Inotropic synthetic drug in tablets. Negative chronotropic (based on inotropic action)

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 ℘; they are not registered in the Russian Federation; allowed only for short courses for circulatory decompensation).
✧ Calcium sensitizers (levosimendan).

MECHANISM OF ACTION AND PHARMACOLOGICAL EFFECTS
Stimulantsβ 1 -adrenoreceptors
Drugs of this group, administered intravenously, affect the following receptors:
β 1- adrenoreceptors (positive inotropic and chronotropic effects);
β 2- adrenergic receptors (bronchodilation, peripheral vasodilation);
dopamine receptors (increased renal blood flow and filtration, dilatation of mesenteric and coronary arteries).
Positive inotropic effects are always combined with other clinical manifestations, which can have both positive and negative effects on the clinical picture of AHF. Dobutamine - selectiveβ 1is an adrenergic agonist, but it also has a weak effect onβ 2 - and α 1-adrenoreceptors. With the introduction of normal doses, an inotropic effect develops, sinceβ 1-stimulating effect on the myocardium predominates. A drug
Regardless of the dose, it does not stimulate dopamine receptors, therefore, renal blood flow increases only due to an increase in stroke volume.

Phosphodiesterase inhibitors. Drugs of this subgroup, while increasing myocardial contractility, also lead to a decrease in peripheral vascular resistance, which makes it possible to simultaneously influence preload and afterload in AHF.

Calcium sensitizers. A drug of this group (levosimendan) increases the affinity of Ca 2+ to troponin C, which enhances myocardial contraction. It also has a vasodilating effect (decreasing the tone of 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 for 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 reduction in mortality achieved in the first 2 weeks after the start of treatment, which persisted further (over 6 months of observation).
Levosimendan has advantages over dobutamine in terms ofstudy of the effect on blood circulation parameters in patients with severe decompensated CHF and low cardiac output.

INDICATIONS
Acute heart failure. Their purpose does not depend on the presence of venous stasis 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 central hemodynamic parameters, and also change the dose of inotropic drugs according to
with the clinical picture.

Dosing
Dobutamine. The initial infusion rate is 2–3 mcg per 1 kg of body weight per minute. When administering dobutamine in combination with vasodilators, monitoring of pulmonary artery wedge pressure is necessary. If the patient received beta-adrenergic blockers, then the effect 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.
In low doses (2 mcg per 1 kg of body weight per minute or less when converted to lean body weight), the drug stimulates D 1 - and D 2-receptors, which is accompanied by dilation of the vessels of the mesentery and kidneys and allows to increase GFR in case of refractoriness to the action of diuretics.
In moderate doses (2–5 mcg per 1 kg of body weight per minute), the drug stimulatesβ 1- adrenoreceptors of the myocardium with an increase in cardiac output.
In high doses (5–10 mcg per 1 kg of body weight per minute), dopamine activatesα 1-adrenergic receptors, which leads to an increase in peripheral vascular resistance, left ventricular filling pressure, and tachycardia. Typically, high doses are prescribed in emergency situations to rapidly increase SBP.

Clinical features:
tachycardia is always more pronounced with the administration of dopamine compared to dobutamine;
dose calculations are carried out only for lean, and not for total body weight;
persistent tachycardia and/or arrhythmia that occurred during the administration of the “renal dose” indicate that the rate of drug administration was too high.

Levosimendan. Administration of the drug begins with a loading dose (12–24 mcg per 1 kg of body weight for 10 minutes), and then proceeds to a long-term infusion (0.05–0.1 mcg per 1 kg of body weight). The increase in stroke volume and decrease in pulmonary artery wedge pressure are dose-dependent. In some cases it is possibleincreasing the dose of the drug to 0.2 mcg per 1 kg of body weight. The drug is effective only in the absence of hypovolemia. Levosimendan is compatible withβ -adrenergic 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 the pronounced adverse effect on the prognosis, non-glycoside inotropic drugs can be prescribed only in short courses (up to 10–14 days) with a clinical picture of persistent arterial hypotension in patients with severe decompensation of CHF and a reflex kidney.

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

General provisions

The goal of inotropic support is to maximize tissue oxygenation (assessed by plasma lactate concentration and mixed venous blood oxygenation) rather than to increase cardiac output.
In clinical practice, catecholamines and their derivatives are used as inotropes. They have a complex hemodynamic effect due to α- and β-adrenergic effects and are characterized by a predominant effect on certain receptors. Below is a description of the hemodynamic effects of the main catecholamines.

Isoprenaline

Pharmacology

Isoprenaline is a synthetic agonist of β-adrenergic receptors (β 1 and β 2) and has no effect on α-adrenergic receptors. The drug dilates the bronchi and, during blockade, acts as a pacemaker, affecting the sinus node, increases conductivity and reduces the refractory period of the atrioventricular node. Has a positive inotropic effect. Affects skeletal muscles and blood vessels. The half-life is 5 minutes.

Drug interactions

The effect increases when combined with tricyclic antidepressants.
β-blockers are isoprenaline antagonists.
Sympathomimetics can potentiate the action of isoprenaline.
Gaseous anesthetics, increasing the sensitivity of the myocardium, can cause arrhythmias.
Digoxin increases the risk of tachyarrhythmia.

Epinephrine

Pharmacology

Epinephrine is a selective β 2 -adrenergic agonist (the effect on β 2 -adrenergic receptors is 10 times greater than the effect on β 1 -adrenergic receptors), but also affects α -adrenergic receptors, without having a differentiated effect on α 1 - and α 2 -adrenergic receptors.
Usually has little effect on the level of mean blood pressure, except when the drug is prescribed against the background of non-selective blockade of β-adrenergic receptors, in which the vasodilatory effect of epinephrine, mediated by the effect on β 2-adrenergic receptors, is lost and its vasopressor effect sharply increases (α 1 -selective blockade does not cause such an effect ).

Application area

Anaphylactic shock, angioedema and allergic reactions.
The scope of use of epinephrine as an inotropic drug is limited only to septic shock, in which it has advantages over dobutamine. However, the drug causes a significant decrease in renal blood flow (up to 40%) and can only be prescribed together with dopamine in a renal dose.
Heart failure.
Open angle glaucoma.
As an adjunct to local anesthetics.

Doses

0.2-1 mg intramuscularly for acute allergic reactions and anaphylaxis.
1 mg for cardiac arrest.
In case of shock, 1-10 mcg/min is administered dropwise.

Pharmacokinetics

Due to rapid metabolism in the liver and nervous tissue and 50% binding to plasma proteins, the half-life of epinephrine is 3 minutes.

Side effects

Arrhythmias.
Intracerebral hemorrhage (in case of overdose).
Pulmonary edema (in case of overdose).
Ischemic necrosis at the injection site.
Anxiety, dyspnea, palpitations, tremor, weakness, cold extremities.

Drug interactions

Tricyclic immunosuppressants.
Anesthetics.
β-Adrenergic blockers.
Quinidine and digoxin (arrhythmia often occurs).
α-Adrenergic agonists block the α-effects of epinephrine.

Contraindications

Hyperthyroidism.
Hypertension.
Angle-closure glaucoma.

Dopamine

Pharmacology

Dopamine affects several types of receptors. In small doses, it activates α 1 and α 2 dopamine receptors. α 1 dopamine receptors are localized in vascular smooth muscle and are responsible for vasodilation in the renal, mesenteric, cerebral and coronary blood flow. α 1 dopamine receptors are located in the postganglionic endings of the sympathetic nerves and ganglia of the autonomic nervous system. In an average dose, dopamine activates β 1 -adrenergic receptors, having positive chronotropic and inotropic effects, and in high doses, it additionally activates α 1 - and α 2 -adrenergic receptors, eliminating the vasodilating effect on the renal vessels.

Application area

Used to improve renal blood flow in patients with impaired renal perfusion, usually due to multiple organ failure. There is little evidence regarding the effect of Dopamine on clinical outcome.

Pharmacokinetics

Dopamine is captured by sympathetic nerves and is quickly distributed throughout the body. The half-life is 9 minutes and the volume of distribution is 0.9 l/kg, but equilibrium occurs within 10 minutes (ie, faster than expected). Metabolized in the liver.

Side effects

Arrhythmias are rarely observed.
Hypertension when using very high doses.
Extravasation may cause skin necrosis. In this case, phentolamine is injected into the ischemic zone as an antidote.
Headache, nausea, vomiting, palpitations, mydriasis.
Increased catabolism.

Drug interactions

MAO inhibitors.
α-blockers can enhance the vasodilating effect.
β-blockers may enhance the hypertensive effect.
Ergotamine enhances peripheral vasodilation.

Contraindications

Pheochromocytoma.
Tachyarrhythmia (without treatment).

Dobutamine

Pharmacology

Dobutamine is a derivative of isoprenaline. In practice, a racemic mixture of a dextrorotatory isomer, selective for β 1 and β 2 adrenergic receptors, and a levorotatory isomer, which has an α 1 -selective effect, is used. The effects on β2-adrenergic receptors (vasodilation of mesentary and skeletal muscle vessels) and α1-adrenergic receptors (vasoconstriction) suppress each other, so dobutamine has little effect on blood pressure unless prescribed in a high dose. It has a smaller arrhythmogenic effect compared to dopamine.

Application area

Inotropic support for heart failure.
In septic shock and liver failure, it can cause vasodilation and is therefore not the most preferred inotropic drug.
Used in functional diagnostics for conducting cardiac stress tests.

Pharmacokinetics

Rapidly metabolized in the liver. It has a half-life of 2.5 minutes and a volume of distribution of 0.21 l/kg.

Side effects

Arrhythmias.
When cardiac output increases, myocardial ischemia may occur.
The hypotensive effect can be minimized by simultaneous administration of dopamine at a vasoconstrictor dose. This combination of drugs may be required to treat patients with sepsis or liver failure.
Allergic reactions are observed extremely rarely.
Skin necrosis may occur at the injection site.

Drug interactions

α-Adrenergic agonists increase vasodilation and cause hypotension.

Contraindications

Low filling pressure.
Arrhythmias.
Cardiac tamponade.
Heart valve defects (aortic and mitral stenosis, hypertrophic obstructive cardiomyopathy).
Established hypersensitivity to the drug.

Norepinephrine

Pharmacology

Norepinephrine, like epinephrine, has α-adrenergic effects, but has a lesser effect on most β 1 -adrenergic receptors and has very low β 2 -adrenergic activity. The weakness of the β 2 -adrenergic effect leads to a predominance of the vasoconstrictor effect, more pronounced than that of epinephrine. Norepinephrine is prescribed for acute hypotension, but due to its minor effect on cardiac output and its ability to cause significant vasospasm, this drug can significantly increase tissue ischemia (especially in the kidneys, skin, liver and skeletal muscle). Norepinephrine infusion should not be interrupted suddenly, as this is dangerous due to a sharp drop in blood pressure.

Drug interactions

Tricyclic antidepressants (which block the reentry of catecholamines into nerve endings) increase the sensitivity of receptors to epinephrine and norepinephrine by 2-4 times. MAO inhibitors (for example, tranylcyprominr and pargyline) significantly potentiate the effect of dopamine, so its administration should be started with a dose equal to 1/10 of the usual starting dose, i.e. 0.2 µg/(kghmin).

Dobutamine is not a substrate for MAO.

Milrinone

Milrinone belongs to the group of phosphodiesterase inhibitors (type III). Its cardiac effects may be due to effects on calcium and fast sodium channels. β-Adrenomimetics enhance the positive inotropic effect of the million.

Side effects

Enoxymonr

Enoxymon is a phosphodiesterase inhibitor (type IV). The drug is 20 times more active than aminophylline, its half-life is approximately 1.5 hours. It is broken down into active metabolites with 10% enoxymonar activity with a half-life of 15 hours. Used for the treatment of congestive heart failure, can be prescribed in tablet form, and intravenously.

Side effects

Patients with hypovolemia may develop hypotension and/or cardiovascular collapse.

Bicarbonate of soda

Pharmacology

Sodium bicarbonate plays an important buffer role in the body. Its effect is short-lived. Administration of sodium bicarbonate results in sodium overload and carbon dioxide formation, which leads to intracellular acidosis and reduces the force of myocardial contraction. Therefore, the drug should be prescribed with great caution. Along with this, sodium bicarbonate shifts the oxyhemoglobin dissociation curve to the left and reduces the effective delivery of oxygen to tissues. Moderate acidosis causes cerebral vasodilation, so its correction may impair cerebral blood flow in patients with cerebral edema.

Application area

Severe metabolic acidosis (there are conflicting data regarding use in diabetic ketoacidosis).
Severe hyperkalemia.
It is best to avoid the use of sodium bicarbonate during cardiopulmonary resuscitation, since cardiac massage and artificial respiration are quite sufficient.

Dose

Available in the form of an 8.4% solution (hypertonic, 1 ml contains 1 mmol bicarbonate ion) and a 1.26% solution (isotonic). Usually administered as a bolus of 50-100 ml under the control of arterial blood pH and hemodynamic monitoring. According to the British Resuscitation Council guidelines, the approximate dose of 8.4% sodium bicarbonate solution can be calculated as follows:
Dose in ml (mol) = [BExt (kg)]/3, where BE is the base deficiency.

Thus, a patient weighing 60 kg and having a base deficiency of -20 requires 400 ml of an 8.4% sodium bicarbonate solution to normalize the pH. This volume contains 400 mmol sodium. From our point of view, this is a lot, so it is advisable to adjust the pH to a level of 7.0-7.1 by prescribing 50-100 ml of sodium bicarbonate, followed by assessment of arterial blood gases and repeated administration of the drug if necessary. This allows you to gain enough time to carry out more effective and safe therapeutic and diagnostic measures and treat the disease that led to the development of acidosis.

Side effects

When extravasation occurs, tissue necrosis occurs. If possible, administer the drug through a central catheter.
When administered simultaneously with calcium preparations, calcifications form in the catheter, which can lead to microembolism.

Adrenalin. This hormone is formed in the adrenal medulla and adrenergic nerve endings, is a direct-acting catecholamine, causes stimulation of several adrenergic receptors at once: α1-, beta1- and beta2- Stimulation of α1-adrenergic receptors is accompanied by a pronounced vasoconstrictor effect - general systemic vasoconstriction, including precapillary vessels skin, mucous membranes, kidney vessels, as well as pronounced narrowing of the veins. Stimulation of beta1-adrenergic receptors is accompanied by a clear positive chronotropic and inotropic effect. Stimulation of beta2-adrenergic receptors causes dilation of the bronchi.

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

Preparation of the solution. Adrenaline hydrochloride is available in the form of a 0.1% solution in 1 ml ampoules (at a dilution of 1:1000 or 1 mg/ml). For intravenous infusion, 1 ml of 0.1% adrenaline hydrochloride solution is diluted in 250 ml of isotonic sodium chloride solution, which creates a concentration of 4 mcg/ml.

Doses for intravenous administration:

1) for 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) for 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) in case of persistent arterial hypotension, the initial rate of administration is 2 mcg/min, if there is no effect, the rate is increased until the required blood pressure level is achieved;

4) action depending on the rate of administration:

Less than 1 mcg/min - vasoconstrictor,

From 1 to 4 mcg/min - cardiac stimulant,

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

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

Side effects: adrenaline can cause subendocardial ischemia and even myocardial infarction, arrhythmias and metabolic acidosis; small doses of the drug can lead to acute renal failure. In this regard, the drug is not widely used for long-term intravenous therapy.

Norepinephrine. A natural catecholamine that is a precursor to adrenaline. It is synthesized in the postsynaptic endings of sympathetic nerves and performs a neurotransmitter function. Norepinephrine stimulates a-, beta1-adrenergic receptors, and has almost no effect on beta2-adrenergic receptors. It differs from adrenaline in having a stronger vasoconstrictor and pressor effect, and a lesser stimulating effect on the 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 low doses of dopamine (1 mcg/kg/min) helps preserve renal blood flow during the administration of norepinephrine.

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

Preparation of the solution. Contents of 2 ampoules (4 mg of norepinephrine hydrotartrate is 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 mcg/min by titration until the effect is obtained. Doses of 1-2 mcg/min increase CO, over 3 mcg/min have a vasoconstrictor effect. For 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 effect of the drug may develop. With extravasal administration of the drug, necrosis may occur, which requires injecting the extravasate area with a phentolamine solution.

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

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

Preparation of the solution. Dopamine hydrochloride (dopamine) is available in ampoules of 200 mg. 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 mcg/ml.

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

2) small doses - 1-3 mcg/(kg-min) administered intravenously; in this case, dopamine acts predominantly 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) large doses - 5-15 mcg/(kg-min) stimulate beta1 receptors of the myocardium, have an indirect effect due to the release of norepinephrine 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, monitoring of hemodynamic parameters is necessary. If tachycardia occurs, it is recommended to reduce doses 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 a complete loss of the hemodynamic response.

Side effects: 1) increased PCWP, possible appearance of tachyarrhythmias; 2) in large doses it can cause severe vasoconstriction.

Dobutamine (Dobutrex). This is a synthetic catecholamine that has a pronounced inotropic effect. The main mechanism of its action is stimulation of beta receptors and increased myocardial contractility. Unlike dopamine, dobutamine does not have a splanchnic vasodilating effect, but has a tendency to systemic vasodilation. It increases heart rate and PCWP 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% from the initial level can cause an increase in the area of myocardial ischemia. In patients with concomitant vascular lesions, ischemic necrosis of the fingers is possible. Many patients receiving dobutamine experienced an increase in systolic blood pressure by 10-20 mmHg, and in some cases hypotension.

Indications for use. Dobutamine is prescribed for acute and chronic heart failure caused by cardiac (acute myocardial infarction, cardiogenic shock) and non-cardiac causes (acute circulatory failure after injury, during and after surgery), especially in cases where the average blood pressure is above 70 mm Hg. Art., and the pressure in the small circle system is higher than normal values. Prescribed for increased ventricular filling pressure and the risk of overload of the right heart, leading to pulmonary edema; with reduced MOS caused by the PEEP mode during mechanical ventilation. During treatment with dobutamine, as with other catecholamines, careful monitoring of heart rate, heart rhythm, ECG, blood pressure and infusion rate is necessary. Hypovolemia must be corrected before starting treatment.

Preparation of the solution. A bottle 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 are not recommended for dilution because SG ions may interfere with dissolution. Dobutamine solution should not be mixed with alkaline solutions.

Side effect. In patients with hypovolemia, tachycardia is possible. 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 a period of 1 to 2 minutes. To create its stable concentration in plasma and ensure maximum action, it usually takes no more than 10 minutes. The use of a loading dose is not recommended.

Doses. The rate of intravenous administration of the drug required to increase the stroke and cardiac output ranges from 2.5 to 10 mcg/(kg-min). Often a dose increase to 20 mcg/(kg-min) is required, in more rare cases - over 20 mcg/(kg-min). Doses of dobutamine above 40 mcg/(kg-min) may be toxic.

Dobutamine can be used in combination with dopamine to increase systemic blood pressure during hypotension, increase renal blood flow and urine output, and prevent the risk of pulmonary circulatory overload observed with dopamine alone. The short half-life of beta-adrenergic receptor stimulants, equal to several minutes, allows the administered dose to be very quickly adapted to hemodynamic needs.

Digoxin. Unlike beta-adrenergic agonists, digitalis glycosides have a long half-life (35 hours) and are eliminated by the kidneys. Therefore, they are less controllable and their use, especially in intensive care units, is associated with the risk of possible complications. If sinus rhythm is maintained, their use is contraindicated. In case of hypokalemia, renal failure against the background of hypoxia, manifestations of digitalis intoxication occur especially often. The inotropic effect of glycosides is due to inhibition of Na-K-ATPase, which is associated with stimulation of Ca2+ metabolism. Digoxin is indicated for atrial fibrillation with VT and paroxysmal atrial fibrillation. For intravenous injections in adults, use a dose of 0.25-0.5 mg (1-2 ml of 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.

Homeometric regulation

The force of contraction of the cardiac fiber can also change with changes in pressure (afterload). An increase in blood pressure increases the resistance to blood expulsion and shortening of the heart muscle. As a result, one would expect a drop in the SV. However, it has been repeatedly demonstrated that the CR remains constant over a wide range of resistance (Anrep phenomenon).

The increase in the force of contraction of the heart muscle with an increase in afterload was previously seen as a reflection of the “homeometric” self-regulation inherent in the heart, in contrast to the “heterometric” mechanism previously established by Starling. It was assumed that an increase in myocardial inotropy takes part in maintaining the SV value. However, it was later revealed that an increase in resistance is accompanied by an increase in the end-diastolic volume of the left ventricle, which is associated with a temporary increase in end-diastolic pressure, as well as myocardial distensibility associated with the influence of increased contraction force [Kapelko V.L. 1992]

In conditions of sports activity, an increase in afterload most often occurs during training aimed at developing strength and performing static physical activity. An increase in average blood pressure during such exercises leads to an increase in cardiac muscle tension, which, in turn, entails a pronounced increase in oxygen consumption, ATP resynthesis and activation of the synthesis of nucleic acids and proteins.

Inotropic effect of heart rate changes

An important mechanism for regulating cardiac output is chronoinotropic dependence. There are two factors that act in different directions on the contractility of the heart: 1 - aimed at reducing the force of subsequent contraction, characterized by the speed of restoration of the ability to fully contract and is designated by the term “mechanical restitution”. Or mechanical restitution is the ability to restore optimal contractile force after a previous contraction, which can be determined through the relationship between the duration of the R--R interval and the subsequent contraction. 2 -- increases the strength of the subsequent contraction with an increase in the previous contraction, is designated by the term “post-extrasystolic potentiation” and is determined through the relationship between the duration of the previous interval (R--R) and the strength of the subsequent contraction.

If the strength of contractions increases with increasing rhythm frequency, this is referred to as the Bowditch phenomenon (the positive activation effect prevails over the negative one). If the strength of contractions increases with a slowdown in rhythm frequency, then this phenomenon is referred to as the “Woodworth's ladder.” The named phenomena are realized in a certain frequency range. When the frequency of contractions goes beyond the range, the strength of the contractions does not increase but begins to fall.

The width of the range of these phenomena is determined by the state of the myocardium and the concentration of Ca 2+ in various cellular reserves.

Experimental studies by F.Z. Meyerson (1975) showed that in trained animals the inotropic effect of increasing heart rate is significantly higher than in control animals. This gives grounds to assert that under the influence of regular physical activity, the power of the mechanisms responsible for ion transport increases significantly. We are talking about increasing the power of the mechanisms responsible for the removal of Ca 2+ from the sarcoplasm, i.e. calcium pump SPR and Na-Ca exchange mechanism of the sarcolemma.

Researchers have gained the opportunity to non-invasively study the parameters of mechanical restitution and post-extrasystolic potentiation through the use of the method of transesophageal electrical stimulation in a stochastic mode. They performed electrical stimulation with a random sequence of pulses, synchronously recording a rheographic curve. Based on changes in the rheowave amplitude and the duration of the expulsion period, changes in myocardial contractility were judged. Later V. Fantyufyev et al. (1991) showed that such approaches can be successfully used not only in the clinic, but also in functional diagnostic studies of athletes. Thanks to the study of curves of mechanical restitution and post-extrasystolic potentiation in athletes, the authors were able to prove that these curves can change significantly with adaptation disorders to physical activity and overexertion, and the introduction of magnesium ions or blockade of calcium current can significantly improve the contractility of the heart in some athletes. With an increase in heart rate, there is also an increase in the rate of relaxation of the heart. This phenomenon was called “rhythmodiastolic dependence” by IT. Udelnov (1975). Later F.Z.Meyerson and V.I. Kapelko (1978) proved that the rate of relaxation increases not only with increasing frequency, but also with increasing amplitude or strength of contractions in the physiological range. They found that the relationship between contraction and relaxation constitutes an important pattern of cardiac activity and is the basis for stable adaptation of the heart to stress.

In conclusion, it should be emphasized that regular sports training contributes to the improvement of cardiac regulatory mechanisms, which ensures economization of the heart at rest and its maximum performance under extreme physical exertion.

INOTROPIC ACTION (literally imputing force"), changes in the amplitude of heart contractions under the influence of various physiological and pharmacological agents. The positive I. effect, i.e., an increase in the amplitude of heart contractions, is caused by irritation of the accelerators; negative I. d. - obtained when the vagus nerves are irritated. Vago- and sympatho-comimetic poisons and salt ions provide corresponding effects. However, the I. d. of one or another agent depends on a number of conditions: pH, the composition of the washing fluid or blood, intracardiac pressure, heart rate, and therefore a prerequisite for observing I. d. is work under constant conditions (artificially excited heart rhythm and etc.), The inotropy of various parts of the heart can change independently of the inotropy of other parts. I. P. Pavlov managed to find a branch in the plexus cardiacus of a dog that gives a positive inotropic effect on the left ventricle alone. The pathways were studied in more detail by I. D. Hoffman (Hofmann): he found that the specific “inotropic nerves” of the frog heart are the nerves of the interventricular septum, the irritation of which gives a purely inotropic effect without chronotropic changes; after cutting these nerves, irritation of the general vago-sympathetic trunk no longer gives any inotropic effect. salts. Potassium salts have a negative effect; this effect is not observed after atropinization. Sodium in high concentrations has the same effect; however, this effect may depend on the fact that the hypertonic. solutions generally have a negative I.D. Reducing the NaCl content in the washing liquid gives +I. e. Lithium and ammonium salts have +I. d.; Rubidium acts like potassium. Calcium acts + inotropically and even leads to systolic. stop. The absence of calcium in the washing fluid gives a negative inotropic effect. Barium and strontium generally act like Ca. Magnesium acts antagonistically towards both Ca and K. Salts of heavy metals give negative results. inotropic action. However, the effect of the above-mentioned salts may be absent or ■ distorted when the pH of the lavage fluid changes and after pre-treatment of the heart with other (often antagonistic) agents. - Of the anions, one can note the negative ID of iodide compounds, lactic acid and cyanide salts, small doses of which have an effect however + inotropic. Drugs and alcohol have negative inotropic effects; in very small doses +I. Carbohydrates (glucose), when added to the washing fluid (as a source of energy), give +I.d. to the isolated heart. Digitalis affects inotropy not only indirectly (acting on blood vessels and the autonomic nervous system), but also directly affecting the heart muscle (small doses - positively, large doses - negatively), especially on the left ventricle. Adrenaline, reducing the latent period of contraction and shortening systole, usually gives +I. d.; this effect in the frog is less pronounced than in warm-blooded animals. However, here, as with many vegetative poisons, everything depends on the dose and the condition of the heart. The effect of camphor also depends on the dose: small doses give +I. d., large -I. d.; it is especially clearly expressed in pathologically altered hearts. Cocaine has a positive inotropic effect in very small doses, and a negative inotropic effect in large doses. Atropine, according to the latest observations of Kisch, in the first phase of its action excites n. vagus and therefore gives a negative ID. Poisons of the muscarine group act like irritation of the vagus nerve. Veratrine and strychnine, used in small doses, give +I. d. Caffeine has an effect on inotropy. arr. indirectly, by changing the heart rate; but when the heart is tired, when used in small doses, it acts directly on the heart muscle + inotropic. (For the relationship between inotropic, dromotropic and chronotropic actions, see the corresponding words.) Lit.: As her L., Intrafcardiales Nervensystem (Hndb. d. norm, u.path. Physiologie, hrsg. v. A. Bethe, G. Bergmann u.a., B. VII, T. 1, V., 1926); Hofmann P., tlber die Funktion der Scheidenwandner-ven des Froschberzens, Arch. f. d. ges. Physiologie, B. LX, 1895; Kisch V., Pharmakologie des Herzens (Hndb. d. norm. u. path. Physiologie, h sg. v. A. Bethe, G. Bergmann u. a., B. VII, T. 1, V., 1926); Pav-1 o f f I., Ober den Einfluss des Vagus auf die Arbeit der linken Herzkammer, Arch. 1. Anat. u. Phvsiology. 1887, p. 452; S t r a u b W., Die Digitalisgruppe (Hndb. d. experimentellen Pharmakologie, hrsg. v. A. Heffter, B. II, Halfte 2, V., 1924).A. Zubkov.