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Pharmacotherapy of cholinergic agent
台大藥理所 邱麗珠老師
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Outlines Cholinergic Transmission Cholinergic Fibers
Autonomic pre-gangalionic fibers Parasympathetic postganglionic fibers Somatic motor nerve fibers Cholinergic Receptors Nicotinic：NM、NN Muscarinic：M1、M2、M3、M4、M5
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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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Cholinergic Neurotransmission
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Cholinergic Neurotransmission
Trafficking & mobilization Synapsins & Rab3 Docking Vesicle membrane Synaptotagmin Synaptobrevin (VAMP) Synaptic plasma membrane Neurexins Syntaxins Pore fusion Synaptophysin
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Main synaptic location
Nicotinic Receptors Receptor (Primary receptor subtype) Main synaptic location Membrane response Molecular mechanism Agonists Antagonists Skeletal muscle (NM) Adult (α1)2β1εδ Fetal (α1)2β1γδ Skeletal NMJ (Post-junctional) Excitatory End-plate depolarization contraction ↑ Cation permeability (Na+、K+) Ach Nicotine Succinylcholine Atracurium Vecuronium d-Tubocurarine Pancuronium α-Bungarotoxin α-Conotoxin Peripheral neuronal (NN) (α3)2(β4)3 Autonomic ganglia Adrenal medulla Depolarization Firing of postganglionic neuron Depolarization & secretion of catecholamines Epibatidine Dimethylphenylpip erazinium (DMPP) Trimethaphan Mecamylamine Central neuronal (CNS) (α4)2(β4)3 (α-Bungarotoxin- insensitive) CNS Pre- and post-junctional Pre- & post- synaptic excitation Pre-junctional control of transmitter release Cytisine Anatoxin A Dihydro-β- erythrodine Erysodine Lophotoxin (α7)5 sensitive) Pre- and post-synaptic (Ca2+) Methyllycaconitine IMI
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Nicotinic Receptors
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Muscarinic Receptors M1 receptor Cellular & tissue location
CNS (Cerebral cortex、Hippocampus、Striatum) Autonomic ganglia Gland (Gastric & salivary)、Enteric nerves Cellular response Activation of PLC ↑ IP3 & DAG → ↑ Ca2+ & PKC Depolarization & excitation (↑ sEPSP) Activation of PLD2、PLA2 →↑ AA Couples via Gq
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Muscarinic Receptors M1 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 M2 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 Ca2+ channels Hyperpolarization & inhibition Couple via Gi/Go (PTX-sensitive)
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Muscarinic Receptors M2 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 M2 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 M3 receptor Cellular & tissue location
Widely expressed in CNS Abundant in smooth muscle & glands Heart Cellular response Same as M1 receptor
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Muscarinic Receptors M3 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 M4 receptor Cellular & tissue location
Preferentially expressed in CNS (Particularly forebrain) Cellular response Same as M2 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 M5 receptor Cellular & tissue location
Expressed in low levels in CNS & periphery Predominant mAchR in dopamine neurons in VTA & SNc Cellular response Same as M1 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 Organ Type Response Eye
Sphincter muscle of iris M3 Contraction (Miosis) Ciliary muscle Contraction for near vision Heart Sinoatrial node M2 Decrease in rate (Negative chronotropy) Atria Decrease in contractile strength (Negative Inotropy) Decrease in refractory period Atrioventricular node Decrease in conduction velocity (Negative dromotrophy) Increase in refractory period Ventricles Small decrease in contractile strength
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Muscarinic Functions Parasympathomimetic Organ Type Response
Blood vessels Arteries M3 Dilation (Via EDRF) Constriction (High-dose direct effect) Veins Lung Bronchial muscle Contraction (Bronchoconstriction) Bronchial glands Stimulation Gastrointestinal tract Motility Increase Sphincters Relaxation Secretion
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Muscarinic Functions Parasympathomimetic Organ Type Response
Urinary bladder Detrusor M3 Contraction Trigone & sphincter Relaxation Glands Sweat gland Secretion Salivary gland Lacrimal gland Nasopharyngeal gland
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Pharmacological effects Muscarinic Antagonists
CNS Drowsiness Scopolamine > atropine Excitement、Agitation、Hallucination、Coma Anti-tremor in Parkinson’s 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 M1 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 (M1 selective) Peptic ulcer Ipratropium、Tiotropium (Inhalational) COPD (better than β-agonist) Asthma (not better than β-agonist) Darifenacin、Solifenacin (M3 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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Site Predominant tone Effect of ganglionic block Arterioles Sympathetic (Adrenergic) Vasodilation ↑ Peripheral blood flow Hypotension Veins Dilation ↓ Venous return ↓ Cardiac output Heart Parasympathetic (Cholinergic) Tachycardia Iris Mydriasis Ciliary muscle Cycloplegia (Focus to far) Gastrointestinal tract ↓ Tone & motility Constipation ↓ Gastric secretion ↓ Pancreatic secretion Urinary bladder Urinary retention Salivary glands Xerostomia Sweat glands Sympathetic (Cholinergic) Anhidrosis Genital tract Sympathetic & 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 ( 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 NM antagonist at motor endplate d-Tubocurarine (d-TC) Protodrug：Reversible blocker α-Bungarotoxin Selective irreversible NM antagonist NM 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 NM 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-Tubocurarine Decamethonium Effect of D-Tubocurarine Administered previously Additive Antagonistic Effect of Decamethonium No effect, or antagonistic Some tachyphylaxis, but may addictive Effect of Anticholinesterase agents on block Reversal of block No reversal Effect on motor end plate Elevated threshold to Ach No depolarization Partial Persistent depolarization Initial excitatory effect on striated muscle None Transient fasciculation Character of muscle response to indirect tetanic stimulation during partial block Poorly sustained contraction Well-sustained contraction
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Nicotinic antagonists
Clinical responses & monitoring of phase I & phase II Response Phase I Phase II End plate membrane potential Depolarized to -55mV Repolarization toward -80mV Onset Immediate Slow transition Dose-dependence Lower Usually higher or follows prolonged infusion Recovery Rapid More prolonged Train of four & tetanic stimulation No fade Fade Acetylcholinesterase inhibition Augments Reverses 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 Ca2+ channel blockers Ca2+、K+、Mg2+ 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 AntiCholinesterase (AntiChE)
Acetylcholinesterase Cholinergic synapses Butyrylcholinesterase Pseudocholinesterase、Plasma AntiCholinesterase (AntiChE) Reversible Carbamates Irreversible Organophosphates Insecticides、Nerve gases
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Approximate duration of action
AntiCholinesterase Therapeutic uses & durations of action of AntiChE Uses Approximate duration of action Alcohol Edrophonium Myasthenia gravis、Ileus Arrhythmias 5~15 minutes Carbamates & related agents Neostigmine 0.5~2 hours Pyridostigmine Myasthenia gravis 3~6 hours Physostigmine Glaucoma Ambenonium 4~8 hours Demecarium 4~6 hours Organophosphate Echothiophate 100 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 Ca2+ 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
Alzheimer’s 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 Bronchosecretion overactive Exocrine secretion
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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 Sjogren’s syndrome Open-angle glaucoma Miosis for cataract surgery
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Cholinergic Agonists
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Cholinergic Agonists Methacholine Carbachol Bethanechol
Asthma diagnosis Carbachol Glaucoma Miotic Bethanechol ↑ GI motility Urinary retention Cevimeline (M3 selective) Xerostomia in Sjogren’s 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
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