MODULE 5: CLASSES OF CHEMICAL CONSTITUENTS (IV) PDF

Preview

Summary

Alkaloids - Nomenclature: end by "ine" - One or more rings of carbon atoms, usually with a nitrogen atom in the ring - The position of the nitrogen atom in the carbon ring varies with different alkaloids and with different plant families. - Produce varying degrees of physiological ...

Description

PHARMACOGNOSY AND PLANT CHEMISTRY

Alkaloids • Nomenclature: end by "ine" • One or more rings of carbon atoms, usually with a nitrogen atom in the ring • The position of the nitrogen atom in the carbon ring varies with different alkaloids and with different plant families. • Produce varying degrees of physiological and psychological responses o In large doses - highly toxic – fatal o In small doses, many have therapeutic value Characteristics • Most alkaloids are crystalline solids o Liquid alkaloids o coniine o nicotine o sparteine • Majority of alkaloids are colorless o Colchicine and berberine are yellow o Salts of sanguinarine are copper-red • Soluble in organic solvents and insoluble in water • Bitter in taste Functions • They may act as protective against insects and herbivores due to their bitterness and toxicity. • They are, in certain cases, the final products of detoxification (waste products). • Source of nitrogen in case of nitrogen deficiency. • They, sometimes, act as growth regulators in certain metabolic systems. • They may be utilized as a source of energy in case of deficiency in carbon dioxide assimilation. Naming of Alkaloids • Genus name of the plant yielding them o Hydrastine and atropine • Species name of the plant yielding them o Cocaine and belladonna • Common name of the plant yielding them o Ergotamine • Physiologic activity o Emetine and morphine • Discoverer o Pelletierine Classification • True alkaloids o Derive from amino acid and they share a heterocyclic ring with nitrogen. o These alkaloids are highly reactive substances with biological activity even in low doses. o Cocaine, quinine, dopamine and morphine, and atropine. • Protoalkaloids

JOSE PHILIP G. MAGLALANG, RPh

1

PHARMACOGNOSY AND PLANT CHEMISTRY

Compounds, in which the N atom derive from an amino acid is not a part of the heterocyclic. o Ephedrine, mescaline, and yohimbine Pseudoalkaloids o Compounds that are not derived from amino acids but have nitrogen in a heterocyclic ring. o These alkaloids can also be derived from non-amino acid precursors. The N atom is inserted into the molecule at a relatively late stage o Caffeine and theobromine o

•

• • • •

•

•

Classification of Alkaloids Precursors involved in the biosynthesis of alkaloids Pyridine- Piperidine Lysine/Ornithine o Upon reduction, the tertiary base, pyridine, is converted into the secondary base, piperidine. These 2 nuclei form the basis of this group, which is sometimes divided into 3 subgroups o Derivatives of lobeline from lobelia o Derivatives of nicotinic acid (arecoline from areca) o Derivative of both pyridine and pyrolidine (nicotine from tobacco) Sources o Tobacco ▪ Sources: dried leaves of Nicotiana tobacum ▪ Family: Solanaceae ▪ Constituents: Nicotine ▪ Uses: CNS stimulant, ganglionic (nicotinic) cholinergic receptor agonist, and smoking deterrent (Nicorette®) (Chewing gum base as a temporary aid to the cigarette smoker seeking to give up smoking.) o Areca, areca nut, betel nut ▪ Sources: Dried, ripe seed of Areca catechu Linn ▪ Family: Arecaceae ▪ Constituents: Arecoline, arecaidine, and guvacoline ▪ Uses: Anthelmintic in veterinary practice: vermicide and taenifuge (usual dose in dogs is 2 to 4g) ▪ Areca is mixed with lime as a masticatory stimulant (a substance chewed to increase saliva) o Lobelia/Indian tobacco ▪ Sources: Dried leaves and tops of Lobelia inflata Linn. ▪ Family: Lobeliaceae ▪ Constituents: Lobeline ▪ Uses: CNS stimulant, ganglionic (nicotinic) cholinergic receptor agonist, and smoking deterrent (2mg of lobeline sulfate intended to break tobacco habit)

JOSE PHILIP G. MAGLALANG, RPh

2

PHARMACOGNOSY AND PLANT CHEMISTRY

▪ • • •

•

Lobeline produces similar, but weaker, pharmacologic effects to those of nicotine

Tropane A dicyclic compound formed by the condensation of a pyrolidine precursor (ornithine) with 3 acetate derived carbon atoms. Biosynthesis o Amino acid is incorporated stereo specifically to form the pyrrolidine ring of tropine. o The remaining 3 carbon atoms are derived from acetate and thus complete the piperidine moiety. o Methylation results via trans methylation from S-adenosylmethionine to complete the tropine nucleus. o Phenylalanine is the precursor of tropic acid ▪ The side chain of the amino acid undergoes a novel type of intramolecular rearrangement during the conversion. o Esterification of tropic acid with tropine produces hyoscyamine. o Formation of scopolamine is by the mediation of a highly specific enzyme hyoscyamine 6B – hydroxylase Sources o Belladonna/Deadly nightshade ▪ Sources: Dried leaf and flowering or fruiting top of Atropa belladonna Linn ▪ Family: Solanaceae ▪ Constituents: Atropine ▪ Uses: Parasympathetic depressant (which accounts for its use as spasmolytic agent) Anticholinergic properties, Antidote for cholinesterase inhibitors, antisialogogue (decrease the flow rate of saliva) o Hyoscyamus/Henbane ▪ Sources: Dried leaf flowering or fruiting top of Hyoscyamus niger Linn and Hyoscyamus muticus (Egyptian henbane) ▪ Family: Solanaceae ▪ Constituents: Hyoscyamine and scopolamine ▪ Egyptian henbane consisting largely of hyoscyamine ▪ Poisonous to swine ▪ Uses: Scopolamine (is used to treat motion sickness), Hyoscyamine (anticholinergic) o Stramonium/Jimson weed/Jamestown weed ▪ Sources: Dried leaf and flowering or fruiting tops with branches of Datura stramonium Linn ▪ Family: Solanaceae ▪ Constituents: Hyoscyamine and scopolamine ▪ It can serve as a source of atropine. ▪ Uses: Anticholinergic (has an action like that of belladonna) and relief of asthma o Withania ▪ Sources: Dried root of Withania somnifera Dunal ▪ Family: Solanaceae JOSE PHILIP G. MAGLALANG, RPh

3

PHARMACOGNOSY AND PLANT CHEMISTRY

▪

Constituents: Tropine and pseudotropine

Duboisia ▪ Sources: Dried leaves of Duboisia myoporoides R. Brown ▪ Family: Solanaceae ▪ Constituents: Hyoscyamine and scopolamine ▪ Currently is a chief source of atropine ▪ Uses: Treatment of motion sickness, stomach disorder, side effects of cancer therapy, and antispasmodic o Mandragora/European Mandrake ▪ Sources: Roots of Mandragora officinarum Linn ▪ Family: Solanaceae ▪ Constituents: Hyoscyamine, scopolamine, and mandragorin ▪ Uses: Mandragorin (emetic) o Coca/ Divine plant of Incas ▪ Sources: Dried leaves of Erythroxylon coca Larmarck ▪ Family: Erythroxylaceae ▪ Constituents: Cocaine, Cinnamylocaine, and α- and β-truxilline ▪ Uses: Local anesthetic, psychomotor stimulant, analgesic, and ingredient in Brompton's cocktail (analgesic for terminally ill patients: cocaine + morphine or methadone) Quinoline Alkaloids containing quinoline as their basic nucleus obtained from cinchona o quinine, quinidine, cinchonjne, and cinchonidine Cinchona and its alkaloids are the only members of this group that are therapeutically important at present Tryptophan is a precursor of quinine in cinchona Biosynthesis o The biosynthetic pathway leading to tryptophan in higher plants is unknown o It has been elucidated in microorganisms using auxotrophic mutants of Escherichia coli and Enterobacter aerogenes that required tryptophan for growth. o In the pathway, shikimic acid, through a series of phosphorylated intermediates, yields chorismic acid, which is an important branch-point intermediate. ▪ One branch leads to prephenic acid and the aromatic amino acids, phenylalanine and tyrosine. ▪ The other leads to anthranilic acid and then to tryptophan. ▪ Chorismic acid is converted to anthranilic acid by aromatization and transfer of the amide nitrogen of glutamine. ▪ The anthranilic acid then reacts with 5-phosphoribosyl-1-phosphosphate to form, via an intermediate 1(o-carboxvphenylamino)1 -deoxyribulose-5phosphate. ▪ 1(o-carboxvphenylamino)1 -deoxyribulose-5-phosphate will undergoes ring closure to produce indole-3-glycerol phosphate. o

• • • • •

JOSE PHILIP G. MAGLALANG, RPh

4

PHARMACOGNOSY AND PLANT CHEMISTRY

▪

•

•

• • •

• • • • •

The final step in the reaction sequence involves replacement of the glycerol phosphate side chain with serine, thereby yielding tryptophan. The most distinctive feature of quinine biosynthesis appears to be cleavage of the benzopyrrole ring of the tryptophan moiety and rearrangement to form the quinuclidine nucleus and then the quinoline nucleus Sources o Cinchona/cinchona bark/Peruvian bark ▪ Sources: Dried bark of the stem or of the root of Cinchona succirubra Pavon et Klotzsch, Cinchona ledgeriana (Howard) Moens et Trirnen, Cinchona calisaya Weddell ▪ Family: Rubiaceae ▪ Constituents: quinine, quinidine, chonine, and cinchonidine ▪ Uses: Quinine continues to be used for malaria, Quinidine is used to treat various cardiac arrhythmias ▪ Cinchonism • Overdoses of cinchona toxicity • Temporary loss of hearing and in impaired sight • Hallmark: tinnitus o Cuprea bark ▪ Sources: Remijia purdieana Triana, Remijia pedunculata Flickiger ▪ Family: Rubiaceae ▪ Constituents: quinidine ▪ Cuprea bark is a commercial source of quinidine. ▪ Uses: Quinidine is used cardiac depressant Isoquinoline They represent the largest single group of plant alkaloids. Important opium alkaloids o Morphine, codeine, thebaine o Exhibit a phenanthrene nucleus o This phenanthrene alkaloids are derived biosynthetically from benzylisoquinoline intermediates Sanguinaria, another member of the Papaveraceae, also contains isoquinoline alkaloids Biosynthesis These compounds result from the condensation of a phenylethylamine derivative with a phenylacetaldehyde derivative. Both of these moieties are derived from phenylalanine or tyrosine Morphine is also formed from 2 molecules of tyrosine o This medicinally important alkaloid is derived from a benzylisoquinoline metabolite. o Norlaudanosoline is the starting compound. There will be enzymatically controlled methylation pattern that gives rise to reticuline. o Thus, facilitating formation of the dienone, salutaridine, which is the first intermediate with a phenanthrene nucleus.

JOSE PHILIP G. MAGLALANG, RPh

5

PHARMACOGNOSY AND PLANT CHEMISTRY

•

•

Another interesting aspect of this pathway biosynthetic relationship of thebaine, codeine, and morphine o Stepwise demethylation of the therapeutically unimportant thebaine leads first to the relatively mild analgesic codeine and then to the potent narcotic morphine Sources o Ipecac ▪ Sources: dried rhizome and roots of Cephaelis ipecacanhua (Brotero) A. Richard ▪ Family: Rubiaceae ▪ Constituents: Emetine, cephaeline, and psychotrine ▪ Uses: • Emetic (The usual dose in adults and children older than one year of age is 15 ml, followed by one to 2 glasses of water and may be repeated once in 20 minutes if emesis does not occur. The syrup should be recovered by gastric Iavage if emesis does not occur after the second dose.) • Ipecac syrup should not be confused with ipecac fluidextract, which is 14 times stronger. • Dover's powder (Ipecac mixed with opium) acts as a diaphoretic • Ipecac syrup is included in poison antidote kits because of its emetic properties ▪ Emeline or methylcephaelin • Alkaloid obtained from ipecac or prepared synthetically by methylation of cephaeline. ▪ Emetine hydrochloride • Hydrated hydrochloride of emetine • It is freely soluble in water and alcohol • Uses: antiamebic (1 mg per kg of body weight IM or SC, but not exceeding 65 mg daily, for not more than 5 days), antiprotozoan (amebic dysentery and pyorrhea alveolari) • The drug is not administered orally because it produces nausea and vomiting. o Hydrastis/Goldenseal ▪ Sources: dried rhizome and roots of Hydrastis canadensis Linn ▪ Family: Ranunculaceae ▪ Constituents: hydrastine, berberine, and canadine ▪ Uses: astringents in inflammation of the mucous membranes o Sanguinaria/blood root ▪ Sources: dried rhizome of Sanguinaria canadensis Linn. ▪ Family: Papaveraceae ▪ Constituents: sanguinarine ▪ Uses: stimulating expectorant and emetic properties (The usual dose is 125 mg) o Curare/south American arrow poison

JOSE PHILIP G. MAGLALANG, RPh

6

PHARMACOGNOSY AND PLANT CHEMISTRY

Sources: crude dried extract from the bark and stems of Strychnus castelnaei Weddell ▪ Family: Loganiaceae ▪ Constituents: tubocurarine or tubocurarine Cl ▪ Uses: skeletal muscle relaxant, used to control convulsions of strychnine poisoning and of tetanus, it is an adjunct to shock therapy in neuropsychiatry and a diagnostic aid in myasthenia gravis. ▪ Assay: by the head drop cross over test in rabbits • d-Tubocurarine hydrochloride is injected into the marginal vein of a rabbit’s ear till the rabbit’s neck muscles are relaxed to such a degree that the animal's head cannot be raised or turned in response to a physical stimulus. Opium/Gum opium ▪ Sources: Air dried milky exudate obtained by incising the unripe capsules of Papaver somniferum Linn ▪ Family: Papaveraceae ▪ Constituents: morphine, codeine, noscapine (formerly narcotine), papaverine, and thebaine ▪ Uses: Pharmaceutic necessity for powdered opium, analgesic, hypnotic and a narcotic and checks excessive peristalsis and contracts the pupil of the eye • It acts chiefly on the central nervous system • Small doses – Stimulates the CNS • Large doses – Depresses the CNS ▪

o

▪ ▪

▪

▪

▪

Products obtained from opium Powdered opium • Yields not less than 10% and not more than 10.5% of anhydrous morphine • Used in making Dover's powder and camphorated opium tincture and is combined with other agents in antidiarrheal preparations. Paregoric/Camphorated opium tincture • Antiperistaltic. • The usual dose of paregoric is 5 to 10 ml, 1 to 4 times a day, and it may be mixed before taking with a small amount of water to form a milky solution Laudanum, opium tincture, or deodorized opium tincture • Antiperistaltic. • Formerly used similarly to paregoric. Its dose is 0.6 ml, 4 times a day Poppy seed/Maw seed • Parenteral formulations • Salad dressings

JOSE PHILIP G. MAGLALANG, RPh

7

PHARMACOGNOSY AND PLANT CHEMISTRY

▪ ▪ ▪

▪

▪

▪

▪ ▪

▪

Alkaloids of Opium Opiates (naturally-occurring) Morphine • Most important of the opium alkaloids. • Phenolic and an alcoholic hydroxyl group • Narcotic analgesic • Strongly hypnotic • Induce nausea, vomiting, constipation, and habit formation. • 10 mg parenterally, 6 times a day as necessary Codeine • Most widely used opium alkaloid • Methylmorphine • Obtained from methylation of morphine (methyl group replaces the hydrogen of the phenolic hydroxyl group) • Narcotic analgesics • Antitussives • Sedative • Less toxic and involves much less danger of habit formation. • Analgesic 15 to 60 mg every 4 hours as needed • Antitussive, 10 to 20 mg every 4 to 6 hours as needed. Noscapine • Commonly called narcotine/anarcotine. • Only Non-narcotic opium alkaloid • Antitussive. • The usual dose is 15 mg, up to 4 times a day • It is available in syrup and chewable tablets Papaverine • Smooth muscle relaxant • The usual dose: orally is 150 mg; intramuscularly, 30 mg. • antitussive in combination with codeine. The dose of each is 15mg. Opioids (derived, synthetic, direct affinity with opioid receptors) Heroin • Diacetylmorphine • Formed by the acetylation of morphine (the hydrogen atoms of both the phenolic and alcoholic hydroxyl groups are replaced by acetyl groups) • Increased danger of habit formation, very potent. • Manufacture in the United States is forbidden by law, and its use in medicine has been discontinued. Hydromorphone • Dihydromorphinone hydrochloride

JOSE PHILIP G. MAGLALANG, RPh

8

PHARMACOGNOSY AND PLANT CHEMISTRY

Differs from morphine hydrochloride because one of the hydroxyl groups of morphine is replaced by a ketone group, and the adjacent double bond is removed. • Powerful narcotic analgesic and tends to strongly depress the respiratory mechanism • Less frequent SE (constipation) Hydrocodone bitartrate • dihydrocodeinone bitartrate • Bears the same relation to codeine as dihydromorphinone does to morphine • One of the hydroxyl groups of codeine is replaced by a ketone group, and the adjacent double bond is removed. • Antitussive (an excellent aid in treating a troublesome cough) • The usual dose is 5 to 10 mg, 3 to 4 times a day, as necessary. Apomorphine • Condensation of morphine + HCl and one molecule of water is lost • Emetic • 100 μg per kg of body weight (maximum 6 mg) SC •

▪

▪

• • • • • • • • • •

Indole Being obtained from the amino acid tryptophan Some indole alkaloids don’t come from the amino acid tryptophan it is believe that non tryptophan portions of the alkaloids are derived from the monoterpenoid precursor. Biosynthesis The alkaloids of ergot are also derived from a combination of tryptophan and acetate metabolism. Dimethylallylpyrophosphate condenses at the 4-position of tryptophan as an initial step in the pathway. Subsequent cyclization reactions involve the formation of chanoclavine-I and agroclavine. Agroclavine undergoes stepwise oxidation to elymoclavine and eventually lysergic acid. The Rauwolfia alkaloids, ajmaline, reserpine, and serpentine, are derived from a Corynanthe type monoterpenoid precursor. Sources o Rauwolfia Serpentina ▪ Sources: Dried root of Rauwolfia serpentina Linn. Bentham ex Kurz ▪ Family: Apocynaceae ▪ Constituents: reserpine ▪ Uses: Treatment of snakebites to insanity (folkloric use only), antihypertensive and tranquilizer. ▪ * The patient should be advised to notify his physician if a change in mood occurs. o Catharanthus/Vinca ▪ Sources: Dried whole plant of Catharanthus roseus G. Don ▪ Family: Apocynaceae

JOSE PHILIP G. MAGLALANG, RPh

9

PHARMACOGNOSY AND PLANT CHEMISTRY

▪ ▪

Constituents: vinblastine, vinleurosine, vinrosidine and vincristine Uses: Antineoplastic

Alkaloids of Catharanthus Vinblastine sulfate • Hodgkin's disease, lymphocytic lymphoma, histiocytic lymphoma, mycosis fungoides, advanced testicular carcinoma, Kaposi's sarcoma, and choriocarcinoma, and breast cancer unresponsive to other therapies. • Effective as a single agent but is usually administered with other antineoplastic agents in combination therapy for an enhanced therapeutic effect without additive toxicity ▪ Vincristine sulfate • The structure of this alkaloid is quite similar to that of vinblastine, differing only in the substitution of an N-formyl group for the N-methyl group of vinblastine. • Acute leukemia and in combination therapy in Hodgkin's disease, lvmphosarcoma, reticulum cell sarcoma, rhabdomyosarcorna, neuroblastoma, and Wilms' tumor. ▪ Yohimbine ▪ Sources: bark of Pausinystalia yohimbe ▪ Family: Rubiaceae ▪ Constituents: yohimbine ▪ Uses: Treatment of impotence/erectile dysfunction, aphrodisiac Nux vomica ▪ Sources: Dried ripe seed of Strychnos nux-vomica Linn and Strychnos ignatii Bergius (St. Ignatius bean) ▪ Family: Loganiaceae ▪ Constituents: strychnine and brucine ▪ St. Ignatius bean commercial source of strychnine and brucine ▪ Uses: Brucine - alcohol denaturant • Strychnine - toxic central stimulant • Excitation of all parts of the central nervous system and blocks inhibitory spinal impulses at the postsynaptic level. (tonic convulsions) Physostigmine/Calabar bean/Ordeal bean ▪ Sources: Dried ripe seed of Physostigma venenosum Balfou ▪ Family: Fabaceae ▪ Constituents: Physostigmine, eseramine, geneserine, and physovenine ▪ Uses: Physostigmine treat glaucoma (decrease in intraocular pressure by increasing the outflow of the aqueous humor.) • Inhibits acetylcholinesterase, the enzyme responsible for the breakdown of used acetylcholine Ergot/Rye ergot/Secale cornutum ▪ ▪

o

o

o

JOSE PHILIP G. MAGLALANG, RPh

10

PHA...