Pulmonary Autonomic Pharmacology 2023 PDF

Pulmonary Autonomic Pharmacology BPS 337 Richard T. Clements 12/4/2023 PNS, acetylcholine and bronchoconstriction Bronchoconstriction and bronchodilation: For the most part : Work similarly to vasoconstriction and vasodilation cascades in vascular smooth...

Pulmonary Autonomic Pharmacology BPS 337 Richard T. Clements 12/4/2023 PNS, acetylcholine and bronchoconstriction Bronchoconstriction and bronchodilation: For the most part : Work similarly to vasoconstriction and vasodilation cascades in vascular smooth muscle. Muscarinic and nicotinic AChR Non-specific agonist drug: Non-specific agonist drug: Muscarine Nicotine Lung autonomics- PNS M1, M2, M3, M4 and M5 receptors are all found in the lung. There are preganglionic M2 receptors in the lung. Stimulation of preganglionic M2 receptors inhibits the secretion of Ach. M3 receptors mediate bronchoconstriction and an increase in secretions including mucus. Anti-cholinergics are used to dilate the bronchioles and decrease mucus production Bronchodilators : M2AchR Ach binding to mAchR3 causes bronchoconstriction Promoting dilation requires a muscarinic M3AchR antagonist The M3 receptor (Gq coupled) controls bronchiolar smooth muscle contraction Parasympathetic 1) Acetylcholine released from nerves nerve binds m3Rs 2)Activated α subunit of Gq activates phospholipase C (PLC), which hydrolizes phosphoinositol 4,5- bis- phosphate (PIP 2 ) into diacylglycerol (DAG), & inositol 1,4,5- trisphosphate(IP 3 ). 3)IP 3 promotes flux of Ca 2+ channels. 4)Myosin light chain kinase activates cross- bridge cycling & muscle contraction. This is a very similar cascade to vasoconstriction  M2 AchR receptors inhibit Ach Bronchodilators: Ach binding to mAchR3 causes bronchoconstriction m3AchR on Airway Smooth muscle Ach binds mAchR2 on neurons: This causes a decrease in Ach release  B2-AR promote bronchodilation Similar mechanism to vascular dilation Increase activation of PKA via adenylate cyclase and cAMP Decreases MLC phosphorylation Agonists used to promote brinchodilation Atropine Gαq coupled muscarinic M3 receptor is responsible for airway smooth muscle contraction There is a 4:1 ratio of muscarinic M2 and M3 receptors Atropine (muscarinic antagonist) blocks all muscarinic receptors thus does not have selectivity for M3 receptors. If given by inhalation it is rapidly absorbed and causes the typical anticholinergic effects - drying of secretions and increased heart rate (M2 mediated responses) Ipratropium limits systemic side effects Ipratropium blocks muscarinic receptors, without selectivity, like atropine. Ipratropium is a quaternary ammonium derivative of atropine The introduction of a positive charge into the molecule limits systemic absorption when given by inhalation. This decreases the possibility of systemic side effects. Anti-cholinergic drugs in COPD- quaternary ammonium limits absorption Tiotropium Tiotropium has a longer half life than ipratropium. It also has a functional specificity for M3 receptors versus M2 receptors This is because of its longer dissociation rate from M3 receptors versus M2 receptors Much longer onset of action – 3-4 hours, but lasts 1-2 days. Gets degraded by esterases much more slowly than other discussed antagonists Adverse effects of antimuscarinics Anticholinergics can cause Dry mouth Constipation Blurry vision Confusion Impaired memory Seizure Summary of properties of anticholinergic bronchodilators Atropine when administered to the lung is rapidly absorbed. Introduction of a quaternary ammonium group limits absorption. There are many more M2 receptors in the lung than M3 receptors Atropine and ipratropium show similar activity against both receptors Tiotropium, glycopyrrolate and aclidinium are either selective or show functional selectivity for the M3 receptor All muscarinic antagonists are degraded by esterase - tiotropium, glycopyrrolate and aclidinium at a slower rate and thus have longer half lives M3AchR receptors on bronchial smooth muscle: Activate G proteins – PLC – IP3/Ca++ release – MLCK – MLC phosphorylation Pulmonary autonomics- SNS Beta 2 receptors mediate dilation bronchiolar smooth muscle in the lungs. Beta 2 agonists are used as bronchodilators to reverse acute bronchoconstriction (short half-life compounds) or for long term control (long half-life compounds). In pulmonary and skeletal muscle blood vessels beta 2 receptors are found in higher concentrations than in the vasculature of other tissues Beta 2 receptors mediate the vasodilation of pulmonary vasculature B2-AR and bronchodilation B2 agonists to increase bronchodilation Similar to vascular smooth muscle Increase AC to produce cAMP Activates PKA PKA inhibits MLCK and activates K+ channels (keeps cell from depolarizing) b2-AR activation in bronchial smooth muscle works similarly to vasodilation in VSMC discussed earlier. Beta-2 Selective Agonists – Albuterol Non-catechol, t-butyl Fairly selective, 2>>1 Inhaler,