Alkaloids Part 1 Notes

Alkaloids: Definition and Occurrence

  • Alkaloids are basic, heterocyclic nitrogenous compounds of plant origin with physiological activity.
  • Rare in lower plants; Dicots > Monocots.

Families Rich in Alkaloids

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

Families Free of Alkaloids

  • Rosaceae (Rose)
  • Labiatae (Mint)

Chemical Properties of Alkaloids

  • Nitrogen-containing:
    • 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: R4−NR_4-N (e.g., d-Tubocurarine)
  • Basicity: R2-NH > R-NH2 > R_3-N
  • Saturated hexacyclic amines > aromatic amines in basicity.

Nomenclature of Alkaloids

  • Based on:
    • Genus (e.g., Atropine from Atropa belladonna)
    • Species (e.g., Cocaine from Erythroxylon coca)
    • Common name (e.g., Ergotamine from ergot)
    • Discoverer (e.g., Pelletierine from Pelletier)
    • Physiological action (e.g., Emetine emetic)
    • Physical character (e.g., Hygrine - hygroscopic).

Solubility of Alkaloids

  • Bases and salts soluble in alcohol.
  • Bases soluble in organic solvents, insoluble in water (generally).
  • Salts soluble in water, insoluble in organic solvents (usually).
  • Exceptions:
    • Salts insoluble in water: quinine monosulphate.
    • Salts soluble in organic solvents: lobeline and apoatropine hydrochlorides (chloroform).
  • Most are crystalline solids; some (coniine, nicotine, sparteine) are liquids if lacking oxygen.
  • Salts are crystalline (microscopic identification).

Classification of Alkaloids (Ring Structure)

  • Pyridine and piperidine (e.g., lobeline, nicotine)
  • Tropane (e.g., Atropine)
  • Quinoline (e.g., quinine, quinidine)
  • Isoquinoline (e.g., papaverine)
  • Indole (e.g., ergometrine)
  • Imidazole (e.g., pilocarpine)
  • Purine (e.g., caffeine)
  • Steroidal (e.g., Solanum and Veratrum alkaloids)
  • Alkaloidal Amines

Alkaloid Precursors (Amino Acids)

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

Biosynthesis Examples

  • Nicotine and Tropane alkaloids

Pyridine and Piperidine Alkaloids

  • Nicotine is tobacco type alkaloid.
  • Pyridine reduces to Piperidine.
  • Subgroups: piperidine derivatives (lobeline), nicotinic acid derivatives (arecoline), pyridine and pyrrolidine derivatives (nicotine).
  • Examples: areca, arecoline hydrobromide, lobelia, lobeline, and nicotine.

Nicotine

  • Biosynthesized from nicotinic acid and proline.
  • Product of root metabolism.
  • Use: Smoking cessation (Nicorette).

Areca

  • Dried ripe seed of Areca catechu.
  • Major producer: India.
  • Alkaloids: arecoline (most active), arecaidine, guvacine, guvacoline (total alkaloids can reach 0.45%).
  • Use: Anthelmintic (veterinary), vermicide, taenifuge.
  • Mixed with lime and Piper betle leaves as a stimulant masticatory.

Lobelia

  • Dried leaves and tops of Lobelia inflata.
  • Contains 14 alkaloids, major one is lobeline.
  • Use: Smoking deterrent (2.0 mg lobeline sulfate).

Tropane Alkaloids

  • Dicyclic compound from pyrrolidine (ornithine) and 3 acetate-derived carbons.
  • Esterification of tropine with tropic acid yields hyoscyamine (racemizes to atropine).

Synthesis

  • Phenylalanine -> Tropic acid
  • Ornithine -> tropane -> Tropine
  • Tropic acid + Tropine -> (-)hyoscyamine -> (+/-)-hyoscyamine (atropine)

Solanaceous Alkaloids

  • Hyoscyamine
  • Scopolamine
  • Atropine
  • Hyoscyamus
  • Stramonium

Tropine Derivatives

  • (-)-Hyoscyamine
  • Atropine [(+/-)-hyoscyamine]
  • Scopolamine (hyoscine)
  • Apoatropine and belladonnine

Hyoscyamine

  • Tropine ester of (-)tropic acid.
  • Isolated from Hyoscyamus or other Solanaceae.
  • Anticholinergic: controls gastric secretion, visceral spasm, hypermotility in spastic colitis, pylorospasm, and cramps.
  • Treats tremors, rigidity, sialorrhea, and hyperhidrosis in Parkinsonism.

Atropine

  • Optically inactive, may contain levorotatory hyoscyamine (limit -0.70°).
  • Anticholinergic.

Belladonna

  • Dried leaf and flowering/fruiting top of Atropa belladonna.
  • Contains up to 1% alkaloids; mostly (-)-hyoscyamine (racemizes to atropine during extraction).
  • Parasympathetic depressant (spasmolytic agent): for digestive disorders, ulcerative colitis, diarrhea, diverticulitis, pancreatitis.
  • Controls motor effect in GIT; antidiarrheal; controls urinary tract spasms.
  • Dose: Tincture (0.6-1.0 ml), extract (15 mg), 3-4 times daily.

Atropine (Surgery)

  • Antisialogogue: controls bronchial, nasal, pharyngeal, and salivary secretions.
  • For pylorospasm, GI spastic conditions, ureteral and biliary colic (with morphine).
  • Dose: Tablets (300-600 ug, 3-4 times daily); injection (400-600 ug, 4-6 times daily).
  • Antidote to cholinesterase inhibitors.

Scopolamine (Hyoscine)

  • Abundant in Datura fastuosa var. alba and D. metel.
  • Yields tropic acid and scopoline upon hydrolysis.
  • Anticholinergic; CNS depressant (unlike atropine which is a stimulant).
  • Uses: Preanesthetic sedation, obstetric amnesia (with analgesics), calming delirium.
  • Dose: 320-650mg (subcutaneously or intramuscularly).
  • Prevents nausea and vomiting associated with motion sickness.
  • Transdermal system releases scopolamine gradually over 3 days.

Hyoscyamus (Henbane)

  • Dried leaf of Hyoscyamus niger.
  • Contains ≥0.04% hyoscyamus alkaloids.
  • Rarely used today as crude drug

Stramonium (Jimson Weed)

  • Dried leaf and flowering/fruiting tops of Datura stramonium.
  • Vapor inhaled for asthma relief (prescription-only since 1968).
  • Toxic symptoms (atropine poisoning): dilated pupils, impaired vision, dry skin, extreme thirst, hallucinations, loss of consciousness (anticholinergic effects).

Other Solanaceous Alkaloids

  • Withania
  • Pituri (Australian tobacco)
  • Duboisia
  • Mandragora
  • Coca

Pituri (Australian Tobacco)

  • Leaf of Duboisia hopwoodii; contains nicotine and nornicotine.

Mandragora (European Mandrake)

  • Root of Mandragora officinarum; superstition and folklore.
  • Contains hyoscyamine, scopolamine, and mandragorine.

Duboisia

  • Dried leaves of Duboisia myoporoides; chief source of atropine.
  • Contains (-)-hyoscyamine, scopolamine, nicotine and nornicotine.

Withania

  • Dried root of Withania somnifera; related to belladonna and hyoscyamus.
  • Sedative action.
  • Contains alkaloids.

Coca

  • Dried leaves of Erythroxylum coca:
    • var. coca (Huanuco coca)
    • var. spruceanum (Truxillo coca)
    • var. novogranatense (Truxillo coca)
Coca Alkaloids
  • Ecgonine derivatives (cocaine, cinnamylcocaine, truxilline)
  • Tropine derivatives (tropacocaine, valerine)
  • Hygrine derivatives (hygroline, cuscohygrine)
Huanuco Coca
  • 0.5-1% ester alkaloids; cocaine is major part.
  • Cuscohygrine is principal nonester alkaloid.
Truxillo Coca
  • Lower ester alkaloids, but up to 75% is cocaine.
Cocaine
  • Prepared semisynthetically from plant-derived ecgonine.
  • Hydrolyzes to ecgonine, benzoic acid, and methyl alcohol.
  • Cinnamylcocaine splits into ecgonine, methyl alcohol, and cinnamic acid.
Cocaine - Mechanism of Action
  • Psychomotor stimulant through dopamine reuptake inhibition.
  • Hydrochloride: local anesthetic (1-4% solution).
  • Brompton's cocktail ingredient: counteracts narcotic-induced sedation.
Cocaine Abuse
  • Inhaled/sniffed; rapid absorption across pharyngeal mucosa.
  • Free-basing: inhalation of vapors of alkaloidal cocaine.
  • Crack
  • Leads to reduced fatigue, increased mental clarity, and a rush of energy.
  • Addicts increase doses resulting in less pleasurable effect.

Quinoline (Cinchona) Alkaloids

  • From Cinchona: quinine, quinidine, cinchonine, cinchonidine
  • From Cuprea bark: quinidine

Biosynthesis

  • Tryptophan precursor to quinine
Cinchona
  • Bark of Cinchona succirubra, C. ledgeriana, or C. calisaya.
  • Alkaloids: Quinine, Quinidine, Cinchonine, and Cinchonidine.
Quinidine
  • Stereoisomer of quinine (0.25-1.25% in cinchona barks).
  • Depresses myocardial excitability, conduction velocity, and contractility.
  • Sulfate form readily soluble in water, alcohol, methanol, and chloroform.
  • Treats cardiac arrhythmias.
  • Dose: 10-20mg/kg/day in 4-6 divided doses (serum levels 3-6 mg/ml).
  • Gluconate and polygalacturonate salts have lower serum levels.
Cinchona Toxicity/Cinchonism
  • Occurs at levels above 8 mg/ml.
  • Symptoms: skin rash, fever, unusual bleeding/bruising, ringing in ears, visual disturbance.
Quinidine Gluconate
  • Controlled uniform absorption; Sustained-release tablets
  • Quinidine Polygalacturonate: Controlled uniformity, less GI irritation than sulfate form
Quinine
  • Antimalarial: Intercalation of quinoline moiety into Plasmodium DNA.
  • Treats chloroquine-resistant falciparum malaria (with pyrimethamine, sulfadiazine, or tetracycline).
  • Dose: 650 mg every 8 hours for 10-14 days.
  • Skeletal muscle relaxant: affects calcium distribution.
  • For nocturnal leg cramps: 260-300 mg at bedtime.