Carvedilol

Carvedilol is a non-selective β-adrenergic receptor blocker and also selectively blocks α-receptor activity.

Does not demonstrate internal sympathomimetic action, reduces the overall load on the atria, selectively blocking α-adrenergic receptors. Non-selective blocking of β-adrenergic receptors leads to inhibition of the renal RAS (reduction in the effect of intraplasmic renin) and a decrease in blood pressure indicators along with heart rate, and in addition, cardiac output. Blocking α-receptors helps peripheral vasodilation, which leads to a decrease in vascular resistance.

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Indications Carvedilol

It is used for the following disorders:

• increased blood pressure (monotherapy or combination with any other antihypertensive drugs);
• stable angina pectoris;
• chronic insufficiency of the cardiovascular system.

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Release form

The drug is produced in tablets with a volume of 12.5 or 25 mg. There are 30 such tablets inside a cell package.

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Pharmacodynamics

The combination of effects such as blockade of β-receptor activity and vasodilation leads to the appearance of such reactions:

• in people with coronary heart disease, prevention of pain development and myocardial ischemia is performed;
• in people with elevated blood pressure levels, they decrease;
• In patients treated for blood flow insufficiency and left ventricular dysfunction, there is a decrease in the size of the left ventricle, accompanied by an increase in its fractional ejection, and an improvement in hemodynamic processes.

The medication does not affect lipid metabolism processes.

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Pharmacokinetics

The bioavailability level of the substance carvedilol is 25%. Cmax values are recorded after 1 hour from the moment of oral administration of the drug. The drug has a linear relationship between blood values and the administered portion. The bioavailability level does not change under the influence of food consumed.

Carvedilol is a highly lipophilic element. About 98-99% of the component is synthesized with blood protein. The half-life is 6-10 hours. The first intrahepatic passage volumes are 60-75%. The distribution volume is 2 l/kg. The intraplasmic clearance values are 590 ml per minute.

Metabolic processes of carvedilol are realized inside the liver during oxidation with glucuronidation occurring with the phenolic ring. Dimethylation and hydroxylation associated with the aromatic ring lead to the formation of 3 metabolic components demonstrating β-blocking activity.

During the preclinical phase, it was found that the metabolic element 4'-hydroxyphenol has a 13-fold increased activity (compared to carvedilol). Blood indices of metabolic elements are approximately ten times lower than the level of carvedilol. The remaining 2 metabolic components (hydroxycarbazole) have intense antioxidant and adrenergic blocking properties. The antioxidant effect of the decay products exceeds the effect of carvedilol by 30-80 times.

Elimination of the drug occurs with bile (and then with feces). A small part of the drug is eliminated through the kidneys.

In elderly people, increased levels of Carvedilol are recorded (50% higher).

The bioavailability values of the substance in patients with liver cirrhosis are four times higher, and blood values are five times higher than in a healthy person.

In individuals with renal impairment (creatinine clearance ≤20 ml per minute) and elevated blood pressure, a 40-55% increase in blood levels of the drug is recorded (compared to individuals without renal impairment).

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Dosing and administration

Carvedilol is taken orally, without reference to food intake. If the patient has cardiovascular insufficiency, the medication should be taken with food (this enhances absorption, reducing the likelihood of orthostatic collapse).

With increased blood pressure values.

The medication should be taken 1-2 times a day. Adults are recommended to take 12.5 mg per day during the first 1-2 days. The size of the maintenance dose per day is 25 mg. If necessary, the dose can be gradually increased with 14-day breaks (minimum) until the maximum recommended dosage of 50 mg is reached.

Elderly people should initially take 12.5 mg of the medicine once a day. This dose is usually sufficient for subsequent use.

In case of increased blood pressure values, it is allowed to take no more than 50 mg of the drug per day.

In case of angina pectoris, which has a stable form.

The first 1-2 days of the course, you need to take 25 mg per day (divide the portion into 2 doses). The maintenance dose is 50 mg (in 2 doses). You can take no more than 0.1 g of the drug per day (in 2 doses).

Elderly people are required to take 12.5 mg of the drug once during the first 1-2 days. After that, a transition to a maintenance dose of 50 mg is made (divided into 2 doses). For elderly patients, this is the maximum dose.

Chronic insufficiency of the cardiovascular system.

Carvedilol is used as an adjunct to standard therapy with ACE inhibitors, digitalis, diuretics and vasodilators. To start taking the drug, the patient must have maintained a stable condition during the last month before switching to carvedilol. Also, to take the drug, the heart rate must be above 50 beats per minute, and the systolic blood pressure must be above 85 mm Hg.

At first, 6.25 mg is taken per day (1 time). If there are no complications, the dose is gradually increased with a minimum 14-day interval: first 6.25 mg 2 times per day, then 12.5 mg 2 times, and then 25 mg (2 times).

People weighing ≤85 kg can take a maximum of 50 mg per day (in 2 doses), and people weighing ≥85 kg - 0.1 g (in 2 doses). In the latter case - except for people with cardiovascular insufficiency. Increasing the dose is only done under the supervision of a doctor.

At the beginning of treatment, a slight deterioration in the manifestations of the disease may be observed (especially in people taking diuretics in large doses, or in severe forms of the pathology). It is not necessary to cancel the drug in case of such violations, you should only refuse to increase its dose.

During therapy, the patient should be constantly monitored by a therapist (or cardiologist). Before increasing the dose, the patient should be additionally examined (weight, liver function indicators, blood pressure with heart rate and heart rhythm stability should be determined). If fluid retention or symptoms of decompensation are registered, symptomatic procedures should be performed (increasing the dose of diuretics). The dose of the medication should not be increased (at least until the general condition of the patient stabilizes).

In some situations, it is necessary to reduce the dose of the drug or temporarily discontinue it (in such cases, dosage titration can be performed).

If the therapy is interrupted, it should be resumed with a minimum dose (6.25 mg once a day). Then the dosage is gradually increased, following the instructions described above.

When discontinuing the medication, a gradual reduction in dosage is required over a 1-2 week period.

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Use Carvedilol during pregnancy

Carvedilol is prohibited for use during breastfeeding and pregnancy. Animal testing has not confirmed the teratogenic effects of the drug, but there have been too few clinical trials examining the safety of its use in this group of women. The drug may reduce placental blood flow, which may cause fetal death in the womb or premature labor. Use of the drug during pregnancy may cause hypoglycemia in the newborn baby or fetus, as well as hypothermia, severe bradycardia, or pulmonary insufficiency and cardiorespiratory complications.

The use of drugs in pregnant women is allowed only in situations where the probable benefit from its administration is more expected than the risk of negative consequences for the child. When taking the drug by a pregnant woman, it must be canceled 2-3 days before the scheduled date of delivery. If this recommendation is not followed, the condition of the newborn must be monitored for the first 2-3 days.

Animal testing revealed the ability of the molecule with its metabolic elements to be excreted in mother's milk. Therefore, when using the drug during this period, breastfeeding should be avoided.

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Contraindications

Main contraindications:

• insufficiency of the cardiovascular system function in the decompensated phase;
• obstructive diseases affecting the bronchopulmonary system (chronic stage);
• AV block (2-3 degree);
• BA;
• cardiogenic shock;
• bradycardia (heart rate is ≤50 beats per minute);
• signs of allergy associated with the active ingredient or other elements of the drug;
• SSSU (this includes sinoatrial cardiac block);
• variant angina;
• untreated pheochromocytoma;
• combination with parenteral injections of verapamil or diltiazem into the vascular area;
• a strong decrease in pressure with systolic blood pressure readings below 85 mm Hg;
• pathologies affecting peripheral vessels;
• glucose-galactose malabsorption;
• hypolactasia, which is hereditary;
• Lapp lactase deficiency.

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Side effects Carvedilol

Side effects include:

• damage to the hematopoietic function: mild stage of thrombocytopenia;
• Metabolic disorders: hypervolemia, -cholesterolemia or -glycemia, fluid retention and peripheral edema. Hyperglycemia usually develops in diabetics;
• CNS related disorders: sleep problems, dizziness, syncope, depression, headaches and paresthesia;
• visual disturbances: eye irritation, visual impairment and decreased tear production;
• problems affecting the urinary system: urinary disorders, peripheral edema and renal failure;
• gastrointestinal disorders: diarrhea, nausea, dry mouth, pain affecting the abdominal area, constipation, vomiting and increased transaminase levels;
• sexual dysfunction: impotence or swelling affecting the genitals;
• damage to the function of the cardiovascular system: disorder of peripheral blood flow processes, bradycardia or orthostatic collapse;
• disorders associated with the functioning of the musculoskeletal system: pain affecting the limbs;
• problems with respiratory function: dyspnea (obstructive syndrome) in people with COPD, and dry nasal mucosa;
• manifestations related to the subcutaneous layers and epidermis: itching, exanthema of an allergic nature, urticaria, symptoms similar to psoriasis or lichen planus. If the patient suffers from psoriasis, his epidermal manifestations may worsen;
• other: systemic weakness;
• rare disorders: AV block, exacerbation of manifestations of diseases affecting peripheral vessels (intermittent claudication, Raynaud's disease, etc.) or angina pectoris.

The use of Carvedilol can provoke the development of previously latent diabetes mellitus, worsening of existing diabetes, as well as improper regulation of serum sugar levels.

As a result of drug titration, myocardial contractile activity may occasionally be weakened.

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Overdose

Overdose can lead to a sharp drop in blood pressure, bradycardia, heart failure, vomiting, bronchial spasm, loss of consciousness, respiratory distress, cardiogenic shock, convulsions and cardiac arrest.

During treatment, it is necessary to monitor the function of the main body systems. Persons with intoxication should be placed in intensive care if necessary.

Supportive measures: to prevent severe bradycardia – intravenous administration of 0.5-2 mg of atropine; maintaining the work of the cardiovascular system – use of glucagon (initially by intravenous jet at 1-10 mg, and then – intravenous infusion of 2-5 mg per hour). Sympathomimetics (dobutamine or isoprenaline with epinephrine) are also used, the dose of which is determined by the patient’s weight.

In case of bradycardia refractory to drug therapy, cardiac electrical stimulation is performed. To eliminate bronchial spasm, β-sympathomimetics are used via intravenous infusion or inhalation; in addition, intravenous administration of aminophylline is effective. Convulsions are eliminated by the administration of diazepam at a low rate.

Because Carvedilol is synthesized at high speed by blood protein, hemodialysis will be ineffective.

In severe intoxication, supportive procedures are performed for a fairly long time, because the redistribution and excretion of drugs occur slowly. The duration of such a course is determined by the patient's condition (until stability is achieved).

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Interactions with other drugs

Antiarrhythmic drugs and Ca antagonists.

Hypotension or bradycardia sometimes occurs after the combined use of carvedilol and diltiazem, amiodarone or verapamil. In such patients, blood pressure and ECG parameters should be monitored.

The synergistic effect of the drug and Ca antagonists can lead to a disorder of cardiac AV conduction with the appearance of decompensation.

Careful monitoring is required in patients who are taking the drug in combination with class 1 antiarrhythmic agents or amiodarone. There are reports of bradycardia, ventricular fibrillation, or cardiac arrest after starting Carvedilol in individuals taking amiodarone.

With parenteral use of antiarrhythmic drugs, insufficiency of cardiovascular function may be observed (antiarrhythmic drugs of classes Ia or Ic).

There are data on the development of bradycardia in case of combination of the substance with methyldopa or guanethidine, and also guanfacine, reserpine or MAOIs (excluding MAOI-B). In such combinations, it is necessary to monitor the heart rate.

It is prohibited to administer the drug with dihydropyridines, because this can lead to cardiovascular failure or a strong drop in blood pressure.

When combined with nitrates, blood pressure readings decrease.

Administration of the drug together with digoxin causes an increase in the equilibrium values of digitoxin with digoxin (by 13% and 16%). When using such a combination, it is necessary to determine the blood values of digoxin before the start of therapy and by the time of completion of the selection of the maintenance dose.

The drug potentiates the antihypertensive activity of drugs from other pharmacological categories (barbiturates, vasodilators, phenothiazines with tricyclics, alcoholic beverages and α1 receptor antagonists).

Administration together with cyclosporine requires determination of its blood values, because they may increase.

Antidiabetic drugs (including insulin).

The drug is able to neutralize the symptoms of hypoglycemia; in addition, it can enhance the effect of hypoglycemic substances and insulin. In this regard, it is necessary to constantly monitor the serum sugar levels in such patients.

When administering the drug together with clonidine and there is a need to discontinue both drugs, Carvedilol should be discontinued first, and then the clonidine dose should be gradually reduced.

If there is a need to use inhalation anesthesia, it is necessary to remember that anesthetics, when combined with medication, lead to the appearance of a negative inotropic and antihypertensive effect.

The therapeutic effectiveness of the drug is weakened when combined with substances that retain sodium and fluid in the body (anti-inflammatory anesthetic drugs, estrogens and GCS).

Individuals using fluoxetine, verapamil, cimetidine with haloperidol, barbiturates, ketoconazole with rifampicin or erythromycin (substances that inhibit or induce the action of hemoprotein P450 enzymes) should be under medical supervision, because the level of Carvedilol may increase (with the introduction of inhibitors) or decrease (with the use of inducers).

Administration together with ergotamine results in the development of a strong vasoconstrictor effect.

Combination with substances that block neuromuscular activity leads to potentiation of the blockade of this effect.

Use in combination with sympathomimetics (α- and β-adrenergic agonists) increases the likelihood of increased blood pressure and the development of severe bradycardia.

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Storage conditions

Carvedilol is stored in a dark place, out of the reach of small children. Temperature values are in the range of 15-25°C.

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Shelf life

Carvedilol can be used within 36 months from the date of release of the drug.

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Application for children

Carvedidol is not prescribed to persons under 18 years of age, because there is no information regarding its therapeutic efficacy and safety for this subgroup of patients.

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Analogues

Analogues of the drug are the substances Corvazan, Dilatrend and Coriol with Acridilol.

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Reviews

Carvedilol receives good reviews from medical professionals - it is considered effective in the treatment of cardiac insufficiency, as well as a means of controlling AV conduction processes in the case of atrial fibrillation. In addition, it is allowed to be prescribed to reduce elevated blood pressure, which increases its value as a medicinal product.

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