Cholinergic Receptor Drugs

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Cholinergic Receptor Drugs

• Dr. Jena Hamra

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Cholinergic Drugs

• Parasympathomimetics
• Muscarinic receptors
• Glaucoma
• Increase GI motility
• Parasympatholytics
• Muscarinic receptors
• Motion sickness
• Pupil dilation
• Bronchodilation
• Decrease GI acid secretion

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Cholinergic Drugs

• Nicotinic receptor ligands
• Antagonists at ganglionic nicotinic receptors
• Hypertensive emergencies
• Antagonists at neuromuscular junction
• Neuromuscular blocking agents

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Acetylcholine

• Synthesis
• Synthesized in nerve terminal from choline
• Choline acetyltransferase
• Choline transfer into terminal rate-limiting step
• Release
• Ca dependent exocytosis
• Termination
• Breakdown by acetylcholinesterase
• Located in synapse

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Cholinergic Receptors

• Nicotinic
• Ligand-gated ion channels
• Muscle (NMJ)
• Ganglionic
• CNS
• Muscarinic
• GPCRs
• M1 CNS
• M2 Cardiac
• M3 Glandular/smooth muscle
• M4 and M5 CNS

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Cholinergic Receptor Agonists

• Direct-acting receptor agonists
• Choline esters
• Plant alkaloids
• Indirect-acting receptor agonists
• Drugs that inhibit acetylcholinesterase
• Reversible
• Irreversible
• Drugs that increase acetylcholine release

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Direct Acting Cholinergic Receptor Agonists

• Choline esters
• Positively charged quaternary ammonium compounds
• Poorly absorbed from GI tract
• Do not pass BBB
• Acetylcholine
• Nicotinic and muscarinic
• Bethanechol
• Muscarinic only
• Carbachol
• Nicotinic and muscarinic

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Direct Acting Cholinergic Receptor Agonists

• Plant Alkaloids
• Muscarine
• Derived from mushrooms
• No medical use
• Nicotine
• Binds nicotinic cholinergic receptors
• Smoking cessation programs
• Pilocarpine
• Binds muscarinic with greater affinity that
  nicotinic

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Direct Acting Cholinergic Receptor Agonists

• Physiological effects (primarily muscarinic)
• Miosis
• Bronchoconstriction
• Slow heart rate
• Stimulate salivary, gastric and other GI
  secretions
• Stimulate contraction of GI smooth muscle
• Increase GI motility
• Promotes micturition

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Acetylcholine

• Clinical use
• Limited
• Miosis during ophthalmic surgery
• Rapidly hydrolyzed by cholinesterase
• Short duration of action

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Bethanechol and Carbachol

• Choline esters of carbamic acid
• Resistant to hydrolysis by cholinesterases
• Clinical use
• Bethanechol
• Muscarinic only
• Postoperative or postpartum urinary retention
• Carbachol
• Chronic open-angle glaucoma
• Miosis during ophthalmic surgery

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Pilocarpine

• Greater affinity for muscarinic receptors
• Clinical uses
• Chronic open-angle glaucoma
• Acute angle-closure glaucoma
• Xerostomia (dry mouth)
• Side effects
• Decreased night vision
• Difficulty focusing on distant objects

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Indirect-Acting Agonists

• Acetylcholinesterase inhibitors
• Reversible
• Competitive enzyme inhibitors
• Edrophonium
• Ambenonium
• Substrate inhibitors
• Neostigmine
• Physostigmine
• Pyridostigmine
• Centrally acting
• Donepezil and tacrine

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Indirect-Acting Agonists

• Acetylcholinesterase inhibitors
• Irreversible
• Organophosphates
• Isoflurophate, malathion
• Drugs that increase acetylcholine release
• Cisapride
• Metoclopramide

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Cholinesterases

• Two types
• Both serine hydrolases
• Acetylcholinesterase (AChE)
• Bound to basement membrane in synaptic cleft in
  cholinergic synapses
• Specific for acetylcholine
• Active site has two regions
• Anionic
• Esteratic
• Butyrylcholinesterase (BChE) or
  pseudocholinesterase
• Found in plasma and tissues
• Liver, skin, brain, GI smooth muscle
• Broader specificity

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Reversible Cholinesterase Inhibitors

• Edrophonium
• Reversibly binds anionic site on AChE
• Prevents hydrolysis of acetylcholine (Ach) while
  bound to enzyme
• Not substrate of enzyme
• Increases Ach in cholinergic synapses
• Short-acting
• Duration of action 10 minutes
• Clinical use
• Diagnosis of Myasthenia gravis

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Reversible Cholinesterase Inhibitors

• Neostigmine, Physostigmine, Pyridostigmine
• Esters of carbamic acid
• Medium duration of action
• Average 2-3 hours
• Bind both sites like Ach
• Slowly hydrolyzed by enzyme
• Clinical Use
• Neostigmine and pyridostigmine Long-term
  treatment of myasthenia gravis, postoperative
  urinary retention, increase GI motility
• Counteract curariform drug toxicity

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Reversible Cholinesterase Inhibitors

• Donepezil and tacrine
• New, centrally acting AChE inhibitors
• Clinical use
• Alzheimers disease
• Donepezil
• Trade name Aricept
• Tacrine
• Trade name Cognex

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Irreversible Cholinesterase Inhibitors

• Organophosphates
• Primarily used as insecticides
• Few used therapeutically
• Chronic glaucoma
• Pediculosis
• Echothiophate, isoflurophate, malathion
• Forms covalent bound with esteratic site
• Phosphorylate the serine hydroxyl group
• Hydrolyzed very slowly by enzyme
• Aging
• Very lipid soluble!

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Organophosphate Poisoning

• Clinical effects
• Severe bradycardia and hypotension
• Difficulty breathing
• Depolarizing neuromuscular block
• CNS effects
• Initial excitement followed by convulsions
  leading to CNS depression
• Delayed neurotoxicity
• Treatment
• Atropine
• Pralidoxime
• Reactivates cholinesterase

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Drugs That Increase ACh Release

• Cisapride and Metoclopramide
• Increase release of Ach from myenteric neurons in
  enteric NS
• Increase GI motility
• Clinical use
• GERD
• Gastroparesis
• Colonic hypomotility
• Cisapride
• Trade name Propulsid

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Cholinergic Receptor Antagonists

• Muscarinic receptor antagonists
• Belladonna alkaloids
• Atropine
• Hyoscyamine
• Scopolamine
• Synthetic antagonists
• Ipratropium
• Dicyclomine, Oxybutynin, Flavoxate
• Tropicamide
• Pirenzepine

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Cholinergic Receptor Antagonists

• Nicotinic receptor antagonists
• Ganglionic blocking agents
• Trimethaphan
• Neuromuscular blocking agents
• Nondepolarizing
• Tubocurarine, Pancuronium, Vecuronium
• Atracurium, Doxacurium, Mivacurium
• Depolarizing
• Succinylcholine

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Belladonna Alkaloids

• Atropine, scopolamine
• Isolated from plants
• Deadly nightshade
• Well absorbed from GI tract
• Cross BBB
• Effects
• Inhibit parasympathetic actions
• Relax smooth muscle, increase heart rate
• Inhibit exocrine gland secretion
• Mydriasis
• Bronchodilation

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Belladonna Alkaloids

• Clinical Use
• Mydriasis for ocular examintaion
• Sinus bradycardia
• Intestinal, urinary bladder spasms
• Motion sickness
• Cholinesterase inhibitor overdose
• Hyoscyamine
• Intestinal spasms

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Synthetic Antagonists

• More selective, well absorbed
• Renal excretion
• Ipratropium
• Obstructive lung diseases
• Inhalation
• Dicyclomine and oxybutynin
• Intestinal hypermotility and spasms
• Urinary bladder spasms
• Tropicamide
• Mydriasis for ocular examination
• Pirenzepine
• Selective for M1 receptors
• Inhibits gastric acid secretion

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Nicotinic Receptor Antagonists

• Ganglionic blocking agents
• Little clinical use
• Extensive side effects
• Trimethaphan
• Hypertensive emergency
• Controlled hypotension during neurosurgery
• Neuromuscular blocking agents
• Two groups
• Nondepolarizing
• Depolarizing

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Nondepolarizing Blocking Agents

• Curariform drugs
• Originally extracted from plants for poison
  arrows
• Not well absorbed from GI tract
• Do not cross BBB
• Mainly differentiated by duration of action,
  histamine release and degree of ganglionic
  blockade
• Effects
• Competitive antagonists at nicotinic cholinergic
  receptors
• Paralyzes skeletal muscle
• Starting with eyes, moving to muscles of limbs
  and trunk, finally paralyzing respiratory muscles

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Nondepolarizing Blocking Agents

• Interactions
• Effects potentiated by
• Inhalational anesthetics
• Halothane, isoflurane
• Aminoglycoside and tetracycline antibiotics
• Calcium channel blockers
• Clinical Use
• Muscle relaxation during surgery
• Adjunct to electroconvulsive therapy
• Facilitate endoscopic procedures

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Nondepolarizing Antagonists
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Depolarizing Blocking Agents

• Succinylcholine
• Only one available for clinical use
• Binds nicotinic receptors
• Causes persistant depolarization of motor
  endplate
• Initially produces transient muscle contractions
  followed by paralysis
• Fasciculations

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Depolarization Block

• Block resulting from persistent activation of
  nicotinic receptors
• Decrease in excitability
• Voltage-sensitive sodium channels refractory

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Depolarizing Blocking Agents

• Clinical Use
• Muscle relaxation during surgery
• Adverse Effects
• Bradycardia
• Potassium release
• Ventricular dysrhythmia
• Prolonged paralysis
• Malignant hyperthermia

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