Unit 3: Parasympathomimetics & Parasympatholytics

Semester 4

BP402T

Introduction to Parasympathomimetics & Parasympatholytics

This unit shifts focus to the Cholinergic (Parasympathetic) nervous system, governed by the neurotransmitter Acetylcholine. It explores direct-acting cholinergic agonists (like Pilocarpine and Carbachol) and indirect-acting cholinesterase inhibitors (like Neostigmine, used in Myasthenia Gravis). Conversely, it covers the drugs that block these receptors—Parasympatholytics/Anticholinergics (like Atropine and Ipratropium)—used to treat asthma, peptic ulcers, and Parkinson-like tremors. Important syntheses include Carbachol, Neostigmine, and Dicyclomine.

Syllabus & Topics

1Parasympathomimetic agents: Direct acting (Acetylcholine, Carbachol, Bethanechol, Pilocarpine).
2SAR of Parasympathomimetic agents.
3Indirect acting/Cholinesterase inhibitors (Reversible & Irreversible): Physostigmine, Neostigmine, Echothiophate.
4Cholinesterase reactivators (Pralidoxime chloride).
5Parasympatholytics / Anticholinergics (Atropine, Scopolamine, Ipratropium bromide, Dicyclomine).
6SAR of cholinolytic agents.
7Synthesis of Carbachol, Neostigmine, Dicyclomine hydrochloride, and Ipratropium bromide.

Learning Objectives

Explain the instability of Acetylcholine and how structural modifications improve clinical utility.

Classify Cholinesterase inhibitors and understand their mechanism in toxicity and therapy.

Describe the mechanism of action of Oximes in organophosphate poisoning.

Elucidate the Structure-Activity Relationships of muscarinic antagonists.

Write the chemical synthesis for the designated marked compounds.

Frequently Asked Questions (FAQs)

Q1. Why is Carbachol More Stable than Acetylcholine?

Acetylcholine contains an ester linkage that is rapidly hydrolyzed by the enzyme Acetylcholinesterase, resulting in a very short duration of action. Carbachol replaces the acetyl group with a carbamate group (NH₂–CO–), which is more resistant to esterase hydrolysis, thereby increasing stability and prolonging its action.

Q2. How Do Cholinesterase Inhibitors Work?

Cholinesterase inhibitors act as indirect parasympathomimetics by inhibiting Acetylcholinesterase. This prevents the breakdown of naturally released acetylcholine in the synaptic cleft, leading to accumulation of acetylcholine and prolonged stimulation of cholinergic receptors.

Q3. What Are Reactivators of Acetylcholinesterase?

Organophosphate compounds irreversibly bind to and phosphorylate the serine hydroxyl group at the active site of Acetylcholinesterase. Reactivators such as Pralidoxime (2-PAM) contain a nucleophilic oxime group that removes the phosphate moiety, thereby freeing and reactivating the enzyme.

Q4. What is the Structural Feature of Parasympatholytics (Anticholinergics)?

Parasympatholytics such as Atropine are typically bulky esters of complex amino alcohols. Their bulky aromatic or cycloaliphatic rings sterically hinder binding of acetylcholine to muscarinic receptors, thereby blocking parasympathetic activity.