Pilocarpine

Oral pilocarpine is moderately effective for treating xerostomia following irradiation of head and neck cancer. It may also be beneficial in relieving refractory xerostomia associated with chronic graft-versus-host disease (see Chapter 14). 

Goblet cell population increased in the guinea pig (body weight 400 to 500 g) trachea after intra-peri toneal application of 12 daily successive doses of 2.5 mg pilocarpine (Ranga and Kleinerman 1982). 

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Pilocarpine [92-32-7] Piloted airblast atomizer Pilot-plant Pilot plants Pilsner Pimaric acid [127-27-5]... 

Initial attempts to treat AD using direct cholinergic agonists were limited by low efficacy and side-effect issues (140—142). Thus trials using RS-86 (25), oxotremorine [70-22-4] (26), arecoline [63-75-2] (27), and pilocarpine [92-32-7] (28) to treat AD were equivocal (Eig. 5). However, the identification of multiple subtypes of muscarinic receptors has stimulated a search for subtype specific muscarinic agonists which may limit side effects while increasing efficacy. 

Ophthalmic dmg dehveiy systems (qv) have been developed to dehvei controlled dmg quantities for a prolonged time (up to seven days) to the eye, eg, pilocarpine [92-13-7J (17). Alza Corp. in conjunction with Ciba-Geigy Corp. originally marketed such a product known as Ocusert to treat glaucoma. 

Fig. 2. Ocusert ocular therapeutic system. The Ocusert system releases pilocarpine at a controUed rate to treat glaucoma. In this schematic representation, the three disks and the ring are shown two-dimension ally. The patient inserts the Ocusert system under the eyeUd, where it releases pilocarpine for seven...

Fig. 3. Release rate of pilocarpine from Ocusert Pilo-20. Data points shown with standard deviation error bars (94).

Hirvonen, M. R., Paljarvi, T., and Savolainen, K. M. (1993). Sustained effects of pilocarpine-induced convulsions on brain inositol and inositol monophosphate levels, and brain morphology in young and old male rats. Toxicol. Appl. Pharmacol. 122, 290-299. 

Cushny has compared the action of d- and Z-hyoscyamines with that of atropine, and of d-homatropine with that of dZ-homatropine in antagonising the action of pilocarpine, and finds that the order of activity of the first three is in the ratio 1 40 20, and of the second two in the ratio 4 2-5. He drew attention also to the important influence of the acyl radical in the tropeines, which exercises the maximum effect when it is a hydroxyalkyl aromatic residue and is laevorotatory and in illustration of this point gives the following table of relative activities on the basis of capacity to antagnonise pilocarpine in the salivary fistula dog —... 

The same author found Z-hyoscine sixteen to eighteen times as active as the d-isomeride in antagonising the action of pilocarpine on the termination of nerves in the salivary glands, -while both isomerides are equally active on nerve ends in striated and unstriated muscle and on the central nervous system. 

Name of Plant Commercial Name Constituents Amount of Total Alkaloid per cent. Amount of Crystalline Pilocarpine Nitrate obtai ned per cent. 

P. microphyllus (Stapf). Maranham jaborandi Pilocarpine isopilocarpine pilosine 0-70-0 78 0 45 ... 

The extraction of alkaloids from jaborandi has been dealt with by Wurtzen, and the estimation of pilocarpine in the drug and its preparations by Jowett and by Bourcet and more recently by Taran and by Shupe.ii Elvidge has devised a colorimetric method based on Ekkert s test, < and a polarographic study has been made by Kirkpatrick. Tlie two first-pamed authors depend on the isolation of pilocarpine nitrate, which is also the basis of the process of manufacture described by Cheninitius.12... 

Pilocarpine, CiiHijOjNj. The base is a colourless oil, b.p. 260°/5 mm. (partially isomerised to iSopilocarpine on distillation), [a]n -f 100-5° (CHCI3), but has been crystallised, m.p. 34° it is freely soluble in water, alcohol or chloroform, but almost insoluble in ether. The salts with acids crystallise well the nitrate, B. HINO3, forms well-defined prisms, m.p. 178°, [a]r, 82-9° (HjO), and dissolves in 6-4 parts of water at 20° or... 

Pilocarpine dissolves in dilute soda solution, and the rotation is thereby reduced, due to the formation of the sodium salt of pilocarpic acid, CiiHigOgNa, of which pilocarpine is the lactone. Amorphous barium and copper salts have been prepared. Pilocarpine in dilute sulphuric acid gives with hydrogen peroxide, followed by potassium dichromate, a bluish-violet colour soluble in benzene. For the identification of the alkaloid Wagenaar recommends precipitation with gold chloride solution. 

Constitvtion of Pilocarpine and isoPilocarpine. Though numerous interesting observations have been made on these two alkaloids by M. and M. Polonovski, knowledge of their constitution is due principally to the work of Jowett and of Pinner. ... 

As a substance of formula (HI) should lose carbon dioxide on heating, whereas pilopic acid is stable even at 200°, it seemed probable that homo-pilopic acid is represented by (II) and pilopic acid by (IV). Jowett also showed that pilocarpine, like wopilocarpine, yields Aomopilopic acid when oxidised by permanganate.In the oxidation of the two alkaloids the two nitrogen atoms are eliminated as ammonia and methylamine. 

From these and other experimental results Pinner and Schwarz suggested that pilocarpine could be represented by formula (V), and subsequently Jowett confirmed this by the preparation of a series of disubstituted glyoxalines from wopilocarpine by distillation with soda-lime, 1 although he pointed out that the reactions of the alkaloid were... 

The construction of d-pilocarpine was effected by converting d-Aomopilopoyl chloride (VI COjH COCl) into diazomethyl drhomo-pilopyl ketone (VIII), transformation of the latter by the action of hydro-... 

Pilocarpidine, CiqHiiOjNj. This alkaloid was obtained by Harnack from P. Jaborandi, and later by Merck from the mother liquors from crystallisation of pilocarpine nitrate. It does not occur in the leaves of P. microphyllus (Jowett, ). The free base is a viscid oil, [a]n + 81-3° (less in presence of alkali). The salts crystallise well the nitrate, B. HNO3, in colourless prisms, m.p. 137°, - -73-2°. The aurichloride, unlike... 

Roylance showed that pilocarpidine on -methylation yielded two products, pilocarpine and neopilocarpine (see below), thus confirming Hamack s suggestion that pilocarpidine is the imino-base corresponding to pilocarpine, Spath and Kunz showed that pilocarpidine, on treatment with alcoholic sodium ethoxide, is converted into isopilocarpidine (nitrate, m.p. 109-111°), which, on quaternary methylation, yields isopilocarpine metho-salts (methopicrate, m.p. 119-120°). The confirmation of these observations by the synthesis of pilocarpidine and isopilocarpidine and their conversion into pilocarpine and isopilocarpine has been described already. 

Pilosine, CjgHjgOgNj, obtained by Pyman (and almost simultaneously by L ger and Roques, who named it carpidine) from mother liquors remaining after the isolation of pilocarpine and isopilocarpine from the total alkaloids of P. mi.crophyllus, crystallises from alcohol in large colourless plates, m.p. 187°, [a]n + 39-9° (EtOH), lasvorotatory in alkaline solution. The salts do not crystallise readily the sulphate,. H SO, forms clusters of plates, m.p. 194-5°, fajD + 21° (HgO) the acid tartrate, B. H2C4HiOg, has m.p. 135-6°, [a]n + 24-2°, and the aurichloride, B. HAuCb, m.p. 143-4°. 

Since pilosine can be recovered unchanged after boiling for a short time with dilute alkali, it is regarded as allied stereochemically to isopilocarpine rather than pilocarpine. 

The foregoing formula has been confirmed by the synthesis of pilosinine by Poljakova and V. A. and N. A. Preobrashenski, who followed the process used for the synthesis of pilocarpine and the allied alkaloids see p. 625), starting with diethyl formylsuccinate to produce pilosinie acid,... 

Pilocarpine is being less used in medicine as a diaphoretic in dropsy and similar diseases because of its depressant action on the heart. It has also been employed as a substitute for physostigmine to contract the pupil and reduce intraocular pressure. It has been used as an antidote to atropine, but it does not antagonise the action of atropine in the central nervous system. 

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