Isosorbide 5-Mononitrate

Pharmacological properties

like all organic nitrates, isosorbide mononitrate (ismn) acts as a donor of nitric oxide (no). but it causes relaxation of vascular smooth muscle by stimulation of guanylate cyclase and a further increase in the concentration of intracellular cGMP. In this way, cGMP-dependent protein kinase is stimulated, as a result of which the phosphorylation of various proteins in the cells of vascular smooth muscle changes. in turn, this leads to dephosphorylation of the light chains of myosin and a decrease in myocardial contractility.

ISMN causes relaxation of the smooth muscles of blood vessels, which determines vasodilation. The expansion of the veins promotes the deposition of blood and reduces the volume of venous blood, which returns to the heart; thus, the ventricular end diastolic pressure and volume are reduced (preload). The effect on arteries, and in high doses on arterioles, leads to a decrease in systemic vascular resistance (afterload). This, in turn, improves heart function. The effect on both pre- and afterload leads to a decrease in oxygen consumption by the heart muscle.

In addition, ISMN causes a redistribution of blood flow to the subendocardial parts of the heart under conditions of atherosclerotic lesions. This effect is probably due to the selective dilatation of large coronary vessels. Dilatation of collateral arteries caused by nitrates can improve myocardial perfusion in vascular stenosis. In addition, nitrates counteract the occurrence and eliminate coronary spasm. In patients with heart failure, which is accompanied by congestion, nitrates improve hemodynamics at rest and during exercise. This positive effect develops due to a number of mechanisms, including a decrease in valvular regurgitation (due to a decrease in dilatation of the left ventricular chamber) and a decrease in oxygen consumption by the myocardium. In addition to affecting the cardiovascular system, ISMN causes relaxation of the muscles of the bronchi, as well as the muscles of the gastrointestinal tract, bile and urinary tracts.

Pharmacokinetics ISMN after oral administration is rapidly and completely absorbed in the digestive tract. ISMN is not subjected to first-pass metabolism in the liver and is characterized by high systemic bioavailability (relative bioavailability of the drug is 80–90%). The therapeutic concentration is achieved 15–20 minutes after taking the drug. Thanks to a special technology for the manufacture of pellets containing ISMN, the release in the preparation is carried out in two stages: 30% of the dose is released immediately, and 70% is released slowly, providing C_max ISMN in blood plasma for 5 hours after administration. T_½ is 4–5 hours. ISMN is metabolized in the liver with the formation of NO (active metabolite) and isosorbide (inactive) by denitration; it can interact with glucuronic acid. 2% of isosorbide and ISMN in an unchanged form are excreted by the kidneys.

Indications

• Prevention of attacks and prolonged treatment of angina pectoris; treatment of chronic heart failure in combination with cardiac glycosides, diuretics, apf inhibitors.

Application

The drug is prescribed for adults in 1 capsule (50 mg ismn) 1 time per day (in the morning). taken after eating without chewing and drinking a small amount of water. the maximum daily dose is 50 mg. elderly patients do not need dose adjustment. the duration of treatment is determined by the doctor and depends on the course of the disease.

Contraindications

• Hypersensitivity to ismn, other nitrate compounds or any excipient; acute circulatory failure (shock, vascular collapse); cardiogenic shock (if adequate measures of the end diastolic hell are not supported by appropriate measures); hypertrophic obstructive cardiomyopathy; constrictive pericarditis; cardiac tamponade; severe arterial hypotension (systolic hell 90 mm RT. Art.); severe anemia; severe hypovolemia.

During nitrate therapy, PDE inhibitors (sildenafil, tadalafil, vardenafil) cannot be used.

Side effects

The frequency of undesirable effects can be defined as very often (10%), often (from 1 to 10%), infrequently (from 0.1 to 1%), isolated cases (from 0.01 to 0.1%) and very rarely ( 0.01%). when using the drug, the following adverse events may occur:

Neurological disorders: very often - headache; often - slight dizziness in an upright position, dizziness, drowsiness.

Cardiac disorders: often - reflex tachycardia; isolated cases - increased symptoms of angina pectoris (paradoxical reaction).

Vascular disorders: often - orthostatic hypotension on rising; isolated cases are collaptoid states, sometimes with bradycardia and syncope.

From the gastrointestinal tract: infrequently - nausea, vomiting; very rarely - heartburn.

On the part of the skin and subcutaneous tissue: infrequently - allergic skin reactions (eg, rash), hyperemia of the skin of the face; isolated cases - exfoliative dermatitis.

General disorders and reactions at the injection site: often - a feeling of weakness. There are reports of severe hypotensive reactions, which were accompanied by nausea, vomiting, a feeling of anxiety, pallor and increased sweating when using organic nitrates. The use of the drug can cause temporary hypoxemia due to the relative redistribution of blood flow in the alveolar zones with hypoventilation. In individuals with coronary artery disease, this can lead to temporary myocardial hypoxia.

With prolonged use of the drug, it is possible to develop tolerance (decreased effectiveness), as well as cross tolerance with other drugs of the nitrate group (decrease in effect in the case of previous therapy with another nitro drug).

special instructions

The drug is not intended for the treatment of acute attacks of angina pectoris because the therapeutic effect is not fast enough. with extreme caution and under the supervision of a doctor, the drug should be used in such cases:

• with reduced pressure of filling the left ventricle, for example, with acute myocardial infarction (increased risk of a further decrease in blood pressure and the occurrence of tachycardia, which can enhance ischemia);
• with left ventricular failure;
• with aortic and / or mitral stenosis;
• in diseases accompanied by an increase in intracranial pressure, including hemorrhagic stroke, craniocerebral injuries;
• with orthostatic dysfunction (decrease in systolic blood pressure by 10–25 mm Hg. Art. 90 mm Hg. Art., arising from a change in body position);
• with a decrease in blood pressure of 90 mm RT. st .;
• with anemia;
• with angle-closure glaucoma;
• with hepatic / renal failure;
• during surgical interventions.

With prolonged use of the drug, it is possible to develop tolerance (decreased effectiveness), as well as cross tolerance with other drugs of the nitrate group (decrease in effect in the case of previous therapy with another nitro drug). To prevent the development of tolerance (reduction or loss of therapeutic effect), including cross tolerance, prolonged use of the drug in high doses should be avoided: after 3-6 weeks of regular use of the drug, it is recommended to take a break for 3-5 days, replacing the drug with other ones antianginal drugs. Patients who are on maintenance therapy with the drug should be informed that they are not allowed to take drugs containing PDE inhibitors (for example, sildenafil, tadalafil and vardenafil). Drug therapy should not be discontinued for the purpose of taking drugs containing PDE inhibitors (for example, sildenafil, tadalafil and vardenafil), due to the risk of an angina attack.

Due to the fact that the drug contains lactose, it cannot be prescribed to patients with such rare genetic diseases as galactose intolerance, Lapps hereditary lactase deficiency, glucose-galactose malabsorption. Since the drug contains sucrose, it cannot be prescribed to patients with rare genetic diseases such as fructose intolerance, malabsorption of glucose and galactose (glucose-galactose malabsorption), sucrose-isomaltase deficiency.

Use during pregnancy and lactation. There are no adequate and well-controlled studies in pregnant women. Therefore, during pregnancy, the drug is used only for health reasons, if the benefits of the application exceed the potential risk, and with constant medical supervision. It is not known whether ISMN is excreted in breast milk. Since many drugs are excreted in breast milk, it is not recommended to prescribe the drug to women who are breast-feeding.

Children. Do not use.

The ability to influence the reaction rate when driving vehicles and working with mechanisms. The drug can affect the reaction rate when driving vehicles and working with mechanisms.

Interactions

It is possible to enhance the hypotensive effect while taking the drug with other vasodilators, β-adrenergic blockers, calcium channel blockers, antipsychotics (antipsychotics), tricyclic antidepressants, novocainamide, acetylcholine, histamine, norepinephrine, and narcotic analgesic. the combined use of the drug with dihydroergotamine can lead to an increase in the concentration of dihydroergotamine in the blood and, thus, enhance its antihypertensive effect. while taking with PDE inhibitors (for example, sildenafil), which are used for erectile dysfunction, the effect of the drug is enhanced, which can lead to life-threatening cardiovascular complications. therefore, patients receiving treatment with the drug are contraindicated in taking PDE inhibitors (e.g. sildenafil, tadalafil and vardenafil).

Overdose

Symptoms of an overdose: a sharp decrease in systolic hell 90 mm RT. Art., pallor, increased sweating, weak pulse, tachycardia, dizziness (including orthostatic reactions with a change in body position), headache, weakness, nausea, vomiting, diarrhea.

There are reports of cases of methemoglobinemia in patients after taking other organic nitrates. During the biotransformation of ISMN, nitrite ions are released that can induce methemoglobinemia and cyanosis, which are sometimes accompanied by tachypnea, a sense of anxiety, loss of consciousness, and cardiac arrest. The possibility of this adverse reaction in case of an overdose of ISMN cannot be ruled out. The use of the drug in very high doses can cause an increase in intracranial pressure, which sometimes leads to the development of cerebral symptoms.

General measures for the treatment of overdose:

• stop using the drug;
• in case of arterial hypotension caused by nitrates, lay the patient on a horizontal surface with his head down on a low headboard;
• provide oxygen;
• carry out special anti-shock therapy (the patient should be in the intensive care unit).

Special measures:

• actions aimed at increasing blood pressure, if it is very low;
• additional use of norepinephrine or other vasoconstrictors; the use of epinephrine in this situation is not recommended (the negative effect prevails over the positive);
• in case of signs of respiratory arrest or blood circulation, resuscitation measures are immediately taken.

Treatment of methemoglobinemia: rehabilitation therapy with vitamin C, methylene blue or toluidine blue; the use of oxygen (if necessary), mechanical ventilation, hemodialysis (if necessary), the introduction of plasma substitutes.

Storage conditions

In a dry place at a temperature not exceeding 25 ° C.