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 QUINOLINE ALKALOIDS

quinoline quinine, quinidine, spp. (), 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  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 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.

• 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® ALKALOIDS

isoquinoline , , narcotine Papaver somniferum () coridaline Corydalis and Dicentra spp. (Fumariaceae) many of the of Berberidaceae, Ranunculaceae hydrastine, Papaveraceae emetine, sefaline Cephaelis spp. (Rubiaceae) tubocurarine curare obtained from the Menispermaceae morfine, 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 , especially papaverine, and codeine alkaloids

• morphine and heroin derived from morphine has been widely used in the world even they are prohibited (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% • 0.5-2.5% papaverine , 0.2-1% Thebaine

• morphinan derivative (): morphine, codeine, thebaine • benzylisoquinoline derivative: papaverine, laudonine • phthalyl isoquinoline: noscapine (narcotine) • sequo phthalyl isoquinoline : narceine • N-methylisoquinoline: cotarnine, hydrocotarnine • : protopine,

• 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 smoke" Fumariae herba (EP) • above-ground parts of the plant, collected and dried on flowering time • annual herbaceous plant, grows widely in Europe

• carries isoquinoline type alkaloids: – protoberberines – spirobenzylisoquinolines – benzophenanthridines – indenobenza zepines

• protopine is the major alkaloid FUMARIA OFFICINALIS (FUMARIACEAE)

• protopine: has spasmolytic, anticholinergic, antiarrhythmic, and antibacterial effects

• raw material is used due to its choleretic effect

protopine (PAPAVERACEAE)

• "tetterwort" Chelidonium herba (EP) • above ground parts are collected and dried on flowering time • perennial herbaceous plant, grown widely in all over Europe, Asia, United States CHELIDONIUM MAJUS (PAPAVERACEAE)

• Chelidonium herba (EP)

• carries 4% alkaloid

• a- and b-, berberine, , protopine alkaloids etc.

• raw material has many traditional use; analgesic, antispasmodic, diaphoretic, diuretic, narcotic and purgative

• homeopathic use in Chinese medicine HYDRASTIS CANADENSIS (RANUNCULACEAE)

• Hydrastis rhizoma (EP)

• dried root and rhizome of the plant

• small, a perennial plant

• grown in Canada and the United States

• plant is under protection

• cultivated in U.S. and European contries in order to obtain the raw material HYDRASTIS CANADENSIS (RANUNCULACEAE)

• raw material contains hydrastine, berberine, (tetrahydroberberine)

• commercial raw material  1.5-4% hydrastine and 0.5-6.0% berberine

• according to the Eur.Ph.  2-5% hydrastine and 3% berberine HYDRASTIS CANADENSIS

• hydrastine has haemostatic effect. Therefore, hydrastine HCl and hydrastinine HCl is used in the control of uterine hemorrhage

hydrastine berberine CURARE

• Chondrodendron sp. (Menispermaceae)

• Strychnos sp. (Loganiaceae)

• curare: used by the South American natives. A soft extract that contains (sometimes) animal poisons and (usually) herbal poisons  prepared as arrow poison

• is ineffective when given orally, but parenterally very toxic

• the root bark is boiled with water, water is concentrated, snake or scorpion venom is added. Toxic soft extract is obtained CURARE

According to the shape of the container: • tube curare: is filled in the bamboo tubes. In Brazil and Peru. Carries Menispermacea alkaloids. Tubocurarine was isolated in 1895

• calabash curare: packed in the fruits of Crescentia sp. (Bignoniaceae). Venezuela, Colombia. Already used in trading. Carries Strychnos alkaloids

• pot curare: filled into the pots made by soil. Carries Loganiaceae / Menispermacea alkaloids CURARE

• pot curare: is a Menispermacea tube curare. Contains tubocurarine

• calabash curare: Loganiacea calabash curare, contains Strychnos alkaloids. S. toxifera has been mainly used to obtain the raw material. Carries toxiferine I and II, calebassine and toxiferine

• (+)-tubocurarine is a bisbenzylisoquinoline alkaloid Chondrodendron tomentosum (+)-TUBOCURARINE

• nowadays curare is used as a source for alkaloids • is a neuromuscular nicotinic acetylcholine receptor antagonist • paralysis the skeletal muscle. Paralysis neck and facial muscles, arms and legs, abdominal muscles  and diaphragm can not move in and with asphyxia  death • this is known as "curariform effect" • antidote  physostigmine (+)-TUBOCURARINE

• tubocurarine HCl salt is registered in Eur.Ph. • neuromuscular blocking effect (skeletal muscle relaxants) • intramuscular injectable form of its salt is used in the abdominal surgery • in muscle cramps seen in tetanus • in neuropsychiatry to relax the patient before electroshock • used in Myasthenia gravis diagnostic as an aid CEPHAELIS IPECACUANHA, C. ACUMINITA (RUBIACEAE)

• "Ipecac" • Ipecacuanhae radix (EP) • are the under-ground dried organs (roots and rhizomes) of the plant of Cephaelis ipecacuanha and Cephaelis acuminata • 20-40 cm in height, shrubs COMPOSITION

• carries emetine (1817) and cephaeline (1894), psychotrine, psychotrine methyl ether and emetamine • alkaloid content varies depending on to the source • it is difficult to find the roots of C. ipecacuanha in trade nowadays. Roots: contains 2-2.4% total alkaloid, 60-75% is emetine • C. acuminata roots carry 2-3.5% total alkaloid, emetine amount varries between 30-50% APPLICATION

• alkaloids can be very easily oxidized

O2 • emetine rubremetine salt (red in colour)

rubremetine APPLICATION

• cephaeline and emetine are used as an expectorant and emetic • emetine is compared to cephaeline more expectorant and has less emetic effect • emetine is not used as emetic due to its side effects • Ipecac syrup prepared from the powder (Ipecac syrup) is used as an emetic • Ipecac powder (Ipecacuanha pulvis normatus-EP) should contain (calculated over emetine) 1.9-2.1% total alkaloid APPLICATION

• emetine is a specific drug of amoebic dysentery • emetine HCl is usually used as an injection in the treatment of amoebic dysentery • psychotrine and psycotrine O-methyl ether are HIV selective inhibitors • due to this effect of psychotrine is a therapeutically candidate for drug development efforts AMARYLIDACEAE ALKALOIDS OH HO

norbelladine O

N O

lycorine

OH MeO H

H

N CH 3 O N CH3 OH O O MeO O galantamine tazettine AMARYLIDACEAE ALKALOIDS

• alkaloids are found in up to 20 genera of the • are bulbous plants  bulbs of this family is characterized by its toxic properties • this family draws the attention/interests due to the use of galantamin in the treatment of Alzheimer's GALANTAMINE

• galantamine was first isolated in 1952 by Russian researchers from Galanthus woronowi • then isolated from G. nivalis • also found in other plants of the family • Leucojum aestivum (0.1-2.0%) is used as a commercial source • Narcissus confusus grown in Spain contains up to 2.5% galantamine GALANTAMINE

• galantamine is an inhibitor • used since the end of 1950 in eastern Europe • through the penetration of the blood brain barrier as a modulator of nicotinic cholinergic receptors  shows central effect. Therefore, used in the palliative treatment of Alzheimer's disease • in clinical studies Alzheimer's patients having mild to moderate symptoms  in memory and intellectual function  enhancing effects reported GALANTAMINE

• galantamine hydrobromide is used orally or parenterally for treatment • galantamine has been approved as a drug in Europe in June 2000

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boldine Peumus boldus (Monimiaceae) PEUMUS BOLDUS (MONIMIACEAE)

"Boldo folium" • grows in Chile and its leaves are exported from here, also barks are used for extraction • carries 0.25-0.50% total alkaloids (major alkaloid: boldine) • boldine has a hypnotic effect • raw material is used in dyspepsia (indigestion and heartburn, etc.) in combination with other plants • for cholagogue effect with artichokes, for constipation with Sennea folium and cascara • By Commission E "spasmolytic, choleretic and stimulates the secretion of gastric secretion. Used in GI cramps and indigestion" PEUMUS BOLDUS (MONIMIACEAE)

boldine QUINOLIZIDINE ALKALOIDS

quinolizidine

especially Leguminosae, Papilionaceae sparteine, citizine, lupanine, subfamily (Cytisus scoparius, Genista laburnine (lupin alkaloids) tinctoria, Laburnum and Lupinus sp.) CYTISUS SCOPARIUS (FABACEAE)

"Scotch broom" • in the branches of the plant  carries a volatile alkaloid called sparteine • raw material is used due to its diuretic effect • strong hepatotoxic. Can lead to cirrhosis, necrosis and liver cancer LUPINUS SP.(FABACEAE)

• bitter due to lupanine and lupinine. Use as animal feed is limited • due to anagyrine they are toxic PYRROLIZIDINE ALKALOIDS

pyrrolizidine symphytine, equimidine Symphytum sp. senecionine, Senecio sp. senecyphylline, etc.

• they do not have medical significance • form toxicity in farm animals • have hepatotoxic effect • some are mutagenic and carcinogenic • interference even in small quantities in herbal products causes these effects SENECIO SP. (ASTERACEAE)

• all parts of the plant carries retroresine esters: senecionine, senecyphilline and jacobine SYMPHYTUM OFFICINALE (BORAGINACEAE)

• alkaloid  symphytine • hepatic toxicity • roots have wound healing due to allantoin • used as emollient, anti-itch and skin protectant IMIDAZOLE ALKALOIDS

imidazole imidazole pilocarpine Pilocarpus sp. (Rutaceae) PILOCARPUS SP. (RUTACEAE)

• leaves of various Pilocarpus species

• Jaborandi folium – P. microphyllus – P. jaborandi – P. pennatifolius – P. trachylophus

• trees or shrubs grown in South America

• today to obtain pilocarpine  cultivation PILOCARPUS SP. (RUTACEAE)

• leaves  carries 0.7-0.8% total alkaloids • pilocarpine, isopilocarpine, pilosine, isopilosine • pilocarpine has parasympathomimetic effect. Increases secretion, performs myozis • atropine antagonist • pilocarpine salts (HCl and nitrates): in the treatment of glaucoma, also in dry eyes and dry mouth, especially in the treatment of head and neck cancer patients undergoing radiation therapy  used to treat dry mouth PILOCARPUS SP. (RUTACEAE)

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