Vasodilators: nitroglycerin and sodium nitroprusside

Nitrovazodilatatory - a group of drugs that have a vasodilating effect and differ among themselves in chemical structure and the primary site of action. They are united by the mechanism of action: with the use of all nitrovazodilators in the body, nitrogen oxide is formed, which determines the pharmacological activity of these drugs. In the anesthesia practice, two drugs of this group are traditionally used: nitroglycerin and sodium nitroprusside. Other nitrovazodilators (isosorbide dinitrate, isosorbide mononitrate, molsidomine) find application in therapeutic practice.

Nitroglycerin is a false ester of glycerol and nitric acid. Strictly speaking, the term "nitroglycerin" is not entirely correct, since the substance is not a true nitro compound (with the basic structure of C-N02), but nitrate, i.e. Glyceryl trinitrate. These preparations, synthesized as far back as 1846 by Sobrero, have become widespread in clinical practice for the relief of angina attacks and have only recently been used to correct hypertension.

Sodium nitroprusside is used as a means for short-term monitoring of severe hypertensive reactions since the mid-1950s, although sodium nitroprusside was synthesized as far back as 1850.

Nitroglycerin and sodium nitroprusside: a place in therapy

Nitroglycerin is widely used in anesthetic practice during CABG operations and in the postoperative period for the correction of hypertension, controlled hypotension, in the treatment of small-bovine SV syndrome in IHD patients, 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 infusions at doses of 1-2 mg / h (17-33 μg / min) or 1-3 μg / kg / min. The duration of action with sublingual admission is about 9 minutes, with IV / 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. Art. Then there is a decrease in SBP, which in the 3rd minute is 17%; DBP decreases by 8% and mean BP - by 16% of the baseline value. At the same time there is a 29% decrease in VO and MOS, left ventricular (LVH) work by 36%, CVP by 37%, and pulmonary artery pressure (DPA). By the 9th minute, the hemodynamic parameters are restored to their original values. A more pronounced hypotensive effect has a one-time IV injection or infusion of it at a dose of 2 mg / h (33 μg / min). Reduction of SBP is about 26%, mean BP - 22% of the initial value. Simultaneously with a decrease in blood pressure, there is a significant reduction in CVP (by approximately 37%), pulmonary vascular resistance is reduced by 36%, and LVH by 44%. By the 11th-13th minute after the end of the infusion, the parameters of hemodynamics do not differ from the initial ones, and unlike nitroprusside sodium there is no tendency to pronounced increase in blood pressure. Internal "phlebotomy" with the infusion of nitroglycerin at a dose of 17 μg / min is 437 ± 128 ml. This can 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 μg / min) with simultaneous infusion of dopamine (200 μg / min) and replacement of bcc is a rather effective method for treating small-bovine asthma syndrome in IHD patients. The dynamics of myocardial function is largely determined by its initial state, intensity of dyskinesia, i.e. State of contractility. In patients with persistent myocardium or unexplained dyskinesia, the administration of nitroglycerin does not lead to a significant change in its function. At the same time, in patients with moderate-intensity dyskinesia, as well as with pronounced impairment of the contractile function of the myocardium, the use of nitroglycerin may lead to an even greater deterioration in contractility and hemodynamic parameters. Therefore, if there is a suspicion of a breach of contractility of the myocardium, with cardiogenic shock due to myocardial infarction, nitroglycerin should be used with caution or completely abandoned its use. Preventive use of nitroglycerin during surgery does not provide protective anti-ischemic action.

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

In a number of situations (with crushing of the thoracic aorta, with 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 powerful and effective antihypertensive drug that is widely used to correct hypertension during anesthesia and surgery, awakening and extubation of patients, and also in the postoperative period. Sodium nitroprusside can also be used in the treatment of acute heart failure, especially with signs of beginning pulmonary edema, hypertension complicated by acute heart failure. Extremely fast start (within 1 - 1.5 minutes) and short duration of action ensure good controllability of medicines. Infusion of sodium nitroprusside at a dose of 1-6 μg / kg / min causes a rapid decrease (within 1 to 3 minutes) of blood pressure by 22-24%, OPS - by 20-25% of the baseline values (compared to 12-13% decrease , observed when using NG). Also DLA decreases (by 30%), myocardial oxygen consumption (by 27%), and MOS and UO (up to the initial value). The drug quickly normalizes blood pressure, VO, MOS and OPS without significant changes in myocardial contractility, dp / dt (maximum rate of aortic pressure buildup) and Q (ratio of duration of expulsion periods (LVET) and pre-injection (PEP)). After the maximum effect is necessary, the introduction of sodium nitroprusside stops or reduces the dosage, regulating the infusion rate to maintain blood pressure at the desired level.

Compared with nitroglycerin, sodium nitroprusside is a more effective and preferred drug for correcting blood pressure during crusting of the thoracic aorta during surgery for aneurysms of the descending aorta. Sodium nitroprusside is considered a drug of choice for the stabilization of blood pressure in patients with a split aneurysm of the thoracic aorta. In these cases, the dose of sodium nitroprusside is selected so as to stabilize the SBP at a level of 100-120 mm Hg. Art. With the aim of preventing further dissection of the aorta during the preparation of the patient for surgery. Since LS causes an increase in the rate of LV ejection (LVET shortening) and often the development of tachycardia, it is often used in combination with beta-blockers (propranolol IV, starting at 0.5 mg and then 1 mg every 5 min, until pulse pressure is 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-adrenoblockers, where the surface of the cell membrane is the application site, organic nitrates act intracellularly. The mechanism of action of all nitrovazodilators is to increase the content in the smooth muscle cells of nitric oxide. Nitric oxide has a potent vasodilating effect (endothelial relaxing factor). The short duration of its action (T1 / 2 is less than 5 sec) causes the short duration of action of nitrovazodilators. In the cell, nitric oxide activates guanylate cyclase, an enzyme that provides cGMP synthesis. This enzyme controls the phosphorylation of a number of proteins involved in the regulation of the free intracellular calcium fraction and the contraction of smooth muscles.

Nitroglycerin, in contrast to sodium nitroprusside, which is a mixed vasodilator, has a predominant venodylating effect. This difference is due to the fact that the cleavage of nitroglycerin with the formation of the active component, nitric oxide, is carried out enzymatically. The decomposition of sodium nitroprusside with the formation of 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 necessary for the digestion of nitroglycerin, so the action of nitroglycerin on the arteriolar bed is much less pronounced than sodium nitroprusside and is manifested when use of large doses. At a concentration of nitroglycerin in the plasma of about 1-2 ng / ml, it causes venodilation, and at concentrations above 3 ng / ml - expansion of both the venous and arterial bed.

The main therapeutic effects of nitroglycerin are due to the relaxation of the smooth muscles of predominantly 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 (antiischemic) action, and in large doses it is antihypertensive.

It is known that in patients with coronary artery disease any increase in oxygen consumption by myocardium (physical activity, emotional reaction) inevitably leads to myocardial hypoxia and thus the development of an attack of angina pectoris. Disturbance of blood supply to the myocardium in turn leads to a decrease in its contractility. In this case, as a rule, there is an increase in the end-diastolic pressure of the left ventricle (CPLD) due to an increase in the residual volume of blood in the LV cavity at the end of the systole. This volume is significantly increased at the end of the diastole due to the incoming inflow of blood. With an increase in the CLD, pressure on the wall of the LV increases, which further disturbs the nutrition of the cardiac muscle by squeezing the arterioles. And the resistance in the coronary arteries progressively increases from the epicardium to the endocardium. Insufficient blood supply of subendocardial layers of the myocardium leads to the development of metabolic acidosis and reduced 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 of which remains even more or less adequate. This causes an uneven reduction in endocardial and epicardial layers of the myocardium, which further violates its contractility. Thus, a peculiar vicious circle develops.

Nitroglycerin causes the deposition of blood in large capacitive vessels, which reduces venous return and preload on the heart. In this case, there is a more pronounced decrease in CTDL compared with diastolic pressure in the aorta. Decrease in CTDL leads to a decrease in the compression of the coronary vessels by the subendocardial zone of the myocardium, which is accompanied by a decrease in myocardial oxygen consumption and an improvement in the blood flow of the subendocardial zone of the myocardium. It is this mechanism that explains its antianginal effect in the development of an attack of angina pectoris.

Nitroglycerin can increase the delivery of oxygen to the zones of myocardial ischemia by expanding coronary arteries, collaterals and eliminating spasm of the coronary arteries. Studies on isolated coronary arteries show that, in contrast to adenosine (a powerful arterial vasodilator), nitroglycerin in large doses (8-32 μg / kg) causes relaxation of the 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 infusion of nitroglycerin and a decrease in the concentration of nitrates in the blood, the coronary blood flow decreases below the baseline level and the hemoglobin saturation of the coronary sinus is normalized. However, a decrease in intravascular volume in patients with normal or slightly elevated CVD, excessive decrease in blood pressure and CB can lead to a decrease in coronary perfusion pressure and aggravation of myocardial ischemia, since myocardial blood flow is more dependent on perfusion pressure.

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

Nitroglycerin dilates the cerebral vessels and disrupts autoregulation of the cerebral blood flow. Increased intracranial volume may cause an increase in intracranial pressure.

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

Sodium nitroprusside has a direct effect on the smooth musculature of the vessels, causing the expansion of the arteries and veins. Unlike nitroglycerin, sodium nitroprusside does not have an antianginal effect. It reduces myocardial oxygen supply, can cause a decrease in myocardial blood flow in the zones of myocardial ischemia in patients with IHD and an increase in the ST segment in patients with myocardial infarction.

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

In some cases, the intake of nitrates can be associated with the development of tolerance, i.e. Weakening, and sometimes the disappearance of their clinical effects. The mechanism of development of tolerance remains unclear. To a large extent, this phenomenon has clinical significance with regular nitrate therapy. On the average, the addiction to nitrates is all the more pronounced, the longer and continuously the concentration of drugs in the blood is maintained. In some patients, addiction to nitrates can develop very quickly - for several days or even hours. For example, often with IV injection of nitrates in intensive care units, the first signs of weakening of the effect appear even 10-12 hours after the start of the injection.

Adapting to nitrates is a more or less reversible phenomenon. If the addiction has developed to nitrate, then after the withdrawal of the drug, sensitivity to it usually recovers within a few days.

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

Pharmacokinetics

When ingesting nitroglycerin is rapidly absorbed from the digestive tract, most of it is cleaved already at the first passage through the liver and only a very small amount enters the bloodstream unchanged. Nitroglycerin does not bind to plasma proteins. Like other organic nitric acid esters, nitroglycerin undergoes nitrogenation under the action of glutathione nitrate reductase, mainly in the liver and erythrocytes. The resulting dinitrites and mononitrite in the form of glucuronides are partially excreted from the body by the kidneys or are further denitrogenated to form glycerol. Dinitrites have a much weaker vasodilating action than nitroglycerin. T1 / 2 NG is only a few minutes (2 minutes after IV introduction and 4.4 minutes with oral administration).

Sodium nitroprusside is an unstable compound, which, in order to obtain a clinical effect, must be administered by the method of constant IV infusion. The molecule of sodium nitroprusside spontaneously decomposes into 5 cyanide ions (CN-) and the active nitroso group (N = O). Cyanide ions enter into three types of reactions: they bind to methhemoglobin with the formation of cyanomhemoglobin; under the influence of rhodanase in the liver and kidneys, they bind to thiosulfate with the formation of thiocyanate; entering into a compound with cytochrome oxidase, 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 insufficiency - significantly more.

Contraindications

The drugs of this group should not be used in patients with anemia and severe hypovolemia because of the possibility of developing hypotension and aggravating myocardial ischemia.

The introduction of NIP is contraindicated in patients with elevated intracranial pressure, optic atrophy. It should be used with caution in elderly patients, as well as those suffering from hypothyroidism, impaired renal function. It is not recommended to administer drugs to children and pregnant women.

Tolerance and side effects

With long-term use of a common side effect, nitroglycerin is the occurrence of headaches (due to the expansion of cerebral vessels and the stretching of sensitive tissues surrounding the meningeal arteries). In anesthesia, this is not significant, since drugs are used in patients during anesthesia.

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

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

Plasma. These effects are more often observed in conditions of concomitant hypovolemia. Nitroprusside sodium causes the development of the syndrome of stealing coronary blood flow.

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

An increase in the level of renin and catecholamines in plasma with sodium nitroprusside is the cause of a marked increase in blood pressure after the cessation of its infusion. The combined use of short-acting beta-blockers, such as esmolol, allows correcting the tachycardia developing with its use, to reduce its dose and to reduce the risk of hypertension after stopping the sodium nitroprusside infusion.

Significantly less frequent undesirable effects are due to the accumulation in the blood of metabolic products of sodium nitroprusside: cyanides and thiocyanates. To this can lead to long-term infusion of drugs (more than 24 hours), its use in large doses or in patients with renal insufficiency. The state of poisoning is manifested by the development of metabolic acidosis, arrhythmias and increased oxygen in venous blood (as a result of the inability of tissues to absorb oxygen). The early sign of poisoning is tachyphylaxis (the need to constantly increase the dose of drugs to achieve the necessary antihypertensive effect).

Treatment of cyanide poisoning consists in conducting ventilation with pure oxygen, in / in the administration of sodium thiosulfate (150 mg / kg for 15 min), which oxidizes hemoglobin to methaemoglobin. Thiosulphate sodium and methemoglobin, actively binding cyanide, reduce its amount in the blood, available for interaction with cytochrome oxidase. In cases of cyanide poisoning, oxycobalamine is also used, which reacts with free cyanide to form cyanocobalamin (vitamin B12). Oksikobalamin (0.1 g in 100 ml of a 5% solution of glucose) is administered iv, then a solution of sodium thiosulfate (12.5 g in 50 ml of a 5% solution of glucose) is slowly added to / in.

For the treatment of methemoglobinemia, which develops with the administration of large doses of nitrovazodilators, 1% solution of methylene blue (1-2 mg / kg for 5 min) is used, restoring methhemoglobin to hemoglobin.

Interaction

The deep level of anesthesia, the preliminary use of neuroleptics, other antihypertensive agents, anti-reergetic 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 in the arterial hypotension caused by it indirectly slows down the development of the SML and increases its duration. The phosphodiesterase inhibitor eufillin promotes an increase in cGMP concentration, thereby potentiating the hypotensive effect of sodium nitroprusside.

Caveats

The use of nitroglycerin causes a decrease in RaO2 on average by 17% of the initial value. Therefore, in patients with impaired oxygenation of the lungs, heart failure, in order to prevent a significant decrease in Pa02, it is necessary to increase the percentage of oxygen in the inhaled mixture and apply PEEP within 5-8 mm of the water column. Caution should be given to nitroglycerin to patients with suspected violation of myocardial contractility, patients with low blood pressure, myocardial infarction, cardiogenic shock, hypovolemia, etc.

Infusion of drugs should be carried out under direct (invasive) control of blood pressure because of the possibility of a sharp drop in blood pressure. In the case of a sharp drop in blood pressure in an anesthesiologist at hand should be vazopressory.

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