Ach Blockers

Pharmacology I, Chapter 8: Ach Blockers (Cholinolytics)

• Case Study 1: A 63-year-old patient with urinary symptoms, on thiazide diuretic and ACE inhibitor for hypertension, developed benign prostatic hypertrophy (BHP) requiring prostatectomy. Now experiencing urinary frequency and urgency. What is the diagnosis and treatment?

• Case Study 2 (Urge Incontinence): Urge incontinence may follow prostate removal, potentially leaving the bladder detrusor muscle unstable. Symptoms typically resolve with time, though a patient may use tolterodine or oxybutynin once daily. Slight muscarinic antagonists reduce detrusor smooth muscle spasms.

Cholinolytics

• Cholinergic antagonists, cholinergic blockers, anticholinergic drugs, and acetylcholine blockers are synonymous with cholinolytics.

Classification of Cholinolytics

• Group I (Antimuscarinics): This group blocks parasympathetic autonomic discharge. This is an important group.
• Group II (Ganglionic Blockers): Has limited clinical use.
• Group III (Neuromuscular Blockers): Further discussed later in the course.

Receptor Organization

• Sympathetic Pathway: CNS → Ach → NE → Adrenergic Receptors (alpha 1, alpha 2, beta 1, beta 2)
• Parasympathetic Pathway: CNS → Ach → Ach → Muscarinic Receptors
• Somatic Pathway: CNS → Ach → Nicotinic Receptors → Skeletal Muscle

Nicotinic and Muscarinic Blockers

• Nicotinic Blockers: Ganglion blockers (Group II), neuromuscular blockers (Group III).
• Muscarinic Blockers: Group I drugs.

Muscarinic Receptor Subtypes

• M1: CNS, sympathetic postganglionic cell bodies
• M2: Myocardium, smooth muscle
• M3: Effector cell membranes (glands and smooth muscle)

Antimuscarinic Drugs

• Atropine (Atropa belladonna)
• Scopolamine
• Propantheline (Pro-Banthine)
• Glycopyrrolate (Robinul)
• Tolterodine (Detrol)
• Dicyclomine (Bentyl)
• Ipratropium (Atrovent)

Atropine Structure

• Atropine has a complex structure containing tropic acid and a base. The structure can vary slightly based on the specific molecule.

Antimuscarinic Mechanisms

• Competitive Antagonists: Block Ach receptors; increasing Ach levels overcomes blockade. More effective blocking drug agonists than endogenous agonists (Ach)
• Non-selective: Atropine is non-selective for the muscarinic receptor subtypes (M1, M2, M3), though certain synthetic types are more selective.

Antimuscarinic Distribution

• Quaternary amine group prevents drug entry to lipid membranes (BBB). Used for antisecretory/antispastic activity in GI and bronchi; limited CNS effects.
• Tertiary amine readily crosses BBB and all tissues; high lipid solubility. Atropine is an example.

Antimuscarinic Effects

• CNS: Sedative at low doses, excitation, agitation, hallucinations, and coma at higher doses.
• Eye: Blocks Ach activation of pupillary constrictor muscles; causes mydriasis (pupil dilation). Renaissance eye drops used to cause dilation.
• Cardiac: Blocks vagus nerve slowing of SA node; causes tachycardia.

Antimuscarinics and Specific Applications

• Respiratory: Ipratropium (analog to atropine) used in inhalant asthma to cause bronchodilation
• Cardiovascular: Blocks reflex vagal discharge in MI with atropine-like drugs
• Gastrointestinal: Lomotil (atropine + diphenoxylate) for traveler's diarrhea to keep opioid dose lower.
• Urinary: Oxybutynin to reduce involuntary voiding

Atropine

• Plant Source: Belladonna (deadly nightshade), jimsonweed, and other plants.
• Action: Blocks Ach receptors. Effects include cardiac slowing, dry mouth, sweat inhibition, pupil dilation, blurred vision, and coma in high doses.
• Overdose Treatment: Increase Ach at the receptor using anticholinesterase drugs which degrade Ach.

Clinical Uses of Atropine

• Heart: Treat excess vagus nerve stimulation causing bradycardia.
• Eye: Cause pupil dilation for retina examination
• GI: Used in irritable colon to block Ach-induced motility increases.
• Motion Sickness: Scopolamine patches to reduce nausea and vomiting.
• Anticholinesterase Poisons: Overcomes wild mushroom, insecticides, and warfare agent inhibition.

Antimuscarinic Therapy Mechanisms

• Mechanism of Action: Agents inhibit AchE, which increases Ach levels, and excess Ach causes paralysis. Drugs block nicotinic and muscarinic receptors to block excess Ach.
• Treatment: Atropine (1-2 mg IV every 5-15 minutes until effect appears) to treat nerve gas and poisoning. Higher doses to support for a month, if necessary.

Mushroom Poisoning

• Rapid onset poisoning: Amanita muscaria contain muscarine (acetylcholine agonist). Treatment: atropine.
• Delayed onset poisoning: Other Amanita species and similar fungi possess amatoxins which cause liver failure; require liver transplant.

Food Examples

• Edible Mushrooms: Shiitake, oyster mushrooms.
• Mold-containing Cheese: Stilton or blue cheese.

Poisonous Mushrooms (Rapid Onset)

• Amanita muscaria: Causes hallucinations, diarrhea, sweating, and pupil constriction (miosis).

Poisonous Mushrooms (Slow Onset)

• Amanita virosa (Death Cap): Causes slow toxic reactions; contains alpha-amanitin, which binds to RNA polymerase in hepatocytes and shuts down protein synthesis. Characterized by liver failure and requires a liver transplant.

Poisoning with Cholinesterase Inhibitors

• Exposure to insecticides, wild mushrooms, and nerve gas causes excess Ach buildup due to cholinesterase (AchE) disruption. Treatment: antimuscarinics such as atropine. High doses.

Nerve Agents (ACE Inhibitors)

• Examples: Sarin, tabun.
• Mechanism: Potent AchE inhibitors, causing excess Ach and paralysis.

Antidotes for Nerve Agents

• Atropine injection: Blocks excess Ach actions on nicotinic and muscarinic receptors.

AchE inhibitor Nerve agents

• Newmark, J. The Birth of Nerve Agent Warfare lessons from Syed Abbas Foroutan, Neurology 62:1590-1596(2004).
• Foroutan, S.A. the world's first physician to report on the treatment of Sarin nerve gas.

Nerve Gas (Iraq -Iran war):

• Sarin Nerve Gases: Used in the Iran-Iraq war.
• Casualties: 450,000
• Dr. Foroutan: Sent by Iran to establish field hospitals and treat wounded combatants.
• Papers Published: 11 papers in the Farsi Kowsar Medical Journal addressing their experiences and treatment protocols.
• Mustard Gas Exposure: Some patients also exposed to WWI mustard gas. Description of disfiguration and how these patients were treated

Treatment

• Atropine: To counteract excess Ach at muscarinic receptors. US, NATO, and Iran each carry 2mg auto injectors.
• 2PAM: (2-pralidoxime): Reactivates AchE, restoring its catalytic activity. US and NATO carry 600mg auto injectors.
• Diazepam: Used to counteract seizures. All forces, including US, NATO, and Iran carry 10mg auto injectors.

Foroutan's Recommendations

• Rest Period: Allowed recovered troops post treatment.
• Dosage Adjustments: Adjust the atropine dose based on pulse rate (60-70 bpm is the target range when increasing/decreasing the dose). High doses required if symptoms severe.
• Mask Fitting: Higher casualties from the Pasdaran due to inadequate mask fitting and beards impeding proper mask seal.
• Large-scale Tragedies: The scale of attacks necessitated triage. Estimates ranged up to 2000 casualties within a 5-hour period.

Tolterodine (Detrol)

• Mechanism: Potent muscarinic antagonist, shows selectivity for the bladder.
• Indication: Overactive bladder.

Antimuscarinics (General Notes)

• Specificity: Non-specific, inducing unwanted effects on various organs.
• Overdose Symptoms: Dry as a bone, red as a beet, mad as a hatter. Symptoms include dry mouth, mydriasis, and tachycardia.

ADRs (Adverse Drug Reactions) and Toxicity

• CNS Toxicity: Sedation, amnesia, delirium, hallucinations. Convulsions might occur. Treatment: supportive care.
• Cutaneous Effects: Vasodilation; atropine flush; diagnostic symptom in overdose cases.

Ganglion Blockers,

• Mechanism: Block the action of Ach on nicotinic receptors in autonomic ganglia.

• Limited Clinical Use: Seldom used due to non-selectivity. Block all sympathetic outflow.

Examples of Ganglion Blockers

• Hexamethonium: First antihypertensive, no longer used.
• Mecamylamine:
• Trimethaphan: Short-acting, IV administration.

Cholinergic Poisoning

• Cause: Excess Ach or other agonist activity. Can be from AchE inhibitors (insecticides and nerve gasses), or mushroom poisoning.
• Treatment: Cholinesterase regenerators (e.g., pralidoxime) and antimuscarinics (e.g., atropine).

AchE Regenerator Drugs

• Pralidoxime (2-PAM): Hydrolyzes the phosphorylated AchE-organophosphate complex, regenerating AchE. Does not cross BBB; does not reverse CNS actions from organophosphates.

Muscarinic Agonists (Summary)

• Causes: Constriction of smooth muscles in gut, bladder; pupil constriction. Decreased heart rate and force; increased glandular secretions; vasodilation via nitric oxide; etc.

Muscarinic Antagonists (Summary)

• Causes: Reduced secretions (dry mouth), tachycardia; pupil dilation; relaxation of smooth muscles; CNS excitation; anti-emetic actions.