Acetylcholine and Muscarinic Receptors

Acetylcholine & Muscarinic Receptor Target

• Acetylcholine (ACh) is a neurotransmitter that interacts with muscarinic receptors.
• Muscarinic receptors are G protein-coupled receptors (GPCRs) involved in various physiological functions.

Muscarinic Receptor Subtypes

• Muscarinic receptors are divided into five subtypes: M1, M2, M3, M4, and M5.
• M1, M3, and M5 activate Gq-PLC pathway, leading to hydrolysis of polyphosphoinositides and mobilization of intracellular Ca2+.
• M2 and M4 inhibit adenylyl cyclase and regulate specific ion channels via coupling to pertussis toxin-sensitive Gi and Go.
• M1 plays a crucial role in modulating nicotinic cholinergic transmission in the ganglia.

Pharmacological Effects of Acetylcholine

• ACh is a quaternary ammonium compound with limited penetration into the CNS due to its chemical structure.
• ACh's systemic administration is limited due to rapid hydrolysis by plasma butyrylcholinesterase (bAChE).

Cardiovascular System

• ACh exerts four primary effects on the cardiovascular system: vasodilation, decreased heart rate (negative chronotropic), decreased AV conduction velocity (negative dromotropic), and decreased force of cardiac contraction (negative inotropic).
• ACh's effects on the heart are primarily mediated by parasympathetic (vagal) stimulation.
• In the SA node, ACh slows down spontaneous depolarization, delaying the attainment of threshold potential, resulting in decreased heart rate.
• ACh's effects on contractility are mediated by inhibiting cAMP production and the release of norepinephrine (NE).
• In the atria, ACh induces hyperpolarization and decreases action potential duration by increasing IK-ACh.
• In the AV node, ACh slows down conduction and increases refractory period by inhibiting calcium channel opening (ICa-L), potentially leading to complete heart block with high doses of cholinergic agonists.

Respiratory Tract

• ACh causes bronchoconstriction, increased tracheobronchial secretions, and stimulation of chemoreceptors of the aortic and carotid bodies, primarily through M3 receptors.

Gastrointestinal Tract

• M3 receptors are primarily responsible for increased amplitude of contractions and secretory activity in the stomach and intestine, while M2 receptors also contribute.

Secretory Effects

• ACh increases secretions in lacrimal, nasopharyngeal, salivary, and sweat glands through M3 receptors.
• M1 receptors significantly contribute to the cholinergic stimulation of salivary secretion.

Eye

• ACh causes miosis (contracting pupillary sphincter muscle) and accommodation (contracting ciliary muscle for near vision), mainly mediated by M3 receptors.

Muscarinic Receptor Antagonists

• Muscarinic receptor antagonists competitively inhibit the actions of ACh and its congeners.

Atropine

• Atropine is a prototypical muscarinic antagonist.
• Atropine's pharmacological effects differ from other muscarinic antagonists.
• Atropine is used for its effects on the cardiovascular, respiratory, and gastrointestinal systems.

Cardiovascular System

• Atropine mainly alters heart rate, primarily causing tachycardia.
• Smaller doses (0.4-0.6 mg) can temporarily induce bradycardia, but this is usually followed by tachycardia.
• Atropine blocks presynaptic M1 receptors in the SA node, reducing the release of ACh and contributing to its tachycardia effect.
• Atropine blocks M2 receptors on the nodal pacemaker cells, further increasing heart rate.
• Large doses of atropine can progressively increase heart rate by blocking M2 receptors on the pacemaker cells.
• Atropine can prevent or abruptly abolish bradycardia.
• Important note:* In infants, elderly patients, and individuals with heart failure, even large doses of atropine may fail to accelerate the heart rate.

Respiratory System

• Atropine dries the mucous membranes of the respiratory tract by inhibiting secretions from the nose, mouth, pharynx, and bronchi.
• Atropine is used to reduce rhinorrhea (runny nose) and prevent irritating inhalational anesthetics (e.g., diethyl ether) from increasing bronchial secretions.
• Quaternary ammonium compounds like ipratropium, tiotropium, aclidinium, and umeclidinium are used primarily for their effects on the respiratory tract.
• Aclidinium undergoes rapid hydrolysis in plasma to inactive metabolites, reducing systemic exposure.
• Ipratropium and tiotropium have minimal inhibitory effects on mucociliary clearance compared to atropine, minimizing the accumulation of lower airway secretions.
• Key takeaway:* For COPD patients, ipratropium and tiotropium are preferred over atropine because atropine also inhibits mucociliary clearance, exacerbating their condition.

Delve into the complexities of acetylcholine and its interaction with muscarinic receptors. This quiz covers the various subtypes of these receptors, their physiological roles, and the pharmacological effects of acetylcholine in the body. Test your knowledge on this vital neurotransmitter and its significance in the cardiovascular system and beyond.