Alkaloids

Drugs Containing Alkaloids

15.1. Introduction

• Alkaloids are one of the largest groups of chemicals produced by plants.

• They are metabolic by-products largely derived from amino acids, consisting of numerous bitter, nitrogenous compounds.

• Over 10,000 different alkaloids have been identified across more than 300 plant families.

• Structural Characteristics:

  • Alkaloids typically contain one or more rings of carbon atoms.

  • A nitrogen atom is often present within the carbon ring, though for some alkaloids (e.g., mescaline), the nitrogen atom is not within the ring.

  • The precise positioning of the nitrogen atom in the ring alters the properties of different alkaloids.

• Pharmacological Activities:

  • Alkaloids are famed for their potent pharmacological activities.

  • Some can immobilize large animals (e.g., elephants, rhinoceroses).

  • Others are clinically significant, being used as analgesics, antimalarials, antispasmodics, and for treating hypertension, mental disorders, and tumors.

• Chemical Nature:

  • Alkaloids are nitrogen heterocycles occurring mainly as salts of common carboxylic acids (e.g., citric, lactic, oxalic, acetic, maleic, tartaric, fumaric, benzoic, aconitic, and veratric acids).

  • Their amine character produces an alkaline solution in water, which is the origin of the name "alkaloids."

• Evolutionary Context:

  • Alkaloids existed prior to human civilization yet share remarkable structural similarities with human neurotransmitters (e.g., dopamine, serotonin, acetylcholine).

  • Their effects on humans have led to the development of both powerful medications and serious addictions.

15.2. Definition

• An alkaloid is defined as a nitrogenous organic molecule with a pharmacological effect on humans and animals.

• Characteristics of Alkaloids:

  • Typically contain nitrogen and have complex ring structures.

  • Naturally occurring in seed-bearing plants, found in various parts (e.g., berries, bark, fruit, roots, leaves).

• Physiological Effects:

  • Alkaloids generally behave as bases with physiological effects.

• Origin of the Name:

  • Derived from the term "alkaline"; originally described any nitrogen-containing base (amines in modern terminology).

• Alkaloid Sources:

  • Found as secondary metabolites in plants (e.g., Vinca and Datura), animals (e.g., shellfish), and fungi.

  • Can be extracted through treatment with acids (hydrochloric, sulfuric, maleic, citric).

• Toxicity and Medical Use:

  • Many alkaloids are toxic (e.g., strychnine, coniine), yet some are therapeutically beneficial (e.g., morphine, codeine, analgesics, and anesthetics).

• General Taste:

  • Most alkaloids possess a bitter taste.

15.3. History

• Historical Use:

  • Alkaloids have been utilized by humanity for thousands of years, with evidence suggesting early use by ancient Sumerians and Egyptians.

• Isolation and Analysis:

  • Systematic analysis of alkaloids began in the early nineteenth century.

  • Advances in techniques like chromatography and mass spectroscopy facilitated the elucidation of alkaloid structure.

• Terminology:

  • The term "alkaloid" is believed to have initially referred to morphine's properties, likened to basic salts (7vegetable alkali7).

• Notable Historical Events:

  • The use of Cinchona bark discovered by Spanish and Portuguese explorers as a cure for malaria noted in the 1630s.

  • The alkaloid narcotine was isolated in 1803; morphine was isolated between 1803-1816, becoming widely used for pain relief by the late 1830s.

  • Other significant alkaloids were isolated shortly thereafter: strychnine (1817), emetine (1817), brucine (1819), piperine (1819), caffeine (1819), quinine (1820), colchicine (1820), and conine (1826).

  • By the latter half of the twentieth century, alkaloids played a significant role in anticancer drug development.

15.4. Classification

• Alkaloids are classified by their molecular precursors and discussed in terms of their structure and origin.

• There are three main types of alkaloids:

  • True Alkaloids: Derived from amino acids containing nitrogen in a heterocyclic ring.

  • Properties:

    • Reactivity: Highly reactive, with biological activity even in low doses.

    • Taste: All share a bitter taste and typically appear as white solids (except for nicotine, which is a brown liquid).

    • Solubility: Form water-soluble salts; often crystalline and unite with acids.

    • Occurrence: Found in limited species and families; derived from decarboxylated amino acids.

  • Examples: Cocaine, quinine, dopamine, morphine.

  • Protoalkaloids: Compounds where the nitrogen atom from amino acids is not part of the heterocyclic structure.

  • They are simple, closed-ring alkaloids and constitute a minority of alkaloids.

  • Examples: Hordenine, mescaline, yohimbine, new alkaloids derived from Boscia angustifolia such as stachydrine.

  • Pseudoalkaloids: Compounds whose primary carbon skeletons do not derive from amino acids but relate to amino acid pathways, frequently involving nonamino acid precursors.

  • The nitrogen can emerge from amino acid sources in a later stage of synthesis.

  • Examples: Coniine, capsaicin, ephedrine, solanidine, caffeine, theobromine.

• Classification can also be based on chemical structure, distinguishing between heterocyclic and non-heterocyclic alkaloids.

15.5. Occurrence in Nature

• Alkaloids have historical and contemporary significance, being used in shamanistic practices, traditional herbal medicine, and as toxins in tribal warfare.

• Alkaloids are prominently found in higher plants; approximately 25% contain alkaloids.

  • Detection: Advanced equipment can detect trace alkaloids (< 10 gg/kg) that generally do not affect biological activity.

  • Defining Alkaloid Plants: Those containing more than 0.01% alkaloids, according to Hegnauer.

• Distribution Patterns: Alkaloids are primarily found in angiosperms but also in some lower plants and animals.

  • Approximately 47-50% of certain bacterial species, e.g. Pseudomonas aeruginosa, contain alkaloids.

• Common Families: Alkaloids are present in many plant families, including:

  • Chenopodiaceae, Lauraceae, Berberidaceae, Menispermaceae, Ranunculaceae, Papaveraceae, Fumariaceae, Leguminosae, Papilionaceae, Rutaceae, Apocynaceae, Loganiaceae, Rubiaceae, Boraginaceae, Convolvulaceae, Solanaceae, Campanulaceae, and Compositae.

• Presence in Plant Parts:

  • Roots (reserpine from Rauwolfia), aerial parts (Ephedra), barks (quinine from Cinchona), leaves (cocaine from coca), seeds (caffeine from coca seeds), or whole plants (vinblastine from Vinca).

• About 300 alkaloids from more than 24 classes found in amphibian skins.

15.6. Properties

• Alkaloids possess similar properties despite the vast diversity:

  • Generally colorless, crystalline, and basic.

  • Characteristically bitter taste and ring structures with definite melting points.

• Exceptions include non-basic and brightly colored alkaloids (e.g., betanidine, beriberine, sanguinarine) as well as liquid forms (e.g., nicotine).

• Many alkaloids are chiral, leading to the presence of isomers with differing chemical properties, resulting in varying physiological effects.

• Solubility:

  • Alkaloid bases are typically soluble in organic solvents, insoluble in water while their acidic salts are water-soluble and partially soluble in organic solvents (e.g., strychnine hydrochloride).

15.7. Extraction

• Alkaloids are extracted based on their basic character and solubility:

Method A

• The powdered material with alkaloidal salts is moistened with alkaline substances (e.g., sodium bicarbonate, ammonia) which release alkaloid bases.

• Extraction is subsequently performed with organic solvents (e.g., ether, petroleum spirit).

• The concentrated organic solution is mixed with aqueous acid, leading to the separation of alkaloid salts (in aqueous phase) from impurities (in organic phase).

Method B

• Powdered material is extracted with water or aqueous alcohol containing a dilute acid.

• Add chloroform or other organic solvents to eliminate pigments and unwanted materials.

• Free alkaloids precipitate upon adding excess alkalies like sodium bicarbonate or ammonia, followed by filtration or organic solvent extraction.

• For volatile alkaloids (e.g., nicotine, coniine), distillation isolates them. The powdered material is extracted with water; the alkaline aqueous extract facilitates steam distillation for collection and purification.

15.8. Chemical Tests

• Performed from a neutral or slightly acidic drug solution.

  • Dragendorff's Test: Formation of orangish-red color with Dragendorff's reagent (Potassium Bismuth Iodide).

  • Mayer's Test: Formation of creamy-white precipitate with Mayer's reagent (Potassium mercuric iodide).

  • Hager's Test: Formation of crystalline yellow precipitate with Hager's reagent (Saturated aqueous solution of Picric acid).

  • Wagner's Test: Formation of reddish-brown precipitate with Wagner's reagent (dilute Iodine solution).

  • Tannic Acid Test: Formation of buff-colored precipitate with tannic acid solution.