Transcript of Pharmacotherapy of cholinergic agent 台大藥理所 邱麗珠老師.
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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
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
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
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
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
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