Lecture 6

Question 1

What are the subtypes of mAChRs?

Answer 1

M1, M2, M3, M4, M5

Question 2

What is the function of the M1 subtype?

Answer 2

• neural - modulation of ganglionic transmission

Question 3

Where is the M1 subtype expressed?

Answer 3

Autonomic ganglia

Question 4

What is the function of the M2 subtype?

Answer 4

• cardiac - cardiac slowing - decreases force of contraction

Question 5

Where is the M2 subtype expressed?

Answer 5

Cardiac atria and conducting tissue

Question 6

What is the function of the M3 subtype?

Answer 6

• glandular - secretion of saliva - increases gut motility

Question 7

Where is the M3 subtype expressed?

Answer 7

Salivary glands and smooth muscles of gut

Question 8

What is the function of the M4 and M5 subtype?

Answer 8

Modulation of synaptic transmission

Question 9

Where are the M4 and M5 receptors expressed?

Answer 9

CNS (substantia nigra for M5)

Question 10

What G protein subtype do M1, 3 and 5 subtypes bind to?

Answer 10

G𝛼q

Question 11

What are the typical second messengers of G𝛼q?

Answer 11

• Protein Kinase C (PKC) - Ca2+

Question 12

What are the physiological responses of G𝛼q activation?

Answer 12

• excitation - secretion - contraction

Question 13

What G protein subtype do M2 and 4 subtypes bind to?

Answer 13

G𝛼I

Question 14

What are the typical second messengers of G𝛼i?

Answer 14

• (Reduced activity of) cAMP and PKA - Gβ𝛾 opens K+ channels

Question 15

What are the physiological responses of G𝛼i activation?

Answer 15

• inhibition - reduced force/rate of contraction

Question 16

What are the mechanisms of G𝛼q activation?

Answer 16

1) stimulates phospholipase C β (PLCβ) 2) breaks down PIP2 to diacylglycerol (DAG) and IP3 - DAG activates PKC - IP3 causes influx of Ca2+

Question 17

What are the mechanisms of G𝛼i activation?

Answer 17

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

Question 18

Is this the activity of G𝛼q or G𝛼i?

Answer 18

G𝛼q

Question 19

Is this the activity of G𝛼q or G𝛼i?

Answer 19

G𝛼I

Question 20

What are parasympathomimetics?

Answer 20

Agonists of parasympathetic systems

Question 21

List physiological effects of mAChR agonists

Answer 21

• 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

Question 22

Name examples of mAChR agonists

Answer 22

• carbachol - pilocarpine - cevimeline - bethanechol

Question 23

List the clinical uses of mAChR agonists

Answer 23

• 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)

Question 24

What are parasympatholytics?

Answer 24

Antagonists of parasympathetic systems

Question 25

What is an example of an mAChR antagonist?

Answer 25

Atropine

Question 26

List the physiological effects of mAChR antagonists

Answer 26

- 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

Question 27

List the clinical uses of mAChR antagonists

Answer 27

- 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

Question 28

What is the myth of the M1 receptor in gastric acid secretion?

Answer 28

No less GA secretion in response to carbachol in KO M1 receptor compared to normal wild type mice

Question 29

What do we see when pirenzipine is used in mice with KO M1 receptors?

Answer 29

Gastric acid secretion is blocked even in mice lacking M1 receptors

Question 30

When does pirenzipine block gastric acid and histamine secretion?

Answer 30

When the M3 receptor gets antagonised

Question 31

What are the two types of cholinesterases?

Answer 31

- true acetylcholinesteraste - pseudo-cholinesterase (butyryl/plasmacholinesterase)

Question 32

Where are true acetylcholinesterases found?

Answer 32

- cholinergic synapses - bound to postsynpatic membrane in the synaptic cleft

Question 33

Where are pseudo-cholinesterases found?

Answer 33

- widely distributed in plasma

Question 34

Why are pseudo-cholinesterases important?

Answer 34

Inactivate depolarising blockers e.g. suxamethonium

Question 35

What are true and psuedo cholinesterases inhibited by?

Answer 35

Clinically relevant anticholinesterases

Question 36

What are the three classes of anticholinesterases?

Answer 36

- alchohol - carbamate - organophosphate

Question 37

What is an example of an alchohol anticholinesterase?

Answer 37

Edrophonium

Question 38

What are examples of carbamate anticholinesterases?

Answer 38

- neostigmine - pyridostigmine - physostigmine

Question 39

What are examples of organophosphate anticholinesterases?

Answer 39

- dyflos - ecothiopate - parathion (P=S)

Question 40

What is an example of a reversible anticholinesterase?

Answer 40

Neostigmine

Question 41

What is an example of an irreversible anticholinesterase?

Answer 41

Dyflos

Question 42

How does neostigmine work?

Answer 42

1) sits in the catalytic pocket of the cholinesterase 2) carbamylates serine residue 3) inactivates cholinesterase 4) inactivation= carbamyl-serine hydrolysed

Question 43

How does dyflos work?

Answer 43

1) phosphorylates serine residue 2) covalently bound - hydrolysis is difficult - oximes can bind to anionic site and can phosphorylate themsleves - frees serine= cholinesterase reactivated

Question 44

Why is ageing a problem for reactivating cholinesterases?

Answer 44

- 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

Question 45

Use of neostigmine

Answer 45

Reversal of neuromuscular paralysis

Question 46

Use of edrophonium

Answer 46

Diagnosis of myasthenia gravis

Question 47

Use of neostigmine and pyridostigmine

Answer 47

Treatment of myasthenia gravis

Question 48

Use of physostigmine and ecothiopate

Answer 48

Treatment of glaucoma (previously)

Question 49

Use of donepzil, galantamine, and rivastigmine

Answer 49

Alzheimer's disease

Question 50

What are the physiological effects of anticholinesterases?

Answer 50

- increased ACh activity at autonomic NEJ, NMJ and CNS - increased secretion (salivary, lacrimal, bronchial, GI glands) - increased peristaltic activity (stimulant laxatives)

Question 51

What are side effects of anticholinesterases?

Answer 51

- depolarisation block at NMJ - bronchoconstriction - bradycardia and hypotension - convulsions, respiratory failure and unconsciousness of the CNS

Question 52

What are the components of the cholinergic hypothesis of Alzheimer's disease?

Answer 52

- loss of cholinergic neurones - loss of muscarinic receptors - loss of nicotinic receptors - reduction in vesicular ACh transporters

Question 53

Why would you use an AChE inhibitor for Alzheimer's disease?

Answer 53

- reduce brain AChE activity - AChE inhibitors improve cognitive performance in the early stages of Alzheimer's

Question 54

What is myasthenia gravis?

Answer 54

- autoimmune disease - characterised by a loss of NMJ nAChRs and NMJ structure - muscular weakness and paralysis

Question 55

What would you expect when you give a patient with myasthenia gravis an anti-AChE?

Answer 55

Reversal of symptoms

Question 56

What are the three categories of organophosphates?

Answer 56

- G agents - V agents - A agents

Question 57

Name three drugs used to reverse organophosphate effects?

Answer 57

- atropine - oximes e.g. pralidoxime - valium

Question 58

Why would you use atropine to reverse nerve agent effects?

Answer 58

Counteract effects of excessive mAChR stimulation

Question 59

Why would you use oximes to reverse nerve agent effects?

Answer 59

Reactivates AChE so acts as an antidote

Question 60

Why would you use valium to reverse nerve agent effects?

Answer 60

- used for seizures - reversible antiAChEs as prophylactics against nerve agents