Lecture 6. Pharmacology of Muscarinic Acetylcholine Receptors & AChE

Question 1

How many subtypes of muscarinic receptors (AChM) are there?

Answer 1

5

Question 2

What is the representative tissue of M₁ ‘neural’ subtype?

Answer 2

Autonomic ganglia

Question 3

What is the physiological response caused by the M₁ ‘neural’ subtype?

Answer 3

Modulation of ganglionic transmission

Question 4

What is the representative tissue of M₂ ‘cardiac’ subtype?

Answer 4

Cardiac atria and conducting tissue

Question 5

What is the physiological response caused by the M₂ ‘cardiac’ subtype?

Answer 5

Cardiac slowing
↓ force of contraction

Question 6

What is the representative tissue of M₃ ‘glandular’ subtype?

Answer 6

Salivary glands
Smooth muscle of gut

Question 7

What is the physiological response caused by the M₃ ‘glandular’ subtype?

Answer 7

Secretion of saliva
↑ gut motility

Question 8

What is the representative tissue of M₄ subtype?

Answer 8

CNS

Question 9

What is the physiological response caused by the M₄ subtype?

Answer 9

Modulation of synaptic transmission

Question 10

What is the representative tissue of M₅ subtype?

Answer 10

CNS - substantia nigra

Question 11

What is the physiological response caused by the M₅ subtype?

Answer 11

Modulation of synaptic transmission

Question 12

What G protein subtype do M₁, M₃, and M₅ subtypes have?

Answer 12

Gαq (queer)

Question 13

What G protein subtype do M₂ and M₄ subtypes have?

Answer 13

Gαi (inhibitory)

Question 14

What are all muscarinic receptors?

Answer 14

G-protein coupled receptors

Question 15

What does Gαq stimulate?

Answer 15

Phospholipase C β (PLCβ) which breaks down phosphatidylinositol 4,5-bisphosphate (PIP2) to diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP₃)

Question 16

What does diacylglycerol (DAG) activate?

Answer 16

Protein Kinase C (PKC)

Question 17

What does IP₃ cause the release of?

Answer 17

Ca²⁺ from internal Ca²⁺ stores

Question 18

What does Gαi inhibit and what are the effects of this inhibition?

Answer 18

Gαi inhibits adenylate cyclase (AC) which results in a reduction in cAMP, reduced activation of PKA and reduced Ca²⁺ channel activity

Question 19

What does Gβγ activate and what does this activation lead to?

Answer 19

Gβγ activates certain K⁺ channels that leads to K⁺ efflux from the cell, membrane hyperpolarisation and reduced excitability

Question 20

What are the physiological effects of carbachol and pilocarpine?

Answer 20

Constriction of circular muscle of iris and ciliary muscle of eye
↑ secretion (lacrymation, salivation, sweating)
Bronchoconstriction and ↑ mucus production

Question 21

What is the clinical uses of carbachol?

Answer 21

Not used clinically

Question 22

What is the clinical uses of pilocarpine?

Answer 22

Topical eye drops for glaucoma - decrease intra ocular pressure by constricting muscles and facilitating drainage of aqueous humour from anterior chamber

Question 23

What are the physiological effects of cevimeline?

Answer 23

↑ gut motility & relaxation of sphincter → defecation

Question 24

What is the clinical use of cevimeline?

Answer 24

Dry mouth (Xerostomia) & dry eyes (Sjögren’s syndrome)

Question 25

What are the psychological effects of bethanechol?

Answer 25

↑ constriction of bladder & relaxation of sphincter → micturition
Vasodilation → ↓BP ↓HR

Question 26

What is the clinical use of bethanechol?

Answer 26

Promotes activity of smooth muscle of GI and urinary tract especially post-operatively

Question 27

What is “true” acetylcholinesterase (AChE/AChase)?

Answer 27

Present at cholinergic synapses
Bound to the postsynaptic membrane in the synaptic cleft

Question 28

What is pseudo-cholinesterase?

Answer 28

(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

Question 29

What are the three classes of anticholinesterases and how long do they last?

Answer 29

Alcohol - Short (5-15 mins)
Carbamate - Medium (2-6 hours)
Organophosphate - Long (weeks)

Question 30

What are the clinical uses of neostigmine?

Answer 30

Reversal of neuromuscular paralysis and treatment of myasthenia gravis

Question 31

What are the clinical uses of edrophonium?

Answer 31

Diagnosis of myasthenia gravis

Question 32

What are the clinical uses of pyridostigmine?

Answer 32

Treatment of myasthenia gravis

Question 33

What are the clinical uses of physostigmine & ecothiopate?

Answer 33

Treatment of glaucoma (previously)

Question 34

What are the clinical uses for donepezil (acricept), galantamine & rivastigmine?

Answer 34

Alzheimer’s disease

Question 35

What do AChE inhibitors reduce?

Answer 35

Human brain AChE activity

Question 36

What do AChE inhibitors improve?

Answer 36

Cognitive performance

Question 37

What is myasthenia gravis and what does it result in?

Answer 37

Auto-immune disease
Loss of NMJ nAChR and NMJ structure
Muscular weakness, paralysis

Question 38

What can reverse the effects of myasthenia gravis?

Answer 38

Anti-AChE (edrophonium)

Question 39

What are the three categories of organophosphate nerve agents?

Answer 39

G-agents (“German”)
V-agents (“Venomous”)
A-agents (Novichoks)

Question 40

What is used to counteract the effects of excessive ACh M stimulation caused by organophosphate nerve agents?

Answer 40

Atropine

Question 41

What is used as an antidote to nerve agent to reactivate the AChE?

Answer 41

Oximes

Question 42

What is used to stop seizures caused by organophosphate nerve agents?

Answer 42

Valium