CPB 404 Pharmacology-I Lecture 1: Introduction to Autonomic Nervous System Pharmacology

CPB 404 Pharmacology-I Lecture 1 Introduction to Autonomic Nervous System Pharmacology Ahmed E. Amer Ph.D. Pharmacology & Toxicology MSc Pharmacology & Toxicology Master of Clinical Nutrition Spring 2024/2025  Prev...

CPB 404 Pharmacology-I Lecture 1 Introduction to Autonomic Nervous System Pharmacology Ahmed E. Amer Ph.D. Pharmacology & Toxicology MSc Pharmacology & Toxicology Master of Clinical Nutrition Spring 2024/2025  Previously on Physiology….. Ahmed E. Amer, Ph.D.  Organization of Nervous System Ahmed E. Amer, Ph.D. Ahmed E. Amer, Ph.D. 5  Sympathetic Nervous System VS Parasympathetic Nervous System Feature Sympathetic Parasympathetic Spinal cord segments T1-L2 Cranial III, VII, IX, and X; spinal cord segments Origin (thoracolumbar) S2-S4 (craniosacral) Type of ganglia Paravertebral and collateral Terminal ganglia: In or near effector organs Length of Short Long preganglionic fiber Length of Long Short postganglionic fiber Mass activation Not activated as whole (activation as a unit → Activation Stimulation of separate affecting all of its effector Parasympathetic nerve organs at the same time) Postganglionic nerve Norepinephrine (except acetylcholine (Ach) Neurotransmitter sweat glands) released Fight & Flight Rest & Digest [Relaxing effect] Function E →(exercise , excitement D → (Digestion , defecation &diuresis) ,emergencies) Ahmed E. Amer, Ph.D.  Sympathetic Nervous System VS Parasympathetic Nervous System 7 Ahmed E. Amer, Ph.D.  Adrenergic receptors Ahmed E. Amer, Ph.D.  Adrenergic receptors (cont.) Present in target tissue cells. Stimulated by: ✓ Norepinephrine released from sympathetic nerve endings. ✓ Epinephrinein the blood (released from adrenal medulla). Types of Adrenergic receptors: 1. Alpha- (α) : Two subtypes → α1 and α2 2. Beta- (β): Three subtypes → β1, β2 and β3 9 Ahmed E. Amer, Ph.D.  General actions of adrenergic receptor stimulation Contraction of smooth muscles. –  e.g. Vasoconstrictionof all blood vessels except coronaries & skeletal muscle vessels. –  Present in heart→ Increase heart functions Relaxation of smooth muscles –  e.g. the digestive tract, bronchioles and uterus – 3 Adipose tissue & urinary bladder Ahmed E. Amer, Ph.D.  Alpha1 adrenergic receptors Produce contraction of smooth muscles located on: Smooth muscle of blood vessels of the skin and splanchnic regions → vasoconstriction → ↓ blood flow The gastrointestinal and bladder sphincters→ contraction → slow passage of food and urine. Radial muscle of the iris in the eye → dilation of eye pupil Ahmed E. Amer, Ph.D.  Alpha 2 adrenergic receptors located on: Sympathetic presynaptic nerve terminal ↓ release of NE → Negative feedback control→ ↓ blood pressure Ahmed E. Amer, Ph.D.  Alpha adrenergic receptors Ahmed E. Amer, Ph.D.  Beta1 adrenergic receptors located in the heart on: Sinoatrial (SA) node → ↑heart rate Atrioventricular (AV) node → ↑ conduction velocity Atrialand Ventricular muscle→ ↑ force of contraction located in the kidney → ↑ renin release → ↑ blood volume→↑blood pressure Ahmed E. Amer, Ph.D.  Beta 2 adrenergic receptors Produce relaxation of smooth muscles Located on: - Smooth muscle of blood vessels in skeletal muscles & coronaries → vasodilation → ↑ blood flow - Bronchioles→ Bronchodilation - The walls of the GI tract and uterus → relaxation - ↑ glycogenolysis & gluconeogenesis Ahmed E. Amer, Ph.D.  Beta 3 adrenergic receptors Located on: - Adipose tissues → ↑ lipolysis - Urinary bladder→ relaxation Ahmed E. Amer, Ph.D.  Beta adrenergic receptors Ahmed E. Amer, Ph.D.  Cholinergic receptors Ahmed E. Amer, Ph.D. 15  Cholinergic receptors (cont.) Stimulated by acetylcholine released from: ✓ Somatic nerveending ✓ preganglionic nerveendings ✓ postganglionic parasympathetic nerve endings ✓ postganglionic sympathetic nerve ending to sweat glands Types of cholinergic receptors: 1. Nicotinic receptors 2. Muscarinic receptors: → M1, M2, and M3 Ahmed E. Amer, Ph.D.  Nicotinic receptors located in: ✓ Gangliaof the sympathetic and parasympathetic nerves → Excitation (N2, Nn) ✓ Adrenal medulla → release of epinephrine (N2, Nn) ✓ Neuromuscular junction → contraction of skeletal muscle (N1, Nm) Ahmed E. Amer, Ph.D.  Muscarinic receptors located in ✓ CNS and Gastric parietal cells (M1) ✓ Heart (M2) ✓ Smooth muscle (M3) and glands(M3). 21 Ahmed E. Amer, Ph.D.  Muscarinic (M1) receptors located in CNS and Gastric parietal cells ❖ Excitatory effects: ✓ On stomach → ↑ gastric acid secretion. ✓ On CNS → CNS stimulatory effect. Deficiency in brain→ dementia & Alzheimer. 22 Ahmed E. Amer, Ph.D.  Muscarinic (M2) receptors located in the heart on: ✓ Sinoatrial (SA) node → ↓heart rate ✓ Atrioventricular (AV) node → ↓ conduction velocity ✓ Atrial muscle only → ↓ force of contraction Ahmed E. Amer, Ph.D.  M3 Cholinergic receptors (Glandular/Smooth Muscle) Produce contraction of smooth muscles and increase secretions of glands. located on: - Bronchioles → bronchoconstriction - The walls of the GI tract and bladder → contraction → ↑ motility - The GI and bladder sphincters → relaxation - Glands → ↑ lacrimal, salivary, GI and pancreatic secretion - Circular muscle of the iris in the eye → constriction Ahmed E. Amer, Ph.D.  Previously on Basic Pharmacology….. Ahmed E. Amer, Ph.D. Ahmed E. Amer, Ph.D. Ahmed E. Amer, Ph.D.  Autonomic Nervous System Pharmacology Autonomic pharmacology studies drugs that affect the autonomic nervous system (ANS), which regulates involuntary physiological functions. The ANS is divided into the sympathetic and parasympathetic nervous systems, each with distinct neurotransmitters and receptors. Ahmed E. Amer, Ph.D.  A-Cholinergic Transmission Step Process Key Players Inhibitors Choline is transported into the neuron and converted to acetylcholine (ACh) Choline transporter Hemicholiniums Synthesis by choline acetyltransferase (ChAT). (CHT), ChAT, Acetyl- (block CHT) Acetyl-CoA (from mitochondria) CoA provides the acetyl group. ACh is transported into vesicles via a Vesamicol (blocks Storage VAT vesicle-associated transporter (VAT). VAT) Triggered by an action potential, leading to N-type Ca²⁺ channels, Botulinum toxin Release Ca²⁺ influx and vesicle fusion with the SNARE proteins (cleaves SNAREs) membrane via SNARE proteins. AChE inhibitors Acetylcholinesterase (AChE) degrades (e.g., Termination AChE ACh into choline and acetate. neostigmine, donepezil) Ahmed E. Amer, Ph.D.  Cholinergic Transmission Drugs affecting cholinergic transmission include: ✓ Cholinomimetics (ACh receptor agonists): Bethanechol, pilocarpine. ✓ Cholinesterase inhibitors: Neostigmine, donepezil. ✓ Cholinergic antagonists: Atropine, scopolamine. Ahmed E. Amer, Ph.D.  B-Adrenergic Transmission Step Process Key Players Inhibitors Tyrosine is converted to dopa, then Tyrosine hydroxylase, Metyrosine Synthesis dopamine, and finally to dopa decarboxylase, (inhibits tyrosine norepinephrine. dopamine β-hydroxylase hydroxylase) Norepinephrine is stored in vesicles via Reserpine Storage the vesicular monoamine transporter VMAT (blocks VMAT) (VMAT). Guanethidine, Triggered by Ca²⁺ influx and vesicle SNARE proteins, N-type Release bretylium fusion with the membrane. Ca²⁺ channels (inhibit release) Norepinephrine is reabsorbed by the Cocaine, Termination norepinephrine transporter (NET) or NET, MAO, COMT antidepressants degraded by MAO and COMT. (block NET) Ahmed E. Amer, Ph.D.  Adrenergic Transmission Ahmed E. Amer, Ph.D.  Adrenergic Transmission Ahmed E. Amer, Ph.D.  Adrenergic Transmission Drugs affecting adrenergic transmission include: Adrenergic agonists (sympathomimetics): Epinephrine, phenylephrine, albuterol. Adrenergic antagonists (sympatholytics): Propranolol, prazosin. Drugs affecting storage and release: Reserpine: Inhibits VMAT, depleting norepinephrine stores. Guanethidine, bretylium: Inhibit norepinephrine release. Cocaine, antidepressants: Inhibit NET, increasing synaptic norepinephrine. Ahmed E. Amer, Ph.D.  Role of the CNS in Autonomic Function Control Sensory feedback is sent These centers process The ANS requires sensory as afferent impulses to the feedback and send input from peripheral CNS centers: efferent impulses via the structures to monitor the Hypothalamus ANS to regulate body’s internal state. Medulla oblongata functions. Spinal cord Ahmed E. Amer, Ph.D.  Role of the CNS in Autonomic Function Control Reflex Arcs Most afferent impulses are translated into involuntary reflex responses. ✓ Example: A drop in blood pressure activates baroreceptors in the heart, aortic arch, and carotid sinuses. ✓ Baroreceptors send fewer signals to cardiovascular centers in the brain, triggering: Increased sympathetic output to the heart and vasculature Decreased parasympathetic output to the heart This leads to a compensatory rise in blood pressure and heart rate.. Clinical Correlation: The baroreceptor reflex helps maintain blood pressure stability, especially during activities like standing up quickly to avoid dizziness Ahmed E. Amer, Ph.D.  Definitions Category Definition Direct Mechanism Indirect Mechanism Drugs that stimulate the Increase NE release, inhibit Directly activate actions of sympathetic NE reuptake or adrenergic receptors (α & Sympathomimetics nervous system by mimicking metabolism (e.g., β) (e.g., epinephrine, the effects of norepinephrine amphetamines, cocaine, albuterol). (NE) and epinephrine (E). MAO inhibitors). Drugs that stimulate the Inhibit Directly activate actions of parasympathetic acetylcholinesterase muscarinic or nicotinic Parasympathomimetics nervous system by mimicking (AChE), increasing ACh receptors (e.g., the effects of acetylcholine levels (e.g., neostigmine, pilocarpine, bethanechol). (ACh). physostigmine). Drugs that inhibit the actions Directly block adrenergic Reduce NE release or of sympathetic nervous Sympatholytics receptors (α & β) (e.g., synthesis (e.g., system by blocking propranolol, prazosin). methyldopa, reserpine). adrenergic activity. Drugs that inhibit the actions Directly block muscarinic Inhibit ACh release or of parasympathetic nervous Parasympatholytics or nicotinic receptors (e.g., synthesis (e.g., botulinum system by blocking atropine, scopolamine). toxin). cholinergic activity. Ahmed E. Amer, Ph.D.  References Preston, Robin R., and Thad E. Wilson. Lippincott® Illustrated Reviews: Physiology. Lippincott Williams & Wilkins, 2018. Whalen, K., Feild, C., & Radhakrishnan, R. Lippincott illustrated reviews: pharmacology (7th ed.). Wolters Kluwer, 2019. Katzung’s Basic & Clinical Pharmacology, 16th Edition Ed. Todd W. Vanderah. McGraw-Hill, 2024. Ahmed E. Amer, Ph.D.