Indole alkaloids Pharmacognosy III Mosul University/ college of Pharmacy By: Noor Hisham Al Atraqchi Indole alkaloids : Numbers of important alkaloids posses an indole ring as part of their structure. The important drugs and their alkaloids of the indole group are: • Rauwolfia reserpine • Nuxvomica strychnine and brucine • Physostigma physostigmine • Catharanthus (Vinca) vinblastine and vincristine • Ergot ergotamine and ergomatrine Rauwolfia serpentine Rauwolfia consists of the dried rhizome and roots of Rauwolfia serpentiana. (Apocynaceae), a small shrub found in India, Pakistan, Burma and Thailand Constituents Rauwolfia contains at least 30 alkaloids which total some 0.7-2.4% , e.g.: o ajmaline ,(rauwolfine) o ajmalinine o ajmalicin o serpentine o serpentinine o The chief therapeutically important alkaloids are reserpine. Other substances present include phytosterols, fatty acids, unsaturated alcohols and sugars. Uses Rauwolfla preparations and reserpine used in the management of essential hypertension and in certain neuropsychiatric disolders. Ajmaline. which has pharmacological properties similar to those of quinidine.is marketed in Japan for the treatment of cardiac arrhythmias Ajmalacine is mostly used as antihypertensive and anti-ischemic agent (both central and peripheral). It has a broad application in the relief of obstruction of normal cerebral blood flow. Catharanthus Or Vinca • is the dried whole plant of catharanthus roseus. F. Apocynaceae. • Folklore uses as an oral hypoglycemic agent. • It contain 150 alkaloids, the most important are the anticancer agents vincristine and vinblastine. • These are complex bisindole (dimeric indole) natural products present in small quantities in the plant material. • Actions and uses Vincristine and vinblastine are mitotic inhibitors, arrest cell division at metaphase. They act by binding to the protein tubulin in the mitotic spindle, preventing polymerization and assembly into microtubule, thus stopping the cell from separating its chromosomes during the metaphase; the cell then undergoes apoptosis. Vinblastine is used mainly for the treatment of generalized Hodgkin's disease and non-Hodgkin's lymphomas. Vincristine is used principally in the treatment of acute lymphocytic leukaemia in children. It has other applications for lymphomas, small cell lung cancer cervical and breast. Vincristine has a superior antitumor activity compared to vinblastine but is more neurotoxic OH N CH2CH3 .H2SO4 N H COOCH3 N CH2CH3 H H3CO N H HO R COOCH3 COOCH3 R= CH3 Vinblastine sulfate R= CHO Vincristine sulfate Nux vomica Dried ripe seed of strychnus nux vomica F. Loganiaceae. Nux vomica usually contains about 1.8-5.3% of the indole alkaloids strychnine and brucine. Strychnine is physiologically much more active than brucine and the seed are therefore assayed for strychnine and not for total alkaloids . They usually contain about 1.23% of strychnine and about 1.55% of brucine. Uses • The action of the whole drug closely resembles that of strychnine. The alkaloid was formerly used as a circulatory stimulant in such cases as surgical shock, but its use is now more limited to that of a respiratory stimulant in certain cases of poisoning. • Like other bitters, strychnine improves the appetite and digestion, but it has been considerably misused as a general tonic. • Brucine: Is less toxic than strychnine and used commercially as an alcohol denaturant Calabar beans Is dried ripe seed of physostigma venenosum (F. leguminosae) ‘ Constituents : Contain several alkaloids : Physostigmine (eserine), eseramine, geneserine. Isophysostigmine physovenine, Norphysostigmine Calabatine and calabacine The structure of geneserine, long regarded as an N-oxide, has been revised to include the oxygen in a ring system. The chief alkaloid, physostigmine, is present to the extent of about 0.15%. It is derived from tryptophan. On exposure to air it oxidizes into a red compound, rubreserine, and should therefore be protected from air and light. The official salt, the salicylate, is more stable than the sulphate and is non-deliquescent. Actions and uses of Physostigmine or eserine: It reversibly inhibits AChE (choline esterase) and enhance the effect of endogenous acetyl choline. Physostigmine salicylate is used for contracting the pupil of the eye, often to combat the effect of mydriatics Physostigmine is used in the treatment of overdoses of drugs with anticholinergic actions, such as atropine. It has also been investigated as an intravenous injection for reversing the effects of a number of sedatives. For Alzheimer's disease : it has shown some evidence of inducing a slight improvement in intellectual and cognitive performance. Ergot alkaloids Ergot (Ergot of Rye) is the dried sclerotium of a fungus, Claviceps purpurea (Clavicipitaceae), arising in the ovary of the rye, Secale cereale. Controlled field cultivation on rye is the main source of the crude drug. Constituents of Ergot Cultivated ergot may contain up to 0.5% of total alkaloids, and 0.15% is a minimum commercial value. The ergot alkaloids (ergolines) can be divided into two classes: (1) the clavine type alkaloids, which are derivatives of dimethylergoline . (1) 6,8- the lysergic acid derivatives. which are peptide alkaloids. It is the latter class that contains the pharmacologically active alkaloids that characterize the ergot sclerotium Six pairs of alkaloids predominate in the sclerotium and fall into either the water-soluble ergometrine (or ergonovine) group or the waterinsoluble ergotamine and 'ergotoxine' groups. Uses Although whole ergot preparations were traditionally used in labour to assist delivery and to reduce post-partum hemorrhage, ergot itself has been largely replaced in the pharmacopoeias by the isolated alkaloids. Only ergometrine produces an oxytocic effect ergotoxine and ergotamine having quite a different action. Ergometrine is soluble in water or in dilute alcohol. It is often known, particularly in the USA, as ergonovine Ergotamine and the semisynthetic dihydroergotamines salts are employed as specific analgesics for the treatment of migraine. Drug in pharmacy: ergotamine and used with caffeine for treatment of migraine headache both act as cerebral vasoconstrictors. Lysergic acid diethylamide (LSD-25), prepared by partial synthesis from lysergic acid, is a potent specific psychotomimetic, cause CNS stimulation and it is drug of abuse .