Pharmacology of the Autonomic Nervous System PDF

Pharmacology of the autonomic nervous system 4MBBS102 (23.24) Dr Dibesh Thapa Pharmacology & Therapeutics, School of Bioscience Vascular Biology & Inflammation School of Cardiovascular medicine and scie...

Pharmacology of the autonomic nervous system 4MBBS102 (23.24) Dr Dibesh Thapa Pharmacology & Therapeutics, School of Bioscience Vascular Biology & Inflammation School of Cardiovascular medicine and sciences King’s College London  Learning outcomes - Describe the fundamental role of of autonomic nervous system. - Describe and understand the distinction between sympathetic and parasympathetic nervous system. - Explain in detail the cholinergic and adrenergic signal transmission. - Understand the pharmacology of drugs used for various treatments that mediate their effect via modulation of autonomic nervous system.  Nervous System Central Nervous Peripheral Nervous System System Somatic Nervous Autonomic Enteric Nervous System Nervous System System Sympathetic Parasympathetic Nervous System Nervous System Servier Medical Art  Autonomic Nervous System (ANS) - ANS conveys signals from the CNS to the rest of the body (except for the somatic motor innervation of skeletal muscle). - Outside CNS but cannot function without it - Involuntary control, autonomic functions such as cardiac function, respiration, digestion, vascular regulation. - Maintains homeostasis (a stable cellular environment) by directly or indirectly (e.g. through controlling the blood supply) facilitating the response of virtually every organ system to changing external and internal demands. Tenor.com Servier Medical Art  Autonomic Nervous System (ANS) Sympathetic NS Parasympathetic NS Enteric NS - flight/fight/fright response - rest/digest or feed/breed system - located within and controls - usually excitatory response - usually inhibitory response gastrointestinal tract - adrenergic receptor at target tissue - muscarinic receptor at target tissue - second brain (can act independent of (exception) - acetylcholine main neurotransmitter CNS) - noradrenaline main neurotransmitter - controls motor movement and enzymatic secretion in gut - Acetylcholine, dopamine, serotonin Primer on the Autonomic Nervous System Parasympathetic NS Wehrwein et al, Compr Physiol, 2016 Sympathetic NS Wehrwein et al, Compr Physiol, 2016 Human Physiology: An Integrated Approach (8th Ed); Chapter 11  Parasympathetic nervous system III eye VII brainstem IX lacrimal glands X salivary glands cranial nerves heart bronchi stomach small intestine large intestine sacral pelvic nerves segments bladder genitalia Adapted from Dr Andy Grant  Parasympathetic nervous system III eye → pupil constricts VII brainstem IX lacrimal glands → tears X salivary glands → watery saliva cranial nerves heart → decrease rate bronchi → constriction stomach → increased motility small intestine → increased motility large intestine → increased motility sacral pelvic nerves segments bladder → contraction → erection genitalia Adapted from Dr Andy Grant  Sympathetic nervous system eye Superior Cervical Ganglion blood vessels SCG T1 first thoracic heart segment Coeliac Ganglion bronchi CG stomach Superior Mesenteric Ganglion SMG liver ADRENAL MEDULLA L2 sympathetic chain small intestine second lumbar segment IMG large intestine Inferior Mesenteric Ganglion bladder genitalia Adapted from Dr Andy Grant  Sympathetic nervous system eye → pupil dilates Superior Cervical Ganglion SCG blood vessels → vessels constrict T1 first thoracic heart → increased rate / force segment Coeliac Ganglion bronchi → dilatation CG stomach → reduced motility Superior Mesenteric Ganglion SMG liver → increased metabolism ADRENAL MEDULLA → release adrenaline L2 sympathetic second lumbar chain small intestine → reduced motility segment IMG large intestine → reduced motility Inferior Mesenteric Ganglion bladder → relaxation genitalia → ejaculation and detumescence Adapted from Dr Andy Grant  Parasympathetic NS Sympathetic NS Receptor Effect Receptor Effect Eye Sphincter muscle M3/M2 Contraction (miosis) Little effect Eye Ciliary muscle M3/M2 Contraction (near vision) Little effect Lacrimal (tear) glands M3/M2 Secretion β (very low expression) Secretion Salivary glands M3/M2 Watery secretion α1, β Thick viscous secretion Bronchial smooth muscle M2/M3 Contraction β2 Relaxation AV node M2/M3 Decrease conduction velocity β1/β2 Increase conduction velocity Ventricular muscle Little effect β1/β2 Increase contractility Gut smooth muscle M2/M3 Increase motility/tone α1, α2, β2 Decrease motility Digestive glands M3/M2 Increase secretion Little effect Sphincter M3/M2 Relaxation α1 Contraction Gallbladder Little effect β2 Relaxation Kidney Little effect β1 Increase renin release Liver Little effect α1, β2 Glycogenolysis/gluconeogenesis Pancreas Acini M3/M1 Increase amylase secretion Little effect Pancreas duct M3/M2 Increase HCO3- Little effect Pancreas Islet (β) cells M3 Increase Insulin α2 Decrease insulin secretion Coronary artery M3 Vasodilation (formation of NO) α1, α2 Constriction Skin/mucosa Little effect α1, α2 Constriction Penis M3 Erection α1 Ejaculation Pilomotor muscle Little effect α1 Contraction Sweat glands Little effect M3/M2 Secretion  pre-synaptic neuron post-synaptic neuron Ach NA SNS cholinergic adrenergic Ach Ach PNS cholinergic cholinergic Ach Somatic cholinergic NS = Nicotinic acetylcholine receptor Ach = Acetylcholine = Muscarinic acetylcholine receptor (M1-M5) NA = Noradrenaline = Adrenergic receptor (alpha/beta)  Cholinergic receptors Nicotinic receptor Muscarinic receptor - Pentameric ligand gated ion channel - G-protein coupled receptors (7 transmembrane domain) - 5 subunits made up of α, β, γ, δ, ε - 5 different types (M1-M5) - Ganglionic nicotinic receptor= α2β3 subunits - M1, M3, M5 coupled with Gq to activate IP3 and DAG - NMJ nicotinic receptor = α2βδε pathway which increases intracellular calcium - 2 Ach molecules need to bind to 2α subunits for (excitatory signalling) activation. - M2, M5 coupled with Gi which decreases the cAMP - Found at autonomic ganglia, NMJ and CNS. pathway and decreases intracellular calcium. It also - Excitatory signalling, increased cation permeability increases K+ conductance (inhibitory signalling). (mainly sodium/potassium) - Found at target tissues (heart, glands, smooth muscles) - Agonists – Acetylcholine, carbachol, Nicotine - Agonists – Acetylcholine, carbachol, muscarine - Antagonists – Tubocurarine, hexamethonium, - Antagonists – Atropine, dicycloverine, oxybutynin mecamylamine  Adrenergic receptors adrenergic receptor (α1, α2, β1, β2, β3) - G-protein coupled receptors (7 transmembrane domain) - Found at target tissues (heart, lungs, glands, smooth muscles) - α1 coupled of Gq which activates phospholipase C (PLC) to increase intracellular calcium and activate PKC. - α2 coupled of Gi which inhibits adenyl cyclase to decrease intracellular calcium and inhibit PKA. - β1, β2, β3 coupled of Gs which activates adenyl cyclase to increase intracellular calcium and activate PKA. - Agonists – Noradrenaline, adrenaline, Isoprenaline, phenylephrine - Antagonists – propranolol, atenolol, prazosin  Parasympathetic signalling - Acetylcholine in the heart activates the M2 receptor. The Gi protein results in downregulation of cAMP and increased conductance of potassium channel which causes hyperpolarization and decrease in heart rate. - Acetylcholine acts on smooth muscle cell in the gut, bladder and bronchioles to activate the M3 receptor. The Gq protein causes increase in calcium via DAG-IP3 pathway which results in increase in myosin-actin filament interaction to cause contraction. Cholinergic synapse Wehrwein et al, Compr Physiol, 2016 Modulation of cholinergic signal transduction Ca2+ How can you modulate this signal Ca2+ transduction? Ca2+ Ach 1. Synthesis 2. Storage 3. Release 4. Receptor Ach 5. Re-uptake 6. Degradation  Modulation of cholinergic signal transduction Ca2+ 1. Synthesis 2. Storage tetrodotoxin vesamicol 3. Release Ca2+ Ca2+ 4. Receptor Ach 5. Re-uptake 6. Degradation AcCoA hemicholinium CA T choline + AcCoA botulinum toxin Ach ACETYLCHOLINE Edrophonium / ESTERASE neostigmine Atropine / Ipratropium bromide Tubocurarine / hexamethonium? Clinical use Neostigmine – Acetylcholine esterase inhibitor Clinical use Clinical use  Clinical use Hyoscine butylbromide – abdominal cramp, oesophageal Bethanechol – treat dry mouth and urinary and bladder spasms retention Muscarinic receptor Sympathetic neuroeffector junction varicosities Post-synaptic neuron Wehrwein et al, Compr Physiol, 2016)  Modulation of sympathetic signal transduction Ca 2+ Tyrosine How can you Tyrosine hydroxylase (RLS) DOPA modulate this signal Dopa decarboxylase Ca2+ Ca2+ Dopamine transduction? Dopamine β-hydroxylase VMAT NA DHMA NA 1. Synthesis MAO NA 2. Storage T 3. Release T NE NE α2 4. Receptor 5. Re-uptake NA 6. Degradation X α1 β1  Modulation of sympathetic signal transduction Tyrosine 2+ Ca Tyrosine hydroxylase (RLS) α-methyl-p-tyrosine DOPA Dopa decarboxylase carbidopa Ca2+ Dopamine Dopamine β-hydroxylase reserpine VMAT NA DHMA NA MAO NA MAO inhibitors T Anti-depressants T NE (imipramine)/cocaine NE α2 COMT NA X guanethidine α1 β1  Sympathomimetics (direct/indirect) - Direct sympathomimetics: drugs that directly activate adrenoceptors and mimic the physiological effects of these receptors. E.g. phenylephrine - Indirect sympathomimetics: drugs that do not directly activate the adrenoceptors but achieve the same effect by increasing the concentration of noradrenaline in the synaptic cleft (increased neurotransmitter release). E.g. amphetamine (stimulant), tyramine (cheese effect with MAO inhibitors), ephedrine (nasal decongestant) Rang & Dale Pharmacology  Clinical use Clonidine – Adrenaline – alpha2 agonist adrenergic receptor agonist Prazosin – alpha 1 antagonist Salbutamol – Beta 2 agonist Mirabegron– Beta 3 receptor  Clinical use Clonidine – Adrenaline – alpha2 agonist- adrenergic Hypertension receptor agonist Restart heart, analphylaxis Prazosin – alpha 1 Salbutamol – antagonist Beta 2 agonist Hypertension Asthma Mirabegron– Beta 3 receptor – Overactive bladder  The SNS and PNS work together to mediate baroreflex in BP control ↑ BP distends arterial wall Afferent nerve endings stimulated by stretch This signal to the NTS, which compares the BP signal to a set point. The NTS acts to: ↑ parasympathetic drive to heart → ↓ heart rate → ↓ cardiac output (CO) ↓ sympathetic drive to heart, arteries, veins ↓ heart rate, force of contraction → ↓ (CO) ↓ arterial constriction → ↓ total peripheral resistance (TPR) ↓ venous constriction → ↓ cardiac output Since BP = CO x TPR, BP falls to the set point If BP falls, opposite effects occur to bring it back up to the set point Adapted from Dr Phil Aranson  The SNS and PNS work together to control micturition Micturition Bladder filling Causes contraction PNS M2, M3 Causes relaxation Bladder b3 SNS a1 Causes contraction Causes relaxation Urethra PNS Causes Nitric oxide External urethral contraction Somatic input Turns off sphincter N Adapted from Dr Phil Aranson ANS is part of a mesh of intricate chemical networks that maintains haemostasis Herring et al, Nat Rev Cardiol, 2019  Learning outcomes - Describe the fundamental role of of autonomic nervous system. - Describe and understand the distinction between sympathetic and parasympathetic nervous system. - Explain in detail the cholinergic and adrenergic signal transmission. - Understand the pharmacology of drugs used for various treatments that mediate their effect via modulation of autonomic nervous system.