Vasodilators: nitroglycerin and sodium nitroprusside

Nitrovasodilators are a group of drugs that have a vasodilatory effect and differ from each other in chemical structure and primary site of action. They are united by the mechanism of action: when using all nitrovasodilators, nitric oxide is formed in the body, which determines the pharmacological activity of these drugs. In anesthesiology, two drugs of this group are traditionally used: nitroglycerin and sodium nitroprusside. Other nitrovasodilators (isosorbide dinitrate, isosorbide mononitrate, molsidomine) are used in therapeutic practice.

Nitroglycerin is a false ester of glycerol and nitric acid. Strictly speaking, the term "nitroglycerin" is not quite correct, since the substance is not a true nitro compound (with the basic structure C-N02), but a nitrate, i.e. glyceryl trinitrate. This drug, synthesized in 1846 by Sobrero, has become widespread in clinical practice for the relief of angina attacks and only comparatively recently has it been used to correct hypertension.

Sodium nitroprusside has been used as a short-term control agent for severe hypertensive reactions since the mid-1950s, although sodium nitroprusside was synthesized as early as 1850.

Nitroglycerin and sodium nitroprusside: place in therapy

Nitroglycerin is widely used in anesthesiology practice during CABG operations and in the postoperative period to correct hypertension, controlled hypotension, in the treatment of low cardiac output syndrome in patients with coronary heart disease, and to correct myocardial ischemia during CABG.

To correct elevated blood pressure during anesthesia, nitroglycerin is used as a 1% solution under the tongue (1-4 drops, 0.15-0.6 mg) or intravenous infusion at doses of 1-2 mg/h (17-33 mcg/min) or 1-3 mcg/kg/min. The duration of action with sublingual administration is about 9 minutes, with intravenous administration - 11-13 minutes. The use of nitroglycerin in a dose of 1-4 drops under the tongue or in the nose is initially accompanied by a short-term increase in blood pressure by 17 ± 5 mm Hg. Then a decrease in SBP is observed, which at the 3rd minute is 17%; DBP decreases by 8% and mean BP - by 16% of the initial value. In this case, there is a decrease in SV and MEF by 29%, left ventricular work (LVW) - by 36%, CVP - by 37%, and a decrease in pulmonary artery pressure (PAP). By the 9th minute, hemodynamic parameters are restored to baseline values. A more pronounced hypotensive effect is provided by a single intravenous administration or infusion of it at a dose of 2 mg / h (33 mcg / min). The decrease in SBP is about 26%, mean BP - 22% of the initial value. Simultaneously with the decrease in BP, there is a significant decrease in CVP (approximately 37%), pulmonary vascular resistance decreases by 36%, LVW - by 44%. By the 11-13th minute after the end of the infusion, hemodynamic parameters do not differ from the initial ones and, unlike sodium nitroprusside, there is no tendency for a marked increase in BP. Internal "phlebotomy" with nitroglycerin infusion at a dose of 17 mcg/min is 437 ± 128 ml. This may explain the positive effect of nitroglycerin in some patients in the treatment of acute left ventricular failure with pulmonary edema.

Infusion of small doses of nitroglycerin (2-5 mcg/min) with simultaneous infusion of dopamine (200 mcg/min) and replenishment of circulating blood volume is a fairly effective method for treating low cardiac output syndrome in patients with coronary artery disease. The dynamics of myocardial function is largely determined by its initial state, the intensity of dyskinesia, i.e. the state of contractility. In patients with intact myocardium or mild dyskinesia, administration of nitroglycerin does not lead to a significant change in its function. At the same time, in patients with moderate dyskinesia, as well as with severe impairment of myocardial contractility, the use of nitroglycerin can lead to even greater deterioration in contractility and hemodynamic parameters. Therefore, if myocardial contractility is suspected, in cardiogenic shock due to infarction, nitroglycerin should be used with caution or completely abandoned. Prophylactic use of nitroglycerin during surgery does not provide a protective anti-ischemic effect.

The use of nitroglycerin in patients with hypovolemia (during operations on large main vessels) leads to a significant decrease in SV. To maintain volemia, infusion of large volumes of fluid is necessary, as a result of which, in the postoperative period, against the background of restoration of venous tone, the development of severe hypervolemia and associated complications is possible.

In a number of situations (when the thoracic aorta is clamped, during awakening and extubation), the use of nitroglycerin to reduce blood pressure is often ineffective and the anesthesiologist has to resort to other antihypertensive drugs (sodium nitroprusside, nimodipine, etc.).

Sodium nitroprusside is a potent and effective hypotensive drug, widely used to correct hypertension during anesthesia and surgery, during awakening and extubation of patients, and in the postoperative period. Sodium nitroprusside can also be used to treat acute heart failure, especially with signs of incipient pulmonary edema, hypertension complicated by acute heart failure. Extremely rapid onset (within 1-1.5 min) and short duration of action provide good controllability of the drug. Infusion of sodium nitroprusside at a dose of 1-6 mcg/kg/min causes a rapid (within 1-3 min) decrease in blood pressure by 22-24%, TPR - by 20-25% of the initial values (compared to a 12-13% decrease observed when using NG). Also, PAP (by 30%), myocardial oxygen consumption (by 27%), as well as MEF and SV (to the initial value) are reduced. The drug quickly normalizes BP, SV, MEF and RV without significant changes in myocardial contractility indices, dp/dt (maximum rate of pressure increase in the aorta) and Q (ratio of the duration of the ejection periods (LVET) and pre-ejection periods - PEP). After the onset of the maximum required effect, sodium nitroprusside administration is stopped or the dosage is reduced, adjusting the infusion rate to maintain BP at the desired level.

Compared with nitroglycerin, sodium nitroprusside is more effective and is the preferred drug for BP correction during thoracic aortic cross-clamping during descending aortic aneurysm surgeries. Sodium nitroprusside is considered the drug of choice for BP stabilization in patients with dissecting thoracic aortic aneurysm. In these cases, the sodium nitroprusside dose is adjusted to stabilize SBP at 100-120 mm Hg in order to prevent further aortic dissection during the patient's preparation for surgery. Since the drug causes an increase in the LV ejection rate (shortening of LVET) and often the development of tachycardia, it is often used in combination with beta-blockers (propranolol intravenously, starting with 0.5 mg and then 1 mg every 5 minutes until the pulse pressure decreases to 60 mm Hg; esmolol, labetalol), as well as with calcium antagonists (nifedipine, nimodipine).

Mechanism of action and pharmacological effects

Unlike calcium antagonists and beta-blockers, the site of application of which is the surface of the cell membrane, organic nitrates act intracellularly. The mechanism of action of all nitrovasodilators is to increase the content of nitric oxide in vascular smooth muscle cells. Nitric oxide has a powerful vasodilating effect (endothelial relaxing factor). The short duration of its action (T1/2 is less than 5 sec) determines the short-term action of nitrovasodilators. In the cell, nitric oxide activates guanylate cyclase, an enzyme that ensures the synthesis of cGMP. This enzyme controls the phosphorylation of a number of proteins involved in the regulation of the fraction of free intracellular calcium and smooth muscle contraction.

Nitroglycerin, unlike sodium nitroprusside, which is a mixed vasodilator, has a predominantly venodilating effect. This difference is due to the fact that nitroglycerin is broken down to form the active component, nitric oxide, by enzymatic means. The breakdown of sodium nitroprusside to form nitric oxide occurs spontaneously. In some parts of the vascular bed, especially in the distal arteries and arterioles, there is a relatively small amount of the enzyme required to break down nitroglycerin, so the effect of nitroglycerin on the arteriolar bed is significantly less pronounced than that of sodium nitroprusside and occurs when using large doses. At a plasma nitroglycerin concentration of about 1-2 ng/ml, it causes venodilation, and at a concentration above 3 ng/ml, it causes expansion of both the venous and arterial beds.

The main therapeutic effects of nitroglycerin are due to the relaxation of smooth muscles, mainly blood vessels. It also has a relaxing effect on the smooth muscles of the bronchi, uterus, bladder, intestines and bile ducts.

Nitroglycerin has a pronounced antianginal (anti-ischemic) effect, and in large doses, an antihypertensive effect.

It is known that in patients with coronary artery disease any increase in myocardial oxygen consumption (physical exertion, emotional reaction) inevitably leads to myocardial hypoxia and thus the development of an attack of angina pectoris. Impaired blood supply to the myocardium in turn leads to a decrease in its contractility. In this case, as a rule, an increase in the left ventricular end-diastolic pressure (LVEDP) is noted due to an increase in the residual blood volume in the LV cavity at the end of systole. This volume increases significantly at the end of diastole due to the inflow of blood. With an increase in LVEDP, the pressure on the LV wall increases, which further disrupts the nutrition of the heart muscle due to compression of the arterioles. Moreover, resistance in the coronary arteries progressively increases from the epicardium to the endocardium. Insufficient blood supply to the subendocardial layers of the myocardium leads to the development of metabolic acidosis and a decrease in contractility. Through the baroreceptors, the body tries to correct the situation by increasing the tone of the sympathetic nervous system, which leads to the development of tachycardia and increased contractility, although only in the outer layers of the myocardium, the blood supply to which remains more or less adequate. This causes uneven contraction of the endocardial and epicardial layers of the myocardium, which further disrupts its contractility. Thus, a kind of vicious circle develops.

Nitroglycerin causes blood deposition in large capacitance vessels, which reduces venous return and preload on the heart. In this case, a more pronounced decrease in LVEDP occurs compared to diastolic pressure in the aorta. A decrease in LVEDP leads to a decrease in the compression of the coronary vessels of the subendocardial zone of the myocardium by tissues, which is accompanied by a decrease in oxygen consumption by the myocardium and an improvement in the blood flow of the subendocardial zone of the myocardium. This mechanism explains its antianginal effect during the development of an attack of angina pectoris.

Nitroglycerin can increase oxygen delivery to myocardial ischemia zones by dilating coronary arteries, collaterals, and eliminating coronary artery spasm. Studies on isolated coronary arteries show that, unlike adenosine (a potent arterial vasodilator), nitroglycerin in high doses (8-32 mcg/kg) causes relaxation of smooth muscles of large coronary arteries (but not coronary arterioles), suppressing coronary autoregulation, as evidenced by an increase in coronary blood flow and oxygen saturation of hemoglobin in the blood of the coronary sinus. After cessation of nitroglycerin infusion and a decrease in the concentration of nitrates in the blood, a decrease in coronary blood flow below the initial level and normalization of hemoglobin saturation in the blood of the coronary sinus are observed. However, a decrease in intravascular volume in patients with normal or slightly increased LVEDP, excessive decrease in BP and CO can lead to a decrease in coronary perfusion pressure and worsening of myocardial ischemia, since myocardial blood flow is more dependent on perfusion pressure.

Nitroglycerin dilates pulmonary vessels and causes an increase in blood shunting in the lungs with a decrease in Pa02 by 30% of the initial value.

Nitroglycerin dilates cerebral vessels and disrupts autoregulation of cerebral blood flow. Increased intracranial volume may cause increased intracranial pressure.

All nitrovasodilators inhibit ADP and adrenaline-induced platelet aggregation and decrease in platelet factor 4 levels.

Sodium nitroprusside has a direct effect on the smooth muscles of blood vessels, causing dilation of arteries and veins. Unlike nitroglycerin, sodium nitroprusside does not have an antianginal effect. It reduces the supply of oxygen to the myocardium, can cause a decrease in myocardial blood flow in areas of myocardial ischemia in patients with coronary heart disease and an increase in the ST segment in patients with myocardial infarction.

Sodium nitroprusside causes cerebral vasodilation, disrupts autoregulation of cerebral blood flow, and increases intracranial pressure and cerebrospinal fluid pressure, further disrupting spinal cord perfusion. Like nitroglycerin, it causes pulmonary vasodilation and pronounced intrapulmonary shunting of blood with a decrease in Pa02 by 30-40% of the initial value. Therefore, when using sodium nitroprusside, especially in patients with heart failure, to prevent a significant decrease in PaO2, the percentage of oxygen in the inhaled mixture should be increased and positive end-expiratory pressure (PEEP) should be applied within 5-8 mm H2O.

In some cases, taking nitrates may be associated with the development of tolerance, i.e. weakening and sometimes disappearance of their clinical effect. The mechanism of tolerance development remains unclear. This phenomenon has a greater clinical significance with regular nitrate therapy. On average, the more prolonged and constant the drug concentration in the blood is, the more pronounced the addiction to nitrates is. In some patients, addiction to nitrates may develop very quickly - within a few days or even hours. For example, often with intravenous administration of nitrates in intensive care units, the first signs of weakening of the effect appear already 10-12 hours after the start of administration.

Addiction to nitrates is a more or less reversible phenomenon. If addiction to a nitrate has developed, then after discontinuing the drug, sensitivity to it is usually restored within a few days.

It has been shown that if the period free from nitrate action during the day is 6-8 hours, then the risk of developing addiction is relatively small. The principle of preventing the development of addiction to nitrates is based on this pattern - the method of their intermittent use.

Pharmacokinetics

When taken orally, nitroglycerin is rapidly absorbed from the gastrointestinal tract, most of it is broken down already during the first pass through the liver and only a very small amount enters the bloodstream unchanged. Nitroglycerin does not bind to plasma proteins. Like other organic esters of nitric acid, nitroglycerin undergoes nitrogenation by glutathione nitrate reductase, mainly in the liver and erythrocytes. The resulting dinitrites and mononitrites in the form of glucuronides are partially excreted from the body by the kidneys or undergo further denitrogenation to form glycerol. Dinitrites have a significantly weaker vasodilatory effect than nitroglycerin. The T1/2 of NG is only a few minutes (2 min after intravenous administration and 4.4 min after oral administration).

Sodium nitroprusside is an unstable compound that must be administered by continuous intravenous infusion to achieve a clinical effect. The sodium nitroprusside molecule spontaneously decomposes into 5 cyanide ions (CN-) and an active nitroso group (N = O). Cyanide ions undergo three types of reactions: they bind to methemoglobin to form cyanmethemoglobin; under the influence of rhodanase in the liver and kidneys, they bind to thiosulfate to form thiocyanate; by combining with cytochrome oxidase, they prevent tissue oxidation. Thiocyanate is slowly excreted by the kidneys. In patients with normal renal function, its T1/2 is 3 days, in patients with renal failure - significantly longer.

Contraindications

Medicines of this group should not be used in patients with anemia and severe hypovolemia due to the possibility of developing hypotension and worsening myocardial ischemia.

The introduction of NNP is contraindicated in patients with increased intracranial pressure, optic nerve atrophy. It should be used with caution in elderly patients, as well as those suffering from hypothyroidism, impaired renal function. The introduction of the drug is not recommended for children and pregnant women.

Tolerability and side effects

With prolonged use, a common side effect of nitroglycerin is the occurrence of headaches (due to the expansion of cerebral vessels and stretching of sensitive tissues surrounding the meningeal arteries). In anesthesiological practice, this is not of significant importance, since the drug is used in patients during anesthesia.

Side effects that occur with short-term administration of nitroglycerin and NPI are mainly due to excessive vasodilation, leading to hypotension. In case of overdose or hypersensitivity to these drugs, as well as in case of hypovolemia, the patient after taking nitrates should take a horizontal position with the foot end of the bed elevated to ensure venous return of blood to the heart.

Hypotension caused by sodium nitroprusside is sometimes accompanied by compensatory tachycardia (increase in heart rate is about 20%) and increased renin activity

Plasma. These effects are more often observed in conditions of concomitant hypovolemia. Sodium nitroprusside causes the development of coronary steal syndrome.

Both nitroglycerin and sodium nitroprusside during operations on the thoracoabdominal aorta can cause the development of spinal cord steal syndrome, reducing the spinal cord perfusion pressure below the level of aortic compression and contributing to its ischemia, increasing the incidence of neurological disorders. Therefore, these drugs are not used to correct blood pressure during such operations. Preference is given to inhalation anesthetics (isoflurane, fluorothane) in combination with calcium antagonists (nifedipine, nimodipine).

Increased plasma renin and catecholamine levels with sodium nitroprusside are the cause of a marked increase in blood pressure after discontinuation of its infusion. Combined use of short-acting beta-blockers, such as esmolol, allows for correction of tachycardia developing with its use, reduction of its dose, and a decrease in the risk of hypertension after discontinuation of sodium nitroprusside infusion.

Much less frequently, undesirable effects are caused by the accumulation of sodium nitroprusside metabolic products in the blood: cyanides and thiocyanates. This can be caused by prolonged infusion of the drug (over 24 hours), its use in large doses or in patients with renal failure. The state of poisoning is manifested by the development of metabolic acidosis, arrhythmia and increased oxygen content in venous blood (as a result of the inability of tissues to absorb oxygen). An early sign of poisoning is tachyphylaxis (the need to constantly increase the dose of the drug to achieve the desired hypotensive effect).

Treatment of cyanide poisoning involves mechanical ventilation with pure oxygen and intravenous administration of sodium thiosulfate (150 mg/kg over 15 min), which oxidizes hemoglobin to methemoglobin. Sodium thiosulfate and methemoglobin actively bind cyanide, reducing its amount in the blood available for interaction with cytochrome oxidase. In cases of cyanide poisoning, oxycobalamin is also used, which reacts with free cyanide to form cyanocobalamin (vitamin B12). Oxycobalamin (0.1 g in 100 ml of 5% glucose solution) is administered intravenously, then sodium thiosulfate solution (12.5 g in 50 ml of 5% glucose solution) is slowly administered intravenously.

To treat methemoglobinemia that develops with the administration of large doses of nitrovasodilators, a 1% solution of methylene blue (1-2 mg/kg for 5 min) is used, which restores methemoglobin to hemoglobin.

Interaction

Deep anesthesia, preliminary use of neuroleptics, other antihypertensive agents, antiadrenergic drugs, Ca2+ blockers, benzodiazepines can significantly potentiate the hypotensive and vasodilating effect of nitroglycerin and sodium nitroprusside.

Sodium nitroprusside does not interact directly with muscle relaxants, but the decrease in muscle blood flow during arterial hypotension caused by it indirectly slows the development of NMB and increases its duration. The phosphodiesterase inhibitor euphyllin promotes an increase in the concentration of cGMP, thereby potentiating the hypotensive effect of sodium nitroprusside.

Cautions

The use of nitroglycerin causes a decrease in PaO2 by an average of 17% of the initial value. Therefore, in patients with impaired oxygenating function of the lungs, heart failure, to prevent a significant decrease in PaO2, it is necessary to increase the percentage of oxygen in the inhaled mixture and use PEEP within 5-8 mm H2O. Nitroglycerin should be prescribed with caution to patients with suspected myocardial contractility disorder, patients with low blood pressure, myocardial infarction, in a state of cardiogenic shock, hypovolemia, etc.

Infusion of the drug should be performed under direct (invasive) control of blood pressure due to the possibility of a sharp drop in blood pressure. In case of a sharp drop in blood pressure, the anesthesiologist should have vasopressors on hand.

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