Pharmacognosy - Alkaloids

ALKALOIDS

Alkaloids, or "alkali-like" substances, are basic heterocyclic nitrogenous compounds primarily of plant origin and known for their physiological activity. They are rare in lower plants and more prevalent in dicots than monocots.

FAMILIES RICH IN ALKALOIDS

  • Apocynaceae (Dogbane Family)
  • Rubiaceae (Coffee family, Bedstraw family)
  • Solanaceae (Nightshade Family)
  • Papaveraceae (Poppy family)

FAMILIES FREE OF ALKALOIDS

  • Rosaceae (Rose Family)
  • Labiatae (Mint Family)

CHEMICAL PROPERTIES

  1. Nitrogen:

    • Primary Amines: R−NH2R-NH_2 (e.g., Norephedrine)
    • Secondary Amines: R2−NHR_2-NH (e.g., Ephedrine)
    • Tertiary Amines: R3−NR_3-N (e.g., Atropine)
    • Quaternary Ammonium Salts (e.g., d-Tubocurarine)

  2. Basicity:

    • Saturated hexacyclic amines are more basic than aromatic amines.

NOMENCLATURE

  • Genus: Atropine (Atropa Belladona)
  • Species: Cocaine (Erythroxylon coca)
  • Common Name: Ergotamine (ergot)
  • Discoverer: Pelletierine (Pelletier)
  • Physiological Action: Emetine (emetic)
  • Prominent Physical Character: Hygrine (hygroscopic)

SOLUBILITY

  • Alkaloidal bases and their salts are soluble in alcohol.
  • Bases are soluble in organic solvents and insoluble in water.
  • Salts are usually soluble in water and insoluble or sparingly soluble in organic solvents.
EXCEPTIONS
  1. Salts insoluble in water: Quinine Monosulphate
  2. Salts soluble in organic solvents: Lobeline and Apoatropine Hydrochlorides (soluble in chloroform)
  3. Most are crystalline solids, though some are amorphous.
  4. Some alkaloids like Coniine, Nicotine, and Sparteine (lacking oxygen) are liquids.
  5. Alkaloidal Salts are crystalline, useful for microscopic identification.

CLASSIFICATION BASED ON RING STRUCTURE

  • Pyridine and Piperidine: Lobeline, Nicotine
  • Tropane: Atropine, Belladonna
  • Quinoline: Quinine and Quinidine
  • Isoquinoline: Papaverine
  • Indole: Ergometrine
  • Imidazole: Pilocarpine
  • Purine: Caffeine
  • Steroidal: Solanum and Veratrum Alkaloids
  • Alkaloidal Amines

AMINO ACIDS (ALKALOIDAL PRECURSORS)

  • Phenylalanine
  • Tyrosine
  • Tryptophan
  • Histidine
  • Anthranilic Acid
  • Lysine
  • Ornithine

CLASSIFICATIONS OF ALKALOIDS

  1. Pyridine & Piperidine Alkaloids
  2. Tropane Alkaloids
  3. Solanaceous Alkaloids
  4. Quinoline Alkaloids
  5. Isoquinoline Alkaloids
  6. Indole Alkaloids
1. PYRIDINE & PIPERIDINE ALKALOIDS
  • Tertiary bases; reduction of pyridine yields piperidine.
  • Three Subgroups:
    1. Derivatives of Piperidine: Lobeline (from Lobelia)
    2. Derivatives of Nicotinic Acid: Areca
    3. Derivatives of Pyridine & Pyrrolidine: Nicotine (from Tobacco)
  • Important alkaloidal drugs in this group: Areca, Areca Hydrobromide, Lobelia, Lobeline, and Nicotine.
NICOTINE
  • Trier proposed it is biosynthesized from nicotinic acid and proline.
  • Primarily a product of root metabolism; demethylation occurs in leaves.
  • Used in chewing gum as a smoking deterrent (Nicorette®).
ARECA
  • AKA: Areca Nut or Betel Nut; dried ripe seed of Areca catechu L. (Fam. Palmae).
  • India is a major producer.
ARECOLINE
  • Classified as an anthelmintic in veterinary practice used as a vermicide and taeniafuge (deworm).
  • Most abundant and physiologically active alkaloid; a liquid.
    1. Arecaidine (N-methyl guvacine)
    2. Guvacine (tetrahydronicotinic acid)
    3. Guvacoline (guvacine methyl ester)
NGANGA
  • Areca mixed with lime and Piper betle leaves.
  • Used as a stimulant masticatory in India and the East Indies for taenicide.
  • AKA: Punsupari
LOBELIA OR INDIAN TOBACCO
  • Consists of dried leaves and tops of Lobelia inflata L. (Fam. Lobeliaceae).
  • Emetic properties observed in 1785; introduced into medicine in 1807.
  • Contains 14 alkaloids; Lobeline is major, with pungent volatile oil, resin, lipids, and gum.
LOBELINE
  • (-)-Lobeline, or Alpha Lobeline.
  • Uses & Dose: 2.0 mg dose of Lobeline Sulfate in tablets or lozenges as smoking deterrents.
2. TROPANE ALKALOIDS
  • Dicyclic compound formed by condensing a pyrrolidine precursor (AA: Ornithine) with 3 acetate-derived carbon atoms.
  • Both pyrrolidine and piperidine ring systems are present in Tropine.
  • Esterification: (-)-tropic acid (Precursor AA: Phenylalanine) -> Hyoscyamine (tropine tropate), which may be racemized to form Atropine.
3. SOLANACEOUS ALKALOIDS
TROPANE DERIVATIVES
  • Principal alkaloids: (-)-Hyoscyamine, Atropine [(±)-Hyoscyamine], Scopolamine (AKA: Hyoscine), Apoatropine (anhydride of atropine) and its stereo-isomer - Belladonnine.
HYOSCYAMINE
  • Tropine ester of (-) tropic acid; asymmetric, causing natural optical isomer occurrence.
  • Hyoscyamine Sulfate: sulfate of alkaloid from Hyoscyamus L. or Solanaceae genera; extremely poisonous.
ATROPINE
  • Optically inactive but contains levorotatory hyoscyamine, with a limit not exceeding 0.70° angular rotation.
  • Formed by racemization during extraction. Other bases in root include Apoatropine, Belladonnine, and Cuscohygrine.
  • Surgical: Antisialogogue to control bronchial, nasal, pharyngeal, and salivary secretions.
  • Anticholinergic: Treatment for pylorospasm, spastic GIT conditions, ureteral and biliary colic (with morphine).
  • Antidote to cholinesterase inhibitors; toxicity includes dry mouth, urination difficulty, eye pain, and light sensitivity.
  • Atropine Sulfate: colorless crystals or white crystalline powder; extremely poisonous, efflorescent in dry air, affected by light; anticholinergic.
BELLADONNA
  • AKA: Deadly Nightshade; dried leaf and flowering/fruiting top of Atropa belladonna L.
  • Leaf yields alkaloids up to 1%; three-fourths are (-)-Hyoscyamine, remainder is Atropine.
  • Parasympathetic Depressant: spasmolytic for digestive disorders, ulcerative colitis, diarrhea, diverticulitis, and pancreatitis.
  • Anticholinergic Effect: controls urinary tract spasms and motor effects at GIT (anti-diarrheal).
SCOPOLAMINE OR HYOSCINE (Buscopan®)
  • Abundant in Datura fastuosa var. alba and D. metel.
  • Ester that yields tropic acid and scopoline upon hydrolysis; levoratatory.
TALUMPUNAY
  • Scientific Name: Datura metel (Fam. Solanaceae); Common Name: Angel’s trumpet or “Talong punai”.
SCOPOLAMINE HYDROBROMIDE
  • AKA: Hyoscine Hydrobromide; colorless or white crystals, odorless, slightly efflorescent; extremely poisonous.
  • Anticholinergic; Scopolamine -> CNS depressant.
  • Used as pre-anesthetic sedation and obstetric amnesia with analgesics.
  • Effective in calming delirium; IM or SQ single dose of 320-650 mg.
  • Also effective in prevention of nausea and vomiting associated with motion sickness.
HYOSCYAMUS OR HENBANE
  • Dried leaf with/without stem and flowering/fruiting top of Hyoscyamus niger L. (Fam. Solanaceae).
  • Contains NLT 0.04% alkaloids of Hyoscyamus; parasympatholytic.
  • Most alkaloids derived from Egyptian Henbane (Hyoscyamus muticus L.).
  • T. Smith and H. Smith developed synthetic atropine from Tropine, but uneconomical; Duboisia and Hyoscyamus muticus remain production sources.
STRAMONIUM, JIMSON WEED, OR JAMESTOWN WEED
  • Dried leaf and flowering/fruiting tops with branches of Datura stamonium L. (Fam. Solanaceae).
  • Powdered stramonium used in preparations that are burned, vapor inhaled for asthma relief; prescription drug category since 1968.
STRAMONIUM SEED
  • Noxious weed; poisoning in children from ingestion.
  • Symptoms of atropine poisoning: dilated pupils, impaired vision, dry skin and secretions, extreme thirst, hallucinations, and loss of consciousness; anticholinergic or atropine-like toxicity.
OTHER SOLANACEOUS ALKALOIDS
  • PITURI OR AUSTRALIAN TOBACCO: From the leaf of D. hopwoodii; contains nicotine and nornicotine.
  • MANDRAGORA OR EUROPEAN MANDRAKE: Root of Mandragora officinarum L.; contains Hyoscyamine, Scopolamine, and Mandragorine; subject of superstitions and folklore; not American Mandrake (Podophyllum).
DUBOISIA
  • Dried leaves of Duboisia myoporoides (Fam. Solanaceae); chief source of Atropine.
  • Contains (-)-hyoscyamine, scopolamine, nicotine, and nornicotine.
WITHANIA
  • Dried root of Withania somnifera (Fam. Solanaceae); related to Belladonna and Hyoscyamus; contains a dozen alkaloids; sedative action.
COCA OR COCA LEAVES
  • Dried leaves of Erythroxylum coca Huanuco coca or of E. novogranatense var. Truxillense (Fam. Erythroxylaceae).
    1. var. coca (E. coca) yields Huanuco (Bolivian) coca
    2. var. spruceanum (E. truxillense) yields Truxillo (Peruvian) coca
    3. var. novogranatense yields Truxillo coca from Colombia.
  • Contains 3 basic types of alkaloids: Derivatives of Ecgonine, Tropine, Hygrine
HUANUCO COCA
  • Contains 0.5 to 1% of ester alkaloids, mainly cocaine; Cuscohygrine is principal non-ester alkaloid.
TRUXILLO COCA
  • Lower content of ester alkaloids, but higher cocaine percentage (up to 75%).
  • Known as “The Divine Plant of the Incas”; natives chew the leaf for energy and endurance.
COCAINE
  • Alkaloid from leaves of Erythroxylum coca; psychomotor stimulant with abuse potential.
  • Prepared semisynthetically from plant-derived ecgonine.
  • Causes reduced fatigue, increased mental clarity, and a rush of energy; tolerance leads to higher doses.
  • Hydrolyzed into ecgonine, benzoic acid, and methyl alcohol; Cinnamylcocaine and a- and (3-truxilline also yield related components.
COCAINE HYDROCHLORIDE
  • Colorless crystals or white crystalline powder; local anesthetic for mucous membrane (1-4% solution).
  • Inhaled or sniffed for cerebral stimulation and euphoria.
  • Free-basing popular due to rapid onset and intensity of euphoric experience.
BROMPTON'S COCKTAIL
  • Controls severe pain with terminal cancer; cocaine counters narcotic-induced sedation and potentiates analgesic effect of morphine or methadone.
  • Cocaine used for abuse is free-base, volatilizing at about 98°C, while the salt volatilizes at 195°C, decomposing some cocaine.
4. QUINOLINE ALKALOIDS
  • Alkaloids containing quinoline from cinchona (quinine, quinidine, cinchonine, and cinchonidine).
  • Biosynthesis: Tryptophan is a precursor of quinine in cinchona.
  • Biosynthetic pathway to tryptophan unknown in higher plants but elucidated in microorganisms (Escherichia coli and Enterobacter aerogenes).
CINCHONA
  • AKA: Cinchona, Cinchona Bark, or Peruvian Bark; dried bark of Cinchona succirubra or its hybrids (red cinchona); C. ledgeriana, C. calisaya, or hybrids (calisaya bark or yellow cinchona) (Fam. Rubiaceae).
  • Alkaloids: Quinine, Quinidine, Cinchonine, and Cinchonidine.
  • Cinchona Bark discoloration caused by oxidase enzyme.
QUINIDINE
  • Stereoisomer of quinine; present in cinchona barks (0.25% to 1.25%).
  • Depresses myocardial excitability, conduction velocity, and contractility.
  • Treatment for cardiac arrhythmias such as premature atrial, AV junctional, and ventricular contractions; atrial and ventricular tachycardia; atrial flutter; and atrial fibrillation.
  • Usual oral dose is 10-20 mg/kg/day in 4-6 divided doses for therapeutic serum levels of 3 to 6 mg/ml.
  • Peak serum levels slightly lower with gluconate and polygalacturonate salt.
QUINIDINE SULFATE
  • Sulfate of alkaloid from Cinchona species and Remijia pedunculata or prepared from quinine.
  • Readily soluble in water, alcohol, methanol, and chloroform.
  • Used as antimalarial, mechanism is intercalation of quinoline moiety into Plasmodium parasite DNA.
  • Anopheles Freeborni Mosquito is intermediate host and vector for Plasmodium spp.
  • Recently regained importance in treatment of chloroquine-resistant falciparum malaria with pyrimethamine and sulfadiazine or tetracycline.
  • Has a skeletal muscle relaxant effect, affecting calcium distribution within the muscle fiber.
QUININE SULFATE
  • Sulfate of an alkaloid from the bark of Cinchona species; white, odorless, bitter, fine, needlelike crystals; brownish when exposed to light.
5. ISOQUINOLINE ALKALOIDS
  • Majority of alkaloids have isoquinoline ring structure derived biosynthetically from benzylisoquinoline intermediates.
OPIUM ALKALOIDS
  • Morphine
  • Codeine
  • Heroin
  • Papaverine
  • Hydromorphone
  • Curare
  • Hydrastis or Goldenseal
  • Sanguinarine
  • Biosynthesis: Condensation of phenylethylamine and phenylacetaldehyde derivatives.
  • AA Precursors: Phenylalanine or Tyrosine; Demethylation: Codeine -> Morphine
IPECAC
  • From dried rhizome and roots of Cephaelis ipecacuanha, known as Rio or Brazilian ipecac, or of Cephaelis acuminata, known as Cartagena, Nicaragua, or Panama ipecac (Fam. Rubiaceae).
  • Principal Alkaloids: Emetine, Cephaeline, and Psychotrine.
  • Uses: Treatment for drug overdose; not given for children less than 1 y/o, dose is 15ml followed by 1-2 glasses of water, repeated once in 20mins.
    • IPECAC Fluidextract 14x stronger than IPECAC Syrup
    • IPECAC Syrup included in poison antidote kits
    • IPECAC with Opium (Dover’s Powder) is a diaphoretic (↑perspiration).
EMETINE OR METHYLCEPHAELIN
  • Alkaloid from IPECAC or synthetic by methylation of cephaeline; discovered by Pelletier and Magendie in 1817.
  • Anti-amoebic agent acting primarily in the intestinal wall and the liver.
  • SQ administration; cannot be given orally due to expectorant and emetic properties.
  • MOA: Interference with protein synthesis (Anti-protozoal)
HYDRASTIS OR GOLDENSEAL
  • From dried rhizome and roots of Hydrastis canadensis (Fam. Ranunculaceae); used by Cherokee Indians as a dye and internal remedy, introduced to settlers.
  • Principal Alkaloids: Hydrastine and Berberine used as astringents in inflammation of the mucous membrane.
  • Hydrastine soluble in chloroform, alcohol, and ether; Berberine soluble in water, insoluble in ether; salts of berberine form bright yellow crystals.
SANGUINARIA OR BLOODROOT
  • Dried rhizome of Sanguinaria canadensis (Fam. Papaveraceae);
  • Used as face stain, acrid emetic, and homemade cough remedies (expectorant); Usual Dose: 125 mg.
  • All alkaloids found in other Papaveraceae members; isoquinoline derivatives.
  • Species of Ranunculaceae, Berberidaceae, Menispermaceae, and Papaveraceae contain alkaloids of this type.
CURARE OR SOUTH AMERICAN ARROW POISON
  • Crude dried extract from bark and stems of Strychnos castelnaei, S. toxifera, S. crevauxii (Fam. Loganiaceae) and Chondodendron tomentosum (Fam. Menispermaceae).
  • Prepared by boiling young bark with other substances; evaporated to a paste.
  • Earliest preparations named by containers: Calabash, Tube, Pot curare; brownish or black, shiny, resinoid mass with a bitter taste.
  • Most important constituent: (+)-Tubocurarine; crude extract exhibits paralyzing effect on voluntary muscle (curariform effect) by blocking nerve impulses to skeletal muscles at the myoneural junction.
  • Toxic action on blood vessels; histamine-like effect.
  • Brought to England by Sir Walter Raleigh in 1595; recently prominent in medical circles.
  • Tubocurarine Chloride standardized by