Nitrates in the treatment of patients with coronary heart disease: focus on isosorbide dinitrate

Pharmacodynamics and pharmacokinetics

The substance increases the level of NO2 ( nitric oxide ) in endothelium . The drug acts as a venous and arterial dilator . Reduces the need for oxygen in the heart muscle, reduces the overall tension of the walls of the ventricles of the heart. Isosorbide dinitrate reduces the load on the heart, dilates the coronary arteries, redistributes coronary blood flow to an area with insufficient oxygen supply, and reduces blood pressure on the walls of blood vessels in the pulmonary circulation.

The drug, as a rule, does not affect the heart rate; sometimes it slightly increases heart rate. Under the influence of the substance, cerebral vessels dilate and pulmonary vascular resistance changes.

After taking the tablets, the medicine is quickly and completely absorbed. The biological availability of the product is no more than 22%. When used sublingually, the bioavailability is 60%. The degree of binding to blood plasma proteins is no more than 30%.

The effect of taking sublingual tablets occurs after 3 minutes, from oral tablets - after 15-40 minutes. When sprayed onto the oral mucosa, the antianginal effect develops within 30 seconds and lasts up to 2 hours.

After injection of the drug, it is half eliminated from the body after 20 minutes; when administered sublingually, the half-life is one hour, when taking tablets - 4 hours. The substance is metabolized in the liver, forming active metabolites: isosorbide-5-mononitrate, isosorbide-2-mononitrate . Metabolites are eliminated by renal glomerular filtration.

Long-term use of the medicine may lead to the development of tolerance.

Publications in the media

Isosorbide dinitrate (Nitrosorbide, Isoket, Cardiket), extended-release capsules, concentrate for the preparation of solution for infusion, films for gluing to the gums, dosed sublingual spray, tablets, extended-release tablets, transdermal therapeutic system

Pharmaceutical group - vasodilating agent - nitrate.

Pharmaceutical action. Peripheral vasodilator with a predominant effect on venous vessels. Stimulates the formation of “first pass” nitric oxide (endothelial relaxing factor) in the vascular endothelium, which causes activation of intracellular guanylate cyclase, resulting in an increase in cGMP (a mediator of vasodilation). Reduces myocardial oxygen demand by reducing preload and afterload (reduces the end-diastolic volume of the LV and reduces the systolic tension of its walls). Has a coronary dilating effect. Reduces blood flow to the right atrium, helps reduce pressure in the “lesser” circulation and regression of symptoms of pulmonary edema. Promotes redistribution of coronary blood flow in areas with reduced blood circulation. Increases tolerance to physical activity in patients with coronary heart disease and angina pectoris. Dilates blood vessels in the brain, which may be accompanied by headaches. As with other nitrates, cross-tolerance develops. After cancellation (break in treatment), sensitivity to it is quickly restored. The onset of action after sublingual administration or chewing is 2-5 minutes, after oral administration of capsules and tablets - 15-40 minutes, prolonged forms - 30 minutes. The duration of action is 1-2 hours, 4-6 and 12 hours, respectively. After spraying onto the oral mucosa, the effect appears after 30 s and lasts 15-120 minutes.

Pharmacokinetics. Absorption for all dosage forms is high. Bioavailability when taken orally is 22% (the “first pass” effect through the liver), when administered sublingually - 60%. TCmax when taken orally - 1 hour. Plasma protein binding - 30%. T1/2 with intravenous administration - 20 minutes, with sublingual administration - 60 minutes, with oral administration - 4 hours. Metabolized in the liver to 2 active metabolites: isosorbide-5-mononitrate (75-85%) with T1/2 5 h and isosorbide-2-mononitrate (15-25%) with T1/2 - 2.5 h. Excreted by the kidneys (almost entirely in the form of metabolites).

Indications. Angina (relief and prevention, including unstable angina), acute myocardial infarction (including complicated by acute left ventricular failure), condition after myocardial infarction. Spasm of the coronary arteries (prevention and treatment when using a cardiac catheter). CHF, pulmonary edema, hypertension in the pulmonary circulation, cor pulmonale (as part of combination therapy). Spasm of peripheral arteries (obliterating endarteritis, angiospastic retinitis). Control of blood pressure when it increases before and during surgery (especially in cardiovascular surgery). Contraindications. Hypersensitivity. For intravenous administration (except in special circumstances) - hemorrhagic stroke, head injury (increases intracranial pressure), intracranial hypertension, cardiac tamponade, constrictive pericarditis, hypovolemia (must be corrected before using nitroglycerin - the risk of a pronounced decrease in blood pressure).

Carefully. For all forms (comparing risk and benefit) - hemorrhagic stroke, recent TBI, acute myocardial infarction (risk of decreased blood pressure and tachycardia, which can increase ischemia), glaucoma (risk of increased intraocular pressure), severe anemia, thyrotoxicosis, arterial hypotension with low systolic blood pressure (can aggravate the condition, causing paradoxical bradycardia and angina attacks), HOCM (possibly increased frequency of angina attacks), severe chronic renal failure, liver failure (risk of developing methemoglobinemia), pregnancy, lactation, childhood (safety of use has not been established). For oral dosage forms - increased gastrointestinal motility, malabsorption syndrome. Category of action on the fetus. C

Dosing. Sublingual, internally, parenterally, locally, externally. Sublingual. Spray: 1-3 doses (1.25-3.75 mg) are injected into the oral cavity at intervals of about 30 s while holding the breath. If after 5 minutes there is no improvement, inhalation is repeated (subject to constant monitoring of blood pressure and heart rate). To prevent coronary spasm in case of catheterization, 1-2 doses should be administered immediately before the procedure. Tablets: 2.5-5 mg, if necessary - every 2-3 hours. To relieve an attack of angina - sublingually (to speed up the action, it is advisable to chew the tablet). Inside. 10-20 mg 4-5 times a day 1 hour before or 2 hours after meals, without chewing, with a glass of water. If the effect is insufficient, from day 3-5 of treatment the dose is increased to 60-120 mg/day. The frequency of administration depends on the duration of action and is 3-4 times for tablets with an average duration of action (tablets containing 5, 10 and 20 mg); for retard tablets 20 mg - 2-3 times; for retard tablets 40 and 60 mg - 2 times; for retard tablets 120 mg - 1 time per day. As part of complex therapy for CHF, 10-20 mg is used 3-4 times a day. Parenterally. IV drip, 0.1 mg/ml at an initial rate of 3-4 drops/min or 0.2 mg/ml at a rate of 1-2 drops/min. The rate of administration can be increased every 5 minutes by 2-3 drops, depending on the patient’s response (subject to monitoring blood pressure, heart rate, ECG and diuresis). The maximum rate of administration is 33 drops/min (for a solution with a concentration of isosorbide dinitrate of 0.1 mg/ml) and 17 drops/min (for a solution with a concentration of 0.2 mg/ml). Transbuccally. Plates (20-40 mg) are glued to the mucous membrane of the gums on the front surface of the upper jaw at the level of the incisors or small molars, alternating sides each time, 1-3 times a day. TTS: the skin area is wiped with ethanol or water; The protective coating is removed from the system, the sticky side is applied to the skin and pressed to ensure contact of the entire surface with the skin. The selected area of ​​skin should be hairless and not subject to intense mechanical stress (the inner surface of the forearm, the side or front surface of the chest, the skin of the back). The following system is glued to another (preferably symmetrical) area of ​​the skin. The dose is proportional to the area and is 0.5-1 mg/sq.cm. To select an individual dose, the system can be cut into pieces of any size. The duration of a single application is 12-24 hours. The course of treatment is 2 weeks. Abrupt withdrawal should be avoided. Spray for skin application: spray 1-2 doses from a distance of 20 cm and rub it with your fingertips. After the spray has dried, the skin can be covered with clothing. After 20 minutes, the skin areas can be washed. Ointment: initial dose - 1 g of ointment 1-2 times a day; applied to the chest area, inner surface of the forearms or abdomen; The minimum application surface area is 20 sq.cm.

Side effect. From the cardiovascular system: headache, dizziness, flushing of the facial skin, feeling of heat, tachycardia, decreased blood pressure. In rare cases, a paradoxical increase in angina attacks and collapse. From the digestive system: nausea, vomiting, a slight burning sensation of the tongue, dry mouth. From the nervous system: stiffness, drowsiness, blurred vision, decreased ability for rapid mental and motor reactions (especially at the beginning of treatment). In rare cases, cerebral ischemia. Allergic reactions: skin rash. Local reactions: burning, itching, skin hyperemia at the site of application. Other: development of tolerance (including cross-tolerance to other nitrates), exfoliative dermatitis.

Overdose. Symptoms: collapse, fainting, headache, dizziness, palpitations, visual disturbances, hyperthermia, convulsions, skin flushing, increased sweating, nausea, vomiting, diarrhea, methemoglobinemia (cyanosis, anoxia), hyperpnea, dyspnea, bradycardia, increased intracranial pressure, paralysis , coma. Treatment: gastric lavage; remove ointment, TTC or buccal tablets (wipe the gums at the site of their application); for methemoglobinemia, depending on the severity, intravenous ascorbic acid in the form of sodium salt is prescribed (previously methylthioninium chloride (methylene blue) was used 0.1-0.15 ml/kg 1% solution up to 50 ml); oxygen therapy, hemodialysis, exchange transfusion. Symptomatic therapy: with a pronounced decrease in blood pressure - intravenous phenylephrine (epinephrine and related compounds are ineffective).

Interaction. Pharmacodynamic: under the influence of beta-adrenergic stimulants, alpha-adrenergic blockers (prazosin, dihydroergotamine, etc.), the severity of the antianginal effect of isosorbide dinitrate (tachycardia and excessive decrease in blood pressure) may be reduced. When combining amiodarone, propranolol, BMCA (verapamil, nifedipine, etc.), ASA and isosorbide dinitrate, the antianginal effect may be enhanced. When isosorbide dinitrate is used together with antihypertensive drugs, vasodilators, antipsychotic drugs (neuroleptics), tricyclic antidepressants, procainamide, ethanol, quinidine, beta-blockers, BMCC, ethanol, dihydroergotamine and sildenafil, the hypotensive effect may be enhanced. When combined with m-anticholinergic blockers (atropine, etc.), the likelihood of increased intraocular pressure increases. Pharmacokinetic: adsorbents, astringents and enveloping drugs reduce the absorption of isosorbide dinitrate in the gastrointestinal tract.

Special instructions. During treatment, especially in the case of a gradual increase in dose, monitoring of blood pressure and heart rate is necessary. To relieve attacks of angina, in acute myocardial infarction (including complicated by acute left ventricular failure), pulmonary edema, unstable angina, spasm of the coronary arteries (prevention and treatment when using a cardiac catheter), sublingual or intravenous routes of administration are used. If necessary, use against the background of arterial hypotension should simultaneously administer drugs that have a positive inotropic effect, or use circulatory support devices. Frequent administration and high doses may cause the development of tolerance; in this case, it is recommended to discontinue it for 24-48 hours or after 3-6 weeks of regular use, take a break for 3-5 days, replacing isosorbide dinitrate with other antianginal agents during this time. While taking isosorbide dinitrate, you should avoid drinking ethanol. Pregnant and lactating women are prescribed the drug only according to strict indications, under the constant supervision of a doctor. Ineffective for heart failure caused by cardiac tamponade and toxic pulmonary edema. Abrupt withdrawal of the drug should be avoided and the dose should be reduced gradually. During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Indications for use

The medicine is prescribed orally, buccally and sublingually:

• for relief and prevention of angina ;
• during rehabilitation treatment after myocardial infarction ;
• as part of complex treatment of chronic heart failure ;
• for certain forms of pulmonary hypertension ;
• as part of combination therapy for cor pulmonale.

The drug is used by inhalation:

• for the relief and prevention of angina pectoris ;
• in case of acute myocardial infarction , acute left ventricular failure ;
• as a prophylaxis or to treat spasm of the coronary arteries if a cardiac catheter is used.

The medicine is administered intravenously:

• in acute myocardial infarction ;
• for unstable angina ;
• patients with pulmonary edema .

It is also possible to use the substance cutaneously to prevent angina pectoris .

Use of the drug Isosorbide dinitrate

Adults - orally 30 minutes before meals, 5-10 mg 3-4 times a day. In some cases, according to indications, single doses are increased to 20–40 mg. In severe forms of heart failure, 20 mg is prescribed every 4–5 hours. Retard forms are prescribed orally at 40–80 mg every 8–12 hours. Sublingually to relieve angina attacks - 2.5–5 mg, if necessary - every 2 –3 hours. IV drip administration is usually started at a rate of 1–2 mg/hour; if necessary, the infusion rate is increased to 8–10 mg/h. Depending on the clinical picture, hemodynamic parameters and ECG, the infusion can be continued for up to 3 days or more. The solution is prepared ex tempore and administered in a diluted state through a long-term intravenous infusion using automatic perfusers under constant monitoring of the state of the cardiovascular system (blood pressure, heart rate, diuresis, ECG). To obtain a 0.01% solution (concentration 0.1 mg/ml), 50 ml of a 0.1% isosorbide dinitrate solution is diluted to obtain 500 ml of the finished solution; to obtain a 0.02% solution (concentration 0.2 mg/ml), 100 ml of a 0.1% isosorbide dinitrate solution is diluted to obtain 500 ml of the finished solution.

Contraindications

Isosorbide dinitrate preparations are not recommended for use:

• with severe arterial hypotension ;
• patients in shock;
• during collapse ;
• patients with constrictive pericarditis ;
• with hypertrophic obstructive cardiomyopathy ;
• patients with TBI , hemorrhagic stroke or simply increased intracranial pressure ;
• in acute myocardial infarction with low blood pressure ;
• with cardiac tamponade ;
• patients with toxic pulmonary edema ;
• for angle-closure glaucoma ;
• if allergic to the active substance.

Special instructions for the use of the drug Isosorbide dinitrate

To prevent hypotension and “nitrate” headache, treatment should begin with the minimum recommended dose. To prevent nitrate tolerance, it is recommended that after 3–6 weeks of regular use of tablets or capsules, take a break for 3–5 days, replacing isosorbide dinitrate with other antianginal agents during this time. Use with caution in patients with acute myocardial infarction with low filling pressures. The use of infusion for myocardial infarction should be carried out with constant monitoring of blood pressure levels to prevent its excessive decrease (below 95 mm Hg). If an infusion is used against the background of arterial hypotension, cardiotonic agents should be administered simultaneously or auxiliary devices should be used to maintain blood circulation. During pregnancy and breastfeeding, use only according to strict indications.

Side effects

After taking the drug, the following may occur:

• headache, facial flushing blood pressure ;
• dizziness, tachycardia , hot flashes and fever;
• paradoxical increase in angina ;
• dryness of the oral mucosa, burning sensation on the tip of the tongue, nausea;
• allergic skin rashes;
• decreased visual acuity, weakness and drowsiness ;
• collapse , cerebral ischemia (very rare).

Nitrates in the treatment of patients with coronary heart disease: focus on isosorbide dinitrate

V.P. LUPANOV

, Doctor of Medical Sciences, Professor,
Research Institute of Clinical Cardiology named after.
A.L. Myasnikov Russian Cardiological Research and Production Complex of the Ministry of Health of Russia The article discusses the pharmacology of nitrates and their place in the complex therapy of coronary heart disease. The mechanisms of action of organic nitrates, especially the short-acting metered-dose spray isosorbide dinitrate (ID), are shown. Indications and contraindications for its use in various forms of IHD are analyzed.

The first drugs for the treatment of angina pectoris are nitrates - drugs from the group of nitrovasodilators. In 1879, Dr. W. Murrell published in the English journal Lancet the results of using a 1% alcohol solution of nitroglycerin to relieve angina attacks and to prevent them before physical activity [1]. Until the advent of b-blockers and calcium channel blockers (calcium antagonists), nitrates were the only representatives of antianginal drugs in the cardiologist’s arsenal. Despite the recent emergence of other effective drugs, nitrates still occupy a strong position in the treatment of patients with various clinical forms of coronary artery disease [2-4].

Fast-acting nitrates are still an unsurpassed means of relieving angina attacks. They are capable of providing a short-term, but quite pronounced and reliable effect [5-7]. The advantage of short-acting nitrates is the ability not only to prevent, but also to stop an already developed attack of angina. Recently, nitrates have been created in the form of aerosols containing either nitroglycerin or isosorbide dinitrate (Isoket-spray). The advantages of nitrate aerosols are dosage accuracy, good preservation of the drug, and ease of use.

The modern classification of nitrates is based on their pharmacological structure (organic nitrates, sydnonimines), duration of action (short-acting, moderate-acting, long-acting). Nitrates are available in various pharmacological forms (for intravenous, oral, transdermal, buccal use), which significantly expands the possibilities of their use both in the stable course of cardiovascular diseases and in emergency conditions.

Currently, three drugs in this group are used: nitroglycerin (NG), isosorbide dinitrate (ID) and isosorbide-5-mononitrate (ISM), which is a natural metabolite of ID.

Classification of organic nitrates [8]:

I. Short-acting organic nitrates for relieving angina attacks:

A. Nitroglycerin group: sublingual - NG tablets; nitroglycerin alcohol solution; Votchal drops (contain nitroglycerin and menthol); spray - Nitrospray, etc. B. Isosorbide dinitrate group: Isoket spray, etc. II. Short-acting organic nitrates: A. Isosorbide dinitrate group: tablets for sublingual use: Iso Mac 5 mg, etc.; tablets for oral administration: Nitrosorbide, Izodinit, etc. B. Isosorbide-5-mononitrate group: Mono Mac; Efox et al.

Mechanism of action and pharmacological effects

The antianginal effect of nitrates in ischemic heart disease plays a role primarily in the powerful dilating effect on the coronary vessels and hemodynamic changes that arise due to the relaxation of the entire system of peripheral vessels, including dilatation of capacitive veins. All this leads to a decrease in end-systolic and distolic pressure in the left ventricle (LV); Peripheral vascular resistance also decreases, which reduces LV afterload and its filling pressure, and also improves coronary blood flow in the subendocardial parts of the myocardium, which are most sensitive to ischemia. Nitrates cause vasodilation of arterioles and veins, which forms the basis for the symptomatic improvement of angina pectoris through the action of the active component of these drugs - nitric oxide (NO) - and by reducing preload [9, 10].

By duration of action

nitrates are divided into short-acting preparations (tablets, aerosols) (up to 1 hour); regular tablets of moderate prolonged action (from 1 to 6 hours) and special tablets, capsules, as well as patches with nitroglycerin of significant prolonged action (from 6 to 16 hours).

Pharmacokinetics

According to the route of entry into the body, nitrates are distinguished, absorbed through the mucous membrane of the mouth or in the gastrointestinal tract, for cutaneous and intravenous use ( Table 1

). By dosage forms: tablets, capsules, sprays, ointments, patches, solutions, etc. The low systemic bioavailability of NG when taken orally and at the same time good absorption through the skin and mucous membranes of NG capsules explain why in recent years depots have been used less and less. (or retard) NG tablets or capsules.

Indications for use and dosage
The clinical effectiveness of nitrates for angina pectoris largely depends on which drug, in what dose and dosage form is used, as well as on the regimen of its administration [11, 12]. There are organic nitrates for every clinical situation. The variety of dosage forms of nitrates makes it possible to select an individual treatment regimen in each specific case. This, on the one hand, allows you to make maximum use of the therapeutic properties of nitrates, and on the other, minimize the risk of side effects.

Table 2

the main forms of organic nitrates and recommended doses are shown.

For proper therapy with nitrates, it is necessary to know the exact diagnosis, document the presence of myocardial ischemia and angina as its manifestations, and establish the features of its occurrence [4, 7].
Short-acting nitrates for the relief of angina attacks

.
The main representative of this group of organic nitrates is nitroglycerin
. The drug has a myotropic antispasmodic effect and directly relaxes the muscles of the coronary vessels. The central inhibitory effect on sympathetic tone plays a certain role in this. The antianginal effect of NG is also due to the restructuring of hemodynamics associated with a general effect on blood vessels, relaxation of smooth muscles of peripheral vessels, especially with dilation of veins. Under the influence of NG, venous blood flow to the heart decreases, pressure in the right atrium and pulmonary artery system decreases, and peripheral vascular resistance decreases. The myocardium is also unloaded, its tension associated with resistance to blood ejection is reduced, and the myocardial oxygen demand and energy costs are reduced. Along with the weakening of ischemia, pain impulses from the ischemic focus gradually disappear and the pain syndrome stops. It is the ability of NG to stop angina attacks and prevent their occurrence that makes it a necessary part of the treatment of patients with coronary artery disease [11].

Isosorbide dinitrate (5 mg sublingual)

helps to interrupt an attack of angina for about 1 hour due to the fact that dinitrate must undergo transformation into mononitrate in the liver in order to exhibit its antianginal effect (after about 3-4 minutes, which is longer than when taking NG). After oral administration, hemodynamic and antianginal effects persist for several hours, which provides longer-term protection against angina pectoris than after taking NG sublingually.

Isosorbide dinitrate in the form of a spray (Isoket-spray)

for spraying onto the oral mucosa, onto the inner surface of the cheek, it is successfully used to relieve attacks of angina pectoris before physical or emotional stress, which usually causes angina pectoris [12]. To do this, you need to inject the aerosol into your mouth and hold your breath. The drug is available in 15 ml glass bottles containing 300 doses of 1.25 mg ID. If after the first injection a painful attack persists, then the injection can be repeated at an interval of 30 seconds once or twice while holding your breath. If a painful attack, typical of an attack of angina, persists, then you can repeat the injection of the aerosol at intervals of 30 seconds one or two more times while holding your breath.

Isosorbide dinitrate metered spray (Isoket)

. One dose of the drug solution contains 1.25 mg of ISDN. After spraying onto the oral mucosa, the effect appears within 1-3 minutes and lasts 90-120 minutes. Directions for use: bring Isoket-spray close to your mouth, holding the bottle vertically. Take a deep breath, exhale. Next, spray 1 dose (press the sprayer) into your mouth (this may cause a slight burning sensation on your tongue). After taking 1 dose, close your mouth and breathe through your nose for 30 seconds. Each time you press the spray nozzle, an equal amount of solution will be sprayed into tiny droplets. The drug easily penetrates the oral mucosa and enters the bloodstream in a matter of seconds. Isoket spray does not contain freon and is environmentally friendly. Another advantage is the transparency of the bottle, which allows you to notice the need for replacement in time.

Indications for the use of isosorbide dinitrate spray: relief of angina attacks, prevention of angina attacks, acute myocardial infarction, acute left ventricular failure.

To relieve an attack of angina pectoris or before physical or emotional stress that can cause an attack, you need to spray it into the mouth 1-3 times with an interval of 30 seconds between injections while holding your breath. A single dose of 3 injections to relieve an attack can be increased only on the strong recommendation of a doctor.

Pharmacodynamics of nitrates are presented in Table 3

.

Isoket spray in patients with angina pectoris can be taken prophylactically in cases where there is reason to expect an attack of angina pectoris, for example, during physical activity after eating, emotional stress, sexual activity, in case of going outside in cold weather, with angina pectoris that occurs with severe and moderate loads
Under tolerance (or addiction)

understand a decrease in the duration and severity of the effect of nitrates with regular use or the need to use a larger and larger dose to achieve the same effect while maintaining a sufficiently high concentration in the blood. The cause of tolerance to nitrates is considered to be: a decrease in the formation of nitric oxide (NO), acceleration of its inactivation due to increased activity of phosphodiesterases and increased formation of endothelin-1, which has a vasoconstrictor effect [13]. The classical hypothesis is associated with an intracellular decrease in the concentration of sulfhydride (SH) groups necessary for the implementation of the effects of NO.

Tolerance to nitrates depends on the prescribed dose and duration of treatment, it reduces the effectiveness of treatment and extends not only to the antianginal and hemodynamic effects, but also to the antiaggregation effect. Tolerance (addiction), a potential problem, can be prevented by changing the dosage and timing of administration, as well as by using slow-release drugs. Habituation is a reversible phenomenon. If nitrate is removed from the body, then sensitivity to it is quickly restored. It also turned out that if long-acting nitrates are not prescribed constantly, but in such a way that a period (7-10 hours) is created during the day when the drug is not in the body, then addiction to them does not develop or develops to a lesser extent than in those cases where they are taken continuously.

Many patients need the effect of nitrates only for a very limited period (this applies to patients with exertional angina of the 1st or 2nd functional class), when they give themselves increased stress (for example, going to or from work). It is for such patients that the aerosol form of nitrates is convenient.

Patients of functional class I (FC). Attacks of angina pectoris occur rarely and only under significant loads; as a rule, they do not require constant use of antianginal drugs. Nitrates are prescribed only intermittently in short-acting dosage forms that provide a quick and pronounced effect: tablets, capsules, NT and ID aerosols. Such forms should be taken 5-10 minutes before the expected physical activity, which usually causes an attack of angina.

For patients with stable angina pectoris class II (with infrequent attacks of angina and rare episodes of myocardial ischemia during the day), intermittent administration of nitrates before situations that can cause an attack of angina is possible. Along with short-acting forms, moderately prolonged-acting forms can be used.

For patients with more severe angina pectoris class III-IV (with frequent attacks of angina and episodes of silent myocardial ischemia during the daytime and also at night), nitrates should be prescribed regularly; in such patients one should strive to maintain the effect throughout the day. For this purpose, long-acting nitrates are convenient, giving an effect lasting 10-12 hours.

For class IV angina (when angina attacks can also occur at night), nitrates should be prescribed in such a way as to ensure an effect throughout the day. For this purpose, it is more convenient to prescribe long-acting nitrates 2 times a day in the morning and evening. Since angina attacks can also occur at night, nitrates should be prescribed to ensure their round-the-clock effect, and, as a rule, in combination with other antianginal drugs, primarily b-blockers.

The effect of nitrates on quality of life.

Quality of life is an integral indicator that includes the physical, social and psycho-emotional well-being of the patient and reflects his physical, social, cognitive and sexual abilities. The immediate task of improving the quality of life is to eliminate pain, change motor activity, psycho-emotional status, etc.; The long-term goal is to improve survival and reduce hospitalizations. In many patients with stable angina, due to periodic attacks leading to significant restrictions in daily life, the quality of life is reduced due to lack of energy, insufficient sleep, decreased physical activity, and the presence of mental disorders. The effect of nitrates on the prognosis of patients with coronary artery disease has not been clearly established.

In patients with angina after an MI, nitrates are most often used in combination with ACE inhibitors, which prevent the development of tolerance.

Nitrates are used for various forms of IHD:

Unstable angina (UA)

. The use of nitrates for NS is considered a generally accepted method of treatment. Intravenous infusion of NG in most cases effectively relieves and prevents the occurrence of angina at rest. In case of acute myocardial infarction or acute left ventricular failure, Isoket spray is taken only under the control of blood pressure, heart rate and medical supervision. At the beginning, 1-3 doses at intervals of 30 seconds, if there is no effect within 10 minutes, an additional dose (only under the supervision of a physician). Intravenous infusion of ID (isoket 0.1%) is more effective for NS than oral medications.

The use of nitrates in myocardial infarction

indicated for persistent signs of myocardial ischemia, as well as for congestive heart failure.

However, nitrates should not be prescribed when systolic blood pressure is <90 mmHg. Art. or when it decreases by more than 30 mm Hg. Art. from baseline, severe bradycardia (heart rate <50 beats/min) or tachycardia (heart rate >100-110 beats/min).

When prescribing drugs with a hemodynamic mechanism of action, in particular nitrates, in elderly patients, the following rules should be observed: start treatment with lower doses, carefully monitor undesirable effects and always consider changing the drug if it is poorly tolerated and insufficiently effective.

Contraindications to the use of nitrates

They can be divided into absolute: increased sensitivity to nitrates, severe arterial hypotension, hypovolemia, left ventricular failure with low end-diastolic pressure in the left ventricle, constrictive pericarditis, hemorrhagic stroke (up to 6 months); and relative: orthostatic arterial hypotension, hypertrophic cardiomyopathy with obstruction of the outflow tract, severe stenosis of the aorta or left atrioventricular orifice, increased intracranial pressure, encephalopathy, angle-closure glaucoma with high intraocular pressure, anemia.

Side effects of nitrates

Side effects that make it difficult to use nitrates (headache, palpitations, dizziness) caused by reflex sinus tachycardia also occur when taking short-acting nitrates. Hypotension is the most serious and headache the most common side effect of nitrates.

Headaches can be relieved with aspirin, but they can also lead to loss of adherence to treatment and even refusal to take nitrates.

During nitrate therapy, drinking alcohol may provoke or worsen hypotension.

Some patients may experience ineffective treatment with nitrates due to resistance to the action of nitric oxide or intolerance to nitrates.

A potential complication of taking long-acting nitrates is worsening endothelial dysfunction, and therefore the common practice of mandatory prescribing long-acting nitrates as first-line drugs in patients with exertional angina needs to be reconsidered [14].

Drug interactions of nitrates.

They are mainly pharmacodynamic in nature and involve increased vasodilation caused by calcium antagonists (nifedipine, amlodipine, felodipine, etc.) and ACE inhibitors.

Sapropterin is a cofactor for the synthesis of nitric oxide. It is recommended to be careful when using sapropterin-containing drugs simultaneously with all vasodilating agents whose action is associated with nitric oxide (NO), including NO donors - nitroglycerin, IDN, IMN, etc.

It should be noted that when nitrates are taken simultaneously with selective inhibitors of phosphodiesterase type 5 (PDE-5) (sildenafil, vardenafil, tadalafil, etc.), prescribed in connection with erectile dysfunction or for the treatment of pulmonary hypertension, uncontrolled arterial hypotension and the appearance of myocardial ischemia due to a sharp decrease in blood flow in stenotic coronary arteries. Sildenafil reduces blood pressure by approximately 8.4/5.5 mmHg. Art. and much more when taken together with nitrates. In case of inadvertent prescribing of a combination of a PDE5 inhibitor and a nitrate, an α-adrenergic agonist or even norepinephrine may be required in the emergency setting. Nitrates cannot be prescribed with α1-adrenergic receptor blockers (prazosin). In men with prostate diseases taking tamsulosin (a1A- and a1B-adrenergic receptor blocker), nitrates can be prescribed. Nitrates should be prescribed with caution to patients with a high degree of mitral regurgitation.

Conclusion

The presence of a pronounced antianginal and anti-ischemic effect allows the successful use of short-acting Izoket-spray nitrate for the prevention and relief of angina attacks in patients with stable coronary artery disease. When using Izoket-spray, patients' tolerance to physical activity significantly increases, the number of angina attacks decreases, and the quality of life improves.

The presence of angina attacks in the absence of contraindications is an indication for the prescription of nitrates. Unfortunately, nitrates used to treat angina pectoris are not able to completely cure the disease, but they change the physiological situation in the myocardium and significantly facilitate the work of the diseased heart.

Isoket spray has been successfully used to treat various forms of coronary artery disease. It has a pronounced antianginal effect if prescribed in an adequate dose, and improves the quality of life of patients in whom angina pectoris significantly limits physical activity.

Nitrates in the form of aerosols can be used as the main antianginal agents in patients with mild angina (FC I-II). The use of Isoket-spray in aerosol form allows you to accelerate the onset of action of the active substance and reduce the time to relieve an attack compared to tablets for sublingual administration.

Nitrates only have the ability to prevent and stop attacks of angina and do not affect the course of IHD itself (the effect of nitrates on the prognosis of patients with IHD has not been proven). Therefore, patients with IHD, in addition to nitrates, need to take a number of other drugs: b-blockers, statins, aspirin, IHD inhibitors.

Literature

1. Murrell W. Nitro-glycerine as a remedy for angina pectoris.
Lancet, 1879; 1: 80-81. 2. Thadani U, Lipicky RJ. Short and long-acting oral nitrates for stable angina pectoris. Cardiovasc Drugs Ther, 1994, 8(4): 611-623. 3. Abrams J. How to use nitrates. Cardiovasc Drugs Ther, 2002, 16(6): 511-514. 4. Aronov D.M., Lupanov V.P. Differentiated use of nitrates in coronary heart disease depending on the form and severity of the disease. Cardiology, 2006, 1: 74-82. 5. Kimch A, Amsterdam E et al. Increased exercise tolerance after nitroglycerin oral spray: a new and after therapeutic modality in angina pectoris. Circulation, 1983, 67: 124-127. 6. Olbinskaya L.I., Sizova Zh.M., Ushakova A.V. Comparative effectiveness, safety, cardiohemodynamic effects of isosorbide dinitrate aerosol and sublingual nitroglycerin tablets. Ter. archive, 1998, 3: 69-72. 7. Metelitsa V.I. Handbook of clinical pharmacology of cardiovascular drugs. M., Medical Information Agency LLC, 2005: 198-203. 8. Kryzhanovsky S.A., Vititnova M.B. Medicines for the treatment of coronary heart disease (basic, clinical and evidence-based pharmacology). Lecture 2, part 1. Organic nitrates and their place in the pharmacotherapy of coronary heart disease. Therapist, 2011, 3: 38-54. 9. Munzel T, Steven S, Daiber A. Organic nitrates: update on mechanisms underlying vasodilation, tolerance and endothelial dysfunction. Vascul Pharmacol, 2014, 63(3): 105-113. 10. Lupanov V.P. Nitrates. Guide to cardiology in four volumes. Ed. acad. Chazova E.I. Ed. "Practice", 2014, 4: 688-703. 11. Mazur N.A. The role of nitrates in the treatment of cardiac patients in accordance with the principles of evidence-based medicine and recommendations for their practical use. Cardiology, 2005, 8: 92-96. 12. Silber S. Nitrates: why and how should they be used today? Current status of the clinical usefulness of nitroglycerin, isosorbide dinitrate, isosorbide-5-mononitrate. Eur J Clin Pharmacol, 1990, 38(1): 35-51. 13. Thadani U. Challenges with nitrate therapy and nitrate tolerance: prevalence, prevention, and clinical relevance journal. Amer J Cardiovasc Drugs, 2014, 14(4):287-301. 14. Lupanov V.P. Nitrates. In the book:. Rational pharmacotherapy of cardiovascular diseases: a guide for practitioners. Compendium Under the general ed. E.I. Chazova, Yu.A. Karpova. 2nd ed. corr. and additional M.: Litterra, 2015, chapter 10: 106-122. Source:
Medical Council, No. 8, 2015

Isosorbide Dinitrate, instructions for use (Method and dosage)

The substance is taken sublingually, orally, inhalation, buccally, cutaneously, or intravenous injections of the drug.

Orally, as a rule, 10 to 120 mg of the drug is prescribed, divided into 1-5 doses per day.

For buccal and sublingual use, up to 10 mg of the substance can be taken at a time. The medicine is taken at different frequencies depending on the indications.

Inhalation of the drug involves injecting 1-3 doses into the oral cavity. Between injections it is necessary to make a gap of 30 seconds, holding your breath.

To provide first aid for acute myocardial infarction or heart failure, use 1 to 3 doses. If after 5 minutes there is no improvement in the patient’s condition, then you can take the medicine again.

As a prophylactic agent during catheterization , to avoid coronary spasm, 1-2 doses of the substance are used before catheterization .

Intravenous injections are performed by medical personnel, the dosage varies, depending on the indications and condition of the patient.

The product is applied to the skin at night, 1 gram. In case of urgent need, the daily intake can be increased to 2 grams.

The course of treatment is determined by the attending physician on an individual basis.

Pharmacological properties of the drug Isosorbide dinitrate

Isosorbide dinitrate is one of the main antianginal agents from the group of organic nitrates. A peripheral vasodilator that affects primarily venous vessels. In addition to the direct coronary effect, it reduces heart function by reducing pre- and afterload, and reduces the myocardial oxygen demand. The use of isosorbide dinitrate improves coronary perfusion without developing the steal sign. Has an antihypertensive effect. It is also used as a peripheral vasodilator in severe forms of heart failure: due to a decrease in the tone of peripheral venous vessels, it reduces the load on the heart, pressure in the pulmonary vessels, shortness of breath, and suffocation. When taken orally in the form of tablets or capsules, the onset of action is noted after 15–40 minutes, the maximum effect develops after 1.5–2 hours, the total duration of action is 4–6 hours or more; when using long-acting dosage forms, the duration of action reaches 12 hours. Bioavailability is 59% after sublingual administration and 22% after oral administration. Metabolized in the liver and blood. The half-life of isosorbide dinitrate when taken orally in the form of capsules or tablets is 4 hours, when administered sublingually - 1 hour. It is excreted in the urine, almost entirely in the form of metabolites.

Overdose

In case of overdose, the following symptoms occur: anoxia , collapse , fainting and dizziness , cyanosis of nails and lips, headaches, general weakness, bradycardia , shortness of breath , increased body temperature, convulsions , diarrhea , blurred vision, decreased intracranial pressure , nausea .

As first aid, it is recommended to perform gastric lavage and use symptomatic therapy. With the development of methemoglobinemia, a solution of methylene blue 1-2 mg per kg of the victim’s weight is administered intravenously.

Overdose of the drug Isosorbide dinitrate, symptoms and treatment

The main symptoms are headache, dizziness, orthostatic hypotension, reflex tachycardia, hyperthermia, convulsions. When administered in high doses, methemoglobinemia may develop (cyanosis of the lips, nails and palms, a feeling of pressure in the head, general weakness, tachypnea). The infusion must be stopped; Place the patient in a horizontal position with raised lower limbs. If blood pressure does not return to normal, the blood volume is corrected; in severe cases, dopamine and sympathomimetics are administered. For methemoglobinemia, 1% methylene blue intravenously, oxygen therapy, mechanical ventilation are prescribed, and if necessary, an exchange transfusion is performed.

List of pharmacies where you can buy Isosorbide dinitrate:

• Moscow
• Saint Petersburg

Interaction

The substance enhances the effect and increases the plasma concentration of dihydroergotamine .

Anticholinergics lead to impairment of memory and attention, especially in older people.

When combining the drug with astringents, enveloping agents and adsorbents, the absorption capacity of isosorbide dinitrate decreases.

Simultaneous use of peripheral vasodilators, beta-blockers, antipsychotics, tricyclic antidepressants, antihypertensive drugs, calcium channel blockers, ethyl alcohol, PDE inhibitors enhances the hypotensive effect.

Sympathomimetics reduce the antianginal effect of the drug.

The medicine reduces the effect of norepinephrine .

When combined with sildenafil, myocardial infarction and a sharp decrease in blood pressure increases .

Drug interactions Isosorbide dinitrate

The hypotensive effect of isosorbide dinitrate is potentiated by other vasodilators, antihypertensive drugs, calcium ion antagonists, cyclic antidepressants, MAO inhibitors and alcohol. With the simultaneous administration of isosorbide dinitrate and dihydroergotamine, the concentration of the latter in the blood may increase, which leads to an increase in its hypotensive effect. Infusion systems made of polyvinyl chloride or polyurethane absorb isosorbide dinitrate, which requires an increase in its dose; Products made of polyethylene, polypropylene, polytetrafluoroethylene and glass do not interact with it. Isosorbide dinitrate solution is compatible with most infusion media: isotonic sodium chloride solution, 5–30% glucose solution, Ringer's solution, protein solutions.

special instructions

Particular care should be taken when treating patients with mitral or aortic stenosis , prone to low blood pressure , elderly people, and with cerebral circulatory disorders.

While undergoing therapy with the drug, you should not drive a car or perform tasks that require high reaction speed and concentration.

To avoid the development of tolerance, it is recommended to take 4 day breaks for every 3-6 weeks of using the substance.

With a gradual increase in the dosage of the drug, it is necessary to monitor blood pressure and heart rate.

Preparations containing (Isosorbide Dinitrate analogues)

Level 4 ATC code matches:
Nitrospray

Nitroglycerine

Efox

Monosan

Nitromint

Pectrol

Isoket

Erinite

Cardiket

Sustak Forte

Nitrosorbide

Trade names of Isosorbide Dinitrate: Aerosonit, Isacardin, Iso Mak spray, Isolong, Cardiket, Nitrosorbide, Nitrosorbide tablets, Dinisorb, Iso Mak retard, Isoket, Isosorbide dinitrate, Cardix, Nitrosorbide-Rusfar, TD-spray Iso Mak .