Propranolol is a hypotensive, antianginal, and antiarrhythmic agent.
Propranolol blocks b1- and b2-adrenoceptors, exhibits membrane-stabilizing action, inhibits sinoatrial node automatism, the occurrence of ectopic sites in the atria, atrioventricular node and to a lesser extent in the ventricles. Reduces the speed of conduction of excitation in the atrioventricular junction along the bundle of Kent mainly in the anterograde direction. Reduces the frequency and strength of heart contractions, myocardial oxygen demand. Reduces cardiac output, blood pressure, renin secretion, renal clearance and glomerular filtration rate. Inhibits the response of aortic arch baroreceptors to a decrease in blood pressure.
Inhibits lipolysis in adipose tissue, preventing the increase in free fatty acid levels (the atherogenicity coefficient may increase). Inhibits glycogenolysis, glucagon and insulin secretion, and the conversion of thyroxine to triiodothyronine. Increases bronchial muscle tone and uterine contractility. Enhances secretory and motor activity of the digestive tract.
In patients with ischemic heart disease, it reduces the frequency of angina attacks, increases exercise tolerance, and reduces the need for nitroglycerin. It has a cardioprotective effect, presumably reducing the risk of recurrent myocardial infarction and sudden cardiac death by 20–50%.
After taking a single dose of propranolol, a decrease in systolic and diastolic blood pressure is observed in both the supine and standing positions; a sustained hypotensive effect develops by the end of the second week of treatment.
Pharmacokinetics
When taken orally, it is quickly and almost completely (90%) absorbed from the digestive tract. Bioavailability is 30–40% (first-pass effect) and depends on the nature of the meal and the intensity of hepatic blood flow, increases with prolonged use. Cmax in blood plasma is reached 1–2 hours after oral administration. It is 90–95% bound to plasma proteins, the volume of distribution is 3–5 l/kg. It exhibits high lipophilicity, accumulates in lung tissue, brain, kidneys and heart. Penetrates through the blood-brain and placental barriers, as well as into breast milk. Metabolized in the liver by glucuronidation (99%). T½ is 3–5 hours, with prolonged use it is extended to 12 hours. It is excreted mainly by the kidneys in the form of metabolites (up to 90%), in unchanged form – less than 1%. Not removed by hemodialysis.
Indication
Control of essential and renal hypertension, angina pectoris, long-term prophylactic therapy after myocardial infarction, control of most forms of cardiac arrhythmias, prevention of migraine, essential tremor, control of excitement and tachycardia of excitement, additional therapy in thyrotoxicosis and thyrotoxic crisis; as part of combination therapy - pheochromocytoma (only in combination with α-blockers).
Contraindication
Hypersensitivity to any component of the drug; cardiogenic shock, atrioventricular block II and III degree, sinoatrial block, sick sinus syndrome, sinus bradycardia (heart rate less than 50 beats/min), Prinzmetal's angina, arterial hypotension, uncontrolled heart failure, bronchial asthma or bronchospasm in history, severe peripheral circulatory disorders, metabolic acidosis (including diabetic acidosis), after prolonged fasting, untreated pheochromocytoma, diabetes mellitus, chronic liver disease.
Interaction with other medicinal products and other types of interactions
Propranolol reverses the tachycardia of hypoglycemia. Diabetic patients should be cautious when using propranolol and hypoglycemic agents simultaneously. Propranolol may prolong the hypoglycemic response to insulin.
Class I antiarrhythmic drugs and amiodarone may potentiate the effect of propranolol on atrial conduction time and cause a negative inotropic effect.
Propranolol should be used with extreme caution in patients receiving concomitant treatment with cardiodepressants (chloroform, ether or related anesthetics), antiarrhythmic drugs (quinidine, lidocaine, procainamide), which exacerbate the depressive effects.
Guanethidine, reserpine, diuretics and other antihypertensive drugs, including vasodilators, may enhance the antihypertensive effect of propranolol.
Concomitant use of β-blockers with calcium channel blockers with negative inotropic effects (verapamil, diltiazem) may lead to an increase in these effects, particularly in patients with impaired cardiac function and/or sinoatrial or atrioventricular conduction. This may lead to severe hypotension, bradycardia and heart failure. Neither β-blocker nor calcium channel blocker should be administered intravenously within 48 hours of discontinuation of the other.
Concomitant use of dihydropyridine calcium channel blockers (e.g. nifedipine) may increase the risk of hypotension and cause heart failure in patients with latent heart failure.
Concomitant use of sympathomimetics (e.g. adrenaline) may block the effects of β-blockers. Caution should be exercised when parenterally administering adrenaline-containing products to patients receiving β-blockers, as in rare cases this may lead to vasoconstriction, hypertension and bradycardia. Caution should also be exercised when used with such products as isoprenaline and noradrenaline.
The use of propranolol during lidocaine infusion may increase the plasma concentration of lidocaine by approximately 30%. Patients who have already used propranolol tend to have higher plasma concentrations of lidocaine than those who have not used propranolol. This combination should be avoided.
Concomitant use of cimetidine or hydralazine, as well as alcohol, increases the level of propranolol in the blood plasma.
β-blockers may exacerbate the hypertension of the "withdrawal syndrome" caused by clonidine withdrawal. When these two drugs are used simultaneously, the β-blocker should be discontinued several days before clonidine is discontinued. When replacing clonidine with a β-blocker, the latter should be started several days after clonidine is discontinued.
Caution should be exercised when propranolol is used concomitantly with ergotamine, dihydroergotamine or related drugs due to the small possibility of vasospastic reactions.
When used simultaneously, prostaglandin synthesis inhibitors (e.g. ibuprofen and indomethacin) may reduce the hypotensive effect of propranolol.
Concomitant use of propranolol and chlorpromazine may increase plasma levels of both drugs. This may lead to an increase in the antipsychotic effect of chlorpromazine and an increase in the antihypertensive effect of propranolol.
Caution should be exercised when using anesthetics with propranolol. The anesthesiologist should be informed about the patient's use of propranolol and the anesthetic agent should be selected with the least negative inotropic effect. The use of β-blockers with an anesthetic may lead to attenuation of reflex tachycardia and increase the risk of hypotension. The use of anesthetics with cardiodepressive effects should be avoided.
The following drugs may interact with propranolol due to their effects on the hepatic enzyme systems that metabolize propranolol and these drugs: quinidine, propafenone, rifampicin, theophylline, warfarin, thioridazine and dihydropyridine calcium channel blockers (nifedipine). Since the plasma concentrations of each of these drugs may be affected, dosage adjustments should be made based on clinical judgment.
Application features
Propranolol, like other beta-blockers, is contraindicated in uncontrolled heart failure, but can be used with caution in patients with controlled heart failure. Caution should be exercised when used in patients with reduced cardiac reserve. Beta-blockers should be discontinued in overt heart failure.
Propranolol should be used with caution in patients with controlled heart failure or a family history of bronchial asthma. If these conditions develop, treatment should be discontinued.
Propranolol is contraindicated in severe peripheral circulatory disorders; use in less severe peripheral circulatory disorders may worsen the condition.
Propranolol should be used with caution in patients with first-degree atrioventricular block due to the negative effect of the drug on conduction time.
Propranolol may block/modify the signs and symptoms of hypoglycemia (especially tachycardia). Propranolol may occasionally cause hypoglycemia even in non-diabetic patients, such as neonates, infants, children, the elderly, patients on hemodialysis, patients with chronic liver disease, and in cases of overdose. In some patients, propranolol may cause severe hypoglycemia, manifested by seizures and/or coma. Caution should be exercised when propranolol is used in patients with diabetes mellitus on hypoglycemic therapy. Propranolol may prolong the hypoglycemic response to insulin.
Propranolol may mask the symptoms of thyrotoxicosis.
Due to the pharmacological action of propranolol, heart rate may decrease. In rare cases, when a patient develops symptoms that may be due to a low heart rate while being treated with propranolol, the dose of the drug should be reduced.
Patients with coronary heart disease should not be abruptly discontinued. The drug should be discontinued gradually or replaced with an equivalent dose of another β-blocker.
In patients with coronary heart disease, abrupt withdrawal of a β-blocker may lead to an increase in the frequency of angina attacks or worsening of the heart condition.
In patients with a history of anaphylactoid reactions, propranolol may cause a more severe reaction to these allergens. In such patients, the usual doses of adrenaline used to treat allergic reactions may be insufficient.
Propranolol should be used with caution in patients with decompensated liver cirrhosis.
Propranolol should be used with caution and with a low initial dose in patients with severe hepatic or renal impairment.
For patients with renal insufficiency, the interval between doses should be increased or the dose of propranolol should be reduced to avoid drug accumulation.
Patients with portal hypertension may have impaired liver function and develop hepatic encephalopathy. The use of propranolol in such cases may increase the risk of hepatic encephalopathy.
Caution is required when performing anesthesia with propranolol. The anesthesiologist should be informed and an anesthetic agent with the least possible negative inotropic effect should be selected.
Use during pregnancy or breastfeeding
Use during pregnancy is not possible except in cases where the expected therapeutic effect for the pregnant woman outweighs the potential risk to the fetus.
There is no evidence of teratogenicity of propranolol. However, β-blockers reduce placental perfusion, which can lead to intrauterine fetal death, early and preterm labor. In addition, adverse reactions may occur, especially hypoglycemia and bradycardia in the newborn and bradycardia in the fetus. There is an increased risk of cardiac and pulmonary complications in the newborn in the postpartum period.
Most β-blockers, especially lipophilic compounds, can pass into breast milk, although to varying degrees. Consequently, breastfeeding is not recommended during treatment with the drug.
Ability to influence reaction speed when driving vehicles or other mechanisms
Due to the possibility of developing side effects from the central nervous and cardiovascular systems, during treatment with the drug, caution should be exercised when driving vehicles or engaging in other potentially dangerous activities that require increased concentration and speed of psychomotor reactions.
Method of administration and doses
Take orally 10–30 minutes before meals, drinking plenty of fluids. The dosage regimen is individual. The dose and duration of treatment are determined by the doctor.
Adults.
Arterial hypertension: the initial dose is 80 mg 2 times a day. If necessary, the dose should be gradually increased every week depending on the patient's response to treatment. Usually daily doses are 160-320 mg.
Angina pectoris, agitation, migraine, essential tremor: the initial dose is 40 mg 2–3 times a day. If necessary, the dose should be gradually increased by the same amount at intervals of 1 week depending on the patient's response to treatment. Usually, for angina pectoris, the daily dose range is 80–320 mg. An adequate response to the treatment of agitation, migraine and essential tremor is observed when treated in the dose range of 80–160 mg per day, for angina pectoris – 120–240 mg per day.
Arrhythmias, tachycardia of excitement, thyrotoxicosis: usually doses are 10–40 mg 3–4 times a day.
Long-term prophylactic therapy after myocardial infarction: Therapy should be initiated 5-21 days after myocardial infarction. The initial dose is 40 mg 4 times a day for 2-3 days; after that, the daily dose can be increased to 80 mg 2 times a day.
Pheochromocytoma (only in combination with an α-blocker): 60 mg per day for 3 days before surgery; in inoperable cases - 30 mg per day.
Summary table of drug dosage (daily doses)
Indication
Minimum daily dose
Maximum daily dose
Arterial hypertension
160 mg
320 mg
Angina pectoris
80 mg
320 mg
Arrhythmias
30 mg
160 mg
Migraine
80 mg
160 mg
Tremor
40 mg
160 mg
Excitation
80 mg
160 mg
Tachycardia of excitement
30 mg
160 mg
Thyrotoxicosis
30 mg
160 mg
Pheochromocytoma:
before surgery
control in non-operated patients
60 mg
30 mg
60 mg
30 mg
After a myocardial infarction
160 mg
160 mg
Elderly patients: Data on the relationship between blood levels and patient age are conflicting. Consequently, the optimal dosage for elderly patients should be determined individually according to clinical response.
Children: Dosage should be individualized according to the condition of the cardiac system and the circumstances that necessitated treatment.
When treating, follow the following schemes:
Arrhythmia, pheochromocytoma, thyrotoxicosis: the drug should be used in children aged 3 years and older at a dosage of 0.25–0.5 mg/kg of body weight 3–4 times a day.
Migraine: children aged 3 to 12 years – 20 mg 2–3 times a day, over 12 years of age – dosage as for adult patients.
Children
The medicine should be prescribed to children aged 3 years and over (see section “Method of administration and dosage”).
Treatment: gastric lavage, administration of adsorbents. In the absence of signs of pulmonary edema, infusions of plasma-substituting solutions should be prescribed; in case of ineffectiveness, epinephrine, dopamine, dobutamine; in case of heart failure, cardiac glycosides, b-adrenomimetics, diuretics, glucagon; in case of convulsions, diazepam intravenously; in case of bronchospasm, β-adrenostimulants by inhalation or parenterally. In the presence of atrioventricular conduction disorders, 1–2 mg of atropine intravenously (adults); in case of low efficiency, installation of a temporary pacemaker. In case of ventricular extrasystole, lidocaine should be used (class IA antiarrhythmic drugs are not used). In case of a decrease in blood pressure, the patient should be in the Trendelenburg position. Hemodialysis is ineffective.
Side effects
The drug is usually well tolerated, but the following adverse reactions may occur.
From the blood system: thrombocytopenia, thrombocytopenic purpura, leukopenia, agranulocytosis.
From the nervous system: asthenia, dizziness, headache, insomnia or drowsiness, nightmares, decreased speed of mental and motor reactions, depression, anxiety, confusion or short-term amnesia, paresthesia, hallucinations, seizures, psychosis, mood changes.
On the part of the organs of vision: impaired visual acuity, decreased tear secretion, dryness and soreness of the eyes, keratoconjunctivitis.
On the part of the respiratory system: pharyngitis, cough, shortness of breath, respiratory distress syndrome, broncho- and laryngospasm.
On the part of the digestive system: nausea, vomiting, epigastric pain, diarrhea or constipation, mesenteric artery thrombosis, ischemic colitis.
Skin and subcutaneous tissue disorders: skin reactions, itching, rash, alopecia, exacerbation of psoriasis, psoriasis-like skin reactions.
From the endocrine system: hypoglycemia.
Vascular: cold extremities, exacerbation of intermittent claudication, Raynaud's syndrome.
