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Cholinergic Receptor Drugs

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Belladonna Alkaloids. Atropine, scopolamine. Isolated from plants ... Belladonna Alkaloids. Clinical Use. Mydriasis for ocular examintaion. Sinus bradycardia ... – PowerPoint PPT presentation

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Title: Cholinergic Receptor Drugs


1
Cholinergic Receptor Drugs
  • Dr. Jena Hamra

2
Cholinergic Drugs
  • Parasympathomimetics
  • Muscarinic receptors
  • Glaucoma
  • Increase GI motility
  • Parasympatholytics
  • Muscarinic receptors
  • Motion sickness
  • Pupil dilation
  • Bronchodilation
  • Decrease GI acid secretion

3
Cholinergic Drugs
  • Nicotinic receptor ligands
  • Antagonists at ganglionic nicotinic receptors
  • Hypertensive emergencies
  • Antagonists at neuromuscular junction
  • Neuromuscular blocking agents

4
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

7
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

8
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

9
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

10
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

11
Acetylcholine
  • Clinical use
  • Limited
  • Miosis during ophthalmic surgery
  • Rapidly hydrolyzed by cholinesterase
  • Short duration of action

12
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

13
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

14
Indirect-Acting Agonists
  • Acetylcholinesterase inhibitors
  • Reversible
  • Competitive enzyme inhibitors
  • Edrophonium
  • Ambenonium
  • Substrate inhibitors
  • Neostigmine
  • Physostigmine
  • Pyridostigmine
  • Centrally acting
  • Donepezil and tacrine

15
Indirect-Acting Agonists
  • Acetylcholinesterase inhibitors
  • Irreversible
  • Organophosphates
  • Isoflurophate, malathion
  • Drugs that increase acetylcholine release
  • Cisapride
  • Metoclopramide

16
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

23
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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26
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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28
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

29
Cholinergic Receptor Antagonists
  • Muscarinic receptor antagonists
  • Belladonna alkaloids
  • Atropine
  • Hyoscyamine
  • Scopolamine
  • Synthetic antagonists
  • Ipratropium
  • Dicyclomine, Oxybutynin, Flavoxate
  • Tropicamide
  • Pirenzepine

30
Cholinergic Receptor Antagonists
  • Nicotinic receptor antagonists
  • Ganglionic blocking agents
  • Trimethaphan
  • Neuromuscular blocking agents
  • Nondepolarizing
  • Tubocurarine, Pancuronium, Vecuronium
  • Atracurium, Doxacurium, Mivacurium
  • Depolarizing
  • Succinylcholine

31
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

34
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

35
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

36
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

37
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

38
Nondepolarizing Antagonists
39
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

40
Depolarization Block
  • Block resulting from persistent activation of
    nicotinic receptors
  • Decrease in excitability
  • Voltage-sensitive sodium channels refractory

41
Depolarizing Blocking Agents
  • Clinical Use
  • Muscle relaxation during surgery
  • Adverse Effects
  • Bradycardia
  • Potassium release
  • Ventricular dysrhythmia
  • Prolonged paralysis
  • Malignant hyperthermia

42
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