"CARDIAC. ANTIARRHYTHMICS "

Cardiotonic

Cardiac glycosidesCardiac glycosides - are substances of plant origin, which have a pronounced cardiotonic action and are used in the treatment of heart failure associated with myocardial dystrophy of different etiology. They increase the efficiency of the myocardium, providing the most economical and yet effective activity of the heart.

Cardiac glycosides are composed of nonglycose part (aglycone or genin) and sugars (glucone). The basis is a steroid aglycone (cyclopentane-perhydro-phenanthrene) structure associated with most glycosides unsaturated lactone ring. Glucones may be represented by different sugars: D-digitoxose, D-tsimarozoy, D-rhamnose, etc... The number of sugars in the molecule ranges from I to 4. Sometimes sugar moiety attached to the remainder acetic acid. Cardiotonic effect linked to the aglycone. Regarding the role of sugar moiety, then it is essential for the solubility of glycosides and their fixation in tissues. Glucones effect on the activity and toxicity of the compounds.

Cardiac glycosides readily undergo hydrolysis (enzymatic, acidic, basic). It is noted that the plants themselves are enzymes hydrolyzing cardiac glycosides. The latter explains the possibility of hydrolytic cleavage of the primary (Genuine) glycosides in the medicinal raw material during storage or preparation for processing. In order to prevent this process, enzymes may be inhibited.

In clinical practice, the most widely used drugs are cardiac glycosides derived from the following plants:• purple foxglove (Digitalis purpurea) - digitoxin;• woolly foxglove (Digitalis lanata) - digoxin tselanid (lanatozid C izolanid);• strophanthus Combe (Strophanthus Kombe) - strofantin K;• lily of the valley (Convallaria) ~ Korglikon;• adonis (Adonis vernalis) - infusion of herbs adonis.

Of greatest interest are individual glycosides. Simple and galenical preparations novogalenase lose their significance.The main property of cardiac glycosides is their selective effect on the heart. Major role in the pharmacotherapeutic effect of cardiac glycosides plays strengthen systole (cardiotonic action positive inotropic effect) due to the direct influence of drugs pas myocardium. Systolic contraction becomes more energetic and fast. This is manifested in the ECG shortening the interval Q-T, from the ventricular complex also typical decreasing S-T segment below the isoelectric line, reduction, smoothing or T wave inversionIn heart failure, cardiac glycosides significantly increased stroke volume and cardiac output. It is important that the work of the heart is increased without increasing their consumption of oxygen (per unit of work).

Cardiotonic mechanism of action of cardiac glycosides is related to their inhibitory effect on the Na +, K + -ATPase membrane cardiomyocytes. This leads to disruption of the current Na + and K +. As a result, the content of K in cardiomyocytes decreases, a Na + - increases. The difference between the intra- and extracellular Na concentration decreases, which reduces the transmembrane Na / Ca3 + exchange. Last reduces the intensity of Ca2 + excretion, which increases its content in the sarcoplasm and accumulation in the sarcoplasmic reticulum. In turn, this stimulates the additional amounts outside Sag + calcium into cardiomyocytes by L-channels. Against this background, the action potential causes increased release of Ca2 + from the sarcoplasmic reticulum. This increases the levels of free Ca2 'in the sarcoplasm that provides cardiotonic effect. Ca2 + ions mutually-interacting with the troponin complex and eliminate its inhibitory effect on the contractile proteins of the myocardium. The interaction of actin and myosin, which is manifested fast and strong contraction of the myocardium.

It is important that the work of the heart rises against the background of deceleration of heart rate (from-negatively chronotropic effect) and lengthening of diastole. This creates the most economical mode of operation of the heart: a strong reduction in systolic replaced by a sufficient period of "rest" (diastole), conducive to the restoration of energy resources in the myocardium. Slowing of heart rate is largely due to the cardio-cardiac reflex. Under the influence of cardiac glycosides are excited by the end of the sensory nerves of the heart and reflex via the vagus nerves occurs bradycardia. It is possible that plays a role in the increased reflexes heart with mechanoreceptors sinoaortic area during systole as a result of high blood pressure. There is an increase in the ECG interval PP.

In addition, cardiac glycosides, providing a direct depressant effect on the conduction system of the heart and toning vagus nerve, reduce the rate of excitation (negative dromotropic action). Refracteric period of atrioventricular (atrioventricular) node and the atrioventricular bundle (bundle of His) increases. P-Q interval becomes longer. In toxic doses of cardiac glycosides can cause atrial-ventricular unit.In large doses, cardiac glycosides increase the automaticity of the heart. This leads to the formation of ectopic foci excitation generating pulses from the sinus node independently. Arrhythmias (for example, extrasystoles).

In this connection, to prevent side effects (e.g., neurite outgrowth) administered simultaneously with isoniazid, pyridoxine (vitamin B6).Allergic reactions eliminate anti-allergic agents.The derivatives of isonicotinic acid hydrazide are also ftivazid, metazid, salyuzid soluble. All of them are less active than isoniazid, and there are no advantages in comparison with it are not. Use them rarely, usually isoniazid intolerance.

Based on experiments on animals, in small doses, cardiac glycosides increase the excitability of the myocardium (batmotropic positive action). This is manifested, in reducing myocardial excitability threshold in response to requests for non-mu stimuli. In large doses, cardiac glycosides reduce the excitability of the heart muscle.Thus, excitability and automatism - two different parameters, which change under the influence of cardiac glycosides ambiguous. Change of automatism and excitability is due to the direct action of cardiac glycosides on the myocardium.

When heart failure increase under the influence of cardiac glycosides his cardiac output has a positive effect on blood circulation in general. The main effect of cardiac glycosides on blood circulation decompensation of heart is to reduce venous stasis. In this case, the venous pressure drops and swelling gradually disappearing. With the elimination of venous stasis occurs reflex rapid heart rhythm (Bainbridge reflex from the mouths of the upper vena cava). Blood pressure did not change or increased (if it was dropped). Total peripheral vascular resistance decreases blood flow and tissue oxygenation improved. Disturbed functions of internal organs (liver, gastrointestinal tract, etc.). Restored. Blood supply to the heart cardiac glycosides may improve by normalizing the overall hemodynamics (from digitalis preparations when administered in high doses, a slight narrows of the coronary direct action).

Renal function as a result of the favorable effect of cardiac glycosides on blood circulation to normal. Diuresis increases. There is evidence that digitalis preparations and strophanthus have a direct effect on the kidneys, reducing the reabsorption of sodium ions. However, this is of secondary importance. Diuresis promotes excretion of excess fluid. The latter condition facilitates the hemodynamics because due to a decrease in circulating blood volume reduces the load on the heart. In addition, decreases or completely disappears tissue edema.Until now it was about the general properties of cardiac glycosides. However, various preparations have certain differences. This applies activity development rate effect and its duration, as well as the pharmacokinetics of substances. Activity on cardiac glycosides differ quite significantly, in determining the activity of medicinal plants and many drugs (herbal, novogalenase et al.) Uses biological standardization. In this case, the activity of cardiac glycosides represent common frog action units (ICE).

comprising a number of cardiac glycosides, and the activity of individual glycosides.Medicinal raw materials: 1 g of digitalis leaf contains 50-66 ICE, 1 g of grass Adonis contains 50-66 ICE, 1 g of grass lily of the valley contains 120 ICE, 1 g of seeds contains strophanthus 2000 ICE.Individual glycosides: 1 g digitoksina contains 8000-10000 ice, 1 g tselanida contains 14000-16000 ice, 1 g Convallatoxin contains 63000-80000 ice, 1 g strofantina It contains 44000-56000 ice.Thus, the biological activity strofantina K and Convallatoxin (glycoside lily of the valley) is considerably higher than digitalis glycosides - digitoxin and tselanida.At the clinic on the activity of cardiac glycosides can be judged by equally effective doses when administered intravenously.

Differences cardiac glycosides are also in the severity of the latent period and the rate of increase of the effect. Thus, when administered intra-vennom strofantin Convallatoxin and begin to act on the heart after 5-10 minutes and tselanid - 5-30 min. When introduced into the effect of digoxin is 30 minutes and upon receiving digitoxin - approximately 2h.In the application of substances equally effective doses and the same way of administration (intravenous) maximum effect comes at a particularly fast and strofantina Convallatoxin (30 minutes, 1.5 hours), followed by tselanid and digoxin (1-5 hours), and then - digitoxin (4-12 hours). Consequently, even among pre-preparations of digitalis speed of response varies. Speed time-development cardiotropic effect cardiac glycosides can be represented by the following series: strofantin Convallatoxin => tselanid> digoxin> digitoxin.

The duration of the effect of cardiac glycosides cardiac determined by the rate of inactivation in the body, binding to plasma proteins and the rate of excretion. Preparations strophanthus, adonis and lily of the valley appear, usually within a few days or longer. Especially long-term effect is purple, digitalis glycosides digitoxin (elimination lasts 2-3 weeks). Occupy an intermediate position glycosides of Digitalis lanata digoxin and tselanid (during their removal 3-6 days).An important characteristic of cardiac glycosides is their ability to cumulation. The longer action of cardiac glycosides, the more they cumulate. We are talking about material accumulation, ie, accumulation of the substance in the body. Particularly pronounced accumulation marked for digitoxin. This is due to the slower is the inactivation and excretion from the body of digitoxin (tl / 2 = 160 h). To a lesser extent cumulate digoxin (t1 / 2 = 34-36 hours) and tselanid.

Approximately 7/8 of the administered dose strofantina displayed in the first 24 hours, so when applied accumulation expressed to a small extent. According to long actions and the ability to cumulate digitalis glycosides and strofantin in the following order: digitoksin> digoxin> tselanid> strofantin. Preparations Adonis and lily of the valley cumulate even less than strofantin.Absorbed drugs cardiac glycosides from the gastrointestinal tract , that is not the same. Very well absorbed more lipophilic digitoxin (90-95%) and digoxin (50-80%), good - tselanid (20-40%). Very poorly absorbed (2-5%) and partially destroyed strofantin. Glycosides lily of the valley in the digestive tract largely destroyed. Therefore, enteral target according to the chief of digitalis drugs (digitoxin, digoxin). Inside are also preparations adonis (Adonis herb infusion).

After absorbtion, cardiac glycosides are distributed among various organs and tissues. In the heart found no more than 1% of the administered dose. The main thrust of the action of cardiac glycosides due to high sensitivity of the heart tissue in this group of drugs.Movement input glycosides reversibly binds to plasma albumin (for example : digoxin 30-35% strofantin less than 5%).Biotransformation of cardiac glycosides are mainly in the liver. One of the main principles of the chemical conversion is that they sequentially cleaved sugar molecules (glucones) under formation nesaharistoy part (aglycone or genin). Furthermore, there may block hydroxylation (e.g. digitoxin) and partial formation of conjugates {glucuronic acid).

Stand cardiac glycosides and their transformation products in the kidneys and gall (from the intestines are partially re-absorbed with ethyl ). When kidney disease duration of action of cardiac glycosides increases.Digitoxin released primarily as metabolites and conjugates. Digoxin is only a small part is exposed to chemical transformations. Strofantin excreted unchanged.Apply cardiac glycosides mainly in acute and chronic heart failure. In acute heart failure, cardiac glycosides are introduced with a short latency period (strofantin, korglikon)

Enter cardiac glycosides more inside (digitalis preparations, Goritsvit ¬ ma) and intravenous (strofantin, digoxin, tselanid, korglikon), sometimes - internal intramuscularly and rectally. Subcutaneous injection advisable as they may cause adverse reactions - irritation at the injection site, pain, abscess.Contraindications to the use of cardiac glycosides are incomplete atrioventricular block, bradycardia, acute infectious myocarditis. Caution should be used cardiac glycosides with calcium and hypokalemia. This is due to the fact that the high content of calcium ions in the blood serum of sensitivity miocard to cardiac glycosides increases and thus increases the possibility of toxic action of these drugs. Similarly, changing the effect of cardiac glycosides with a decrease in the content of potassium ions (which can occur when using diuretics saluretics from the group, with diarrhea in the postoperative period).

Toxic effects associated with overdose of cardiac glycosides. More often observed when the LRA digitalis preparations with severe contributed to cumulation. Drug digitalis intoxication by cardiac and extracardiac disordersThe most common cause of death from poisoning - ventricular fibrillation. From other systems are marked deterioration of vision (including the color), fatigue, muscle weakness, dyspeptic symptoms (nausea, vomiting, diarrhea) may be mental disorders (agitation, hallucinations ), headache, skin rash.Treatment of poisoning drugs digitalis and other cardiac glycosides is primarily aimed at addressing the adverse changes in heart. In addition to the drug or reducing the dose, apply a number of physiological antagonists. Given that the cardiac glycoside binding you decrease the content of potassium ions in cardiomyocytes shows examples ¬ tion products of potassium (potassium chloride, etc.). Administered orally or intravenously them but in such quantities as to the content of potassium in the blood serum did not exceed normal values.

Potassium supplements are used for prevention of ¬ toxic effects of glycosides on the heart, especially arrhythmias cuts. With the same purpose prescribers magnesium (magnesium orotate) and Pananginum (containing potassium aspartate and magnesium aspartate) and analogous composition tablets "Asparkam". Note: reducing the concentration of potassium in the blood (a number of diuretics, corticosteroids), contribute to the manifestation of cardiotoxic action cardiac glycosides.Arrhythmias using phenytoin, lidocaine, amiodarone, which have pro-tivoaritmicheskoe action. When the atrio-ventricular block to eliminate the effect of the vagus nerve on the heart administered atropine.

Some beneficial effect in cardiac glycoside intoxication also gives containing in its molecule sulfhydryl groups unitiol. Presumably, this is due to the fact that he reactivates transport ATPase myocardial cells inhibited cardiac glycosides. However, it is rarely used.Based on the fact that the action of cardiac glycosides to be more involved calcium ions is proposed to use drugs that bind calcium ions and brought down their content in blood serum. These properties are the disodium salt of ethylenediaminetetraacetic acid (EDTA, disodium salt, disodium edetate, Na, EDTA, Trilon B), and citrates.Enter the disodium salt of EDTA intravenously arrhythmias arising from the poisoning cardiac glycosides. However, the effect is to a small degree and isn’t to long, so it is rarely used.

Cardiac facilities nonglicoside structureStimulating effect on the heart have also agonists, dopamine, methylxanthines, glucagon. However, they cause many undesirable side effects of the cardiovascular system (tachycardia, arrhythmia, etc.), that limit the use of these means as a cardiotonic. On the mechanism of action of these substances can be summarized as follows:

Tools to increase the content of cAMP in cardiomyocytes1. Means stimulating beta1-adrenergic receptors - dopamine, dobutamine2. Phosphodiesterase inhibitors - Amrinon, Milrinone

Of these groups, the most interesting materials for cardiac stimulation are dopamine and dobutamine derivative.

Dopamine (dopmin) act on dopamine receptors, as well as being a precursor of noradrenaline indirectly stimulates alpha-and beta-adrenoreceptors. At therapeutic doses, dopamine has a positive inotropic effect (due to the beta1-adrenergic stimulation of the heart), which is combined with the expansion of the renal and mesenteric vessels (excites dopamine receptors in smooth muscle). Dopamine is used in cardiogenic shock. The drug may cause tachycardia, arrhythmia, excessive increase in peripheral vascular resistance and heart.More selective to dobutamine, which is a beta1-agonists. It is characterized by a pronounced cardiotonic activity. Apply for a brief dobutamine stimulation of the heart with his decompensation. The drug may cause tachycardia, arrhythmia, hypertension, etc. Enter dopamine and dobutamine infusion intravenously.

Amrinon (a derivative bispiperidina) increases the contractile activity of the myocardium and causes vasodilation. The need of the heart for oxygen it does not increase the rhythm of the heart and blood pressure at therapeutic doses is not significantly affected. On the mechanism of the positive inotropic action is different from cardiac glycosides and catecholamines, which is associated with increased levels of free calcium ions and cAMP in the cells of the myocardium. Apply amrinon in heart failure refractory to treatment with cardiac glycosides. Administered intravenously and inside. For enteral administration acts to 7 hours. But amrinon often causes side effects (thrombocytopenia, nausea and vomiting, jaundice, hypotension, etc.), thus limiting its use. Similar in structure and action is milrinone. It amrinona active and apparently causes no thrombocytopenia.