Indirectly acting cholinergic drugs

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Chapter: Medicinal Chemistry : Cholinergic Drugs

Indirectly acting cholinergic drugs : Synthesis and Drug Profile - A. Reversible blockers i. Physostigmine (Isopto-Eserine) ii. Neostigmine Bromide (Synonym: Prostigmine, Myostigmin, Tilstigmin) iii. Pyridostigmine Bromide (Synonym: Mestion, Pyrido, Trostigmin) iv. Edrophonium Chloride (Tensilon) B. Irreversible blockers i. Pralidoxime Chloride ii. Echothiophate - Structure, Properties, uses, Synthesis, Assay, Storage, Dosage forms, Dose | Synthesis and Drug Profile


SYNTHESIS AND DRUG PROFILE


Indirectly acting cholinergic drugs


(A). Reversible blockers

i. Physostigmine (Isopto-Eserine)


Properties and uses: It exists as a white or almost white crystalline powder, hygroscopic, very soluble in water, and freely soluble in alcohol. It gradually becomes red when exposed to air and light; the colour develops more quickly when the substance is also exposed to moisture. Aqueous solutions are unstable. It melts at about 145°C with decomposition. It is an alkaloid obtained from the dried ripe seeds of Physostigma venenosum. It occurs as a white, odourless, microcrystalline powder, slightly soluble in H2O, freely soluble in alcohol, CHCl3 and fixed oils. Physostigmine is an oldest anticholinesterase agent. It is used in the treatment of glaucoma. It can penetrate the blood brain barrier and is employed to antagonize the toxic CNS effects of antimuscarinic drugs, tricyclic depressants, H1 antihistamines, and benzodiazepines. It is also used in the treatment of Alzheimer’s disease.

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.

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

Synthesis


Dose: Topically for open-angle glaucoma, 0.1 ml of 0.25 to 5% solution instilled into the conjunctival sac 2 or 4 times/day.


ii. Neostigmine Bromide (Synonym: Prostigmine, Myostigmin, Tilstigmin)


3-{[(Dimethyl amino) carbonyl] oxy}-N, N, N-trimethyl benzene ammonium bromide.

Synthesis

Route I. From: Meta nitro aniline


Route II. From: m-Chloro-N,N-dimethyl amino benzene


Properties and uses: It exists as white, odourless, crystalline powder with a bitter taste, freely soluble in water, alcohol, and insoluble in ether. Its solutions are neutral to litmus. It acts as a cholinesterase inhibitor.

Assay: Dissolve the sample in anhydrous formic acid, and then add acetic anhydride. Titrate with 0.1 M perchloric acid and determine the end point potentiometrically.

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

Dosage forms: Neostigmine bromide tablets I.P., Neostigmine methyl sulphate injection I.P., Neostigmine tablets B.P.


iii. Pyridostigmine Bromide (Synonym: Mestion, Pyrido, Trostigmin)


Properties and uses: It exists as white, crystalline powder with a characteristic odour and bitter taste, soluble in water, alcohol, chloroform, slightly soluble in hexane, and insoluble in ether. It is hygroscopic in nature. It is used in the treatment of myasthenia gravis and it antagonizes the effects of neuromuscular blocking (NMB) agents.

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

Synthesis

Route I. From: 3-Pyridinol


Route II. From: Pyridine-3-sulphonic acid


Storage: It should be stored in well-closed airtight container, protected from light. The sterile substance should be stored in airtight, tamper-proof containers, and protected from light.

Dose: Initially, 60 mg every 4 to 8 h, but 120 to 300 mg 6 times/day is the usual dose.

Dosage forms: Pyridostigmine tablets B.P.


iv. Edrophonium Chloride (Tensilon)


Synthesis

Route I. From: Meta dimethylamino phenol


Route II. From: 3-Aminophenol


Properties and uses: It exists as a white crystalline powder, soluble in water and alcohol, insoluble in methylene chloride. On parenteral administration, edrophonium has a more rapid onset and shorter duration of action than neostigmine, pyridostigmine, or ambenonium. It is used as an antiarrhythmic drug in paroxymal atrial tachycardia. It is also used in the diagnosis of myasthenia gravis.

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

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

Dose: By I.V. 2 to 10 mg; usually 2 mg is injected initially and if no adverse reaction takes place within 30 sec, the remaining 8 mg may be injected.

Dosage form: Edrophonium injection B.P.


(B) Irreversible blockers


i. Pralidoxime Chloride


Synthesis


Properties and uses: It exists as a white to pale yellow crystalline powder, odourless, soluble in water. Used as an antidote for parathion and related pesticides poison.


ii. Echothiophate


2-[(Diethoxyphosphonyl) thio] N,N,N-trimethyl ethan ammonium iodide

Synthesis


Properties and uses: It exists as white crystalline hygroscopic solid with slight mercaptane-like odour, soluble in water, methanol, or dehydrated alcohol, but insoluble in organic solvents. It is a long-acting irreversible anti-AchE drug, used in the treatment of glaucoma.

Dose: Topically for adult in the treatment of glaucoma, 1 drop of 0.03% to 0.25% solution.


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