Cardiac glycosides

Cardiac glycosides Prepared By Arafat Siddiqui East-West University Dept. of Pharmacy Dhaka,Bangladesh


Cardiac glycosides

ABSTRACT This assignment is based on cardiac glycosides. It contains brief description of its history, sources, cultivation of plant sources, assay, crude drugs and their main constituents, chemical and pharmacological aspects of chief constituents, description of some well recognized active ingredients and so on. Key Words:  Cardiotonics  Steroidal glycosides  Positive inotropic effect  Heart failure  Effective refractory period (ERP)


Cardiac glycosides

HISTORY OF THE DEVELOPMENT OF CARDIAC GLYCOSIDES Cardiotonics have been used for centuries before our common era. Extracts from several plants containing glycosides were known to natives of ancient peoples. Squill is mentioned in the Ebers Papyrus, and was used by Egyptians and Romans as a heart tonic and diuretic. Walsh physicians mentioned foxglove, the common name of digitalis, as early as 1250, and Fuchsius made a botanical description of it in 1542. The historical period of cardiotonics started in 1785, when the botanist and physician William Withering published his classical treatise entitled An Account of the Foxglove and Some of Its Medical Uses, in which he indicated digitalis for the treatment of certain forms of dropsy, John Ferriar, in 1799, ascribed to digitalis its action on the heart. In 1835, Homolle prepared for the first time a purified extract from Digitalies purpurea leaves. Nativelle, in 1869, by improving Homolle’s process obtained the so-called Crystallized digitalin, usually demoninated digitalin Nativelle, which was used for several decades. Fraser, in 1872, ascribed glycosidic nature to the active principles of digitalis, in 1875; Schmiedeberg isolated digitoxin from digitalis, and demonstrated it to be identical to crystallized digitalin Nativelle. In 1930, from the same source Smith isolated and evaluated digoxin. Independent classical researches of Cloetta, Windaus, Tschesche, Jocobs, Elderfied, Reichstein, Stoll, and other investigators, from 1920 on, resulted in the elucidation of the structure of digitalis glycosides. The pharmacological action of these drugs was studied and clarified by Cushny, Mackenzie, Lewis, Chen, and other scientists, during the same period and until recently. In 1938, Cattell and Gold demonstrated unequivocally that digitalis exerts a direct effect on myocardial contractility and this is responsible for its effects produced on the heart.


Cardiac glycosides Efforts directed toward development of safer cardiotonics have resulted in several synthetic drugs, chemically unrelated to cardiac glycosides, and some have shown promising activity, among them sulmazole and amrinone. Sulmazole was synthesized by Kutler and coworkers in 1974 and evaluated pharmacologically by several researchers. Amrinone was synthesized by Lesher and Opalka in 1977 and its cardiotonic activity was studied by Alousi in 1978. In 1982, Godfraind and co-workers recovered an endogenous factor, “cardiodigin,” with digitalis-link activity, from the postnuclear particulate material of heart homogenates of some mammals. This factor inhibited Na+, K+ -ATPase in a dose-dependent manner and its affinity for the digitalis receptor was 10 to 100 times higher than that of digoxin. (Korolkovas, A., 1988) CULTIVATION OF DIGITALIS Until 1981, digitalis was cultivated in Pennsyl vania by the S.B Penick Company. After 1981; however, digitalis and the digitalis glycosides used in the U.S are obtained principally from England and Germany. In Germany, D.Purpurea seeds, which have been developed though strain selection to yield plants with maximum drug potency and with resistance to plant diseases, are sown in greenhouses in March. From the middle of May until the beginning of June, the young plants are planted outside in relatively small plots (1 to 10 acres). The areas of cultivation are centered on a commercial drying unit for medicinal plants at a distance of not more than 20 km. To ensure potency, the leaves must be rapidly and gently dried at 50 to 60 ◦C as soon as the plants are harvested. This procedure must be followed because the leaf contains hydrolytic enzymes which, if not rapidly inactivated, cleave the glycosidic linkages, thereby giving rise to the less active genins. Also excess heat may split off water from the tertiary hydroxyl group at position 14 of the steroid nucleus, thereby forming the inactive anhydrous compound.


Cardiac glycosides The annual crop is harvested from the middle of September to the end of October. The weight of a fresh plant ranges from 200 to 500g. The yield per acres, depending on the quality of the soil and effort and skill of the farmer, may vary from 2.5 to 5.5 tons fresh weight/acres which correspond to approximately 0.6 to1.4 tons dry weight/acres. The harvested crop utilizes only the first year‘s leaves, which develop as a dense rosette. Some of the plants remain undisturbed to permit development of the flowering stalk during the second season. These flowering stems are the source of seeds for future use. With the exception of other plants are harvested, consequently, fresh cultivation of young plants is begun each year. (Tyler, V. E., 1981) CONSTITIEUNTS OF DIGITALIS The drug contains alarge number of glycosides, of which the most important from a medicinal viewpoint are digitoxin, gitoxin and gitaloxin.The total concentration of these 3 glycosides varies appreciable with the plant source and the condition of growth. Also, because all are secondary glycosides derived by hydrolysis of some of the sugars from the primary or parent glycosides occurring in the leaf, their concentration depends on the manner of treatment of the plant material following harvesting. Careful experiments have revealed that the secondary glycosides content in the leaf is about 10 to 20% of the primary glycosides concentration. Reported total concentration of digitoxin, gitoxin, and gitaloxin range from 0.09% in a poor quality Spanish sample to 0.225% in a superior Japanese leaf, the average concentration approximates 0.16%. Nearly 30 other glycosides have been identified in the drug. The major glycosides in terms of concentration, include purpurea glycosides A, purpurea glycosides B, glucogitaloxin, glucodigitoxgenin-bis-digitoxiisde , glucogitaloxigenin-bis-digitosode , glucoevatromonoside, glucogitoroside, glucolanadoxin. . (Tyler, V. E., 1981)


Cardiac glycosides ASSAY OF DIGITALIS Digitalis and its preparations must be assayed biologically to ensure their potency; however, because the crystalline glycosides are definite chemical entities, they can be assayed chemically. A number of test animals have been used in the past: guinea pigs, frogs, and cats. The animals now employed in the assay procedure Is the pigeon. Standardization is determined by comparison of the effect of a known dilution of the drug with that of a similar dilution of USP Digitalis Reference Standard. Adult pigeons are anesthetized lightly with ether, immobilized, and their alary vein is exposed and cannulated. Definite volumes of the diluted preparations are produced at 5 minute intervals until the pigeon dies from cardiac arrest. The bioassay of digitalis leaf can be criticized because of the inability of the method to predict oral potency of the drug. For example, gitoxin in the leaf would contribute to the

intravenous assay potency, but because it is poorly absorbed from the GIT, it would not contribute significantly to the cardiac effect. This observation assumes additional significance when one considers that the amount of gitoxin present in the leaf vary greatly, depending on the genetics of the plant or manner in which the drug is harvested and prepared for market. As a precautionary measure, care should be taken to maintain patients on one brand of digitalis tablets. This precaution decreases the chances of dispending a preparation or greater than that obtained by the patient from a prior prescrption. In monitoring patient therapy with digitoxin and digoxin, radio immune assay techniques have been developed that allowed for the measurement of nanogram quantities of these glycosides in the blood serum. The underlying principle is that nonradioactive glycosides will compete with radioactively labeled glycosides for combining sites on antidigitalis antibody. If one mixes varying quantities of unlabeled glycosides with a standard amount of radio labeled


Cardiac glycosides glycosides, the amount of radioactivity bound by a standard amount of antibody will decrease as increasing amount of unlabeled glycosides are added. A standard curve can then be constructed from which the concentration of glycosides in a patient’s blood serum can be determined on the binding of radioactive glycoside by specific antibody. Radiolabeled glycosides and antisera are commercially available. If stored properly, antibodies are stable for many years, and 1 ml of antiserum may be employed in more than 100,000 determinations. . (Tyler, V. E., 1981) CHEMISTRY OF CARDIAC GLYCOSIDES Cardiac glycosides are naturally occurring steroidal glycosides obtained from plant sources. Digitoxin is obtained from Digitalis purpurea, digoxin from Digitalis lanata and ouabain from Strophanthus gratus. Cardiac glycosides are closely related structurally, consisting of one or more sugars (glycone portion) and a steroidal nucleus (aglycon or genin portion) bonded through an ether linkage. These agents also have an unsaturated lactone substituent (cyclic ester) on the genin portion. The prototypical agent is digitoxin. Digoxin has an additional hydroxyl group at position 12. Ouabain has a rhamnose glycone portion and additional hydroxyl groups at positions 1, 5, 11 and 19. Removing the glycone portion causes decreased activity and increased toxicity from changes in polarity that causes erratic absorption from the gastrointestinal tract. The duration of action of a cardiac glycoside is inversely proportional to the number 0of hydroxyl groups, which increase polarity. Increased polarity results in decreased protein binding, decreased liver biotransformation, and decreased renal tubular reabsorption. Digitoxin has a long duration of action and may accumulate. Ouabain, in contrast has short duration of action and is effective intravenously. (Shargel, L., 2007)


Cardiac glycosides PHARMACOLOGY OF CARDIAC GLYCOSIDES Cardiac glycosides increases myocardial contractility and efficiency, improve systemic circulation, improve renal perfusion, and reduce edema. The electrophysiological effects of cardiac glycosides are summarized in table 1. Angiotensin converting enzyme inhibitors and perhaps AT1 angiotensin receptor antagonists, vasodilators such as nitro-prusside, nitroglycerin and hydralazine, and diuretics may be important adjuncts to cardiac glycosides. ACE inhibitors may be considered as first line treatment. When given in therapeutic doses cardiac glycosides produces positive inotropic effects by inhibiting membrane bound Na+ /K+ activated ATPase.

Figure 1: Mechanism of action of cardiac glycosides. (Harvey, R. A., 2009) These effects of cardiac glycosides increase the rate of tension development, the contractility, and the rate of relaxation of cardiac muscle. The effects include • • •

Increase in intracellular sodium concentration. Reduction in calcium transport from the cell by the sodium calcium exchanger Facilitation of calcium entry via voltage gated channels Increased release of calcium from sarcoplasmic reticulum. Ca2+ interacts with

troponin which then through its binding sites on actin that bind myosin, allowing the formation of the contractile protein actomyosin. (Shargel, L.,2007)


Cardiac glycosides

Figure 2: Ventricular function curves in the normal heart, in heart failure (HF), and in HF treated with Digitalis. (Harvey, R. A., 2009)

Therapeutic doses also cause: • • A negative chronotropic effect from increased vagal tone of the sinoatrial node Diminished central nervous system sympathetic outflow from increased carotid sinus baroreceptor sensitivity • Systemic arteriolar and venous constriction which increases venous return and thus increases cardiac output


Cardiac glycosides Table 1: Effects of Cardiac glycosides on the heart Effects Direct Atria Contractility↑ ERP↑ Conduction velocity↓ Indirect ERP↓ Conduction velocity↑ ERP↑ Conduction velocity↓ AV Node ERP↑ Conduction velocity↓ Ventricles Contractility↑ ERP↓ Automaticity↑ No effect


P changes

PR interval↑

QT↓ T and ST


Extraasystole Tachycardia

AV depression /block Extraasystole Tachycardia (Shargel, L.,2007)

Therapeutic indication:

Heart failure ( stage C only) Atrial fibrillation Atrial flutter Paroxysmal atrial tachycardia

• • •

Adverse effects:


Cardiac glycosides • Early adverse effects of cardiac glycosides represent the early stages of

toxicity including: 1. GI effects like anorexia, nausea, vomiting and diarrhea 2. CNS effects like headache, visual disturbances, confusion, muscle


Later adverse effects represent intoxication and include such serious cardiac

disturbances as premature ventricular contractions, paroxysmal and nonparoxymal atrial tachycardia, AV dissociation or block, ventricular tachycardia and ventricular fibrillation. (Shargel, L.,2007) Factors predisposing to digitalis toxicity: Electrolytic disturbances: Hypokalemia can precipitate serious arrhythmia. Reduction of serum potassium levels is most frequently observed in patients receiving thiazide or loop diuretics, and this usually can be prevented by use of a potassium-sparing diuretic or supplementation with potassium chloride. Hypercalcemia and hypomagnesemia also predispose to digitalis toxicity. Drugs: Quinidine, verapamil, and amiodarone, to name a few, can cause digoxin intoxication, both by displacing digoxin from tissue protein-binding sites and by competing with digoxin for renal excretion. As a consequence, digoxin plasma levels may increase by 70 to 100 percent, requiring dosage reduction. Potassium-depleting diuretics, corticosteroids, and a variety of other drugs can also increase digoxin toxicity (Figure 16.11). Hypothyroidism, hypoxia, renal failure, and myocarditis are also predisposing factors to digoxin toxicity. (Bannett, P. N., 2003)

Treatment of overdose:


Cardiac glycosides Overdose with digoxin is now uncommon. For severe digoxin poisoning infusion of the digoxin-specific binding (Fab) fragment (Digibind) of the antibody to digoxin, neutralizes digoxin in the plasma and is an effective treatment. Because it lacks the Fc segment, this fragment is nonimmunogenic and it is sufficiently small to be eliminated as the digoxin-antibody complex in the urine. It may interfere with the subsequent radioimmunoassay of digoxin in plasma. Phenytoin i.v. may be effective for ventricular arrhythmias, and atropine for bradycardia. Electrical pacing may be needed, but direct current shock may cause ventricular fibrillation. (Bannett, P. N., 2003) USES AND DOSES Dose must be reduced by 25 to 50% for the elderly, for patients with metabolic or electrolytic disorders. The onset of action is 2to 4 hours, and maximal effect occurs in 10 to 14 hours. Complete dissipation of the drug from the body takes 2 to 3 weeks. Table 2: Dosages schedule of cardiac glycosides. Drug Digitalis Digitoxin Dosage Form Tablets/capsules Tablets Injection Digoxin Tablets Capsules Injection Route of administration Oral Oral IV Oral Oral IV Usual maintenance dose 100-200 mg daily 50-300 µg daily 100-200 µg daily 125-500 µg daily 50- 350 µg,1or2dose/day 125-500 µg 1 dose/day (Tyler, V. E., 1981) SOME ACTIVE INGREDIENTS Digitoxin:


Cardiac glycosides


The side chain consists of 3 molecules of digitoxose in glycoside linkage.

Removal of side chain by hydrolysis yeilds the aglycone, digitoxigenin. Description: White or pale buff, odorless, microcrystaline powder. Solubility: Practically insoluble in water; 1g in about 150 ml alcohole or 40 ml of

chloroform; slightly soluble in ether. Comments: This drug is currently not available in the United States. It is absorbed

almost completely after oral administration. Action is maximal in 4 to 12 hr. After full digitalization, the duration of action is about 14 days. In plasma, about 97% is protein-bound. The volume of distribution is about 0.6ml/g. Plasma concentration of 15 to 25mg/ml are considered to betherateutic, and 35 to 45 mg/ml or more to be toxic. Hepatic metabolism accounts for 52% to 70% of elimination. The β-half-life ranges from 2.4 to 9.6 (av 7.6) days. Caution: Handle digitoxin with exceptional care, since it is highly potent. Digoxin: Digoxin has the molecular formula C41H64O14, a molecular weight of 780.95 and melting and decomposition points above 235oC. The drug is practically insoluble in water and in ether; slightly soluble in diluted (50%) alcohol and in chloroform; and freely soluble in pyridine. Digoxin powder is composed of odorless white crystals.


Cardiac glycosides


The side chain of digoxin consists of three molecules of digitoxose in

glycosidic linkage. Hydrolytic cleavage yields aglycone, digoxigenin. Description: Clear to white crystals or a white crystalline powder, odorless; melts with decomposition above 235° Solubility: Practically insoluble in water or ether, slightly soluble in diluted alcohol or chloroform. Comments: In plasma 20% to 30% is protein-bound. It has a high volume of

distribution, with volume of distribution of about 7 L/kg in normal adults and neonates and even larger in infants; in renal failure the volume of distribution is approximately 4-6 L/kg. The

therapeutic concentration in plasma is 0.5 to 2.0 ng/mL, efficacy in heart failure has been obsreved with plasma concentrations ranging from 0.8 to 1.2 ng/mL. Concentrations above 2.0 ng/mL are considered toxic, although symptoms of toxicity may occur at lower concentrations when other conditions, such as hypokalemia and hypocalcaemia, exist. In adults, renal excretion accounts for 60% to 90% of elimination. Biliary secretion and enterohepatic recirculation account for about 7% to 30%. The elimination half-life is 29 to 135 (usually 36-41) hours in normal adults. In renal failure, the β-half-life may be as long as 89 to 177 hours. By the oral route, about 50% to 85% is absorbed from solid dosage forms, but it is 90% to 100% absorbed from hydroalcoholic solutions in capsules. (Troy, D. B., 2005)


Cardiac glycosides Deslanoside: Deslanoside is desacetyllantoside C, which on hydrolysis yields 1 molecule of digoxigenin, 3 of digitoxose, and 1 of glucose. Desalanoside occurs as a white, crystalline powder. It is hygroscopic, absorbing about 7% of moisture when exposed to air, and is highly potent. Desalanoside is frequently used to attain rapid initial loading by parenteral administration. Onset of action is 10 to 30 min, maximal effects occur in 2 to 3 hours, with dissipation in 3 to 6 days. The usual dosage schedule, intramuscularly or intravenously. Table 3: Other cartdioactive drugs: Name Convallaria Apocynum Adnois Botanical Sources Usable Parts Chief Constituents Convallaria majalis Linne Dried rhizome and roots Convallatoxin Apocynum cannabinum Adnois vernalis Linne Dried rhizome and roots Cymarin

Dried overgrown portion Adonoxin, cymarin Dried rhizome and roots Hellebrin K-stropthanside Scillaren A

Black hellebore Helleborous niger Linne Strophanthus Squill

Stropthanthus kombe Oliver Seeds Urginea maritima Linne Cut and dried, freshly inner scales of the bulb

(Tyler, V. E., 1981) Conclusion Cardiac glycosides represent the unavoidable importance of medicinal plants which are found in Mother Nature. Though these are replaced by new synthetic drugs, these naturally occurring compounds made it easy for new research. Reference Bannett, P. N., Brown, M. J. (2003). (9th edition). Clinical Pharmacology (pp. 505). England: Churchill Livingstone.


Cardiac glycosides Harvey, R. A. et al (2009). (4th edition). Lippincott’s Illustrated Reviews: Pharmacology (pp. 191). United States of America: Lippincott Williams and Wilkins. Korolkovas, A. (1988). (2nd edition), Essentials of Medical Chemistry (pp. 478). Canada: A Wiley- Interscience Publication. Shargel, L. et al (2007). Medicinal Chemistry and Pharmacology: Cadiovascular and Diuretics. In Moreton, J. E. (6th edition), Comprehensive Pharmacy Review (pp. 339). New Delhi: Wolters Kluwer Health Pvt. Ltd. Troy, D. B. et al (2005). Cardiovascular Drugs. In Woldinge, A. M. (21st edition), Remington: The Science and Practice of Pharmacy (pp. 1350). United States of America: Lippincott Williams and Wilkins. Tyler, V. E. et al (1981). (9th edition), Pharmacognosy (pp. 165). United States of America: Lea & Febiger.

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