Direct-acting cholinergic drugs

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Chapter: Medicinal Chemistry : Cholinergic Drugs

Direct-acting cholinergic drugs : Synthesis and Drug Profile - i. Acetylcholine chloride (Miochol) ii. Methacholine chloride (Provocholine) (a) Cholinomimetic Alkaloids i. Carbachol (Synonym: Carcholin, Moistat) ii. Bethanechol chloride (Synonym: Urecholine, Myotonachol, Bethacol, Urotonin) (b) Cholinomimetic alkaloids i. Pilocarpine (Pilicar, Carpine, Locarp) - Structure, Properties, uses, Synthesis, Assay, Storage, Dosage forms, Dose | Synthesis and Drug Profile


SYNTHESIS AND DRUG PROFILE


Direct-acting cholinergic drugs

The direct-acting agents exert their effects by stimulating muscarinic/nicotinic receptors.


i. Acetylcholine chloride (Miochol)


Synthesis


Properties and uses: It is a white or almost white crystalline powder or colourless crystals, very hygroscopic in nature, slightly soluble in methylene chloride, soluble in water and alcohol. It is a topical ophthalmic drug to induce miosis, during certain intraocular surgical procedures, such as cataract surgery, ridectomy, penetrating keratoplasty, and other anterior-segment surgery. Systemically administered Ach is rapidly hydrolyzed by acetylcholinesterase, hence, it has no clinical use. It is a cardiac depressant and effective vasodilator.

Assay: Dissolve the sample in water and neutralize with 0.01 M sodium hydroxide using phenolphthalein solution as indicator. Add 0.1 M sodium hydroxide solution, allow it to stand for 30 min and titrate with 0.1 M hydrochloric acid.

Storage: It should be stored in well closed ampoules and protected from light.

Dose: Topically as a 1% solution.


ii. Methacholine chloride (Provocholine)


Synthesis


Properties and uses: It is highly deliquescent, has faint fishy odour, and aqueous solutions are neutral, soluble in water, alcohol, and CHCl3. It is used to treat Reynaud’s syndrome and glaucoma.

Dose: For usual paroxysmal tachycardia, 10 to 25 mg; by S.C. for peripheral vascular disease 10 to 25 mg.


(a) Cholinomimetic Alkaloids

i. Carbachol (Synonym: Carcholin, Moistat)


Properties and uses: It is a white crystalline, hygroscopic powder, soluble in water, sparingly soluble in alcohol, insoluble in acetone. It is an ester of carbamic acid, the terminal methyl group of Ach is replaced by amino group. It possesses both muscarinic and nicotinic properties by cholinergic receptor stimulation. It is more slowly hydrolyzed by acetylcholinesterase. It is used for its miotic actions in the treatment of glaucoma to reduce intraocular pressure.

Assay: Dissolve the sample in a mixture of anhydrous acetic acid and acetic anhydride. Titrate with 0.1 M perchloric acid and determine the end point potentiometrically.

Synthesis

Route I: From Ethylene chlorohydrin


Route II: From Carbamic acid


Storage: It should be stored in well-closed airtight containers and protected from light.

Dose: Topically 0.1 ml of 0.75 to 3% solution.


ii. Bethanechol chloride (Synonym: Urecholine, Myotonachol, Bethacol, Urotonin)


2-[(Amino carbonyl) oxy] N, N, N trimethyl propan ammonium chloride

Properties and uses: It is a white crystalline hygroscopic powder, and it exhibits polymorphism, soluble in water and alcohol. It has pharmacological properties similar to those of methacholine. The presence of –CH3 gives prolonged activity due to steric hindrance. It produces smooth muscle contractions. It is not well absorbed from the gastro-intestinal tract. It can be given subcutaneously, but not by intramuscular (IM) or intravenous (IV) because of its severe side effects. It is used to relieve urinary retention and abdominal distention after surgery. This is one of the postvagotomy gastric drug.

Synthesis

Route I. From: propylene chlorhydrin


Route II. From: Beta methyl choline chloride


Route III. From: Carbamic acid


Dose: By oral 5 to 30 mg 3 or 4 times/day; By S.C. 2.5 to 10 mg 3 or 4 times/day.


(b) Cholinomimetic alkaloids


i. Pilocarpine (Pilicar, Carpine, Locarp)


Synthesis


Properties and uses: It is a white or almost white crystalline powder or colourless crystals, hygroscopic, very soluble in water and in alcohol. Pilocarpine is an alkaloid obtained from the dried leaflets of Pilocarpus jaborandi and Pilocarpus microphyllus in which it occurs to the extent of about 0.5% together with other alkaloids. Pilocarpine is a nonselective agonist on the muscarinic receptors. It acts on M3 receptors in smooth muscles and cause contractions in the gut, trachea, and eyes. It is used for the treatment of symptoms of dry mouth caused by radiotherapy for cancer of head and neck and the symptoms associated with Sjogren’s syndrome.

Assay: Dissolve the sample in alcohol and add 0.01 M hydrochloric acid. Titrate with 0.1 M sodium hydroxide and determine the end point potentiometrically.

Storage: It should be stored in well-closed airtight containers, and protected from light. 

Dose: Topically 0.1 ml of 0.5 to 6% solution into the conjunctival sac 1 to 5 times/day. 

Dosage forms: Pilocarpine hydrochloride eye drops B.P.


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