PHARMACOGNOSY II PHAR306 6th Semester 9th Lecture Prof. Dr. Müberra Koşar Ass. Prof. Dr. Aybike Yektaoğlu Eastern Mediterranean University Faculty of Pharmacy Department of Pharmacognosy QUINOLINE ALKALOIDS QUINOLINE ALKALOIDS quinoline quinine, quinidine, Cinchona spp. (Rubiaceae), cinchonine, Remijia spp. (Rubiaceae) cinchonidine Angostura or cusparia bark, cusparine Galipea officinalis (Rutaceae) CINCHONA sp. (RUBIACEAE) • "quina tree" • C. pubescens (syn. C. succirubra), C. calisaya, C. ledgeriana or varieties and hybrids of these species whole or cut, dried barks • Cinchona cortex (Eur.Ph.) • besides bark of the stem also bark of the root carries alkaloids CINCHONA sp. (RUBIACEAE) • Cinchonae cortex according to the Eur.Ph. the stem bark should not contain less than 6.5% alkaloids • carries 30-60% quinine-type alkaloids • Cinchona bark and alkaloids (quinine) have been used to treat malaria • quinine was used as molecular model in the development of synthetic drugs used against malaria CINCHONA sp. (RUBIACEAE) • naturally in tropical America (Peru, Bolivia, Colombia, Ecuador) growing large trees • is cultivated in South-East Asia and Africa CINCHONA sp. - COMPOSITION • the bark of the plant carries quinoline alkaloids • the composition from the bark contains the major stereoisomers quinine and quinidine and their 6-demethoxy derivatives cinchonidine and cinchonine respectively • other alkaloids quinezine and cinchonizine, etc. • alkaloid amount and ratio can vary according to the different species and hybrids. The environment in which the tree grows, age, bark and collecting method is also affecting the alkaloid amount and the ratio CINCHONA sp. - COMPOSITION • alkaloids are found in the bark parenchyma as salts of quinic acid (5-8%) and cinchotannic acid • cinchotannic acid is a pholabaphane decomposition product is present relatively in high amounts in the bark "red cinchona" quinic acid CINCHONA sp. - COMPOSITION • other components quinovine (up to 2%) is a glycoside through hydrolysis quinovaic acid and qiunovose is formed • through the infection of the plant with the Phytophthora cinnamomi alkaloid production decreases formation of anthraquinones (results as a defense product of phytoalexin mechanisms) CINCHONA sp. (RUBIACEAE) • C. succirubra (syn. C. pubescens) Red Cinchona “Cinchona rubra” • C. calisaya, C. ledgeriana Yellow Cinchona “Cinchona flava” APPLICATION • for a long time Cinchona extracts enters into the composition of appetizing tonic for its bitter taste and into the composition of the syrup as stomachic • due to its astringent effect, its decoctions and acid infusions are used as mouthwash • quinine possesses strong antipyretic effects • in addition quinine has potent antimalarial effect against Plasmodium vivax and other Plasmodium species forming malaria QUININE • before II. world war quinine was used to treat malaria. But with the development of synthetic antimalarial compounds derivatives are used today in large quantity • however, in the third world countries resistance against chloroquine and similar synthetic compounds has been developed (used in the treatment of the Plasmodium falciparium infections). Therefore, the quinine is still in use as an important drug in therapy QUINIDINE • quinidine is antiarrhythmic effective • used in the treatment of prophylaxis of cardiac arrhythmias and in the atrial fibrillation • also quinidine has antimalarial effect and is effective against chloroquine resistant organisms Longacor® Natisedine® Quinicardine® ISOQUINOLINE ALKALOIDS isoquinoline papaverine, narceine, narcotine Papaver somniferum (Papaveraceae) coridaline Corydalis and Dicentra spp. (Fumariaceae) many of the genus of Berberidaceae, Ranunculaceae hydrastine, berberine Papaveraceae emetine, sefaline Cephaelis spp. (Rubiaceae) tubocurarine curare obtained from the Menispermaceae plants morfine, codeine Papaver somniferum (Papaveraceae) erythraline Erythrina spp. (Leguminosae) galantamine Leucojum aestivum (Amaryllidaceae) PAPAVER SOMNIFERUM (PAPVERACEAE) • “poppy” • an annual, 50-150 cm in height, herbaceous plant • stems and leaves dull green • leaves shortly periolate but above sessile and amplexicaul • flowers with 2 sepals (caducous) • flattened globe-shaped fruit is a capsule PAPAVER SOMNIFERUM (PAPVERACEAE) there are two subtypes of Papaver somniferum: • P. somniferum subsp. spontaneum (Poppy) (holes in the top of the capsule is opened by ripening and the seeds are poured into the soil) • P. somniferum subsp. anatolicum (Blind poppy) (capsules does not open at maturity) varieties: • var. album (white flowers) • var. nigrum (purple flowers) • var. setigerum (dark purple flowers) • var. glabrum (red-purple flowers) PAPAVER SOMNIFERUM (PAPVERACEAE) • plant is cultivated: in Turkey, Australia, France, Spain, India, Hungary, in recent years the Czech Republic and China have been legally producting poppy as well • In Turkey: cultivated species of P. somniferum subsp. anatolicum: var. album (white flowers) var. nigrum (purple flowers) since the very earliest time in Anatolia the plant has been cultivated PAPAVER SOMNIFERUM (PAPVERACEAE) • alkaloid content in capsules are used in the treatment • seeds are used in the manufacturing of cooking oil and food, the pulp is used as animal feed • alkaloids found in pericarp of the capsule are important pharmaceutical raw materials, such as particularly morphine, especially papaverine, thebaine and codeine alkaloids • morphine and heroin derived from morphine has been widely used in the world even they are prohibited OPIUM (EP) • obtaining of opium starts early in the morning with scratching of the yet ripening capsule • there should be enough scratching depth ‘til the mesocarp but capsule must not be ruptured. Latex coming out from the capsule at the beginning is smooth and light coloured. This latex flows out from the capsule after scratching as droplets and are collected. Toward evening, the colour darkens and browns OPIUM (EP) • darkening opium is collected by peeling with a help of a special knife called opium knife (with a broad face). The pellets are wrapped in a poppy leaves and allowed to dry • raw opium is an aromatic compound, ranging from yellow to brown and to black in colour as fresh elastic and when dried hardening mass FORMS REGISTERED IN THE EUR. PH. • Opium, raw (Opium crudum) is the starting material for the preparation of galenic preparations • Opium dry extract, standardised (Opii extractum siccum normatum) is prepared from raw opium. 19.6-20.4% morphine, must contain 2% codeine • Opium, prepared (Opii pulvis normatus) is the raw opium powder, dried at a temperature not exceeding 70 °C should carry 9.8-10.2% morphine and minimum 1% codeine • Opium tinctura, standardised (Opii tinctura normata) is prepared from raw opium. Should contain 0.95-1.05% morphine and min. 0.1% of codeine. Is prepared with equal volumes of ethanol (70% v / v) / water OPIUM • The main producers of legal opium poppy cultivation in some countries – Turkey 48% – India 14% – France 10% – Australia 8% – Spain 8% – Hungary 7% – Other 5% • World production of opiate raw materials equivalent to morphine – Australia 23% – France 19% – Turkey 18% – Spain 16% – India 13% – Hungary 6% – Other 5% OPIUM - COMPOSITION • 10-25% total alkaloid (up to 40 alkaloids) • 5-25% morphine, 0.5-3% codeine, 2-10% noscapine • 0.5-2.5% papaverine , 0.2-1% Thebaine • morphinan derivative (phenanthrene): morphine, codeine, thebaine • benzylisoquinoline derivative: papaverine, laudonine • phthalyl isoquinoline: noscapine (narcotine) • sequo phthalyl isoquinoline : narceine • N-methylisoquinoline: cotarnine, hydrocotarnine • protopine: protopine, cryptopine • in plant: organic salts such as meconic, lactic, fumaric acid are also found DETERMINATION OF OPIUM ALKALOIDS morphine • alkaloid extract + Marquis reagent (con. sulfuric acid + formaldehyde) purple colour codeine • alkaloid extract + Froehd reagent (conc. sulfuric acid + sodium molybdate) green brown colour narcotine • alkaloid extract + sulfuric acid + nitric acid red colour EFFECT AND APPLICATION morphine • narcotic analgesic (pain reduction, induces sleep) effect • used orally or parenterally as morphine hydrochloride, sulfate or tartrate salts • before and after surgical operations, in the terminal pain of cancer patients • stops diarrhea by suppressing peristalsis movements • develops tolerance and is addictive EFFECT AND APPLICATION codeine • has analgesic effect. However, has less narcotic analgesic effect than morphine • is used as phosphate salt • shows synergistic effect with other analgesics (acetaminophen, etc.) • used because of its antitussive effect • addictive EFFECT AND APPLICATION papaverine • has relaxing effect on smooth muscle • in GIS spasms, in bronchial asthma used as antispasmodic • used as HCl salt noscapine • has antitussive effect • used as HCl salt • does not create dependency EFFECT AND APPLICATION apomorphine • morphine + HCl apomorphine (- H2O ) • has emetic effect • used as HCl salt ethylmorphine (dionine) • has antitussive effect • used as HCl salt DIACETYLMORPHINE (HEROINE) • is a semi-synthetic derivative of morphine • in 1898 released by Bayer Pharmaceuticals as non-addicting compound that is more effective than morphine and codeine • However, is six times more addictive than morphine • used in tonics, pain relievers and cough syrups between 1898-1914 • 1914 onwards are considered as an illegal drug in the United States FUMARIA OFFICINALIS (FUMARIACEAE) • "earth