Ugrás a tartalomhoz

Pharmacognosy 2

Dr. Györgyi Horváth, Prof. Dr. Péter Molnár, Dr. Tímea Bencsik (2014)

UP MS Department of Pharmacognosy

5.5 Cardenolides and bufadienolides

5.5 Cardenolides and bufadienolides

Cardioactive glycosides are a kind of steroid glycosides, which act on the human heart. We can distinguish two main aglycone types of the cardioactive glycosides: cardenolides and bufadienolides. Medicinally the cardenolide group is more important. Cardenolides have a steroid skeleton with 23 C-atoms and contain γ-lacton (butenolide) ring, e.g. digitoxygenin.

Bufadienolides with 24 C-atoms contain, on the C-17 carbon atom, a δ-lacton ring (α, β - γ, δ doubly unsaturated), e.g. scillarenin (Figure ‎5.142-148).

Figure ‎5.142-‎5.‎5.143The structure of cardenolides and bufadienolides.

In both types of aglycones, a sugar molecule or a side chain containing sugar molecules is connected to the β-OH group of C-3 carbon atom. The sugar components of cardioactive glycosides are mainly deoxy-sugars and glucose. If glucose is present in the chain, it can always be found at the end of the chain. The deoxy-sugars are 6-deoxy-sugars (e.g. L-rhamnose, D-fucose, D-digitalose, L-tevetose) or 2,6-deoxy-sugars (e.g. D-digitoxose, D-cymarose, L-oleandrose) (Figure ‎5.144). Recently, 2-O-methyl and 2-O-acetyl sugars have also been discovered.

The biosynthesis of cardenolides and bufadienolides starts from cholesterol (C27) through pregnane derivatives [(by side-chain shortening (C21); e.g. progesterone)] (Figure ‎5.145). In the formation of these compounds the incorporation of the active acetyl group of acetyl-CoA plays an important role. Cardenolides dissolve in alcohols (eg. methanol, ethanol). Cardioactive glycosides occur rarely in higher plants, their occurrence is not characteristic even at the level of plant families, they are associated rather with some genera or species. Some families with cardiac glycoside-containing taxa are: Apocynaceae, Liliaceae, Ranunculaceae, Fabaceae, Moraceae, Scrophulariaceae, Euphorbiaceae. Cardioactive glycosides exert their pharmacological effect on the heart muscles. In therapeutic dose they improve cardiac output by increasing the force of heart muscle contraction and increasing the volume of blood pumped into the vascular system (positive inotropic action). They can decrease heart rate (negative chronotropic action) and venous pressure, while diuresis shows an upward tendency. The action of cardenolic glycosides is always greater than the action of the corresponding aglycones. Cardenolide glycosides are employed in the case of heart insufficiency, which occurs as a consequence of aherosclerosis, hypertonia, asthma cardiale or problems with a cardiac valve (valvular or cardiac insufficiency).

Figure ‎5.144The structure of D-digitoxose and D-cymarose.

Figure ‎5.145The formation of cardenolides from cholesterol.

Drugs

Digitalis purpureae folium

Plant

Digitalis purpurea  L.– Purple foxglove (Scrophulariaceae)

This biennial or short-lived perennial plant is native to most of temperate-Europe and North-Africa. It is cultivated as an ornamental and medicinal plant.

Figure ‎5.146Purple foxglove (Digitalis purpurea L.)

Drug

Digitalis purpureae folium (Purple foxglove leaf)

The drug consists of the dried first- or second-year leaves of Digitalis purpurea L. It contains not less than 0.3% of total cardenolides calculated as digitoxin.

Constituents

The characteristic constituents of the drug are cardenolide glycosides (0.15-0.4%). Their aglycones are: digitoxigenin, gitoxigenin and gitaloxigenin. The main glycosides include purpurea glycoside A, purpurea glycoside B and purpurea glycoside C, digitoxin, gitoxin and gitalotoxin. Other constituents are steroidal saponins, flavonoids (e.g. apigenin, luteolin), derivatives of cinnamic acid such as caffeic acid and chlorogenic acid and anthraquinone-derivatives.

Figure ‎5.147-‎5.148‎5.149‎5.150‎5.151‎5.152‎5.153‎5.154‎5.155The structure of digitoxigenin, gitoxigenin, gitaloxigenin, purpurea glycoside A, purpurea glycoside B, purpurea glycoside C, digitoxin, gitoxin and gitalotoxin.

Uses

The isolated constituents act on the heart. They have positive inotropic effects. The fine powder of the dried leaves is used in pharmaceutical technology for preparing pellets. Digitoxin prepared in a pure crystalline form is used to make tablets.

The drug or extracts or its pure constituents are very toxic, therefore they should not be used without medical advice.

Digitalis lanatae folium

Plant

Digitalis lanata  Ehrh.– Woolly foxglove (Scrophulariaceae)

This perennial or biennial plant is native to central and south-eastern Europe. It can be cultivated. This plant is protected in Hungary.

   

Figure ‎5.156Woolly foxglove (Digitalis lanata Ehrh.)

Drug

Digitalis lanatae folium (Woolly foxglove leaf)

The drug consists of the dried first-year leaves of Digitalis lanata Ehrh.

Figure ‎5.157Digitalis lanatae folium (Woolly foxglove leaf)

Constituents

The characteristic constituents of the drug are cardenolide glycosides (1%). Their aglycones are: digitoxigenin, gitoxigenin, digoxigenin, diginatigenin and gitaloxigenin. The main glycosides include lanatoside A, lanatoside B, lanatoside C, lanatoside D, lanatoside E, digitoxin, digoxin, acetyldigoxin and glucoverodoxin. Other constituents are steroidal saponins, flavonoids (e.g. apigenin, luteolin), caffeic acid and p-coumaric acid and anthraquinone-derivatives.

Figure ‎5.158-‎5.159‎5.160‎5.161‎5.162‎5.163‎5.164The structure of digitoxigenin, gitoxigenin, digoxigenin, diginatigenin, gitaloxigenin, digoxin and lanatoside C.

Uses

The isolated constituents act on the heart. They have positive inotropic effects. The leaves are used principally for the preparation of lanatosides and digoxin. Digoxin has become the most widely used drug in the treatment of congestive heart failure. Digoxin is more rapidly absorbed from the gastrointestinal tract than the purpurea glycosides. Lanatoside C is less well absorbed than digitoxin but it is less cumulative.

Overall the pharmacological effects of the Digitalis glycosides start approx. 6 to12 hours after administration, but the constituents break down completely after 10 to 20 days.

The drug or extracts or its pure constituents are very toxic, therefore they should not be used without medical advice.

Strophanthi semen

Plant

Strophanthus kombe  Oliver– Strophanthus (Apocynaceae)

This plant is a climbing shrub and native to tropical East-Africa.

Drug

Strophanthi semen (Strophanthus seed)

The drug consists of the the seeds without their feathery hairs of Strophanthus kombe Oliver.

Constituents

The characteristic constituents of the drug are cardenolide glycosides (8-10%). The main glycosides are K-strophanthoside, K-strophanthin-β and cymarin, all based on the aglycone of strophanthidin. The other constituents of the seeds include 30% of fatty oil, trigonelline, choline and mucilage.

Figure ‎5.165-‎5.166‎5.167‎5.168The structure of K-strophanthoside, K-strophanthin-β, strophanthidin and

G- strophanthin (= ouabain).

Uses

The cardioactive constituents of the drug in a pure crystalline form are used for the preparation of injections. Cardioactive glycosides of the drug administered in intravenous injections act within a few minutes, and their effect lasts for approx. 36 hours. Their pharmacological activity is similar to that of Digitalis glycosides, but Strophanthus glycosides do not accumulate, therefore these cardenolides are used in the case of acute cardiac insufficiency as life-saving medicines. Strophanthus gratus seeds (Strophanthi grati semen) contain 4-8% cardioactive glycosides with G-strophanthin (= ouabain), which can also be used in injections. Strophanthus gratus is native to West-Africa.

The drug or extracts or its pure constituents are very toxic, therefore they should not be used without medical advice.

Convallariae herba

Plant

Convallaria majalis  L. – Lily of the valley(Liliaceae)

This perennial plant is native to Europe and in the temperate zones of Asia. It occurs in oak-woods and other deciduous forests.

   

Figure ‎5.169Lily of the valley (Convallaria majalis L.)

Drug

Convallariae herba (Lily of the valley)

The drug consists of the dried aerial parts (collected when the flowers are beginning to open) of Convallaria majalis L.

Figure ‎5.170Convallariae herba (Lily of the valley)

Constituents

The characteristic constituents of the drug are cardenolide glycosides (0.2-0.5%). The principal glycoside is convallatoxin which on hydrolysis yields strophanthidin and (-)-rhamnose. The plant contains several minor cardenolides (about 40 glycosides associated with nine different aglycones). Other constituents are steroidal saponins, flavonoids (mainly apigenin, luteolin, kaempferol, quercetine and their derivatives) and azetidin-2-carboxylic acid.

Figure ‎5.171-‎5.172‎5.173The structure of strophanthidin, convallatoxin and azetidin-2-carboxylic acid.

Uses

The therapeutic indications include the treatment of cardiac insufficiency, cor pulmonale and cardiac failures associated with oedema formation. It has diuretic effect. The drug or extracts or its pure constituents are very toxic, therefore they should not be used without medical advice.

Adonidis herba

Plant

Adonis vernalis  L.– Spring pheasant’s eye(Ranunculaceae)

This perennial plant is native to Europe, Caucasus and Siberia. In Hungary it is protected because of its rare occurrence. It occurs in Mecsek and Bakony mountains.

Figure ‎5.174Spring pheasant’s eye (Adonis vernalis L.)

Drug

Adonidis herba (Spring pheasant’s eye)

The drug consists of the dried aerial flowering parts of Adonis vernalis L.

Constituents

The characteristic constituents of the drug are cardenolide glycosides (0.25-0.5%). The principal glycoside is adonitoxin which is the glycoside of adonitoxigenin. The drug also contains strophanthidin-type cardenolides. Other constituents are flavonoid-glycosides, ascorbic acid (vitamin C) and sugar alcohols.

Figure ‎5.175-‎5‎5.176The structure of adonitoxigenin and adonitoxin.

Uses

The cardenolides of the drug are poorly absorbed from the gastrointestinal tract, but they are broken down more quickly than Digitalis cardenolides, therefore they cannot accumulate. The therapeutic indications include nervous cardiac troubles, angina pectoris, cardiac failures associated with oedema formation. It has diuretic effect. The drug or its extracts and pure constituents are very toxic, therefore they should not be used without medical advice.

Nerii folium

Plant

Nerium oleander  L. – Oleander(Apocynaceae)

This perennial woody shrub (or small tree) is native to South-Europe and West-Asia. It is cultivated as ornamental plant.

   

Figure ‎5.177Oleander (Nerium oleander L.)

Drug

Nerii folium (Oleander leaf)

The drug consists of the dried leaves (collected during flowering period) of Nerium oleander L.

Figure ‎5.178Nerii folium (Oleander leaf)

Constituents

The characteristic constituents of the drug are cardenolide glycosides (1-2%). The principal glycosides are oleandrin, adynerin, odoroside A and oleasides A-F. The main aglycones include oleandrigenin (=16-acetylgitoxigenin), adynerigenin (= 3-hydroxy-8,14-epoxycardenolide), digitoxigenin, oleagenin and uzarigenin (= 5α-digitoxigenin). The drug also contains flavonoids such as rutin and kaempferol-3-O-rhamnoglucoside; as well as ursolic and oleanolic acids.

Figure ‎5.179-‎5.180‎5.181‎5.182‎5.183‎5.184‎5.185The structure of oleandrigenin, oleandrin, adynerigenin, adynerin, digitoxigenin, oleagenin and oleaside A.

Uses

The cardenolides of the drug act similarly to the Digitalis cardenolides. The industrial preparations of the drug can be used for the treatment of arrhythmia and circulatory disorders, as well as other cardiac complaints associated with changes in the weather. The drug or its extracts and pure constituents are very toxic, therefore they should not be used without medical advice.

Erysimi herba et semen

Plant

Erysimum diffusum  Ehrh.Gray diffuse wallflower (Brassicaceae)

This perennial, overwintering, herbaceous plant is native to Europe and Asia.

Drug

Erysimi herba et semen (Gray diffuse wallflower flowering shoot and seed)

The drug consists of the dried aerial flowering parts and seeds of Erysimum diffusum Ehrh.

Constituents

The characteristic constituents are cardenolides based on strophanthidin aglycone. The principal cardenolides include helveticoside and erizimoside (= glucohelveticoside). The seeds contain glucosinolates, sterols and fatty oil. Flavonoids occur mostly in the aerial parts of the plant.

Figure ‎5.186-‎5.187‎5.188The structure of strophanthidin, helveticoside and erizimoside (= glucohelveticoside).

Uses

Formerly the drug was used for the treatment of mild cardiac insufficiency. At present the plant is not frequently used.

Leonuri cardiacae herba

Plant

Leonurus cardiaca  L. – Motherwort(Lamiaceae)

This perennial plant is native to Mediterranean countries, Europe and Asia.

Figure ‎5.189Motherwort (Leonurus cardiaca L.)

Drug

Leonuri cardiacae herba (Motherwort, Ph. Eur.)

The drug consists of the whole or cut, dried flowering aerial parts of Leonurus cardiaca L. It contains minimum 0.2% of flavonoids, expressed as hyperoside, and calculated with reference to the dried drug.

Figure ‎5.190Leonuri cardiacae herba (Motherwort)

Constituents

The characteristic constituents of the drug are bufadienolides. They are glycosides of scillarenin and 5,6-dehydro-scillarenin. Other constituents include diterpenes (e.g. marrubiin), iridoids (e.g. ajugoside), flavonoids, stachidrin (dimethyl-pirrolidinium-2-carboxilate) and triterpenes such as ursolic and oleanolic acid.

Figure ‎5.191-‎5.192The structure of scillarenin and 5,6-dehydro-scillarenin.

Uses

The drug can be used for the treatment of mild cardiac insufficiency and nervous heart complaints. Leonuri cardiacae herba may be combined with Crategi folium cum flore (hawthorn leaf and flower) in herbal teas.

Dosage

Adult and elderly daily dose: 4 g of the drug as an infusion.

Scillae bulbus

Plant

Urginea maritima  (L.) Baker– Squill(Liliaceae)

Squill occurs wild as an aggregate of at least six species of varying chromosome number. The plant is native to Mediterranean countries and West Asia. White squill can be found in Spain, Portugal, Sardinia, Malta, Cyprus and Greece; red squill is native to Algeria and Marocco.

Drug

Scillae bulbus (Squill bulb)

The drug consists of the dried sliced bulbs of Urginea maritima (L.) Baker, from which the membranous outer scales have been removed.

Constituents

The characteristic constituents of the drug are bufadienolides. In white squill there is a mixture of 15 bufadienolides: the aglycone is scillarenin and the principal glycosides are scillaren A, glucoscillaren A and proscillaridin A. In red squill the principal glucosides are scillirozide and glucoscillirozide, their aglycone part is scillirosidine.

Figure ‎5.193-‎5.194‎5.195‎5.196‎5.197‎5.198The structure of scillarenin, scillaren A, glucoscillaren A, proscillaridin A, scillirozide and scillirosidine.

Uses

In pharmaceutical industry white squill is used principally. Scillaren A and proscillaridin A can be absorbed from the gastrointestinal tract (almost in 25%), therefore these compounds are administered orally. The therapeutic indications include aorta-insufficiency, angina pectoris, oedema associated with nephritis. In small doses the drug provokes mild gastric irritation causing a reflex secretion from the bronchioles, therefore it can be used as an expectorant, but in large doses it causes vomiting.

The drug should not be used without medical advice.

Hellebori radix (et rhizoma)

Plant

Helleborus niger  L.– Black hellebore(Ranunculaceae)

This perennial plant is indigenous to Central Europe. In Hungary Helleborus species are protected.

   

Figure ‎5.199Black hellebore (Helleborus niger L.)

Drug

Hellebori radix (et rhizoma)(Black hellebore root et rhizome)

The drug consists of the whole or cut, dried roots and rhizomes of Helleborus niger L.

Figure ‎5.200Hellebori radix (et rhizoma)(Black hellebore root et rhizome)

Constituents

The characteristic constituents of the drug are bufadienolides. The principal constituent is hellebrin which is the glycoside of the aglycone hellebrigenin. The drug also contains steroidal saponins, but their structure has not been identified yet.

Figure ‎5.201-‎5.202The structure of hellebrin and hellebrigenin.

Uses

The bufadienolides of the drug have a digitalis-like action. The aglycone hellebrigenin is the bufadienolide analogue of strophanthidin. The drug which has cardiotonic as well as abortifacient properties is considered dangerous and is now obsolete in ordinary medicine. The drug is used principally in veterinary medicine: Hellebori rhizoma is placed into the ears of pigs, sheep or in the chest of cows, where the drug causes inflammation, and it increases the resistance of these animals against different infections (so called stimulus therapy).