Cardiac Glycosides (Medicinal Chemistry) MANIK

Glycosides: chemical and clinical aspects of digoxin and other digitalis glycosides

1. Md. Imran NurManik
Lecturer
Department of Pharmacy
Northern University Bangladesh

5. Cardiotonics:
Cardiotonicsaredrugsthatactsbyincreasingtheforceofcontractionof
myocardialfiberimprovecardiacexcitability,automaticity,conductionvelocityandrefractory
period.
Inanotherwords,cardiotonicsincreasethetonicityofthehearti.e.increasesthecardiac
muscletone.
Indicationsofcardiotonics:
1.Congestivecardiacfailure.
2.Atrialfibrillation(Theatrialcontractionsarerapidandirregular.Theatrialcontractionoccurs
atarateof300-400/minute).
3.Atrialflutter(Theatrialcontractionsarerapidbutregular.Theatrialratecanriseto250-350/
min.Paroxysmalatrialtachycardia(asuddenlyoccurringarrhythmiawheretheatrialrate
becomeshigher–usually160-200beatsperminute).ItisalsoknownasParoxysmal
supraventriculartachycardia.

6. Thecardiotonicsincreasetheforceof
contractionofmyocardialfibers.Bydoingthisa
cardiotonicdrug–Increasescardiacoutput(thevolume
ofbloodpumpedoutbyanyventricleperminute).
Increasedcardiacoutputalsoleadstoincreased
diuresis.Lowersvenouspressureandvenousblood
volume.InCCF,thepumpingisimproperandblood
volumeinheartincreasesleadingtoedemainheart.
Thisincreasesthesizeoftheheart.Thecardiotonic
counteractsthisanddecreasesthesizeofheartto
normal.

7. Generallythecardiacglycosidesareconsideredascardiotonics.Therearealso
somesyntheticdrugsthatmaybeusedforpositiveinotropiceffect.
Inacuteconditions(acuteventricularfailure,tachyarrythmia)synthetic
drugs(orouabain,deslanoside)areusedforrapidresponse.Forlessacute,
chronicorstabilizedcardiacfailurecardiacglycosidesareused.Then,digitalisleaf
ordigitoxinis1
st
choice,digoxinis2
nd
choice.
Cardiacglycosides:
Introduction:
Glycosides:
Glycosidesarecompoundswhichuponhydrolysisyieldaglycone(sugar)
part(suchasglucose,rhamnose,digitoxose,ribose,cymarose)andanaglycone
(alsocalledgenin,thenon-sugarpart)part.

8. Cardiacglycosidesareglycosidescontainingasteroidalaglyconeandhavehighly
specificandpowerfulactiononcardiacmuscle.
Theyarealsocalledcardio-activeglycosidesandcardiotonicglycosides.
Theprinciplesourcesofcardiacglycosidesare–
–Digitalis
–Strophanthus
–Squill
Digitalisglycosides:
Thereareabout80speciesofDigitalisbutonlyDigitalispurpureaand
D.lanataaremainsourcesofcardiacglycosides.
ThedigitalisleafreferstodriedleavesofDigitalispurpurea.Digitoxinis
obtainedfromtheseleaves.DigoxinisobtainedfromdriedleavesofD.lanata.
Digitoxinanddigoxinaretheglycosideswhicharefrequentlyemployedasmedicine.

9. •Increasedintracellularconcentrationsof
calcium may promote
activationofcontractileproteinstoincrease
theforceofcontraction.
•Cardiac glycosides also stimulate the vagus
nerve which decreases heart rate.
The definite
mechanismofactionisnot
known.Somehypotheseshave
beenpostulated–
Cardiac glycosides inhibit Na/K
adenosine triphosphatase, the
“sodium pump” which causes
more Na to remain inside
myocardial cells
IncreasedintracellularNa
stimulatesNa/Caexchange
thatbringsmoreCainside
heartcells.

10. Structure of cardiac glycosides:
The following structural features of cardiac glycosides are deemed
important –
1.Steroidalaglyconesknownasgenins
2.Sugars:Attachedtothegeninsinsequence.
Mostcommon sugarsareD-galactose,
D-glucoseandL-rhamnose.
3.14β-OHgroup.
4.17-α,β-unsaturatedlactonering(6-membere
dorfivemembered).Ifthelactoneringis
5-memberedthentheyarecalledcardenolides
(akabutenolides);ifthelactoneringis
6-membered thentheyarecalled
bufadienolides(akapentadienolides).

11. Twodrugsdigoxinanddigitoxinarecommerciallyavailableforadministration.
Digoxin:
Source:ObtainedfromthedriedleavesofD.lanata(familyScrophulariaceace).
Ithasnotbeensuccessfullysynthesizedinlaboratoryyet.
Use:Itisthemostwidelyusedcardiacglycosideforthetreatmentofcongestive
heartfailureandmostsupraventriculartachyarrythmias.
ItisgiveninoralorIVroute.
Dose:Doseisindividualized.Theaverageloadingdose(theinitialdose)is
0.75-1.5mgin1daywhenorallygivenand0.5-1mgwhengiveninIVroute.The
maintenancedose(thedosegiventomaintaintheplasmaconcentrationofthedrug
totherapeuticlevel)issmaller.

12. Source:
ObtainedfromthedriedleavesofD.purpureaandD.lanata(family
Scrophulariaceace).
Use:
Itisusedinthetreatmentofcongestiveheartfailureandmost
supraventriculartachyarrythmias.
Dosage:
Doseisindividualized.Thegeneralloadingdoseis1-1.5mgin1day;or
200µgtwicedailyfor4days;or400µg/dayfor2-3days.
Maintenancedoseissmaller.Generally100µgdailyoronceintwodays.
Thedosemayberaisedto200µg/dayifnecessary.