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Pharmacotherapy of cholinergic agent

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Outlines Cholinergic Transmission Cholinergic Fibers Autonomic pre-gangalionic fibers Parasympathetic postganglionic fibers Somatic motor nerve fibers Cholinergic Receptors Nicotinic N M N N Muscarinic M 1 M 2 M 3 M 4 M 5

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Outlines Cholinergic Pharmacology Muscarinic receptor antagonists Nicotinic receptor antagonists Ganglion blockers Neuromuscular blockers Anticholinesterase Cholinergic receptor agonists

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Cholinergic Neurotransmission

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Trafficking & mobilization Synapsins & Rab3 Docking Vesicle membrane Synaptotagmin Synaptobrevin (VAMP) Synaptic plasma membrane Neurexins Syntaxins Pore fusion Synaptophysin

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Nicotinic Receptors Receptor (Primary receptor subtype) Main synaptic location Membrane response Molecular mechanism AgonistsAntagonists Skeletal muscle (N M ) Adult ( 1 ) 2 1 Fetal ( 1 ) 2 1 Skeletal NMJ (Post-junctional) Excitatory End-plate depolarization Skeletal muscle contraction Cation permeability (Na + K + ) Ach Nicotine Succinylcholine Atracurium Vecuronium d-Tubocurarine Pancuronium -Bungarotoxin -Conotoxin Peripheral neuronal (N N ) ( 3 ) 2 ( 4 ) 3 Autonomic ganglia Adrenal medulla Excitatory Depolarization Firing of postganglionic neuron Depolarization & secretion of catecholamines Cation permeability (Na + K + ) Ach Nicotine Epibatidine Dimethylphenylpip erazinium (DMPP) Trimethaphan Mecamylamine Central neuronal (CNS) ( 4 ) 2 ( 4 ) 3 (-Bungarotoxin- insensitive) CNS Pre- and post- junctional Pre- & post- synaptic excitation Pre-junctional control of transmitter release Cation permeability (Na + K + ) Cytisine Epibatidine Anatoxin A Mecamylamine Dihydro-- erythrodine Erysodine Lophotoxin ( 7 ) 5 (-Bungarotoxin- sensitive) CNS Pre- and post- synaptic Pre- & post- synaptic excitation Pre-junctional control of transmitter release Cation permeability (Ca 2+ ) Anatoxin A Methyllycaconitine -Bungarotoxin -Conotoxin IMI

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Nicotinic Receptors

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Muscarinic Receptors M 1 receptor Cellular & tissue location CNS (Cerebral cortex Hippocampus Striatum) Autonomic ganglia Gland (Gastric & salivary) Enteric nerves Cellular response Activation of PLC IP 3 & DAG Ca 2+ & PKC Depolarization & excitation ( sEPSP) Activation of PLD 2 PLA 2 AA Couples via G q

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Muscarinic Receptors M 1 receptor Functional response Increased cognitive function (Learning & memory) Increased seizure activity Decrease in dopamine release & locomotion Increase in depolarization of autonomic ganglia Increase in secretions

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Muscarinic Receptors M 2 receptor Cellular & tissue location CNS Heart Smooth muscle Autonomic nerve terminals Cellular response Inhibition of adenylyl cyclase cAMP Activation of inwardly rectifying K + channels Inhibition of voltage-gated Ca 2+ channels Hyperpolarization & inhibition Couple via G i /G o (PTX-sensitive)

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Muscarinic Receptors M 2 receptor Functional response Heart SA node Slowed spontaneous depolarization Hyperpolarization Heart rate AV node Conduction velocity Atrium Refractory period & contraction Ventricle Slight contraction

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Muscarinic Receptors M 2 receptor Functional response Smooth muscle Contraction Peripheral nerves Neural inhibition via autoreceptors & heteroreceptor Ganglionic transmission CNS Neural inhibition Tremors Hypothermia Analgesia

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Muscarinic Receptors M 3 receptor Cellular & tissue location Widely expressed in CNS Abundant in smooth muscle & glands Heart Cellular response Same as M 1 receptor

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Muscarinic Receptors M 3 receptor Functional response Smooth muscle Contraction (Predominant in bladder) Glands Secretion (Predominant in salivary gland) Food intake & body weight & fat deposits Inhibition of dopamine release Synthesis of NO

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Muscarinic Receptors M 4 receptor Cellular & tissue location Preferentially expressed in CNS (Particularly forebrain) Cellular response Same as M 2 receptor Functional response Autoreceptor & heteroreceptor-mediated inhibition of transmitter release in CNS & periphery Analgesia Cataleptic activity Facilitation of dopamine release

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Muscarinic Receptors M 5 receptor Cellular & tissue location Expressed in low levels in CNS & periphery Predominant mAchR in dopamine neurons in VTA & SNc Cellular response Same as M 1 receptor Functional response Mediator of dilation in cerebral arteries & arterioles Facilitates dopamine release Augmentation of drug seeking behavior & reward Opiates Cocaine

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Muscarinic Functions Parasympathomimetic OrganTypeResponse Eye Sphincter muscle of irisM3M3 Contraction (Miosis) Ciliary muscleM3M3 Contraction for near vision Heart Sinoatrial nodeM2M2 Decrease in rate (Negative chronotropy) AtriaM2M2 Decrease in contractile strength (Negative Inotropy) Decrease in refractory period Atrioventricular nodeM2M2 Decrease in conduction velocity (Negative dromotrophy) Increase in refractory period VentriclesM2M2 Small decrease in contractile strength

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Muscarinic Functions Parasympathomimetic OrganTypeResponse Blood vessels ArteriesM3M3 Dilation (Via EDRF) Constriction (High-dose direct effect) VeinsM3M3 Dilation (Via EDRF) Constriction (High-dose direct effect) Lung Bronchial muscleM3M3 Contraction (Bronchoconstriction) Bronchial glandsM3M3 Stimulation Gastrointestinal tract MotilityM3M3 Increase SphinctersM3M3 Relaxation SecretionM3M3 Stimulation

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Muscarinic Functions Parasympathomimetic OrganTypeResponse Urinary bladder DetrusorM3M3 Contraction Trigone & sphincterM3M3 Relaxation Glands Sweat glandM3M3 Secretion Salivary glandM3M3 Secretion Lacrimal glandM3M3 Secretion Nasopharyngeal glandM3M3 Secretion

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Pharmacological effects Muscarinic Antagonists CNS Drowsiness Scopolamine > atropine Excitement Agitation Hallucination Coma Anti-tremor in Parkinsons disease Reduce motion sickness

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Pharmacological effects Muscarinic Antagonists CV system Bradycardia (Low dose) Central vagal stimulation Presynaptic Muscarinic receptor block Disinhibition of Ach release Tachycardia (Intermediate dose) Peripheral vagalytic PR interval in patients with high vagal tone Atria contractility inhibition, less effect on ventricle Vasotone in skeletal muscle

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Pharmacological effects Muscarinic Antagonists Respiratory system Bronchodilation Bronchosecretion For Asthma & COPD Premedication of general anesthesia Sweat glands Sweat secretion (Sympathetic cholinergic fibers) Atropine fever Infants & children

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Pharmacological effects Muscarinic Antagonists Eye Mydriasis Inhibition of Iris contraction Cycloplegia Loss of lens accommodation Dry eyes Narrow angle glaucoma

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Pharmacological effects Muscarinic Antagonists Gastrointestinal Tract Dry mouth (Low dose) Gastric secretion (High dose) GI motility, especially selective M 1 antagonist Presynaptic muscarinic excitation Gastric empty time Intestinal transit time Genitourinary Tract For neurogenic bladder Precipitating urinary retention Elder men with prostate hyperplasia No effect on uterus

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Pharmacological effects Muscarinic Antagonists Tissue sensitivity to Atropine Atropine sensitivity (High to low) Salivary Bronchial Sweat glands Smooth muscle Cardiac function Gastric acid secretion

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Clinical Considerations Muscarinic Antagonists Contraindication Narrow-angle glaucoma Prostatic hypertrophy Elderly Cognitive impairment Side effect Dry mouth Blurred vision Urinary retention Fever Sedation Tachycardia Ileus CNS hyperexciation Delirium Hallucination Seizures Agitation

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Muscarinic antagonists Atropine Salivation & mucus secretion Organophosphate intoxication Prolong mydriasis & cycloplegia for eye surgery For symptomatic sinus bradycardia Scopolamine Motion sickness (Transdermal patch) Chemotherapy induced nausea (IV) Methscopolamine Glycopyrrolate Peptic ulcer GI spasms Prevent bradycardia

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Muscarinic antagonists Pirenzepine (M 1 selective) Peptic ulcer Ipratropium Tiotropium (Inhalational) COPD (better than -agonist) Asthma (not better than -agonist) Darifenacin Solifenacin (M 3 selective) Less adverse effect Oxybutynin Propantheline Tolterodine Trospium Over-reactive bladder Incontinence Less dry mouth in Tolterodine

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Nicotinic antagonists Autonomic Ganglia

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SitePredominant toneEffect of ganglionic block ArteriolesSympathetic (Adrenergic) Vasodilation Peripheral blood flow Hypotension VeinsSympathetic (Adrenergic) Dilation Venous return Cardiac output HeartParasympathetic (Cholinergic)Tachycardia IrisParasympathetic (Cholinergic)Mydriasis Ciliary muscleParasympathetic (Cholinergic)Cycloplegia (Focus to far) Gastrointestinal tractParasympathetic (Cholinergic) Tone & motility Constipation Gastric secretion Pancreatic secretion Urinary bladderParasympathetic (Cholinergic)Urinary retention Salivary glandsParasympathetic (Cholinergic)Xerostomia Sweat glandsSympathetic (Cholinergic)Anhidrosis Genital tractSympathetic & Parasympathetic Stimulation

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Nicotinic antagonists Ganglion Blockers Autonomic ganglia blockers Mecamylamine Trimethaphan Used in hypertension in patient with acute aortic dissection or pulmonary edema Decrease sympathetic reflex Lower blood pressure

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Nicotinic antagonists Neuromuscular Junction Miniature endplate potential (0.5-1.2 mV) Spontaneous release Quantal release Endplate Potential (2~8 mV) Evoked release Action potential (100mV) Muscle contraction

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Nicotinic antagonists Neuromuscular Blockers Competitive nicotinic receptor blockers D-tubocurarine Pancuronium Gallamine (Long) Vecuronium Rocuronium (Intermediate) Mivacurium Atracurium (Short) Depolarization blockers Succinylcholine Decamethonium

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Nicotinic antagonists Competitive nicotinic receptor blockers Selective N M antagonist at motor endplate d-Tubocurarine (d-TC) Protodrug Reversible blocker -Bungarotoxin Selective irreversible N M antagonist N M receptor occupancy 75-80% occupied Neuromuscular block >95% occupied Muscle relaxation Reversed by Anti-ChE Single twitch inhibition & tetanic fade

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Nicotinic antagonists Depolarizing blockers Phase 1 Membrane depolarization Muscle contracture No tetanic fade Potentiated by Anti-ChE Phase 2 N M Desensitization, Na + channel inactivation No depolarization Single twitch inhibition Tetanic fade Reversed by Anti-ChE

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Nicotinic antagonists Comparison of neuromuscular blockers D-TubocurarineDecamethonium Effect of D-Tubocurarine Administered previously AdditiveAntagonistic Effect of Decamethonium Administered previously No effect, or antagonistic Some tachyphylaxis, but may addictive Effect of Anticholinesterase agents on block Reversal of blockNo reversal Effect on motor end plate Elevated threshold to Ach No depolarization Partial Persistent depolarization Initial excitatory effect on striated muscle NoneTransient fasciculation Character of muscle response to indirect tetanic stimulation during partial block Poorly sustained contractionWell-sustained contraction

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Nicotinic antagonists Clinical responses & monitoring of phase I & phase II ResponsePhase IPhase II End plate membrane potentialDepolarized to -55mVRepolarization toward -80mV OnsetImmediateSlow transition Dose-dependenceLower Usually higher or follows prolonged infusion RecoveryRapidMore prolonged Train of four & tetanic stimulation No fadeFade Acetylcholinesterase inhibitionAugmentsReverses or antagonizes Muscle response Fasciculation Flaccid paralysis

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Nicotinic antagonists Therapeutic Uses of Neuromuscular Blockers During surgery Muscle relaxation Endotracheal intubation Maintaining controlled ventilation Muscle fasciculation Nonsurgical uses Myasthenia gravis diagnosis Muscle spasms Adjunct relaxation during electroshock therapy

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Nicotinic antagonists Clinical Considerations of Neuromuscular Blockers (SCh) Pharmacogenomic variation of butyrylcholinesterase Normal metabolizer < 15min Slow metabolizer > 2hr Electrolyte imbalance Malignant hyperthermia during anesthesia Patient states affecting duration Trauma Alcoholism Pregnancy Oral contraceptives Local anesthetics

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Nicotinic antagonists Clinical Considerations of Neuromuscular Blockers Drug Interactions Inhalated anesthetics Aminoglycoside antibiotics Ca 2+ channel blockers Ca 2+ K + Mg 2+ plasma levels Bupivacaine Potentiation of both types of NM blockers Lidocaine Procaine Potentiation of SCh block

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Nicotinic antagonists Clinical Considerations of Neuromuscular Blockers Histamine release (Tubocurarine) Cardiovascular system Arrhythmia Non-selective block at muscarinic receptor Tachycardia Gallamine Patients with renal impairment Neonatal SCh is less potent Atracurium & dTC are more potent

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AntiCholinesterase Cholinesterase Acetylcholinesterase Cholinergic synapses Butyrylcholinesterase Pseudocholinesterase Plasma AntiCholinesterase (AntiChE) Reversible Carbamates Irreversible Organophosphates Insecticides Nerve gases

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AntiCholinesterase Therapeutic uses & durations of action of AntiChE UsesApproximate duration of action Alcohol Edrophonium Myasthenia gravis Ileus Arrhythmias 5~15 minutes Carbamates & related agents Neostigmine Myasthenia gravis Ileus 0.5~2 hours PyridostigmineMyasthenia gravis3~6 hours PhysostigmineGlaucoma0.5~2 hours AmbenoniumMyasthenia gravis4~8 hours DemecariumGlaucoma4~6 hours Organophosphate EchothiophateGlaucoma100 hours

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AntiCholinesterase Action sites Autonomic ganglion Central nervous system Exocrine Eyes Heart Gastrointestinal tract Neuromuscular junction Respiratory tract

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AntiCholinesterase Therapeutic uses of AntiChE Ophthalmology Open angle glaucoma (Echothiophate) Accommodative esotropia (Physostigmine) Predisposing cataract after long term use Neurology Myasthenia gravis treatment (Pyridostigmine Neostigmine) Diagnose Eaton-Lambert syndrome (Edrophonium) Autoantibody against Ca 2+ channels (Presynaptic) Muscle weakness by NM blocker but not by depolarizing

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AntiCholinesterase Therapeutic uses of AntiChE Cardiology AV nodal reentrant tachycardia (Edrophonium) Abdominal distention (Neostigmine) Intoxication of atropine (Physostigmine)

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AntiCholinesterase Clinical Considerations of AntiChE Alzheimers Disease-mild to moderate Tacrine Hepatotoxicity Donepezil Rivastigmine Galantamine Contraindication Cardiac disease Peptic ulcer Epilepsy Side Effects GI disturbance Nausea Vomiting Anorexia Diarrhea Abdominal cramping Tremor Anxiety Depression

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AntiCholinesterase Organophosphate Intoxication Acute toxicity Respiratory failure Respiratory muscle paralysis Tetanic fade of skeletal muscle Nicotinic Ach receptor activation Respiratory center inhibition Muscarinic Ach receptor activation Bronchoconstriction Bronchial smooth muscle contraction Muscarinic Ach receptor activation Bronchosecretion overactive Exocrine secretion Muscarinic Ach receptor activation

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AntiCholinesterase Treatments for organophosphate acute toxicity Atropine Anti-muscarinic actions, peripherally & centrally Oximes Pralidoxime (PAM) or Obidoxime Reactivators of AChE but not aged AChE Aged AChE De-alkylation of AChE-P Diazepam Anti-convulsion Partially reverse muscle paralysis Microsomal enzyme inhibitors Preventing parathion being converted to toxic paraxon

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AntiCholinesterase Nerve gases The most toxic substances in the word Diisopropyl fluorophosphate (DFP) Tabun (GA) Sarin(GB) Soman VX Easily aging of phosphorylated cholinesterase Prevention Carbamates (Pyridostigmine) Cholinesterase Fetal calf serum AChE Human butyl cholinesterase Antibody

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Cholinergic Agonists Therapeutic Uses GI motility Post-operation Post-partum For Urinary retention Salivation For xerostomia in Sjogrens syndrome Open-angle glaucoma Miosis for cataract surgery

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Cholinergic Agonists

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Methacholine Asthma diagnosis Carbachol Glaucoma Miotic Bethanechol GI motility Urinary retention Cevimeline (M 3 selective) Xerostomia in Sjogrens syndrome

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Cholinergic Agonists Clinical Considerations Side Effects Asthma attacks Blood pressure Flushing Cramps Diarrhea Nausea Sweating Contraindications Urinary tract obstruction Peptic ulcer Intestinal resection or anastomosis