Lecture 6 Flashcards
What are the subtypes of mAChRs?
M1, M2, M3, M4, M5
What is the function of the M1 subtype?
- neural - modulation of ganglionic transmission
Where is the M1 subtype expressed?
Autonomic ganglia
What is the function of the M2 subtype?
- cardiac - cardiac slowing - decreases force of contraction
Where is the M2 subtype expressed?
Cardiac atria and conducting tissue
What is the function of the M3 subtype?
- glandular - secretion of saliva - increases gut motility
Where is the M3 subtype expressed?
Salivary glands and smooth muscles of gut
What is the function of the M4 and M5 subtype?
Modulation of synaptic transmission
Where are the M4 and M5 receptors expressed?
CNS (substantia nigra for M5)
What G protein subtype do M1, 3 and 5 subtypes bind to?
G𝛼q
What are the typical second messengers of G𝛼q?
- Protein Kinase C (PKC) - Ca2+
What are the physiological responses of G𝛼q activation?
- excitation - secretion - contraction
What G protein subtype do M2 and 4 subtypes bind to?
G𝛼I
What are the typical second messengers of G𝛼i?
- (Reduced activity of) cAMP and PKA - Gβ𝛾 opens K+ channels
What are the physiological responses of G𝛼i activation?
- inhibition - reduced force/rate of contraction
What are the mechanisms of G𝛼q activation?
1) stimulates phospholipase C β (PLCβ) 2) breaks down PIP2 to diacylglycerol (DAG) and IP3 - DAG activates PKC - IP3 causes influx of Ca2+
What are the mechanisms of G𝛼i activation?
1) inhibits adenylate cyclase (AC) 2) reduction in cAMP, PKA activation and Ca2+ activity 3) Gβ𝛾 activates K+ channels leading to an efflux from the cell - hyperpolarisation and reduced excitability
Is this the activity of G𝛼q or G𝛼i?
G𝛼q
Is this the activity of G𝛼q or G𝛼i?
G𝛼I
What are parasympathomimetics?
Agonists of parasympathetic systems
List physiological effects of mAChR agonists
- constriction of circular muscle of iris and cilliary muscle of eye - increases secretion (salivation, sweating) - bronchostriction and mucus production - increased gut motility and relxation of sphincter - bladder constriction and relxation of sphincter - vasodilation= decreased BP and HR
Name examples of mAChR agonists
- carbachol - pilocarpine - cevimeline - bethanechol
List the clinical uses of mAChR agonists
- dry mouth (Xerostomia) and dry eyes (Sjögren’s syndrome)= Cevimeline - eye drops for glaucoma (decrease intra ocular pressure by constricting muscles)= Pilocarpine - promote activity of smooth muscle of GI and urinary tract (bethanechol)
What are parasympatholytics?
Antagonists of parasympathetic systems
What is an example of an mAChR antagonist?
Atropine
List the physiological effects of mAChR antagonists
- dilated pupils (loss of focusing) - decreased secretion of tears- reduced sweating (dry skin and increased body temperature) - reduced gut motility (constipation) - reduced saliva production - increased heart rate (tachycardia) - relaxation of bladder - bronchodilation, relxation of airway smooth muscle - reduced bronchial secretions
List the clinical uses of mAChR antagonists
- eye exams= tropicamide - diarrhoea treatment= co-phenotrope - chronic bronchitis= ipratropium and oxitropium - tremor and rigidity in Parkinson’s= CNS benzhexol - adjunct to anaesthesia - reversal of neuromuscular blockade and nerve gas poisoning
What is the myth of the M1 receptor in gastric acid secretion?
No less GA secretion in response to carbachol in KO M1 receptor compared to normal wild type mice
What do we see when pirenzipine is used in mice with KO M1 receptors?
Gastric acid secretion is blocked even in mice lacking M1 receptors
When does pirenzipine block gastric acid and histamine secretion?
When the M3 receptor gets antagonised
What are the two types of cholinesterases?
- true acetylcholinesteraste - pseudo-cholinesterase (butyryl/plasmacholinesterase)
Where are true acetylcholinesterases found?
- cholinergic synapses - bound to postsynpatic membrane in the synaptic cleft
Where are pseudo-cholinesterases found?
- widely distributed in plasma
Why are pseudo-cholinesterases important?
Inactivate depolarising blockers e.g. suxamethonium
What are true and psuedo cholinesterases inhibited by?
Clinically relevant anticholinesterases
What are the three classes of anticholinesterases?
- alchohol - carbamate - organophosphate
What is an example of an alchohol anticholinesterase?
Edrophonium
What are examples of carbamate anticholinesterases?
- neostigmine - pyridostigmine - physostigmine
What are examples of organophosphate anticholinesterases?
- dyflos - ecothiopate - parathion (P=S)
What is an example of a reversible anticholinesterase?
Neostigmine
What is an example of an irreversible anticholinesterase?
Dyflos
How does neostigmine work?
1) sits in the catalytic pocket of the cholinesterase 2) carbamylates serine residue 3) inactivates cholinesterase 4) inactivation= carbamyl-serine hydrolysed
How does dyflos work?
1) phosphorylates serine residue 2) covalently bound - hydrolysis is difficult - oximes can bind to anionic site and can phosphorylate themsleves - frees serine= cholinesterase reactivated
Why is ageing a problem for reactivating cholinesterases?
- ageing= ageing of the bound between the phosphate group and serine residue - longer you wait to deliver oxime= more difficult it is to reactivate cholinesterase
Use of neostigmine
Reversal of neuromuscular paralysis
Use of edrophonium
Diagnosis of myasthenia gravis
Use of neostigmine and pyridostigmine
Treatment of myasthenia gravis
Use of physostigmine and ecothiopate
Treatment of glaucoma (previously)
Use of donepzil, galantamine, and rivastigmine
Alzheimer’s disease
What are the physiological effects of anticholinesterases?
- increased ACh activity at autonomic NEJ, NMJ and CNS - increased secretion (salivary, lacrimal, bronchial, GI glands) - increased peristaltic activity (stimulant laxatives)
What are side effects of anticholinesterases?
- depolarisation block at NMJ - bronchoconstriction - bradycardia and hypotension - convulsions, respiratory failure and unconsciousness of the CNS
What are the components of the cholinergic hypothesis of Alzheimer’s disease?
- loss of cholinergic neurones - loss of muscarinic receptors - loss of nicotinic receptors - reduction in vesicular ACh transporters
Why would you use an AChE inhibitor for Alzheimer’s disease?
- reduce brain AChE activity - AChE inhibitors improve cognitive performance in the early stages of Alzheimer’s
What is myasthenia gravis?
- autoimmune disease - characterised by a loss of NMJ nAChRs and NMJ structure - muscular weakness and paralysis
What would you expect when you give a patient with myasthenia gravis an anti-AChE?
Reversal of symptoms
What are the three categories of organophosphates?
- G agents - V agents - A agents
Name three drugs used to reverse organophosphate effects?
- atropine - oximes e.g. pralidoxime - valium
Why would you use atropine to reverse nerve agent effects?
Counteract effects of excessive mAChR stimulation
Why would you use oximes to reverse nerve agent effects?
Reactivates AChE so acts as an antidote
Why would you use valium to reverse nerve agent effects?
- used for seizures - reversible antiAChEs as prophylactics against nerve agents
