Med Phys Pharm 551 L12 Smooth Muscle Pharm

Diagraming the BIG picture together…again! LO4,5,6  Lecture #12: Smooth Muscle Pharmacology Julia Hum, PhD Primary Course Instructor Course Meets: Monday/Wednesday/Friday: 2:00-2:50pm Office Hours: Monday/Wednesday/Friday 11:00am-12:00p...

Diagraming the BIG picture together…again! LO4,5,6  Lecture #12: Smooth Muscle Pharmacology Julia Hum, PhD Primary Course Instructor Course Meets: Monday/Wednesday/Friday: 2:00-2:50pm Office Hours: Monday/Wednesday/Friday 11:00am-12:00pm (317B or WebEx)  L12: Learning Objectives 1. Compare and contrast the regulators of smooth muscle contraction and relaxation 2. Identify the mechanism of action of the bronchodilators 3. Recognize the mechanism of action of calcium channel blockers and direct vasodilators 4. Distinguish the mechanism of actions of the smooth muscle relaxants class of drugs 5. Characterize the mechanism of action of prostaglandin agonist 6. Distinguish the mechanism of action of the agent for gastrointestinal smooth muscle Unless otherwise noted, figures in today’s lecture are from: Lippincott Illustrated Reviews: Physiology 1e Wilson (Ch. 19) Outline of Smooth Muscle Pharmacology 1. Bronchodilators 2. Antihypertensives 3. Smooth Muscle Relaxants 4. Prostaglandins 5. Agents for Gastrointestinal Smooth Muscle 6. Agents Acting on Uterine Smooth Muscle Outline of Smooth Muscle Pharmacology 1. Bronchodilators Beta-2 Agonists Albuterol: asthma and COPD Anticholinergics Ipratropium: variety of respiratory conditions 2. Antihypertensives Calcium Channel Blockers Amlodipine: hypertension Diltiazem: hypertension and cardiac function Direct Vasodilators Hydralazine: hypertension and heart failure Outline of Smooth Muscle Pharmacology 3. Smooth Muscle Relaxants Nitric Oxide Donors Nitroglycerin: angina and heart failure Phosphodiesterase Inhibitors Sildenafil: erectile dysfunction 4. Prostaglandins Misoprostol: induction of labor 5. Agents for Gastrointestinal Smooth Muscle Antispasmodics Hyoscine: gastrointestinal spasms  1. Bronchodilators – Beta 2 Agonists LO1,2  1. Bronchodilators: Direct-Acting Adrenergic Agonists Al-bu-ter-ol Short-acting β2 agonists used primarily as bronchodilators “SABA” administered by a metered-dose inhaler Albuterol is the short-acting β2 agonist (SABA) of choice for the management of acute asthma symptoms LO1,2  1. Bronchodilators – Anticholinergics Ipratropium Blocks the action of acetylcholine at muscarinic receptors Type of receptor in the parasympathetic nervous system These receptors are found throughout the body, including in the smooth muscle of the airways LO1,2  2. Antihypertensives LO1,3  2. Antihypertensives Calcium Channel Blockers MOA: limit intracellular calcium = promotes vasodilation of arterioles Block the inward movement of calcium by binding to L- type calcium channels in the heart and in smooth muscle of the coronary and peripheral arteriolar vasculature Amlodipine – selectively binds L-type calcium channels in vascular smooth muscle Main use is hypertension; very few drug interactions Diltiazem - binds L-type calcium channels in smooth muscle Use is hypertension and other cardiac disfunction; many drug interactions LO1,3  ↑ 𝑪𝑎𝑙𝑐𝑖𝑢𝑚 = 𝑉𝑎𝑠𝑜𝒄𝑜𝑛𝑠𝑡𝑟𝑖𝑐𝑡𝑖𝑜𝑛 ↓ 𝐶𝑎𝑙𝑐𝑖𝑢𝑚 = 𝑉𝑎𝑠𝑜𝑑𝑖𝑙𝑎𝑡𝑖𝑜𝑛 Endothelial Control of Blood Flow: NO Highly localized effect due to short half-life Raises cGMP, causes cGMP- dependent kinase to phosphorylate and inhibit myosin light-chain kinase Phosphorylates SERCA to increase activity – causing intracellular Ca++ to fall Mediates the response of many vasodilators LO1,3  2. Antihypertensives Direct Vasodilators MOA: mimic nitric oxide’s affect on vascular smooth muscle Hydralazine – leads to the activation of guanylate cyclase, resulting in increased levels of cGMP within the smooth muscle cells cGMP causes relaxation of the smooth muscle, contributing to vasodilation LO1,3  3. Smooth Muscle Relaxants Nitric Oxide Donors Nitroglycerin: angina and heart failure MOA: acts by releasing NO in the vascular smooth muscle Nitric oxide stimulates guanylate cyclase, increasing intracellular cGMP This leads to relaxation of smooth muscle LO1,4  3. Smooth Muscle Relaxants Phosphodiesterase Inhibitors Sildenafil: erectile dysfunction Nitric Oxide and Erection: Sexual stimulation leads to the release of NO in the corpus cavernosum of the penis NO stimulates the enzyme guanylate cyclase, which increases levels of cGMP Phosphodiesterase Type 5 Inhibition: Sildenafil inhibits the action of PDE5, the enzyme that breaks down cGMP Sildenafil increases cGMP levels, enhancing and prolonging the erection in response to sexual stimulation LO1,4  ↑ 𝑪𝑎𝑙𝑐𝑖𝑢𝑚 = 𝑉𝑎𝑠𝑜𝒄𝑜𝑛𝑠𝑡𝑟𝑖𝑐𝑡𝑖𝑜𝑛 ↓ 𝐶𝑎𝑙𝑐𝑖𝑢𝑚 = 𝑉𝑎𝑠𝑜𝑑𝑖𝑙𝑎𝑡𝑖𝑜𝑛 Endothelial Control of Blood Flow: Prostaglandins Endothelium is an important source of Prostaglandins Family of both vasodilators and vasoconstrictors Depends on which PG type and which receptor LO1,5  4. Prostaglandins: Misoprostol MOA: Prostaglandin Analog (PGE1) Mimics the action of naturally occurring prostaglandins Clinical use: induce labor by promoting uterine https://www.ajog.org/cms/10.1016/j.ajog.2023.02.009/asset/149c92ac-59ae-4de5-85bf-ec1afbc4a491/main.assets/gr3_lrg.jpg contraction LO1,5  5. Agent for GI Smooth Muscle Antispasmodics with Anticholinergic Effects: Hyoscine: MOA - blocking the action of acetylcholine at muscarinic receptors In the peripheral nervous system, blocking muscarinic receptors leads to decreased GI motility and secretion Help manage conditions like irritable bowel syndrome (IBS) by reducing spasms and secretion in the gut LO1,6 Muscle Drug Map