Cholinergic Agonists and Cholinesterase Inhibitors Flashcards
Sites of ACh Action
Post Ggl Nerve Endings: Muscarinic
Symp and Parasymp Ggl: Nicotinic
NMJ: Nicotinic
CNS: Muscarinic and Nicotinic
Definition of Cholinergic Agonists
Substances which activate nicotinic or muscarinic Rs
Nicotinic R
Localisation
Structure
Muscle (NMJ): Stimulation
Ggl: Stimulation
CNS
Adrenal Medulla: Secretion of epinephrine and NE
Ionotropic
Agonist binding-> ion channel (Na/K) opening
Muscarinic R
Types
M1: Neural Gq
M2: Cardiac Gi and modulates muscarinic K Channels
M3: Glandular/SM Gq
Also have M4 and M5
Cholinergic Agonists
All 4 Amine, can’t cross BBB
ACh: Endogenous, nonselective; no medical use
Muscarine: Muscarinic R Agonist, fungal toxin
No medical use
Carbachol: Non specific, no medical use
Bethanchol: M R agonist
Uses: SV Arrythmias, Atonic Bladder Paralytic Ileus
Prokinetic: Increase GIT motility
Pilocarpine: M R agonist
Uses: Glaucoma; contracts ciliary muscles, opens
Schlemm canal
Pharmacological Effects of Agonists
General
Occular
Cardiac
Vascular
Pulmonary
GIT
Urogenital
Other glands: Tear, sweat
Pharmacological Effects of Agonists
Occular
Via M3: Gq
Miosis
Accommodation
–> decrease intraocular pressure
Pharmacological Effects of Agonists
Cardiac
Via M2: Gi
Negatve chrono-, bromo- bathmo- and inotropic
–> Bethanchol
Pharmacological Effects of Agonists
Vascular
Via M3: Gq
Usually no PS innervation of blood vessels, but increase ACh-> release of NO by endothelial cells-> relaxation
Pharmacological Effects of Agonists
Pulmonary
Via M3: Gq
Vagus Nerve innervates bronchial SM-> bronchoconstriction and increased bronchial secretion
Pharmacological Effects of Agonists
GIT
Via M1 and M3
M1: Parietal cells: Stimulation of gastric acid secretion
M3: Increased motility; relaxation of sphincters
–> Betanchol
Pharmacological Effects of Agonists
Urogenital
Via M3
Contraction of M. Detrussor Urinae-> urination
–> Betanchol
Pharmacological Effects of Agonists
General SE
Muscarinic Effects Diarrhoea Vomiting Bronchoconstriction Bradycardia Lacrimation Salivation Sweating CNS Stimulation
Nicotinic Effects:
Skeletal muscle excitation, then paralysis
CNS stimulation
Cholinesterase Inhibitor
General Background
Indirect cholinomimmetics
Inhibit degradation
Types:
Acetylcholinesterase (mainly synaptic cleft)
Butyrylcholinesterase (plasma, skin, brain, liver, GIT)
Cholinesterase Inhibitor
Short Duration of Action
Edrophonium
4, useless for therapy
Used in diagnosis of Myasthenia Gravis
Cholinesterase Inhibitor
Intermediate Duration of Action
Neostigmine
4, decurarisation
Physostigmine
3
Clinical uses: Glaucoma, MG, reverse action of
tuburocuranine, bladder and intestinal atonia
((Alzheimers))
Cholinesterase Inhibitor
Irreversible
Echothiophate: Eyedrops for chronic glaucoma
Parathion and Malathion: Insecticides
Are organophosphates
Sarin: Nerve gas–> Atropine to prevent (against M effects)
Also organophosphate
Can cause cholinergic crisis
Cholinergic Crisis
Stimualtion of ggl-> depolarising block (desensitisation)
No antidote against ggl stimulation: anticonvulsants
activates PS-> brady, bronchoconst, diarrhoea, miosis
NMJ depolarising block
convulsions, tremor, ataxia, inhibition of resp center
Treatment
Decontamination: wash skin, remove clothing
IV Atropine until salivation stops
Pralidoxine and Obidoxine
-> Removal of irreversible cholinesterase inhibitors
Can be given up to 6 hrs post poisoning
But as 4-> can’t enter CNS-> still need artificial ventilation
Rivastigmine
Inhibits Acetyl- and Butyrylcholinesterase
Used in Alzheimers th
Toxicity of Insecticides (Activation)
Parathion (inactive) activated by CYP450-> Paraoxon
Paraoxon (active) via CYP450-> Inactive compounds
Cholinergic ‘Pathway’
Choline + Acetyl CoA–> ACh
by Choline Acetyl Transferase
ACh then exists cell-> cleft where acts on either M or N R
Or degraded into Choline and Acetate
by Acetylcholine esterase
