Study Notes: Cholinergic Antagonists-ANTICHOLINERGICS

Overview:

Cholinergic antagonists (also known as anticholinergic drugs) inhibit the actions of acetylcholine at cholinergic receptors.
They are divided into three main groups:

1. Antimuscarinic agents

2. Ganglionic blockers

3. Neuromuscular blockers

1. Antimuscarinic Agents (Anticholinergic Drugs)

• Mechanism: Block muscarinic (M) receptors, inhibiting parasympathetic (muscarinic) functions.

• Prototype: Atropine

A. Atropine

Sites of Action:

• Eye

• GI tract

• Heart

• Salivary, sweat, and lacrimal glands

Effects:

System	Mechanism	Effect
Eye	Blocks M₃ receptors → relaxation of ciliary muscle	Mydriasis (pupil dilation), cycloplegia (loss of accommodation), unresponsiveness to light
GI Tract	Blocks M₃ receptors	↓ GI motility → prolonged gastric emptying, lengthened intestinal transit
Heart	Blocks M₂ receptors (SA & AV nodes)	Tachycardia (↑ HR 30–40 bpm)
Glands	Blocks M receptors	Dry mouth, dry skin, ↑ body temperature (due to ↓ sweating)

Clinical Uses:

• Ophthalmic exams and eye surgery

• Treat ocular inflammation (rarely used; replaced by shorter-acting agents)

Ophthalmic Alternatives:

• Cyclopentolate and Tropicamide (shorter duration)

  • Cyclopentolate/Tropicamide: mydriasis lasting hours

  • Atropine: effects last days

B. Scopolamine

• Greater CNS effect and longer duration than Atropine.

• Uses:

  • Prevention of motion sickness

  • Post-operative nausea/vomiting

• Formulation: Transdermal patch (effective up to 3 days)

C. Ipratropium & Tiotropium

• Mechanism: Non-selective muscarinic blockers → ↓ smooth muscle contractility → bronchodilation & ↓ mucus secretion.

• Uses: Maintenance therapy for COPD and bronchospasm.

• Formulations:

  • Inhalation (main use)

  • Ipratropium nasal spray: for rhinorrhea.

• Difference:

  • Tiotropium: long-acting, once daily

  • Ipratropium: short-acting, up to four times daily

D. Agents for Overactive Bladder

Drug	Selectivity	Notes
Tolterodine	Variable	↓ bladder overactivity
Darifenacin	M₃ selective	—
Solifenacin	M₃ selective	—
Oxybutynin	Nonselective	Oral or patch; dry mouth common
Trospium	Nonselective	Quaternary compound; minimal CNS effect
Fesoterodine	Variable	Similar to Tolterodine

Effect: Relax detrusor muscle → ↑ bladder capacity → ↓ urgency and frequency.

E. CNS Agents for Parkinson-like Disorders

Drug	Mechanism	Use
Benztropine	Blocks central M receptors	Parkinson’s disease, drug-induced extrapyramidal symptoms
Trihexyphenidyl	Same	Parkinson-like disorders

Mnemonic: Anticholinergic Adverse Effects – “ABCDS”

Letter	Meaning
A	Agitation
B	Blurred vision
C	Constipation & Confusion
D	Dry mouth
S	Stasis of urine & sweating (↓ urination, ↓ perspiration)

2. Ganglionic Blockers

Main Agent: Nicotine

• Mechanism:

  • Acts on nicotinic receptors (Nn) in autonomic ganglia (both sympathetic & parasympathetic).

  • Initially stimulates, then blocks ganglionic transmission.

  • Thus, acts as both agonist and functional antagonist.

Effects:

• CNS:

  • Stimulation → increased alertness, well-being

  • High doses → convulsions → CNS depression → respiratory paralysis

• Adrenal medulla: ↑ epinephrine & norepinephrine → ↑ BP, ↑ HR

• GI tract: ↑ motility → nausea, vomiting

• Addiction potential: Strong due to CNS dopamine release.

Clinical Use:

• Limited to smoking cessation therapies (patches, gums, lozenges).

3. Neuromuscular Blockers (Skeletal Muscle Relaxants)

• Mechanism: Block cholinergic transmission between motor nerves and nicotinic (Nm) receptors on skeletal muscle.

• Clinical Uses: Facilitate intubation, mechanical ventilation, and muscle relaxation during surgery.

Physiology Review: Muscle Contraction

1. ACh release → binds Nm receptors on muscle fiber.

2. Na⁺ influx → depolarization → muscle action potential.

3. Action potential travels along sarcolemma → through T-tubules.

4. Ca²⁺ release from sarcoplasmic reticulum → muscle contraction.

Neuromuscular blockers interfere with this process.

A. Nondepolarizing Agents

Mechanism:

• Competitive antagonists at Nm receptors.

• Prevent depolarization → inhibit muscle contraction.

Uses:

• Facilitate mechanical ventilation, tracheal intubation, surgical relaxation.

Pharmacology:

• Not absorbed orally → must be IV administered.

• Onset: Rapid (<2 minutes).

• Paralysis pattern:

  1. Small, fast muscles (eyes, face, fingers)

  2. Neck, trunk, limbs

  3. Diaphragm (last)

  • Recovery in reverse order.

Common Nondepolarizing Agents

Drug	Duration (approx.)	Notes
Cisatracurium	90 min	No hepatic/renal metabolism → safe in organ failure
Pancuronium	90 min	Excreted unchanged in urine; may ↑ HR
Rocuronium	40 min	Hepatic metabolism; rapid onset
Vecuronium	40 min	Hepatic metabolism; minimal side effects
Atracurium	40 min	Causes histamine release (↓ BP, flushing, bronchoconstriction); metabolite laudanosine may cause seizures

Notes:

• Atracurium largely replaced by Cisatracurium due to better safety.

• Vecuronium/Rocuronium may last longer in hepatic dysfunction.

B. Depolarizing Agent

Drug: Succinylcholine

Mechanism:

• Acts as ACh receptor agonist at Nm receptors.

• Causes persistent depolarization (resistant to AChE degradation).

Phases:

1. Phase I Block: Persistent depolarization → fasciculations → flaccid paralysis.

2. Phase II Block: Receptor desensitization → membrane repolarizes but unresponsive to ACh.

Clinical Use:

• Rapid sequence intubation

• Electroconvulsive therapy (ECT) for muscle relaxation

• Onset: ~1 minute

• Duration: ~10 minutes (rapid hydrolysis by plasma pseudocholinesterase)

Adverse Effects of Succinylcholine

Effect	Mechanism / Description
Prolonged apnea	In patients with low or abnormal plasma pseudocholinesterase
Hyperkalemia	Prolonged depolarization → K⁺ efflux → may cause arrhythmias or asystole (especially in burns, trauma, or high baseline K⁺)
Malignant hyperthermia	Genetic susceptibility → severe muscle rigidity, high fever (up to 43°C), potentially fatal

Summary Table: Neuromuscular Blockers

Class	Mechanism	Prototype	Duration	Key Use	Major Adverse Effect
Nondepolarizing	Competitive antagonist at Nm receptor	Cisatracurium	40–90 min	Surgical relaxation, ventilation	Hypotension (Atracurium), Tachycardia (Pancuronium)
Depolarizing	Persistent agonist (Phase I & II block)	Succinylcholine	~10 min	Rapid intubation, ECT	Hyperkalemia, Malignant hyperthermia

Takeaways

• Antimuscarinic agents: Block parasympathetic M receptors (Atropine, Scopolamine, Ipratropium, Tiotropium, etc.).

• Ganglionic blockers: Act on Nn receptors; Nicotine is both agonist and antagonist.

• Neuromuscular blockers: Act on Nm receptors to cause paralysis (nondepolarizing or depolarizing).

• Mnemonic for Anticholinergic Toxicity: ABCDS – Agitation, Blurred vision, Constipation/Confusion, Dry mouth, Stasis of urine/sweat.

• Mnemonic for Neuromuscular Side Effects: Depolarization → Fasciculations → Paralysis.