Innervation of the heart. chronotropic effect. dromotropic effect. inotropic effect. bathmotropic effect. Approximate maximum infusion rate

General provisions

The goal of inotropic support is to provide maximum tissue oxygenation (assessed by plasma lactate concentration and mixed venous blood oxygenation), and not 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 differ in their 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 does not affect α-adrenergic receptors. The drug dilates the bronchi, during blockade it acts as a pacemaker, affecting the sinus node, increases conductivity and reduces the refractory period of the atrioventricular node. It has a positive inotropic effect. It has an effect on skeletal muscles and blood vessels. The half-life is 5 minutes.

Drug Interactions

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

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 differentially affecting α 1 - and α 2 -adrenergic receptors.
Usually it has little effect on the level of mean blood pressure, with the exception of cases of prescribing the drug against the background of non-selective blockade of β-adrenergic receptors, in which the vasodilating effect of epinephrine mediated by the action 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 epinephrine as an inotropic agent 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 administered together with dopamine in the 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 in cardiac arrest.
In case of shock, 1-10 mcg / min is administered drip.

Pharmacokinetics

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

Side effects

Arrhythmias.
Intracerebral hemorrhage (with overdose).
Pulmonary edema (with overdose).
Ischemic necrosis at the injection site.
Restlessness, dyspnea, palpitations, tremors, weakness, cold extremities.

drug interaction

Tricyclic immunosuppressants.
Anesthetics.
β-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 circulation. α 1 dopamine receptors are located in the postganglionic endings of the sympathetic nerves and ganglia of the autonomic nervous system. At an average dose, dopamine activates β 1 -adrenergic receptors, having positive chronotropic and inotropic effects, and at 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 against the background of multiple organ failure. There is little evidence regarding the effect of dopamine on the clinical outcome of the disease.

Pharmacokinetics

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

Side effects

Arrhythmias are rarely seen.
Hypertension at very high doses.
Extravasation can 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-Adrenergic blockers may enhance the vasodilatory 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 adrenoreceptors and a levorotatory isomer having an α 1 selective effect is used. The effects on β2-adrenergic receptors (vasodilatation of mesenteric and musculoskeletal vessels) and α 1 -adrenergic receptors (vasoconstriction) suppress each other, so dobutamine has little effect on blood pressure unless administered at a high dose. It has less, compared with dopamine, arrhythmogenic effect.

Application area

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

Pharmacokinetics

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

Side effects

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

drug interaction

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

drug interaction

Tricyclic antidepressants (blocking the re-entry 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 it should be started with a dose equal to 1/10 of the usual initial dose, i.e. 0.2 µg/(kghmin).

Dobutamine is not a substrate for MAO.

Milrinone

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

Side effects

Enoximonr

Enoximone is a phosphodiesterase (type IV) inhibitor. The drug is 20 times more active than aminophylline, its half-life is approximately 1.5 hours. It is broken down to active metabolites with 10% enoximonar activity with a half-life of 15 hours. It is used to treat congestive heart failure, it can be prescribed both in tablet form, as well as intravenously.

Side effects

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

Bicarbonate of soda

Pharmacology

Sodium bicarbonate plays an important role as a buffer in the body. Its effect is short-lived. The 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 administered 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 vasodilation of the brain, 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.
The use of sodium bicarbonate in CPR is best avoided, as cardiac massage and artificial respiration are sufficient.

Dose

Released in the form of 8.4% solution (hypertonic, 1 ml contains 1 mmol bicarbonate ion) and 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 recommendations of the British Council for Resuscitation, an 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 with a body weight of 60 kg, having a base deficiency of -20, needs 400 ml of 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 desirable to adjust the pH to the level of 7.0-7.1 by prescribing 50-100 ml of sodium bicarbonate, followed by an assessment of arterial blood gases and repeated administration of the drug if necessary. This allows you to gain enough time to conduct more effective and safer diagnostic and treatment measures and treat the disease that led to the development of acidosis.

Side effects

Extravasation results in tissue necrosis. If possible, the drug is administered through a central catheter.
With simultaneous administration with calcium preparations, calcifications are formed in the catheter, which can lead to microembolism.

Test

"Inotropic and angiotropic drugs"

What is the purpose of cardiovascular drugs?

With the help of cardiovascular drugs, which are in the arsenal of a modern doctor, it is possible to influence all components of cardiac output and organ perfusion.

Preload (end-diastolic volume), afterload (peripheral vascular resistance), heart rate and force, and even myocardial blood supply, oxygenation, and oxygen demand can be affected by prescribing certain drugs. The Frank-Starling theory underlies the understanding of the mechanisms of the heart and the action of drugs. It establishes a direct relationship between preload (the length of the muscle fiber) and the strength of the subsequent contraction of the heart muscle. According to this theory, up to a certain point (the point of final decompensation), an increase in preload leads to an increase in cardiac output.

Explain the possibilities and limits of action of drugs that change vascular tone.

Preload can be modified with drugs that dilate or constrict vessels, with the most important being the change in venous volume, or reservoir vessels. In addition, arterial vasodilators improve the contractility of the affected myocardium by reducing afterload and peripheral resistance. However, vasodilators, unlike inotropic support drugs, do not have a positive inotropic effect.

The positive effect of arterial vasodilators in most cases is limited by their parallel effect on the venous bed (expressed to a lesser extent), which leads to a decrease in ventricular preload.

Maintaining preload with fluid therapy is important, especially in the presence of venodilation. The only exception to this rule is the vasodilator nicardipine, which is significantly limited by systemic circulation (see question 24).

Describe the action of cardiovascular drugs

All cardiovascular drugs according to the mechanism of action can be divided into antagonists and agonists. Interacting with the receptor, which is most often located on the surface of the cell membrane, agonists change its configuration, which, in turn, causes a cascade of intracellular reactions. As a result of all of the above, one or another clinical effect develops. Antagonists, on the contrary, block receptors on the surface of the cell membrane and thereby prevent the undesirable action of agonists.

Name the sympathomimetics that are often used in practical medicine. What is their role?

Sympathomimetics used in heart failure

Most of the cardiovascular drugs used by practitioners to obtain a positive inotropic effect or increase vascular tone, especially in critical conditions, are sympathomimetic amines. They contain p-phenylethylamine. All sympathomimetics can be divided into two groups according to their chemical structure: catecholamines and those drugs that are not catecholamines. The basis for such a division is, respectively, the presence or absence of a catecholamine component in their structure or, more simply, the presence of a hydroxyl group in the benzene ring in the 3rd and 4th positions. Sympathomimetics act through the system of adrenergic receptors.

What is the classification of adrenergic receptors? What physiological response develops when they are stimulated?

Adrenergic receptors (AR) can be divided into two groups: calamus. Those, in turn, are divided into subgroups. From the standpoint of classical pharmacology, a, -, a 2 -, Rg and p 2 -adrenergic receptors are isolated depending on their effect on the cardiovascular system. However, modern genetic technologies make it possible to distinguish additional subtypes. The classification of AR in the chronological order of their detection and depending on the changes that occur during their stimulation (in the cardiovascular system and from the bronchi) is shown in the figure.

How selective are cardiovascular drugs that act on AR?

Most AR agonists and antagonists that are used in practice are not strictly selective. For example, dopamine can act on all types of ARs and on dopamine receptors depending on the rate of administration (see question 28).

What factors determine the blood supply to the myocardium and its need for oxygen (PM0 2)?

Delivery of oxygen to the myocardium depends on the oxygen content in arterial blood and coronary perfusion. The latter, in turn, depends on heart rate (the lower the heart rate, the longer diastole lasts, during which subendocardial blood flow in the left ventricle is maintained), diastolic blood pressure (on which coronary perfusion pressure depends) and coronary blood flow (which is regulated by the intensity of metabolic processes in myocardium, autoregulatory system and coronary vascular tone). PM0 2 depends on preload, afterload, heart rate and heart rate. An increase in preload (increase in ventricular diameter) or inotropic support increases PMOg - A decrease in afterload leads to a decrease in stroke volume resistance and, thus, leads to a decrease in PM0 2 due to improved oxygenation and blood supply to the myocardium. All this happens until the blood supply deteriorates due to a decrease in the IOC. An increase in heart rate has a directly opposite effect on myocardial blood supply and PM0 2 .

List the drugs that are often taken by patients with diseases of the cardiovascular system

Glycosides. 4. p-blockers.

Diuretics. 5. Calcium channel blockers.

Coronary vasodilators (nitrates) .6. ACE inhibitors.

Which of the following drugs are used in the treatment of coronary artery disease?

The basis of drug therapy for coronary heart disease are 3 groups of drugs: nitrates, calcium channel blockers and β-blockers.

What is the main purpose of inotropic support? Describe the ideal drug with a positive inotropic effect.

Increase in IOC by increasing myocardial contractility.

Reducing the size of the ventricles, myocardial tension and, thus, a decrease in PM0 2.

Optimization of tissue perfusion and blood pressure.

Decrease in pulmonary vascular resistance and load on the right side of the heart.

The ideal drug should provide inotropic support without increasing heart rate or increasing myocardial oxygen demand. It should not have an arrhythmogenic effect and increase blood pressure.

Describe the mechanism of action of cardiac glycosides (CG).

The main factor causing the development of heart failure is a violation of the distribution of intracellular calcium. SG bind to the a-subunit of sodium-potassium adenosine triphosphatase of the sarcolemma. Thus, the process of ion transfer through the membrane is disrupted and the content of sodium and calcium ions inside the cell increases. An increase in the content of sodium ions in the cell provides a more active binding of calcium ions to contractile proteins. Sodium ions reduce the transport of calcium out of the cell and thereby also increase the content of calcium into the cells. Calcium binds to troponin C. Troponin C is a regulatory protein that is directly associated with myosin. The number of cross-links between actin and myosin increases. This leads to an increase in contractile function. The strength of contractions is directly proportional to the number of application points on tropomyosin that are occupied by calcium ions.

What is the positive effect of SH in patients with chronic heart failure (CHF)?

SG increase myocardial contractility, reduce end-systolic volume and end-systolic pressure. Reducing the size of the heart reduces myocardial tension, PM0 2 and reduces the manifestations of angina pectoris. In addition, SG reduces systemic vascular resistance and venous vascular tone in patients with CHF, and has a positive effect on PM0 2 . In fact, those doses of SG that have a beneficial effect on CHF do not have a significant positive inotropic effect. Improvement in well-being occurs as a result of a change in the body's reflex response to CHF.

Name the factors predisposing to SG overdose.

Advanced age.

Hypothyroidism.

Hypoxia.

Hypokalemia.

Hypomagnesemia.

Hypocalcemia.

The use of certain drugs (propranolol, amiodarone, verapamil, quinidine).

Describe the clinical picture of SG overdose.

On the part of the cardiovascular system, it is due to an increase in automatism (in this case, a new source of impulse is almost always located in the atrioventricular node or in the ventricles) and the development of atrioventricular blockade. Extracardiac symptoms (mostly neurological) include (in order of importance) nausea, vomiting, diarrhea, confusion, delirium, and seizures.

How to treat an overdose of SG?

Treatment includes drug therapy and normalization of electrolyte balance. In severe intoxication, arrhythmias caused by SH may require the appointment of lidocaine, novocainamide, phentoin, propranolol, and even electrical impulse therapy (EIT). However, in these cases, EIT itself can lead to deadly arrhythmias. This problem can be solved by applying a minimally sufficient discharge and administering lidocaine to suppress ventricular arrhythmias.

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: a 1 -, beta 1 - and beta 2 - Stimulation a 1-adrenergic receptors is accompanied by a pronounced vasoconstrictor effect - a general systemic vasoconstriction, including precapillary vessels of the skin, mucous membranes, kidney vessels, as well as a pronounced narrowing of the veins. Stimulation of beta 1 -adrenergic receptors is accompanied by a distinct positive chronotropic and inotropic effect. Stimulation of beta 2 -adrenergic receptors causes bronchial dilatation.

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

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

Doses for intravenous administration:

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

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

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

4) action depending on the rate of administration:

Less than 1 mcg / min - vasoconstrictor,

From 1 to 4 mcg / min - cardiostimulating,

5 to 20 mcg/min - a- adrenostimulating,

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

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

Norepinephrine . Natural catecholamine, which is the precursor of adrenaline. It is synthesized in the postsynaptic endings of the sympathetic nerves and performs a neurotransmitter function. Norepinephrine stimulates a-, beta 1 -adrenergic receptors, almost no effect on beta 2 -adrenergic receptors. It differs from adrenaline in a stronger vasoconstrictor and pressor action, less stimulating effect on automatism and contractile ability of the myocardium. The drug causes a significant increase in peripheral vascular resistance, reduces blood flow in the intestines, kidneys and liver, causing severe renal and mesenteric vasoconstriction. The addition of small doses of dopamine (1 µg/kg/min) helps to preserve renal blood flow when norepinephrine is administered.

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

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

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

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

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

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

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

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

2) small doses - 1-3 mcg / (kg-min) are administered intravenously; while dopamine acts mainly on the celiac and especially the renal region, causing vasodilation of these areas and contributing to an increase in renal and mesenteric blood flow; 3) with a gradual increase in speed to 10 μg/(kg-min), peripheral vasoconstriction and pulmonary occlusive pressure increase; 4) high doses - 5-15 mcg / (kg-min) stimulate beta 1-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, it is necessary to monitor hemodynamic parameters. If tachycardia occurs, it is recommended to reduce the dose or discontinue further administration. Do not mix the drug with sodium bicarbonate, as it is inactivated. Long-term use a- and beta-agonists reduces the effectiveness of beta-adrenergic regulation, the myocardium becomes less sensitive to the inotropic effects of catecholamines, up to the complete loss of the hemodynamic response.

Side effect: 1) increase in DZLK, the appearance of tachyarrhythmias is possible; 2) in high doses can cause severe vasoconstriction.

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

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

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

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

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

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

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

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

VASODILATORS

Nitrates are used as fast-acting vasodilators. The drugs of this group, causing the expansion of the lumen of blood vessels, including coronary ones, affect the state of pre- and afterload and, in severe forms of heart failure with high filling pressure, significantly increase CO.

Nitroglycerine . The main action of nitroglycerin is the relaxation of vascular smooth muscles. In low doses, it provides a venodilating effect, in high doses it also dilates arterioles and small arteries, which causes a decrease in peripheral vascular resistance and blood pressure. Having a direct vasodilating effect, nitroglycerin improves the blood supply to the ischemic area of the myocardium. The use of nitroglycerin in combination with dobutamine (10-20 mcg/(kg-min) is indicated in patients at high risk of myocardial ischemia.

Indications for use: angina pectoris, myocardial infarction, heart failure with an adequate level of blood pressure; pulmonary hypertension; high level of OPSS with elevated blood pressure.

Solution preparation: 50 mg of nitroglycerin is diluted in 500 ml of solvent to a concentration of 0.1 mg / ml. Doses are selected by titration.

Doses for intravenous administration. The initial dose is 10 mcg / min (low doses of nitroglycerin). Gradually increase the dose - every 5 minutes by 10 mcg / min (high doses of nitroglycerin) - until a clear effect on hemodynamics is obtained. The highest dose is up to 3 mcg / (kg-min). In case of overdose, hypotension and exacerbation of myocardial ischemia may develop. Intermittent administration therapy is often more effective than long-term administration. For intravenous infusions, systems made of polyvinyl chloride should not be used, since a significant part of the drug settles on their walls. Use systems made of plastic (polyethylene) or glass vials.

Side effect. Causes the conversion of part of hemoglobin into methemoglobin. An increase in the level of methemoglobin up to 10% leads to the development of cyanosis, and a higher level is life-threatening. To lower the high level of methemoglobin (up to 10%), a solution of methylene blue (2 mg / kg for 10 minutes) should be administered intravenously [Marino P., 1998].

With prolonged (from 24 to 48 hours) intravenous administration of a solution of nitroglycerin, tachyphylaxis is possible, characterized by a decrease in the therapeutic effect in cases of repeated administration.

After the use of nitroglycerin with pulmonary edema, hypoxemia occurs. The decrease in PaO 2 is associated with an increase in blood shunting in the lungs.

After using high doses of nitroglycerin, ethanol intoxication often develops. This is due to the use of ethyl alcohol as a solvent.

Contraindications: increased intracranial pressure, glaucoma, hypovolemia.

Sodium nitroprusside is a fast-acting balanced vasodilator that relaxes the smooth muscles of both veins and arterioles. It does not have a pronounced effect on heart rate and heart rate. Under the influence of the drug, OPSS and blood return to the heart are reduced. At the same time, coronary blood flow increases, CO increases, but myocardial oxygen demand decreases.

Indications for use. Nitroprusside is the drug of choice in patients with severe hypertension associated with low CO. Even a slight decrease in peripheral vascular resistance during myocardial ischemia with a decrease in the pumping function of the heart contributes to the normalization of CO. Nitroprusside has no direct effect on the heart muscle, it is one of the best drugs in the treatment of hypertensive crises. It is used for acute left ventricular failure without signs of arterial hypotension.

Solution preparation: 500 mg (10 ampoules) of sodium nitroprusside are diluted in 1000 ml of solvent (concentration 500 mg/l). Store in a place well protected from light. Freshly prepared solution has a brownish tint. The darkened solution is not suitable for use.

Doses for intravenous administration. The initial rate of administration is from 0.1 μg / (kg-min), with a low CO - 0.2 μg / (kg-min). With a hypertensive crisis, treatment begins with 2 mcg / (kg-min). The usual dose is 0.5 - 5 mcg / (kg-min). The average rate of administration is 0.7 µg/kg/min. The highest therapeutic dose is 2-3 mcg / kg / min for 72 hours.

Side effect. With prolonged use of the drug, cyanide intoxication is possible. This is due to the depletion of thiosulfite reserves in the body (in smokers, with malnutrition, vitamin B 12 deficiency), which is involved in the inactivation of cyanide formed during the metabolism of nitroprusside. In this case, the development of lactic acidosis, accompanied by headache, weakness and arterial hypotension, is possible. Intoxication with thiocyanate is also possible. Cyanides formed during the metabolism of nitroprusside in the body are converted to thiocyanate. The accumulation of the latter occurs in renal failure. The toxic concentration of thiocyanate in plasma is 100 mg/L.

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

Increase in the intracellular content of calcium ions.

Increased sensitivity of contractile proteins to calcium ions.

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

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

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

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

14.1. CARDIAC GLYCOsideS

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

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

Classification

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

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

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

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

Mechanism of action and main pharmacodynamic effects

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

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

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

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

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

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

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

Pharmacokinetics

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

Table 14-1. Basic pharmacokinetic parameters of cardiac glycosides

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

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

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

Indications for use and dosing regimen

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

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

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

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

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

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

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

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

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

The dosing regimen for lanatoside C has not been developed in detail, since the drug is used much less frequently than digoxin. Calculation of these parameters for strophanthin-K is impractical, since drugs are used for a short time and there is no dosage form for taking strophanthin-K inside.

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

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

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

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

For women, the result is multiplied by 0.85.

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

Therapeutic drug monitoring

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

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

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

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

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

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

Side effects

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

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

Elderly age.

Late stage CHF.

Severe dilatation of the heart.

Acute myocardial infarction.

Severe myocardial ischemia.

Inflammatory lesions of the myocardium.

Hypoxia of any etiology.

Hypokalemia and hypomagnesemia.

Hypercalcemia.

Dysfunction of the thyroid gland.

Increased activity of the sympathetic nervous system.

Respiratory failure.

Renal and liver failure.

Acid-base disorders (alkalosis).

Hypoproteinemia.

Electropulse therapy.

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

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

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

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

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

Hematological disorders: thrombocytopenic purpura, epistaxis, petechiae.

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

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

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

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

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

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

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

Contraindications

Glycoside intoxication is considered an absolute contraindication to the appointment of cardiac glycosides. Relative contraindications are the syndrome of weakness of the sinus node and AV blockade of I-II degree (danger of aggravating sinus node dysfunction and further slowing down conduction through the AV node), ventricular arrhythmias (danger of increased arrhythmias), atrial fibrillation in combination with Wolff-Parkinson syndrome- White, sinus bradycardia. It is inappropriate to use cardiac glycosides in cases of heart failure without impaired systolic function of the left ventricle (hypertrophic cardiomyopathy, aortic stenosis, mitral stenosis with sinus rhythm, constrictive pericarditis).

Efficacy and safety assessmentEfficiency mark

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

Safety assessment

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

Questioning the patient to identify symptoms of intoxication.

Pulse and heart rate control.

ECG analysis.

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

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

Control of the content of digoxin in blood plasma.

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

Interaction

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

14.2. ADRENORECEPTOR AGONISTS

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

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

Table 14-2. Effects of adrenoceptor agonists

The end of the table. 14-2

dobutamine

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

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

Indications

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

Side effects

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

Contraindications

Dobutamine is contraindicated in case of hypersensitivity to it.

Precautionary measures

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

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

dopamine

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

Indications

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

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

Side effects

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

Contraindications

Dopamine is contraindicated in pheochromocytoma, ventricular arrhythmias.

Precautionary measures

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

Pharmacokinetics and dosing regimen

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

epinephrine

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

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

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

Side effects

Side effects of epinephrine include tachycardia, arrhythmias, headache, agitation, chest pain, and pulmonary edema.

Contraindications

Epinephrine is contraindicated in pregnancy.

Pharmacokinetics and dosing regimen

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

norepinephrine

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

Indications

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

Side effects

Side effects of norepinephrine are tachycardia, arrhythmias, headache, agitation.

Contraindications

Norepinephrine is contraindicated in pregnancy.

Pharmacokinetics and dosing regimen

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

14.3. PHOSPHODIESTERASE INHIBITORS

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

Indication

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

Contraindications

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

Pharmacokinetics and dosing regimen

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

Side effects

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

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

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

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

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

Doses for intravenous administration:

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

4) action depending on the rate of administration:

Less than 1 mcg / min - vasoconstrictor,

From 1 to 4 mcg / min - cardiostimulating,

5 to 20 mcg/min - a- adrenostimulating,

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

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

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

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

Side effect: 1) increase in DZLK, the appearance of tachyarrhythmias is possible; 2) in high doses can cause severe vasoconstriction.

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

VASODILATORS

Indications for use: angina pectoris, myocardial infarction, heart failure with an adequate level of blood pressure; pulmonary hypertension; high level of OPSS with elevated blood pressure.

Solution preparation: 50 mg of nitroglycerin is diluted in 500 ml of solvent to a concentration of 0.1 mg / ml. Doses are selected by titration.

After the use of nitroglycerin with pulmonary edema, hypoxemia occurs. The decrease in PaO 2 is associated with an increase in blood shunting in the lungs.

After using high doses of nitroglycerin, ethanol intoxication often develops. This is due to the use of ethyl alcohol as a solvent.

Contraindications: increased intracranial pressure, glaucoma, hypovolemia.