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Cardiac glycosides
Cardiac glycosides
Prepared By
Arafat Siddiqui
East-West University
Dept. of Pharmacy
Dhaka,Bangladesh
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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
Key Words:
Cardiotonics
Steroidal glycosides
Heart failure
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
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
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.
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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 co-
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.
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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
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
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
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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)
Cardiac glycosides are naturally occurring steroidal glycosides obtained from plant
sources. Digitoxin is obtained from Digitalis purpurea, digoxin from Digitalis lanata and
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
circulation, improve renal perfusion, and reduce edema. The electrophysiological effects of
cardiac glycosides are summarized in table 1. Angiotensin converting enzyme inhibitors and
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.
contractility, and the rate of relaxation of cardiac muscle. The effects include
• Reduction in calcium transport from the cell by the sodium calcium exchanger
troponin which then through its binding sites on actin that bind myosin, allowing the
Figure 2: Ventricular function curves in the normal heart, in heart failure (HF), and in HF treated
with Digitalis. (Harvey, R. A., 2009)
• A negative chronotropic effect from increased vagal tone of the sinoatrial node
• Systemic arteriolar and venous constriction which increases venous return and
T and ST
Tachycardia Extraasystole
Tachycardia
(Shargel, L.,2007)
Therapeutic indication:
• Atrial fibrillation
• Atrial flutter
Adverse effects:
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Cardiac glycosides
• Early adverse effects of cardiac glycosides represent the early stages of
toxicity including:
weakness
• Later adverse effects represent intoxication and include such serious cardiac
of serum potassium levels is most frequently observed in patients receiving thiazide or loop
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
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:
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Cardiac glycosides
Overdose with digoxin is now uncommon. For severe digoxin poisoning infusion of the
digoxin in the plasma and is an effective treatment. Because it lacks the Fc segment, this
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.
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.
Digitoxin:
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Cardiac glycosides
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.
accounts for 52% to 70% of elimination. The β-half-life ranges from 2.4 to 9.6 (av 7.6) days.
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.
Description: Clear to white crystals or a white crystalline powder, odorless; melts with
chloroform.
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
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)
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Cardiac glycosides
Deslanoside:
powder. It is hygroscopic, absorbing about 7% of moisture when exposed to air, and is highly
Black hellebore Helleborous niger Linne Dried rhizome and roots Hellebrin
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
Reference
Bannett, P. N., Brown, M. J. (2003). (9th edition). Clinical Pharmacology (pp. 505). England:
Churchill Livingstone.
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Cardiac glycosides
Harvey, R. A. et al (2009). (4th edition). Lippincott’s Illustrated Reviews: Pharmacology (pp.
Korolkovas, A. (1988). (2nd edition), Essentials of Medical Chemistry (pp. 478). Canada: A
In Moreton, J. E. (6th edition), Comprehensive Pharmacy Review (pp. 339). New Delhi:
The Science and Practice of Pharmacy (pp. 1350). United States of America: Lippincott
Tyler, V. E. et al (1981). (9th edition), Pharmacognosy (pp. 165). United States of America: Lea
& Febiger.