Pharmacological properties
Pharmacodynamics. Verapamil belongs to phenylalkylamine derivatives. Selective calcium channel blocker. The drug exhibits antihypertensive, antianginal, antiischemic and antiarrhythmic properties. The mechanism of pharmacological action of the drug consists in the blockade of Ca 2+ channels and inhibition of transmembrane movement of Ca 2+ ions mainly in the cells of vascular smooth muscles and myocardium. In myocardial ischemia, verapamil eliminates the imbalance between the need for and supply of oxygen to the heart, reduces myocardial contractility, and has a vasodilating effect. A decrease in the tone of peripheral arteries contributes to a decrease in OPSS and hell. Verapamil inhibits sinoatrial and AV conduction, exhibits antiarrhythmic action. The normal level of heart rate does not change or decreases slightly.
Pharmacokinetics. After taking the drug, the active substance verapamil is gradually released from the capsule mass, due to which its constant concentration in the blood is maintained. The time to reach C max in blood plasma is 5-7 hours. The release of the drug occurs almost linearly within 8-12 hours. It is metabolized during the first passage through the liver with the formation of several metabolites. The main one is norverapamil, which has less pronounced hypotensive activity than unchanged verapamil. Binding to blood plasma proteins is 90%.
Due to the effect of the first passage through the liver, the bioavailability of the drug with a single dose is 30%, and T ½ is about 7 hours. With repeated administration, T ½ is an average of 12 hours, which is associated with the saturation of liver enzyme systems and an increase in the concentration of verapamil in the blood plasma. Excreted mainly with urine (70%) in the form of metabolites, partly with feces.
Indication
Ag; CHD: stable angina pectoris, variant angina (Prinzmetal's angina); arrhythmia: paroxysmal supraventricular tachycardia; atrial flutter/fibrillation with rapid AV conduction (except wpw c-ma).
Application
The dose of the drug is selected by the doctor individually. The average daily dose for all indications is 180-360 mg. At the beginning of treatment, 1 capsule (180 mg) is prescribed once a day, in the morning. If necessary, the dose is increased to 360 mg/day (1 capsule in the morning and evening, with an interval of about 12 hours between doses). Exceeding the dose is possible only for a very short time and under the close supervision of a doctor.
In patients with impaired liver function, depending on the severity, the effect of verapamil hydrochloride is enhanced and prolonged due to the slowing down of the drug's breakdown. Therefore, in such cases, the dosage should be set with special caution and start with low doses (for example, 40 mg 2-3 times a day, respectively 80-120 mg/day). Verapamil preparations with the possibility of such a dosage are used.
Verapamil can be taken before, during, or after meals, without chewing or dissolving, with a small amount of water.
Do not take the drug while lying down.
Verapamil hydrochloride should not be administered to patients with myocardial infarction within 7 days of its development.
After prolonged therapy, the drug should be discontinued by gradually reducing the dose.
The duration of treatment is determined by the doctor individually - it depends on the patient's condition and the course of the disease.
Contraindication
Hypersensitivity to verapamil or to other components of the drug; cardiogenic shock; acute phase of myocardial infarction with complications (bradycardia 50 beats / min, arterial hypotension (systolic blood pressure below 90 mm Hg), left ventricular failure); severe conduction disorders: sinoatrial and AV block II-III degree (except for patients with an artificial pacemaker); sick sinus syndrome (except for patients with an artificial pacemaker); congestive heart failure; atrial fibrillation / flutter (against the background of WPW S-MA and Laun - Genome - Levine syndrome (LGL). simultaneous i / v administration of β-adrenoceptor blockers (except for intensive care).
Pregnancy and breastfeeding.
Side effects
From the cardiovascular system: angina pectoris, arterial hypotension, sinoatrial and AV block (AV block I, II or III degree), bradycardia, bradyarrhythmia with atrial fibrillation, sinus node arrest, asystole. risk of exacerbation / development of heart failure, orthostatic reactions. in rare cases - tachycardia. also noted pain behind the sternum, myocardial infarction, palpitations, peripheral edema of the ankles, syncope, inflows.
Gastrointestinal: Gastrointestinal disorders such as nausea (sometimes vomiting), flatulence, intestinal atony, constipation. Dry mouth, gingival hyperplasia (gingivitis and bleeding), abdominal discomfort, intestinal obstruction, pain have been reported.
From the side of the central nervous system: cerebrovascular accident, confusion, balance disorders, fatigue, insomnia, nervousness, muscle cramps, psychosis, neuropathy, extrapyramidal syndrome, drowsiness, headache, sensory disorders such as tinnitus, paresthesia, tremor, dizziness.
From the side of the organs of hearing and vestibular apparatus: dizziness, ringing in the ears.
Musculoskeletal system: muscle weakness, muscle pain, joint pain.
Skin and subcutaneous tissue: skin rash (including urticaria), itching, alopecia, hyperkeratosis, pigmentation disorders, erythromelalgia, erythema multiforme, maculopapular rashes, in isolated cases - Stevens-Johnson syndrome, hemorrhage, Quincke's edema, photodermatitis. In isolated cases - purpura.
On the part of the hepatobiliary system: there may be an increase in the level of transaminases, alkaline phosphatase and bilirubin. Liver damage with clinical manifestations (malaise, fever and / or pain in the right hypochondrium) is possible, therefore it is advisable to periodically monitor liver function. In some cases, these changes disappear on their own with prolonged therapy.
Immune system disorders: Hypersensitivity has been reported in isolated cases. Allergic hepatitis, bronchospasm have been reported in rare cases.
Other manifestations: blurred vision, increased prolactin levels in the blood plasma. Sometimes a decrease in glucose tolerance was noted. Paralysis (tetraparesis) associated with the combined use of verapamil and colchicine has been reported, therefore the combined use of colchicine and verapamil is not recommended.
Special instructions
When using verapamil and determining its dose, special attention should be paid to patients with first-degree AV block; with arterial hypotension (systolic blood pressure 90 mm Hg); with bradycardia (heart rate 50 beats / min).
With caution appoint:
patients with heart failure - may cause asymptomatic second-degree AV block or transient bradycardia. If AV block develops, the dose should be reduced or the drug should be discontinued; patients with hypertrophic cardiomyopathy, including those complicated by left ventricular obstruction, high pulmonary capillary wedge pressure, and sinus node dysfunction; patients with atrial fibrillation/flutter and concomitant WPW syndrome (risk of ventricular tachycardia); in diseases with neuromuscular transmission disorders (myasthenia gravis, Lambert-Eaton syndrome); patients with Duchenne muscular dystrophy - verapamil reduces neuromuscular conduction and prolongs the recovery period after neuromuscular blockade caused by vecuronium. The dose of the drug should be reduced; patients with impaired liver function - depending on the severity, the effect of verapamil hydrochloride is enhanced and prolonged due to the slowing down of the drug's breakdown, so the dosage must be followed with extreme caution; patients with renal failure (under close supervision); elderly people with hypersensitivity to the drug's effects, even under normal dosage conditions; during surgical interventions due to potentiation of the inhibitory effects of general anesthetics on the myocardium and muscle relaxants on skeletal muscles.
It is necessary to monitor the duration of the P-Q interval on the ECG, as well as other signs of a possible verapamil overdose (regular monitoring of heart rate, etc.).
When using the drug, it is necessary to avoid eating foods and drinks with grapefruit, as it may increase the level of verapamil hydrochloride in the blood plasma.
Use during pregnancy and breastfeeding.
The drug should not be taken in the I and II trimesters of pregnancy. The use of the drug in the III trimester of pregnancy is possible only in case of extreme necessity, when the positive effect for the mother outweighs the potential risk to the fetus / child. Verapamil penetrates the placenta into the umbilical cord blood.
The biologically active substance penetrates into breast milk. Limited data on oral administration indicate that the dose of verapamil that enters the newborn is low (0.1-1% of the dose taken by the mother), so the use of verapamil can be combined with breastfeeding. Taking into account the risk of serious adverse reactions in breastfed newborns, verapamil should be used during this period only if absolutely necessary for the mother.
Children. The drug in this dosage form is not prescribed to children.
Ability to influence the reaction rate when driving vehicles or working with other mechanisms. Depending on the individual reaction, the ability to drive vehicles or work with mechanisms may be impaired. This is especially true in the initial phase of treatment, when increasing the dose, changing the antihypertensive drug.
Interactions
Single use:
with β-adrenergic blockers increases the mutual inhibitory effect on sinoatrial node automatism, AV conduction and myocardial contractility, as a result, the risk of developing severe arterial hypotension, AV and SA blockade, bradycardia, heart failure increases, especially when using high doses of β-blockers or when they are administered intravenously - appointment only according to clear indications and under strict medical supervision;
with antihypertensive drugs (e.g. vasodilators, ACE inhibitors, diuretics, α-adrenoblockers, prazosin and terazosin) - potentiation of their action;
with tricyclic antidepressants, neuroleptics - potentiate the hypotensive effect of verapamil;
with digitoxin - decreased digitoxin clearance (27%) and extrarenal clearance (29%);
The combination of verapamil with:
class I-III antiarrhythmic drugs (including amiodarone);
disopyramide, the use of which must be discontinued 48 hours before starting verapamil and resumed no earlier than 24 hours after stopping its administration;
acetylsalicylic acid - increased risk of bleeding;
flecainide - significantly changes the mutual inhibitory effect on the myocardium, slows down AV conduction and increases the duration of repolarization;
quinidine - severe hypotension may develop in patients with hypertrophic cardiomyopathy;
oral contraceptives, hydantoins, salicylates, sulfonamides and sulfonylurea derivatives - due to the high degree of binding, like verapamil, to proteins;
calcium salts and vitamin D - the pharmacological effect of verapamil is reduced;
propranolol, metoprolol - their clearance may decrease;
rifampicin, phenobarbital - may reduce the effectiveness of verapamil;
buspirone - increase in AUC and C max by 3-4 times;
sulfinpyrazone - a decrease in the hypotensive effect may be observed;
midazolam - increase in AUC by 3 times and C max by 2 times;
lithium salts - their concentration in the blood serum may vary, so patients should be under close supervision;
cyclosporine, everolimus, sirolimus, tacrolimus, serotonin receptor inhibitors (such as almotriptan), carbamazepine, theophylline; with substrates of cytochrome P450 isoenzyme 3A4, for example, CSE inhibitors (lovastatin or atorvastatin) - increase in their level in blood serum;
imipramine - increase in AUC (15%) without effect on the active metabolite desipramine;
H2 receptor antagonists (cimetidine),
antiretroviral drugs (ritonavir, indinavir) - possible increase in verapamil plasma concentration. Prescribe with caution, it may be necessary to reduce the dose of verapamil with:
inhalation anesthetics or neuromuscular transmission blockers - the doses of the drugs must be adjusted to avoid a depressing effect on the heart;
macrolides (e.g. erythromycin, clarithromycin) - mutual increase in blood plasma levels;
HMG-CoA reductase inhibitors (simvastatin, atorvastatin, lovastatin) in high doses - the risk of myopathy, rhabdomyolysis increases. The dosage should be adjusted accordingly. If a patient already taking verapamil needs to be prescribed an HMG-CoA reductase inhibitor, it should be remembered that the dose of statins should be reduced, and the dosage should be selected in accordance with the concentration of cholesterol in the blood plasma;
antidiabetic drugs (glyburide) - C max of glyburide increases by 28%;
doxorubicin - increases bioavailability and maximum plasma levels of doxorubicin in patients with small cell lung cancer;
X-ray contrast agents - may potentiate the suppressive effect of verapamil on sinoatrial node automaticity, AV conduction and myocardial contractility;
ethanol - decomposition is delayed and its level in blood plasma increases, thereby enhancing the effect of alcohol;
grapefruit juice - increases the bioavailability of verapamil;
John's wort perforated - AUC of R- (78%) and S-verapamil (80%) decreases with a corresponding decrease in C max.
Fluvastatin, pravastatin, and rosuvastatin have virtually no interaction with verapamil.
Verapamil may increase the effects of colchicine. Combined use is not recommended.
Overdose
The main symptoms of verapamil overdose: decreased blood pressure (in some cases to a level that cannot be determined); symptoms of shock, loss of consciousness; AV block I and II degree, often in the form of Wenckebach periods; complete AV block, AV dissociation, sinus bradycardia, sinus node block, cardiac arrest or asystole, dizziness up to coma, stupor, hyperglycemia, hypokalemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary edema, impaired renal function and convulsions.
Treatment: therapeutic measures aimed at removing the substance from the body and restoring stability to the cardiovascular system.
General measures: gastric lavage is recommended even if more than 12 hours have passed since the drug was taken and gastrointestinal motility is not determined (absence of intestinal sounds). General resuscitation measures include indirect heart massage, artificial respiration, defibrillation, cardiac pacing.
Hemodialysis is not indicated. Hemofiltration and possibly plasmapheresis may be effective (calcium antagonists bind well to plasma proteins).
Special measures: eliminate cardiodepressive effects, hypotension and bradycardia. The specific antidote is calcium: 10-20 ml of 10% calcium gluconate solution (2.25-4.5 mmol) is administered intravenously. If necessary, the administration can be repeated or an additional slow drip infusion (5 mmol / h) can be carried out.
In case of hypotension due to cardiogenic shock and arterial vasodilation, dopamine (up to 25 μg/kg/min), dobutamine (up to 15 μg/kg/min) or noradrenaline are used. The serum calcium concentration should correspond to the upper limit of normal or be slightly higher. In connection with vasodilation, fluid replacement (Ringer's solution or 0.9% sodium chloride solution) is carried out in the early stages.
Storage conditions
In the original packaging at a temperature not exceeding 25 °C.
