Pulmonary Autonomic Pharmacology Overview

Pulmonary Autonomic Pharmacology

• This course covers pulmonary autonomic pharmacology, specifically focusing on bronchoconstriction and bronchodilation.
• The parasympathetic nervous system (PNS) plays a crucial role in bronchoconstriction.
• Acetylcholine (ACh) is the primary neurotransmitter released by the PNS to cause bronchoconstriction.
• The PNS utilizes cholinergic nerves, preganglionic and postganglionic cholinergic nerve pathways to induce bronchoconstriction.
• The cholinergic nerves stimulate smooth muscle (ASM).
• Acetylcholine (ACh) binds to muscarinic receptors (mAchR) on the smooth muscle.
• ACh binding to M3 muscarinic receptors (M3AchRs) causes bronchoconstriction.
• Bronchoconstriction involves similar mechanisms to vasoconstriction, encompassing cascades in vascular smooth muscle.

M3 receptors and Bronchoconstriction

• M3 receptors mediate bronchoconstriction and increase secretion, including mucus.
• A cascade of events occurs when ACh binds to M3 receptors on airway smooth muscle
• This activation leads to an increase in intracellular calcium, resulting in muscle contraction.
• Anticholinergics are used to inhibit M3 receptors to relax bronchial smooth muscles and decrease mucus secretion.

M2 receptors and Bronchodilation

• Pre-ganglionic M2 receptors are found in the lung and modulate ACh release.
• The stimulation of M2 receptors inhibits ACh release from the vagus nerve, preventing bronchoconstriction, thus promoting bronchodilation.

AChRs and drugs

• Muscarine and Nicotine are non-specific agonists
• The autonomic pathways to the lung result in smooth muscle constrictions on the lung tissues..
• ACh binding to mAchR3 on airway smooth muscle causes bronchoconstriction.

Bronchodilators

• Bronchodilators promote dilation.
• They require muscarinic antagonists to counteract the effects of ACh, thereby relaxing the smooth muscle cells.
• The release of ACh is inhibited by M2 receptors allowing bronchodilation.
• mAchRs cause bronchoconstriction and require muscarinic antagonists to oppose the effect of ACh in inducing relaxation.

The M3 receptor (Gq coupled)

• This receptor controls bronchial smooth muscle contraction.
• Acetylcholine (ACh) binding to the receptor activates a Gq subunit, which activates PLC, producing diacylglycerol (DAG) and inositol triphosphate (IP3) leading to an increase in intracellular calcium.
• This increase in calcium triggers muscle contraction.
• This mechanism is similar to vasoconstriction.

M2 Receptor Inhibition of ACh

• M2 receptors on neurons inhibit ACh release.
• This inhibition reduces the amount of ACh available to bind to M3 receptors, leading to a relaxation in bronchiolar smooth muscle.
• Bronchodilation occurs due to the decreased ACh release.

Control of Bronchoconstriction and Bronchodilation using Agonists and Antagonists

• Beta-2 agonists promote bronchodilation.
• Anticholinergics mediate bronchodilation by preventing the constriction caused by acetylcholine.

Anticholinergic Drugs

• Ipratropium: This quaternary ammonium derivative of atropine, is less systemically absorbed, particularly when inhaled.
• Ipratropium inhibits muscarinic receptors without selectivity like atropine.
• Limits systemic side effects by limiting absorption, especially when given by inhalation.
• Atrophine: A more potent anticholinergic that blocks all muscarinic receptors.
• Tiotropium, glycopyrrolate, and aclidinium: These agents selectively or functionally target M3 receptors.

Tiotropium

• Tiotropium has a longer half-life than ipratropium.
• Features functional selectivity for the M3 receptor versus M2.
• Has a prolonged therapeutic effect due to slow degradation by esterases.
• Longer duration of action.

Adverse Effects of Anticholinergics

• Anticholinergics can cause several adverse effects, such as dry mouth, constipation, blurred vision, confusion, impaired memory, and seizures.

Beta-2 Agonists

• Beta-2 receptors mediate bronchodilation in the lungs.
• Beta-2 agonists are used as bronchodilators to reverse acute bronchoconstriction (short-acting) or for long-term control (long-acting).
• These receptors have higher concentrations in the pulmonary and skeletal muscle blood vessels compared to other tissues.
• Beta-2 receptors mediate vasodilation of pulmonary vasculature

B2-AR and Bronchodilation

• B2-Agonists stimulate bronchodilation, similar to vascular smooth muscle.
• Activation of adenylate cyclase causes an increase in cAMP.
• cAMP activates PKA, inhibiting MLCK, resulting in smooth muscle relaxation.
• Theophylline is used as a bronchodilator.

Beta-2 Selective Agonists

• Albuterol, a non-catechol, t-butyl compound, is a fairly selective beta-2 agonist with a short duration of action.
• Salmeterol, Formoterol, Arformoterol, and Vilanterol are all long-acting beta-2 agonists.

Long-Acting Beta Agonists

• These beta-2 agonists are lipophilic and form depots in the cell membrane, enabling slow release for prolonged effects.
• They are typically used for prevention of bronchoconstriction.

Adverse Effects of Beta-2 Agonists

• Adverse effects include tachycardia, muscle tremors, hypokalemia, and possible hypoxia due to V/Q mismatch.

V/Q (Ventilation/Perfusion) Mismatch

• This is an imbalance between air flow and blood flow.
• Can lead to reduced oxygen delivery due to a mismatch between ventilation and perfusion.