Medications to prevent and correct heart failure

The problem of maintaining the contractile activity of the heart and, to some extent, controlling it, is key in cardiogenic shock, but it often occurs during the therapy of shock of any genesis in patients with a diseased, weakened or "worn out" heart, suffering ischemic heart disease, microbial toxins, effects on the myocardium of chemical factors of anaphylaxis, etc. The general strategy of drug prevention and therapy of acute heart failure (OCH) is not limited to additional Use of the heart reserve by stimulation of the myocardium and suggests:

1. creation of conditions facilitating the work of the heart: the pre-and / or post-loading permissible in a given hemodynamic state with a decrease in OPS, pressure in the vessels of the small circle, filling pressure of the left heart chambers, left ventricular work and the general heart 02 request;
2. the use of beta-adrenoblockers (beta-adrenolytics) in order to reduce sympathetic hyperactivation leading to a rapid depletion of the heart reserve, deepening of hypoxia and rhythm disturbances;
3. use of drugs that improve the delivery of oxygen (coronary arteries, oxygen therapy, including oxygenehyperbarotherapy) and the energy status of the myocardium (creatine phosphate, repolarizing solution, riboxin);
4. the use of cardiotonic and pacemakers with a marked decrease in contractile function of the left ventricle, which can not be prevented by other means.

The first approach to the prevention and treatment of DOS has strict indications, is realized with the help of vasodilators . The second approach involves the use of beta-adrenolytic drugs, mainly anaprilin (indial, obzidan, propranolol) in the initial stage of myocardial infarction, when, as a result of psychoemotional stress and pain, sympatoadrenal activation of the heart usually increases (growth of heart rate, oxygen request, deepening of myocardial hypoxia in the ischemic zone and the border zone, the occurrence of arrhythmias, etc.). Unjustified by the state of hemodynamics, the hyperkinetic type of circulation is often detected in the initial phase of myocardial infarction, creates an additional burden on the affected left ventricle, accelerates the development and deepens the subsequent OCH.

Under these conditions, the use of anaprilin (an approximate dose of 0.1 mg / kg per vein) in the first 6 hours after the onset of signs of myocardial infarction reduces by 20-30% of the heart rate, reduces the necrosis zone by 20-25% (according to clinical indices) , three times reduces the incidence of ventricular fibrillation in the first 48 hours and the subsequent death rate of patients who underwent an acute phase of myocardial infarction. The use of beta-adrenergics (selective beta-1 adrenolytics (AL) have no obvious advantages over anaprilin or even give way to it) is shown with an HA of at least 110 mm Hg. Art. And heart rate not lower than 60 per minute. The presence of bradycardia, blocks of conduction is a contraindication, in a similar situation, beta-AP can aggravate the block and provoke the weakness of the sinus node. In the shock of a different origin, apparently, there are no pathophysiological justifications for the use of beta-AL. Moreover, their introduction may complicate the course of the process.

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

Calcium ions are assigned the role of a universal conjugating factor, which in various tissues, including the myocardium, realizes the excitation of the membrane into a corresponding cellular response. The intake of Ca2 + into cardiomyocytes is carried out by slowly conducting ("slow") ionic channels of two types. Potential-dependent calcium channels (type 1) are opened following the propagation of the membrane excitation wave due to the successive "explosive" opening of the 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 appears to be the main stimulus, which opens the slowly-conducting potential-dependent calcium channels; the initial entry of Ca2 + into the cytosol leads to a massive exit from the intracellular depot (phase 2 of the electrical cycle). It is also believed that in the process of depolarization of the cell membrane from its lipids, inosine triphosphate (ITP) can be cleaved-a chemical mediator that opens calcium channels in the sarcoplasmic network. In the cytosol of cardiomyocytes, calcium ions (their concentration in the myofibril region grows by an order of magnitude or more) specifically bind to the protein of the actomyosin complex with troponin. The latter changes its conformation, as a result of which an obstacle is removed for the interaction of actin and myosin, spasmodically increases from near-zero to peak ATP-ase activity of myosin and the ability of the complex to transfer the energy of the chemical bond of ATP to the mechanical work of the heart.

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 cardiac function. The interaction of the receptor with the agonist (norepinephrine, adrenaline and their analogs) leads to the activation of adenylate cyclase, the formation of cAMP in cardiomyocytes, which binds to inactive protein kinase and transforms it into an active form. The latter phosphorylates one of the calcium channel proteins, as a result of which the channel opens and passes calcium ions into the cytosol in accordance with the concentration gradient. Hormonependent slow-conducting channels in the cell membrane, sarcoplasmic and mitochondrial membranes exert an amplifying, modulating effect on the function of the potential-dependent channels and increase the occurrence of Ca2 + in cardiac fibers 2-4 times. In the sinus node, this leads to an increase in automatism and heart rate, in the jaundice system, to an improvement in conduction (to a certain extent, overload of the Ca2 + cell worsens the conductivity), and in the presence of prerequisites (for example, hypoxia) to the appearance of heterotrophic foci of excitation, in cardiomyocytes to intensification of heart contractions. Vagal influences through M-holinoretseptory membranes inhibit the function of adenylate cyclase and in this way delay the entry of Ca2 + through hormone-dependent channels and a further chain of reactions.

Many cardiotropic drugs exert their influence on the strength and frequency of heartbeats, other properties of the myocardium (conductivity, metabolic shifts, 02-query) due to a change in the conductivity of the calcium channels and the entry of Ca + into the cytosol. These effects can be either positive - increased ion input (positive inotropic and chronotropic effects), and negative - inhibition of the Ca + input (antiarrhythmic and cardioprotective effects). Both groups of drugs are used in emergency cardiology and intensive care. The mechanism of action of preparations on the conductivity of calcium channels is different, which determines their properties.

In this section of the chapter, the properties and general principles of the use of drugs with a positive inotropic effect for the prevention and treatment of OCH in shock of different genesis are discussed. These drugs vary considerably in their effect on heart function and systemic hemodynamics. In their clinical evaluation, the following criteria are important:

1. speed of approach and reliability of positive inotropic effect, its dose-dependence (regulating);
2. the degree of increase in the 02-request of the myocardium, which is especially important in the presence of a focus of ischemia;
3. influence on heart rate in doses providing the necessary inotropic effect;
4. the nature of the effect on the tone of the vessels in general (OPS) and in certain areas (mesenteric, pulmonary, renal, coronary vessels);
5. influence on the conductivity of impulses in the heart, especially with defects in conduction, arrhythmogenic risk of the drug.

Effect of drugs on the conductivity of calcium channels

Drug Groups	Mechanism of action
Increase the entry of calcium ions into the cytosol
Cardiac glycosides	The Na + K + -ATPase of membranes are inhibited, the Na + exchange is increased to Ca +, the extracellular Ca enters and its release by the sarcoplasmic network predominantly through potential-dependent channels
Beta-adrenomimetics	Selectively activate the hormone-dependent input of Ca2 +, coupled with the function of adenylate cyclase and cAMP; are agonists of beta-AP in the sinus node, conductive and contractible tissue of the heart
Inhibitors of phosphodiesterase	Delay inactivation of cAMP in the heart fibers, strengthen and prolong its influence on the conduct of CA + through hormone-dependent channels
Calcium agonists	They bind on specific receptors of calcium channels and open them for Ca +
Inhibit the entry of calcium ions into the cytosol
Calcium agonists *	Interact with the calcium receptor protein channels, prevent their opening and inhibit the occurrence of Ca + through hormone-dependent and (weaker) voltage-dependent channels
Beta-adrenolytics (beta-blockers)	Selectively block synaptic and extra-synaptic beta-AP, interfere with the activating effect of the sympathoadrenal system on the input of Ca + - through hormone-dependent channels
M-cholinomimetics, anticholinesterase agents	Inhibition of adenylate cyclase hormone-dependent channels and the formation of cAMP, activating the entrance of Ca
Antiarrhythmic agents of the quinidine group, local anesthetics, large doses of barbiturates	The entrance of Na + by the "fast" channels and the secondary opening of the calcium channels inhibit the weaker direct inhibitory effect on the entrance of Ca
* - A promising group of substances intensively studied by pharmacologists of drugs with a cardioselective agonist effect on the conductivity of calcium channels has not yet been revealed.

When choosing and using drugs with a positive inotropic effect in the shock or threat of shock of different genesis, it is necessary to bear in mind the relationship of various aspects of the pharmacodynamics of the drugs. In any case, the inotropic effect is accompanied by an additional expenditure of macroergists and, as a consequence, an increase in the 02 request of the heart, mobilization (before exhaustion) of its functional and biochemical reserves. However, the degree of growth _{of the} O2-demand and the probability of depletion of reserves depend more on the increase in heart rate than on the inotropic effect. Therefore, enhancement of contractility of the heart while reducing the initial high heart rate may be accompanied by a relative decrease in consumption of about ₂ left ventricle of the heart and the efficiency will increase. Lowering O ₂ Requesting contributes to reduction of load, ie. E. Simultaneous with inotropic vasodilator drug action (activation of vascular beta2-AR, a combination of a vasodilator), whereas the vasoconstrictor effect and increased GPT (activation of vascular alpha-AP) to give additional inotropic action increase in consumption О ₂. With cardiogenic shock and the threat of its development, the ability of an inotropic agent to expand the coronary vessels, improve blood flow in the ischemic and marginal zones of the myocardium, reduce the end-diastolic pressure of the left ventricle (CVDL) and the load on the affected heart, the minimal arrhythmogenic danger becomes important.

[1], [2], [3], [4], [5], [6], [7], [8], [9], [10]

Cardiac fast-acting glycosides

These medicines are traditionally considered as one of the first appointments of a physician in the OCH of a different genesis. The mechanism of action is explained by the selective inhibition of the Na + + K + -ATPase of the membranes (the receptor for glycosides, as well as the putative endogenous regulator of contraction force), which increases the intramembrane exchange of Na + with Ca2 + and increases the entry of the latter into the cell from outside and from the depot into sarcoplasmic network. 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 the potential-dependent channels and, apparently, have little effect on hormone-dependent ones. Direct effects on beta-AP do not have, therefore, their impact on the heart rate is secondary and ambiguous (reflex activation of vagal influences, release of endothelial sympathetic fibers). Decrease in heart rate is more typical, especially for digitalis glycosides. The small therapeutic latitude, the negative effect on the conductivity in the atrioventricular node and in the His-Purkinje fibers (in the presence of prerequisites) are well known, as well as a high arrhythmogenic hazard. Various violations of the heart rhythm - the most frequent complication in overdosing drugs and reducing their tolerance to the patient, as well as when combined with a number of medicines.

The positive inotropic effect of cardiac glycosides is not pronounced clearly, it does not come at once and comparatively slowly reaches a peak, but lasts for a long time and practically does not depend on the dose. Their positive effect on hemodynamics and survival was proven in traumatic, burn and toxic shock in the experiment. In connection with the peculiarities of pharmacokinetics, cardiac glycosides should be considered as a means of preventing OOS in these types of shock rather than 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 applied, and the risk of arrhythmias and blockades is dramatically increased. 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 availability

Factors that reduce the tolerability of cardiac glycosides and cause complications

Pathophysiologically

• Elderly patient's age
• Gykopoalliaemia
• Hypercalcemia
• Gympomagneaemia
• Respiratory and metabolic alkalosis
• High body temperature
• Hypoxemia
• Gipotireodizm
• Pulmonary heart
• Myocardial infarction

Medications that are dangerous in combination with cardiac glycosides

• Beta-adrenomimetics, euphyllin
• Cyclopropane, halogen containing preparations
• General anesthetics
• Dietylin
• Calcium preparations
• Quinidine and analogues
• Amiodarone
• Calcium antagonists

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

When deciding on the appointment of cardiac glycosides in case of shock of a different origin, factors that reduce tolerance to these agents (hypokalemia is more often observed), and the saturation phase is achieved by intravenous administration of fractional doses, which somewhat reduces the probability of complications, but does not guarantee against them. To eliminate possible arrhythmias at the ready, there must be a repolarizing solution or a solution of panangin.

[11], [12], [13], [14], [15], [16], [17],

Adrenomimetics

Adrenomimetic drugs form the basis of inotropic therapy for severe OOS in the shock of any genesis. Their action is primarily directed to the hormone (mediator) -dependent input of Ca2 + and is associated with the involvement of the adenylate cyclase mechanism in the cell reaction. The positive chrono-, dromo-, and inotropic effects of adrenomimetics are due to their interaction with beta-AR. Representations of the role of a few myocardial alpha-ARs are inconsistent and, apparently, receptors of this type do not play a significant role in regulating the strength and frequency of cardiac contractions.

Drugs with a non-selective alpha-beta-adrenomimetic action (noradrenaline, metamyinol, etc.) due to beta-AR activation have a positive inotropic effect, but it is largely devalued by a stronger effect of these drugs on alpha-AR vessels, leading to a sharp increase in OPS and increase the burden on the heart. As cardiotropic drugs, they are almost not used now, but in the treatment of acute hypotension, their inotropic action is useful and should be taken into account, as is usually the resultant reflex bradycardia.

The main place in the treatment of OCH belongs to adreno and dopaminomimetics with a marked selective effect on beta-AP. The ratio of positive inotropic and chronotropic actions is determined by the degree of activation of the cells of the sinus node and the contractible tissue, as well as the beta-AR subtype, to which the effect of the drug predominates. The degree of selectivity of the action of adrenomimetics on beta1 and beta-2-AP is relative and with the increase in the rate of infusion (dose, concentration) of drugs, the differences between them can be erased. In general, selective beta-1-adrenomimetics to a greater extent activate the force of the heartbeat than their frequency, and have a more economical pacemaker effect compared to beta2 and nonselective beta1-beta2-adrenomimetics.

The influence of adrenomimetic agents on cardiac function and the basic parameters of hemodynamics

Index	Alpha-beta-AM		Non-selective beta-AM	Selective beta1-AM	Selective beta2-AM	Dopaminomimetics
	NA, methanamine	A	Isoproterenol, orciprenalin	Dobutamine, prenalaterol, and others.	Salbutamol, terbutaline, and others.	Dopamine, zepamin, and others.
Heart rate	- +	+++	++++	0+	++	0+
Systolic heart volume index	+	++	++++	+++	++	+++
Minute heart volume index	+	+++	+++	+++	++	+++
Consumption of O2 by myocardium	++	+++	++++	0+	+	+
Coronary blood flow	- +	++	++	+	++	+
Conductivity in the A-V node	+	+	++	+	+	0+
Arrhythmogenic Danger	+++	+++	++++	0+	+	+
Systolic blood pressure	+	+++	+++	++	+	++
Diastolic blood pressure	+++	-	-	0+	-	-0 ++
Pressure in the pulmonary capillaries	+++	++	-	-0+	-	- +
Pressure of filling of the left ventricle	++	++		0-		- +
Final diastolic pressure in the left ventricle	- +
Kidney blood flow	---	---	+	0+	0-	+++
Blood flow in internal organs	---	---	++	0	++	++ -
Total peripheral resistance of blood vessels	+++	+	-	-	-	-0+
* The direction of action of a number of adrenomimetics can change with increasing rate of infusion (dose).

In accordance with the prevalence of action on a particular subtype of beta-AR, adrenomimetics are divided into the following subgroups.

Non-selective beta1-beta2-adrenomimetiki - isoproterenol (isadrin), orciprenaline (alupent), adrenaline (additionally activates alpha-AR). Have a pronounced cardiostimulating effect with positive chronotropic (somewhat predominant), inotropic and dromotropic effects, significantly increase the 02-request of the myocardium, easily provoke or enhance rhythm disturbances and increase the necrosis zone in myocardial ischemia. They differ in the effect on vascular tone: the first two drugs, due to the activation of vasodilating beta2-AP, reduce the tone of the vessels and OPS, can also reduce the mean and diastolic blood pressure and secondary coronary blood flow. The drugs expand the bronchi and reduce the "wedging pressure" in the capillaries of the lungs. On the whole, they are distinguished by high reliability of inotropic action, but also by its maximum price for the heart, have a rather short-term (controlled) effect. Adrenaline remains a means of choice at the beginning of anaphylactic shock therapy; After him, massive doses of glucocorticoid are injected into the vein. 

Selective beta1-adrenomimetics - dobutamine, prenalterol, xamaterol, etc. Positive inotropic response (increase in SI, dp / dt of the left ventricle, reduction of end-diastolic pressure of the left ventricle - CTRL) is not accompanied by a significant increase in heart rate and 02-request of the heart; the risk of arrhythmias is less than with the use of drugs from the previous group. In the experiment and clinic, dobutamine was better studied, which also has a weak activating effect on alpha-AP vessels, and therefore does not reduce blood pressure, on the contrary, it contributes to its recovery and maintenance without significant growth in OPS. It lasts longer than isoproterenol and the controllability of the effect is worse. As emphasized, the selectivity of the drugs of the group is relative: the ratio of beta1 / beta2-adrenergic effect is 1/2. With an increase in the rate of infusion (dose), heart rate and blood pressure increase. 

Selective beta2-adrenomimetics - salbutamol, terbutaline, fenoterol, etc. The ratio of beta2 / beta1-mimetic activity is 1/3. Apparently, due to the smaller representation of beta2-AP in the atria and ventricles of the human heart (about 1/3 of the total beta-AP), the drugs of this subgroup have a less distinct positive inotropic effect, which is accompanied by a marked increase in heart rate. Due to the activation of beta2-AP, these drugs cause vasodilation with a decrease in OPS and blood pressure. In considerably smaller doses (10-20 times less than cardiotropic), they exert a strong bronchodilating effect (preferable for asthmatic status, with anaphylactic shock with bronchospasm phenomena). For correction of DOS, they are now used in a limited way, because of tachycardia and the possibility of rhythm disturbances. 

Dopaminomimetics-dopamine (dopamine), zepamin, etc. The positive inotropic effect is due not so much to activation of DA-P, as to direct action on beta 1-AP and release of HA from nerve endings with increasing infusion rate (dose, concentration). The effect on beta2-AR is weak (in bronchial tests, 2000 times weaker adrenaline). Dopamine today, perhaps, the most used means of therapy of OSN in the shock of different genesis. The possibility of sequential activation of dopamine, beta 1 -A-AR and vascular alpha-AP with an increase in the rate of infusion allows one to obtain relatively selective action on the desired types of receptors or their total excitation with appropriate pharmacological responses. A positive inotropic effect is similar to that of beta1-adrenomimetics, combined with a dopaminomimetic effect on vessels (renal and mesenteric expansion, narrowing of cutaneous and muscular), and with further acceleration of infusion - with noradrenaline-like. Increase in heart rate is small, but increases with increasing dose, as does arrhythmogenic danger (associated with HA release); in this respect dopamine is inferior to dobutamine. With the use of vasopressor doses, OPS grows and "wedging pressure" in the capillaries of the lung can increase. In addition to treating OCH, dopamine is used to enhance renal function, especially in combination with furosemide. The action 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 small.

Thus, pharmacology has a fairly large arsenal of drugs of different types, the use of which forms the basis of cardiostimulating therapy of acute sensitization in particularly critical situations.

[18], [19], [20], [21], [22], [23], [24], [25]