Muscarinic Receptors - Normal Functions

Overview

• G-protein coupled receptors (GPCRs) activated by acetylcholine (ACh)
• Found on autonomic effector cells innervated by postganglionic parasympathetic nerves
• 5 subtypes: M1-M5

Receptor Subtypes & Signaling

Functions by Organ System

• ↓ Heart rate (negative chronotropy) via SA node
• ↓ AV conduction (negative dromotropy)
• ↓ Atrial contractility

• Bronchoconstriction
• ↑ GI motility and tone
• Urinary bladder detrusor contraction (voiding)
• Uterine contraction

• ↑ Salivary, lacrimal, sweat, bronchial, and gastric secretions
• M1 also stimulates gastric acid secretion

• Miosis (pupillary constrictor muscle)
• Accommodation for near vision (ciliary muscle contraction)

• Releases nitric oxide → vasodilation (indirect)
• Note: vessels lack direct parasympathetic innervation

• Cognition and memory (hippocampus, cortex)
• Motor control (striatum)
• Modulation of dopamine release (M5)

• Modulates nicotinic transmission

Key Mnemonic - SLUDD (M3-mediated secretions)

Pharmacological Actions of Atropine

CNS

• Low dose: Mild vagal stimulation → slight bradycardia (central vagal nucleus stimulation)
• Therapeutic dose: Mild CNS stimulation → restlessness, excitement
• Toxic dose: Hallucinations, delirium, coma
• Reduces tremor and rigidity in Parkinsonism (anti-muscarinic action in striatum)
• Antiemetic effect (vestibular apparatus suppression)

CVS

• Heart rate: ↑ HR (tachycardia) by blocking M2 on SA node
• Low dose paradox: Transient bradycardia (central vagal stimulation before peripheral block)
• ↑ AV conduction velocity
• Little effect on blood pressure (vessels lack cholinergic innervation)
• At high doses → peripheral vasodilation → flushing (mechanism unclear)

Eye

• Mydriasis - dilates pupil (blocks M3 on sphincter pupillae)
• Cycloplegia - paralyzes accommodation (blocks ciliary muscle)
• ↑ Intraocular pressure (dangerous in closed-angle glaucoma)
• Effects last days (long duration - 7-12 days for 1% atropine)

Glands

• ↓ Salivary secretion → dry mouth (most sensitive gland)
• ↓ Sweat secretion → dry, hot skin → may cause hyperthermia
• ↓ Lacrimal secretion → dry eyes
• ↓ Bronchial secretion → thickened, viscid mucus
• ↓ Gastric secretion (reduces volume and acidity - requires large doses)

Smooth Muscle

• Bronchi: Bronchodilation (blocks M3)
• GI tract: ↓ Motility and tone → relieves spasm
• Urinary bladder: Relaxes detrusor, contracts sphincter → urinary retention
• Uterus: Minimal effect

Local Anesthetic Action

• Atropine has weak local anesthetic (membrane-stabilizing) property
• Due to blockade of Na⁺ channels - unrelated to muscarinic blockade
• Clinically not significant at therapeutic doses
• Only relevant at high/toxic concentrations

Atropine - Pharmacological Actions

• Low dose → transient bradycardia (central vagal stimulation)
• Therapeutic → mild stimulation, restlessness
• Toxic → hallucinations, delirium, coma
• Anti-Parkinsonian (↓ tremor, rigidity)
• Antiemetic

• ↑ HR (tachycardia) - blocks M2/SA node
• Low dose paradox - brief bradycardia first
• ↑ AV conduction
• High dose - flushing (vasodilation)

• Mydriasis (sphincter pupillae block)
• Cycloplegia (ciliary muscle paralysis)
• ↑ IOP - contraindicated in glaucoma
• Long duration (7-12 days)

• Dry mouth (most sensitive - ↓ saliva)
• Dry skin (↓ sweat → hyperthermia risk)
• ↓ Lacrimal, bronchial, gastric secretions

• Bronchodilation
• ↓ GI motility → relieves spasm
• Urinary retention (relaxes detrusor, contracts sphincter)

• Weak Na⁺ channel block
• Not clinically significant at therapeutic doses

Beta-Adrenergic Blockers (Beta Blockers)

Introduction

• Competitive antagonists at β-adrenergic receptors
• Prototype: Propranolol
• Block effects of catecholamines (adrenaline, noradrenaline) at β receptors

Classification

• Without ISA: Propranolol, Nadolol, Timolol, Sotalol
• With ISA: Pindolol, Oxprenolol, Penbutolol

• Without ISA: Metoprolol, Atenolol, Bisoprolol, Esmolol, Betaxolol, Nebivolol
• With ISA: Acebutolol, Celiprolol

• Carvedilol, Labetalol

• Butoxamine (no clinical use)

Properties

Pharmacological Actions

• ↓ HR (negative chronotropy) - blocks β1/SA node
• ↓ Force of contraction (negative inotropy)
• ↓ Cardiac output
• ↓ BP (antihypertensive effect - multiple mechanisms)
• ↓ AV conduction velocity (negative dromotropy)
• ↓ Automaticity of ectopic pacemakers (antiarrhythmic)
• ↓ Myocardial O2 demand (anti-anginal)

• ↓ Cardiac output
• ↓ Renin release (blocks β1 on JGA cells) → ↓ Angiotensin II → ↓ aldosterone
• Central ↓ sympathetic outflow
• ↓ Noradrenaline release (presynaptic β block)
• Resetting of baroreceptors

• Bronchoconstriction (blocks β2) - contraindicated in asthma
• Cardioselective agents safer but not completely safe

• ↓ Glycogenolysis → masks hypoglycemia symptoms (dangerous in diabetics)
• ↓ Lipolysis → ↑ triglycerides, ↓ HDL
• Non-selective agents impair recovery from hypoglycemia

• ↓ Intraocular pressure (↓ aqueous humor production)
• Used topically in glaucoma (Timolol, Betaxolol)

• Lipid-soluble agents (propranolol) enter CNS
• Anti-anxiety, sedation
• Vivid dreams, nightmares
• Used in essential tremor, migraine prophylaxis

• ↓ Renin secretion
• ↓ GFR slightly (due to ↓ CO) - not clinically significant

• Blocks β2 → may increase uterine tone

Pharmacokinetics (Propranolol)

• Oral, well absorbed but high first-pass metabolism
• Bioavailability ~30%
• Highly lipid soluble → crosses BBB, placenta
• Metabolized in liver
• Half-life ~4 hours (but pharmacological effect longer)
• Protein binding ~90%

Therapeutic Uses

1. Hypertension - first line (especially with angina/post-MI)
2. Angina pectoris (stable) - ↓ O2 demand
3. Cardiac arrhythmias - SVT, AF, atrial flutter, sinus tachycardia
4. Post-MI - ↓ mortality, prevent reinfarction
5. Heart failure - Carvedilol, Metoprolol, Bisoprolol (paradoxical benefit - long-term reverse remodeling)
6. Hyperthyroidism / thyroid storm - ↓ peripheral conversion of T4→T3, ↓ sympathetic symptoms
7. Phaeochromocytoma - only after alpha blockade (never alone)
8. Migraine prophylaxis - Propranolol
9. Essential tremor - Propranolol
10. Anxiety/situational panic - Propranolol
11. Glaucoma - Timolol (topical)
12. Hypertrophic obstructive cardiomyopathy (HOCM)
13. Portal hypertension / esophageal varices prophylaxis
14. Dissecting aortic aneurysm

Adverse Effects

• Bradycardia, heart block
• Worsening of heart failure (acute use)
• Bronchospasm (avoid in asthma/COPD)
• Cold extremities (↓ peripheral blood flow)
• Fatigue, lethargy
• Vivid dreams, nightmares (lipid-soluble agents)
• Masking of hypoglycemia symptoms
• ↑ Triglycerides, ↓ HDL
• Rebound phenomenon on sudden withdrawal (↑ angina, MI risk)
• Impotence

Contraindications

• Bronchial asthma / COPD
• Bradycardia, heart block (2nd/3rd degree)
• Cardiogenic shock / decompensated heart failure
• Peripheral vascular disease (relative)
• Diabetes mellitus on insulin (relative)
• Phaeochromocytoma (without prior alpha blockade)

Drug Interactions

• Verapamil/Diltiazem + beta blocker → severe bradycardia, heart block
• Antidiabetics → enhanced hypoglycemia + masked symptoms
• NSAIDs → attenuate antihypertensive effect
• Clonidine withdrawal + beta blocker → hypertensive crisis

Withdrawal Syndrome

• Sudden stoppage → rebound tachycardia, hypertension, angina, MI
• Due to upregulation of β receptors during prolonged blockade
• Always taper gradually over 1-2 weeks