/hour or adrenomimetics (such as isoprenaline or orciprenaline) in portions of 0.5-1 mg;
• if a positive inotropic effect is required, a decision must be made to use PDE inhibitors;
• if a predominant peripheral vasodilating effect is observed, norepinephrine is used in repeated doses equal to 5-10 mcg, or in an infusion of 5 mcg/minute, with subsequent titration depending on blood pressure values;
• to relieve bronchial spasms - use of β2-adrenomimetics in aerosol form or, if there is no effect, intravenously. In addition, intravenous administration of aminophylline can be carried out - through a slow infusion or injection;
• in case of seizures – slow intravenous administration of clonazepam or diazepam;
• in case of severe poisoning and development of cardiogenic shock, supportive procedures continue to be carried out until the patient's condition is normalized, taking into account the half-life of carvedilol;
• In case of development of bradycardia resistant to treatment, it is necessary to use a pacemaker.

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Interactions with other drugs

Digoxin.

Combination with Medocardil increases digoxin values by approximately 15%. Both drugs inhibit AV conduction velocity. Increased monitoring of digoxin values is required at the initial stage of therapy, during dose adjustments, or after discontinuation of carvedilol.

Insulin or antidiabetic drugs taken orally.

Medicines with β-blocking effects can potentiate the blood glucose lowering effect and the effect of insulin with oral antidiabetic drugs. Symptoms of hypoglycemia may be weakened or masked (especially tachycardia), which is why people taking oral antidiabetic drugs or insulin need to constantly monitor their blood sugar levels.

Substances that slow down or stimulate liver metabolism processes.

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

Special attention should be paid to people taking drugs that stimulate mixed-function oxidases (rifampicin), because this may decrease serum carvedilol levels. Also, drugs that inhibit the above process (cimetidine) should not be used, because serum levels may increase. However, given the weak effect of cimetidine on drug levels, the possibility of any therapeutically significant interaction is minimal.

Medicines that lower catecholamine levels.

In people using drugs with β-blocking effect and substances capable of lowering catecholamine levels (in this list methyldopa and gaunethedine with reserpine and guanfacine, as well as MAOIs, excluding MAOI-B), it is necessary to carefully monitor the development of signs of hypotension or severe bradycardia.

Cyclosporine.

In kidney transplant recipients with chronic vascular rejection, a moderate increase in mean minimum cyclosporine values was observed after initiation of therapy with Medocardil. The cyclosporine dose should be reduced to maintain its values in the drug-effective range in approximately 30% of patients, while others do not require such adjustment. In such patients, the cyclosporine dose was reduced by approximately 20% on average.

Careful monitoring of cyclosporine values is required from the time of initiation of carvedilol treatment, because clinical responses vary widely among patients.

Diltiazem, verapamil or other antiarrhythmic drugs.

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

As with other drugs with β-blocking action (when using the drug orally in combination with Ca channel blockers - diltiazem or verapamil), it is necessary to monitor blood pressure values and perform ECG procedures. Such drugs are prohibited to be administered via intravenous injection.

The patient's condition should be closely monitored when the drug is used in combination with amiodarone (orally) or antiarrhythmic drugs of category I. Ventricular fibrillation, bradycardia and cardiac arrest have been observed in people taking amiodarone shortly after the start of β-blocker therapy. There is a possibility of cardiac failure when treated with intravenous substances of category Ia or Ic.

Clonidine.

The combination of drugs with β-blocking activity and clonidine may lead to potentiation of the hypotensive effect and the effect on heart rate. When concomitant therapy with β-blockers and clonidine is terminated, the β-blocker should be discontinued first. Then, after a few days, clonidine treatment is also discontinued by gradually reducing the dose.

Antihypertensive drugs.

Like other drugs with a β-blocking effect, carvedilol can potentiate the effect of other drugs with a hypotensive effect used with it (for example, antagonists of the activity of α1-endings), or cause a decrease in blood pressure in accordance with its profile of negative reactions.

Anesthetics.

The drug should be used with caution during anesthesia, because carvedilol and anesthetics develop a synergistic negative hypertensive and inotropic effect.

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Storage conditions

Medokardil should be kept in a place out of reach of small children. Temperature values should not exceed 25°C.

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Shelf life

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

Application for children

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

Analogues

The drug's analogues are the following medications: Atram, Kardivas, Karvedigamma, Dilator with Karvid and Karvedilol, as well as Karvium, Cardilol, Corvazan with Karvetrend, Coriol with Karvidex, Protecard, Cardoz and Talliton.

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Reviews

Medokardil receives a large number of positive reviews on medical forums. Both patients and doctors say that the medication copes well with its therapeutic function - it treats diseases affecting the cardiovascular system.