Plants containing toxic alkaloids

1. Plants containing toxic alkaloids

2. Ergot Alkaloids Opium Alkaloids

3. Ergot Alkaloids • Ergot refers to a group of fungi of the genus Claviceps. • The most prominent member of this group is Claviceps purpurea . • Parasitic on different grasses and cereals Fam. Graminae (Poaceae).

4. Ergot • Ergot is the fungus, at the sclerotium stage. • Claviceps purpurea most commonly affects species such as rye, wheat and barley الشعير. • It affects oats الشوفانonly rarely. • Ergot of rye (Secale cornutum) is the variety used medicinally. • Controlled field cultivation on rye is the main source of the crude drug.

5. Life cycle • An ergot sclerotium develops when the ovary of floret of grass or cereal is infected by spores of a fungal species of the genus Claviceps. • The proliferating fungus destroys the plant ovary and connects with the vascular tissue of the plant.

6. The first stage of ergot infection is a white soft tissue (known as sphaceliastage) producing sugary honeydew (sugar-rich sticky substance), which often drops out of the infected ovaries. • This honeydew contains millions of spores which are dispersed to other florets by insects. • Later, the sphacelia convert into a hard dry sclerotium inside the ovaries. • At this stage, alkaloids (mycotoxins) accumulate in the sclerotium.

7. When a mature sclerotium drops to the ground, the fungus remains dormant until proper conditions (onset of spring, rain period, climate etc). • It germinates, forming one or several fruiting bodies with head and stalk. • In the head, spores are formed, which are ejected simultaneously (at the same time).

8. Ergot fungus on wheat

9. Ergot mycotoxins • The ergot sclerotium contains high concentrations of alkaloids. • They contains (up to 2% of dry mass) of the ergot alkaloids (ergolines).

10. Ergot mycotoxins • They are medicinally important indole alkaloids. • Biogenetically they are derived from the amino acid tryptophan.

11. Indole • Tryptamine • Tryptophan

12. Classification • There are two main groups of ergot alkaloids : • A-The clavine type . • B-The lysergic acid derivatives type.

13. Classification (cont.) • B- The lysergic acid derivatives group is further subdivided into: • i- The simple lysergic acid amides (lysergic acid and simple amine) • ii- The polypeptide alkaloids (complex amides of lysergic acid with several different amino acids).

14. Ergot alkaloids Clavine type Lysergic acid type Simple LS Amide Polypeptide Amide

15. Ergot alkaloids • The clavine type alkaloids as well as the lysergic acid derivative alkaloids are product of condensation of tryptophan (or tryptamine) with isoprenyl moiety ( 5 Carbons ) • Ergot alkaloids

16. A-The clavine type alkaloids • Alkaloids of this class all end with the suffix (-clavine) e.g. agroclavine, elemoclavine….. • They are all simple water soluble bases. • Not physiologically active as the lysergic acid derivatives. • Recently few examples show significant oxytocic activity. • Agroclavine is a powerful uterine stimulant.

17. Example of clavine type alkaloids • Agroclavine

18. The Peptide Bond • A peptide bond is a covalent bond that is formed between two molecules of amino acids. • When the –COOH gp. of one molecule reacts with the –NH2 gp. of the another molecule, releasing a molecule of water. • This is a condensation reaction and usually occurs between amino acids. • The resulting O=C- NH bond is called a peptide bond, and the resulting molecule is an amide.

19. Formation of the peptide bond • The carboxylic acid group of one amino acid reacts with the amine group of the other. For example, two amino acids (glycine) combining through the formation of a peptide bond to form a dipeptide.

20. Amide O O NH3 • R C OH R C NH2

21. Peptides • Peptide includes wide range of compounds. • Varying from low to very high molecular wt. • The lowest members are derived from two molecules of amino acids.

22. Peptides (cont.) • Any number of amino acids can be joined together in chains called polypeptides. • Over 100 amino acids called proteins. • A number of hormones, antibiotics, antitumor agents and neurotransmitters are peptides (proteins).

23. Ergot alkaloids Clavine type Lysergic acid type Simple LS Amide Polypeptide Amide

24. B-The lysergic acid derivatives i-The simple lysergic acid amides • All are water soluble alkaloids. • Low molecular weight. • All are amides of lysergic acid with simple amines.

25. NH3 • (+)lysergic acid Ergine

26. The simplest naturally existing is ergine (lysergic acid amide, LSA) and erginine (isolysergic acid amide). • Ergine is a psychoactive component, it is known as natural LSD. • The semithynthetic LSD is more potent than ergine as a psychedelics drug. • Psychedelics are part of a wider class of psychoactive drugs known as hallucinogens.

27. i-The simple lysergic acid amides (cont.) • The most important members of this group is the potent oxytocic alkaloid ergometrine (ergonovine in USA). • Ergometrine (Ergonovine) is the amide of lysergic acid with 2-amino propanol. • And the famous hallucinogen (LSD) lysergic acid diethylamide. • LSD is a semisynthetic drug with a very potent action on the CNS in extremely small doses.

28. LSD • LSD was first semi-synthesized by Albert Hofmann in 1938 from ergot. • The short form LSD comes from its early code name LSD-25, which is an abbreviation for the German "Lyserg Säure-diethylamid" followed by a sequential number. • It is commonly semi-synthesised by: • reacting diethylamine with lysergic acid. • or from ergine (lysergic acid amide, LSA).

29. General structure of lysergic acid amides

30. Ergometrine • Is a potent oxytocic alkaloid. • Contraction of uterus. • Facilitate labour. • Prevent postpartum hemorrhage. • Metre رحم

31. ii-The polypeptide lysergic acid amides • Complex in structure. • High molecular weight. • Water insoluble. • They are build up from a lysergic acid moiety forming an amide with a complex polycyclic polypeptide moiety. • The polypeptide moiety is formed of three different amino acids.

32. The polypeptide alkaloids(cont.) • From this group are the ergotamine and the ergotoxine alkaloids. • Ergotamine has been used extensively to relieve migraine headaches through the constriction of blood vessels.

33. Lysergic and isolysergic acid alkaloids • Members related to lysergic acid (e.g.ergotamine and ergometrine). • They are levorotatory. • Pharmacologically more active. • Designated by the suffix “– ine” • Members related to isolysergic acid(e.g. ergotaminine and ergometrinine). • They are dexorotatory. • Pharmacologically less active. • Designated by the suffix “– inine”

34. Medical applications • Ergot alkaloids have a wide range of biological activities. • 1- Ergotamine is used in the treatment of migraine. • It has the ability to constrict dilated blood vessels in the cerebral membranes. • Hypertension is a side effect. • 2- Ergometrine is used after childbirth –after expulsion of the placenta– to stimulate uterine contractions and to prevent postpartum hemorrhage.

35. Medical applications (cont.) ● Some ergot alkaloids are used in the treatment of dementia (brain disorders and psychosis).

36. Ergotism (ergot poisoning) • Ergotism is due to consuming cereals contaminated with the fungus. • Ergotism is the effect of long-term ergotpoisoning. • More recently by the action of a number of ergoline-based drugs.

37. Ergotism, other sources • Similar toxins are present in certain plants. • The seeds of the Ipomoea tricolor and Rivea corymbosa (Convulvulaceae) • It is structurally related to ergot alkaloids.

38. Ergotism, synonyms • It is also known as ergotoxicosis, ergot poisoning, ergot intoxication.

39. Dose-dependent ergotism • Human disease can occur when cereals contains 1% ergot. • An ergot content of 2% can result in epidemics . • At 7% there is a high mortality rate (dose dependent) . • Alkaloids can also pass through lactation from mother to child, causing ergotism in infants.

40. Ergotism, clinical aspects • People who ingest ergot mycotoxins with their food may develop various symptoms. • The symptoms can be divided into: • 1- Convulsive symptoms (neurological) . • 2- Gangrenous symptoms (vasospastic or spasm of blood vessels). The effect is upon circulation.

41. 1- Neurological Convulsivesymptoms • Usually the gastrointestinal effects precede central nervous system effects. • There is diarrhea, itching, headaches, nausea and vomiting. • There will be mental confusion with hallucinations (resembling those produced by LSD ), for instance seeing brightly coloured objects, wild animals, or visions of blood running down the walls. • The victim has involuntary muscular contractions, convulsions (seizure).

42. Neurological symptoms (cont.) • Seizures are symptoms of abnormal electrical activity in the brain. . • These convulsions end to an extreme arching of the back, with the head thrown backwards, even touching the heels. • The convulsive symptoms are caused by clavinealkaloids and simple lysergic acid derivatives. • The victims describe a pronounced burning or itching sensation of the skin or a tingling like insects crawling under the skin.

43. Neurological symptoms • Gastrointestinal disturbances. • Central nervous system effects. • Hallucinations. • Convulsions (seizure). • Pronounced burning or itching sensation of the skin.

44. 2- VasospasticGangrenoussymptoms • Gangrene is the result of vasoconstriction induced by the ergotamine alkaloids of the fungus. • It affects the more poorly vascularized distal structures, such as the fingers, hands, feet, ears and nose. Symptoms include weak of pulse, loss of peripheral sensation, death and loss of the affected tissues.

45. General ergotism symptoms Intense pain in the lower abdomen, low body temperatures and cold fingertips, extreme convulsions, hallucinations and burning skin sensation .

46. Ergotism, historical overview • In middle ages, ergotism is known to have occurred on a large scale in some regions of Europe. • In 857, for example, there was an epidemic in Germany characterized by necrosis of limbs and culminating in death. • In 944, some 40,000 people in the south of France died from ergot poisoning. • Between 837 and 1347, some fifty epidemics were recorded in Central Europe.

47. Ergotism, historical overview (cont.) • It was a common belief that the symptoms were caused by witchcraft. • In the Salem witchcraft (USA), entire communities in and around Salem Village had symptoms of ergotism (including some animals). • Rumors soon spread that witchcraft was involved, but subsequent investigation showed that the symptoms had been caused by ergotism.

48. Ergotism, historical overview (cont.) ● In 1670, a French physician, Dr Thuillier, suggested that food could play a role in this disorder. • Later, others showed that when ergot was fed to animals, they died. • All the victims had eaten rye bread. • In August 1951, in France more than a hundred people were poisoned and several died as a result. • During the 1st half of the twenty century an intoxication have been reported in Egypt and was owed to ergot-contaminated wheat flour.

49. Ergotism, treatment • In acute poisoning with a risk of gangrene, treatment consists of vasodilators, anticoagulants and low molecular weight dextrans (plasma expander). • If necessary, a sympathetic nerve blockade may be carried out. • (Sympathetic nervous system causes vasoconstriction) • Temporary sedation will be necessary in hallucination (e.g. haloperidol, major tranquillizer). Diazepam (minor tranquillizer is used for convulsions). • There is no specific antidote.

50. A floatation method can be used to separate the infected grains from the non-infected grains . • The grain is immersed in a 30% KCl solution. • The infected grains are lighter and float to the surface. • They can then be skimmed off and destroyed. • There are no ergot-resistant cereal varieties currently available. • Fungicides may be used.