pharmachologic effect
Verapamil blocks the transmembrane entry of calcium ions (and possibly sodium ions) into the cells of the myocardial conduction system and the smooth muscle cells of the myocardium and blood vessels. The antiarrhythmic effect of verapamil is probably due to its effect on the “slow” channels in the cells of the cardiac conduction system.
The electrical activity of the sinoatrial and atrioventricular nodes largely depends on the entry of calcium into the cells through “slow” channels. By inhibiting this calcium entry, verapamil slows atrioventricular conduction and increases the effective refractory period in the AV node in proportion to heart rate. This effect leads to a decrease in the ventricular rate in patients with atrial fibrillation and/or atrial flutter. By stopping the reentry of excitation in the atrioventricular node, verapamil can restore correct sinus rhythm in patients with paroxysmal supraventricular tachycardia, including Wolff-Parkinson-White syndrome. Verapamil has no effect on conduction along additional pathways, does not affect the unchanged atrial action potential and intraventricular conduction time, but reduces the amplitude, depolarization rate and conduction in altered atrial fibers. Verapamil does not cause spasm of peripheral arteries and does not change the total calcium content in the blood plasma. The maximum therapeutic effect is observed 3 to 5 minutes after a bolus intravenous administration of verapamil.
Pharmacokinetics
Metabolized during first pass through the liver. Binds to plasma proteins by 90%. Penetrates through the blood-brain and placental barrier and into breast milk (in small quantities).
Rapidly metabolized in the liver by N-dealkylation and O-demethylation to form several metabolites. The accumulation of the drug and its metabolites in the body explains the increased effect during a course of treatment.
The most significant metabolite is the pharmacologically active norverapamil (20% of the antihypertensive activity of verapamil). The metabolism of the drug involves isoenzymes CYP3A4, CYP3A5 and CYP3A7. The half-life is two-phase: about 4 minutes - early and 2-5 hours - late. Excreted by the kidneys 70% (unchanged 3-5%), with bile 25%. Not excreted during hemodialysis.
Under conditions of intravenous administration, the antiarrhythmic effect develops within 1-5 minutes (usually less than 2 minutes), hemodynamic effects - within 3-5 minutes. The antiarrhythmic effect lasts about 2 hours, the hemodynamic effect lasts 10-20 minutes. Excreted mainly by the kidneys and feces (about 16%). Penetrates into breast milk and passes through the placenta. Rapid intravenous administration causes maternal hypotension leading to fetal distress. With prolonged use, clearance decreases and bioavailability increases. Against the background of severe liver dysfunction (liver failure), plasma clearance decreases by 70% and the half-life increases to 14-16 hours.
Manufacturer's instructions
Clinical studies have not shown sufficient information about the effect of the drug on the body of pregnant women. The use of the drug is allowed after assessing the real risk to the health of the fetus and the benefits to the maternal body.
Verapamil is used:
- when there is a threat of spontaneous abortion;
- placental insufficiency;
- nephropathy.
The drug is prescribed by the obstetrician-gynecologist leading the pregnancy strictly according to indications. Self-medication is unacceptable and can provoke any results.
Indications for use
For the treatment of supraventricular tachyarrhythmias, including:
- restoration of sinus rhythm in paroxysmal supraventricular tachycardia, including conditions associated with the presence of additional pathways in Wolff-Parkinson-White (WPW) and Lown-Ganong-Levine (LGL) syndrome;
- control of the frequency of ventricular contractions during atrial flutter and atrial fibrillation (tachyarrhythmic variant), except for cases when atrial flutter or fibrillation is associated with the presence of additional pathways (WPW and LGL syndromes).
Contraindications
Hypersensitivity, severe left ventricular (LV) dysfunction, second and third degree atrioventricular block (except in patients with an artificial pacemaker), sick sinus syndrome (bradycardia-tachycardia syndrome) except in patients with an artificial pacemaker, atrial flutter and fibrillation and WPW -syndrome or Lown-Ganong-Levine syndrome (except for patients with a pacemaker), chronic heart failure (except for those caused by supraventricular tachycardia, subject to treatment with verapamil), severe arterial hypotension (systolic blood pressure less than 90 mm Hg) or cardiogenic shock, ventricular tachycardia with wide QRS complexes (>0.12 sec.), simultaneous use with colchicine, with intravenous beta-blockers, use of disopyramide 48 hours before and 24 hours after the administration of verapamil, pregnancy, lactation.
Prescription of Verapamil
The abstract advises the use of the medication:
- with supravenricular and sinus tachycardia;
- stable angina pectoris and pathology with supraventricular rhythm disturbances;
- atrial fibrillation;
- hypertensive crisis;
- supraventricular extrasystole;
- hypertension.
Verapamil is contraindicated in patients:
- with a pronounced slow heartbeat;
- disorders of the left ventricle;
- intolerance to the component composition;
- low blood pressure levels.
The drug is not prescribed to pregnant and nursing mothers. Particular caution is needed during therapeutic procedures in patients with bradycardia, sinoatrial, atrioventricular block, chronic heart, renal, and liver failure. Doctor's supervision is required in old age.
special instructions
Arterial hypotension, decreased neuromuscular transmission (for example, Duchenne muscular dystrophy), atrioventricular (AV) block I stage, bradycardia, idiopathic hypertrophic subaortic stenosis (IGSS), hypertrophic obstructive cardiomyopathy, simultaneous use with cardiac glycosides, quinidine, flecainide, ritonavir , lovastatin, simvastatin, atorvastatin; elderly age, age under 18 years (efficacy and safety of use have not been studied), chronic heart failure, liver and/or kidney failure
Directions for use and doses
Administer intravenously only, slowly, over at least 2 minutes, with continuous monitoring of the electrocardiogram, heart rate and blood pressure.
In elderly patients, administration is carried out over at least 3 minutes to reduce the risk of unwanted effects.
To relieve paroxysmal cardiac arrhythmias or hypertensive crisis, 2-4 ml of a solution of 2.5 mg/ml (5-10 mg) is administered intravenously, in a stream (under ECG and blood pressure control). If there is no effect, repeated administration after 30 minutes at the same dose is possible. A verapamil solution is prepared by diluting 2 ml of a 2.5 mg/ml solution of the drug in 100-150 ml of 0.9% sodium chloride solution.
Verapamil therapy
The instructions include the exact dosage of the drug and the specifics of its administration. The standards depend on the type of tablet:
- With a standard duration of action - before meals from 40 to 80 mg, three times a day for registered angina or increased heart rate. For hypertension, the daily dose is divided into two procedures and is 480 mg. For children under five years of age, no more than 60 mg of medication is allowed per day.
- With prolonged action - for hypertension, 240 mg in the morning, therapy begins with a dosage of 120 mg, which is gradually increased. The dose is increased after 14 days, the maximum volume of the drug does not exceed 480 mg (taken in 2 doses, observing a twelve-hour break).
An intravenous solution is used to suppress the symptoms of a hypertensive crisis. From 5 to 10 ml of Verapamil is injected in a stream. A similar amount is used for paroxysmal pathologies; in the absence of the expected result, the procedure is duplicated.
Maintenance therapy involves the use of the drug in conjunction with sodium chloride or dextrose. When treating children under 5 years of age, the dosage does not exceed 3 mg.
Side effect
Often -1-10%; sometimes - 0.1-1%; rarely - 0.01-0.1%; very rarely - less than 0.001%, including isolated cases.
From the cardiovascular system: severe bradycardia (less than 50 beats/min), marked decrease in blood pressure, development or worsening of heart failure, tachycardia; rarely possible development of angina, up to myocardial infarction (especially in patients with severe obstructive lesions of the coronary arteries), arrhythmia (including ventricular fibrillation and flutter); with rapid administration - third degree atrioventricular block, asystole, collapse.
From the central nervous system: dizziness, headache, fainting, anxiety, lethargy, fatigue, asthenia, drowsiness, depression, extrapyramidal disorders (ataxia, mask-like face, shuffling gait, stiffness of arms or legs, trembling of hands and fingers, difficulty swallowing ), a single case of the development of paralysis (tetraparesis) under the condition of combined use of verapamil and colchicine.
From the digestive system: nausea, constipation (rarely - diarrhea), gum hyperplasia (bleeding, soreness, swelling), increased appetite, increased activity of liver transaminases and alkaline phosphatase.
Allergic reactions: skin itching, rash, facial skin flushing, exudative erythema multiforme (including Stevens-Johnson syndrome).
Other: weight gain, very rarely - agranulocytosis, gynecomastia. hyperprolactinemia, galactorrhea, arthritis, transient loss of vision against the background of maximum concentration, pulmonary edema, asymptomatic thrombocytopenia, peripheral edema (swelling of the ankles, feet and legs).
Overdose
Symptoms: marked decrease in blood pressure, sinus bradycardia, turning into atrioventricular block, sometimes asystole, hyperglycemia, stupor, sinoatrial block, metabolic acidosis. There have been reports of deaths due to overdose.
Treatment: supportive symptomatic therapy should be carried out. To increase blood pressure, vasopressor drugs are prescribed, for atrioventricular block - an artificial pacemaker, for asystole - intravenous administration of vasopressor drugs or resuscitation measures. Hemodialysis is not effective.
Adverse reactions
The drug can become a source of non-standard responses in the body. Veramil provokes:
- slowing of cardiac activity;
- cephalgia with dizziness;
- dyspeptic disorders;
- facial hyperemia;
- weight gain.
Less commonly, the medication leads to the appearance of:
- digestive disorders, gum tissue hyperplasia;
- lethargy, nervousness, fatigue;
- skin rash, obsessive itching;
- gynecomastia, arthritis, galactorrhea.
The drug causes the development of pulmonary and peripheral edema.
Interaction with other drugs
Alpha blockers
— Prazosin: an increase in Cmax of prazosin (~40%) does not affect the half-life of prazosin.
— Terazosin: increase in AUC of terazosin (~24%) and Cmax (~25%).
Antiarrhythmic drugs
— Flecainide: minimal effect on the clearance of flecainide in blood plasma (<~10%); does not affect the clearance of verapamil in blood plasma.
- Quinidine: decreased oral clearance of quinidine (~35%).
Drugs for the treatment of bronchial asthma
- Theophylline: decreased oral and systemic clearance of theophylline (~20%). In smoking patients there is a decrease of ~11%.
Anticonvulsants
— Carbamazepine: increased AUC of carbamazepine (~46%) in patients with resistant partial epilepsy.
Antidepressants
— Imipramine: increase in AUC of imipramine (~15%). Does not affect the level of the active metabolite, desipramine.
Hypoglycemic agents
— Glyburide: glyburide Cmax increases (~28%), AUC (~26%).
Antimicrobials
- Erythromycin: possible increase in the concentration of verapamil in the blood plasma.
— Rifampicin: decrease in verapamil AUC (~97%), Cmax (~94%), bioavailability ~92%.
- Telithromycin: possible increase in the concentration of verapamil in the blood plasma.
Antitumor agents
- Doxorubicin: an increase in AUC of doxorubicin (89%) and Cmax (61%) when taking verapamil orally in patients with small cell lung cancer. The administration of verapamil intravenously in patients with progressive neoplasms does not affect the pharmacokinetic parameters of doxorubin.
Barbiturates
— Phenobarbital: increase in oral clearance of verapamil ~5 times.
Benzodiazepines and other tranquilizers
— Buspirone: increase in buspirone AUC, Cmax ~ 3.4 times
— Midazolam: increase in midazolam AUC (~ 3 times) and Cmax (~ 2 times).
Beta blockers
— Metoprolol: increase in metoprolol AUC (~32.5%) and Cmax (~41%) in patients with angina pectoris.
— Propranolol: increase in AUC of propranolol (~65%) and Cmax (~94%) in patients with angina pectoris.
Cardiac glycosides
— Digitoxin: decrease in total clearance (~27%) and extrarenal clearance (~29%) of digitoxin.
— Digoxin: in healthy volunteers, Cmax of digoxin increases by ~45-53%, Css of digoxin by ~42% and AUC of digoxin by ~52%.
Immunological agents
- Cyclosporine: increase in AUC, Css, Cmax of cyclosporine by ~45%.
- Everolimus: plasma levels of everolimus may increase.
- Sirolimus: the level of sirolimus in the blood plasma may increase.
- Tacrolimus: the level of tacrolimus in the blood plasma may increase.
Lipid-lowering drugs (HMG-CoA reductase inhibitors)
- Atorvastatin: the level of atorvastatin in the blood plasma may increase.
- Lovastatin: an increase in the level of lovastatin in the blood plasma is possible.
— Simvastatin: increase in AUC (~2.6 times) and Cmax (~4.6 times) of simvastatin.
Serotonin receptor agonists
— Almotriptan: increase in AUC (~20%) and Cmax (~24%) of almotriptan.
Uricosuric drugs
— Sulfinpyrazone: increased clearance of verapamil (~ 3 times) and decreased bioavailability (~ 60%).
Other
— Grapefruit juice: increase in AUC R- (~49%) and S-(~37%) verapamil and Cmax R- (~75%) and S-(~51%) verapamil. The half-life and renal clearance were unchanged.
— St. John's wort: the AUC of R- (~78%) and S-(~80%) verapamil decreases with a corresponding decrease in Cmax.
Other types of interaction
- Cimetidine: reduces the clearance of verapamil when administered intravenously.
Verapamil, as a drug that is highly bound to plasma proteins, should be used with caution when used simultaneously with other drugs that have a similar ability. When using drugs for inhalational general anesthesia and blockers of “slow” calcium channels, which include verapamil, together, the dose of the drug for inhalational general anesthesia should be carefully titrated until the desired effect is achieved in order to avoid excessive depression of the cardiovascular system. Verapamil may enhance the effect of drugs that block neuromuscular conduction (such as curare-like and depolarizing muscle relaxants). Therefore, the dose of verapamil and/or the dose of drugs that block neuromuscular conduction should be reduced when used simultaneously. Potentially increased neurotoxicity of lithium. Verapamil may also reduce serum lithium levels in patients receiving lithium for a long time. If these drugs are used concomitantly, patients should be closely monitored.
— Prazosin, terazosin: additive antihypertensive effect.
- Ritonavir and others: may inhibit the metabolism of verapamil, leading to
antiviral (HIV) to increase its concentration in the blood plasma, therefore
verapamil dosage should be reduced.
- Carbamazepine: an increase in the level of carbamazepine in the blood plasma and the appearance of adverse reactions such as diplopia, headache, ataxia or dizziness.
- Rifampicin: may reduce the antihypertensive effect of verapamil.
- Colchicine: is a substrate for the isoenzymes CYP3A and P-glycoprotein, which in turn inhibit the metabolism of verapamil. Therefore, when used simultaneously with verapamil, the concentration of colchicine in the blood may increase significantly.
- Sulfinpyrazone: may reduce the antihypertensive effect of verapamil.
— Acetylsalicylic acid: increased bleeding. (aspirin)
— Antihypertensive drugs: enhanced antihypertensive effect. diuretics, vasodilators
Lipid-lowering drugs. HMG-CoA reductase inhibitors (statins)
- Simvastatin/lovastatin/atorvastatin: Concomitant use with verapamil may cause atorvastatin to increase serum concentrations of simvastatin or lovastatin. In patients receiving verapamil, treatment with HMG-CoA reductase inhibitors (i.e. simvastatin, atorvastatin, lovastatin) should be started with the lowest possible doses and then increased. If it is necessary to prescribe verapamil to patients already receiving HMG-CoA reductase inhibitors, it is necessary to review and reduce their doses according to the concentration of cholesterol in the blood serum. Similar tactics should be followed when concomitantly prescribing verapamil with atorvastatin, although there is no clinical data confirming their interaction.
- Fluvastatin, pravastatin: not metabolized by CYP3A4 isoenzymes,
and rosuvastatin, therefore their interaction with verapamil is least likely. Although intravenous verapamil has been used in conjunction with digitalis drugs without serious side effects, given that these drugs slow AV conduction, monitoring of patients is necessary for timely detection of AV block or severe bradycardia.
- Quinidine: the development of arterial hypotension is possible with the combined use of quinidine and verapamil intravenously, so this combination of drugs must be used with caution.
Beta blockers: Concomitant intravenous administration of verapamil and beta blockers has resulted in serious side effects (severe bradycardia), especially in patients with cardiomyopathy, heart failure or recent myocardial infarction. Beta blockers should be prescribed several hours before or several hours after verapamil. Disopyramide should not be given 48 hours before or 24 hours after verapamil. When verapamil and flecainide are used together, an additive effect is possible with a decrease in myocardial contractility, prolongation of AV conduction and myocardial repolarization.
