Cholinergic Drugs 1 Richard D Ye Professor of Pharmacology College of Medicine Tel 996 5087 Room 4143 COMRB E mail yer uic edu Cholinergic receptors Nicotinic vs Muscarinic The Nicotinic actions similar to those induced by nicotine action mediated by nicotinic cholinergic receptors stimulation of all autonomic ganglia NN stimulation of voluntary muscle NM secretion of epinephrine from the adrenal medulla NN 1 Cholinergic receptors Nicotinic vs Muscarinic The Muscarinic actions reproduced by injection of muscarine from Amanita muscaria Similar to those of parasympathetic stimulation Multiple muscarinic cholinergic receptors distributed in different tissues Therefore the muscarinic actions are dependent on the receptors in different tissues and cells Neural M1 CNS PNS gastric parietal cells excitatory Gq Cardiac M2 atria conducting tissue presynaptic inhibitory Gi Glandular M3 exocrine glands smooth muscle excitatory Gq Nicotinic acetylcholine receptor Structure All nAchRs have a pentameric structure consisting of subunits in different combinations A total of 9 different subunits and 4 different subunits have been identified In skeletal muscle 1 2 is replaced by in adult muscle In autonomic ganglion 3 5 7 2 4 Other combinations of and subunits are found among the nAchRs in CNS nAchRs with different composition have different affinities for some ligands For example bungarotoxin binds to nAchR in motor end plate with high affinity 2 Nicotinic acetylcholine receptor Function Ligand gated ion Na channel Acetylcholine binds to the subunits at the boundary of and and and subunits Channel opening requires binding of 2 acetylcholine molecules with positive cooperativity Structurally and functionally similar to the sodium channel which can be blocked by local anesthetics Acetylcholine binds to the subunits of the receptor making the membrane more permeable to cations sodium and causing a local depolarization The local depolarization spreads to an action potential or leads to muscle contraction when summed with the action of other receptors The ion channel is open during the active state Nicotine in small doses stimulates autonomic ganglia and adrenal medulla When large doses are applied the stimulatory effect is quickly followed by a blockade of transmission In addition to bungarotoxin there are other blocking agents for autonomic ganglions that include hexamethonium tetraethylammonium mecamylamine and trimethaphan Blocking at this level stops all autonomic outflow and produces a broad effect 3 Muscarinic acetylcholine receptors mAChR M1 neural Agonist M2 cardiac Gq Agonist Agonist M3 glandular Gi Gq IP3 DAG cAMP IP3 Depolarization Inhibition Ca2 channel Stimulation K conductance K conductance Intracellular Ca2 Excitation slow EPSP Slow IPSP Mostly excitatory CNS excitation Gastric acid secretion Gastrointestinal motility Mostly inhibitory Cardiac inhibition Presynaptic inhibition Neural inhibition Mostly excitatory Glandular secretion Contraction of visceral smooth muscle Vasodilation via NO Intracellular signaling triggered by acetylcholine in the Heart Main molecular players M2 heterotrimeric G Protein Gi Adenylyl cyclase 4 Effects of Ach on blood pressure Adrenal extracts are known to produce a rise in blood pressure due to its content of epinephrine In 1900 Reid Hunt observed that after depleting epinephrine the adrenal extracts produced a fall in blood pressure instead of a rise Later studies comparing various choline derivatives found that Ach was 100 000 times more potent than choline in lowering blood pressure in rabbits Sir Henry Hallett Dale Nobel laureate 1936 Arterial pressure of an anesthetized cat was measured Two kinds of effects produced by Ach A Ach causes a fall in BP due to vasodilation B A larger dose of Ach also produces bradycardia further reducing BP C Atropine blocks the effect of Ach in lowering BP D Still under the influence of atropine a much larger dose of Ach causes a rise in BP and tachycardia A B Muscarinic effects of Ach M C Muscarinic antagonistic effect M D Stimulation of sympathetic ganglia NN 5 CNS Pre ganglionic Ganglion Post ganglionic Cranial Effectors Ach Ach Parasympathetic Nicotinic Ach Sympathetic NE Ach Adrenergic Ach Nicotinic Muscarinic Nicotinic Thoracolumbar Muscarinic Sympathetic Cardiac smooth muscles gland cells nerve terminals Sweat glands Ach Sympathetic D Dopaminergic D1 Nicotinic Ach Sympathetic adrenal medulla Renal vascular smooth muscle Released into blood Epi Nicotinic Sacral Cardiac smooth muscles gland cells nerve terminals Ach Motor somatic Skeletal muscle Nicotinic Ach acetylcholine D dopamine Epi epinephrine NE norepinephrine Intracellular signaling triggered by acetylcholine in the endothelium eNOS Nitric oxide synthase eNOS L Arg L Citruline NO Major molecular players M3 heterotrimeric G Protein Gq Ca 2 CaM eNOS NO 6 Nitric oxide NO A signaling molecule for SMC relaxation Robert F Furchgott Louis J Ignarro Second messenger Ferid Murad Acetylcholine NO is internally produced gas through deamination of arginine NO production is mediated by NO synthase There are 3 types of NOS nNOS and eNOS are calciumdependent and constitutive iNOS is calcium independent and inducible NO acts in paracrine and autocrine manner NO binds to guanylyl cyclase and increases cGMP Inhibition of PDE causes sustained level of cGMP that maintains SMC relaxation Sildenafil Viagra is an inhibitor for PDE 5 SMC relaxation Experiments that examines the functions of muscarinic receptors M1 Neurotransmission in Cortex and Ganglia mice abrogation of pilocarpine induced seizures M2 Agonist mediated bradycardia tremor autoinhibition of release in several brain regions mice loss of oxytremorine induced tremors loss of agonist induced bradycardia diminished hypothermia M3 Smooth muscle contraction gland secreation pupil dilation food intake and possibly weight gain mice loss of agonist induced bronchoconstriction higher basal pupil dilation reduction of agonist induced salivation M4 and M5 Central Nervous System CNS roles 7 Classes of cholinergic stimulants Direct acting Indirect acting Receptor agonists Cholinesterase inhibitors Carbamates Choline esters ACETYLCHOLINE BETHANECOL Alkaloids PILOCARPINE PHYSOSTIGMINE NEOSTIGMINE PYRIDOSTIGMINE EDROPHONIUM Phosphates ISOFLUROPHATE Antidote PRALIDOXIMINE Chemical Structure of Cholinergic agonists Quaternary ammonium Tertiary amine 8 Muscarinic agonists Drug Receptor specificity Hydrolysis by AchE mAChR nAchR
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