1. Alkaloids

2. Definition
Alkaloids may be defined as basic nitrogenous compounds which occur abundantly in the plant kingdom. They contain one or more nitrogen usually in a heterocyclic ring and have a marked physiological action on man & animals.
The nitrogen may exist as primary (1° amines), secondary (2° amines) or tertiary (3° amines) amine.
These compounds are basic but the degree of their basicity depends on the structure of the molecule and presence and location of other functional groups.

3. Examples:

4. Functions of Alkaloids in plants
The possible functions of alkaloids in plants are:
They are poisonous agents that protect the plants against insect & herbivores.
Alkaloids are reserve substances capable of supplying nitrogen or other necessary elements to the plant.
They may regulate growth/work as growth regulatory factor.
They are end product of detoxification reactions representing a metabolic locking-up of compounds otherwise harmful to the plant.

5. Properties
Most alkaloids are well defined crystalline solids and they unite with acids to form salts. In the plants they may exist in the Free State or as alkaline salts.
The alkaloids are usually insoluble or sparingly soluble in water but their salts with acids are freely soluble in water.
The free alkaloids are soluble in Ether, Chloroform or other non-polar solvents in which the salts are insoluble. This property now permits a ready mean for the isolation and purification of alkaloids.
The alkaloids usually possess a bitter taste.

6. Pharmacological actions:
The alkaloids have a wide range of pharmacological actions:
Pharmacological action
Example 1
Analgesic & narcotic
Morphine, Codeine 2
CNS stimulant
Strychnine 3
Mydriatic
Atropine 4
Miotic/Glaucoma
Pilocarpine 5
Hypertensive
Ephedrine 6
Antihypertensive
Reserpine 7
Antineoplastic/anti cancer
Vinblastine, Vincristine 8
Emetic
Emetine, Sanguinarine 9
Cardiac arrhythmia/dysrhythmia
Quinidine 10
Skeletal muscle relaxant
(+)-Tubocurarine 11
Oxitocic
Ergonovine (also known as Ergometrine) and it’s derivatives

7. Test for Alkaloids
Most alkaloids are precipitated from neutral or slightly acid solutions by various re-agents. The precipitate may be amorphous or crystalline and are of various colures such as:-
Reagents
Color
Mayer’s reagent (Potassium mercuric iodide solution)
Cream
Wagner’s reagent (solution of I₂ in KI)
Reddish brown
Dragendorff’s reagent (solution of potassium bismuth iodide)
Hager’s reagent (saturated solution of picric acid)
Yellow

8. Classification
Alkaloids may be classified in a number of ways. For example: they may be classified according to source, chemical structure or pharmacological actions etc. Each system has its advantages and disadvantages.
Usually they are classified on the basis of the ring structure or nucleus of the alkaloid as follows
Pyridine-Piperidine group
Tropane group
Quinoline group
Isoquinoline group
Indole group
Imidazole group
Steriodal group
Alkaloidal amino group
Lupinane group
Purine group

9. Pyridine-Piperidine group:
The alkaloids in this group contain Pyridine or Piperidine in the molecule. The important alkaloids in this group are Nicotine, Coniine, Arecoline, Lobeline etc.

10. Areca/areca nut/betel nut
Biological source:
Areca is the dried, ripe seed of Areca catechu Linne of Palmae family. The plant is a tall beautiful palm.
Constituents:
The total alkaloid content is areca can reach 0.45% containing
Arecoline. The most abundant and physiologically most active alkaloid. It is liquid and may exist upto 0.20% of total content in areca.
Arecaidine
Guvacine
Guvacoline
Areca also contains
Tannins (15%)
Lipid
Volatile oils and gum

11. Use: Anthelmintic in vaterinary practice as vermicide (expel intestinal worms) and taenifuge (expel tapeworms).

12. Tropane Alkaloids
Tropane is a dicyclic compound where both Pyrrolidine and Piperidine ring systems are present.
The important alkaloids in this group are Atropine, Hyoscyamine, Hyoscine (scopolamine) etc.

14. Biosynthesis of Tropane alkaloids:
Tropane is formed by the condensation of Pyrrolidine compound with 3 acetate derived carbon atoms.
The Pyrrolidine ring is formed from amino acid ornithine.
The remaining 3 carbon atoms are derived from acetate and methylation results in the completion of the tropine nucleus.
The 3-hydroxy derivative of tropane is called tropine.

15. On the other hand from phenylalanine tropic acid is formed via rearrangement and other reactions.
Esterification of tropine and tropic acid results in the formation of Hyoscyamine and thus other Tropane alkaloids are synthesized.

17. Biosynthesis of Tropane Alkaloid

19. Biosynthesis of Cocaine

20. Belladonna/ deadly nightshade:
Biological source:
Belladonna leaf consists of dried leaf and flowering or fruiting tops of Atropa belladonna Linne or its variety acuminata of Solanaceae family.
Belladonna root consists of dried roots of Atropa belladonna LInne of Solanaceae family.
The plant is a perennial herb that grows to 1m in height. “Atropa” is from greek “atropos” meaning inflexible.
Atropos is the name of Greek Fate who cuts the thread of life and probably refers to the poisonous character of the drug.
“Belladonna” is from two Italian words “bella” meaning beautiful and “donna” meaning lady.
This probably refers to the fact that, juice of the berry of plant when placed in the eyes causes dilation of the pupils giving an outstanding appearance.

21. Constituents:
Belladonna leaf yields about 0.4% (no less than 0.35%) and belladonna root yields about 0.6% alkaloids containing
About ¾th of the mixture is Hyoscyamine
Remaining is atropine
Use:
As Mydriatics
As parasympatholytic agent (depress or block parasympathetic nerve). Thus it decreases the flow of most secretions like saliva, sweat, milk, gastric secretion etc. Thus it is used as adjunct therapy in peptic ulcer and different GIT disorders.

22. Stramonium/thorn apple/jimson weed/Jamestown weed
Biological source:
It consists of dried leaf and flowering or fruiting tops (with branches) of Datura stramonium Linne or its variety Tatula torrey of Solanaceae family.
The plant is an annual herb that attains height of about 2m.

23. Constituents:
The drug contains % alkaloids (it yields no less than 0.25% if ideal). The alkaloids present are Tropane alkaloids-
Hyoscyamine. This is more abundant
Scopolamine
Use:
Its actions are similar to belladonna. It is used as
Parasympatholytic
Anticholinergic
It is used in preparations intended to burn to yield vapor that relief asthma.

24. Hyoscyamus/henbane: Biological source:
Hyoscyamus or henbane is the dried leaf with or without the flowering or fruiting top of Hyoscyamus niger Linne of Solanaceae family.
Constituents:
The drug contains about 0.05 – 0.15% alkaloids (no less than 0.04%). Alkaloids include
Hyoscyamine (3/4th)
Scopolamine

25. Use:
As parasympatholytic but its use is as crude drug in medicine is rare.
Egyptian henbane (Hyoscyamus muticus) yields about 1.5% alkaloids most of which is Hyoscyamine

26. Coca/Coca Leaf Biological source:
It is the dried leaves of Erythoxylum coca Lamack (Huanuco coca) or E. truxillence Rusby (Truxillo coca) of Erythroxylaceae family.
The plant is a shrub or small tree attaining a height of about 2m.
There are several varieties
Huanuco coca
Truxillense coca
Colombian coca

27. Constituents:
Coca contains three basic types of alkaloids
Derivatives of ecgonine
Derivatives of tropine
Derivatives of hygrine
With different variety the composition of alkaloid mixture varies. But cocaine is the major alkaloid. Cocaine is the methyl ester of benzoyl ecgonine. Where hydrolyzed it splits into ecgonine, benzoic acid and methyl alcohol.
Huanuco coca yields about 0.5-1% of alkaloids whereas Truxillense coca give lower amount but higher percentage of cocaine.
Use:
Cocaine and its hydrochloride salt are local anesthetic (applied as 1-4%).
When taken internally it is CNS stimulant.
When taken in larger dose or used continuously it becomes narcotic.

28. Quinoline Alkaloids
Alkaloids containing the Quinoline ring as the principal nucleus are Quinine, Quinidine, Cinchonine, cinchonidine etc.

29. Biosynthesis of Quinoline alkaloids
The precursor of quinine and other Quinoline alkaloids is Tryptophan.
Its biosynthesis in plant is not fully understood but in microorganisms it is obtained via shikimic acid pathway.
In this pathway, shikimic acid through a series phosphorylation reaction yields chorismic acid.
Chorismic acid is an important branch point where one branch leads to prephenic acid and then to aromatic amino acids like tyrosine, phenylalanine where the other branch lead to anthralinic acid and then to Tryptophan.
Tryptophan and corynanthe like monoterpene form corynantheine which yield quinine.

30. Biosynthesis of tryptophan in microorganism

33. Cinchona/Peruvian bark/ cinchona bark
Biological source:
It is the dried bark of the stem or the roots of Cinchona succirubra or its hybrids (red cinchona) and C. ledgeriana, C. calisaya or hybrids of these with other Cinchona species (Yellow cinchona) of Rubiaceae family.
The plant is a tall tree attaining m.

34. Constituents:
Cinchona contains about 25 closely related alkaloids. The average yield is 6-7%. The alkaloids include
Quinine
Quinidine
Cinchocine
Cinchonidine
In the red cinchona Cinchonidine exist in greater proportion (as much as 18%) whereas in yellow bark two third is quinine.

35. Use:
As febrifuge. Cinchona bark and its alkaloids have been used in the treatment of malaria fever for many years. Quinine is still used in material treatment in many parts of the world.
Quinidine is cardiac depressant and used to prevent auricular (atrial) fibrillation to coordinate contraction of the auricular (atrial) muscle.

36. Cuprea bark: Biological source:
Cuprea bark is obtained from Remijia purdieana Traina and R. pedunculata Fluckiger of Rubiaceae family.
The plant is a tree.
Constituent:
It yields about 2-6% alkaloids containing
One third quinine
Quinidine and cuprea bark is the major commercial source of quinidine.
Use:
Quinidine is used as cardiac depressant.

37. Isoquinoline alkaloids:
The Isoquinoline alkaloids ring occurs in a member of alkaloids in widely separated plant families. For example: Papaverine, Morphine, Emetine etc.

39. Biosynthesis of Isoquinoline alkaloids:
From phenylalanine of tyrosine Phenylethylamine derivatives and phnylacetaldehyde derivatives are obtained which are condensed to give Isoquinoline alkaloids.
Morphine (and codeine, thebaine) is also formed from tyrosine (2 molecules) and in the biosynthetic pathway Norlaudanosoline is a key intermediate.

41. Opium/gum opium: Biological source:
The air dried milky exudates obtained by incising the unriped capsules of Papaver somniferum Linne of Papaveraceae family.
The plant poppy is an annual herb with large, showy, solitary, flowers having color of pink to purple.

42. Constituents
More than 30 alkaloids are found in opium. The most important are the alkaloids
Morphine: It is the most important opium alkaloid. It is a phenanthrene derivative containing an alchoholic and phenolic OH group. Morphine and its salts occur as white silky crystals, odorless and having a bitter taste. They are classified as narcotic analgesics and are strong hypnotic and narcotic. Their use tends to induce habit formation as well as common side-effects as nausea, vomiting and constipation.
Codeine: It is the most widely used opium alkaloid. It is obtained from opium, or by methylation of morphine or by appropriate reduction and demethylation of thebaine. If methyl group replaces the hydrogen of phenolic OH in morphine it becomes codeine

43. The drug and its salts are narcotics and antitussives
The drug and its salts are narcotics and antitussives. They are used as sedatives especially in allaying coughs. Its action is similar to that of morphine but is less toxic.
Heroin: Diacetylmorphine or heroine is formed by acetylation of morphine, where the hydrogen atoms of both the phenolic and alchoholic hydroxyl groups are replaced by acetyl groups. Its action is similar but more pronounced than that of morphine. Due to its potency and the danger of habit formation it is not used in medicine.
Noscapine
Thebaine
Papaverine

44. Also contains alkaloids like
Narceine
Protopine
Laudanine
Codamine
Cryptopine
Lanthopine
Mecondine
Use: The drug acts on CNS and first stimulates then depresses nerve response. It serves as
Analgesic
Hypnotic
Narcotic

45. Ipecac Biological source:
It is dried rhizomes and roots of Cephaelis ipecacuanha A. Richard (known as Rio ipecac) and C. acuminate (panama ipecac)of Rubiaceae family.
The plants are low, straggling shrubs with slender rhizomes bearing annulated wiry roots.
Constituents:
Ipecac yields 2-2.5% alkaloids (not less than 2%) containing 5 alkaloids 3 of which are
Emetine
Cephaeline
Psychotrine

46. Use:
It is emetic and used in poisoning treatment
It is also used in amoebic dysentery.

47. Sanguinaria/ blood root:
Biological source:
It is dried rhizome of Sanguinaria Canadensis Linne of papaveraceae family. The plant is a perennial herb with horizontal branching rhizome that bears slender.
Constituents:
It contains protopine alkaloids like
Sanguinarine (1%)
Chelerythrine
Protopine
Allocryptopine
Use: As stimulating expectorant and emetic

48. Curare/South American arrow poison:
Biological source:
It is the dried crude extrac from the bark and stems of Strychonos castelnaei Weddell, S. toxifera Bentham , S. crevauxii G. Planchon of Loganiaceae family and Chondodendron Tomentosum Ruiz et Pavon of Menispermaceae family.
The plants are trees.
Constituents:
It contains several alkaloids and quaternary compounds. Specific composition varies with the plant material and preparation method. But (+/-) Tubocurarine is the most important constituent.

49. Use:
Indians used it as poisons.
Curare is rarely used in medicine but (+/-) tubocuratine chloride is used as a skeletal muscle relaxant in surgery and to control convulsions of strychinine poisoning and of tetanus.

50. Indole alkaloids:
A number of important alkaloids possess an indole ring in their structure. For example: Strychnine, Reserpine, Brucine, Vinblastine, Vincreistine etc.

51. Biosynthesis of Indole alkaloids
The precursor of indole alkaloids is tryptophan and monoterpenoid skeleton.
Alkaloids like reserpine, serpentine are synthesized from tryptamine and corynanthe monoterpenoid precursor.
The ergot alkaloids are synthesized by alkylation of Tryptophan by DMAPP as illustrated below:

53. Ergot/Rye ergot/Secale cornutum
Biological source:
Ergot is obtained on a commercial scale from both parasitic and saprophytic source.
Parasitic source: It is the dried selerotium (resting body of the ergot fungus given next) plants (Secale cerale Linne. Of Graminae family).
Saprophytic source: In this case the ergot alkaloids are obtained from the fermentation broth in which the mycelium of selected strains of Claviceps Paspali Stervens & Hall has been grown saprophytically in submerged culture.

54. Constituents:
Ergot contains no less than 0.15% total alkaloids. It contains a large number of alkaloids. The most important ones are
Ergonovine (principlal water soluble alkaloid)
Ergotamine
Ergotoxine (mixture of egocristine, ergokrypine, ergocornine)
Significant semsynthesis alkaloids include
Methylergonovine
Dihyddroergotamine
Hydergine

55. Use:
Ergonovine is an oxytocic, producing stimulation of the uterine muscle. It is used for the prevention and treatment of postpartum hemorrhage due to uterine atony.
Ergotamine is used as a specific analgesic in migraine.

56. Rauwolfia serpentine Biological source:
Rauwolfia serpetina is the dried root of Rauvolfia serpentina (also Rauwolfia serpentina) Bentham ex Kurz of Apocynaceae family.
The plant is an erect shrub that reaches 1 m in height and has cylindric stems.
Constituents
Three series of alkaloids have been reported
Weakly basic Indole alkaloids: Reserpine, Resinnamine, Deserpidine etc.
Intermediately basic indole alkaloids: ajmaline, isoajmaline, rauwolfinine etc.
Strong anhydronium bases: serpentine, serpentinine, alstonine etc.

57. Use:
Hypotensive
The chief alkaloid reserpine is antihypertensive and used and tranquilizer drug.

58. Nux-vomica Biological source:
Nux-vomica is the dried, ripe seed of Strychnos nux-vomica Linne of loganiaceae family.
The plant is a small tree of about 12m.
Constituents
It contains about 1.5-5% alkaloids.
Strychinine (chief constituents, about ⅓rd of total alkaloid content)
Brucine
Isostrychnine etc.

59. Use:
Strychnine is extremely toxic due stimulant effects and used as insecticide
Brucine is less toxic and used as alcohol denaturant

60. Catharanthus/Vinca Biological source:
It is dried whole plant of Catharanthus roseus G. Don (formerly vinca rosea Linne) of Apocynaceae family.
The plant is an erect ever blooming pubescent herb or subshrub attaining cm and iti is widely cultivated as ornamental plant. The flowers of the plant are violet, rose or white.

61. Constituents:
More than 70 alkaloids have been isolated. Important alkaloids are Indole Dihydroindole derivatives like
Vinblastine
Vincristine
Vinleurosine
Vinrosidine
Also contains
Ajmalicine
Tetrahyddroalstonine
Serntine
Lochnerine etc.

62. Use:
Catharanthus has anticancer properties
Vinblastine is used in Hodgkin disease and choriocarcinoma
Vincristine is used in the treatment of leukemia in children

63. Imidazole Alkaloids
Imidazole ring occurs in the alkaloids Pilocarpine, Isopilocarpine etc.

64. Pilocarpus Biological source:
It consists of the leaflets of Pilocarpus jaborandi Holmes, P. microphyllus stapf or P. pinatifolius Lamaire of Rutaceae family.
Constituents:
It contains
Pilocarpine
Isopiocarpine
Pilosine
Isopilosine etc.
Use: The principal constituent Pilocarpine is used to great glaucoma

65. Steroidal Alkaloids
The steroidal alkaloids are characterized by the cyclopentanoperhydrophenanthrene nucleus. The important alkaloids Protoveratrine A &B, Aconitine, Conessine etc.

66. Veratrum viride/green hellebore
Biological source:
It is dried rhizome and roots of Veratrum viride of Liliaceae family.
It is a perennial herb attaining 0.7 to 2 m height.
Constituents:
It contains a large number of alkaloids as follows-
Esters of alkamines (steroidal bases): Germidine, germitrine, cevadine, protoveratrine etc.
Glucosides of alkamines: Pseudojervine, veratrosine.
The alkamines: Jervine, rubijervine, germine etc.
Among them germidine and germitrine are most important therapeutically.

67. Use:
It possesses hypotensive, cardiac depressant and sedative properties.
It is used in the treatment of hypertension.
As insecticide.

68. Veratrum album/ white hellebore
Biological source:
It is dried rhizomes of Veratrum album Linne of Liliaceae family. It is also a perennial herb but the external color is lighter compare to V. viride.
Constituents:
Similar to V. viride. Two ester alkaloids protoveratrine A and B are most active.
Use:
It has hypotensive properties
As insecticides

69. Aconite Biological source:
It is dried tuberous roots of Aconitum napellus of Renunculaceae family. The plant is perennial herb.
Constituents:
It contains aconitine, aconine and aconitic acid etc.
Use:
Has cardiac effect but
Principally used as local analgesic in liniments

70. Alkaloidal Amino Group
The alkaloids in this group do not contain heterocyclic nitrogen atoms. For example: Colchicine. Some are derivatives of Phenylethylamine like Ephedrine, Mescaline etc.

71. Example

72. Ephedra/ Ma huang Biological source:
It is the entire plant or the overground portion of Ephedra sinica stapf of Gnetaceae family.
The plant is a low, dioecious (male and female reproductive organs on different plants) practically leafless shrub that attain cm height.
Constituents:
The important constituent is ephedrine. It may also contain pseudoephedrine and some other related compounds.
Use:
Ephedrine is a potent sympathomimetic (excites the sympathetic nervous system).
It raises blood pressure and causes mydriasis and act as bronchodilator.

73. Colchicum Seed Biological source:
It is dried, ripe seed (or corn) of Colchicum autumnale Linne of Liliaceae family.
Two to six flowers with long perianth tube develop from the underground plant. The arabs had recommended the use of colchicum in the treatment of gout.
Constituents:
It contains colchicine, colchicine like alkaloids, resin, fixed oil and reducing sugars. The seed contains upto 0.8% colchicine (corn contains 0.6% colchicine).
Use:
It is in the treatment of gout.

74. Lupinane Alkaloids
The alkaloids in the group contain a dicyclic Lupinane structure/ring . For example: Sparteine, Lupinine etc.

75. Lupinus Biological source:
Lupinus is obtained from Lupinus luteus of Fabaceae family.
The plant is an annual herb and cultivated as ornamental plant.
Constituents
Important constituents is Lupinine.
Use:
Not medicinally important.

76. Scoparius
It is the dried tops of Cytisus coparius of Leguminosae family.
Constituents:
Its main constituents are Lupinane alkaloids including Sparteine and flavonoids.
Use:
It is and oxitoxic and is used in the treatment of uterine inertia.

77. Purine Alkaloid
The alkaloids in this group contain the Purine nucleus which consists of the six membered Pyridine ring fused to the five membered Imidazole ring.
The important examples in this group are Caffeine, Theobromine etc.

78. Coffee/Coffea Biological source:
It is dried, ripe seeds of Coffea Arabica Linne of Rubiaceae family.
The plant is small evergreen tree or shrub.
Constituents: It contains:
Caffeine (1-2%)
Trigonelline (0.25%)
Tannin (3-5%)
Sugar (15%)
Fatty oil (10-13%)
Protein (10-13%)
Use:
Caffeine is the main principle which is CNS stimulant.

79. Tea/Thea Biological source:
Tea is the prepared leaves or leaf buds of Camelia Sinensis O. Kuntze of Theaceae family.
It is shrub or small tree with alternate, evergreen leaves.
Constituents:
Tea contains:
Caffeine (1-4%)
Adenine
Theobromine
Theophylline
Xanthine
15% gallotannic acid
0.75% of a yellow volatile oil.
Use:
As beverage
As smooth muscle relaxant attributed to theophylline

80. Cocoa Biological source:
It is obtained from the dried, ripe seeds of Theobroma cacao Linne of Sterculiaceae family. The plant is a moisture loving rainforest tree.
Constituents:
It contains
Theobromine
Caffeine
Cocoa butter
Use:
It is a nutrient, stimulant and diuretic.
Theobromine is diuretic and smooth muscle relaxant
Cocoa butter as base for semisolid drugs.

81. Exraction of alkaloids
Powderd Materials
Free alkaloids and other plant constituents
Organic layer containing alkaloids and other plant constitutents
Aqueous layer containing alkaloidal salts
Precipitaion of free alkaloids
organic layer containing other organic compounds
Aqueous layer containing water soluble compounds
Process-I

82. Description
The powdered material is moistened with aqueous alkali [water and mixed with lime which combines with acids, tannins and other phenolic substances and sets free the alkaloids (if they exist in the plant as salts)].
The alkaloids are set free with other plant constituents.
Extraction is then carried out with organic solvents such as Benzene or chloroform (either or petroleum spirit).
The concentrated organic liquid which contains alkaloids and other plant constituents is then dilute acid (aqueous acid) and allowed to separate.
Alkaloid salts are now in the aqueous liquid, while many impurities remain behind in the organic liquid.
Aqueous alkali is added to the aqueous layer giving precipitation of free alkaloids.

83. Aalkaloidal salts and other plant constituents
Powderd Materials
Aalkaloidal salts and other plant constituents
Organic layer containing pigments and other Organic compounds.
Aqueous layer containing Alkaloidal salts
Precipitation of free alkaloids
Moisten with water or aqueous alcohol containing dilute acids
Process-II
Extract with organic solvent like Benzene, Chloroform etc.
Add aqueous alkali

84. Description
The powdered material is extracted with water of aqueous alcohol containing dilute acid.
We get Alkaloidal salts and other plant constituents.
Pigments and other unwanted materials are removed by shaking with chloroform or other organic solvents.
Then we get aqueous layer containing Alkaloidal salts.
The free alkaloids are then precipitated by the addition of aqueous alkali (excess sodium bicarbonate or ammonia) and separated by filtration or by extraction with organic solvents.