The term "cardiac glycosides" was strongly included into medical terminology. It is about the connections of specific chemical structure which are contained in a number of plants and having characteristic cardiotonic activity. These are the complex organic compounds of type of ethers which are split at hydrolysis on sugar (glycanes) and a bessakharisty part (aglikona or genina). The medicines, similar in structure and action, received in the semi-synthetic or synthetic way belong to the same group.
Aglikona have steroid (cyclopentaperhydrophenanthrene) structure, with various radicals in different provisions of a kernel and with the five-membered monounsaturated lactone ring attached in the 17th situation at the majority of active cardiac glycosides. At some cardiac glycosides emitted from sea onions (stsillaren And, stsillarenv), a hellebore (korelborin), etc., instead of a five-membered ring six-membered twice nonsaturated lactone ring contains. Glycosides with a five-membered lactone ring make group of kardenolid, with a six-membered ring - group of bufadiyenolid.
Different types of a foxglove belong to the plants containing cardiac glycosides (Digitalis purpurea L., Digitalis Lanata Ehrh., etc.), adonis (Adonis vernalis L., etc.), lily of the valley (Convallaria majalis L.), obvoynik (Periploca graeca L.), different types of an erysimum (Erysimum canescens Roth., Erysimum cheiranthoides L., etc.), Strophanthus (Strophanthus gratus, Strophanthus Kombe), oleander (Nerium oleander L.), hellebore (Helleboruspurpurascens W. et K.), jute long (Corchorus olitorius L.), hargkustarnikovy (Gomphocarpus fruticosus A. Br.), etc. The applied earlier cardiac glycosides from an obvoynik (Periplocinum), an erysimum (Erysiminum, Erysimosidum), an oleander (Neriolinum, Cornerium), a hellebore (korelborin), a dogbane hemp (tsimarin), jute long (Olitorisidum, korkhorozid), a harga shrubby (gomfotin) and also konvallotoksiniz a lily of the valley, are excluded from the nomenclature of medicines as have no advantages before the main modern cardiac glycosides. Specific cardiotonic action of the glycosides which are contained in these plants is caused mainly by existence and the nature of the aglikon which are a part of their molecule. Some cardiac glycosides can imetyodin and the same aglikon, but the remains of different sugars; others - contain the same sugar, but various aglikona; separate glycosides differ, at last, from others as a sugary part, and aglikony. In a molecule there can be one (convallatoxin), two (strophanthin, Olitorisidum, etc.), three (digitoxin, digoxin, etc.) or four parts of sugar (Digilanidums A, B and C). At Digilanidums A, B and C and acetyldigitoxin residue of acetic acid is attached to the sugar remains.
The remains of sugars have no cardiotonic activity, but they influence degree of solubility of glycosides, their permeability through cellular membranes, ability to contact proteins of plasma and fabrics and also a natoksichnost.
Physical and chemical properties of separate glycosides and their pharmacokinetic parameters have essential value.
On physical and chemical properties cardiac glycosides subdivide na2 groups: polar and unpolar. Polar (hydrophilic) glycosides which main representative is strophanthin (and also the convallatoxin which is a part of Korglykonum) are a little soluble in lipids and are badly soaked up from digestive tract. Therefore they are applied parenterally (intravenously). At intravenous administration the effect of strophanthin develops quickly - in 5 - 10 min., the maximum action - through 25 - ZO min. The period of biological semi-removal from blood plasma is in srednem23 h, and is completely terminated in 2 - 3 days.
Polar glycosides are removed substantially by kidneys, in svyazis what at disturbance of secretory function of kidneys their dose (in order to avoid cumulation) has to be reduced.
Unpolar (lipophilic) glycosides are easily soluble in lipids; they are well soaked up in intestines, quickly contact proteins of plasma, mainly albumine. A significant amount of the unpolar glycoside which is soaked up in intestines, comes to a liver and is distinguished with bile, then again reabsorbirutsya in digestive tract.
The main representative of unpolar glycosides is digitoxin. Effect of digitoxin begins to be shown in 2 - 4 h after intake, reaches a maximum in 8 - 12 h. Plasma elimination half-life averages 5 days, and is terminated completely in 14 21 day.
Unpolar glycosides in small degree are allocated with urine, disturbance of secretory function of kidneys influences their excretion a little.
Because they are well soaked up and do not collapse in digestive tract, they are rather effective at intake. Because of action duration, unpolar glycosides rather easily can cause the cumulation phenomena.
At impossibility of introduction of glycosides of this group to a stomach (for example, in vomiting) they are entered sometimes rektalno (in the form of candles).
Some glycosides are intermediate between the most polar (strophanthin) and unpolar (digitoxin) glycosides. So, digoxin is well soaked up from digestive tract, otnositelnomat communicates proteins of plasma, considerably (about 3O of %) is removed by kidneys. Like strophanthin, it renders fast effect at intravenous administration; its action at intake begins in 20 30 min., and at introduction to a vein - in 5 - 20 min.
After absorption and receipt in blood cardiac glycosides fiksiruyutsyav fabrics, including in a cardiac muscle. Duration action depends on durability of linking with proteins, the speed of destruction and removal from an organism. These factors define also ability of drug to collect in an organism (extent of cumulation). From foxglove drugs, most strongly contacts proteins and digitoxin possesses the most long action and cumulative effect, these properties at acetyldigitoxin, Celanidum, digoxin are a little less significant. Less than others contact proteins, quicker strophanthin and some other glycosides are removed and have rather small cumulative effect.
The choice of a method of administration and drug depends on indications. At acute cardiovascular insufficiency and suddenly arisen decompensation of willows other cases when the immediate help is necessary, resort to intravenous administration of the drugs rendering fast strong, though rather short, action (strophanthin, Korglykonum). In chronic heart failure, because of a long disease and also for maintenance therapy after elimination of the phenomena of acute warmly vascular insufficiency, usually apply the cardiac glycosides rendering full effect at oral introduction (digitoxin, digoxin, etc.).
Glycosides apply to treatment of chronic heart failure in the doses providing creation of stable therapeutic concentration of drug in blood. At the same time in the I phase of treatment ("saturating") reach compensation of warm activity and in the II phase ("supporting") appoint cardiac glycosides in the small doses sufficient for maintenance of the reached compensation. For some patients the "supporting" phase can be very long, sometimes lifelong. In the I phase drugs are appointed: parenterally (intravenously) or inside, and in the II phase, - as a rule, inside.
There are 3 methods of digitalization: a) the fast digitalization counted on creation "saturating", concentration of drug during pervykh24 - Z6 of h. For this purpose high doses of drug are required that is connected with danger of overdose. Due to the frequent emergence of toxic by-effects, this method use only in rare instances (only in clinical conditions); b) moderately fast digitalization, provides use of average doses with approach of effect through 2 - 5 - 7 days; drug is appointed fractionally, gradually selecting a dose, optimum for this patient; c) method of slow digitalization by small doses.
The digitalization method is most extended by moderately fast speed.
At intravenous administration, the necessary amount of solution of cardiac glycoside is parted usually in 10 - 20 ml of 5%, 20% or 40% of solution of glucose, and in the presence of contraindications to glucose use - in the same volume of isotonic solution of sodium of chloride. Enter slowly. For drop infusions dissolve glycoside solution in 5% solution of glucose or isotonic solution of sodium of chloride.
Effect of cardiac glycosides is shown in change of all main functions of heart. Under the influence of therapeutic doses of cardiac glycosides it is observed: a) strengthening of systolic reductions of heart; duration of a systole is reduced, this effect is connected mainly with direct impact on heart; b) lengthening of a diastole; the heart rhythm slows down, inflow of blood to ventricles improves; in connection with simultaneous strengthening of systolic reduction the stroke output of heart increases. Delay of a rhythm is substantially caused by increase in a tone of the center of vagus nerves; it is not observed after atropinization. Increase in a tone of the center of vagus nerves is reaction to the excitement of reflexogenic vascular zones which is caused systolic effect of cardiac glycosides when strengthening a pulse wave; c) lowering of excitability of the carrying-out system of heart; the conductivity on a ventriculonector slows down, the interval between reductions of auricles and ventricles (delay of atrioventricular conductivity) is extended.
The main therapeutic effect of cardiac glycosides is shown in heart failure. Strengthening of reductions of a myocardium caused by them, promotes exile of the blood which came to heart cameras at a diastole and blood circulation improvement. At the same time it is necessary to consider that the optimum effect depends on the correct selection of a dose. Optimum doses improve power balance of a myocardium, inadequate doses can lower it.
Cardiac glycosides are effective in different types of heart failure (left- and right ventricular), especially in heart failure owing to a myocardium overload in hypertensia, defeats of valves of heart and an atherosclerotic cardiosclerosis.
Use of cardiac glycosides in the initial or latent heart failure is not only a preventive, but also therapeutic action by means of which it is possible to correct the available functional disturbances and to prevent development of obvious insufficiency of heart.
Due to the bradikardichesky action, some cardiac glycosides are effective in an atrial fibrillation, an atrial flutter, Bouveret's atrial and nodal atrioventricular disease. However it is necessary to consider that in high doses cardiac glycosides can cause a supraventricular Bouveret's disease with partial atrioventricular block in this connection it is dangerous to take these drugs if the cause of arrhythmia is not established. In ventricular tachycardia cardiac glycosides increase danger of fibrillation of ventricles.
Influence of cardiac glycosides on arterial blood pressure non-constantly. At developments of stagnation and the lowered ABP, it raises in process of improvement of warm activity, at the raised ABP, noticeable changes of his sizes usually are not observed. Pressure in peripheral veins at blood circulation improvement usually goes down. Vessels of abdominal organs are narrowed, vessels of kidneys slightly extend. Cardiac glycosides raise tonuskoronarny arteries. This effect is caused by the fact that cardiac glycosides are synergists of calcium ions. Therefore at patients with an ischemic heart disease and with atherosclerotic defeats of coronal vessels at use of cardiac glycosides the stenocardia can become aggravated. Aggravation of symptoms of patients can also be explained with increase in shock cardiac performance and increase in need of a myocardium for oxygen. In recent years for prevention of these effects anti-anginal drugs from group of antagonistovion of calcium are recommended.
The diuresis under the influence of cardiac glycosides amplifies; this action is connected mainly with the general improvement of blood circulation.
Data on influence on blood clotting are contradictory, however it is reasonable to control at treatment by cardiac glycosides coagulability indicators.
Cardiac glycosides affect also central nervous system. Drugs of an adonis and lily of the valley often apply together with bromides and drugs of a valerian as the means calming and improving action of the heart.
In high doses cardiac glycosides can make sick and vomiting that is connected with their direct influence on the emetic center and hemochuvstvitelny receptor zones (See Vomitives) and also with the reflexes caused (at intake) irritant action on a mucous membrane of a stomach. The emetic effect is partly caused by the reflexes arising at excitement of receptors of heart.
At high doses the loss of appetite, a diarrhea, disturbances of activity of central nervous system (headache, concern, insomnia, the depressive phenomena, disorders of vision) are possible.
At overdose, cardiac glycosides can lead to sharp bradycardia, polytopic premature ventricular contraction, a bigeminal pulse or a trigeminy, delay of atrioventricular conductivity. Toxic doses can cause trembling of ventricles and cardiac arrest.
Due to the ability to cumulation, toxic action can be shown to a degree at prolonged use cordial glikozidovv usual doses.
In intoxication connected with overdose of cardiac glycosides take a break in their use which duration depends on cumulative properties of the used drug and a clinical picture; if necessary give drugs of potassium and antiarrhytmic drugs (See Difenin). Potassium is especially shown at simultaneous use of cordial diuretics of a glikozidova (saluretics).
At introduction to hypodermic fatty tissue, solutions of cardiac glycosides render irritant action.
The general contraindications to use of cardiac glycosides: the profound bradycardia, atrioventricular block of various degree, Adams's syndrome - Stokes - Morganya, stenocardia (use in stenocardia is possible only in the presence of heart failure). The care is necessary in a myocardial infarction (use is possible only in the profound heart failure with myocardium dilatation); at shock or lack of symptoms of heart failure cardiac glycosides are contraindicated.
Biochemical and physical and chemical elements of the mechanism of effect of cardiac glycosides include a number of the interconnected processes. Small doses increase the maintenance of catecholamines in a myocardium, stimulate "Na + - K+ - the pump" and render the positive inotropic effect correlating with increase in concentration of catecholamines. Higher doses oppress Na + - K+ - to ATFaz of sarcolemmas and "Na + - K+ - the pump", increase the intracellular maintenance of Na + and activate the transsarcolemmic system of exchange Na + - Sa ~+, causing increase in receipt in cells of ions of Sa that promotes further positive inotropic effect. Besides, under the influence of cardiotonic means there is an inhibition of activity of enzyme of phosphodiesterase (mainly phosphodiesterases III) that leads to slowing down of disintegration of cyclic adenosinemonophosphate (tsAMF) - the "secondary mediator" participating in power ensuring sokratitelny process in myocardium cells.
Certain significance is attached to influence of cardiac glycosides on adenosine receptors and antagonism with the endogenous adenosine having negative inotropic effect (see Theophylline).
Toxic doses of cardiac glycosides cause oppression "Na + - pump K+", loss of intracellular potassium that can lead to aritmogenny effect of these drugs.
In medical practice apply the individual cardiac glycosides (emitted from plants) and their semi-synthetic derivatives and also galenovy and neogalenovy drugs (powders, infusions, tinctures, extracts) now. As these drugs are strong substances, their standardization is necessary. For this purpose use the physical and chemical and also biological methods providing determination of activity in animal experiments (frogs, cats, pigeons).
When using biological methods the activity is estimated in comparison with standard crystal drug and expressed in terms of action. One FUA (frog unit of action) corresponds to a dose of the standard drug causing in certain experimental conditions, a heartstone in the majority of experimental standard frogs. Under one cat's or pigeon unit of action (1 KED, 1 GED), mean the dose of standard drug at the rate on 1 kg of body weight causing cardiac arrest of a cat and pigeon in certain experimental conditions.
It is necessary to consider that the size of a therapeutic dose for different cardiac glycosides depends not only on their biological activity established in the specified ways but also on their absorption from a digestive tract, firmness in an organism and ability to a kumulition at repeated use.