Drugs to prevent and correct heart failure

The problem of maintaining the contractile activity of the heart and, to a certain extent, managing it is key in cardiogenic shock, but it often arises during the treatment of shock of any genesis in victims with a diseased, weakened or "worn out" heart, suffering from ischemic heart disease, with a massive release of microbial toxins, exposure of the myocardium to chemical factors of anaphylaxis, etc. The general strategy of drug prevention and therapy of acute heart failure (AHF) is not limited to additional use of the cardiac reserve by stimulating the myocardium and involves:

1. creation of conditions that facilitate the work of the heart: pre- and/or afterload acceptable for a given state of hemodynamics with a decrease in the OPS, pressure in the vessels of the pulmonary circulation, filling pressure of the chambers of the left heart, work of the left ventricle and the total O2-demand of the heart;
2. the use of beta-blockers (beta-adrenergic blockers) to reduce sympathetic hyperactivation, which leads to rapid depletion of cardiac reserves, deepening hypoxia and rhythm disturbances;
3. the use of drugs that improve oxygen delivery (coronary dilators, oxygen therapy, including oxygen hyperbarotherapy) and the energy status of the myocardium (creatine phosphate, repolarizing solution, riboxin);
4. the use of cardiotonic and cardiac stimulants in the case of a significant decrease in the contractile work of the left ventricle, which cannot be prevented by other means.

The first approach to the prevention and treatment of AHF has strict indications and is implemented using vasodilators. The second approach involves the use of beta-adrenolytics, mainly anaprilin (inderal, obzidan, propranolol) in the initial stage of myocardial infarction, when, due to psychoemotional stress and pain, sympathoadrenal activation of the heart usually increases sharply (increase in heart rate, oxygen demand, deepening myocardial hypoxia in the ischemic zone and border zone, occurrence of arrhythmias, etc.). Hyperkinetic type of blood circulation, unjustified by the state of hemodynamics, is often detected in the initial phase of myocardial infarction, creates an additional load on the affected left ventricle, accelerates the development and deepens the subsequent AHF.

In these conditions, early (within the first 6 hours after the onset of myocardial infarction signs) administration of anaprilin (approximate dose of 0.1 mg/kg intravenously) reduces heart rate by 20-30%, decreases the necrosis zone by 20-25% (according to clinical indicators), reduces the incidence of ventricular fibrillation in the first 48 hours and subsequent mortality in patients who have suffered the acute phase of myocardial infarction threefold. The use of beta-blockers (selective beta1-blockers (AB) have no obvious advantages over anaprilin or are even inferior to it) is indicated for BP of at least 110 mm Hg and heart rate of at least 60 beats per minute. The presence of bradycardia, conduction blocks is a contraindication; in such a situation, beta-ARs can aggravate the block and provoke sinus node weakness. In shock of other origins, there appears to be no pathophysiological justification for the use of beta-AL. Moreover, their administration may complicate the course of the process.

Cardiotonic and cardiac stimulants are used when the cardiac output is reduced if it could not be prevented by other means, often in combination with vasodilators. In connection with the discovery and introduction into practice of treating AHF of a number of new cardiotropic drugs that occupy an intermediate position between typical cardiotonic (cardiac glycosides) and cardiac stimulants (isoproterenol, adrenaline) drugs, the boundaries between these groups have become less clear. Although the primary mechanism of action of drugs in these groups differs significantly, their positive inotropic effect, for which they are actually used to treat AHF, is the same and is ultimately determined by an increase in the amount of calcium ions entering cardiomyocytes from the outside (about 10-15%) and released from sarcoplasmic depots and mitochondria (about 85-90%) in the excitation phase (depolarization) of the cell membrane. Since many cardiotropic agents, mediators and hormones influence this process, it makes sense to consider it in a little more detail.

Calcium ions play the role of a universal coupling factor, which in various tissues, including the myocardium, implements membrane excitation into the corresponding cellular response. The entry of Ca2+ into cardiomyocytes is carried out through slowly conducting ("slow") ion channels of two types. Potential-dependent calcium channels (type 1) open following the propagation of a membrane excitation wave caused by the sequential "explosive" opening of fast-conducting sodium channels and the incoming sodium current (phases 0 and 1 of the electrical cycle). An increase in the concentration of sodium ions in the thickness of the membrane and in the cytosol is apparently the main stimulus opening the slowly conducting potential-dependent calcium channels; the initial entry of Ca2+ into the cytosol leads to its massive release from intracellular depots (phase 2 of the electrical cycle). It is also believed that inosine triphosphate (ITP), a chemical mediator that opens calcium channels in the sarcoplasmic reticulum, can be split off from the lipids during depolarization of the cell membrane. In the cytosol of cardiomyocytes, calcium ions (their concentration in the myofibril region increases by an order of magnitude or more) specifically bind to the protein of the actomyosin complex, troponin. The latter changes its conformation, as a result of which the obstacle to the interaction of actin and myosin is removed, the ATPase activity of myosin and the ability of the complex to convert the energy of the chemical bond of ATP into the mechanical work of the heart increase abruptly from close to zero to peak.

The second stage of slow-conducting membrane channels for calcium ions is called hormone- or mediator-dependent, since they are associated with adrenergic receptors (possibly with other factors of humoral regulation) and mediate the stimulating effect of the sympathoadrenal system on the work of the heart. The interaction of the receptor with the agonist (norepinephrine, adrenaline and their analogues) leads to the activation of adenylate cyclase, the formation of cAMP in cardiomyocytes, which binds to inactive protein kinase and converts it into an active form. The latter phosphorylates one of the proteins of the calcium channel, as a result of which the channel opens and passes calcium ions into the cytosol in accordance with the concentration gradient. Hormone-dependent slow-conducting channels in the cell membrane, sarcoplasmic and mitochondrial membranes have an enhancing, modulating effect on the function of potential-dependent channels and increase the entry of Ca2+ into cardiac fibers by 2-4 times. In the sinus node this leads to an increase in automatism and heart rate, in the vascular system - to an improvement in conductivity (to a certain extent; overloading the cell with Ca2+ worsens conductivity), and in the presence of prerequisites (for example, hypoxia) - to the emergence of heterotropic excitation foci, in cardiomyocytes - to an increase in heart contractions. Vagal influences through the M-cholinergic receptors of the membrane inhibit the function of adenylate cyclase and thus delay the entry of Ca2+ through hormone-dependent channels and the subsequent chain of reactions.

Many cardiotropic agents influence the strength and frequency of heart contractions, other properties of the myocardium (conductivity, metabolic shifts, O2-request) by changing the conductivity of calcium channels and the entry of Ca + into the cytosol. These effects can be both positive - an increase in the entry of ions (positive inotropic and chronotropic effects), and negative - inhibition of Ca + entry (antiarrhythmic and cardioprotective effects). Both groups of agents are used in emergency cardiology and resuscitation. The mechanism of action of drugs on the conductivity of calcium channels is different, which determines their properties.

This section of the chapter examines the properties and general principles of using drugs with positive inotropic action for the prevention and treatment of AHF in shock of various origins. These drugs differ significantly in their effect on cardiac function and systemic hemodynamics. In their clinical evaluation, the following criteria are of great importance:

1. the speed of onset and reliability of the positive inotropic effect, its dose dependence (adjustability);
2. the degree of increase in the myocardial 02 demand, which is especially important in the presence of a focus of ischemia;
3. influence on heart rate in doses that provide the necessary inotropic effect;
4. the nature of the influence on vascular tone in general (OPS) and in individual areas (mesenteric, pulmonary, renal, coronary vessels);
5. influence on the conduction of impulses in the heart, especially in case of conduction defects, arrhythmogenic danger of the drug.

Effect of drugs on calcium channel conductivity

Groups of drugs	Mechanism of action
Enhance the entry of calcium ions into the cytosol
Cardiac glycosides	They inhibit Na++ K+-ATPase of membranes, increase the exchange of Na+ for Ca +, the entry of extracellular Ca and its release by the sarcoplasmic reticulum mainly through potential-dependent channels.
Beta-agonists	Selectively activate hormone-dependent Ca2 + entry, coupled with the function of adenylate cyclase and cAMP; are beta-AR agonists in the sinus node, conductive and contractile tissue of the heart
Phosphodiesterase inhibitors	Delay the inactivation of cAMP in cardiac fibers, enhance and prolong its effect on the conduction of SA + through hormone-dependent channels
Calcium agonists	They bind to specific calcium channel receptors and open them for Ca +
Inhibit the entry of calcium ions into the cytosol
Calcium agonists*	Interact with the calcium channel receptor protein, preventing their opening and inhibiting the entry of Ca + through hormone-dependent and (weaker) potential-dependent channels
Beta-blockers (beta-blockers)	Selectively block synaptic and extrasynaptic beta-AR, preventing the activating effect of the sympathoadrenal system on the entry of Ca + - through hormone-dependent channels
M-cholinomimetics, anticholinesterase agents	Inhibit adenylate cyclase of hormone-dependent channels and the formation of cAMP, which activates the entry of Ca
Antiarrhythmic drugs of the quinidine group, local anesthetics, high doses of barbiturates	They inhibit the entry of Na+ through “fast” channels and the secondary opening of calcium channels, and have a weaker direct inhibitory effect on the entry of Ca
* - A promising group of substances, intensively studied by pharmacologists; drugs with cardioselective agonistic action on calcium channel conductivity have not yet been identified.

When selecting and using drugs with a positive inotropic effect in shock or the threat of shock of various genesis, it is necessary to keep in mind the relationship between various aspects of the pharmacodynamics of drugs. In any case, the inotropic effect is accompanied by an additional expenditure of macroergs and, as a consequence, an increase in the O2-demand of the heart, mobilization (up to depletion) of its functional and biochemical reserves. However, the degree of growth of the O2 _- demand and the probability of depletion of reserves depend to a greater extent on the increase in heart rate than on the inotropic effect. Therefore, an increase in the contractile work of the heart with a simultaneous decrease in the initially high heart rate can be accompanied by a relative decrease in O2 consumption by _the left ventricle, and the efficiency of the heart will increase. A decrease in O2 _demand is facilitated by a decrease in the load, i.e., the simultaneous vasodilator effect of the drug with the inotropic effect (activation of vascular beta2-AR, combination with a vasodilator), while the vasoconstrictor effect and increase in the OPS (activation of vascular alpha-AR) will provide an additional increase in O2 consumption to the inotropic effect _. In cardiogenic shock and the threat of its development, the ability of the inotropic agent to dilate coronary vessels, improve blood flow in the ischemic and border zones of the myocardium, reduce the left ventricular end-diastolic pressure (LVEDP) and the load on the affected heart, and minimal arrhythmogenic risk are of great importance.

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Fast acting cardiac glycosides

These drugs are traditionally considered as one of the first prescriptions of a doctor for acute heart failure of various genesis. The mechanism of action is usually explained by selective inhibition of membrane Na+ + K+-ATPase (glycoside receptor, as well as a putative endogenous regulator of contraction force), resulting in an increase in the intramembrane exchange of Na+ for Ca2+ and an increase in the entry of the latter into the cell from the outside and from the depot in the sarcoplasmic reticulum. A number of factors do not fit into the classical theory, but it still remains the leading one. Cardiac glycosides increase the flow of Ca2+ through potential-dependent channels and, apparently, have little effect on hormone-dependent ones. They do not have a direct effect on beta-AR, therefore their effect on HR is secondary and ambiguous (reflex activation of vagal influences, release of NA by the endings of sympathetic fibers). A decrease in HR is more typical, especially for digitalis glycosides. The small therapeutic range, negative effect on conduction in the atrioventricular node and in the His-Purkinje fibers (if there are prerequisites) are well known, as is the high arrhythmogenic danger. Various cardiac arrhythmias are the most common complication in case of drug overdose and decreased patient tolerance to them, as well as in their combination with a number of drugs.

The positive inotropic effect of cardiac glycosides is not pronounced, does not occur immediately and reaches its peak relatively slowly, but continues for a long time and is practically independent of the dose. Their positive effect on hemodynamics and survival has been proven in traumatic, burn and toxic shock in an experiment. Due to the peculiarities of pharmacokinetics, cardiac glycosides should be considered to a greater extent as a means of preventing AHF in these types of shock than as a treatment, especially in extremely acute critical situations.

The effectiveness of glycosides in myocardial infarction and cardiogenic shock is problematic, since there is evidence of an increase in the necrosis zone when they are used, and the risk of arrhythmia and conduction block increases sharply. According to most clinicians, the use of cardiac glycosides in cardiogenic shock and for its prevention in patients with myocardial infarction is unreliable and risky. The only indication is the presence of

Factors that reduce tolerance to cardiac glycosides and provoke the development of complications

Pathophysiological

• Old age of the patient
• Hypokalemia
• Hypercalcemia
• Hypomagnesemia
• Respiratory and metabolic alkalosis
• High body temperature
• Hypoxemia
• Hypothyroidism
• Pulmonary heart
• Myocardial infarction

Medicines dangerous in combination with cardiac glycosides

• Beta-agonists, aminophylline
• Cyclopropane, halogenated preparations
• General anesthetics
• Ditiline
• Calcium supplements
• Quinidine and analogues
• Amiodarone
• Calcium antagonists

Veroshpiron sinus tachyarrhythmia and atrial fibrillation. In such cases, preference is given to digitalis preparations, although there are experimental data on their moderate coronary constrictor effect.

When deciding on the administration of cardiac glycosides in shock of other origin, factors that reduce tolerance to these agents should be excluded (hypokalemia is more common), and the saturation phase is achieved by intravenous administration of fractional doses, which somewhat reduces the likelihood of complications, but does not guarantee against them. To eliminate possible arrhythmias, a repolarizing solution or panangin solution should be ready.

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Adrenergic agonists

Adrenomimetic agents form the basis of inotropic therapy of severe AHF in shock of any genesis. Their action is primarily aimed at hormone (mediator)-dependent entry of Ca2+ and is associated with the involvement of the adenylate cyclase mechanism in the reaction of cells. The positive chrono-, dromo- and inotropic effects of adrenomimetics are due to their interaction with beta-AR. Ideas about the role of the few myocardial alpha-AR are contradictory and, apparently, receptors of this type do not play a significant role in the regulation of the strength and frequency of heart contractions.

Drugs with non-selective alpha-beta-adrenomimetic action (norepinephrine, metaraminol, etc.) have a positive inotropic effect due to activation of beta-AR, but it is largely devalued by the stronger effect of these drugs on the alpha-AR of the vessels, leading to a sharp rise in OPS and an increase in the load on the heart. They are now almost never used as cardiotropic drugs, but when treating acute hypotension, their inotropic effect is useful and should be taken into account, as well as the usually caused reflex bradycardia.

The main place in the therapy of AHF belongs to adreno- and dopamine mimetics with a pronounced selective effect on beta-AR. The ratio of positive inotropic and chronotropic effects is determined by the degree of activation of the cells of the sinus node and contractile tissue, as well as the beta-AR subtype on which the effect of the drug predominates. The degree of selectivity of the action of adrenomimetics on beta1- and beta-2-AR is relative and with an increase in the rate of infusion (dose, concentration) of drugs, the differences between them can be erased. In general, selective beta1-adrenomimetics activate the force of heart contractions to a greater extent than their frequency, and have a more economical cardiostimulating effect compared to beta2- and non-selective beta1-beta2-adrenomimetics.

The influence of adrenomimetic agents on cardiac function and the main hemodynamic indices

Indicator	Alpha-beta-AM		Non-selective beta-AM	Selective beta1-AM	Selective beta2-AM	Dopamine mimetics
	NA, metaraminol	A	Isoproterenol, orciprenaline	Dobutamine, prenalterol, etc.	Salbutamol, terbutaline, etc.	Dopamine, ibopamine, etc.
Heart rate	-+	+++	++++	0+	++	0+
Heart systolic volume index	+	++	++++	+++	++	+++
Cardiac output index	+	+++	+++	+++	++	+++
Myocardial O2 consumption	++	+++	++++	0+	+	+
Coronary blood flow	-+	++	++	+	++	+
Conductivity in the A-V node	+	+	++	+	+	0+
Arrhythmogenic danger	+++	+++	++++	0+	+	+
Systolic blood pressure	+	+++	+++	++	+	++
Diastolic blood pressure	+++	-	—	0+	—	-0++
Pulmonary capillary pressure	+++	++	-	-0+	—	-+
Left ventricular filling pressure	++	++		0-		-+
Left ventricular end-diastolic pressure	-+
Renal blood flow	---	---	+	0+	0-	+++
Blood flow in internal organs	---	---	++	0	++	++-
Total vascular resistance	+++	+	—	-	—	-0+
* The direction of action of a number of adrenomimetics may change with an increase in the rate of infusion (dose).

In accordance with the predominance of action on one or another subtype of beta-AR, adrenomimetics are divided into the following subgroups.

Non-selective beta1-beta2-adrenergic agonists - isoproterenol (isadrin), orciprenaline (alupent), adrenaline (additionally activates alpha-AR). They have a pronounced cardiostimulating effect with a positive chronotropic (somewhat predominant), inotropic and dromotropic effects, significantly increase the O2 request of the myocardium, easily provoke or increase rhythm disturbances and increase the necrosis zone in myocardial ischemia. They differ in their effect on vascular tone: the first two drugs, due to the activation of vasodilators beta2-AR, reduce vascular tone and TPR, can also reduce mean and diastolic blood pressure and secondarily - coronary blood flow. The drugs dilate the bronchi and reduce the "wedge pressure" in the pulmonary capillaries. In general, they are characterized by high reliability of inotropic action, but also by its maximum cost to the heart, and have a rather short-term (controlled) effect. Adrenaline remains the drug of choice at the beginning of anaphylactic shock therapy; after it, massive doses of glucocorticoid are administered intravenously.

Selective beta1-adrenergic agonists - dobutamine, prenalterol, xamoterol, etc. A positive inotropic response (increase in CI, left ventricular dp/dt, decrease in left ventricular end-diastolic pressure - LVEDP) is not accompanied by a significant increase in HR and cardiac output; the risk of arrhythmia is less than with the drugs of the previous group. Dobutamine has been better studied experimentally and clinically; it also has a weak activating effect on vascular alpha-AP, and therefore does not reduce blood pressure; on the contrary, it helps to restore and maintain it without a significant increase in TPR. It acts longer than isoproterenol and the effect is less controllable. As emphasized, the selectivity of the action of drugs in this group is relative: the ratio of beta1-/ beta-2-adrenergic agonist action is 1/2. With an increase in the infusion rate (dose), the heart rate and blood pressure increase.

Selective beta2-adrenergic agonists - salbutamol, terbutaline, fenoterol, etc. The ratio of beta2/beta1-mimetic activity is 1/3. Apparently, due to the smaller representation of beta2-AR in the atria and ventricles of the human heart (about 1/3 of the total number of beta-AR), drugs of this subgroup have a less pronounced positive inotropic effect, which is also accompanied by a pronounced increase in heart rate. Due to the activation of beta2-AR, these drugs cause vasodilation with a decrease in TPR and blood pressure. In significantly smaller doses (10-20 times less than cardiotropic), they have a strong bronchodilator effect (preferred in asthmatic status, in anaphylactic shock with bronchospasm). They are currently used sparingly for the correction of acute heart failure due to tachycardia and the possibility of rhythm disturbances.

Dopamine mimetics - dopamine (dopamine), ibopamine, etc. The positive inotropic effect is due not so much to the activation of DA-R, as to the direct effect on beta1-AR and the release of NA from nerve endings with an increase in the infusion rate (dose, concentration). The effect on beta2-AR is weak (when tested on the bronchi, 2000 times weaker than adrenaline). Dopamine today is perhaps the most widely used agent in the therapy of acute heart failure in shock of various origins. The possibility of sequential activation of dopamine, beta1-AR of the heart and vascular alpha-AR with an increase in the infusion rate allows one drug to achieve a relatively selective effect on the desired types of receptors or their total excitation with the corresponding pharmacological responses. The positive inotropic effect is similar to that with the introduction of beta1-adrenergic agonists, combined with a dopamine-mimetic effect on blood vessels (dilation of renal and mesenteric vessels, constriction of cutaneous and muscular vessels), and with further acceleration of infusion - with a norepinephrine-like effect. The increase in heart rate is small, but increases with increasing dose, as does the arrhythmogenic risk (associated with the release of NA); in this regard, dopamine is inferior to dobutamine. When using vasopressor doses, the TPR increases and the "wedge pressure" in the pulmonary capillaries may increase. In addition to the treatment of AHF, dopamine is used to enhance renal function, especially in combination with furosemide. The effect of dopamine is quite well controlled. Ibofamine, used orally, is well resorbed and has a prolonged effect. It can be used for maintenance therapy in the post-shock period, but clinical experience with its use is still limited.

Thus, pharmacology has a fairly large arsenal of drugs of various types, the use of which forms the basis of cardiac stimulating therapy for acute heart failure in particularly critical situations.

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