Autonomic Nervous System and Cardiovascular Function PDF

Introduction to the Autonomic Nervous System and Cardiovascular function Todd W. Vanderah Professor and Chair, Pharmacology Joint Apt. Anesthesiology & Neurology, MD/PhD Co –Director, Director of the Comprehensive Pain and Addiction...

Introduction to the Autonomic Nervous System and Cardiovascular function Todd W. Vanderah Professor and Chair, Pharmacology Joint Apt. Anesthesiology & Neurology, MD/PhD Co –Director, Director of the Comprehensive Pain and Addiction Center CBL: Pharmacology Reinforcement Case CBL: Pharmacology Reinforcement Case Learning Objective 1) Apply principles of pharmacodynamics to the Autonomic Nervous System, including autonomic receptors within the cardiovascular system  Case 62 year old man comes into the emergency room with a complaint that he feels his heart is “racing”, feels a bit ”light-headed” and is short-of-breath. Upon examination the patient’s heart rate is at 176 bpm and irregular with a blood pressure of 105/75 mmHg. What might be causing the heart to increase its activity and why does this result in a decrease in blood pressure?  Case 62 year old man comes into the emergency room with a complaint that he feels his heart is “racing”, feels a bit ”light-headed” and is short-of-breath. Upon examination the patient’s heart rate is at 176 bpm and irregular with a blood pressure of 105/75 mmHg. What might be causing the heart to increase its activity and why does this result in a decrease in blood pressure? Atrial fibrillation Causes of A fib Coronary artery disease-Heart attack Congenital heart defect Heart valve problems High blood pressure Lung diseases Problem with the heart's natural pacemaker Physical stress due to surgery, pneumonia or other illnesses Use of stimulants, including certain medications, caffeine, tobacco and alcohol decrease in blood pressure due to poor affective pumping action of the heart What Controls/Regulates the Heartbeat???  Autonomic Nervous System (ANS) - Regulates Involuntary activity 2 Divisions - Sympathetic “fight or flight” - Parasympathetic “rest and digest” Development of the ANS  Autonomic Nervous System (ANS) Development of the ANS - What cells in the periphery originate from Neural Crest Cells Craniofacial cartilage and bone Smooth muscle Schwann and Satellite cells Post-ganglionic sympathetic and parasympathetic nerves Enteric nerves Chromaffin Cells in Adrenal Medulla  Autonomic Nervous System (ANS) Development of the ANS - Originate from Neural Crest Cells Pigment Cells (melanocytes) Neural crest Schwann Cells Dorsal Root Ganglia Satellite Cells Pigment Cells Pseudounipolar Cells Postganglionic Sympathetic Cells Chromaffin Cells in Adrenal Medulla Sympathetic Ganglion Prevertebral plexus Developing Adrenal Gland Parasympathetic roots to Plexus in Gut Wall enteric Nervous system  Sympathetic Parasympathetic ANS Superior cervical ganglia Brainstem CN III, VII, IX, X Thoracic Lumbar Sympathetic ganglia (prevertebral) Sacral Sympathetic chain ganglia (paravertebral)  ANS Sympathetic Parasympathetic Anatomical differences Brainstem Thoracic Lumbar Sacral Sympathetic Parasympathetic - Come from Thoracic and Lumbar regions - Come from Brainstem and Sacral regions - Preganglionic fibers are short - Preganglionic fibers are long - Postganglionic fibers are short - Postganglionic fibers are long - Preganglionic fibers synapse onto - Preganglionic fibers synapse onto postganglionic fibers in ganglia on tissue postganglionic fibers in para-vertebral or specialized ganglia (i.e., ciliary-, otic-, and pre-vertebral ganglia pterygopalantine-, submandibular-ganglia)  Case 62 year old man comes into the emergency room with a complaint that he feels his heart is “racing” and feels a bit ”light-headed”. Upon examination the patient’s heart rate is at 176 bpm and irregular with a blood pressure of 105/75 mmHg. What medication could be used to help with this issue? Beta Adrenergic Blockers Calcium Channel Antagonists Propranolol (non-selective - 𝜷1 KD =2nM; 𝜷2 KD =0.6nM) Diltiazem Metoprolol - 𝜷1 selective Verapamil Atenolol - 𝜷1 selective Gs Gs Gs Increase heart rate, Increase vasodilation, Increase lipolysis conduction velocity, Bronchodilation, force of contraction Decrease peripheral resistance (slight) SA and AV Nodes & Cardiac Regulation Sympathetic Cardiac Regulation Take Home Message: Norepinephrine and Epinephrine, via B1 adrenergic receptors (GPCRs-Gs) in cardiac muscle increases cAMP and PKA increasing Na+ and Ca+2 channel influx – increasing cardiac activity Sympathetic Beta1 receptor Blocker Beta 1 adrenergic receptor Sympathetic Beta2 receptor and smooth muscle relaxation Smooth Muscle relaxation contraction Take Home Message: Norepinephrine and Epinephrine, via B2 adrenergic receptors (GPCRs-Gs) on smooth muscle increases cAMP that inhibits Myosin Light Chain Kinase (MLCK) to inhibit muscle contraction – causing vasodilation  Case 62 year old man comes into the emergency room with a complaint that he feels his heart is “racing” and feels a bit ”light-headed”. Upon examination the patient’s heart rate is at 176 bpm and irregular with a blood pressure of 105/75 mmHg. What medication could be used to help with this issue? Beta Adrenergic Blockers Calcium Channel Antagonists Propranolol (non-selective - 𝜷1 KD =2nM; 𝜷2 KD =0.6nM) Diltiazem Metoprolol - 𝜷1 selective Verapamil Atenolol - 𝜷1 selective What might be the side effect of the medication that you should be warning the patient about and monitoring for? feeling dizzy or tired, constipation, cold hands or feet, dizziness/tired, nausea, low difficulties sleeping blood pressure and headache and nightmares  Brainstem ANS Cardiac Regulation Increases heart Decreases rate & force of heart rate contraction Thoracic Spinal cord SA node AV node Parasympathetic Cardiac Regulation M2 Take Home Message: Acetylcholine, via M2 muscarinic receptors (GPCRs-Gi) in cardiac muscle decreases cAMP and PKA decreasing Ca+2 channel influx and increasing K+ efflux– decreasing cardiac activity  Case Continuation of our 62 year old patient Patient was prescribed both a beta blocker and a calcium channel antagonist. Due to the inability of the patient remembering whether he took his medications, he took a second dose of both medications and soon there after a third dose prior to going to bed. His partner found him in a comatose state, cold to the touch and called 911. Upon arrival to the ED, the patient had a temperature of 93.2°, blood pressure (BP) 50/30 mm Hg, and heart rate (HR) 25–30 beats per minute (bpm). What can be done too help this patient?  Case What can be done too deal with the low BP and HR Alpha 1 receptors and smooth muscle contraction Recap of our Sympathetic Adrenergic Receptors Beta 1 Gs All increase Beta 2 Gs cAMP and PKA Beta 3 Gs Alpha 1 Gq Increase Ca+2 and PKC Alpha 2 Gi Decrease cAMP and PKA Recap of our Parasympathetic Muscarinic Receptors M 1 Gq M 3 Gq Increase Ca+2 and PKC M 5 Gq M 2 Gi decrease cAMP and PKA M 4 G1 Are these the only acetylcholine receptors in the human body? Acetylcholine Receptors Neuromuscular Junction parasympathetics Central Nervous System Autonomic Nervous System  Putting things into play When a person walks into a poorly lit room from outside on a bright sunny day the pupil of the eye will get smaller. This is an ANS response. There are two types of muscles in the eye that control the size of the pupil - one being striated muscle for dilation and one being a sphincter muscle for constriction. What division of the ANS system is making the pupil get smaller? parasympathetic What is the type of receptor on the muscle that makes the pupil get smaller and what was the neurotransmitter? Muscarinic M Acetylcholine 3, What type of medication might one use to make the pupil get larger – in the case of an eye exam? Sympathetic agonist (i.e., phenylephrine acting at 𝞪1) and muscarinic antagonist If you wanted to increase the fluid on the cornea of an eye what division of the ANS would you want to activate? What type of receptor would be involved? parasympathetic Muscarinic M3, Acetylcholine Questions ANS