Cardiac Remedies

CARDIAC REMEDIES in the general sense of the word are medicinal substances used for the therapy of disorders of cardiac activity. These include representatives of various pharmacological groups that have to a greater or lesser degree a cardiac action. In a narrower sense, cardiac remedies are called the agents of the digitalis group, which contain "cardiac" glycosides possessing an exceptional selective action on the heart. This includes a number of plants, namely various species of Digitalis (see); Adonis vernalis and other species thereof, various species of Strophanthus, Scilla maritima, Convallaria majalis, Apocynum cannabinum, Helleborus viridis, H. niger, Periploca graeca, Antiaris toxicaria, Acocanthera Ouabaia, Thevetia neriifolia, Cheiranthus Cheiri, Coronilla scorpioides, Nerium Oleander, Evonymus atropurpurea, Tanghinia venenifera, and others. In addition, from the plant Erythrophloeum guineense has been isolated the alkaloid erythrophleine, close in pharmacological properties to cardiac glycosides, and from toad glands—substances also close to them in action, bufonin and bufotalin. The active principles of plants of the digitalis group are nitrogen-free toxins—glycosides; they are chemically characterized by the splitting off of a sugar molecule during their decomposition with the formation of substances bearing the general name of genins. Thus, the main active principle of digitalis, digitoxin, breaks down into sugar, digitoxose, and the corresponding genin, digitoxigenin; another digitalis glycoside, gitalin, upon breakdown yields digitoxose and gitaligenin. Genins are partly present already in the plants themselves alongside their glycosides, and partly liberated from the latter in the organism under the influence of enzymes and in vitro upon exposure to acid. Glycosides of various plants belonging to the digitalis group are very close to each other in their action on the heart. They differ from one another mainly in the speed and duration of action and in their capacity for summation. The longest duration of action and cumulative capacity among cardiac glycosides is possessed by digitoxin, while strophanthin has a significantly shorter duration alongside greater speed of action. Summation is almost absent in the weaker-acting adonis glycosides. Genins also exhibit a certain cardiac action, although weaker than the corresponding glycosides. In addition, unlike glycosides, their action sets in rapidly and is reversible. In most cases, herbal cardiac remedies are used as galenical preparations. Among pure glycosides, strophantins are of great practical importance as being sufficiently stable and water-soluble; the latter circumstance makes it possible to use their solutions intravenously. Recently, a water-soluble and intravenously administrable preparation, Lanadigin, has been isolated from Digitalis lanata. Of great clinical significance are new-galenical preparations of cardiac remedies, purified from various ballast substances. Examples of new-galenical preparations are adonylen, digalen, and diginorm. Locally, cardiac glycosides cause irritation to a greater or lesser degree, after which anesthesia may be observed. Cardiac glycosides are absorbed slowly by mucous membranes; their absorption is increased in the presence of saponins, which are present in most herbal cardiac remedies alongside glycosides. A characteristic pharmacological feature of cardiac glycosides is their highly pronounced selective action on the cardiac muscle. This selectivity is manifested particularly brightly in experiments on the frog, whose central nervous system is relatively little sensitive to circulatory disturbances. By injecting a frog with a solution of a cardiac glycoside, one can obtain its maximal action on the heart—systolic arrest—without a noticeable effect on other functions, in particular on the activity of the central nervous system; the frog retains reflexes for some time and jumps like a normal one. In the therapeutic stage of action of cardiac glycosides, one notes, on the one hand, an intensification of systoles (muscular effect), and on the other, a lengthening of the diastolic pause and slowing of the pulse (vagal effect). The stroke volume increases in this process. The improvement in the activity of the heart as a pump transferring blood from the venous bed to the arterial bed appears especially sharply under the action of cardiac glycosides on a failing heart. Under the influence of these remedies, a failing heart that cannot cope with the blood flowing in from the venous system once again becomes capable of performing its physiological load (for details see Digitalis). The ability to restore the work of a failing heart makes cardiac glycosides irreplaceable agents in circulatory disorders of cardiac origin. As a result of the restoration of cardiac activity, congestive phenomena and the accompanying symptoms of cardiac decompensation (edema, circulatory dyspnea, cyanosis, etc.) are eliminated. A new conception of the essence of the action of cardiac glycosides on the heart is provided by recent studies by Gremels. This author studied the oxygen consumption of the heart in a heart-lung preparation. It turned out that a failing heart with low work capacity consumes significantly more oxygen than a normal one. Under the influence of cardiac glycosides (strophanthin, lanadigin), not only is the work capacity of the failing heart restored, but even before this, oxygen consumption decreases while the heart performs the same or even greater work. Undoubtedly, the restoration of the metabolic economy of the heart is an essential aspect of the therapeutic action of cardiac glycosides. The diuretic effect observed upon the administration of cardiac glycosides to patients, which is especially significant in the presence of edema, is also explained by the improvement in circulation. However, Gremels' studies on a heart-lung-kidney preparation argue for a direct diuretic effect of the glycosides. In the opinion of most clinicians, adonis preparations possess the greatest diuretic effect. Therapeutic doses of cardiac glycosides do not have a significant effect on blood vessels and the vasomotor center and therefore are unable to raise blood pressure and improve circulation in vascular collapse. In these cases, cardiac remedies that stimulate the vital centers of the medulla oblongata are indicated. A characteristic representative of such agents is caffeine. Caffeine increases the contractile force of the cardiac muscle, but in its action on the heart differs from the cardiac glycosides of the digitalis group. It lacks the lengthening of the diastolic pause characteristic of digitalis. On the contrary, with the direct action of caffeine on the heart, it causes an acceleration of rhythm (chronotropic action on the Keith-Flack node). On the other hand, the inotropic action of caffeine on the heart does not possess that selective power and duration which are characteristic of the digitalis group. But caffeine, as a poison exciting the central nervous system, stimulates the centers of the medulla oblongata that regulate blood circulation, namely the vagal center and the vasomotor center. Upon giving therapeutic doses of caffeine in most subjects, the excitation of the vagal center predominates over the directly accelerating action on the heart, which is why a slowing of the pulse with a certain lengthening of the diastolic pauses is observed. In large doses and in individuals with an excited heart, acceleration predominates instead. A large role in the therapeutic action of caffeine belongs to its stimulating effect on the vasomotor center with a simultaneous direct dilating action on the vessel wall itself. One can assume that thanks to such antagonistic—central and peripheral—influences, some vascular regions dilate (kidneys, coronary vessels, pulmonary vessels), while others constrict (abdominal organs), which improves the general conditions of circulation. Especially essential for the nutrition and activity of the heart is the dilating influence of caffeine on the coronary vessels. No small significance for the restoration of circulation and heart work in collapse is also possessed by the stimulating action of caffeine on the respiratory center, since the entire central nervous system and heart depend extremely on proper gas exchange. Thus we see that along with a direct cardiac action, caffeine also possesses a therapeutically important vascular action and an indirect effect on the heart by improving heart nutrition, restoring blood pressure, and stimulating respiration. A predominantly indirect character distinguishes the cardiac action of another remedy that is usually classified as cardiac, namely camphor. Despite the wide use of camphor in the clinic for "cardiac weakness," its significance as a cardiac remedy is controversial. Experimentally, it is very easy to show the depressing action of camphor on the heart; on the contrary, its stimulating action is observed only on the heart of certain species (frog, rat) and only under the condition of their preliminary poisoning. In any case, the positive action of camphor on the cardiac muscle cannot in any way compare with the action of caffeine and especially cardiac glycosides. Judging by Gremels' experiments, camphor leads to uneconomic oxygen expenditure by the heart under the same load.

From this it can be concluded that the therapeutic significance of camphor is based chiefly on its vascular action, and the improvement in heart function is merely an indirect consequence. On this basis, the main indication for the use of camphor as a cardiovascular agent is circulatory disorders caused by vascular collapse. The mechanism of action of camphor in this case reduces to the excitation of the vasomotor and respiratory centers, as well as, perhaps (Savich), to a direct action on arterioles and capillaries. A certain importance is attached to the dilation of the coronary vessels caused by camphor. A number of stimulants proposed to replace camphor, namely leptazol, coramin, cardiazol, contrary to the names of some of them, also cannot lay claim to the significance of true cardiac remedies. Their favorable effect in circulatory disorders is related mainly to the excitation of the centers of the medulla oblongata. The role of the sympathetic nerves as reinforcing and accelerating nerves of the heart prompts attention to the cardiac action of sympathicotonic substances. It is known that for the isolated heart of warm-blooded animals there is no stronger chrono- and inotropic stimulating agent than adrenaline. It is capable of "reviving" an isolated heart even in those cases when it no longer contracts without artificial measures (e.g., upon isolation long after the death of the animal). Adrenaline excitation affects not only the whole heart with the leading node of Keith-Flack, but also automatically contracting ventricles and even segments from various parts of the heart that do not exhibit automatism without the action of adrenaline. Despite the powerful effect of adrenaline on the heart, its therapeutic value as a cardiac remedy is very limited. First of all, it should be pointed out that adrenaline, while increasing the work capacity of the heart muscle, to an even greater extent increases the oxygen consumption of the heart and thus leads to uneconomical energy expenditure, which explains the well-known fact that in an isolated heart following the passage of adrenaline in a concentration causing strong excitation, depletion of heart work—a drop in the amplitude of contractions—is inevitably observed. In the whole organism, the effect of adrenaline on the heart is complicated by those unfavorable conditions that are created by the spasm of the vessels of the systemic circulation. Due to resistance to blood flow, the heart receives an exorbitant load and acutely dilates; the pressure in the right atrium and large veins rises. At the same time, thanks to the reflex and direct excitation of the vagus nerve centers, a slowing of the pulse is observed. At the same time, as a rule, with sufficient doses of adrenaline, rhythm disorders are observed in the form of conduction disturbances and extrasystole. In a weakened heart, e.g., during chloroform anesthesia, adrenaline can cause a complete disruption of cardiac activity and provoke ventricular fibrillation. All this makes one treat adrenaline with extreme caution in heart failure. Still, in certain cases, adrenaline can restore heart activity when all other means prove to be already ineffective: a timely intracardiac injection of adrenaline can make an already stopped heart contract, which has been proven by experiments and clinical observations. In these cases, with complete circulatory arrest and zero blood pressure, there is no threat of vascular spasm. Since the extremely strong vasoconstrictor effect of adrenaline, which prevails over its cardiac effect, is one of the main reasons diminishing its significance as a cardiac remedy, substances close to adrenaline chemically, possessing a sympathicotonic action similar to it, but differing in a comparatively lesser influence on vessels, are of great interest. Such agents include so-called sympatol (see), proposed by Trendelenburg as a remedy for acute heart failure. The constriction of the vessels of the systemic circulation caused by sympatol is not so great as to create an excessive load on the heart, the contractility of which increases under the influence of sympatol. The advantage of sympatol is also its longer duration of action compared to adrenaline. It should still be thought that sympatol is not entirely free from the described shortcomings of adrenaline. According to the experiments of A. I. Kuznetsov, although in a smaller number of cases than adrenaline, it still causes ventricular fibrillation during chloroform anesthesia. According to the experiments of Gremels, just like adrenaline, it increases the unproductive oxygen consumption of the heart. In the pharmacotherapy of heart diseases, the clinic uses not only stimulating cardiac remedies, but in some cases also substances that depress heart activity. In particular, this applies to ventricular extrasystole and atrial fibrillation. In such rhythm disorders, quinine and especially its isomer quinidine are used. The therapeutic effect of these agents is based on their property of lowering the excitability of the heart and prolonging the refractory phase. The group of isoquinoline alkaloids—papaverine and narcotine (Zakusov)—possesses the same negative bathmotropic properties. The disadvantage of the listed substances as agents used in the clinic of heart diseases is their negative inotropic action (decrease in contractility, which inevitably accompanies their effect on excitability, Trusevich). Because of this, it is recommended when prescribing quinidine to first conduct a course of treatment with digitalis. One can also resort to other combinations to neutralize the unfavorable effect of quinidine and papaverine on the heart contractility. According to the study of Anichkov and Zakusov, with the combined action of quinidine and sympatol, a significant decrease in heart excitability is observed with a simultaneous increase in the strength of heart contractions. Sparteine, which is used by some clinicians, especially French ones, for heart neuroses and to which digitalis action was previously erroneously attributed, should also be classified among the alkaloids that depress cardiac activity. When considering cardiac remedies, one should dwell on substances that improve blood circulation and nutrition of the heart muscle. These primarily include vasodilators of the nitrous acid group (amyl nitrite, sodium nitrite, nitroglycerin, etc.). Their vasodilating effect is expressed particularly strongly on the coronary vessels, which explains their therapeutic effect in those pathological states the basis of which is assumed to be insufficiency of heart nutrition due to spasm of the coronary vessels. Comparative toxicity does not allow their continuous use. Another widely used vasodilator, diuretin, is inferior to nitrites and nitrous acid esters in its vasodilating effect, but on the other hand is significantly less poisonous. The mechanism of its action is closer to caffeine, but the latter is distinguished by a stronger central action, which weakens the direct influence on the vessel walls. Along with the vasodilating action, diuretin also possesses a caffeine-like action on the heart muscle. Recently, a number of organopreparations possessing a rather strong dilating action on the coronary vessels have been proposed. These include myohl of Prof. Schwartzman, spermolyenol (Pharmakon), lacarnol (Bayer). Apparently, the active principles of these agents are breakdown products of nucleoproteins and, in particular, adenylic acid. A hormonal type preparation that provides dilation of the coronary vessels is the so-called padutin (kallikrein) of Prof. Frey, obtained from urine, the source of which, according to the author, is the pancreas. Directly from the pancreas, vasodilating preparations are also obtained, e.g., angioxyl and angiotrophin (Pharmakon); the latter exerts a strong vasodilating effect on the coronary vessels. According to French authors, the active principle of the pancreas that regulates blood circulation is the substance isolated by them—vagotonin. The significance and pharmacodynamics of the named preparations remain still insufficiently elucidated. Finally, substances that are nutritional in the literal sense of the word include glucose, the intravenous administration of which improves the work of the deficient heart. This action is explained not only by the nutritional significance of glucose, but also by its direct stimulating effect on the heart. Let us briefly summarize the comparative characteristics of various agents used as cardiac remedies. Cardiac remedies in the direct sense are agents of the digitalis group; the indication for their use is heart muscle failure manifested by stagnant phenomena. Caffeine and camphor, as well as the preparations replacing them, act chiefly by exciting the vasomotor and respiratory centers, thereby restoring blood circulation; the main indication for their use is vascular collapses. In heart activity disorders caused by a spastic state of the vessels, vasodilators (nitrites, diuretin, certain organopreparations) are indicated, which can be regarded as agents that improve the nutrition of the heart and ease its work. Agents that depress heart excitability (of the quinidine type) are used in cases of extrasystole and atrial fibrillation.

Lushnikov N., Normal and Pathological Circulation, Voronezh, 1933; Anitschkow und Sakussow W., Über die kombinierte Wirkung des Chinidins und Sympatols auf das Herz, Ztschr. f. d. ges. exp. Med., B. LXXXVIII, H. 5/6, 1933; Anitschkow S. u. Trendelenburg P., Die Wirkung des Strophanthins auf das suffiziente und auf das insuffiziente Warmblüterherz, Dtsch. med. Woch., B. LIV, 1928; Bijlsma U. u. a., Die Digitalis u. ihre ther. Anwendung, B., 1923; Cushny A., The action and uses in medicine of digitalis a. its allies, L., 1925; Gremels H., Zur Physiologie und Pharmakol. der Energetik des Säugetierherzens, Arch. f. exp. Path. u. Pharmak., B. CLXIX, H. 6, 1933; Henrijean F. et Waucomont R., La digitale, P., 1931; Sakussow W., Über die Wirkung des Papaverins u. des Narkotins auf das Herz, Arch. f. exp. Path. u. Pharmak., B. CXLIV, 1929; Trendelenburg P., Über die Wirkung einiger neuerer Kreislaufmittel bei Kreislaufinsuffizienz, Med. Klinik, B. XXV, 1929. See also literature to the article Heart.