Lecture 12 - Cholinergic effects

Question 1

Uses of Muscarinic Receptor Agonists (3)

Answer 1

ON OTHER FC

Question 2

Uses of Muscarinic Receptor Antagonists (6)

Answer 2

ON OTHER FC

Question 3

Cholinergic neurons (4)

Answer 3

• SN usually have a bead like structure.
• ACh made put into vesicles.
• ACh in synapse acts at nicotinic or muscarinic receptors.
o Nic receptor – skeletal muscle (NMJ), ganglia (ANS).
o Mus receptors – e.g. Heart (M2), smooth muscle (e.g. M3 in airways/eye etc).
• This leads to a biological response, e.g. decrease heart rate, bronchoconstriction, skeletal muscle contraction.
• ACh has to be broken down so it can be taken up.

Question 4

Facilitation of release - decreases cholinergic actions (2) and effects (4)

Answer 4

Clostridium botulinum – causes botulism
Bacteria produces toxin (1kg enough to kill world population)
Toxin enters terminals and degrades Ach-containing vesicles
ANS and motor fibres are inhibited – paralysis Clinical Scenario?

Botox - Very low levels of botulinum toxin used to produce local paralysis (cosmetic, clinical uses)
Also, used to prevent excess sweating (hyperhidrosis)

e.g. tachycardia, dry mouth, blurred vision, GI tract disturbance, skeletal muscle paralysis.

Question 5

Termination inhibition (4) - increases cholinergic actions

Answer 5

Anti-cholinesterases – dementia!!!
Classified by duration / mode of action

Short acting (Edrophonium) – diagnostic, improves myasthenia gravis
Medium acting (Neostigmine) – reverse neuromuscular block and atonic states of GI tract/bladder after surgery 
Long acting (Organophosphorus insecticides, VX agent (Kim Jong Nam), Novichok (Salisbury poisoning))
– irreversible, need new AchE synthesis, hence very dangerous -

Question 6

Direct and indirect regulation (2)

Answer 6

• Direct – Drugs that act at cholinergic receptors.

* Indirect – Drugs that act at altering release/termination of transmission.

Question 7

Uses of Nicotinic Receptor Agonists/Antagonists (4)

Answer 7

Nic receptors found at autonomic ganglia and NMJ (+ CNS)

Receptors are different at ganglia vs. NMJ
due to different subunits composing the ligated-gated receptors
Different Pharmacology

Most clinically relevant drugs act at nicotinic receptors at the NMJ

Agonists, e.g. Suxamethonium and Competitive antagonists, e.g. Vecuronium, are used to cause muscle relaxant -important during surgery.

Question 8

How do nicotinic agonists and antagonists both produce muscle relaxation? (4)

Answer 8

Suxamethonium
Agonist, poor dissociation
Stays at Ach site for long time

Produces sustained EJP
Sustained depolarisation mean voltage-gated Na channels become inactivated (cannot open)

Prevents AP generation
No contraction

Vecuronium
Acts as a classical competitive antagonist
Outcompetes Ach for the
same binding site on NIC receptors
Reduces stimulation of NIC receptors by Ach

Question 9

Nicotinic Acetylcholine receptors (nAChR) (6)

Answer 9

• Nicotinic Acetylcholine receptors found mainly in the neuromuscular junction and every single autonomic ganglion.

1) Activation of nicotinic acetylcholine receptors was covered in receptor mechanisms I.
2) ACh binding produces a conformational change that opens channel pore.
3) Allows influx of cations.
4) Produces an Excitatory Junction Potential in the target cell.
5) Effect terminated by unbinding of ACh.

Question 10

Nicotinic Acetylcholine receptors (nAChR) - types (3)

Answer 10

Different types of nAChR:
o Muscle nicotinic AChRs (adult neuromuscular junction): α1-ε-α1-β1-δ
o Muscle nicotinic AChRs (foetal extra junctional): α1-ϒ- α1- β1-δ
o Neuronal nicotinic AChRs/ Autonomic ganglia: α2 – α8 and β2- β4

Question 11

Parasympathomimetics (1)

Answer 11

A cholinomimetic drug, is a substance that stimulates the parasympathetic nervous system (PSNS). These chemicals are also called cholinergic drugs because acetylcholine (ACh) is the neurotransmitter used by the PSNS.

Question 12

Parasympathomimetics - Directly acting (3)

Answer 12

o	PILOCARPINE (mAchR agonist) is used to treat glaucoma & dry mouth. Used in sweat tests.
o	BETHANECOL (mAchR agonist) occasionally used to aid bladder / gastric emptying.
o	SUCCINYLCHOLINE high affinity nAChR agonist  used in surgery –depolarising paralysis.

Question 13

Parasympathomimetics - Indirectly acting (2)

Answer 13

o AChE inhibitors such as TACRINE, DONEPEZIL or RIVASTIGMINE used in dementia.
o Neuromuscular diseases such as MYASTHESIA GRAVIS or EATON-LAMBERT syndrome.

Question 14

Synthesis of Acetylcholine (4)

Answer 14

Acetyl CoA + Choline –> Acetylcholine + CoA
Acetyl CoA - Produced by cellular respiration
Choline - Diet (Liver/ Fish)
Enzyme used is ChAT (Choline acetyltransferase) = e.g. fa64a, dangerous biological weapons.