Lecture 6. Pharmacology of Muscarinic Acetylcholine Receptors & AChE Flashcards
How many subtypes of muscarinic receptors (AChM) are there?
5
What is the representative tissue of M₁ ‘neural’ subtype?
Autonomic ganglia
What is the physiological response caused by the M₁ ‘neural’ subtype?
Modulation of ganglionic transmission
What is the representative tissue of M₂ ‘cardiac’ subtype?
Cardiac atria and conducting tissue
What is the physiological response caused by the M₂ ‘cardiac’ subtype?
Cardiac slowing
↓ force of contraction
What is the representative tissue of M₃ ‘glandular’ subtype?
Salivary glands
Smooth muscle of gut
What is the physiological response caused by the M₃ ‘glandular’ subtype?
Secretion of saliva
↑ gut motility
What is the representative tissue of M₄ subtype?
CNS
What is the physiological response caused by the M₄ subtype?
Modulation of synaptic transmission
What is the representative tissue of M₅ subtype?
CNS - substantia nigra
What is the physiological response caused by the M₅ subtype?
Modulation of synaptic transmission
What G protein subtype do M₁, M₃, and M₅ subtypes have?
Gαq (queer)
What G protein subtype do M₂ and M₄ subtypes have?
Gαi (inhibitory)
What are all muscarinic receptors?
G-protein coupled receptors
What does Gαq stimulate?
Phospholipase C β (PLCβ) which breaks down phosphatidylinositol 4,5-bisphosphate (PIP2) to diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP₃)
What does diacylglycerol (DAG) activate?
Protein Kinase C (PKC)
What does IP₃ cause the release of?
Ca²⁺ from internal Ca²⁺ stores
What does Gαi inhibit and what are the effects of this inhibition?
Gαi inhibits adenylate cyclase (AC) which results in a reduction in cAMP, reduced activation of PKA and reduced Ca²⁺ channel activity
What does Gβγ activate and what does this activation lead to?
Gβγ activates certain K⁺ channels that leads to K⁺ efflux from the cell, membrane hyperpolarisation and reduced excitability
What are the physiological effects of carbachol and pilocarpine?
Constriction of circular muscle of iris and ciliary muscle of eye
↑ secretion (lacrymation, salivation, sweating)
Bronchoconstriction and ↑ mucus production
What is the clinical uses of carbachol?
Not used clinically
What is the clinical uses of pilocarpine?
Topical eye drops for glaucoma - decrease intra ocular pressure by constricting muscles and facilitating drainage of aqueous humour from anterior chamber
What are the physiological effects of cevimeline?
↑ gut motility & relaxation of sphincter → defecation
What is the clinical use of cevimeline?
Dry mouth (Xerostomia) & dry eyes (Sjögren’s syndrome)
What are the psychological effects of bethanechol?
↑ constriction of bladder & relaxation of sphincter → micturition
Vasodilation → ↓BP ↓HR
What is the clinical use of bethanechol?
Promotes activity of smooth muscle of GI and urinary tract especially post-operatively
What is “true” acetylcholinesterase (AChE/AChase)?
Present at cholinergic synapses
Bound to the postsynaptic membrane in the synaptic cleft
What is pseudo-cholinesterase?
(Butyrylcholinesterase or plasmacholinesterase; BuChE )
Widely distributed and found in plasma
Important in inactivating the depolarising neuromuscular blocker, suxamethonium
Both true and pseudo cholinesterases are inhibited equally by most clinically-relevant anticholinesterases
What are the three classes of anticholinesterases and how long do they last?
Alcohol - Short (5-15 mins)
Carbamate - Medium (2-6 hours)
Organophosphate - Long (weeks)
What are the clinical uses of neostigmine?
Reversal of neuromuscular paralysis and treatment of myasthenia gravis
What are the clinical uses of edrophonium?
Diagnosis of myasthenia gravis
What are the clinical uses of pyridostigmine?
Treatment of myasthenia gravis
What are the clinical uses of physostigmine & ecothiopate?
Treatment of glaucoma (previously)
What are the clinical uses for donepezil (acricept), galantamine & rivastigmine?
Alzheimer’s disease
What do AChE inhibitors reduce?
Human brain AChE activity
What do AChE inhibitors improve?
Cognitive performance
What is myasthenia gravis and what does it result in?
Auto-immune disease
Loss of NMJ nAChR and NMJ structure
Muscular weakness, paralysis
What can reverse the effects of myasthenia gravis?
Anti-AChE (edrophonium)
What are the three categories of organophosphate nerve agents?
G-agents (“German”)
V-agents (“Venomous”)
A-agents (Novichoks)
What is used to counteract the effects of excessive ACh M stimulation caused by organophosphate nerve agents?
Atropine
What is used as an antidote to nerve agent to reactivate the AChE?
Oximes
What is used to stop seizures caused by organophosphate nerve agents?
Valium
