Inotropic effect of changes in heart rate. Innervation of the heart. chronotropic effect. dromotropic effect. inotropic effect. Bathmotropic effect Negative inotropic effect

Inotropic drugs are drugs that increase myocardial contractility. The most well-known inotropic drugs are cardiac glycosides. At the beginning of the 20th century, almost all cardiology was based on cardiac glycosides. And even in the early 80s. glycosides remained the main medicines in cardiology.

The mechanism of action of cardiac glycosides is the blockade of the sodium-potassium "pump". As a result, the flow of sodium ions into cells increases, the exchange of sodium ions for calcium ions increases, which, in turn, causes an increase in the content of calcium ions in myocardial cells and a positive inotropic effect. In addition, glycosides slow down AV conduction and reduce heart rate (especially with atrial fibrillation) - due to vagomimetic and antiadrenergic action.

The effectiveness of glycosides in circulatory failure in patients without atrial fibrillation was not very high and was even questioned. However, specially conducted studies have shown that glycosides have a positive inotropic effect and are clinically effective in patients with impaired left ventricular systolic function. The predictors of the effectiveness of glycosides are: an increase in the size of the heart, a decrease in the ejection fraction and the presence of a III heart sound. In patients without these signs, the likelihood of an effect from the appointment of glycosides is low. Currently, digitalization is no longer applied. As it turned out, the main effect of glycosides is precisely the neurovegetative effect, which manifests itself when prescribing small doses.

In our time, indications for the appointment of cardiac glycosides are clearly defined. Glycosides are indicated in the treatment of severe chronic heart failure, especially if the patient has atrial fibrillation. And not just atrial fibrillation, but a tachysystolic form of atrial fibrillation. In this case, glycosides are the drugs of first choice. The main cardiac glycoside is digoxin. Other cardiac glycosides are now almost never used. With tachysystolic form of atrial fibrillation, digoxin is prescribed under the control of the frequency of ventricular contractions: the goal is a heart rate of about 70 per minute. If, while taking 1.5 tablets of digoxin (0.375 mg), it is not possible to reduce the heart rate to 70 per minute, P-blockers or amiodarone are added. In patients with sinus rhythm, digoxin is prescribed if there is severe heart failure (stage II B or III-IV FC) and the effect of taking an ACE inhibitor and a diuretic is insufficient. In patients with sinus rhythm with heart failure, digoxin is prescribed at a dose of 1 tablet (0.25 mg) per day. At the same time, for elderly people or patients who have had a myocardial infarction, as a rule, half or even a quarter of a tablet of digoxin (0.125-0.0625 mg) per day is enough. Intravenous glycosides are prescribed extremely rarely: only in acute heart failure or decompensation of chronic heart failure in patients with tachysystolic form of atrial fibrillation.
Even in such doses: from 1/4 to 1 tablet of digoxin per day, cardiac glycosides can improve the well-being and condition of severe patients with severe heart failure. When taking higher doses of digoxin, an increase in mortality in patients with heart failure is observed. With mild heart failure (stage II A), glycosides are useless.
The criteria for the effectiveness of glycosides are improved well-being, a decrease in heart rate (especially with atrial fibrillation), an increase in diuresis, and an increase in working capacity.
The main signs of intoxication: the occurrence of arrhythmias, loss of appetite, nausea, vomiting, weight loss. When using small doses of glycosides, intoxication develops extremely rarely, mainly when digoxin is combined with amiodarone or verapamil, which increase the concentration of digoxin in the blood. With timely detection of intoxication, temporary discontinuation of the drug with a subsequent dose reduction is usually sufficient. If necessary, additionally use potassium chloride 2% -200.0 and / or magnesium sulfate 25% -10.0 (if there is no AV blockade), for tachyarrhythmias - lidocaine, for bradyarrhythmias - atropine.

In addition to cardiac glycosides, there are non-glycoside inotropic drugs. These drugs are used only in cases of acute heart failure or severe decompensation in patients with chronic heart failure. The main non-glycoside inotropic drugs include: dopamine, dobutamine, epinephrine and norepinephrine. These drugs are administered only intravenously in order to stabilize the patient's condition, to bring him out of decompensation. After that, they switch to taking other medicines.

The main groups of non-glycoside inotropic drugs:
1. Catecholamines and their derivatives: adrenaline, norepinephrine, dopamine.
2. Synthetic sympathomimetics: dobutamine, isoproterenol.
3. Phosphodiesterase inhibitors: amrinone, milrinone, enoximone (drugs such as imobendan or vesnarinone, in addition to inhibiting phosphodiesterase, directly affect the sodium and / or calcium current through the membrane).

Table 8
Non-glycoside inotropic drugs

Norepinephrine. Stimulation of 1- and α-receptors causes increased contractility and vasoconstriction (but the coronary and cerebral arteries dilate). Reflex bradycardia is often noted.

dopamine. The precursor of norepinephrine and promotes the release of norepinephrine from nerve endings. Dopamine receptors are located in the vessels of the kidneys, mesentery, in the coronary and cerebral arteries. Their stimulation causes vasodilation in the vital important organs. When infused at a rate of up to about 200 micrograms / min (up to 3 micrograms / kg / min), vasodilation is provided (“renal” dose). With an increase in the rate of dopamine infusion of more than 750 μg / min, stimulation of α-receptors and a vasoconstrictor effect (“pressor” dose) begin to predominate. Therefore, it is rational to administer dopamine at a relatively low rate, approximately in the range from 200 to 700 µg/min. If a higher rate of dopamine administration is needed, they try to connect dobutamine infusion or switch to norepinephrine infusion.

Dobutamine. Selective stimulator of 1-receptors (however, there is also a slight stimulation of 2- and α-receptors). With the introduction of dobutamine, a positive inotropic effect and moderate vasodilation are noted.
In refractory heart failure, dobutamine infusion is used lasting from several hours to 3 days (tolerance usually develops by the end of 3 days). The positive effect of periodic infusion of dobutamine in patients with severe heart failure can persist for quite a long time - up to 1 month or more.

Heart - plentiful innervated organ. Among the sensitive formations of the heart, two populations of mechanoreceptors, concentrated mainly in the atria and left ventricle, are of primary importance: A-receptors respond to changes in the tension of the heart wall, and B-receptors are excited when it is passively stretched. Afferent fibers associated with these receptors are part of the vagus nerves. Free sensory nerve endings, located directly under the endocardium, are the terminals of afferent fibers that pass through the sympathetic nerves.

Efferent innervation of the heart carried out with the participation of both departments of the autonomic nervous system. The bodies of sympathetic preganglionic neurons involved in the innervation of the heart are located in the gray matter of the lateral horns of the upper three thoracic segments. spinal cord. Preganglionic fibers are sent to the neurons of the upper thoracic (stellate) sympathetic ganglion. The postganglionic fibers of these neurons, together with the parasympathetic fibers of the vagus nerve, form the upper, middle, and lower cardiac nerves. Sympathetic fibers permeate the entire organ and innervate not only the myocardium, but also elements of the conduction system.

The bodies of parasympathetic preganglionic neurons involved in innervation of the heart, located in medulla oblongata. Their axons are part of the vagus nerves. After the vagus nerve enters chest cavity branches depart from it, which are included in the composition of the cardiac nerves.

The processes of the vagus nerve, passing through the cardiac nerves, are parasympathetic preganglionic fibers. From them, excitation is transmitted to intramural neurons and then - mainly to the elements of the conduction system. The influences mediated by the right vagus nerve are addressed mainly to the cells of the sinoatrial node, and the left - to the cells of the atrioventricular node. The vagus nerves do not have a direct effect on the ventricles of the heart.

Innervating pacemaker tissue, autonomic nerves are able to change their excitability, thereby causing changes in the frequency of generation of action potentials and heart contractions ( chronotropic effect). Nervous influences change the rate of electrotonic transmission of excitation and, consequently, the duration of the phases of the cardiac cycle. Such effects are called dromotropic.

Since the action of mediators of the autonomic nervous system is to change the level of cyclic nucleotides and energy metabolism, autonomic nerves in general are able to influence the strength of heart contractions ( inotropic effect). Under laboratory conditions, the effect of changing the value of the excitation threshold of cardiomyocytes under the action of neurotransmitters was obtained, it is designated as bathmotropic.

Listed pathways of the nervous system on the contractile activity of the myocardium and the pumping function of the heart are, although extremely important, modulating influences secondary to myogenic mechanisms.

Training video of the innervation of the heart (nerves of the heart)

Inotropic drugs are a group of drugs that increase the force of myocardial contraction.

CLASSIFICATION
Cardiac glycosides (see section "Cardiac glycosides").
Non-glycoside inotropic drugs.
✧ Stimulants β 1-adrenergic receptors (dobutamine, dopamine).
✧ Phosphodiesterase inhibitors (amrinone℘ and milrinone ℘; in Russian Federation they are not registered; allowed only for short courses with circulatory decompensation).
✧ Calcium sensitizers (levosimendan).

MECHANISM OF ACTION AND PHARMACOLOGICAL EFFECTS
Stimulantsβ 1 -adrenergic receptors
The drugs of this group, administered intravenously, affect the following receptors:
β1- adrenoceptors (positive inotropic and chronotropic action);
β2-adrenergic receptors (bronchodilation, expansion of peripheral vessels);
dopamine receptors (increased renal blood flow and filtration, dilatation of the mesenteric and coronary arteries).
A positive inotropic effect is always combined with other clinical manifestations, which can have both positive and negative effects on clinical picture OSN. Dobutamine - selectiveβ1- adrenomimetic, but it also has a weak effect onβ 2 - and α 1-adrenergic receptors. With the introduction of conventional doses, an inotropic effect develops, sinceβ1-stimulating effect on the myocardium prevails. A drug
does not stimulate dopamine receptors regardless of dose, therefore, renal blood flow increases only due to an increase in stroke volume.

Phosphodiesterase inhibitors. The drugs of this subgroup, increasing myocardial contractility, also lead to a decrease in peripheral vascular resistance, which allows you to influence both preload and afterload in AHF.

calcium sensitizers. The drug of this group (levosimendan) increases the affinity of Ca 2+ to troponin C, which increases myocardial contraction. It also has a vasodilating effect (reducing the tone of the veins and arteries). Levosimendan has an active metabolite with a similar mechanism of action and a half-life of 80 hours, which causes a hemodynamic effect within 3 days after a single dose of the drug.

Clinical Significance
Phosphodiesterase inhibitors may increase mortality.
In acute left ventricular failure secondary to acute myocardial infarction, the administration of levosimendan was accompanied by a decrease in mortality, achieved in the first 2 weeks after the start of treatment, which persisted in the future (for 6 months of observation).
Levosimendan is superior to dobutamine fornii effects on blood circulation in patients with severe decompensation of CHF and low cardiac output.

INDICATIONS
Acute heart failure. Their purpose does not depend on the presence of venous congestion or pulmonary edema. There are several algorithms for prescribing inotropic drugs.
Shock due to an overdose of vasodilators, blood loss, dehydration.
Inotropic drugs should be prescribed strictly individually, it is necessary to evaluate the indicators of central hemodynamics, and also change the dose of inotropic drugs in accordance with
with the clinical picture.

Dosing
Dobutamine. The initial infusion rate is 2–3 μg per 1 kg of body weight per minute. With the introduction of dobutamine in combination with vasodilators, control of the pulmonary artery wedge pressure is necessary. If the patient received beta-adrenergic blockers, then the action of dobutamine will develop only after the elimination of beta-adrenergic blocker.

Algorithm for the use of inotropic drugs (national recommendations).

Algorithm for the use of inotropic drugs (American Heart Association).

Dopamine. The clinical effects of dopamine are dose dependent.
At low doses (2 μg per 1 kg of body weight per minute or less in terms of lean body weight), the drug stimulates D 1 - and D 2-receptors, which is accompanied by vasodilatation of the mesentery and kidneys and allows you to increase GFR in case of refractoriness to the action of diuretics.
In medium doses (2-5 mcg per 1 kg of body weight per minute), the drug stimulatesβ1-adrenergic receptors of the myocardium with an increase in cardiac output.
At high doses (5–10 micrograms per kg of body weight per minute), dopamine activatesα 1-adrenergic receptors, which leads to an increase in peripheral vascular resistance, LV filling pressure, tachycardia. Usually, high doses appointed to emergency cases for a rapid increase in SBP.

Clinical features:
tachycardia is always more pronounced with dopamine compared with dobutamine;
the calculation of the dose is carried out only on lean, and not on the total body weight;
persistent tachycardia and / or arrhythmia that occurred with the introduction of a "renal dose" indicate that the rate of administration of the drug is too high.

Levosimendan. The introduction of the drug begins with a loading dose (12–24 μg per 1 kg of body weight for 10 minutes), and then they switch to a long-term infusion (0.05–0.1 μg per 1 kg of body weight). An increase in stroke volume, a decrease in pulmonary artery wedge pressure are dose-dependent. In some cases it is possibleincreasing the dose of the drug to 0.2 μg per 1 kg of body weight. The drug is effective only in the absence of hypovolemia. Levosimendan is compatible withβ -blockers and does not lead to an increase in the number of rhythm disturbances.

Features of prescribing inotropic drugs to patients with decompensated chronic heart failure
Due to a pronounced adverse effect on the prognosis, non-glycoside inotropic drugs can only be prescribed in the form of short courses (up to 10-14 days) with a clinical picture of persistent arterial hypotension in patients with severe CHF decompensation and a reflex kidney.

SIDE EFFECTS
Tachycardia.
Supraventricular and ventricular arrhythmias.
Subsequent increase in left ventricular dysfunction (due to increased energy consumption to ensure increasing myocardial work).
Nausea and vomiting (dopamine in high doses).

Adrenalin. This hormone is produced in the adrenal medulla and adrenergic nerve endings, is a direct-acting catecholamine, causes stimulation of several adrenergic receptors at once: a1-, beta1- and beta2- Stimulation of a1-adrenergic receptors is accompanied by a pronounced vasoconstrictor effect - a general systemic vasoconstriction, including precapillary vessels of the skin, mucous membranes, kidney vessels, as well as a pronounced constriction of the veins. Stimulation of beta1-adrenergic receptors is accompanied by a distinct positive chronotropic and inotropic effect. Stimulation of beta2-adrenergic receptors causes bronchial dilatation.

Adrenaline is often indispensable in critical situations, since it can restore spontaneous cardiac activity during asystole, increase blood pressure during shock, improve the automatism of the heart and myocardial contractility, and increase heart rate. This drug stops bronchospasm and is often the drug of choice for anaphylactic shock. It is used mainly as a first aid and rarely for long-term therapy.

Solution preparation. Adrenaline hydrochloride is available as a 0.1% solution in 1 ml ampoules (diluted 1:1000 or 1 mg/ml). For intravenous infusion 1 ml of a 0.1% solution of epinephrine hydrochloride is diluted in 250 ml of isotonic sodium chloride solution, which creates a concentration of 4 μg / ml.

Doses at intravenous administration:

1) in any form of cardiac arrest (asystole, VF, electromechanical dissociation), the initial dose is 1 ml of a 0.1% solution of adrenaline hydrochloride diluted in 10 ml of isotonic sodium chloride solution;

2) with anaphylactic shock and anaphylactic reactions - 3-5 ml of a 0.1% solution of adrenaline hydrochloride diluted in 10 ml of isotonic sodium chloride solution. Subsequent infusion at a rate of 2 to 4 mcg / min;

3) with persistent arterial hypotension, the initial rate of administration is 2 μg / min, if there is no effect, the rate is increased until the required level of blood pressure is reached;

4) action depending on the rate of administration:

Less than 1 mcg / min - vasoconstrictor,

From 1 to 4 mcg / min - cardiostimulating,

From 5 to 20 mcg / min - a-adrenergic stimulant,

More than 20 mcg / min - the predominant a-adrenergic stimulant.

Side effect: adrenaline can cause subendocardial ischemia and even myocardial infarction, arrhythmias and metabolic acidosis; small doses of the drug can lead to acute kidney failure. In this regard, the drug does not find wide application for long-term intravenous therapy.

Norepinephrine. Natural catecholamine, which is the precursor of adrenaline. It is synthesized in the postsynaptic endings of the sympathetic nerves and performs a neurotransmitter function. Norepinephrine stimulates a-, beta1-adrenergic receptors, almost no effect on beta2-adrenergic receptors. It differs from adrenaline in a stronger vasoconstrictor and pressor action, less stimulating effect on automatism and contractile ability of the myocardium. The drug causes a significant increase in peripheral vascular resistance, reduces blood flow in the intestines, kidneys and liver, causing severe renal and mesenteric vasoconstriction. The addition of small doses of dopamine (1 µg/kg/min) helps to preserve renal blood flow when norepinephrine is administered.

Indications for use: persistent and significant hypotension with a drop in blood pressure below 70 mm Hg, as well as a significant decrease in OPSS.

Solution preparation. The contents of 2 ampoules (4 mg of norepinephrine hydrotartrate are diluted in 500 ml of isotonic sodium chloride solution or 5% glucose solution, which creates a concentration of 16 μg / ml).

Doses for intravenous administration. The initial rate of administration is 0.5-1 μg / min by titration until the effect is obtained. Doses of 1-2 mcg/min increase CO, more than 3 mcg/min - have a vasoconstrictor effect. With refractory shock, the dose can be increased to 8-30 mcg / min.

Side effect. With prolonged infusion, renal failure and other complications (gangrene of the extremities) associated with the vasoconstrictor effects of the drug may develop. With extravasal administration of the drug, necrosis may occur, which requires chipping the extravasate area with a solution of phentolamine.

Dopamine. It is the precursor of norepinephrine. It stimulates a- and beta-receptors, has a specific effect only on dopaminergic receptors. The effect of this drug is largely dependent on the dose.

Indications for use: acute heart failure, cardiogenic and septic shock; the initial (oliguric) stage of acute renal failure.

Solution preparation. Dopamine hydrochloride (dopamine) is available in 200 mg ampoules. 400 mg of the drug (2 ampoules) are diluted in 250 ml of isotonic sodium chloride solution or 5% glucose solution. In this solution, the concentration of dopamine is 1600 µg/ml.

Doses for intravenous administration: 1) the initial rate of administration is 1 μg / (kg-min), then it is increased until the desired effect is obtained;

2) small doses - 1-3 mcg / (kg-min) are administered intravenously; while dopamine acts mainly on the celiac and especially the renal region, causing vasodilation of these areas and contributing to an increase in renal and mesenteric blood flow; 3) with a gradual increase in speed to 10 μg/(kg-min), peripheral vasoconstriction and pulmonary occlusive pressure increase; 4) high doses - 5-15 mcg / (kg-min) stimulate myocardial beta1 receptors, have an indirect effect due to the release of noradrenaline in the myocardium, i.e. have a distinct inotropic effect; 5) in doses above 20 mcg / (kg-min), dopamine can cause vasospasm of the kidneys and mesentery.

To determine the optimal hemodynamic effect, it is necessary to monitor hemodynamic parameters. If tachycardia occurs, it is recommended to reduce the dose or discontinue further administration. Do not mix the drug with sodium bicarbonate, as it is inactivated. Long-term use of a- and beta-agonists reduces the effectiveness of beta-adrenergic regulation, the myocardium becomes less sensitive to the inotropic effects of catecholamines, up to the complete loss of the hemodynamic response.

Side effects: 1) increased DZLK, tachyarrhythmias may occur; 2) in high doses can cause severe vasoconstriction.

Dobutamine (dobutrex). It is a synthetic catecholamine that has a pronounced inotropic effect. The main mechanism of its action is the stimulation of beta receptors and an increase in myocardial contractility. Unlike dopamine, dobutamine does not have a splanchnic vasodilating effect, but tends to systemic vasodilation. It increases heart rate and DZLK to a lesser extent. In this regard, dobutamine is indicated in the treatment of heart failure with low CO, high peripheral resistance against the background of normal or elevated blood pressure. When using dobutamine, like dopamine, ventricular arrhythmias are possible. An increase in heart rate by more than 10% of the initial level can cause an increase in the zone of myocardial ischemia. In patients with concomitant vascular lesions, ischemic necrosis of the fingers is possible. In many patients treated with dobutamine, there was an increase in systolic blood pressure by 10-20 mm Hg, and in some cases, hypotension.

Indications for use. Dobutamine is prescribed for acute and chronic heart failure caused by cardiac ( acute infarction myocardial infarction, cardiogenic shock) and non-cardiac causes ( acute insufficiency blood circulation after injury, during and after surgery), especially in cases where the average blood pressure is above 70 mm Hg, and the pressure in the pulmonary system is above normal values. Assign when high blood pressure filling of the ventricle and the risk of overloading the right heart, leading to pulmonary edema; with a reduced MOS due to the PEEP regimen during mechanical ventilation. During treatment with dobutamine, as with other catecholamines, careful monitoring of heart rate, heart rate, ECG, blood pressure and infusion rate is necessary. Hypovolaemia must be corrected before starting treatment.

Solution preparation. A vial of dobutamine containing 250 mg of the drug is diluted in 250 ml of 5% glucose solution to a concentration of 1 mg / ml. Saline solutions not recommended for dilution because SG ions may interfere with dissolution. Do not mix dobutamine solution with alkaline solutions.

Side effect. Patients with hypovolemia may experience tachycardia. According to P. Marino, ventricular arrhythmias are sometimes observed.

Contraindicated in hypertrophic cardiomyopathy. Due to its short half-life, dobutamine is administered continuously intravenously. The effect of the drug occurs in the period from 1 to 2 minutes. It usually takes no more than 10 minutes to create its stable plasma concentration and ensure the maximum effect. The use of a loading dose is not recommended.

Doses. The rate of intravenous administration of the drug, necessary to increase the stroke and minute volume of the heart, ranges from 2.5 to 10 μg / (kg-min). It is often necessary to increase the dose to 20 mcg / (kg-min), in more rare cases - more than 20 mcg / (kg-min). Dobutamine doses above 40 µg/(kg-min) may be toxic.

Dobutamine can be used in combination with dopamine to increase systemic BP in hypotension, increase renal blood flow and urine output, and prevent the risk of pulmonary congestion seen with dopamine alone. The short half-life of beta-adrenergic receptor stimulants, equal to several minutes, allows you to very quickly adapt the administered dose to the needs of hemodynamics.

Digoxin. Unlike beta-adrenergic agonists, digitalis glycosides have a long half-life (35 hours) and are eliminated by the kidneys. Therefore, they are less manageable and their use, especially in intensive care units, is risky. possible complications. If sinus rhythm is maintained, their use is contraindicated. With hypokalemia, renal failure against the background of hypoxia, manifestations of digitalis intoxication occur especially often. The inotropic effect of glycosides is due to the inhibition of Na-K-ATPase, which is associated with the stimulation of Ca2+ metabolism. Digoxin is indicated for atrial fibrillation with VT and paroxysmal atrial fibrillation. For intravenous injections in adults, it is used at a dose of 0.25-0.5 mg (1-2 ml of a 0.025% solution). Introduce it slowly into 10 ml of 20% or 40% glucose solution. In emergency situations, 0.75-1.5 mg of digoxin is diluted in 250 ml of a 5% dextrose or glucose solution and administered intravenously over 2 hours. The required level of the drug in the blood serum is 1-2 ng / ml.

The contractile function of the myocardium is one of the key links in the circulatory system. Contractility is due to the interaction of myocardial contractile proteins and cytosol calcium ions. There are the following main pathophysiological approaches to enhance contractility.

Increase in the intracellular content of calcium ions.

Increased sensitivity of contractile proteins to calcium ions.

The first approach can be implemented using the following mechanisms (Figure 14-1).

Inhibition of Na +, K + -dependent ATPase and slowing down the exchange of sodium and potassium ions. The drugs that act in this way include cardiac glycosides.

An increase in cAMP concentration with β-adrenergic stimulation (dobutamine, dopamine) or phosphodiesterase inhibition (milrinone * amrinone *). cAMP activates protein kinases that phosphorylate voltage-gated calcium channel proteins, which increases the entry of calcium ions into the cell.

An increase in the sensitivity of contractile proteins of cardiomyocytes to calcium ions is noted when prescribing a new group of inotropic drugs - "calcium sensitizers" (levosimendan).

14.1. CARDIAC GLYCOsideS

Due to the negative chronotropic, neuromodulatory and positive inotropic effects, cardiac glycosides are often used in heart failure. For more than 200 years of use, interest in this group of drugs has faded and intensified again. Even at present, some aspects of the clinical use of cardiac glycosides remain unspecified, so the history of the study of these drugs continues.

Rice. 14.1. The mechanism of action of drugs with a positive inotropic effect. AC - adenylate cyclase, PK - protein kinase, PDE - phosphodiesterase, SR - sarcoplasmic reticulum.

Classification

Traditionally, cardiac glycosides are divided into polar (hydrophilic) and non-polar (lipophilic). Polar (hydrophilic) cardiac glycosides dissolve well in water, but poorly in lipids, are not sufficiently adsorbed in the gastrointestinal tract, bind poorly to plasma proteins, hardly undergo biotransformation, and are excreted mainly by the kidneys. This group of cardiac glycosides includes strophanthin-K, acetylstrophanthin * and lily of the valley glycoside.

More lipophilic drugs are better absorbed in the gastrointestinal tract, more associated with blood proteins and metabolized in the liver. According to the increase in lipophilicity, cardiac glycosides can be arranged as follows: lanatoside C, digoxin, methyldigoxin, digitoxin.

IN clinical practice currently, as a rule, digoxin, lanatoside C and strophanthin-K are prescribed. Digitoxin is rarely used due to its long half-life. The pharmacodynamic effects of lily of the valley glycoside are the least pronounced among cardiac glycoside preparations. Strofantin-K is used in stationary conditions. Thus, digoxin is most widely used in clinical practice. Methyldigoxin differs from digoc-

more complete absorption, but this does not significantly affect the main pharmacodynamic parameters, so methyldigoxin is practically not used.

Mechanism of action and main pharmacodynamic effects

The mechanism of action of cardiac glycosides is to inhibit Na +, K + -dependent ATPase, which leads to an increase in the intracellular content of sodium ions, which are exchanged for calcium ions. As a result of these changes, the intracellular concentration of calcium ions in the sarcoplasmic reticulum increases. When an action potential occurs, more calcium ions enter the cytosol of cardiomyocytes and interact with troponin C. The end result of the action of cardiac glycosides is an increase in the number of actin active sites available for communication with another contractile protein, myosin, which is accompanied by an increase in cardiomyocyte contractility. At the same time, due to an increase in the content of calcium ions and a decrease in the concentration of potassium ions in myocardial cells, in certain situations, electrical instability of cardiomyocytes develops, which is manifested by various arrhythmias (positive bathmotropic effect).

The positive inotropic effect of cardiac glycosides is to increase the strength and speed of myocardial contraction. As a result of an increase in myocardial contractility, the stroke and minute volumes of blood circulation increase. Due to the decrease in end-systolic and end-diastolic volumes of the heart, its size is reduced and the need for oxygen in this organ is reduced.

The negative dromotropic effect of cardiac glycosides is manifested in the prolongation of the refractory period of the atrioventricular node, so the number of impulses passing through this connection per unit of time decreases. Due to this effect, cardiac glycosides are prescribed for atrial fibrillation. With atrial fibrillation, 400-800 impulses per minute enter the atrioventricular node, but only 130-200 impulses pass into the ventricles (depending on the age and functional state of the atrioventricular node, this range can be wider and reach 50-300 impulses per minute). Cardiac glycosides increase the refractory period and reduce throughput» atrioventricular node up to 60-80 per minute. In this case, the diastole is lengthened, resulting in improved ventricular filling and, consequently, an increase in cardiac output.

In patients with atrioventricular blockade, the appointment of cardiac glycosides may further worsen atrioventricular

cular conduction and occurrence of seizures Morgagni-Adams-Stokes. With atrial fibrillation in combination with Wolff-Parkinson-White syndrome, cardiac glycosides, lengthening the time of passage of excitation through the atrioventricular junction, reduce the refractory period of additional pathways for conducting impulses bypassing the atrioventricular node, which is accompanied by an increase in the number of impulses conducted to the ventricles.

The negative chronotropic effect of cardiac glycosides is characterized by a decrease in heart rate due to a decrease in the automatism of the sinus node. This occurs as a result of an increase in the tone of the vagus nerve during stimulation of the baroreceptors of the aortic arch and carotid sinus.

IN last years great importance is attached to the neuromodulatory effect of cardiac glycosides, which develops when taking drugs even at low doses. At the same time, inhibition of the activity of the sympathoadrenal system is noted, which is manifested by a decrease in the content of norepinephrine in the blood plasma. With inhibition of Na + , K + -dependent ATPase in the epithelial cells of the renal tubules, the reabsorption of sodium ions decreases and the concentration of these ions in the distal tubules increases, which is accompanied by a decrease in renin secretion.

Pharmacokinetics

The absorption of digoxin largely depends on the activity of the enterocyte transport protein glycoprotein P, which “throws” the drug into the intestinal lumen. The metabolism of cardiac glycosides in the liver depends on the polarity of drugs (this figure is higher for lipophilic drugs) (Table 14-1). As a result, the bioavailability of digoxin is 50-80%, and lanatoside C - 15-45%.

Table 14-1. Basic pharmacokinetic parameters of cardiac glycosides

Once in the blood, cardiac glycosides bind to plasma proteins to varying degrees. The highest affinity for blood plasma proteins is noted for low-polarity, and the smallest - for polar cardiac glycosides.

Cardiac glycosides have a large volume of distribution, i. accumulate mainly in tissues. For example, the volume of distribution of digoxin is about 7 L/kg. This is due to the fact that the drugs of this group bind to Na +, K + -dependent ATPase of skeletal muscles, therefore, in the body, cardiac glycosides are deposited mainly in skeletal muscles. Drugs of this group penetrate poorly into adipose tissue, which is of practical importance: in patients with obesity, the dose should be calculated taking into account not real, but ideal body weight. On the other hand, it is necessary to take into account the presence of cachexia in severe heart failure.

Approximately 10% of patients note "intestinal" metabolism, which consists in the processing of digoxin into inactive dihydrodigoxin under the influence of intestinal microflora. This may be the reason for the low content of drugs in the blood plasma.

Indications for use and dosing regimen

Indications for the appointment of cardiac glycosides, in fact, have changed little over 200 years of the use of these drugs in clinical practice: these are heart failure and atrial fibrillation. Sometimes cardiac glycosides are used to prevent AV reciprocal tachycardia.

Thanks to the development of ideas about the pathogenesis of heart failure, the creation of new drugs, the introduction into clinical practice of the principles of therapy based on evidence-based medicine, pharmacotherapy with cardiac glycosides has fundamentally changed.

Considering the indications for the appointment of cardiac glycosides, first of all, heart failure with sinus rhythm and atrial fibrillation should be distinguished. At the turn of the 80-90s of the last century, after the development of ACE inhibitors, approaches to the treatment of heart failure changed, due to which it is now possible to effectively treat severe patients with this disease and sinus rhythm without the use of cardiac glycosides. The need to be careful when prescribing cardiac glycosides was confirmed by the results of clinical trials of drugs with a positive inotropic effect: an increase in mortality was found with the ingestion of vesnarinone *, xamoterol *, milrinone * and a number of other inotropic drugs. In heart failure with atrial fibrillation, cardiac glycosides continued to be the drugs of choice, since β-blockers have not yet been widely used in clinical practice, and blockers of slow calcium channels of the non-dihydropyridine series, on the one hand,

do not cause such a significant decrease in heart rate as cardiac glycosides, on the other hand, they adversely affect the prognosis of the disease. In 1997, the results of a large placebo-controlled study (7000 patients with heart failure with sinus rhythm) were published, in which it was proved that digoxin does not affect the prognosis of the disease; however, by improving the clinical picture of heart failure, digoxin retains its value in the treatment of some patients with this disease and sinus rhythm, for example, in patients with symptoms of severe heart failure that persist despite the appointment of adequate doses of ACE inhibitors, diuretics and β-blockers .

Currently, β-blockers are beginning to be widely used in patients with atrial fibrillation and heart failure, i.e. in a situation in which cardiac glycosides have traditionally been used. It is becoming common to add small doses of metoprolol, carvedilol, or bisoprolol to digoxin and then titrate them. As the heart rate decreases, the dose of digoxin can be reduced (up to complete abolition).

A high volume of distribution is considered a sign that it takes time for the drug to accumulate in the tissues before an equilibrium concentration is established. To accelerate this process, a loading dose regimen (digitalization) is used with the transition to a maintenance dose of the drug. According to the classical principles of clinical pharmacology, digitalization is a mandatory step in the treatment of heart failure. Currently, digitalization is rarely performed, since it is impossible to predict the individual sensitivity of the patient to cardiac glycosides. In addition, the introduction of new approaches to the treatment of heart failure, such as the use of vasodilators (nitrates), neurohumoral antagonists (ACE inhibitors, angiotensin II receptor antagonists), inotropic drugs (dobutamine and dopamine), makes it possible to achieve stabilization of the patient's state of digitalization. It should also take into account the presence of various risk factors for glycoside intoxication in patients with heart failure (electrolyte balance and acid-base disorders, taking drugs that increase the concentration of cardiac glycosides in the blood). Digitalization is sometimes carried out with a tachysystolic form of atrial fibrillation in the absence of pronounced signs of heart failure. The loading dose of digoxin can be calculated using the following formula.

Loading dose \u003d (7 l / kg x ideal body weight x 1.5 μg / l) 0.65, where 7 l / kg is the volume of distribution of digoxin, the "ideal body weight" is calculated

according to the nomogram for patients with obesity (with cachexia, real body weight is taken into account), 1.5 μg / l is the therapeutic concentration of the drug in blood plasma, 0.65 is the bioavailability of digoxin.

If saturation is carried out by intravenous administration of digoxin, the same formula is used, except for bioavailability. Digitalization with the appointment of a loading dose is called fast.

The dosing regimen for lanatoside C has not been developed in detail, since the drug is used much less frequently than digoxin. Calculation of these parameters for strophanthin-K is impractical, since drugs are used for a short time and dosage form for taking strophanthin-K inside is not.

The maintenance dose of digoxin is 0.0625-0.5 mg/day, depending on the age of the patient, the state of kidney function, heart rate, concomitant therapy and individual tolerability of the drug. Based on basic pharmacokinetic principles, a maintenance dose of digoxin can be calculated. First, the clearance of digoxin is determined by the following formula:

In heart failure, a different formula is used (taking into account reduced perfusion of the kidneys and liver):

This formula was derived from the processing of pharmacokinetic parameters obtained from a large number of patients with heart failure taking digoxin. The value expressed in ml/min is converted to l/day.

Creatinine clearance can be determined using the Cockcroft-Goll formula.

For women, the result is multiplied by 0.85.

Currently, digoxin therapy is started immediately with a maintenance dose, while the equilibrium concentration of the drug is noted after 4-6 half-lives. This rate of saturation is called slow digitalization.

Therapeutic drug monitoring

Determination of the concentration of digoxin in blood plasma is a standard method for monitoring the effectiveness and safety of the drug. The therapeutic range of digoxin in the blood is 1-2 ng / ml (0.5-1.5 μg / l). It is known that the main pharmacodynamic effects of the drug (positive inotropic and negative chronotropic) depend on the dose, therefore, according to the fundamental principles of clinical pharmacology, the usual practice in the management of patients with heart failure was to prescribe the maximum tolerated doses. medicinal product for the greatest therapeutic effect. However, based on the results of several large studies, this approach has been revised.

It became known that therapeutic and toxic concentrations of digoxin in blood plasma often "overlap".

It has been shown that with the abolition of digoxin, the course of heart failure worsens, but this is not related to the concentration of the drug in the blood plasma before withdrawal (low or high).

It has been proven that the neuromodulatory effect of digoxin (decrease in renin activity and concentration of norepinephrine in the blood) appears already at a low content of digoxin in the blood plasma, and this effect does not increase with an increase in the concentration of the drug.

The highest lethality among patients with heart failure and sinus rhythm is noted in the group with plasma digoxin content of more than 1.5 ng/ml.

Thus, at present, the main trend in the clinical use of cardiac glycosides is the rejection of the maximum tolerated doses.

Side effects

The frequency of glycoside intoxication is 10-20%. This is due to the small breadth of the therapeutic action of cardiac glycosides (toxic doses of drugs exceed the optimal therapeutic doses by no more than 1.8-2 times). Cardiac glycosides are characterized by a pronounced ability to accumulate, and individual tolerance to these drugs in patients varies over a very wide range. The lowest tolerance is noted, as a rule, in severe patients.

Factors contributing to the development of glycoside intoxication are presented below.

Elderly age.

Late stage CHF.

Severe dilatation of the heart.

Acute myocardial infarction.

Severe myocardial ischemia.

Inflammatory lesions of the myocardium.

Hypoxia of any etiology.

Hypokalemia and hypomagnesemia.

Hypercalcemia.

Dysfunction of the thyroid gland.

Increased activity of the sympathetic nervous system.

Respiratory failure.

Renal and liver failure.

Acid-base disorders (alkalosis).

Hypoproteinemia.

Electropulse therapy.

Genetic polymorphism of the glycoprotein P. Clinical manifestations digitalis intoxication are listed below.

Cardiovascular system: ventricular extrasystole (often bigeminy, polytopic ventricular extrasystole), nodal tachycardia, sinus bradycardia, sinoatrial block, atrial fibrillation, AV block.

Gastrointestinal: anorexia, nausea, vomiting, diarrhea, abdominal pain, intestinal necrosis.

Organ of vision: yellow-green coloring of objects, flies before the eyes, decreased visual acuity, perception of objects in a reduced or enlarged form.

Nervous system: sleep disorders, headaches, dizziness, neuritis, paresthesia.

Hematological disorders: thrombocytopenic purpura, epistaxis, petechiae.

Intoxication should be suspected if even one symptom appears from any organ or system. As a rule, the earliest symptom of intoxication with cardiac glycosides is anorexia and / or nausea.

Volume medical measures with glycoside intoxication, it depends primarily on the damage to the CCC, i.e. arrhythmias. If intoxication is suspected, cardiac glycosides should be discontinued, an ECG should be performed, and the content of potassium and digoxin in the blood plasma should be determined. If there are indications for the appointment of antiarrhythmic drugs in the case of ventricular arrhythmias, class IB drugs (lidocaine or mexile-

tin), since these drugs do not affect the conduction of the atrial myocardium and the AV node. Antiarrhythmic drugs are used only intravenously, since in this case, depending on the effect, it is possible to quickly adjust the dose. Inside, antiarrhythmic drugs are not prescribed.

If there are indications for the treatment of supraventricular arrhythmias, β-blockers or slow calcium channel blockers can be used, but only if AV conduction is controlled.

With severe bradycardia, sinoatrial or AV blockade, m-anticholinergics are administered. β-Adrenergic agonists are dangerous to use due to the possible increase in the arrhythmogenic effect of cardiac glycosides. With the ineffectiveness of drug therapy, the issue of temporary pacing is decided.

With concomitant hypokalemia, potassium preparations are prescribed intravenously. Drugs containing potassium are also indicated with a normal content of this element in the blood, if the patient has arrhythmias. However, it should be remembered that potassium causes a slowdown in AV conduction, therefore, in case of violations of conduction along the AV node (blockade of I-II degree) in the case of glycoside intoxication, potassium preparations should be administered with caution.

The most effective, but expensive method of treatment is the introduction of antibodies to digoxin. A positive effect (stopping arrhythmias) develops within 30-60 minutes. Traditional antidotes (sodium dimercaptopropanesulfonate, edetic acid) for intoxication with cardiac glycosides from the standpoint of evidence-based medicine did not appreciate.

Contraindications

Glycoside intoxication is considered an absolute contraindication to the appointment of cardiac glycosides. Relative contraindications are sinus node weakness syndrome and AV blockade of I-II degree (danger of aggravating sinus node dysfunction and further slowing of conduction through the AV node), ventricular arrhythmias (danger of increased arrhythmias), atrial fibrillation in combination with Wolff-Parkinson syndrome- White, sinus bradycardia. It is not advisable to use cardiac glycosides in cases of heart failure without impaired systolic function of the left ventricle (hypertrophic cardiomyopathy, aortic stenosis, mitral stenosis with sinus rhythm, constrictive pericarditis).

Efficacy and safety assessmentEfficiency mark

When evaluating the effectiveness of therapy with cardiac glycosides, stable and decompensated heart failure should be separated. With decompensation, pharmacotherapy provides for an integrated approach, which consists in changing the dosing regimen (or prescribing) of all major groups of drugs (diuretics, ACE inhibitors, angiotensin II receptor antagonists, nitrates). Cardiac glycosides are an integral part of this approach. The results of treatment will depend on the rational use of all drugs. For example, it is difficult to achieve a decrease in heart rate in atrial fibrillation in conditions of insufficient effectiveness of diuretic therapy. On the other hand, it is incorrect to assume that the increase in cardiac contractility is caused only by the prescription of cardiac glycosides, since the patient receives drugs that affect preload and afterload and, according to the Frank-Starling law, change the inotropic function of the heart. For these reasons, the assessment of the effectiveness of cardiac glycosides in decompensation reflects the impact of the entire complex of therapeutic measures (provided that the content of digoxin in the blood is within the therapeutic range). In stable heart failure, in a situation where the doctor adds cardiac glycosides to the ongoing treatment, the dynamics of dyspnea, the results of a 6-minute walk test, heart rate reflect the effect of only cardiac glycosides (if concomitant therapy was not changed).

Safety assessment

Safety assessment is necessary for the prevention and diagnosis of glycoside intoxication. "Intoxication with cardiac glycosides" is a historically established term that reflects a set of undesirable clinical and instrumental changes that occur when taking cardiac glycosides. It should be noted that symptoms of intoxication may appear before the development clinical effect, and earlier such cases differed from the actual intoxication and were called intolerance to this group of drugs. Currently, the term "glycoside intoxication" includes the concept of intolerance. The main measures to prevent intoxication are given below.

Questioning the patient to identify symptoms of intoxication.

Pulse and heart rate control.

ECG analysis.

Monitoring the content of potassium in the blood, kidney function (concentration of creatinine and urea in the blood).

Dose adjustment of concomitant drugs that interact adversely with cardiac glycosides.

Control of the content of digoxin in blood plasma.

It should be noted that changes in the electrocardiogram that occur during treatment with cardiac glycosides (“trough-shaped” depression of the segment ST, interval shortening QT, tooth changes T), do not correlate with the concentration of these drugs in the blood plasma and in isolation they are not regarded as indicators of saturation or intoxication with cardiac glycosides.

Interaction

Digoxin interacts with a number of drugs (app. 3, see). Pharmacodynamic interaction must be considered when prescribing digoxin with virtually all antiarrhythmic drugs (with the exception of class IB), since in this case inhibition of conduction through the atria and atrioventricular node is possible.

14.2. ADRENORECEPTOR AGONISTS

The drugs of this subgroup of inotropic drugs include dobutamine, dopamine, epinephrine and norepinephrine. The positive inotropic effect of adrenoreceptor agonists is due to stimulation of β 1 -adrenergic receptors of the heart, activation of the G-protein system that interacts with adenylate cyclase, which leads to an increase in cAMP production, an increase in the calcium content in the cytosol and the development of a positive inotropic effect.

Adrenoreceptor agonists also have a vasoconstrictor effect, due to which these drugs are used in acute and chronic heart failure, including those refractory to diuretic drugs, cardiac glycosides and vasodilators. A positive inotropic effect is a consequence of stimulation of β 1 -adrenergic receptors, but depending on the additional properties and the doses used, the drugs have a different effect on peripheral vascular tone, renal blood flow and blood pressure (Table 14-2).

Table 14-2. Effects of adrenoceptor agonists

The end of the table. 14-2

dobutamine

Dobutamine is a synthetic agonist consisting of two isomers. Stimulation of β-adrenergic receptors is associated with the (+)-isomer, and α-adrenergic receptors - with the (-)-isomer. However, the α-adrenergic effects of the drug are practically not expressed due to the ability of the (+)-isomer to block α-adrenergic receptors. With intravenous administration of dobutamine, a dose-dependent increase in cardiac output is noted due to an increase in myocardial contractility, a decrease in preload and afterload. When prescribed in medium doses, dobutamine has little effect on blood pressure (probably, peripheral vasoconstriction due to blockade of α-adrenergic receptors is leveled by vasodilation mediated by the effect on β 2 -adrenergic receptors). The vascular resistance in the pulmonary circulation decreases during the use of the drug. Due to the short half-life, dobutamine should be administered continuously. Dobutamine activity may decrease if the patient is taking β-blockers. In this case, a latent α-adrenergic effect (narrowing of peripheral vessels and an increase in blood pressure) is possible. On the contrary, with the blockade of α-adrenergic receptors, there is a possibility of a greater severity of the effects of stimulation of β 1 and β 2 -adrenergic receptors (tachycardia and peripheral vasodilation).

With prolonged continuous therapy (more than 72 hours), addiction to the drug develops.

Indications

Indications for prescribing dobutamine are acute (pulmonary edema, cardiogenic shock) and severe CHF, heart failure in the acute stage of myocardial infarction or cardiac surgery, and an overdose of β-blockers. An acute pharmacological test with dobutamine is used to diagnose coronary artery disease (evaluate local contractility of the left ventricle using echocardiography or radionuclide ventriculography).

Side effects

Side effects of dobutamine are heart rhythm disturbance and angina pectoris.

Contraindications

Dobutamine is contraindicated in hypersensitivity to him.

Precautionary measures

It is necessary to control the content of potassium in the blood plasma. Be aware of the incompatibility of dobutamine with alkaline solutions.

The half-life of the drug is 2-4 minutes. Dobutamine is administered intravenously at a rate of 2.5-20 μg/kg body weight per minute (according to indications, the rate of administration can be increased to 40 μg/kg body weight per minute). A stable concentration of the drug in the blood plasma is noted 10-15 minutes after dose adjustment. Dobutamine is used under the control of blood pressure, heart rate and ECG. Catheterization as indicated pulmonary artery with direct measurement of hemodynamic parameters.

dopamine

Dopamine is an endogenous catecholamine that serves as a precursor to norepinephrine. Dopamine acts indirectly through the release of norepinephrine from nerve endings. The pharmacodynamic effects of the drug are associated with a stepwise activation of D 1 - and D 2 -receptors for dopamine (at a dose of less than 2 μg / kg of body weight per minute) and β-adrenergic receptors (at a dose of 2-10 μg / kg of body weight per minute) and α -adrenergic receptors (at a dose of more than 10 mcg / kg of body weight per minute). As a result of stimulation of dopamine receptors, not only renal, but also mesenteric and cerebral blood flow increases, while OPSS decreases. At doses above 15 micrograms/kg body weight per minute, the drug (in some patients at a dose of 5 mg/kg body weight per minute) acts virtually like norepinephrine. With prolonged administration of dopamine, even at the optimal rate, there is a gradual accumulation of norepinephrine, which inevitably leads to an increase in heart rate and total peripheral vascular resistance.

Indications

Dopamine is prescribed in case of arterial hypotension with cardiogenic and septic shock heart failure (heart attack

myocardium, after surgical operations), as well as in acute renal failure.

Side effects

Side effects of dopamine are heart rhythm disturbance and angina pectoris.

Contraindications

Dopamine is contraindicated in pheochromocytoma, ventricular arrhythmias.

Precautionary measures

It is necessary to control the content of potassium in the blood plasma. Due to the decrease in peripheral vascular resistance, which may occur with the appointment of dopamine in low doses, the use of the drug in patients with obstruction of the outflow tract of the left ventricle (aortic stenosis, hypertrophic cardiomyopathy) should be limited. The risk of developing life-threatening arrhythmias depends on the dose of drugs.

Pharmacokinetics and dosing regimen

The half-life of dopamine is 2 minutes. The introduction begins with a dose of 0.5-1 mg / kg of body weight per minute and increase it until the required blood pressure is reached. The dose of the drug is titrated depending on blood pressure, heart rate and diuresis. If the goal of therapy is to increase diuresis, then maximum dose the drug is 2-2.5 mg / kg of body weight per minute. As a rule, optimal hemodynamic parameters are noted at an infusion rate of 5 to 10 µg/kg of body weight per minute. Higher doses of the drug lead to a decrease in renal blood flow and peripheral vasoconstriction. At doses above 15 mcg/kg body weight per minute, dopamine acts virtually like norepinephrine. With prolonged administration of dopamine, even at the optimal rate, there is a gradual accumulation of norepinephrine, which inevitably leads to an increase in heart rate and OPSS. In practice, one should strive to use the minimum active doses of dopamine, given that the greatest increase in renal blood flow occurs at an infusion rate of 6-7 μg/kg of body weight per minute.

epinephrine

Epinephrine - α-, β 1 - and β 2 -adrenomimetic. Indications

Positive chronotropic and inotropic effects of the drug are not used in clinical practice. The main goal is

epinephrine values ​​- peripheral vasoconstriction. For this purpose, drugs are used for cardiopulmonary resuscitation(cardiac arrest) to increase the tone of the coronary and cerebral vessels and during an anaphylactic reaction to increase blood pressure and reduce swelling of the mucous membranes. In a situation of anaphylaxis, epinephrine is useful in bronchospasm. An overdose of β-blockers is not considered an indication for the appointment of epinephrine, since in this case the α-stimulating effect predominates, leading to a sharp increase in blood pressure.

Side effects

TO side effects epinephrine include tachycardia, arrhythmias, headache, agitation, chest pain, pulmonary edema.

Contraindications

Epinephrine is contraindicated in pregnancy.

Pharmacokinetics and dosing regimen

The half-life of the drug is 2 minutes. Epinephrine is prescribed subcutaneously, intramuscularly, intravenously and endotracheally at a dose of 0.5-1 mg. If necessary, the drug is administered repeatedly every 3-5 minutes under the control of heart rate, blood pressure and ECG.

norepinephrine

Norepinephrine mainly acts on α- and β 1 -adrenergic receptors, and to a lesser extent - on β 2 -adrenergic receptors. Norepinephrine is an active vasoconstrictor with little effect on cardiac output. Since the drug mainly stimulates α-adrenergic receptors, its use may reduce mesenteric and renal blood flow, up to acute renal failure. With the appointment of norepinephrine, there is also a possibility of a decrease in heart rate due to stimulation of carotid baroreceptors.

Indications

Since the drug causes significant vasoconstriction, it is used in septic shock, and in cardiogenic shock, norepinephrine is prescribed for persistent arterial hypotension against the background of the introduction of other inotropic drugs.

Side effects

Side effects of norepinephrine - tachycardia, arrhythmias, headache, excitement.

Contraindications

Norepinephrine is contraindicated in pregnancy.

Pharmacokinetics and dosing regimen

The elimination half-life of norepinephrine is 3 minutes. The drug is prescribed intravenously at a dose of 8-12 mcg / min. Infusion of drugs should always be carried out in the central veins because of the risk of developing necrosis of superficial tissues with prolonged administration.

14.3. PHOSPHODIESTERASE INHIBITORS

This group of drugs includes amrinone*, milrinone* and enoximone* The drugs inhibit phosphodiesterase, inhibit the destruction of cAMP and increase myocardial contractility. In addition, these drugs have a vasodilating effect and moderately reduce blood pressure. Due to the combination of positive inotropic and vasodilatory effects, this class of drugs is also called inodilators.

Indication

Phosphodiesterase inhibitors are indicated for pulmonary edema and decompensation of CHF. It is believed that in heart failure in conditions of reduced sensitivity of β-adrenergic receptors to endogenous catecholamines and sympathomimetics, it is better to prescribe phosphodiesterase inhibitors (in the absence of arterial hypotension).

Contraindications

Phosphodiesterase inhibitors are contraindicated in aortic stenosis and hypertrophic cardiomyopathy with outflow tract obstruction.

Pharmacokinetics and dosing regimen

The half-life of milrinone is 3-5 hours. After a bolus administration of the drug at a dose of 50 μg / kg of body weight, milrinone is administered intravenously at a rate of 0.375-0.75 μg / kg of body weight for up to 48 hours. The drug is used under the control of blood pressure, heart rate and EKG. Due to the fact that thrombocytopenia often develops when prescribing amrinone, this drug is used very rarely. clinical efficacy enoximone continues to be studied.

Side effects

Side effects of phosphodiesterase inhibitors - arterial hypotension and cardiac arrhythmias.

14.4. DRUGS THAT INCREASE THE SENSITIVITY OF CONTRACTIBLE PROTEINS TO CALCIUM ("CALCIUM SENSITIZERS")

This group of drugs includes levosimendan. The drug binds to troponin C in the presence of calcium ions, stabilizing the structure of troponin C and prolonging the interaction time between actin and myosin. As a result, new places are formed for the connection of contractile proteins, and the contractility of cardiomyocytes increases. It is important to note that the transmembrane gradient of calcium ions does not change, so the risk of arrhythmias does not increase. The relationship of levosimendan and troponin C depends on the initial intracellular concentration of calcium ions, so the effect of the drug is manifested only with an increased content of calcium ions in the cell. In diastole, reuptake of calcium by the sarcoplasmic reticulum occurs, the concentration of calcium ions in the cytoplasm decreases, the connection between the drug and troponin C stops, and the process of myocardial relaxation is not disturbed.

In high doses, levosimendan can inhibit phosphodiesterase. In addition, the drug promotes the activation of ATP-dependent potassium channels in peripheral vessels, which leads to vasodilation.

Levosimendan is administered intravenously. Indications for its appointment are decompensation of CHF and heart failure in myocardial infarction.