Cardiac glycosides

Digitalis

2. Organicnaturalcompoundspresentinalotofplantsandsomeanimals,these
compoundsuponhydrolysisgiveoneormoresugars(glycone)moietiesand
nonsugar(aglycone)moieties
Glycoside=sugargroup+non-sugargroup
 (aglyconeorgenin)
Glycosidiclinkageisformedbetween–OHgroupofsugarand–Hgroupof
non-sugarmoietiesORothersugarwithlossofwatermolecule
glycoside=glycone{---o---}aglycone+Water
Sugaringlycosidesismostlybeta-Dglucosebutothersugarslikegalactose,
mannose,rhamnose,digitoxosecanpresent.
Glycosidescanbealphaorbetabutplantscontainsonlybetaglycosides
Therapeuticeffectofglycosidesisonlyduetoaglyconepartonlyandsugar
moietyfacilitateabsorptionofglycoside,transportationofaglyconetositeof
action.

3. Classification based on type of aglycone in glycoside
Anthraquinone or anthracene glycoside
Sterols or cardiac glycoside
Saponin glycoside
Cyanogenic glycoside
Isothiocynate glycoside
Coumarins and furanocoumarins
Aldehyde glycoside
phenol glycoside
Steroidal
Miscellaneous glycosides

4. classification based on type of linkage between glycone
and aglycone
Linkagebetween–OHgroupofglyconeand–Hgroupof
RADICALSLIKE–CH,-OH,-SH,-NHofaglycone.
Glycosideisnamedbyperfixlike
C-glycoside,-sugarlinkedtocarbonatomofaglycone
N-glycoside,-sugarlinkedtonitrogenatomofaglycone
O-glycoside,-sugarlinkedtooxygenatomofaglycone
S-glycoside-sugarlinkedtosulfuratomofaglycone
classification based on there use
Cathartics, cardio tonics, analgesics, anti-rheumatics, anti-ulcer
etc

5. 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 assassinate people, arrow poisons
Historical sources:
South American toad skins, African plant extracts
Modern uses
To treat congestive heart failure
For treatment of atrial fibrillation and flutter.
Aglycone structure important for activity.
Group of steroidal glycosides act as cardiotonic agent.
They increase tone, excitability and contractility of cardiac muscles.
General properties of Cardiac Glycosides :
1. Amorphous powder 2. Bitter taste 3. Solubility in H2O
4. Insolubility in Organic solvents 5.Very toxic compounds 6. Odourless

6. Solubility:
Glycosidesaresolubleinwaterandalcohols.
Increasenumberofsugarsincreasewatersolubility.
AglyconessolubleinCHCl
3andEtOAc.
cardiacglycosidesisasmallgroupofplantglycosidesactdirectlyon
theheartmuscle.
Theseinclude(butarenotlimitedtocardiacglycosidesor
cardenolides)
Cardenolidesaresteroidalglycosides
exertaslowingandstrengtheningeffectonthefailingcardiacmuscle.
Accordingtotheirtherapeuticeffects:
CHF(congestiveheartfailure)andcardiacmusclestimulatorssuchas:
Digitalisglycosides:digoxin,digitoxin,gitoxin(Foxgloveleaves).
Ouabain:Strophanthusgratusseeds.
K-strophanthin:Strophanthuskombeseeds.
ScillarenA,BwhichisolatedfromredandwhiteSquillbulbs.

7. Cardenolide (one double bond, lactone ring) :
Has five member lactone ring (unsaturated) attached at C17 B position of steroidal
nucleus.
Examples:Digitalis glycosides: Digoxin, Digitoxin,Gitoxin
Strophanthus gratus glycoside:
Oubain
Strophanthus kombe glycoside
K-strophanthin
Bufadienolide: (contain two double bonds, lactone ring):
Has six member ( unsaturated ) lactone ring attached at C-17 alpha position
Example: Squill bulb glycoside: Scillaren
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

8. Sugar moiety(glycone) :
Theglycosidesusuallycontain3to4sugarsattachedatC-3OH.
ThesugarsmostcommonlyusedincludeL-rhamnose,D-glucose,D-digitoxose,
D-digitalose
BesideGlucoseandRhamnosetheyusuallycontaindeoxysugars
Thesesugarspredominantlyexistinthecardiacglycosidesinthe
β-conformation.
Structure:
These are composed of two structural features :
the sugar (glycone) moiety and
the non-sugar (aglycone -steroid) moieties.
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.

10. STRUCTURE FEATURES:
Steroidal nucleus must be present.
3-OH group involved in glycosidic linkage.
14-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

11. General test for steroids:
Liebermann’s test:
Glycoside in acetic anhydride + Few drops of conc. H
2SO
4
Reddish violet turns to Green
Test for Deoxysugars:
Keller-Kiliani’s Test:
Glycoside in acetic anhydride containing traces of FeCl
3 + conc.
H
2SO
4 on the wall of the tube
Acetic acid layer acquire Bluish-green colour (Digitalis)
Acetic acid layer acquire Red colour (Squill)
Test for 5-membered lactone ring:
Legal’s test:
Cardenolide in pyridine + Na nitroprusside + NaOH-------Deep red
colour.
Kedde’s test :
Cardenolide+ 3,5 dinitrobenzoic acid (Kedde’s reagent A) + NaOH
(Kedde’s reagent B)-----------------violet colour.

12. 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
Digitalis lanata leaf –white, Mediterranean
used for manufacture of pure glycosides
i.e. digoxin, lanatoside C
commercially produced in Holland, Equador, USA
DIGITALIS PURPUREA –PURPLE FOXGLOVE
DigitalisconsistsofthedriedleavesofDigitalispurpurea.
It is required to contain at least 0.3% of total cardienolides calculated as
digitoxin.

13. 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

14. DigitalislanatacontainscardiacglycosideslikelanatosideA,B,CandE.
LanatosidesAandBareacetylderivativesofpurpureaglycosidesAandB
respectively.
HydrolysisofLanatosideCyieldsdigoxin,acrystallineactiveglycoside.
BiochemicalMechanismofAction
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.

16. Medicinal Uses
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 phase last longer so decrease heart rate.
it stimulates the flow of urine which lowers the volume of the
blood and lessens the load on the heart