CARDIAC GLYCOSIDES

Presented by;

M Pharm (Pharmaceutical Chemistry) students Gunturu .Aparna

Akshintala. Sree Gayatri

Thota. Madhu latha

Kamre. Sunil

Daram. Sekhar

University college of pharmaceutical sciences

Department of pharmaceutical chemistry

Acharya Nagarjuna University

Guntur

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CARDIAC GLYCOSIDES These are an important class of naturally occurring drugs

whose actions include both beneficial and toxic effects on the heart.

Plant glycosides with specific action on heart.

Historical use: to assasinate people, arrow poisons

Historical sources: South American toad skins, African plant extracts

Modern use: to treat congestive heart failure (dropsy). for treatment of atrial fibrillation and flutter. aglycone structure important for activity.

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SOURCES Scrophulariaceae

Digitalis purpurea leaves (foxglove) Digitalis lanata leaves – white flowers

Apocyanaceae Strophanthus vine seeds – Africa

Liliceae Urginea bulbs (squill) – Europe, India Convallaria leaves (lily of the valley) –

also produces a volatile oil perfume

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Cardio-active Glycosides

•Group of steroidal glycosides act as cardiotonic agent.

•They increase tone, excitability and contractility of cardiac muscles.

General properties of Cardiac Glycosides : Amorphous powder Bitter taste

Solubility in H2OInsolubility in Organic solventsVery toxic compounds Odorless

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PHYSICAL AND CHEMICAL PROPERTIES OF CARDIAC GLYCOSIDES: Solubility:

Glycosides are soluble in water and alcohols. Increase number of sugars increase water solubility. Aglycones soluble in CHCl3 and EtOAc.

Stability: Acid hydrolysis:

Split sugars from the aglycone first. Enzymatic hydrolysis:

Split sugars stepwise starting from the terminal sugar. Elevated temperature:

Cause dehydration by removal of C-14 OH group to give inactive anhydro-form

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CARDIO-ACTIVE GLYCOSIDES A small group of plant glycosides act

directly on the heart muscle. These include (but are not limited to cardiac

glycosides or cardenolides) Cardenolides are steroidal glycosides

exert a slowing and strengthening effect on the failing cardiac muscle.

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CLASSIFICATIONS OF GLYCOSIDES:

According to their therapeutic effects:

CHF(congestive heart failure) and cardiac muscle stimulators such as:

Digitalis glycosides: digoxin, digitoxin, gitoxin (Fox glove leaves).

Ouabain: Strophanthus gratus seeds. K-strophanthin: Strophanthus kombe seeds. Scillaren A,B which isolated from red and

white Squill bulbs. Convolloside:Convallaria majalis: Lily of the

Valley.

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According to the type of lactone ring:

1. Cardenolide (one double bond, lactone ring) : Has five member lactone ring (unsaturated) attached at C17

B position of steroidal nucleus. Examples:

Digitalis glycosides: Digoxin

DigitoxinGitoxinStrophanthus gratus glycoside :

OubainStrophanthus Kombe glycoside :K- strophanthin

2. Bufadienolide: (contain two double bonds, lactone ring):Has six member ( unsaturated ) lactone ring attached at C-17 alpha – positionExample:

Squill bulb glycosideScillaren

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Digitalis purpureaDigitoxin

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Nomenclature : The cardiac glycosides occur mainly in plants from which the names have been derived.

Digitalis purpurea, Digitalis lanata, Strophanthus kombe are the major sources of the

cardiac glycosides.

Aglycone moiety: The term 'genin' at the end refers to only the aglycone portion (without the sugar). The aglycone portion of cardiac glycosides is more important than the glycone portion.

Aglycone part has steroidal nucleus

cyclopentanoperhudrophenanthrene

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Sugar moiety(glycone) :

The glycosides usually contain 3 to 4 sugars attached at C-3 OH.The sugars most commonly used include L-rhamnose, D-glucose, D-digitoxose, D-digitalose, D-digginose. Beside Glucose and Rhamnose they usually contain deoxysugars.These sugars predominantly exist in the cardiac glycosides in the β-conformation.

Digitoxose Digitose

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STRUCTURE: These are composed of two structural features :

the sugar (glycone) moiety and the non-sugar (aglycone - steroid) moieties.

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The R group at the 17-position defines the class of cardiac glycoside.

Two classes have been observed in Nature:1. cardenolides and 2. bufadienolides .

The cardenolides have an unsaturated butyrolactone ring While the bufadienolides have an a-pyrone ring. 

STRUCTURE FEATURES:

Steroidal nucleus must be present. 3b-OH group involved in glycosidic linkage. 14b-OH group at C-14. A/B ring junction cis B/C ring junction trans C/D ring junction cis Additional oH groups at C-5, C-11 and C-16 may be

present. The presence of lactone ring

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Structural actiity and relationship :-

1) The presence of OH group in C-14 position makes the glycoside very active and gives rapid action in the body, but if we change it to (H+) group the drug will be inactive or less active.

2) The presence of Alpha & Beta unsaturated lactone ring increases the activity of Cardiac Glycosides, but if we make it saturated the Cardiac glycosides will lose its activity.

3) The ring junctions Cis, Trans, Cis make the nucleus very stable so more active.

4) The sugar part increases absorption and distribution of Cardiac glycoside in the body.

Sugar part : Glucose, Rhamnose, Cymarose, Digitoxose

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DIGITALIS: Scrophulariaceae family:

foxglove - biennial flowering plants cases of poisoning rare natural emetic if eaten in excess

Digitalis purpurea leaf – purple, British Digitalis Tablets B.P. Tincture of Digitalis B.P. commercially grown Holland, E. Europe NB no extraction for these products

Digitalis lanata leaf – white, Mediterranean

used for manufacture of pure glycosides i.e. digoxin, lanatoside C commericially produced Holland,

Equador, USA

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DIGITALIS PURPUREA – PURPLE FOXGLOVE

Digitalis consists of the dried leaves of Digitalis purpurea.

It is required to contain at least 0.3% of total cardinolides calculated as digitoxin.

Parts Used: Leaves

Habitat: Native to Western Europe. Although the plant is cultivated, wild plants are thought to be superior.

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CHEMISTRY OF D.PURPUREA Glycosides

purpurea glycoside A purpurea glycoside B Glucogitaloxin

Steroid cardenolides contains 30 glycosides, 6 main ones only has 3 aglycones

At C-3 of the genin: a linear chain of 3 digitoxose sugar moieties terminated by glucose.

On drying: enzyme degradation takes place loss of the terminal glucose. Produces Digitoxin Gitoxin Gitaloxin

also contains anthraquinone glycosides Saponins Sopogenins Flavonoids

CHEMISTRY OF D.LANATA

compounds belong to cardenolide series 5 membered lactone

ring approx 96 compounds

[1930-1950 Stroll worked on structures]R1 R2 Names 1y 2y

H H digitoxigenin A A digitoxin

H OH gitoxigenin B B gitoxin

OH H digoxigenin C C digoxin

OH OH diginatigenin D D diginatin

H formylester gitaloxigenin E E gitaloxin

*

* Acetyl group confers crystalline properties - makes compounds more easily isolated

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Some cardioactive glycosides from D.lanata:

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DIGITOXOSE sugar found on primary glycosides of D.lanata. glucose on the end of a chain of O-linked digitoxose

sugars at C3.

expect about 10 compounds from D.lanata important ones:

Digoxin “Lanoxin” – Wellcome – 0.25 μg white tablet

Digitoxin “Digitalin” 0.25 μg small pink tabletLanatoside “Cedilanid” 0.10 μg – less well absorbed but used for rapid digitalisation

Others not marketed, used experimentally

DIGITALOSE:This glycone part found in both species.

only strospeside important as emergency injection for heart attacks.

quickest acting cardiac glycoside.23

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Biochemical Mechanism of Action:

The mechanism whereby cardiac glycosides cause a positive inotropic effect.

Several mechanisms have been proposed.

but the most widely accepted involves the ability of cardiac glycosides to inhibit the membrane bound Na+-K+-ATPase pump responsible for Na+-K+ exchange.

The process of membrane depolarization / repolarization is controlled by the movement of three cations, Na+, Ca+2, and K+, in and out of the cell.

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MEDICINAL IMPORTANCE:

They are Cardiotonics used to treat Congestive heart failure(CHF).

They increase force of contraction of cardiac muscles without increase oxygen consumption.

Increase cardiac output.

The diastolic phse last longer so decrease heart rate.

Have diuretic effect due to increase amount of blood passing through the kidney.

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CHEMICAL IDENTIFICATION:

General test for steroids:Liebermann’s test:

Glycoside in acetic anhydride + Few drops of conc. H2SO4

Reddish violet Green

Test for Deoxysugars:Keller-Kiliani’s Test:

Glycoside in acetic anhydride containing traces of FeCl3 + conc. H2SO4 on the wall of the tube

Acetic acid layer acquire Bluish-green colour (Digitalis)

Acetic acid layer acquire Red colour (Squill)

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Test for 5-membered lactone ring:

Legal’s test: Cardenolide in pyridine + Na nitroprusside + NaOHdeep

red colour.

Kedde’s test :

Cardenolide+ 3,5 dinitrobenzoic acid (Kedde’s reagent A) + NaOH (Kedde’s reagent B) violet colour.