Br Heart 7 1985; 54: 258-61

Plants and cardiac glycosides

A HOLLMAN

From the Cardiac Department, University College Hospital, London

It is often asked why plants contain such remarkablecompounds, sometimes beyond the practical reach ofthe synthetic chemist. What use are these com-pounds to the plant itself? Defence against predatorsis one answer although it has to be said that many oftoday's predators did not exist when the floweringplants, the angiosperms, evolved 80-100 millionyears ago. It has been shown for example that themethylxanthines in tea and coffee have static andcidal activity against insect pests.'

Glycosides are usually compounds of plant origin.They are made up of one or more sugars combinedwith an alcohol, a phenol, or a complex moleculesuch as a steroid nucleus. The non-sugar moiety oraglycone is also called a genin. Because they do notcontain nitrogen it is wrong to call them alkaloids. Inaddition to the cardiac glycosides with their cyclo-pentanoperhydrophenanthrene nucleus in the geninmoiety there are other glycosidal plant substancessuch as the anthraquinone derivatives senna, rhu-barb, aloe, and cascara; saponins; cyanogenetic gly-cosides such as amygdalin from bitter almond;terpene and sterol glycosides; glycosidal dyes andpigments; and finally gums and tannins. The venomglands of the skin of the toad (Bufo) contain digitalislike compounds and this animal gives its name to thatgroup of the glycosides which have a steroid skeletonof 24 carbon atoms (C24), the bufadienolides. A fewplant glycosides also belong to this group, notablythose from squill, but all others have a C23 skeletonand belong to the cardenolides group.The genus Digitalis is named after the shape of the

flowers (digitus, a finger). Although ingenious alter-natives have been proposed to explain the commonname, foxglove, there is no doubt that this title doesmean the glove of a fox. The genus comprises bien-nial or perennial herbs, or rarely small shrubs, withleaves which are simple, arranged alternately, andsometimes with the lowest leaves forming a rosette.They are natives of Europe, North Africa, andWest Asia but not of China. The formerly named

Requests for reprints to Dr A Holhnan, Cardiac Department,University College Hospital, London WCIE 6AU.

D chinensis has been reclassified as Adenosmagrandiflorum. The showy flowers are purple, yellow-ish brown, or white, carried in terminal racemes.The calyx has five equal lobes and there are fourstamens. Other characteristics are variable and onthe basis of these differences the genus is dividedinto twelve species and seven subspecies. The fulltaxonomy' of Digitalis is as follows: class, Angio-spermae; subclass, Dicotyledon; superorder, Aster-idae; order, Scrophulariales; family, Scrophularia-ceae; subfamily, Rhinanthoideae; tribe, Digitalideae;genus, Digitalis. D purpurea is the only species nativeto Britain. It is also found in Western Europe and isa complex polytypic species with at least three sub-species. The flowers are purple, pale pink, or whiteand being usually calcifuge it is rare in calcareousdistricts such as Cambridgeshire and the Jura. Thespecies D lanata which comes from Hungary, Ro-mania, and the Balkan peninsula has white or yello*-ish white flowers with brown or violet veins and wasintroduced to Britain in 1789. This species is namedafter its characteristically downy flowers. Otherspecies3 include D obscura, D thapsis, D dubia, and Dparviflora from Spain; D viridiflora and D laevigatafrom the Balkan peninsula; D lutea, D grandiflora,and D ferruginea from western, eastern, and south-ern Europe respectively; D leucophaea from northernGreece; D orientalis from the Levant; D sibirica fromSiberia.The native glycoside is susceptible to hydrolysis

by enzymes during the extraction process. Theacetyl group and glucose are split off, but fortunatelythe partly hydrolysed glycosides such as digoxin anddigitoxin are as biologically active as the parent com-pound. Were this not so the action of digitalis mightnever have been established since the native com-pounds were first isolated by A Stoll as late as 1935.The native compounds in D lanata are lanatosides A,B, and C which yield digitoxin, gitoxin, and digoxin(Table 1). Dpurpurea has purpurea glycosides A andB but no glycoside corresponding to lanatoside C.Digitoxin comes from Dferruginea, D grandiflora, Dlanata, D lutea, and four varieties of D purpurea.Digoxin comes from D grandiflora, D lanata, and Dorientalis.

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Plants and cardiac glycosides

It was the poisonous nature of other plants whichcontain cardiac glycosides which first drew attentionto them not the typical chemical structure of theglycosides that they contain. In 1898 LauderBrunton wrote, "various drugs stimulate the vagusroots in the medulla oblongata or the terminal end-ings of the heart itself ... many of the arrow poisonsand ordeal poisons act on the heart in this way,among them are strophanthus, erythrophloeum, tan-ghinia, manganja, carravol, vao, oleander, squill,hellebore ...".4 Many plants contain cardiacglycosides and some species contain up to six. Oneglycoside may be present in several species; stro-phanthidin for example is found in 10 genera from 7families.There are 36 cardiac genins of plant origin and

they are divided into six groups according to theiraccompanying sugars. There is no obvious patternfor the occurence of glycosides in different plants.

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They occur both in monocotyledons (for exampleLiliaceae) and in dicotyledons, and their geographi-cal distribution is irregular, as is the distribution ofother important plant medicines. For example,podophyllotoxin from which the anticancer drugetoposide is derived is found in two Podophyllumspecies, one from the Himalayas and the other fromNorth America. Because the taxonomy of plants ac-cording to their chemical composition is not fullydeveloped, the list of the families and their generawhich contain cardiac glycosides given in Table 2 isbased on the Linnaean classification.5A few glycosides and plants may be picked out for

special mention. Ouabain, which is ineffective whengiven by mouth, comes from the wood of Aco-canthera schimperi, the Ouabaio tree, and also fromthe seeds of Strophanthus gratus. It is more familiarto pharmacologists than to clinicians, as is stro-phanthin K a glycoside mixture from Strophanthus

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Digitalis purpurea (L) (Source: Curtis W. FloraLondinensis, Vol 1. London, 1777.)

Digitalis lanata (Ehr) (Source: Lindley J. Digitaliummonographia. London, 1821.)

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Table 1 Botanical sources and major chemical components of cardiac glycosides of clinical importance

Hollman

Plant Precursor Split off by Glycoside Split off by Aglycone or geninsource glycoside enzymatic acid hydrolysis*

and mildalkalinehydrolysis*

DigitalisD purpurea Purpurea-glycoside A Glucose Digitoxin Digitoxose (3) Digitoxigenin

(leaf) (deacetyldigilanid A)Purpurea-glycoside B Glucose Gitoxin Digitoxose (3) Gitoxigenin

(deacetyldigilanid B)-- Gitalin Digitoxose (2) Gitaligenin

(gitoxigenin hydrate)D lanata Lanatoside A Glucose + Digitoxin Digitoxose (3) Digitoxigenin

(leaf) (digilanid A) acetic acidLanatoside B Glucose + Gitoxin Digitoxose (3) Gitoxigenin

(digilanid B) acetic acidLanatoside C Glucose + Digoxin Digitoxose (3) Digoxigenin

(digilanid C; acetic acidcedilanid)

StrophanthusS kombe K-strophanthoside Glucose K-strophanthin-I Glucose + Strophanthidin

(seed) (strophanthin) cymaroseK-strophanthoside Glucose (2) Cymarin Cymarose StrophanthidinK-strophanthin-3 Glucose Cymarin Cymarose Strophanthidin-- Cymarol Cymarose Strophanthidol

S gratus - - Ouabain Rhamnose Ouabagenin(seed) (G-strophanthin) (G-strophanthidin)

Scilla (squill)Urginea Scillaren A Glucose Proscillaridin A Rhamnose Scillaridin Amaritima orindica (bulb)

* One mole of sugar or acetic acid is split off, unless the number of moles is otherwise indicated in parentheses.(From The Pharmacological Basis of Therapeutics. Goodman LS, Gilman A. 5th ed. Macmillan, New York, 1975. Reproduced by permissionof the authors and publisher.)

Table 2 Families and genera containing cardiac glycosidesAPOCYANACEAEAcokantheraAdeniumApocyanumCarissaCerberaNeriumStrophanthusTanghiniaThevetia

ASCLEPIADACEAEAsclepiasCalotropisCryptostegiaGomphocarpusMenabeaPachycarpusPeriplocaXysmalobium

CELASTRACEAEEuonymus

CRUCIFERAECheiranthusErysimum

LILIACEAEBowieaConvallariaOrnithogalumRohdeaUrginea

MORACEAEAntiarisAntiaropsisCastillaOgcodeia

LEGUMINOSAECoronilla

RANUNCULACEAEAdonisHelleborus

SCROPHULARIACEAEDigitalisIsoplexis

STERCULIACEAEMansonia

TILIACEAECorchorus

kombe' seeds. Since the times ofthe ancient Egyptiansand Romans, squill from the bulb of the white ormediterranean squill, Urginea maritima, has beenused as a diuretic and expectorant (and in large dosesas an emetic and purgative). It had fame as a constit-uent ofGuy's pill, in which it was combined with onegrain each of prepared digitalis and mercury bluepill. Its active principles are scillarin A and B. Olean-drin is the glycoside in the mediterranean oleanderor rose bay, Nerium oleander. This plant has causedaccidental poisoning with heart block in Australianchildren (J B Hickie, personal communication), andpeople have died after eating food cooked on olean-der wood fires. Several glycosides come from the lilyof the valley, Convallaria majalis.

Gardeners will have already recognised the gen-eric names of the star of Bethlehem, wallflower, andChristmas rose, while gourmets will be relieved tolearn that although the family Moraceae is included,the mulberry, Morus nigra, does not contain cardiacglycosides. Many large plant families do not haveany members containing cardiac glycosides. One ex-ample is the family Rosaceae to which the hawthorn,Crataegus monogyna, belongs. This plant, however,contains a flavinoid glycoside which has a weak dig-italis like action.

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Plants and cardiac glycosides

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Urginea maritima (Baker) (Source: Redoute P J. LesLiliacees, Vol 2. Paris, 1805.)

Anticipating by 100 years Pasteur's dictum, "dansles champs de l'observation, le hasard ne favorise queles esprits prepares . . .", it was certainly chance act-ing on Withering's prepared mind that gave Digitalispurpurea its scientific start in therapeutics, but manyother species contain cardioactive principles and it isto be hoped that more will be discovered among theworld's 250 000 species, unless the accelerating paceof tropical deforestation eliminates a species beforewe have studied it.

I thank Mrs Gina Douglas, Librarian to the LinneanSociety of London, for her help.

Nerium oleander (L) (Source: Sibthorp J. Flora Graeca,Vol 3. London, 1819.)

References

1 Nathanson JA. Caffeine and related methylxanthines:possible naturally occurring pesticides. Science 1984;226: 184-7.

2 Heywood VH, ed. Flowering plants of the world. Oxford:Oxford University Press, 1978.

3 Tutin TG, ed. Flora Europea. Vol 3. Diapensiaceae tomyoporaceae. Cambridge: Cambridge UniversityPress, 1972.

4 Brunton TL. The use of remedies in diseases of theheart and blood vessels. JAMA 1898; 31: 815-7.

5 Hoch JH. A survey of cardiac glycosides and genins.Charleston: University of South Carolina Press, 1961.

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