Pharmacological properties of the drug Carvedilol
Combined α1- and non-selective β-adrenergic receptor blocker without BCA; the ratio of α1- and β-adrenergic blocking activity is 1:100. It has antioxidant properties and moderately expressed antagonistic activity against calcium ions. Used for hypertension (arterial hypertension), stable angina pectoris; reduces morbidity and mortality in heart failure. With long-term use, it has a positive effect on the lipid spectrum of blood serum and does not change the level of glucose in the blood. Reduces left ventricular hypertrophy. After oral administration, bioavailability is 25–35% due to first pass metabolism through the liver. Bioavailability increases in patients with liver disease and in the elderly (up to 50%). Concomitant food intake slows down the absorption of carvedilol, but does not reduce its volume. The maximum concentration in blood plasma is reached 1–2 hours after administration and has a linear dependence on the dose taken. Duration of action - more than 15 hours. Extensively metabolized in all tissues of the body; passes into breast milk. 98% of carvedilol binds to plasma proteins. The content in erythrocytes is 69% of the concentration in blood plasma. Metabolized by oxidation of the aromatic ring and glucuronidation with the participation of cytochrome P450 2D6. Forms three main metabolites with β-adrenergic blocking and weak α-antagonistic activity. One of them, 4′-hydroxyphenylcarvedilol, has β-adrenergic blocking activity that is almost 13 times greater than the parent compound. The terminal half-life is 7–11 hours for the S-enantiomer and 5–9 hours for the R-enantiomer. Less than 2% of carvedilol is excreted unchanged in the urine.
Carvedilol
Pharmacokinetic interaction
Effect of carvedilol on the pharmacokinetics of other drugs
Since carvedilol is both a substrate and an inhibitor of P-glycoprotein, the bioavailability of the latter may be increased when administered concomitantly with drugs transported by P-glycoprotein. In addition, the bioavailability of carvedilol may be altered by P-glycoprotein inducers or inhibitors.
Digoxin
In studies in healthy volunteers and patients with heart failure, there was a 20% increase in digoxin exposure. However, a more pronounced effect was observed in men. Thus, it is recommended to monitor digoxin concentrations at the time of initiation of therapy, dose selection and discontinuation of carvedilol therapy (see section "Special Instructions"). However, carvedilol does not affect the pharmacokinetics of intravenously administered digoxin.
Cyclosporine
In two studies, increased cyclosporine concentrations were observed when carvedilol was administered to kidney and heart transplant patients receiving oral cyclosporine. It turned out that carvedilol increases the exposure of cyclosporine when taken orally by an average of 10-20%. To maintain cyclosporine concentrations within the therapeutic range, a cyclosporine dose reduction of an average of 10-20% was required. The mechanism of this interaction is unknown, but it cannot be ruled out that carvedilol inhibits the activity of P glycoprotein in the intestine. Due to pronounced individual fluctuations in cyclosporine concentrations, careful monitoring of cyclosporine concentrations is recommended after initiation of carvedilol therapy and, if necessary, appropriate adjustment of the daily dose of cyclosporine. In the case of intravenous administration of cyclosporine, no interaction with carvedilol is expected.
Effect of other drugs on the pharmacokinetics of carvedilol
Inhibitors and inducers of the CYP2D6 and CYP2C9 isoenzymes can stereoselectively alter the systemic and/or presystemic metabolism of carvedilol, leading to an increase or decrease in the concentrations of R and S stereoisomers of carvedilol in blood plasma. Some examples of such interactions observed in patients or healthy volunteers are listed below, however, this list is not complete.
Rifampicin
In a study of 12 healthy volunteers, concomitant administration of rifampicin reduced carvedilol exposure to approximately 60% and a decreased effect of carvedilol on systolic blood pressure was observed. The mechanism of this interaction is unknown, but most likely it is due to the induction of P-glycoprotein by rifampicin in the intestine. Close monitoring of beta-blocking activity is recommended in patients receiving carvedilol in combination with rifampicin.
Amiodarone
In vitro studies
with human liver microsomes showed that amiodarone and desethylamiodarone inhibited the oxidation of the R and S stereoisomer of carvedilol. Compared with patients receiving carvedilol monotherapy, in patients with heart failure receiving carvedilol concomitantly with amiodarone, the concentrations of the R and S stereoisomers of carvedilol immediately before taking the next dose increased by 2.2 times. The effect of the S stereoisomer of carvedilol is due to desethylamiodarone, a metabolite of amiodarone, which is a potent inhibitor of the CYP2C9 isoenzyme. It is recommended to monitor beta-blocking activity in patients receiving carvedilol in combination with amiodarone.
Fluoxetine and paroxetine
In a randomized crossover study in 10 patients with heart failure, coadministration of fluoxetine (a CYP2D6 inhibitor) resulted in stereoselective inhibition of carvedilol metabolism, resulting in a 77% increase in mean AUC for R(+) and a non-statistical increase in mean AUC for S( -) by 35% compared to the group of patients receiving placebo. However, there were no differences in side effects, blood pressure, or heart rate between the two groups. The effect of a single orally administered dose of paroxetine (a potent CYP2D6 inhibitor) on the pharmacokinetics of carvedilol was studied in 12 healthy volunteers. Despite the significant reduction in exposure to the R and S stereoisomers of carvedilol, it was not clinically significant.
Pharmacodynamic interaction
Insulin or oral hypoglycemic agents
Drugs with beta-blocking properties may enhance the hypoglycemic effect of insulin or oral hypoglycemic agents. Symptoms of hypoglycemia, especially tachycardia, may be masked or weakened. For patients receiving insulin or oral hypoglycemic agents, regular monitoring of blood glucose concentrations is recommended.
Drugs that reduce catecholamine levels
Patients taking drugs with beta-blocking properties and drugs that reduce catecholamine levels (for example, reserpine and monoamine oxidase inhibitors) simultaneously should be carefully monitored due to the risk of developing arterial hypotension and/or severe bradycardia.
Digoxin
Combination therapy with drugs with beta-blocking properties and digoxin may lead to additional slowing of atrioventricular conduction.
Non-dihydropyridine slow calcium channel blockers (NSCBs), amiodarone or other antiarrhythmic drugs
Concomitant use with carvedilol may increase the risk of atrioventricular conduction disorders. With the simultaneous administration of carvedilol and diltiazem, isolated cases of conduction disturbances were observed (rarely with disturbances in hemodynamic parameters). As with other drugs with beta-blocking properties, it is recommended that carvedilol be administered together with NBMCBs such as verapamil or diltiazem, amiodarone or other antiarrhythmic drugs under ECG and blood pressure monitoring.
Clonidine
Concomitant administration of clonidine with drugs with beta-adrenergic blocking properties may potentiate the antihypertensive and bradycardic effect. If it is planned to discontinue combination therapy with a drug with beta-blocking properties and clonidine, the beta-blocker should be discontinued first, and after a few days the clonidine can be discontinued, gradually reducing its dose.
Antihypertensive drugs
Like other drugs with beta-blocking activity, carvedilol may potentiate the effects of other concomitantly administered antihypertensive drugs (eg, alpha1-blockers) or drugs that cause hypotension as an adverse reaction.
General anesthesia products
Careful monitoring of the body's vital signs should be carried out during general anesthesia due to the possibility of a synergistic negative inotropic effect of carvedilol and general anesthesia.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
The combined use of NSAIDs and beta-blockers may lead to an increase in blood pressure and worsening blood pressure control.
Bronchodilators (beta-adrenergic agonists)
Because non-cardioselective beta-blockers interfere with the bronchodilator effect of beta-adrenergic stimulants, careful monitoring of patients receiving these drugs is necessary.
Side effects of the drug Carvedilol
At the beginning of treatment (the effect of the first dose) and with increasing doses, a pronounced decrease in blood pressure is possible. Typically, symptomatic hypotension resolves spontaneously and does not require drug correction. When using carvedilol, general weakness, increased fatigue, headache, bradycardia, increased tone and intestinal motility are possible; Less commonly observed are disturbances of peripheral blood flow, attacks of angina pectoris, AV block, episodes of intermittent claudication, as well as allergic exanthema, skin itching, urticaria, reactions resembling lichen planus, the appearance of psoriatic plaques or exacerbation of a pre-existing psoriatic process. In some cases, the following were noted: sleep disturbance, depression, paresthesia, increased manifestations of heart failure, nasal congestion, thrombocytopenia, leukopenia, increased transaminase activity in the blood serum.
Special instructions for the use of the drug Carvedilol
Before starting treatment with carvedilol for heart failure, adequate therapy should be carried out to eliminate decompensation. When used in patients with coronary artery disease, carvedilol should be discontinued gradually to avoid the development of angina attacks. In patients with endocrine disorders, carvedilol may mask the symptoms of hyperthyroidism and hypoglycemia. At the beginning of treatment, as well as when increasing the dose of carvedilol during treatment, you should refrain from driving and other activities that require increased concentration and quick reaction. During the treatment period, alcohol consumption should be avoided. Although there is no direct evidence of embryo- or fetotoxic effects of carvedilol, it is known to cross the placenta and is found in breast milk. Blockade of α- and β-adrenergic receptors in the fetus or newborn can induce perinatal or neonatal distress syndrome, manifested by bradycardia, respiratory depression, hypothermia and hypoglycemia. There is no clinical experience with the use of carvedilol in pediatrics.
Drug interactions Carvedilol
When using carvedilol, calcium channel blockers (verapamil) and class I antiarrhythmic drugs should be prescribed with caution. It is necessary to avoid intravenous administration of these drugs while using carvedilol. Carvedilol increases the concentration of digoxin in the blood plasma. The hypotensive effect of carvedilol is enhanced by anesthetic agents. The concentration of carvedilol in the blood plasma is reduced by inducers of microsomal liver enzymes (including rifampicin).
List of pharmacies where you can buy Carvedilol:
- Moscow
- Saint Petersburg
Carvedilol, 12.5 mg, tablets, 30 pcs.
Pharmacokinetic interaction
Carvedilol is both a substrate and an inhibitor of P-glycoprotein, and when used concomitantly with drugs transported by P-glycoprotein, the bioavailability of the latter may increase. In addition, the bioavailability of carvedilol may be altered by P-glycoprotein inducers or inhibitors.
Inhibitors and inducers of CYP2D6 and CYP2C9 may stereoselectively alter the systemic and/or first-pass metabolism of carvedilol, leading to an increase or decrease in plasma concentrations of the R(+) and S(-) stereoisomers of carvedilol. Some examples of such interactions observed in patients or healthy volunteers are listed below, but this list is not complete.
Digoxin.
Concomitant use of carvedilol and digoxin increases digoxin concentrations by approximately 15%. At the beginning of therapy with carvedilol, when selecting its dose or discontinuing the drug, it is recommended: regular monitoring of the concentration of digoxin in the blood plasma.
Cyclosporine.
Carvedilol increases the plasma concentration of cyclosporine when taken orally. To maintain cyclosporine concentrations in the therapeutic range, a reduction in the cyclosporine dose by an average of 10–20% is required. Due to pronounced individual fluctuations in cyclosporine concentrations, careful monitoring of cyclosporine concentrations is recommended after initiation of carvedilol therapy and, if necessary, appropriate adjustment of the daily dose of cyclosporine. No interaction with carvedilol is expected when cyclosporine is administered intravenously (IV).
Rifampicin, phenobarbital.
Rifampicin and phenobarbital accelerate metabolism and reduce plasma concentrations of carvedilol, leading to a decrease in its antihypertensive effect.
Amiodarone.
In patients with heart failure, amiodarone decreased the clearance of the S(-) stereoisomer of carvedilol by inhibiting CYP2C9. The average concentration of the R(+) stereoisomer of carvedilol did not change. Therefore, due to the increased concentration of the S(-) stereoisomer of carvedilol, there may be a risk of increased beta-blocking activity.
Inhibitors of the CYP2D6 isoenzyme
The use CYP2D6
isoenzyme, incl . quinidine, fluoxetine, paroxetine, propafenone, may lead to stereoselective suppression of carvedilol metabolism (possibly increasing the concentration of the R(+) stereoisomer).
Pharmacodynamic interaction
Insulin or oral hypoglycemic agents
Drugs with beta-blocking properties may enhance the hypoglycemic effect of insulin or oral hypoglycemic agents. Symptoms of hypoglycemia, especially tachycardia, may be masked or weakened. For patients receiving insulin or oral hypoglycemic agents, regular monitoring of blood glucose levels is recommended.
Drugs that reduce catecholamine levels
Patients taking concomitant drugs with beta-blocking properties and drugs that reduce catecholamines (for example, reserpine and monoamine oxidase inhibitors (MAO)) should be closely monitored due to the risk of developing arterial hypotension and/or severe bradycardia.
Digoxin
Combination therapy with beta-blockers and digoxin may lead to additional slowing of AV conduction.
Verapamil, diltiazem, amiodarone or other antiarrhythmic drugs
Their simultaneous use with carvedilol may increase the risk of AV conduction disturbances.
With the simultaneous use of carvedilol and diltiazem, isolated cases of cardiac conduction disturbances (rarely with disturbances in hemodynamic parameters) were observed. The use of carvedilol together with blockers of “slow” calcium channels (for example, verapamil or diltiazem) is recommended under ECG and blood pressure monitoring.
Clonidine
Concomitant use of clonidine with beta-blockers may potentiate the hypotensive and bradycardic effect. If it is planned to discontinue combination therapy with a beta-blocker drug and clonidine, the beta-blocker should be discontinued first, and after a few days the clonidine can be discontinued, gradually reducing its dose.
Antihypertensive drugs
Like other drugs with beta-blocking activity, carvedilol may potentiate the effects of other concomitantly administered antihypertensive drugs (eg, alpha-blockers) or drugs that cause hypotension as a side effect.
General anesthesia products
Vital signs should be closely monitored during general anesthesia due to the possibility of a synergistic negative inotropic effect between carvedilol and general anesthesia agents.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
The simultaneous use of NSAIDs and beta-blockers reduces the antihypertensive effect of carvedilol.
Bronchodilators (beta-adrenergic agonists)
Because non-cardioselective beta-blockers interfere with the bronchodilator effect of bronchodilators that are beta-adrenergic receptor stimulants, careful monitoring of patients receiving these drugs is necessary.
Inhibitors of microsomal oxidation (cimetidine), diuretics and ACE inhibitors enhance the antihypertensive effect of carvedilol.
