Anthraquinone Glycosides

2. Anthraquinone Glycosides

3. Introduction to Anthraquinones • Historically: Rhubarb, Senna, Aloes and Cascara were all used as purgative drugs. • Monocotyledons: Only Liliaceae. • Most commonly C-glycoside: barbaloin. • Dicotyledons: Rubiaceae, Leguminosae, Polygonaceae, Rhamnaceae, Ericaceae, Euphorbiaceae, Lythraceae, Saxifragaceae, Scrophulariaceae and Verbenacacea. Also in certain fungi and lichen.

4. Reduced derivatives of anthraquinones • Oxanthrones, anthranols and anthrones • Compounds formed by the union of 2 anthrone molecules • Dianthrones • Aglycones: • Chrysophanol/Chrysophanic acid Rhubarb and Senna. • Rhein  Rhubarb and Senna • Aloe-emodin Rhubarb and Senna • Emodin Rhubarb and Cascara

5. Anthraquinones – Chemical Properties • Anthraquinone derivatives: orange-red compounds • Soluble in hot water/dilute alcohol. • Identified via Borntrager’s test • Powdered drug – macerated with ether • Filter • Add ammonia/caustic • Shake  pink, red or violet colour – positive for anthraquinone derivatives • If the Anthraquinones are reduced (within the herb) or stable (glycosides) test will be negative

6. Anthraquinone Structure

7. Anthranonls and Anthrones • Reduced anthraquinone derivatives • Occur either freely (aglycones) or as glycosides. • Isomers • Anthrone: Parent structure (pale yellow, non-soluble in alkali, non-fluorescent) • Anthronol: brown-yellow, soluble in alkali, strongly fluorescent • Anthronol derivatives (e.g. in Aloe – have similar properties – fluorescence used for identification)

8. Oxanthrones • Found in Cascara bark • Intermediate products (between anthraquinones and anthranols) • When oxidised  form anthraquinones • Accomplished via Modified Borntrager’s Test (oxanthrones oxidised using hydrogen peroxide)

9. Derived from 2 anthrone molecules 2 molecules may/not be identical Form easily due to mild oxidation of anthrones Form important aglycones Cassia Rheum Rhamnus Dianthrones

11. Definition: Consists of the dried leaflets of Cassia senna (Alexandrian senna), or Cassia angustifolia (Tinnevelly senna). Senna - Leguminosae

12. Indigenous to Africa (tropical regions) Used since 9th – 10th century Introduced into medicine by Arab physicians (used both the leaves and pods) Exported by Alexandria – name of the Sudanese drug. Cassia spp - Senna

13. Collected in September Whole branches bearing leaves are dried in the sun. Pods and large stalks are separated with sieves. Leaves are graded (whole leaves, whole leaves and half-leave mix, siftings). Whole leaves – sold to public Rest – used for galenicals. Senna - Collection

14. Senna - Constituents • 2 active glycosides: Sennoside A Sennoside B • Both hydrolyse: 2 molecules glucose + aglycones: Sennidin A and Sennidin B. • Sennoside C & Sennoside D • Rhein • Aloe-emodin • Palmidin A (Rhubarb)

16. Kaempferol (yellow flavanol) + glucoside (kaempferin) Mucilage Calcium oxalates Resin Senna - Constituents

17. Macroscopical Seldom larger than 4 cm in length Grey-green Asymmetric at base Broken and curled at edges Few press markings Macroscopical Seldom exceeds 5cm in length Yellow-green Less asymmetric at base Seldom broken and normally flat Often shows impressions (mid vein) Comparison of Alexandrian and Tinnevelly Senna

18. Microscopical Hairs – numerous (approximately 3 epidermal cells apart) Most stomata have 2 subsidiary cells Microscopical Hairs less numerous (approximately 6 epidermal cells apart) Stomata have 2-3 subsidiary cells with the respective ratio 7:3 Comparison between Alexandrian and Tinnevelly Senna

19. Chemical Tests Ether extract of hydrolysed acid solution of herb with methanolic magnesioum acetate solution gives Pink colour in daylight Pale green-orange colour in filtered UV light Chemical Tests Same Test Orange colour in daylight Yellow-green colour in filtered UV light Comparison between Alexandrian and Tinnevelly Senna

20. TLC Hydroxymusizin glycoside present TLC Tinnevellin glycoside present Comparison between Alexandrian and Tinnevelly Senna

21. Bombay, Mecca and Arabian Sennas (found in Cassia angustifolia from Arabia). Dog senna – Cassia obovata Cassia auriculata – Indian Senna Cassia podocarpa Substitutes or Adulterants Argel leaves – Solenostemma argel Coriario myrtifolia Senna – Allied Drugs &Substitutes

22. Definition: Senna pods are the dried, ripe fruits of Cassia senna and Cassia angustifolia, which are commercially known as Alexandrian and Tinnevelly senna pods respectively. Both have separate monographs Senna Fruit

23. Pods are collected with the leaves and dried in a similar fashion. After separation of the leaves, the pods are hand-picked into various qualities, the finer being sold (commercially), while the finer pieces are used to make galenicals. Senna Fruit - Collection

24. Active constituents – found in the pericarp Similar to those actives of the leaves Sennoside A Sennidin Senna Fruit - Constituents

25. Senna - Uses • Laxatives (habitual constipation or occasional use). • Lacks astringent after-effect (Rhubarb)

26. Medicinal Actions Vermifuge, diuretic, febrifuge Other uses: laxative candy (bitter taste). Also used to treat flatulence, gout, fever. Topically: poultice prepared with vinegar to treat pimples. NOTE: Senna may cause urine to become reddish – no clinical significance. Contra-indications Gout, colitis, GI inflammation. Should not be used with cardiac glycosides. Seeds/pods give gentler action than leaves: more appropriate for the young, elderly and those prone to stomach cramps. NB: Over-use causes dependency. Overdose: nausea, bloody diarrhoea, vomiting and nephritis. Long-term use: dehydration & electrolyte depletion, worsening constipation and weakening intestinal muscles. Senna - Additional

27. Definition: Official cascara sagrada is the dried bark of Rhamnus purshianus. Bark is collected from wild trees (depletion is leading to the increase of cultivation) Cascara Bark- Rhamnaceae

28. Etymology Rhamnos – Greek, branch, shiny shrub. Purshiana after Pursh, botanist 1st described herb in 1814. Other Common Names Bearwood, bitterbark, buckthorn, coffeeberry, mountain cranberry, persiana, sacred bark. Rhamnus purhsianus - Cascara

29. Recently introduced to Modern Medicine. Known to early Mexican and Spanish priests. Not introduced to medicine until 1877. Cascara Bark - History

30. Collected form mid-April to end of August, when it separates readily from the rest of the trunk. Longitudinal incisions are made 10cm apart and the bark removed. Tree is then usually felled and the branch bark separated. Bark is then dried in the shade with the cork facing upwards. This is referred to as ‘natural’ cascara. Commercial supplies are comminuted to give small, even fragments called ‘evenized’, ‘processed’, or ‘compact’ cascara. Cascara – Collection & Preparation

31. Cascara Bark - Storage • During preparation and storage the bark should be protected from rain and damp (partial extraction of constituents may occur or bark may become mouldy). • Should be stored for at least 1 year before use (although no longer a BP requirement). • Bark appears to increase in medicinal value up unto its 4 years old (stored bark)

32. When stored for at least a year – better tolerated by patient (less griping pains due to increased peristalsis) Yet as effective as fresh bark. Reason? Due to Hydrolysis and other changes that occur during storage. Bitter taste of Cascara can also be reduced by treating the bark with alkali (alkali earths or MgO). Cascara Bark – Why Stored for a Year?

33. Cascara Bark – Constituents 1 • 4 main glycosides – Called Cascarosides • Cascaroside A • Cascaroside B • Cascaroside C • Cascaroside D

34. Cascara Bark – Constituents 2 • 2 aloins: • C – Glycosides • Breakdown products of Cascarosides A-D • Barbaloin (derived from aloe-emodin) • Chrysaloin (derived from chrysopanol anthrone)

35. Cascara Bark – Constituents 3 • O-glycosides • Derived from • Emodin • Emodin oxanthrone • Aloe emodin • chrysophanol

36. Cascara Bark – Constituents 4 • Dianthrones • Those from • Emodin • Aloe-emodin • Chrysophanol • Hetrodianthrones • Palmidin A, B and C (Rhubarb)

37. Cascara Bark – Constituents 5 • Emodin • Aloe-emodin • Chrysophanol (in the free state)

38. Cascara Bark - Substitutes • Rhamnus alnifolia (too rare) • Rhamnus crocea (bark is very different from official drug) • Rhamnus californica (so closely related to Rhamnus purshianus some botanists do not consider them to be separate species). • Rhamnus fallax

39. Cascara Bark - Uses • Purgative • Similar to Senna • Normally as a tablet • Also used on animals

40. Physiological Action Astringent (bark – tannins), bitter tonic, chologogue, emetic, hepatic, stomachic. Medicinal Uses Move stagnation, clear heat. The most widely used laxative world-wide. Topically: Used as a wash for herpes lesions Excessive use: nausea, vomiting, heamatorrhoea. Long term use: Weakens intestinal muscles. Contra-indications: children younger than 14, during pregnancy, lactation, IBS, Crohn’s, intestinal obstruction, and idiopathic abdominal pain. Cascara Bark – Additional

41. Definition: Rhubarb/Chinese Rhubarb is the rhizome of Rheum palmatum. Other species and hybrids of Rheum, exceptR. rhaponticum, may also be included. Rhubarb - Polygonaceae

42. Chinese Rhubarb has a long history. Mentioned in a herbal of 2700BC. Formed an important article of commerce on the Chinese trade routes to Europe. Still used medicinally today. Chinese Rhubarb - History

43. Rhizomes are grown at high altitudes (+3000m). Collected in Autumn or spring (6-10yrs old) Cork is removed, cut. Artificially dried. Packed in tin-lined wooden cases. Inferior quality herbs are packed in hessian bags Chinese Rhubarb – Collection & Preparation

44. Anthraquinoneswithout a carboxyl group – chrysophanol, emodin, aloe-emodin & physcion. Also the glycosides of these substances. 2. Anthraquinoneswith a carboxyl group (rhein and its glycoside: glucorhein). Chinese Rhubarb - Constituents

45. Anthrones and dianthrones of chrysophanol, emodin, aloe-emodin or physcoin. 4. Dianthrone glucosides of rhein (Sennosides A and B). 5. Hetrodianthrones derived from 2 different anthrone molecules: Palmidin A and Palmidin B. Chinese Rhubarb - Constituents

46. Free anthraquinones: chrysophanol, emodin, aloe-emodin and rhein. Some of the above constituents may also occur as glycosides. Chinese Rhubarb - Constituents

47. Bitter stomachic Diarrhoea (low doses) – contains tannins Purgative (high doses) – followed by an astringent effect. Suitable only for occasional for occasional use, not for chronic constipation. Chinese Rhubarb - Uses

48. Etymology Rheo – Greek, ‘to flow’, in reference to the purgative properties. Medicinal Actions Anti-helminthic, anti-bacterial, anti-inflammatory, antiseptic, astringent (low doses), sialagoge, vulnerary Topical Uses: Poultice to treat boils, burns, wounds. Used to stop bleeding (tannins – stypic and astringent). Used as a mouthwash for oral ulcers. Other uses: Acid content: fresh root can be used to polish brass. Caution Leaves should be avoided – high calcium oxalate - toxic Rhubarb - Additional

49. Definition: Aloes are the solid residue obtained by evaporating the liquid which drains from the transversely cut leaves of various Aloe species. The juice is usually concentrated by boiling and solidifies on cooling. Official varieties are the Cape Aloes from SA and Kenya (Aloe ferox), and the Curacao Aloes from West Indies (Aloe barbadensis). Aloe - Liliaceae

50. Preparation of Cape Aloes Cape Aloes are prepared from the wild plants of Aloe ferox. Leaves are cut transversely near the base. 200 leaves arranged around a shallow hole in the ground (lined with canvas or goatskin). Cut ends overlap & drain into the canvas. After 6hrs all the juice is collected. Transferred to a drum. Boiled for 4hrs on an open fire. Poured into tins while hot  solidifies.