TOPIC 1: Introduction to Autonomic Pharmacology

Your syllabus covers 5 major topics. We start with Topic 1. Let me know when you want Topic 2 and I'll continue.

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1. What is the Autonomic Nervous System (ANS)?

• Smooth muscle (blood vessels, gut, bladder, bronchi)
• Cardiac muscle and pacemaker cells
• Exocrine and endocrine glands
• Adipose tissue and liver

1. Sympathetic nervous system (fight-or-flight)
2. Parasympathetic nervous system (rest-and-digest)
3. Enteric nervous system (gut)

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2. Anatomy - The Two-Neuron Chain

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3. Sympathetic vs. Parasympathetic - Key Differences

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4. Neurotransmitters and Receptor Summary

• ALL preganglionic fibres (sympathetic and parasympathetic) release ACh onto Nicotinic receptors (Nn) at the ganglion
• Parasympathetic postganglionic fibres release ACh onto Muscarinic receptors at effectors
• Sympathetic postganglionic fibres release NE onto Adrenergic receptors at effectors
• The somatic system releases ACh onto Nicotinic (Nm) receptors at skeletal muscle

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5. Cholinergic Receptors - Detailed

A. Muscarinic Receptors (M1-M5)

• Type: G protein-coupled receptors (GPCRs) - metabotropic
• Named after: Muscarine (from poisonous mushrooms)
• Location: Effector organs of parasympathetic system; also heart, smooth muscle, glands, CNS

• M1/M3: Gq → activates Phospholipase C → produces IP3 and DAG → IP3 raises intracellular Ca²+ → smooth muscle contraction, gland secretion; DAG activates protein kinase C
• M2: Gi → inhibits adenylyl cyclase → ↓cAMP + ↑K+ conductance → slows heart

B. Nicotinic Receptors (Nn and Nm)

• Type: Ligand-gated ion channels (ionotropic) - fast response
• Named after: Nicotine (from tobacco)
• Mechanism: Opening of cation channel → Na+/Ca²+ influx → depolarisation

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6. Adrenergic Receptors - Overview

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7. Outline of Effects: Sympathetic vs. Parasympathetic

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8. Summary of Pharmacological Targets in the ANS

1. Synthesis of neurotransmitter (e.g., reserpine blocks NE storage)
2. Storage in vesicles
3. Release from nerve terminals (e.g., guanethidine blocks NE release)
4. Receptor activation (agonists - mimic NT)
5. Receptor blockade (antagonists - block NT)
6. Degradation of NT (e.g., anticholinesterases - prevent ACh breakdown)
7. Reuptake inhibition (e.g., cocaine blocks NE reuptake)

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Quick Recall Points (for exams)

• All preganglionic fibres → ACh → Nicotinic receptor
• Parasympathetic postganglionic → ACh → Muscarinic receptor
• Sympathetic postganglionic → NE → Adrenergic receptor (exception: sweat glands use ACh → Muscarinic)
• Adrenal medulla = modified sympathetic ganglion, releases EPI + NE into blood
• Muscarinic receptors = GPCRs (slow)
• Nicotinic receptors = ion channels (fast)
• M2 on heart: Gi → ↓HR; M1/M3: Gq → smooth muscle/gland effects

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1. Introduction to Autonomic Pharmacology ✅
2. Cholinergic Receptor Agonists / Cholinomimetics (acetylcholine, bethanechol, pilocarpine, neostigmine + glaucoma/MG/OP poisoning management)
3. Cholinergic Receptor Antagonists (atropine and substitutes)
4. Adrenergic Receptor Agonists / Sympathomimetics (epinephrine, NE, dopamine, alpha/beta agonists)
5. Adrenergic Receptor Antagonists (alpha blockers, beta blockers)

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TOPIC 2: Cholinergic Receptor Agonists / Cholinomimetics

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1. Definition & Classification

CHOLINERGIC AGONISTS
├── DIRECT-ACTING (bind receptors directly)
│   ├── Choline Esters → Acetylcholine, Bethanechol, Carbachol, Methacholine
│   └── Alkaloids → Pilocarpine, Muscarine, Nicotine
└── INDIRECT-ACTING (inhibit AChE → ↑ ACh at synapse)
    ├── Reversible AChE inhibitors → Physostigmine, Neostigmine, Pyridostigmine
    └── Irreversible AChE inhibitors → Organophosphates (parathion, echothiophate, nerve agents)

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2. Direct-Acting Agents - Choline Esters

Key Properties Table

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A. Acetylcholine (ACh)

• Quaternary ammonium compound - cannot cross cell membranes or BBB
• Acts on BOTH muscarinic and nicotinic receptors
• Not clinically used systemically (too rapid degradation, too diffuse effects)
• Clinical use: Topical ophthalmic solution → produces miosis during cataract/lens implant surgery

• Heart: Bradycardia, ↓ cardiac output (M2 on SA node)
• Blood vessels: Vasodilation + ↓ BP via M3 on endothelium → NO production → smooth muscle relaxation
• GI: ↑ motility, ↑ salivation, ↑ gastric acid
• Lungs: Bronchoconstriction, ↑ secretions
• Bladder: Contracts detrusor → urination
• Eye: Miosis + accommodation (ciliary muscle contraction)

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B. Bethanechol ⭐ (Most Clinically Important Ester)

• Pure muscarinic agonist - NO nicotinic activity
• Not hydrolysed by AChE - carbamic acid ester
• Strong action on bladder and GI smooth muscle
• Oral or SC administration

• ↑ intestinal motility and tone
• Stimulates detrusor muscle of bladder → relaxes trigone and sphincter → urination

1. Postoperative/postpartum urinary retention (non-obstructive, atonic bladder) - main use
2. Neurogenic bladder atony
3. Toxic megacolon (rarely)

• Sweating, salivation, flushing
• ↓ BP with reflex tachycardia
• Nausea, abdominal cramps, diarrhea
• Bronchospasm

• Asthma (bronchoconstriction)
• Peptic ulcer (↑ gastric acid)
• Urinary or GI obstruction (never give if mechanical obstruction exists!)
• Hyperthyroidism, coronary artery disease

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C. Pilocarpine ⭐ (Most Clinically Important Alkaloid)

• Tertiary amine alkaloid - lipid soluble, well absorbed, can cross BBB
• Mainly muscarinic activity
• Source: leaves of Pilocarpus jaborandi (plant)

• Powerful stimulant of exocrine glands (sweating, salivation, lacrimation)
• Eye: Miosis + ciliary muscle contraction (spasm of accommodation) → ↓ intraocular pressure (IOP)

1. Glaucoma - most important use (open-angle AND narrow-angle)
2. Xerostomia (dry mouth) after radiation therapy for head/neck cancer
3. Sjögren's syndrome (dry mouth/eyes)

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D. Carbachol

• Both muscarinic AND nicotinic activity
• Resistant to AChE hydrolysis
• Uses: Topical ophthalmic - miosis during surgery; alternative to pilocarpine in glaucoma (when tolerance develops)

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E. Methacholine

• Mainly muscarinic, resistant to AChE
• Methacholine challenge test - inhaled provocatively to diagnose bronchial hyperresponsiveness in asthma

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F. Muscarine

• Naturally occurring alkaloid (from Amanita muscarina mushrooms)
• Purely muscarinic activity
• Not used clinically - toxicological importance (mushroom poisoning)
• Causes: SLUD syndrome (Salivation, Lacrimation, Urination, Defecation) + bradycardia, bronchospasm

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3. Indirect-Acting Agents - Anticholinesterases

How AChE Normally Works:

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Reversible AChE Inhibitors

A. Physostigmine (Eserine) ⭐

• Natural alkaloid from Calabar bean (Physostigma venenosum)
• Tertiary amine → lipid soluble → crosses BBB → acts in CNS
• Carbamic acid ester - reversibly binds AChE for 30 min - 2 hours

• Stimulates muscarinic receptors (GI motility, ↑ secretions, bradycardia, miosis)
• Stimulates skeletal muscle (via ↑ ACh at NMJ)
• CNS effects (since it crosses BBB) - can reverse CNS anticholinergic effects

1. Glaucoma (historically, now replaced by better agents)
2. Antidote for atropine poisoning / anticholinergic overdose - key use! (including tricyclic antidepressant OD)
3. Reversal of CNS effects of antimuscarinics

• Bradycardia, ↓ BP
• GI cramps, diarrhea
• Convulsions at high doses
• Skeletal muscle paralysis (rarely)

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B. Neostigmine ⭐

• Synthetic compound, carbamic acid ester
• Quaternary ammonium → does NOT cross BBB → no CNS effects
• Greater effect on skeletal muscle (NMJ) than physostigmine
• Duration: 30 min - 2 hours

• Strong stimulation of GI tract and bladder
• Strong facilitation of NMJ (↑ skeletal muscle contraction)
• No CNS penetration

1. Myasthenia gravis (symptomatic treatment) ⭐
2. Reversal of non-depolarising neuromuscular blockade (post-surgery, e.g., reversal of tubocurarine, rocuronium)
3. Postoperative urinary retention and abdominal distension (Ogilvie syndrome)

• Salivation, nausea, diarrhea, abdominal cramps
• Bronchospasm
• Bradycardia
• No CNS effects (cannot cross BBB - important distinction from physostigmine)

• Intestinal or urinary bladder obstruction (mechanical)
• Asthma

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C. Pyridostigmine

• Similar to neostigmine (quaternary amine, no CNS penetration)
• Longer duration than neostigmine (3-6 hours)
• Main use: Chronic management of myasthenia gravis (preferred over neostigmine for long-term)
• Also used as prophylaxis against nerve agent (soman) poisoning in military

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D. Edrophonium

• Very short-acting (5-15 min), reversible AChE inhibitor
• Tensilon test - IV injection used to diagnose myasthenia gravis (brief improvement in muscle strength confirms diagnosis)
• Now largely replaced by antibody tests, but still classic exam question

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Irreversible AChE Inhibitors - Organophosphates

• Agricultural insecticides: Parathion, Malathion, Diazinon
• Nerve agents (chemical warfare): Sarin, Soman, Tabun, VX
• Ophthalmic (historical): Echothiophate (open-angle glaucoma - now withdrawn)

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4. Organophosphate (OP) Poisoning - Principles of Management ⭐⭐

Signs and Symptoms - "Cholinergic Crisis"

• Muscle fasciculations → weakness → paralysis (including respiratory muscles - LETHAL)
• Tachycardia, hypertension (at ganglia)
• Pallor, diaphoresis

• Anxiety, restlessness, seizures, coma
• Respiratory depression (central + peripheral)

Management of OP Poisoning

• Blocks muscarinic effects only
• Dose: 2-4 mg IV every 5-10 minutes until drying of secretions (atropinisation)
• Endpoint: dry mouth, clear lungs - NOT pupil dilation
• Very large doses may be needed (10s to 100s of mg in severe cases)
• Does NOT reverse nicotinic effects (muscle weakness/paralysis)

• Must be given early (before aging occurs!)
• Reactivates phosphorylated AChE by binding the organophosphate and removing it from the enzyme
• Restores both muscarinic AND nicotinic function
• Dose: 1-2 g IV over 15-30 minutes
• Ineffective after aging - hence urgency of early administration
• Cannot cross BBB well - poor for CNS effects

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5. Myasthenia Gravis - Principles of Management ⭐⭐

What is Myasthenia Gravis?

• Characteristic: fatigable weakness - worse with activity, better with rest
• Commonly affects ocular muscles (ptosis, diplopia), facial, bulbar, limb, and respiratory muscles
• Thymoma association (20% of patients have thymoma; thymus is removed in treatment)

Pharmacological Management

• Pyridostigmine (Mestinon) - drug of choice for chronic management
  • Inhibits AChE → ↑ ACh at NMJ → stimulates remaining functional Nm receptors
  • Dose: 30-60 mg orally every 4-6 hours
  • Adverse effects: muscarinic (SLUDGE symptoms), controlled with atropine/glycopyrrolate
• Neostigmine - used for acute/short-term management, quicker onset

• Prednisolone (corticosteroids) - first-line immunosuppressant
• Azathioprine - steroid-sparing agent
• Mycophenolate, cyclosporine - alternatives

• For myasthenic crisis (acute severe deterioration)
• Rapidly removes anti-AChR antibodies from circulation

• Indicated if thymoma present or in generalised MG in patients < 60 years
• Can induce long-term remission

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6. Glaucoma - Principles of Management ⭐⭐

What is Glaucoma?

• Normal IOP: 10-21 mmHg
• Aqueous humor is produced by the ciliary body and drains via the trabecular meshwork into the Canal of Schlemm

Types:

• Open-angle glaucoma (most common, 90%) - trabecular meshwork gradually becomes less efficient; drainage is not blocked
• Narrow/Closed-angle glaucoma (acute angle closure) - iris physically blocks the drainage angle; medical emergency

How Cholinergic Drugs Lower IOP:

• Contract the ciliary muscle (M3 activation) → pulls on trabecular meshwork → opens drainage channels → aqueous humor outflow increases → ↓ IOP
• Contract the sphincter pupillae → miosis → iris is pulled away from the drainage angle → especially useful in narrow-angle glaucoma

Complete Management of Glaucoma (Drug Classes):

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7. Adverse Effects of Cholinergic Agonists - Visual Summary

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8. Physostigmine vs. Neostigmine - Key Comparison (High Yield)

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Quick Recall Points

• Bethanechol = muscarinic only (no nicotinic), used for urinary retention
• Pilocarpine = best for glaucoma and dry mouth (Sjögren's, radiation)
• Methacholine = bronchial challenge test for asthma diagnosis
• Physostigmine = crosses BBB → antidote for atropine/anticholinergic OD
• Neostigmine = does NOT cross BBB → myasthenia gravis + NMJ reversal
• Pyridostigmine = chronic MG management (longer acting)
• Pralidoxime (2-PAM) = reactivates AChE in OP poisoning - give EARLY before aging
• Atropine = first drug in OP poisoning - treats muscarinic symptoms

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1. Cholinergic Receptor Antagonists (Atropine prototype + substitutes)
2. Adrenergic Receptor Agonists (Epinephrine, NE, Dopamine, α & β agonists)
3. Adrenergic Receptor Antagonists (α-blockers, β-blockers, Propranolol)