Cholinomimetics

Question 1

Recall the synthesis and break down of acetylcholine

Answer 1

Acetyl CoA + Choline => ACh + CoA; catalysed by Choline acetyltransferase (CAT)

Acetylcholine => Choline + Acetate; catalysed by Acetylcholinesterase

Question 2

Why are the receptors described as nicotinic and muscarinic?

Answer 2

Muscarinic effects are those that can be replicated by muscarine.
Nicotinic effects are those that can be replicated by nicotine

Question 3

Name a competitive muscarinic receptor antagonist

Answer 3

Atropine

Question 4

Name a nicotinic receptor antagonist

Answer 4

Tubocararine

Question 5

Briefly state where nicotinic and muscarinic receptors are found in the ANS

Answer 5

Nicotinic: found ‘between pre- and post-ganglionic neurones’ in both SNS and PNS pathways; as well as the NMJ

Muscarinic: found on PNS effectors and sweat glands (innervated by SNS)

Question 6

State where you would find the different types of muscarinic receptor

Answer 6

M1: Salivary glands, Stomach, CNS
M2: Heart
M3: Salivary glands, Bronchial/visceral SM, Sweat glands, Eye

M4: CNS
M5: CNS

Question 7

What types of receptor are each of the muscarinic receptors

Answer 7

M1, M3, M5 = stimulatory GPCR; IP3 and DAG mediated transduction

M2 and M4 = inhibitory GPCR; decrease cAMP production

Question 8

Describe the structure of nicotinic receptors

Answer 8

• Ionotropic type 1/ligand-gated ion channel

- 5 subunits (any of α β γ δ ε) which determine ligand binding properties

Question 9

What combination of subunits are found at the NMJ, and at ganglia

Answer 9

Muscle type: 2α β δ ε

Ganglion type: 2α 3β

Question 10

How do the effects of acetylcholine on nicotinic receptors compare to its effects on muscarinic receptors?

Answer 10

Relatively weak on nicotinic compared to muscarinic

Question 11

What three effects does muscarinic stimulation have on the eye?

Answer 11

1. Ciliary muscle contraction => accommodation for near vision
2. Sphincter pupillae contraction => constricts pupil (miosis) and improves intraocular fluid drainage
3. Lacrimation

Question 12

What is glaucoma?

Answer 12

Sustained raised intraocular pressure – this can cause damage to the optic nerves and retina and can lead to blindness

Question 13

Describe the passage of aqueous humour through the eye

Answer 13

• Aqueous humour is produced by capillaries in the ciliary body (via the actions of carbonic anhydrase)
• Aqueous humour passes into the anterior chamber
• Contraction of sphincter pupillae (iris circular muscle) opens pathway for aqueous humour, allowing drainage via the trabecular meshwork and canals of Schlemm => reduced intraocular pressure

Question 14

Describe the muscarinic effects on the heart

Answer 14

Binding of ACh to the M2 receptors in the atria and nodes => decreased cAMP production => decreased Ca2+ influx and increased K+ efflux => decreased CO and decreased HR

Question 15

Describe the muscarinic effects on the vasculature

Answer 15

• ACh binds to M3 receptors on vascular endothelial cells to stimulate NO release which induces vascular smooth muscle relaxation/vasodilation (due to K+ efflux)
• Note however that most blood vessels do not have parasympathetic innervation (only coronary) but M3 receptors ARE found in many blood vessels

Question 16

Describe the muscarinic effects on Non-Vascular Smooth Muscle

Answer 16

Smooth muscle that does have PNS innervation responds in the opposite way to vascular muscle – i.e. it contracts (because the M3 receptor is Gq)

e.g. bronchoconstriction, increased peristalsis, increased micturition

Question 17

State the muscarinic effects on exocrine glands

Answer 17

• Salivation
• Increased bronchial secretions
• Increased gastro-intestinal secretions (including gastric HCl production)
• Increased sweating (SNS-mediated)

Question 18

What is the difference between directly and indirectly acting cholinomimetic drugs

Answer 18

Direct = Muscarinic receptor agonist

Indirect = Anticholinesterase (Increase effect of normal parasympathetic nerve stimulation by increasing duration of acetylcholine activity in the synapse)

Question 19

Name two muscarinic receptor agonists

Answer 19

Bethanechol (choline esters)

Pilocarpine (alkaloids)

Question 20

State the characteristics and clinical use of pilocarpine

Answer 20

• Non-selective; good lipid solubility; t1/2 ≈ 3-4h

- Local treatment for glaucoma

Question 21

What are the side effects of pilocarpine

Answer 21

Blurred vision, sweating, gastro-intestinal disturbance and pain, hypotension, respiratory distress

Question 22

State the characteristics and clinical use of bethanechol

Answer 22

• Produced by adding methyl group to ACh => M3 selective
• Resistant to degradation, orally active and with limited access to the brain; t1/2 ≈ 3-4h
• Used to assist bladder emptying and to enhance gastric motility

Question 23

What are the side effects of bethanechol

Answer 23

Sweating, impaired vision, bradycardia, hypotension, respiratory difficulty

Question 24

Name three reversible and three irreversible anticholinesterase

Answer 24

Physostigmine, neostigmine, donepezil (‘Aricept’)

Ecothiopate, dyflos, sarin (organophosphates)

Question 25

What are the two types of cholinesterase

Answer 25

Acetylcholinesterase (true or specific cholinesterase) Butyrylcholinesterase (pseudocholinesterase)

Question 26

Summarise the main differences between acetylcholinesterase and butyrylcholinesterase

Answer 26

Acetylcholinesterase: - Found in all cholinergic synapses - Very rapid action - Highly selective for acetylcholine Butyrylcholinesterase: - Found in plasma and most tissues but not cholinergic synapses - Broad substrate specificity (hydrolyses other esters e.g. suxamethonium) - Causes low plasma acetylcholine - Shows genetic variation

Question 27

Describe the effects of increasing the dosage of cholinesterase inhibitors

Answer 27

LOW = enhanced muscarinic activity MODERATE = Increased transmission at ALL autonomic ganglia (nAChRs) and further enhancement of muscarinic activity HIGH = Depolarising block at autonomic ganglia & NMJ (toxic)

Question 28

How do reversible anticholinesterase drugs work?

Answer 28

- They compete with acetylcholine for the active site on the cholinesterase enzyme. - They donate a carbamyl group to the enzyme, blocking the active site and preventing acetylcholine from binding - Carbamyl group is removed by slow hydrolysis

Question 29

State the characteristics and clinical use of physostigmine

Answer 29

- Tertiary amine that primarily acts at the postganglionic parasympathetic synapse; t1/2 ≈ 30 mins - Used to treat glaucoma and atropine poisoning

Question 30

How do irreversible anticholinesterase drugs work?

Answer 30

- They rapidly react with the cholinesterase active site, leaving a large blocking group that is stable and resistant to hydrolysis - Recovery may require the production of new enzymes (days/weeks)

Question 31

State the characteristics and clinical use of ecothiopate

Answer 31

- Potent anticholinesterase | - Used as eye drops to treat glaucoma (prolonged action)

Question 32

What are the side effects of ecothiopate?

Answer 32

Sweating, blurred vision, GI pain, bradycardia, hypotension, respiratory difficulty

Question 33

Which anticholinesterases can cross the blood brain barrier? State the effects of low and high doses

Answer 33

Non-polar anticholinesterases (e.g. physostigmine; nerve agents). LOW = CNS excitation with possibility of convulsions HIGH = Unconsciousness, respiratory depression, death

Question 34

Describe the treatment of organophosphate poisoning

Answer 34

Pralidoxime (iv): 'unblocks' cholinesterase enzyme (used within first few hours of poisoning) Atropine (iv): inhibit muscarinic receptors Artificial respiration