Cholinergic Agonists (Parasympathomimetics)

Introduction

• Cholinergic Agonists (Parasympathomimetics): Drugs that stimulate cholinergic receptors.
• Website Resources: Additional notes and illustrations available for better understanding.

Cholinergic System Overview

• Cholinergic System: Involves neurons releasing acetylcholine.
• Cholinergic Pathways: Important in understanding pharmacology.

Parasympathetic Fibers and Target Organs

• Cranial Nerves with Parasympathetic Fibers:
  • Cranial Nerve III (Oculomotor Nerve): Innervates eye structures (e.g., ciliaris muscle, pupil)
    • Functions: Pupillary constriction (myiosis) and accommodation.
  • Cranial Nerve VII (Facial Nerve): Lacrimal and salivary glands.
    • Functions: Lacrimation (tears) and salivation.
  • Cranial Nerve IX (Glossopharyngeal Nerve): Parotid glands.
    • Functions: Salivation.
  • Cranial Nerve X (Vagus Nerve): Heart, bronchioles, and upper GI tract.
    • Functions:
      • Heart: Negative chronotropic action, bradycardia, decrease in cardiac output.
      • Bronchioles: Bronchoconstriction.
      • GI Tract: Increased secretions and motility.
• Sacral Spinal Cord Fibers (S2-S4):
  • Innervates lower GI tract (motility, defecation) and bladder (urination).

Sympathetic Nervous System and Cholinergic Pathway

• Sympathetic Fibers (T1-L2):
  • Preganglionic: Release acetylcholine (ACh).
  • Postganglionic: Usually release norepinephrine, except for fibers going to the skin which release ACh.
  • Action: Induces sweating.

Somatic Nervous System

• ACh on Skeletal Muscles: Released from somatic motor neurons.
  • Receptors: Nicotinic receptors causing muscle contraction.
  • ACh Breakdown: Acetylcholinesterase enzyme.

Types of Receptors

• Nicotinic Receptors: Ligand-gated ion channels.
  • Locations: Skeletal muscle at the neuromuscular junction, preganglionic sites.
• Muscarinic Receptors: G-protein coupled receptors.
  • Locations: Smooth muscle, cardiac muscle, glands in target organs.
  • Types:
    • Inhibitory (M2, M4): Decrease activity, slow heart rate (e.g., heart's AV node).
    • Stimulatory (M1, M3, M5): Increase activity via Gq proteins (e.g., smooth muscle of GI).

ACh Lifecycle in Synapse and Drug Interaction

1. ACh Synthesis: Choline + Acetyl-CoA (via Choline Acetyltransferase) -> ACh.
2. ACh Release: Action potential -> Voltage-gated calcium channels -> Exocytosis.
3. ACh Receptors: Binds to nicotinic/muscarinic receptors -> Cellular response.
4. ACh Breakdown: Acetylcholinesterase degrades ACh -> Choline + Acetate.
5. Drug Mechanisms:

• Direct Agonists: Mimic ACh (bind receptors).
  • Indirect Agonists: Inhibit acetylcholinesterase (increase ACh levels).

Cholinergic Agonists Drugs

• Direct Agonists
  • Muscarinic Receptors: Bethanechol, Methacholine, Pilocarpine, (sometimes Carbachol).
  • Nicotinic + Muscarinic Receptors: Carbachol (rarely used).
• Indirect Agonists (Acetylcholinesterase Inhibitors)
  • Reversible: Edrophonium (short-acting), Physostigmine, Neostigmine, Pyridostigmine (longer-acting).
  • Lipid Soluble (CNS Penetration): Physostigmine, Donepezil, Rivastigmine.
  • Irreversible: Echothiophate, Organophosphates (e.g., nerve agents like sarin).

Therapeutic Uses

• Postoperative/Postpartum Issues:
  • Drugs: Bethanechol, Neostigmine, Pyridostigmine.
  • Conditions: GI motility issues, urinary retention.
• Bronchial Provocation Tests:
  • Drug: Methacholine (diagnose asthma).
• Glaucoma:
  • Drugs: Pilocarpine (primary), Carbachol.
  • Actions: Decrease intraocular pressure, improve fluid drainage.
• Lacrimation/Salivation:
  • Conditions: Sjogren's syndrome, radiation-induced damage.
• Myasthenia Gravis:
  • Drug: Pyridostigmine (preferred), Neostigmine, Edrophonium (diagnosis).
  • Action: Increase ACh levels, improve muscle contraction by outcompeting antibodies.
• Alzheimer's Disease:
  • Drugs: Donepezil, Rivastigmine, Galantamine.
  • Action: Increase ACh levels to improve cognitive function.
• Anticholinergic Overdose:
  • Drug: Physostigmine.
• Reversing Neuromuscular Blockers:
  • Drug: Neostigmine.

Cholinergic Crisis

• Symptoms: Meiosis, lacrimation, salivation, bradycardia, bronchospasm, increased GI motility, urination, skeletal muscle weakness, convulsions.
• Mnemonic: DUMBBELLS (Diarrhea, Urination, Meiosis, Bradycardia, Bronchospasm, Excitation, Lacrimation, Salivation, Sweating).
• Causes: Excessive cholinergic agonist or acetylcholinesterase inhibitor.
  • Treatment: Atropine, Pralidoxime (before aging for irreversible inhibitors).

Key Concepts

• Mechanism of Action for Drugs: Direct mimicry vs. increased ACh via acetylcholinesterase inhibition.
• Understanding Receptor Types: Nicotinic (ion channels) vs. Muscarinic (G-protein coupled).
• Drug Choices Based on Conditions: Differentiating between short-term and long-term therapies.