Pilocarpine-Synonyms Ocusert Pilo-Pilocarpus jaborandi, Pilocarpus pennatifolius, Pilocarpus microphyllus, Pilocarpus selloanus , Pilocarpus trachylophus, Pilocarpus spicatus, Pilocarpus heterophyllus, Pilocarpus racemosus

2.3.1 Pilocarpine


Synonyms Ocusert Pilo.
Biological Source Pilocarpine is obtained from the leaves of closely related plants of the genus Pilocarpus, belonging to the natural order Rutaceae. However, the genus comprised of a variety of species commonly known by various names, such as: Pilocarpus jaborandi (Pernambuco Jaborandi), (Pilocarpus pennatifolius (Paraguay Jaborandi); Pilocarpus microphyllus (Maranham Jaborandi); Pilocarpus selloanus (Rio Jaborandi); Pilocarpus trachylophus (Ceara Jaborandi); Pilocarpus spicatus (Aracati Jaborandi); Pilocarpus heterophyllus (Barqui Simento Jaborandi); and Pilocarpus racemosus (Guadeloupe).
It is worthwhile to mention here that P. microphyllus is the major commercial source of this drug.
Chemical Structure

(3S-cis)-3-Ethyldihydro-4-[1-methyl-1H-imidazol-5-yl) methyl]-2(3H)-furanone (C11H16N2O2).
Pilocarpine is a monoacidic tertiary base comprising of a lactone ring and an imidazole nucleus. It is the lactone of pilocarpic acid, an acid with a glyoxaline nucleus, as given below:


lactone of pilocarpic acid, an acid with a glyoxaline nucleus
Isolation The finely powdered leaves of Jaborandi is first extracted with ethanol (95% v/v) containing 1% HCl. The ethanol is distilled off under vacuo and the residue is taken up with a little water and neutralized carefully by the addition of dilute ammonia. The resins separating out are filtered off and the filtrate is concentrated to a small volume. The resulting concentrated filtrate is alkalified with an excess of ammonia and the liberated alkaloids are shaken out with at least three successive portions of chloroform. The chloroform is removed from the combined extract under vacuo.
The residue is dissolved in a minimum volume of distilled water and neutralized with dilute HNO3 (6N). The mixture of nitrates of pilocarpine and isopilocarpine crystallizes out upon cooling; which may be further separated by fractional crystallization from ethanol.
Characteristic Features
1. It is found as oil or crystals having mp 34°C.
2. It boils at bp5 260°C with partial conversion to its isomer isopilocarpine.
3. Its specific rotation is [ α]D18  +106o (C = 2) and dissociation constant pK1 (20°C) 7.15; and pK2 (20°C) 12.57.
4. It is soluble in water, alcohol, chloroform, sparingly soluble in ether and benzene; and practically insoluble in petroleum ether.
5. It exhibits an absorption maximum at 263 nm.
6. It behaves as a monoacidic base.
7. It usually gives distinct precipitates with a number of reagents, such as: Wagner’s Reagent, Mayer’s Reagent, Hager’s Reagent, silicotungstic acid, phosphomolybdic acid, gold and platinic halides.
Note: Some of these precipitates do help in the identification of pilocarpine.
8. Cessation of Lactone-Ring: The lactone ring is opened-up (undergoes cessation) by treatment with strong alkalies like NaOH, KOH, which ultimately form salts with the formation of pilocarpic acid as given below:

Cessation of Lactone-Ring: salts with the formation of pilocarpic acid
Note: The cessation of the lactone-ring absolutely destroys the physiological activity of pilocarpine; and the lactone-ring is not affected by either ammonia or alkali carbonates.
9. KMnO4-Oxidation: KMnO4 oxidation destroys the imidazole ring in pilocarpine and yields ammonia, methyl amine, pilopic acid, homopilopic acids plus other products.

Kmno4-oxidation yields ammonia, methyl amine, pilopic acid, homopilopic acids
Isomerism Pilocarpine and isopilocarpine are stereoisomers, that essentially exhibit the stereochemical difference in the lactone moiety of the molecule as shown below:

Isomerism Pilocarpine and isopilocarpine are stereoisomers
However, the above observation is based on the experimental evidence, which specifically depicts that the isomerism of the above two alkaloids still persists, even when the imidazole moiety undergoes destruction under mild experimental conditions.
Identification Tests
1. Helch’s Violet-Colour Test: Pilocarpine readily forms a violet coloured compound when a solution of either the base or its salt is first treated with hydrogen peroxide (H2O2) and then with potassium dichromate (K2Cr2O7) in the presence of few drops of dilute sulphuric acid (Helch, 1902).
Note:
(i) The violet-coloured compound (i.e., pilocarpine perchromate) is soluble in chloroform and benzene. It was further characterized as pilocarpine perchromate by Biedebach (1933).
(ii) Shupe successfully employed the Helch’s reaction to determine pilocarpine quantitatively by the colourimetric assay.
2. Ekkert’s Colour Tests: Add to 1 ml of 1% (w/v) solution of pilocarpine hydrochloride (C11H16N2O2.HCl) 1 ml of sodium nitroprusside solution (2% w/v) and 1 ml of NaOH solution (1N). Allow the reaction mixture to stand for 6-8 minutes and then acidify with dilute HCl when a wine or red colour develops.
(Note: Isopilocarpine hydrochloride also gives a similar colour test.)
Further, when a few drops of 0.1 N sodium thiosulphate solution are added to the wine or red colour solution, it changes to distinct green colouration.
Note: Elvidge (1947) put forward a method for the assay of the total alkaloids of Pilocarpus leaves based on the Ekkert’s colour test.
Uses
1. Pilocarpine possesses miotic and diaphoretic actions.
2. Pilocarpine nitrate is used extensively as an ophthalmic drug having cholinergic action.
3. It is also employed to reduce the intra-ocular pressure in glaucoma patients.

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