Nitroglycerin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NITROGLYCERIN (NITROGLYCERIN)

Composition:

Active substance: 1 sublingual tablet contains 2 % nitroglycerin on lactose, equivalent to 0.5 mg of nitroglycerin;

Excipients: lactose monohydrate, pregelatinized starch, microcrystalline cellulose, sodium croscarmellose, calcium stearate.

Pharmaceutical form. Sublingual tablets.

Main physicochemical properties: single-layer, round-shaped tablets with flat upper and lower surfaces and beveled edges, marked with a score line, white or white with a creamy shade. Marbling on the tablet surface is permissible. Under magnification, a relatively homogeneous structure is visible at the break.

Pharmacotherapeutic group.

Vasodilators used in cardiology. Organic nitrates.

ATC code C01D A02.

Pharmacological properties.

Pharmacodynamics.

Nitroglycerin is a peripheral vasodilator with predominant effects on peripheral vessels.

Nitroglycerin acts directly on smooth muscle cells, primarily in venous and arterial vessels, via the nitrate receptor located in the smooth muscle layer of the vessel wall. Within smooth muscle cells, nitroglycerin is enzymatically converted to produce nitric oxide (NO), which stimulates soluble guanylate cyclase, leading to the formation of cyclic guanosine-3',5'-monophosphate (cGMP), a mediator of relaxation.

It affects processes of central regulation of vascular tone and cardiac activity. It promotes the release of catecholamines in the brain and heart, resulting in central suppression of sympathetic and vasomotor tone, indirect sympathomimetic action on the myocardium, and conformational changes in the troponin-tropomyosin complex. The nature and intensity of nitroglycerin’s effects on the heart and peripheral vessels depend on the interaction between central and peripheral mechanisms. Suppression of vasoconstrictor reflexes in coronary vessels, resulting from central inhibition of pain impulses, contributes to the relief of angina attacks. The antianginal effect of nitroglycerin is due to its normalizing influence on myocardial electrolyte metabolism and energetics, particularly on key parameters of the respiratory chain—the ratio of oxidized to reduced forms of nicotinamide coenzymes and the activity of NAD-dependent dehydrogenases. It affects cardiac function and systemic hemodynamics. Under the influence of nitroglycerin, retrograde blood flow increases due to the dilation and increased number of functioning collaterals. Indirect sympathomimetic action, as well as accumulation of cyclic AMP in the myocardium, leads to enhanced contractility. Additionally, nitric oxide effectively inhibits both platelet aggregation and adhesion. Reduction in peripheral resistance and decreased venous return—effects associated with relaxation of vascular smooth muscles—result in decreased preload and afterload on the heart. Venodilation leads to reduced blood volume returning to the heart and thus decreased preload, while arterial dilation reduces total peripheral resistance and afterload, ultimately reducing cardiac workload and improving coronary circulation.

Redistribution of myocardial blood flow occurs in favor of ischemic areas, and myocardial inotropic function is enhanced. End-diastolic pressure in the left ventricle and cardiac size are reduced, improving blood supply to the subendocardial region, which is most vulnerable to ischemia. Reduced peripheral venous and arterial resistance and decreased cardiac filling pressure contribute to lower energy expenditure by the left ventricle and reduced myocardial oxygen demand. Pulmonary capillary pressure decreases, which justifies the use of nitroglycerin in myocardial infarction complicated by pulmonary edema and in heart failure. In ischemic hypokinesia of certain myocardial segments, contractility is restored. Meningeal vessels dilate, while vessels of internal organs constrict; pulmonary artery pressure decreases due to the vasodilatory and systemic effects of nitroglycerin. Nitroglycerin relaxes smooth muscles of the bronchi, biliary tract, gastrointestinal tract, and urinary tract. Teratogenic or embryotoxic effects were not observed in experimental studies.

Pharmacokinetics.

After sublingual administration, the effect begins within 0.5–2 minutes; 75% of patients report improvement within the first 3 minutes, and another 15% within 4–15 minutes.

Sublingually administered nitroglycerin is absorbed through the mucous membrane and primarily enters the systemic circulation. Approximately 60–75% of the administered dose is absorbed. Maximum plasma concentration—2.3 µg/L—is reached within 2–4 minutes after administration; by the 8th minute, the concentration decreases by 50%, and nitroglycerin is almost undetectable in the blood within 20 minutes. It is rapidly metabolized in the liver. Nitrate esters of polyhydric alcohols undergo rapid denitration. Denitrated metabolites, such as 1,2- and 3,4-dinitrates, are less active but have a longer elimination half-life compared to nitroglycerin. The elimination half-life of nitroglycerin is approximately 30 minutes. Nitro groups are sequentially cleaved both via formation of inorganic nitrites and nitrates. The organic portion of nitrate ester molecules yields alcohols, aldehydes, and organic acids. Four hours after administration, nitrate esters (the initial compound) are almost undetectable. They are most actively metabolized in the liver, kidneys, and blood. Nitrate esters are degraded via two pathways: by glutathione-dependent reductase, primarily located in the soluble fraction of hepatocytes, and by an enzyme independent of reduced glutathione. The drug is primarily metabolized in the arterio-venous vascular bed, diffuses into smooth muscle cells, where it is converted to nitric oxide. A small portion of the drug, mainly under the influence of glutathione-S reductase, is biotransformed in the liver into di- and mononitrates and glycerol. When administered orally, the majority of the drug undergoes hepatic metabolism (first-pass effect). A significant portion of dinitrate and mononitrate forms conjugates with glucuronic acid. Excretion of nitroglycerin metabolites occurs primarily via the kidneys; some metabolites are excreted through the lungs with exhaled air. Total clearance of nitroglycerin is 25–30 L.

Elimination half-life is 4–5 minutes. The elimination half-life of metabolites is 4 hours.

Clinical characteristics.

Indications.

Angina pectoris (for termination of angina attacks and short-term prophylaxis).

Contraindications.

Hypersensitivity to nitrates and excipients of the drug; cerebral ischemia, hemorrhagic stroke, intracranial hemorrhage, increased intracranial pressure, recent head trauma, bradycardia (less than 50 beats/min), arterial hypotension (systolic blood pressure below 90 mm Hg), shock, collapse, hypertrophic obstructive cardiomyopathy, aortic stenosis, conditions associated with reduced left ventricular filling pressure (acute myocardial infarction, isolated mitral stenosis, constrictive pericarditis), cardiac tamponade, toxic pulmonary edema, closed-angle glaucoma with high intraocular pressure, concomitant use of phosphodiesterase-5 (PDE-5) inhibitors (sildenafil, tadalafil, vardenafil).

Interaction with other medicinal products and other forms of interactions.

When used concomitantly with other vasodilators, antihypertensive agents, ACE inhibitors, calcium channel blockers ("slow" calcium channel blockers), diuretics, tricyclic antidepressants, MAO inhibitors, ethanol and ethanol-containing medications, beta-adrenergic blockers, procainamides, quinidine, and novocainamide, the hypotensive effect of nitroglycerin is enhanced.

Phosphodiesterase inhibitors (sildenafil, tadalafil, vardenafil) – concomitant use of nitroglycerin with these drugs is contraindicated due to the potential risk of uncontrolled arterial hypotension and life-threatening cardiovascular complications.

Atropine and other drugs with M-cholinolytic action may reduce the efficacy of nitroglycerin due to decreased secretion and bioavailability of the drug.

Concomitant use with dihydroergotamine may lead to increased plasma concentration of dihydroergotamine and elevated blood pressure (due to increased bioavailability of dihydroergotamine).

When used concomitantly with heparin, a reduced anticoagulant effect of heparin may occur (after discontinuation of the drug, a significant decrease in blood coagulation may occur, which may require a reduction in heparin dose).

Phenobarbital enhances the metabolism of nitrates in the liver. Alpha-adrenergic agonists, histamine, pituitrin, corticosteroids, CNS stimulants, bee and snake venom, and sunlight reduce the antianginal effect of nitroglycerin. Salicylates increase the blood level of nitroglycerin; barbiturates accelerate its metabolism. Donors of sulfhydryl groups (captopril, acetylcysteine, unithiol) restore reduced sensitivity to nitroglycerin.

Special precautions.

The drug should be used with caution, weighing the risks against the benefits, in patients with: uncontrolled hypovolemia, heart failure with normal or low pulmonary arterial pressure, severe anemia, hyperthyroidism, severe renal and/or hepatic insufficiency (risk of developing methemoglobinemia).

Extreme caution is required when administering the drug to patients with marked cerebral atherosclerosis and elderly patients. Alcohol consumption is strictly prohibited during treatment; visiting saunas, steam baths, or taking hot showers is contraindicated.

The tablet must not be chewed, as an excessive amount of the active substance may enter systemic circulation through the oral mucosa.

With frequent use, tolerance (tolerance development) may develop to nitroglycerin, as well as to other organic nitrates, requiring an increase in dosage. To prevent the development of tolerance during prolonged nitroglycerin therapy, intermittent dosing within a 24-hour period (with a 10–12 hour nitrate-free interval) is recommended, or concomitant administration of calcium antagonists, ACE inhibitors, or diuretics. If tolerance develops, temporary discontinuation of nitroglycerin (for several days) may be necessary, with substitution by antianginal agents from other pharmacotherapeutic classes.

Prior to first use of the drug, consult a physician!

Patients must inform their physician about any previous reactions to medications of this group.

Nitroglycerin may cause significant hypotension and dizziness upon sudden transition from a lying or sitting position to an upright position, as well as when consuming alcohol, or during physical exertion in hot weather.

If blurred vision or dry mouth persists or is pronounced, treatment must be discontinued.

Headache associated with drug intake may be reduced by lowering the dose and/or concomitant use of valerian tincture (validol).

The risk of methemoglobinemia, manifested by cyanosis and blood discoloration, increases with prolonged uncontrolled use of nitroglycerin and administration of high doses in patients with hepatic insufficiency. In case of methemoglobinemia, nitroglycerin must be urgently discontinued and an antidote administered—methylene blue (methylthioninium chloride). If further nitrate therapy is required, mandatory monitoring of methemoglobin levels is necessary.

The drug contains lactose; therefore, it should not be administered to patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Nitroglycerin use during pregnancy or breastfeeding is contraindicated.

Ability to affect reaction speed while driving or operating machinery.

When driving vehicles or operating machinery requiring heightened attention, it should be remembered that nitroglycerin intake may reduce reaction speed.

Method of Administration and Dosage.

To be used by adults.

When prescribing the drug for the first time, its effect on arterial blood pressure should be monitored. Efficacy of Nitroglycerin should be monitored by heart rate and arterial blood pressure.

The drug should be taken immediately at the first signs of angina attack.

Immediately after the onset of pain, place 1 tablet under the tongue and hold it in the mouth until completely dissolved, without swallowing. The usual dose is 1 tablet sublingually. If there is no antianginal effect within 3–5 minutes, another 1 tablet of Nitroglycerin should be taken.

If there is no therapeutic effect after taking 2–3 tablets, a doctor must be called.

In cases of frequent angina attacks, prolonged-action formulations are recommended.

Tolerance to sublingual forms of nitroglycerin develops rarely; however, if it occurs, in some patients the dose may need to be gradually increased up to 2–3 tablets.

Children.

There is no experience with the use of this drug in children; therefore, it is not recommended for use in this age group.

Overdose.

Symptoms: decreased arterial blood pressure (below 90 mm Hg) with orthostatic dysregulation, headache, severe dizziness, fainting, rapid heartbeat, nausea and vomiting, shortness of breath, marked weakness, drowsiness, increased body temperature, sensation of warmth, arterial hypotension, excessive sweating, chills.

When high doses are used (more than 20 mcg/kg): collapse, cyanosis of lips, nails, or palms, methemoglobinemia, dyspnea, and tachypnea.

Treatment: place the patient in a horizontal position with legs elevated; in severe cases, administer plasma substitutes, sympathomimetics, oxygen; methylene blue should be administered in case of methemoglobinemia.

Adverse reactions.

Central nervous system side effects: blurred vision, "nitrate" headache (especially at the beginning of treatment; decreases with prolonged therapy), dizziness and feeling of weakness, anxiety, psychotic reactions, drowsiness, disorientation.

Cardiovascular system side effects: decreased arterial blood pressure, reflex tachycardia, rarely (especially in overdose) – orthostatic collapse, cyanosis, methemoglobinemia, facial flushing.

Gastrointestinal side effects: dryness in the mouth, nausea, vomiting, abdominal pain.

Immune system side effects: allergic reactions, including skin rashes, urticaria, itching; skin hyperemia, pallor, anaphylactic shock.

Other side effects: excitability, visual disturbances, exacerbation of glaucoma, hypothermia, sensation of warmth, respiratory disturbances, weakness.

There have also been reports of isolated adverse reactions: exacerbation of ischemic heart disease due to hypoxia, complete block, asystole, angioneurotic edema.

Sometimes, a sudden drop in arterial blood pressure may lead to worsening of angina symptoms (paradoxical "nitrate" reactions).

Shelf life. 2.5 years.

Storage conditions.

Store in original packaging at a temperature not exceeding 25 ºC. Keep out of reach of children.

Packaging.

20 or 40 sublingual tablets in a container; 1 container per carton.

Availability.

Over-the-counter.

Manufacturer.

JSC "Tekhnolohiya".

Manufacturer's address and place of business.

8 Stara Prorizna Street, City of Uman, Cherkasy Region, Ukraine, 20300.