UNIVERSITY OF SANTO TOMAS

FACULTY OF PHARMACY DEPARTMENT

CARDIAC GLYCOSIDES Group no. 4

Fidel, Angelique Folloso, Emil Mari Garcia, Ephraim Remann Francisco, Patricia Denise Gimenez, Jazthene

Definition Sterols or Cardiac Glycosides are an important class of naturally occurring drugs whose actions include both beneficial and toxic effects on the heart. Plants containing cardiac steroids have been used as poisons and heart drugs at least since 1500 B.C. Throughout history these plants or their extracts have been variously used as arrow poisons, emetics diuretics and heart tonics. It is defined as any of a group of glycosides occurring in certain plants (Digitalis, etc.), having a characteristic action on the contractile force of the heart muscle. Cardiac Steroids are widely used in the modern treatment of congestive heart failure and for treatment of atrial fibrillation and flutter. Yet their toxicity remains a serious problem. These drugs all act by affecting the availability of intracellular Ca+2 for myocardial contraction or increasing the sensitivity of myocardial contractile proteins. Structure of Cardiac Glycosides Cardiac glycosides are composed of two structural features: the sugar (glycone) and the nonsugar (aglycone steroid) moieties.

Nonsugar (Aglycone steroid)

Sugar (Glycone)

Fig 1. Oleandrin Chemical Structure, an example of cardiac glycoside

The steroid nucleus has a unique set of fused ring system that makes the aglycone moiety structurally distinct from the other more common steroid ring systems. The steroid nucleus has hydroxyls at 3- and 14- positions of which the sugar attachment uses the 3-OH group. 14-OH is normally unsubstituted. Many genins have OH groups at 12- and 16- positions. These additional hydroxyl groups influence the partitioning of the cardiac glycosides into the aqueous media and greatly affect the duration of action. The lactone moiety at C-17 position is an important structural feature. The size and degree of unsaturation varies with the source of the glycoside. Normally plant sources provide a five-membered unsaturated lactone while animal sources give a six-membered unsaturated lactone. One to four sugars are found to be present in most cardiac glycosides attached to the 3-OH group. The sugars most commonly used include L-rhamnose, D-glucose, D-digitoxose, D-digitalose, D-digginose, Dsarmentose, L-vallarose and D-fructose. These sugars predominantly exists in the cardiac glycosides in the -conformation. The presence of acetyl group in the sugar affects the lipophilic character and the kinetics of the entire glycoside.

Classes of Cardiac Glycosides Two classes have been observed in the nature. The cardenolides and the bufadienolides. Cardenolides Cardenolide is a type of steroid. Many plants contain derivatives, collectively known as cardenolides, including many in the form of cardenolide glycosides (cardenolides that contain structural groups derived from sugars). Cardenolide glycosides are often toxic; specifically, they are heart-arresting. Supposedly, the term derives from Greek kardi, "heart" and the suffix -enolide. It should not be confused with cardanolides. Cardanolides are a class of steroids (or aglycones if viewed as cardiac glycoside constituents), and cardenolides are a subtype of this class. Cardenolides are C(23)-steroids with methyl groups at C-10 and C-13 and a five-membered lactone (specifically a butenolide) at C-17. They are aglycone constituents of cardiac glycosides and must have at least one double bond in the molecule. The class includes cardadienolides and cardatrienolides. Bufadienolides Bufadienolide is a type of steroid. Its derivatives are collectively known as bufadienolides, including many in the form of bufadienolideglycosides (bufadienolides that contain structural groups derived from sugars). These are a type of cardiac glycoside, the other being the cardenolide glycosides. Both bufadienolides and their glycosides are toxic; specifically, they are heart-arresting. The term derives from the toad genus Bufo that contains bufadienolide glycosides, the suffix -adien- that refers to the two double bonds in the lactone ring, and the ending -olide that denotes the lactone structure. Consequently, related structures with only one double bond are called bufenolides and the saturated equivalent is bufanolide. The cardenolides have an unsaturated butyrolactone ring while the bufadienolides have a pyrone ring. The lactone of cardenolides has a single double bond and is attached at the C-17 position of the steroid

nucleus. They are five-membered lactone ring and form a C23 steroids(Leguminosae, Crucifirae, Euphorbiacceae, etc.). While the lactone of bufadenolides have two double bond which is attached at the 17-position of the steroidal nucleus. They are six-membered lactone ring and form C24 steroids (Liliaceae, Ranuculaceeae).

Fig. 1.1. Chemical structure of cardenolides

Fig. 1.2. Chemical structure of bufadienolides

Therapeutic Use of Cardiac Glycosides The essential therapeutic use of digoxin which is more used than digitoxin is the treatment of cardiac failure. Digoxin improves the cardiac function and decreases the frequency of hospitalizations without delaying mortality. The second therapeutic use of digoxin is the treatment of supra-ventricular arrhythmias, particularly atrial fibrillation. The initial dosage, generally high and called loading dosage, is followed by a lower dosage, called maintenance dosage. It is advised to control the plasma level of digoxin to reach the best dosage Adverse effects of Cardiac Glycosides The majority of adverse effects of digoxin and other cardiac glycosides are dose-related. It is thus essential, when an undesirable effect is suspected, to control blood concentrations. Moreover its adverse effects in women seem more marked (increased mortality) than in men, which does not encourage to prescribe digoxin to women with congestive heart failure. One observes:

digestive disorders: frequently, anorexia, nausea, vomiting, salivation; more rarely, diarrhea or constipation and stomach pains. neurosensory disorders: frequently, headache, insomnia, sometimes confusions, depression, dizziness, visual disturbances of colors, micropsy or macropsy, amblyopia, pain (neuralgia of the trigeminal nerve), seizures, paresthesias, delirium. cardiac manifestations, generally linked to an overdose and beginning generally by bradycardia, then extrasystoles, tachycardia or fibrillation. endocrine adverse effects, such as gynecomastia in men, related to the steroid structure of cardiac glycosides which can have metabolites with an estrogen effect.

The treatment of poisoning by cardiac glycoside involves first the cessation of the glycoside, possibly the use of a drug able to reduce digitalis effects: potassium in case of hypokalemia, atropine in case of bradycardia, lidocaine, chelating agent of calcium, or electric stimulation. In severe overdose, digoxin-specific antibody fragments can be used to neutralize circulating free digoxin by binding to it. This neutralization induces a displacement of digoxin from tissues towards plasma where it is neutralized. The beneficial effects of the antibody administration appear quickly, in less than one hour, but can last less long than the effects of digoxin with reappearance of the signs of poisoning. These relapses are seen in case of administration of an insufficient antibody dose. The administration of digoxin-specific antibody fragments can elicit allergic reactions.