Classification and mechanism of action of nitrates. Modern views on nitrate therapy in patients with coronary heart disease Vasodilators nitrates

Esters of nitric acid (nitrates) are one of the oldest and most widely used groups of drugs for angina pectoris. The main mechanism of their antianginal action is venous dilatation, leading to a decrease in venous return, a decrease in ventricular pressure, and a decrease in myocardial oxygen demand.

Relief of an anginal attack

It is usually carried out with the help of fast-acting forms of nitrates, administered under the tongue or inhaled. For sublingual administration, nitroglycerin (0.5-1 mg) or isosorbidine (5-10 mg) is used. If the antianginal effect from the first dose is insufficient, the drug is repeated after 5 minutes.
Aerosol forms of nitrates (nitroglycerin or isosorbide dinitrate) have a good stopping effect. For example, isoket aerosol - one press on the sprayer releases 1.25 mg of isosorbide dinitrate. The solution is sprayed into the mouth. The antianginal effect occurs faster than when taking tablets under the tongue. To stop the attack, 1-3 inhalations are performed with an interval of 30 seconds. If within 5 minutes the effect is not achieved, the inhalation should be repeated. Preparations of isosorbide dinitrate, both taken under the tongue and inhaled forms, unlike nitroglycerin, have a prolonged (up to 1.5 hours) effect, so they can also be used to prevent angina attacks.

Seizure Prevention

angina With a stable course coronary disease heart therapy with nitrates is advisable to carry out, focusing on exercise tolerance. With the 1st functional class of angina pectoris, nitrates can be prescribed intermittently, before significant physical exertion. For this purpose, nitroglycerin tablets are used for taking under the tongue (given that the duration of their action is on average 15 minutes) or, if the upcoming load is long enough, they are used for a longer time. active drugs: nitrosorbide 5-10 mg for sublingual intake or isoket-aerosol. It is believed that patients with angina pectoris of the 2nd functional class, as a rule, also do not need regular intake of nitrates. They usually need to take these drugs only before increased physical or emotional activity that causes angina attacks. This is true for patients with a relatively low level of physical activity: administrators, engineering and technical workers, etc. Persons whose work is associated with significant physical exertion (builders, locksmiths, etc.) require regular intake of nitropreparations with prolonged action before starting work. Patients should be warned that if the duration of the load is longer than the duration of the expected effect of the drug, it is necessary to take the drug again in advance. For intermittent administration of nitrates in such patients, it is advisable to use dosage forms of short and medium duration actions (nitroglycerin, nitrosorbide, buccal plates of nitroglycerin, isoket-aerosol, kardiket-20). Unjustified universal appointment dosage forms long action.
Patients with angina of the 3rd and 4th functional class often need multiple intake of short-acting nitrates during the day. It is advisable for them to recommend long-acting dosage forms in order to limit the frequency of administration. However, with a low level of physical activity, and therefore rare attacks of angina pectoris, taking prolonged forms of nitrates is not necessary.
Thus, the need for taking prolonged forms of nitrates is determined, rather, by the frequency of angina attacks than by functional class.

Long acting nitrates

In the form of dosage forms used topically and orally, nitroglycerin and isosorbide dinitrate are most widely used. Nitrates taken orally are completely adsorbed in the intestine and enter the liver, where they are partially metabolized. The liver is the greatest obstacle for nitroglycerin (NG): it is almost completely metabolized into di- and mononitrates, only about 1% of trinitroglycerin enters the systemic circulation. The low bioavailability of NG and the short lifespan of metabolites with vasodilating effects limit the effectiveness of its oral dosage forms. Therefore, in order to prevent anginal attacks, NG is used in the clinic, mainly in the form of forms applied to the skin and mucous membranes (ointments, films and patches). 2% nitroglycerin ointment. When applying the ointment to the skin of the trunk and extremities, a prolonged (3-6 hours) antianginal effect is provided. Dosing is carried out along the length of the extruded ointment roller using the attached ruler. The disadvantage of this dosage form is that the individual absorption rate of nitroglycerin from the skin surface has a large variability. These shortcomings were eliminated by creating a nitro-plaster - a transdermal system that provides a continuous flow of NG at a certain rate into the bloodstream, bypassing the hepatic barrier. The patch is glued to clean areas of the skin without pronounced hairline. Used in patients who do not require high doses of nitrates. Unlike ointments, the patch provides a uniform dosed, practically independent of skin properties, intake of NG into the bloodstream. This was achieved by slowing down the rate of drug release from the system. For example, a deponit patch releases less NG than poorly permeable skin can absorb. Thus, the skin always absorbs as much NG as the patch releases it. Dosing of the injected NG is carried out due to the size of the surface of the adhesive patch. The drug is produced in two dosages: deposit 5 and deposit 10, releasing during the day, respectively, 5 and 10 mg of NG. The maximum effect develops after 2-3 hours. The duration of a distinct antianginal action is 7-8 hours, followed by a gradual decrease in activity throughout the day. The nitro patch is designed for 24-hour wear and is usually applied to the skin once a day. If there are no angina attacks at night and early in the morning, it is advisable to remove it in the evening. The bioavailability of isosorbide dinitrate (ISDN) when taken orally is ten times higher than that of nitroglycerin. The pronounced and prolonged antianginal effect of ISDN preparations and its metabolite isosorbide-5-mononitrate led to their most widespread use for oral administration.

ISDN preparations (nitrosorbide, kardiket, etc.).
20 mg is the minimum effective dose when taken orally (5 and 10 mg of ISDN can achieve therapeutic concentrations in the blood only when taken sublingually). With this dose, treatment is usually started. The antianginal effect of ISDN increases with increasing dose. Therefore, with insufficient therapeutic effect, it is advisable to increase the single dose of ISDN to 30-40-60 mg (Fig. 3). The approximate dosage of ISDN for angina pectoris of varying severity is presented in Table 1. It is well known that patients respond differently to equal doses of the same drug. However, individual sensitivities are ignored and drugs are usually prescribed in a pattern, 1 tablet 3-4 times a day. It should be taken into account that the choice of the dose of ISDN is determined not only by the severity of angina pectoris, but also by the state of hemodynamics. Patients with high blood pressure filling of the left ventricle (LVDN) is well tolerated by nitropreparations: an increase in the dose of nitrates is accompanied by a decrease in peripheral resistance in a large circle and an increase in stroke output, blood pressure does not change. In patients with normal or reduced LVDN, as a result of venous dilatation under the influence of nitrates and deterioration of left ventricular filling, stroke output, systolic blood pressure decrease, peripheral resistance does not change or slightly increases. To determine the maximum effective dose of nitrates in a particular patient, it is recommended, by measuring the initial systolic blood pressure, to give the drug and repeat the measurement after 1-2 hours, at the peak of the manifestation of the hemodynamic effect of the drug. If systolic blood pressure decreases by 10-15 mm Hg, then this dose should be considered the maximum for this patient. Its further increase usually does not increase the antianginal effect, and the likelihood of side effects becomes high. If no decrease has occurred and there are no side effects, a single dose should be increased to enhance the antianginal effect.

Table 1 Approximate dosage of ISDN in the treatment of patients with angina pectoris

angina pectoris	A drug	Multiplicity of reception	Duration of action per day with a single dose
I - Ordinary physical activity does not cause angina Attacks rarely occur only with high-intensity exercise	Nitroglycerin 0.5mg sublingually or spraying 1-2 doses of isoket before oral aerosol loading	During an attack or for its prevention before exercise, usually causing angina pectoris	Nitroglycerin-15 min, isoketaaerosol - up to 15 hours
I I- The disease causes minor restrictions on physical activity, anginal pain occurs during normal exertion	Cardicket retard 20 Cardicket retard 40	1-3 times 1-2 times	5 o'clock up to 7 hours
III - a marked limitation of physical activity, angina pectoris occurs with little physical exertion At rest, the state of health is good	Cardicket retard40 Cardicket retard 60 Cardicket retard 120	2-3 times 1-2 times once	6-7 hours 8 ocloc'k 14-15 hours
IV - any physical activity is difficult due to anginal pain, angina may even at rest	Cardicket retard 40 Cardicket retard 60 Cardicket retard 120	3-4 times 2-3 times once	up to 6 hours up to 8 hours 14-15 hours

If the severity of the achieved antianginal effect satisfies the doctor and the patient, then it is not necessary to continue increasing the dose, even if there is no decrease in blood pressure. Signs of left ventricular failure (shortness of breath during seizures, ECG signs overload of the left atrium and ventricle) are eliminated more quickly and reliably when taking 40 and 60 mg of ISDN (see Fig.). The venous system expands to the maximum after taking 20 mg of ISDN (Fig. 4).

Arterial dilation begins at relatively low doses of nitrates and increases as the dose increases. A progressive decrease in afterload facilitates the ejection of blood by the left ventricle, leads to a decrease in stagnation and an increase in the rate of blood circulation in the pulmonary circulation, and an increase in lung capacity. Treatment of patients with a low frequency of angina attacks (less than 10 per day) begins with a single dose of ISDN 20 mg. With insufficient effectiveness, a single dose is increased: 30, 40, 60 mg.

With a greater frequency of seizures, therapy is usually started with a single dose of 40 mg. In patients with angina pectoris and signs of LV failure, a single dose of 60 mg is more commonly used.
The frequency of taking the drug is determined by the duration of its action and the duration of the time interval during which it is necessary to ensure an increase in exercise tolerance. With an increase in the dose of ISDN, an increase is noted not only in the severity, but also in the duration of the antianginal action. Anti-anginal action after a single dose of kardiket 20 is clearly expressed for 5 hours. The duration of the antianginal action of kardiket 40 averages 6.5, and kardiket 60 - 8 hours. Based on the need, the frequency of taking kardiket can be from 1 to 5 doses per day. The daily dose, if necessary, can reach 200-240 mg.
Cardiquet-120 is a different dosage form from Cardiquet 20,40 and 60. The fundamental difference of the drug is that it contains two fractions: a rapidly soluble fraction, which ensures the achievement of a therapeutic concentration in the blood after 20 minutes, and a supporting, delayed release of which prolongs its action. Biphasic release of ISDN from this dosage form provides a stable concentration of the drug in the blood and antianginal effect for 14-15 hours, gradually disappearing by the end of the day. In terms of antianginal effect, it is equivalent to 3 doses during the day of kardiket 20. The drug is very convenient and well tolerated. Cardiket-120 is taken 1 time per day.

Isosorbide-5-mononitrate (IS-5-MN), the main metabolite of ISDN, has become widely used for the treatment of stable angina. Its advantages are high (close to 100%) bioavailability and the fact that the mononitrate itself has a long-lasting antianginal effect. Its most famous representatives are drugs: efox, monocinque and olicard.
Tablets containing 20 mg of isosorbide-5-mononitrate - monophasic drug. The prolongation of the effect is provided by the properties of the active substance. It is intended for the prevention of angina attacks. Therapeutic concentration is reached in 30 minutes. The duration of antianginal action is up to 8 hours. It is applied according to the need, usually 1-2, less often 3 times a day. The antianginal effect is equivalent to 20 mg of ISDN.

Tablets containing 50 mg of isosorbide-5-mononitrate (efox long, monocinque retard) - a dosage form with a delayed release of the drug. Provides a protective effect throughout the active part of the day (up to 16 hours). This form of the drug is intended for a single daily dose for a long period of time (years). The severity of antianginal action is equivalent to 20 mg of ISDN. When choosing between the use of ISDN or IS-5-MN, it must be taken into account that the prolonged forms of IS-5-MN, despite the increase in the content of the active substance in them, provide a longer duration of antianginal action, but its strength. IS-5-MN tablets, not containing a slowly dissolving phase, are equivalent in antianginal effect to an equal dose of ISDN

International name:

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Deposit 10

International name: Nitroglycerin (Nitroglycerin)

Dosage form: sublingual metered aerosol, sublingual drops, sublingual capsules, prolonged-release capsules, concentrate for solution for infusion, films for sticking on the gums, sublingual dosed spray, sublingual tablets, t

Pharmachologic effect: Venodilator from the group of nitrates. Nitrates are able to release nitric oxide from their molecule, which is a natural endothelial ...

Indications: IHD: angina pectoris (treatment, prevention), myocardial infarction (rehabilitation). For intravenous administration - acute myocardial infarction (including complicated by acute ...

Deposit 5

International name: Nitroglycerin (Nitroglycerin)

Pharmachologic effect: Venodilator from the group of nitrates. Nitrates are able to release nitric oxide from their molecule, which is a natural endothelial ...

Indications: IHD: angina pectoris (treatment, prevention), myocardial infarction (rehabilitation). For intravenous administration - acute myocardial infarction (including complicated by acute ...

Dilkoran 80

International name: Pentaerythrityl tetranitrate (Pentaerithrityl tetranitrate)

Dosage form: tablets

Pharmachologic effect: Venous vasodilator, has an antianginal effect. Stimulates the formation of nitric oxide in the wall of blood vessels, which is an endothelial ...

Indications: IHD, angina pectoris (prevention, including in the post-infarction period); CHF (as part of complex therapy).

Dinite

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Pharmachologic effect:

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Dinitrosorbilong

International name: Isosorbide dinitrate (Isosorbide dinitrate)

Dosage form: sublingual metered aerosol, capsules of prolonged action, concentrate for solution for infusion, films for sticking on the gums, sublingual metered spray, tablets, tablets of prolonged action, transdermal

Pharmachologic effect: Peripheral vasodilator with a predominant effect on venous vessels. Stimulates the formation of "first pass" nitric oxide (endothelial...

Indications: Angina pectoris (stopping and prevention, including unstable angina), acute myocardial infarction (including complicated by acute left ventricular ...

ditrate

International name: Isosorbide dinitrate (Isosorbide dinitrate)

Pharmachologic effect: Peripheral vasodilator with a predominant effect on venous vessels. Stimulates the formation of "first pass" nitric oxide (endothelial...

Indications: Angina pectoris (stopping and prevention, including unstable angina), acute myocardial infarction (including complicated by acute left ventricular ...

From 5 mono-Ratiopharm

International name: Isosorbide mononitrate (Isosorbide mononitrate)

Dosage form: long-acting capsules, tablets, long-acting tablets

Pharmachologic effect: Peripheral vasodilator with a predominant effect on venous vessels. Stimulates the formation of nitric oxide (endothelial relaxing...

There are few long-lived drugs in modern pharmacology that can compete with nitroglycerin, which was discovered in 1847 by the Italian Ascanio Sobrero. True, initially nitroglycerin found not at all medical application- in 1851, Alfred Nobel invented dynamite on its basis, another long-lived substance that is still used in the national economy and in military affairs. Over time, as medicine and pharmacology develop, nitroglycerin becomes one of the main drugs for the treatment of angina pectoris. And today, nitroglycerin is widely used in the treatment of coronary artery disease, due to its extremely fast and effective action, which makes it to this day the main drug for the relief of angina attacks.

Nitrates are used as antianginal agents for the treatment of unstable and vasospastic angina. In / in dosage forms of nitrates are prescribed for acute MI.

Nitrate classification:

Trinitrates: nitroglycerin; nitroglycerin depot preparations.
Isosorbide dinitrates: nitrosorbide, kardiket, kardiket retard, isoket.
Isosorbide-5 mononitrates.

Classification of nitrates by time of action:

short-acting (up to 1 hour) - aerosols of nitroglycerin and isosorbide dinitrate, ensure good preservation of the active substance, provide a quick effect;
moderately prolonged action (1-6 hours) - tablet preparations of isosorbitol dinitrate (kardiket, kardiks, iso-mac retard), begin to act after 10-20 minutes, the duration of the effect is an average of 3-4 hours;
significantly prolonged action (6-24 hours) - retard forms of isosorbide dinitrate and isosorbide-5-mononitrate.

Classification of nitrates by the nature of the dosage form:

absorbed through the oral mucosa - nitroglycerin tablets under the tongue, aerosols of nitroglycerin and isosorbide dinitrate, which have a quick and reliable effect;
for oral administration - various tablets, capsules of isosorbitol dinitrate, nitroglycerin, isosorbitol mononitrate;
cutaneous application - ointments and patches of nitroglycerin (lost their clinical significance);
intravenous injections - ampoules with a solution of nitroglycerin and isosorbide dinitrate (perlinganite 0.1% - 10 ml; isoket 10 ml) are dissolved in 200 ml of glucose, injected intravenously at a rate of 10 drops / min.

The mechanism of action of nitrates is the formation of nitric oxide, which has a vasodilating effect. The effect of the use of nitrates is to dilate the veins and reduce the preload on the heart, thereby reducing myocardial oxygen demand. In addition, nitrates have a direct coronary dilating effect. Higher doses of the drug cause dilation of the arteries, even larger ones lead to the expansion of arterioles and the development of systemic hypotension.

In patients receiving transdermal dosage forms of nitrates, which maintain a uniform concentration throughout the day, addiction (tolerance) to nitrates (tachyflaxia) may occur. Tachyflaxia develops especially rapidly with intravenous administration - the first signs of tolerance can be observed 10-12 hours after the start of administration. In most cases, nitrate tolerance is lost after discontinuation of the drug. At the time of development of tolerance, the load should be reduced, replaced with other antianginal drugs. ACE inhibitors, captopril can somewhat reduce the development of tolerance to nitrates.

Fundamentals of Nitrate Therapy

with angina pectoris of functional class I (FC), pain occurs only against the background of significant physical exertion: nitrates are prescribed before exercise; nitroglycerin is taken 5 minutes before the load, the preparation of isosorbide dinitrate - 1 hour before;
with angina II FC, it is also possible to take nitroglycerin before exercise, with frequent attacks take an extended form of the drug;
with angina pectoris III FC, drugs with a duration of action of up to 12 hours are indicated (for daytime attacks, the drug is taken in the morning);
with IV FC angina pectoris, it is necessary to provide an antianginal effect during the day: isosorbide-5-mononitrate forms are used with a duration of action of 16 hours; it is believed that the lack of effect of nitrates within 8 hours will prevent the development of tolerance to them.

Contraindications to the appointment of nitrates:

absolute contraindications: arterial hypotension (BP less than 90/60 mm Hg), hypovolemia, shock, cardiac tamponade, right ventricular myocardial infarction, left ventricular failure with low filling pressure, hypersensitivity to nitrates;
relative contraindications: increased intracranial pressure, hypertrophic cardiomyopathy, severe aortic stenosis, mitral stenosis, tendency to orthostatic arterial hypotension, angle-closure glaucoma;

The classic attack of angina pectoris is stopped by short-acting dosage forms of nitroglycerin and isosorbide dinitrate (a tablet of nitroglycerin 0.5 mg under the tongue stops the attack within 1-3 minutes, provided that the factors that provoke the attack itself cease to act). The maximum effect occurs after 5-6 minutes, the total duration of the drug when taken sublingually does not exceed 10-20 minutes. If there is no effect, it is recommended to repeat the drug after 5 minutes. To stop an attack of angina pectoris, a short-acting form of nitrosorbide 10 mg can be used.

The advantage of sublingual administration of nitroglycerin is that the active substance is rapidly absorbed through the oral mucosa, bypassing the liver, immediately entering the systemic circulation.

Patients with angina pectoris, in the event of seizures due to physical exertion, are recommended sporadic intake of nitrates (nitrates of short or moderately prolonged action are used) - immediately before physical exertion.

Patients who have a severe course of the disease (angina attacks occur with small physical activity or at rest) prescribe drugs with a moderately or significantly prolonged action in order to ensure their antianginal effect during the day.

In the treatment of coronary artery disease, a withdrawal syndrome is possible (deterioration of the condition of patients with a sharp cessation of nitrates).

Side effects(most often develop during the first application, due to severe dilatation of the intracranial veins and obstructed outflow of blood from the brain):

promotion intracranial pressure, the appearance of throbbing headaches, a feeling of fullness in the head, tinnitus, flushing of the face;
typical side effect- tachycardia, which is especially pronounced with nitrate monotherapy (tachycardia is leveled by beta-blockers, calcium channel blockers (verapamil, nicardipine, amlodipine, but not nifedipine);
a rare side effect is bradycardia, which can occur with the on / in the introduction of nitroglycerin against the background of a pronounced decrease in blood pressure (atropine is used for correction);
intermittent side effect - increased intraocular pressure;
possible heartburn, nausea, vomiting, diarrhea;
rarely seen allergic reactions, often in the form of a skin rash;
high doses may cause methemoglobinemia;
exacerbation of myocardial ischemia may occur in patients with angina in combination with anemia;
a sharp decrease in blood pressure, tachycardia, chest pain, nausea, vomiting, anxiety, accumulation of cyanides with the development of deadly hypoxia can cause sodium nitroprusside.

drug interaction

nitrates are incompatible with Viagra;
the ability of nitrates to reduce blood pressure is enhanced in combination with vasodilators, narcotic analgesics, with alcohol;
the hypotensive effect of nitrates is enhanced in combination with vasodilators, antihypertensive drugs, ACE inhibitors, beta-blockers, calcium antagonists, procainamide, tricyclic antidepressants, MAO inhibitors, diuretics, ethanol;
a sharp decrease in blood pressure may occur when nitrates are combined with sildenafil, other phosphodiesterase inhibitors;
orthostatic collapse can develop while taking quinidine and novocainamide;
increased blood pressure - in combination with dihydroergotamine;
the combination of nitropreparations with heparin can cause a decrease in the effectiveness of the latter, which may require an increase in its dose.

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Nitrovasodilators combine drugs whose effects are associated with the formation of nitric oxide (NO): glycerin trinitrate, isosorbide di- and mononitrate, sydnonimines. In 1879, nitroglycerin was first used for angina pectoris. Since then, nitrates have remained an important drug in the treatment of coronary artery disease. In 1998 R.F. Furchgott, L.J. Ignarro, F. Murad was awarded the Nobel Prize for elucidating the role of NO as a physiological endothelium-dependent relaxation factor that determines vascular tone. NO deficiency plays a significant role in the pathogenesis of coronary artery disease, arterial hypertension, heart failure, diabetes Type II, which allows us to consider nitrates as replacement therapy drugs.

Keywords: glyceryl trinitrate, isosorbide dinitrate, isosorbide 5-mononitrate, sydnonimines, tolerance, pharmacokinetics, side effects.

THE MECHANISM OF ACTION OF NITROVASODILATORS

The mechanism of action of nitrates at the cell level is identical to the effect of the endothelial relaxation factor. In the presence of endothelial dysfunction, an imbalance occurs between the relaxing and contractile factors produced by the endothelium in case of a deficiency (with the exception of septic shock) of the formation of endogenous nitric oxide. Nitropreparations act as exogenous nitric oxide donators. NO stimulates soluble guanylate cyclase with the assistance of free calcium ions and calmodulin. In the presence of guanylate cyclase, cyclic guanosine monophosphate (cGMP) is formed from guanosine triphosphate, the calcium-ATPase transporting sarcoplasmic reticulum is stimulated, calcium intake into the sarcoplasmic reticulum increases and its concentration in the cytosol decreases. The result of a decrease in intracellular calcium concentration is the relaxation of the muscle cell. Thus, exogenous organic nitrates replace the deficiency of its own endogenous NO.

The main effects of nitrates are the relaxation of the smooth muscles of the vascular wall, the gastrointestinal tract and other organs. Vasodilatory effect organic nitrates leads to a significant decrease in pre- and afterload of the ventricles and, as a result, to a significant decrease in the work of the heart and myocardial oxygen consumption.

The greater tropism of nitrates to the venous wall than to the arterial wall determines the most pronounced effect of nitrates on venous capacitive vessels, especially in the visceral regions and extremities. In patients with a good anti-ischemic effect of nitrates, there is a decrease in the end-diastolic volume of the left ventricle at rest by an average of 25% and during exercise - by 19%. These changes in the volumes of the heart chambers contribute to an increase in the ejection fraction (EF) of the left ventricle at rest (from 50% to 60%) and during exercise (from 36% to 48%) after taking sublingual NTG and a single dose of 80 mg of ISDN in sustained release forms. (from 52% to 64%).

As a result of a decrease in preload and filling of the heart chambers, the tension of their walls decreases, blood circulation improves in the subendocardial and intramural areas of the myocardium during

diastole, blood supply to ischemic areas of the myocardium increases. An additional anti-ischemic effect of nitrates is provided by dose-dependent coronary vasodilation. Nitrates dilate coronary collateral vessels and increase coronary blood flow, while there is no coronary steal syndrome.

Nitrates expand the lumen of the subepicardial coronary arteries in places of eccentric stenosis with partially preserved vascular smooth muscles; do not have a significant vasodilating effect on stenosing areas due to concentrically located atherosclerotic plaques. With sublingual administration of NTG, the cross-sectional area of normal coronary arteries increases by 20%, and with its intracoronary administration, by about 40%. In moderately stenotic segments (68% on average), intracoronary nitroglycerin increased the cross-sectional area of the vessel by 40%, and in severe stenoses (85%), by 36%. The good vasodilating effect of ISDN in comparison with IGT is supplemented by its greater efficiency in the post-stenotic areas of the coronary arteries and a longer duration of action.

There is evidence of the possibility of restoring the function of the endothelium after the introduction of small doses of nitrates that are not capable of exerting an independent hemodynamic effect.

For nitrates, an antiplatelet effect is shown due to the effect on intracellular guanylate cyclase.

Nitric oxide (NO) produced by intact endothelium creates an antithrombotic barrier over the endothelium. When the endothelium is damaged, the nature of the reaction of vessels to vasodilating substances changes. Histamine, acetylcholine and 5-dihydroxytryptomine increase coronary spasm, causing paradoxical vasoconstriction. Over the area with damaged endothelium, the nature of the blood flow changes, promoting adhesion and aggregation of platelets.

The role of nitrates is to donate free NO-groups, which increase the synthesis of cyclic guanosine monophosphate (cGMP). CGMP blocks slow calcium channels, preventing the entry of calcium ions into cells (platelets) from the extracellular environment, exerting an antiaggregatory effect due to inhibition of the receptor-dependent increase in the level of intracellular

calcium, which may manifest as a reduction in primary thrombosis, regardless of the hypotensive effect, having a systemic effect on aggregation.

Moreover, NTG infusion reduced rethrombosis after thrombolysis. Y.Y. Chirkov et al. note that the antiplatelet effect of NTG in vitro manifests itself at low, clinically attainable concentrations. However, in patients with angina, the sensitivity of platelets to sources of NO in vivo reduced hundreds of times due to the lower ability of platelets to respond even to elevated levels of cGMP and their increased ability to aggregate. The antiaggregation effect was found for all groups of nitrates:

NTG, ISDN, IS5MN.

One possible explanation for the antiplatelet effect of nitrates is synergism with prostacyclin at the site of its local production. It is known that prostacyclin, being an activator of adenylate cyclase, increases the level of cyclic adenosine monophosphate (cAMP). An increase in the concentration of cAMP in platelets causes blocking of the receptor-dependent increase in the concentration of calcium, which also prevents their adhesion and aggregation.

The chemical structure of sydnonimines differs significantly from that of organic nitrates. The presence of several nitrogen atoms in the molsidomine molecule, the similarity of the mechanism of action gave reason to combine it with nitrates into one group called nitrovasodilators (“nitrate-like” drug).

The lower risk of developing tolerance to molsidomine compared to nitrates with regular use indicates some advantages over organic nitrates.

Molisidomine is a member of the sydnonimines.

Dosage forms of the drug - tablets for sublingual, oral administration, ampoules for intravenous administration.

Sydnonimines belong to the group of nitrovasodilators due to a similar chemical structure (presence of several nitrogen atoms) and hemodynamic (vasodilating) effects.

CONVERSION OF NITROVASODILATORS TO NITRIC OXIDE

Nitrates act as a substitute for an endothelium-dependent relaxing factor in endothelial dysfunction. Endothelium dependent relaxing factor (EDRF) was discovered in 1980 by R.F. Furchgott, who noticed that isolated vascular segments relaxed under the influence of acetylcholine only with preserved endothelium. The role of thrombin, serotonin, bradykinin in vasodilation was revealed. It turned out that it is mediated by the release of EDRF. A clue to the structure of EDRF has been found through the similarity between EDRF activity and vasodilation by nitrates.

EDRF, like HTN and sodium nitroprusside (NP), stimulates soluble guanylate cyclase (GC), resulting in increased cellular release of cGMP. This is the identity of the molecular mechanism of action of EDRF and organic nitrates.

Nitrates are denitrated in smooth muscle cells vascular wall with the formation of NO or a closely related nitrosothiol variety.

Under physiological conditions in the endothelial cell, the enzyme NO-synthetase in the reaction of N-hydroxylation releases nitric oxide from the water-soluble part of the L-argenin molecule, converting NO, if it is formed in sufficient quantities, into nitrosothiol, which is a storage form of NO and has 100 times more activity than NO in relation to the activation of guanylate cyclase.

In order to become pharmacologically active, organic nitrates must be converted to nitrites.

There are two ways of NO formation from organic nitrates: enzymatic and non-enzymatic. In the enzymatic pathway, this reaction is catalyzed by glutathione reductase of organic nitrates. The same reaction can proceed without enzymes in the presence of thiols, in particular cysteine, as well as thiosalicylic acid and glutathione. Nitrates are in equilibrium with nitrous acid, which reacts with other thiols to form nitrosothiols. The rate of this reaction is slow at pH 7.4 and increases at low pH values. Nitrosothiols, as well as NO, stimulate guanylate cyclase, thus causing smooth muscle cell relaxation.

The final step in the participation of cGMP in reducing the tension of the smooth muscle wall, apparently, is protein phosphorylation and interference with calcium metabolism on the sarcolemmal membrane.

Nitrates are prodrugs that are denitrated inside the smooth muscle cell of the vessel to the active form - nitric oxide. NO, identical to EDRF, induces vasodilatation, inhibits platelet aggregation, reduces platelet adhesion, and has an anticoagulant and fibrinolytic effect.

The pathway of transformation of sydnonimines is similar to that of nitropreparations. In the final stage of the conversion of sydnonimines, nitric oxide is formed. The conversion of sydnonimines does not require the presence of sulfhydryl groups necessary for the same conversion of organic nitrates, which excludes the deficiency of sulfhydryl groups as one of the ways to develop tolerance to the drug with long-term regular use.

CHARACTERISTICS OF NITRATE DOSAGE FORMS

Organic nitrates are represented by three pharmacologically active substances: glyceryl trinitrate, or nitroglycrin (NTG), isosorbide dinitrate (ISDN) and the active metabolite of isosorbide dinitrate - isosorbide-5-mononitrate (IS5MN).

There are parenteral, aerosol, transdermal, buccal and oral forms of NTG and ISDN. Two active denitrated metabolites of ISDN - isosorbide-2-mononitrate (IS2MN) and isosorbide-5-mononitrate (IS5MN) - are comparable in effectiveness with ISDN and are used both in emergency cardiology (parenteral solutions of IS2MN, IS5MN) and in the prevention of angina attacks ( regular and sustained release oral dosage forms of IC5MN). The validity of the use of nitrates in the treatment of patients with coronary artery disease is determined by their high efficiency in stopping angina attacks and preventing episodes of painless myocardial ischemia. A significant decrease in the number of angina attacks, a decrease in 5G-segment depression against the background of pain and painless episodes were revealed.

ischemia with the use of sublingual, parenteral and transdermal forms of NTG, parenteral administration of ISDN, IS5MN, regular and sustained release forms.

Dosage forms of NTG and ISDN are used for the prevention and relief of anginal pain; dosage forms of IS-5-MN are used only to prevent seizures.

Currently, there are three dosage forms of NTG that provide prolongation of its action:

1) oral microencapsulated;

2) application (on the mucous membrane or skin);

3) injection (solution for intravenous administration). ISDN is a medium-acting nitrate.

The hemodynamic and antianginal effects of ISDN are associated with the action of its metabolites (IS2MN and IS5MN). Dosage forms of ISDN are represented by infusion solutions, oral forms regular and sustained release (tablets and capsules with sustained release). There are transdermal therapeutic systems for ISDN (plasters, disks) that provide controlled release and entry of the drug through the skin.

Isosorbide-5-mononitrate is an active metabolite of ISDN resulting from the first pass metabolism of ISDN. The ratio of the values of the level of ISDN and its metabolites - IS2MN and IS5MN - in blood plasma after a short time is 1:4:18, respectively. IS2MN is a "short-lived" ISDN metabolite. IS5MN has an extended duration of action, which gives a prolongation of antianginal and antiischemic effects. IS5MN preparations are presented in oral dosage forms of regular release and sustained release (matrix tablets, capsules with microgranules of the substance), providing a prolonged action, as well as solutions for intravenous administration.

FEATURES OF PHARMACOKINETICS

NITROVASODILATORS

Nitrate preparations: glyceryl trinitrate (nitroglycerin) isosorbide dinitrate and its main long-acting metabolite

Isosorbide-5-mononitrate - the most commonly used in clinical practice, differ from each other in pharmacokinetic parameters (Table 12.1).

Table 12.1

Comparative pharmacokinetic characteristics of nitrates

Nitrates, when administered sublingually or buccally (on the gums), are well absorbed through the mucous membranes of the oral cavity, are practically not metabolized during the first passage through the liver, and quickly penetrate into the systemic circulation and coronary vessels.

When ingested, nitrates are well absorbed through the intestinal mucosa, penetrate into the portal system of the liver, but then undergo a rapid and intensive metabolism during the first passage through the liver. In the body, they are denitrated either into mononitrates or glyceryls and then form conjugates with glucuronic acid, which are excreted from the body.

Pharmacokinetics of NTG. When taking 0.5 mg under the tongue, NTG is determined in the blood after 5 seconds, the maximum concentration is reached after 5 minutes and is 3 ng / ml, and after 7.5 minutes it is 1.4 ng / ml.

The bioavailability of the sublingual form of NTG is 50%. NTG has a large volume of distribution, is subject to first pass metabolism, is rapidly metabolized in the liver by denitration by glutathione reductase, located in the liver cells and erythrocytes. As a result, glyceryl dinitrate, which has vasodilating activity, and mononitrate are formed, which are further degraded to glyceryl and eliminated in the urine as glucuronides. The total clearance of NTG is 25-30 l / min, the half-life (T 1/2) is 2-5 min.

Transdermal forms (TTS NTG), used at a dose of 0.5 square meters. cm / kg, maintain an effective concentration of the drug in the blood plasma, equal to 0.5-1.0 ng / ml.

The duration of NTG action is short (10-30 min), there is a good correlation between the concentration of the drug in the blood and heart rate, systolic blood pressure, left ventricular function.

important place in the treatment emergency conditions in cardiology belongs to the dosage form for intravenous infusions, which allows you to quickly achieve a controlled clinical effect and, if necessary, quickly reduce or stop the effect of the drug.

Intravenous infusion of nitroglycerin starts at 10 µg/min and increases by 5-10 µg/min every 5-10 minutes until the desired hemodynamic effect is obtained. Clinical effect may be delayed. An infusion rate of 30-40 µg/min mainly causes venodilation, 150-500 µg/min leads to arteriole dilatation. There are no recommendations on the maximum possible dose of nitroglycerin, but it usually does not exceed 200 mcg / min.

Pharmacokinetics of ISDN. Isosorbide dinitrate is rapidly and completely absorbed both when taken sublingually and in the gastrointestinal tract after oral and cutaneous application. When taken orally, the drug substance is detected in the blood after 15-20 minutes, reaching a maximum concentration after an hour. A single dose of 10 mg of the drug creates a concentration of ISDN in the blood of 6.7 ng / ml; with prolonged use, the concentration of the drug in the blood increases. When ingested, ISDN undergoes rapid and extensive metabolism during its first passage through the liver. In the biophase, three substances act with different kinetics and, as a result, different vasodilating effects.

The bioavailability of ISDN with sublingual administration is 59%, with oral administration - 22% (1-75%), with the use of TTS - 93%. When using TTS with ISDN at a dose of 0.5-1.0 cm 2 /kg, the concentration of ISDN in blood plasma is 3-5 ng/ml.

ISDN is characterized by high variability in serum concentrations, so there is a poor correlation between the administered dose, serum concentration and pharmacological effect. A large area under the concentration-time curve (AUC) is detected with constant administration of the drug. The volume of distribution is 600 liters, about 30% of ISDN is protein bound.

The half-life after a single injection is 30-60 minutes, after repeated administration - about 7 hours, therefore, non-linear kinetics are observed due to inhibition of the product by the resulting metabolites. The duration of action for sublingual use is 36-60 minutes, for oral administration - 180-360 minutes.

Pharmacokinetics of IS5MN. IS5MN in regular release tablets is quickly and completely absorbed in the gastrointestinal tract and is detected in the blood after 15-20 minutes, reaching a maximum concentration in an hour (436 ng / ml). The effective therapeutic plasma concentration (over 100 ng / ml) lasts 10-13 hours. The absence of the “first pass” effect ensures 100% bioavailability after oral administration. In the biophase, only one active substance with a certain kinetics acts. IS5MN is characterized by relatively low coefficients of variability in serum concentration, therefore, there is a good correlation between the administered dose, the achieved concentration in blood serum and the pharmacological effect. The area under the curve "concentration - time" with a constant intake of IS5MN at a dose of 2 x 20 mg is 5843 ng / ml x hour.

After denitration or conjugation in the liver, IS5MN is excreted in the urine mainly in the form of isosorbide (37%), D-sorbide (7%), IS5H-glucuranide (25%), about 2% is excreted through the kidneys unchanged and about 1% is excreted with feces. T 1/2 after a single and repeated administration does not change (4-5 hours), so there is a strictly linear and dose-corresponding kinetics (no inhibition of the product).

The use of the pharmacokinetic advantages of IS5MN made it possible to develop drugs with a delayed release of the substance (retard forms), which allows them to be taken once a day and most fully meets the requirements for medicines for the treatment of IBS.

Due to the high bioavailability and the characteristic dynamics of plasma concentrations that maintain the therapeutic level active substance during the active period of the day, subject to the subthreshold level at night (fluctuating dynamics of plasma concentration), IS5MN retard forms meet the following most important requirements of therapy:

Rapid onset of drug action, dose-dependent effect;

Reliable long-term protection of the patient during the active part of the day;

Improving the patient's compliance with treatment with a daily single dose of the drug (compliance with the patient's regimen and treatment regimen).

Pharmacokinetic characteristics of the retard forms of IS5MN with a high degree of probability guarantee the absence of the development of tolerance to the drug.

Transdermal nitrate therapeutic systems (TTS). Along with oral prolonged forms of antianginal drugs, TTS were created - application dosage forms for long-term continuous administration of a drug into the bloodstream through intact skin with controlled release of the active principle according to a predetermined kinetic program. Providing TTS to achieve and maintain the concentration of the drug in the blood at a constant, close to the minimum therapeutic level throughout the entire period of application allows for effective maintenance therapy and prevention. chronic diseases. It should be taken into account that a change in regional blood flow at the site of patch attachment affects the rate of entry of the active substance from the TTS reservoir into the systemic circulation. The use of TTC to deliver rapidly metabolized drugs, such as nitroglycerin, to the bloodstream can replace the frequent use of pills and increases the reliability of preventing angina attacks. TTS are presented in the form of ointments,

patches and discs with different technological characteristics.

The disadvantage of cutaneous application of nitrates (ointment forms, discs, patches) is that their use is accompanied by unstable bioavailability of the drug.

At long-term use dosage forms of nitrates of the prolonged action the probability of development of tolerance is high.

molsidomine able to be absorbed from the oral cavity. After oral administration, it is rapidly and completely absorbed in the intestine. Bioavailability after oral administration is 60-70%. About 30% of the drug is converted to various metabolites (most pharmacologically active) during the first passage through the liver. The onset of action of the drug after oral administration is 15-20 minutes. Eating slows down the onset of action without affecting the total bioavailability. The peak concentration of the drug is reached after 30-60 minutes and ranges from 10 to 15 ng / ml. In liver diseases, the maximum concentration of the drug in the blood can increase significantly. After 6 hours after oral administration, regular release tablets in the blood are determined only by residual concentrations of the substance. The duration of antianginal action after taking 2-4 mg of the drug orally averages 3-4 hours, may vary significantly in different patients (from 1 to 6 hours). Effective doses are 2 mg in 30-40% of patients, 4 mg in 40-50% of patients, single doses of 6-8 mg, and sometimes more, are required in 10-20% of patients to achieve the effect. It is recommended to start treatment with 2 mg of molsidomine, with good tolerance, it is possible to increase a single dose to an effective one (up to 6-8 mg). In practice, the criterion for an effective dose for a particular patient can be a decrease in the level of systolic blood pressure by 15-20 (and sometimes by 25) mm Hg. 1-1.5 hours after taking the drug. For the drug, absolute tolerance is possible, its administration to such patients is futile.

According to the severity of antianginal action, 2 mg of molsidomine corresponds to approximately 10 mg of ISDN.

INDICATIONS FOR THE USE OF NITROVASODILATORS

Nitrovasodilators are effective in myocardial ischemia, relief of emergency conditions associated with arterial hypertension, heart failure (including mitral or aortic regurgitation).

The main indications for the use of infusion forms of nitroglycerin are:

Unstable angina, refractory to treatment with β-blockers;

Intractable anginal attack;

myocardial infarction;

Acute left ventricular failure;

The need for controlled hypotension during surgical interventions;

Control of blood pressure in perioperative hypertension that occurred during intubation, anesthesia, surgery, extracorporeal circulation.

With prolonged use, nitrovasodilators are a means of symptomatic treatment, relief and prevention of anginal attacks and myocardial ischemia.

Indications for the use of nitrates are:

Nitroglycerin under the tongue or spray for immediate relief or relief of an angina attack;

Long-acting nitrates as first choice for reducing angina symptoms when beta-blockers or potassium antagonists are contraindicated;

Long-acting nitrates in combination with beta-blockers or calcium antagonists, if monotherapy with beta-blockers or calcium antagonists is not effective enough;

Long-acting nitrates as a substitute for beta-blockers or calcium antagonists, if the use of beta-blockers or calcium antagonists is accompanied by unacceptable side effects;

Long-acting nitrates are preferable for sinus node dysfunction and severe atrioventricular conduction disturbances.

Table 12.2

Nitrates and nitrate-like drugs

Note. The original drug is in bold, * - single dose

The antianginal doses and the frequency of taking nitrates and nitrate-like drugs in patients with stable angina pectoris and equivalent daily doses proposed by the Russian recommendations (Committee of Experts of the VNOK, 2004) are presented in Table. 12.2.

CONTRAINDICATIONS TO THE USE OF NITROVASODILATORS

Contraindications to the use of nitrovasodilators are:

Systolic blood pressure below 90 mm Hg;

Heart rate less than 50 beats / min;

Severe tachycardia;

Pronounced contractile dysfunction of the right ventricle, when its release depends on preload;

The use of sildenafil in the interval less than 24 hours of nitrate use.

In severe aortic stenosis, there is a high risk of a pronounced decrease in blood pressure and loss of consciousness against the background of the use of nitrates. It is possible to exacerbate obstruction and mitral regurgitation in hypertrophic obstructive cardiomyopathy.

TOLERANCE TO NITRODRUGS

The decrease in the effectiveness of nitrovasodilators in terms of the severity and / or duration of antianginal, antiischemic, antiplatelet, hypotensive action with repeated use of a standard dose is called tolerance. The rate of emergence of tolerance depends on the dose and duration of treatment, it becomes significant after a 24-hour continuous intravenous infusion of the drug.

The mechanism of development of tolerance to nitro-drugs is multifactorial, including molecular biochemical changes, physiological compensation and, possibly, receptor regulation.

There is the concept of extravascular tolerance, including violations of neurohormonal regulation and vascular volume overload (the so-called false tolerance), and tolerance based on a decrease in the ability of vascular smooth muscle cells to convert nitrates into nitric oxide (true vascular tolerance).

The decrease in blood pressure against the background of taking nitro-drugs is accompanied by stimulation of the baroreflex, leading to the activation of neurohumoral effects, including an increase in the level of catecholamines and the rate of their release, the level of vasopressin, an increase in plasma renin activity and aldosterone concentration, while the degree of neurohormonal stimulation is determined by the dose of nitrate. The consequence of such mechanisms is a significant increase in intravascular volume caused by transcapillary fluid movement due to a change in Starling forces and a decrease in natriuresis and diuresis in conditions of increased aldosterone levels (Table 12.3).

Table 12.3

Components of mechanisms for the development of extravascular tolerance to nitrates

The mechanisms of intravascular tolerance include disturbances in the biotransformation of organic nitrates as a result of possible intracellular depletion of sulfhydryl groups, disentization of guanylate cyclase, and an increase in phosphodiesterase activity, leading to increased degradation of cGMP. The hypothesis of "SH-group depletion" consists in a decrease in the degree of affinity of nitrate receptors, configurationally altered by long-term use of nitropreparations, as a result of interaction with SH-groups and the formation of disulfide bridges, which reduce the degree of interaction of receptors with nitrates.

Decreased sensitivity of guanylate cyclase, which acts as a target for the action resulting from metabolism

NO nitrates with long-term use of nitropreparations, was subjected to Boesgaard et al. experimental verification, and it turned out that higher concentrations of nitrates activate rather than reduce the activity of HC, and it is unlikely that soluble HC of smooth muscle cells is responsible for the decrease in the vasodilating effects of nitrates.

New concepts of the mechanisms of true tolerance to nitrates include the role of oxidative stress in the development of tolerance to nitrates based on elevated levels peroxides in tolerant vessels in comparison with the control. The development of tolerance can be completely avoided by limiting oxidative stress with the use of liposomal superoxide dismutase preparations. NAD(P)-regulated oxidases are cofactors for the production of superoxide by vascular tissues through mitochondrial enzymes, nitroxide synthetase and xanthine oxidase. A threefold increase in the activity of NAD oxidases in tissues tolerant to nitrates is noted, while angiotensin II infusion also increases the production of superoxide through the activation of NAD-bound oxidase, which confirms the tolerantogenic role of neurohumoral stimulation.

A certain role of increased vasoconstriction in the development of tolerance is played by the activation of protein kinase C. An increased vasoconstrictor sensitivity of tolerant vessels to adrenaline, serotonin, angiotensin II, potassium chloride was revealed, which confirms the nonspecificity of increased agonistic sensitivity, can be explained by activation of protein kinase C and include a common intracellular signaling process. The use of protein kinase C antagonists prevented the development of hypersensitivity to vasoconstrictors (phenylephrine, thromboxane) and the development of tolerance, while the contractions caused by endothelin 1, the classic activator of protein kinase C, are paradoxically reduced in nitrate tolerance.

An increase in the level of circulating angiotensin II in vascular smooth muscle cells activates membrane-bound regulated NAD(P) oxidases, which are the main sources of superoxides, and causes the formation of pre-endothelin mRNA through AT stimulation. 1 -receptors and the participation of protein kinase C, which plays a major role in initiating processes at the cellular level and can further lead to a decrease in the vasodilating effects of nitrates during their long-term use.

The role of ACE inhibitors and AT 1 receptor blockers in preventing the development of tolerance is determined by blocking angiotensin II-induced superoxide. Tolerance can be prevented by the production of endothelin by antioxidants, endothelin-1 receptor blockers, or protein kinase C antagonists.

A significant factor on which the development of tolerance (TN) may depend is the dosage, frequency and regularity of taking the drug, which ultimately determines the relationship between the constancy of the level of concentration of the active substance in the blood and the likelihood of developing TN. It has been shown that the development of TN is due to the presence of stably high concentrations of nitrate in the blood, while the effect of the drug is preserved when the concentrations of the active substance fluctuate during the day and the concentration decreases to subthreshold values.

To reduce the risk of developing tolerance to nitrates, it is necessary to observe an 8-12-hour "nitrate-free" interval during the day with regular use of a nitrovasodilator. Therefore, it is recommended that nitropreparations be taken no more than 2 times a day, thereby ensuring fluctuations in blood serum concentrations during the day with a decrease at a minimum below the therapeutically effective one.

POSSIBLE WAYS TO OVERCOME

TOLERANCE TO NITRODRUGS

Ways known to date to overcome tolerance include:

1) ensuring intermittent intake of the drug during the day so that the free period from the entry of nitrate into the blood is 10-12 hours. It was shown that the asymmetric intake of low doses of IS5MN with a 17-hour break during the day does not allow the development of tolerance and does not cause the syndrome "zero hour". However, S.Yu. Martsevich points out that such a regimen of nitrate intake can lead to the “rebound” syndrome with the appearance of not only anginal attacks, but also episodes of painless myocardial ischemia;

2) alternation during the day of taking nitropreparations and calcium antagonists. This is justified not only by the need to ensure a break in the intake of nitro-drugs, but also by research data in which the effect of nitrates is explained by an indirect effect through cGMP on the entry and exit of calcium ions from the cytoplasm of myocytes;

3) introduction of SH-group donors. One of the most effective donors of SH-groups in terms of its ability to convert NTH into NO is N-acetylcysteine, the beneficial effect of which depends on its effect on the venous circulation. An ACE inhibitor containing an SH group, captopril, which does not have an independent antianginal effect due to insufficient release of the endothelium-dependent relaxing factor by atherosclerotic segments of the coronary vessels, can act as donors of SH groups;

4) combination of nitrates with ACE inhibitors without SH-group. It is assumed that the potentiating effect of ACE inhibitors that do not contain an SH group in combination therapy with nitrates is mainly due to the effect on the production of counter-regulatory neurohumoral factors, as well as the ability to stimulate the endogenous synthesis of nitric oxide and prostacyclin in the vascular endothelium, due to the local accumulation caused by ACE inhibitors. endogenous bradykinin originating from the endothelium”;

5) combined therapy with nitrates and calcium antagonists and / or beta-adrenergic receptor blockers, using additional indirect effects of drugs added to the treatment on cGMP or neurohumoral regulation.

Alternative approaches:

1) the use of molsidomine, the active metabolite of which SIN-1 mediates the antianginal effect through the activation of guanylate cyclase. A significant hemodynamic activity of molsidomine was revealed with already developed tolerance to nitrates;

2) the use of nicorandil, which has a powerful vasodilation of the coronary arteries without affecting pre or afterload, the drug dilates arterial segments of various diameters, both small and large, increases the duration of the load, the time before the onset of ischemia provoked by the load, reduces

reduces the number of anginal pains and the need for additional sublingual NTG. Nicorandil has an antiplatelet effect, which is due to an intraplatelet increase in cGMP levels, the drug inhibits the binding of fibrinogen to the surface of platelets;

3) the use of a new vasodilator combining the effects of the Na-channel regulator - KRN2391.

Synthesized a new class of tolerant-resistant nitrates - furoxans - vasodilators with greater tropism for isolated segments of arteries and less - for veins. The effect of the drugs correlated with the ability to release nitric oxide, which was assessed by the degree of cGMP activity by electron resonance spectroscopy, which made it possible to put forward a hypothesis about the stimulating effect of furoxan on soluble guanylate cyclase in the smooth muscle wall of the vessel to spontaneous release of NO. The addition of N-acetylcysteine did not increase the relaxation of vessel segments, which indicates that relaxation is thiol-independent. The presence of an inhibitor of K-Ca channels (tetrabutylammonium) significantly increased the dilating effect. Preliminary processing vascular segments with an inhibitor of cytochrome P450 (SKF525a) also reduced the relaxation induced by furoxan. These data made it possible to suggest the mechanism of the vasodilating effect of furoxan as a spontaneous release of NO due to its accelerated biotransformation in the vessel wall and regulated by interaction with K-Ca channels of smooth muscle cells. Moreover, the preliminary exposure of venous segments to a solution of glyceryl-3-nitrate did not change the vasodilating effect of furoxan, which suggested that there was no development of tolerance to the drug.

The tolerantogenicity of nitrates themselves is obvious. Monitoring the level of concentration of the active substance of the nitropreparation in the patient's serum during the day while maintaining the period of subthreshold concentrations led to the creation of retarded forms of drugs that provide the least likelihood of developing tolerance.

Thus, nitrates can be more than vasodilators, reducing ischemia and influencing the course of atherosclerosis, they act as a substitute for physiological nitric oxide in the vascular endothelium. These effects are attenuated with long-term nitrate therapy. Although

the basis of the phenomenon of tolerance to nitrates is not completely clear, the depletion of SH-groups, neurohumoral activity, and an increase in plasma volume as a result of venodilation may play a role in this.

DRUG INTERACTIONS

NITROVASODILATORS

Table 12.4

Drug Interactions

17381 0

The first mention of the effectiveness of organic nitrates in angina refers to 1867, but the drugs in this group are still widely used in the treatment of cardiac patients. They are indispensable in cases where it is necessary to quickly eliminate myocardial ischemia or acute manifestations left ventricular heart failure.

Classification

The composition distinguishes propanetriol trinitrate (nitroglycerin), isosorbide dinitrate and isosorbide mononitrate.

Exists a large number of dosage forms of nitrates:

for intake under the tongue or use in the form of an aerosol (nitroglycerin, isosorbide dinitrate);
for parenteral administration (nitroglycerin, isosorbide dinitrate);
for sticking to the gums in the form of films (nitroglycerin, isosorbide dinitrate);
for dermal application in the form of patches, ointments (nitroglycerin, isosorbide dinitrate);
for oral administration (nitroglycerin, isosorbide dinitrate, isosorbide mononitrate).

Mechanism of action and pharmacological effects

Penetrating into smooth muscle cells, nitrates serve as a source of nitric oxide (NO), which stimulates the activation of guanylate cyclase. As a result, the formation of cGMP increases, which leads to a decrease in the calcium concentration inside smooth muscle cells and their relaxation. Nitrates act independently of the ability of endothelial cells to produce endogenous nitric oxide.

Nitrates contribute to the expansion of the coronary arteries and arterioles of a sufficiently large diameter. This leads to a decrease in the severity of spastic reactions in coronary arteries, improve blood supply to the subendocardial layers of the myocardium and increase collateral blood flow. In addition, nitrates affect blood vessels great circle blood circulation, causing expansion of both peripheral venous vessels that deposit blood and arterioles. Under their influence, the extensibility of large arteries improves. As a result, venous return and SBP in the aorta are reduced. Accordingly, the preload, afterload and tension of the walls of the ventricles of the heart decrease, which leads to a decrease in myocardial oxygen demand. Reducing the filling pressure of the ventricles improves the blood supply to the subendocardial layers of the myocardium. These mechanisms underlie the anti-ischemic action of nitrates and their ability to reduce the severity of manifestations of left ventricular heart failure.

The vasodilating effect of nitrates is manifested mainly in the venous vascular bed (high doses are required to affect arterioles). Expansion of the arterioles of the systemic circulation, leading to a decrease in blood pressure, may contribute to the activation of the sympathetic division of the autonomic nervous system with the occurrence of reflex tachycardia and increased myocardial contractility.