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Inotropic action. Classification and mechanism of action of inotropic drugs Drugs with a positive inotropic effect

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.

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 drugs- These are drugs that increase myocardial contractility. The most well-known inotropic drugs include 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 drugs in cardiology.

The mechanism of action of cardiac glycosides is blockade of the sodium-potassium “pump”. As a result, the supply of sodium ions into the cells increases, the exchange of sodium ions for calcium ions increases, this, in turn, causes an increase in the content of calcium ions in the 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 effects.

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

Nowadays, the indications for the use 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 first choice drugs. The main cardiac glycoside is digoxin. Other cardiac glycosides are currently almost never used. For the tachysystolic form of atrial fibrillation, digoxin is prescribed under control of the ventricular rate: the target 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 diuretic is insufficient. In patients with sinus rhythm and heart failure, digoxin is prescribed at a dose of 1 tablet (0.25 mg) per day. In this case, for elderly people or patients who have had a myocardial infarction, as a rule, half or even a quarter of a digoxin tablet (0.125-0.0625 mg) per day is enough. Intravenous glycosides are prescribed extremely rarely: only for acute heart failure or decompensation of chronic heart failure in patients with a 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. Increased mortality in patients with heart failure has been observed with higher doses of digoxin. In 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 performance.
The main signs of intoxication: the occurrence of arrhythmias, loss of appetite, nausea, vomiting, weight loss. When small doses of glycosides are used, intoxication develops extremely rarely, mainly when digoxin is combined with amiodarone or verapamil, which increase the concentration of digoxin in the blood. If intoxication is detected in a timely manner, temporary withdrawal of the drug followed by 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 block), 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 in severe decompensation of patients with chronic heart failure. The main non-glycoside inotropic drugs include: dopamine, dobutamine, epinephrine and norepinephrine. These drugs are administered only intravenously by drip in order to stabilize the patient’s condition and bring him out of decompensation. After this, they switch to taking other medications.

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, enoxymone (drugs such as imiobendan or vesnarinone, in addition to phosphodiesterase inhibition, directly affect sodium and/or calcium current through the membrane).

Table 8
Non-glycoside inotropic drugs

A drug	Initial infusion rate, mcg/min	Approximate maximum infusion rate
Adrenalin		10 µg/min
Norepinephrine		15 µg/min

Dobutamine (dobutrex)
Isoproterenol
		700 µg/min
Vasopressin

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

Dopamine. A precursor to norepinephrine and promotes the release of norepinephrine from nerve endings. Dopamine receptors are located in the vessels of the kidneys, mesentery, coronary and cerebral arteries. Their stimulation causes vasodilation in vital organs. When infused at rates up to approximately 200 mcg/min (up to 3 mcg/kg/min), vasodilation is achieved (“renal” dose). When the dopamine infusion rate increases above 750 mcg/min, the stimulation of α-receptors and the 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 mcg/min. If a higher rate of dopamine administration is necessary, they try to connect an infusion of dobutamine or switch to an infusion of norepinephrine.

Dobutamine. Selective stimulator of 1-receptors (however, slight stimulation of 2- and α-receptors is also noted). When dobutamine is administered, a positive inotropic effect and moderate vasodilation are observed.
For refractory heart failure, dobutamine infusion is used for a duration of 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 last quite a long time - up to 1 month or more.

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 follow-up).
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 their 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).

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Positive inotropic drugs influence the correction of preload and afterload. The main principle of their action is to increase the force of myocardial contraction. It is based on a universal mechanism associated with the effect on intracellular calcium.

The following requirements are put forward for drugs in this group:

intravenous route of administration;
the possibility of dose titration under the control of hemodynamic parameters;
short half-life (for rapid correction of side effects).

Classification

In modern cardiology, in the group of drugs with a positive inotropic mechanism of action, it is customary to distinguish two subgroups.

Cardiac glycosides.

Non-glycoside inotropic drugs (stimulants):

β1-adrenergic receptor stimulants (norepinephrine, isoprenaline, dobutamine, dopamine);
phosphodiesterase inhibitors;
calcium sensitizers (levosimendan).

Mechanism of action and pharmacological effects

β1-adrenergic receptor stimulants. When β-adrenergic receptors are stimulated, G-proteins of the cell membrane are activated and a signal is transmitted to adenylate cyclase, which leads to the accumulation of cAMP in the cell, which stimulates the mobilization of Ca²+ from the sarcoplasmic reticulum. Mobilized Ca²+ leads to increased myocardial contraction. Catecholamine derivatives have a similar effect. In clinical practice, dopamine (a natural precursor to the synthesis of catecholamines) and the synthetic drug dobutamine are prescribed. Drugs of this group, administered intravenously, affect the following receptors:

β1-adrenergic receptors (positive inotropic and chronotropic effects);
β2-adreoreceptors (bronchodilation, peripheral vasodilation);
dopamine receptors (increased renal blood flow and filtration, dilatation of mesenteric and coronary arteries).

Thus, the main effect of β1-adrenergic receptor stimulants - a positive inotropic effect - is always combined with other clinical manifestations, which can have both positive and negative effects on the clinical picture of acute heart failure.

Phosphodiesterase inhibitors. In clinical practice, another mechanism for enhancing myocardial contractility is also used, based on reducing the breakdown of cAMP. Thus, the basis is to maintain a high level of cAMP in the cell, either by increasing synthesis (dobutamine) or by decreasing breakdown. Reducing the breakdown of cAMP can be achieved by blocking the enzyme phosphodiesterase.

In recent years, another effect of these drugs (in addition to blockade of phosphodiesterase) has been discovered - increased synthesis of cGMP. An increase in the content of cGMP in the vessel wall leads to a decrease in its tone, that is, to a decrease in peripheral vascular resistance.

So, drugs of this subgroup, increasing myocardial contractility (due to blockade of cAMP destruction), also lead to a decrease in peripheral vascular resistance (due to the synthesis of cGMP), which makes it possible to simultaneously influence preload and afterload in acute heart failure.

Calcium sensitizers. The classic representative of this subclass is levosimendan. The drug does not affect the transport of Ca²+, but increases its affinity for troponin C. As is known, Ca²+, released from the sarcoplasmic reticulum, destroys the troponin-tropomyosin complex, which inhibits contraction, and binds to troponin C, which stimulates myocardial contraction.

Arutyunov G.P.

Inotropic drugs