Pharmacology of the Neuromuscular Junction

Question 1

Why is the neuromuscular junction a special type of synapse?

Answer 1

it always works, every time there is a presynaptic event, muscle contraction occurs

Question 2

How many subunits is the nicotinic ACh receptor formed of?

Answer 2

5

Question 3

How many binding sites for ACh are there on a nicotinic ACh receptor?

Answer 3

2

Question 4

How does the nicotinic ACh receptor work?

Answer 4

two molecules of ACh need to bind to the receptor in order for a structural change to occur which opens the pore which allows ions (K and Na) to move through it. Na in and K out

Question 5

What enzyme synthesises ACh?

Answer 5

choline acetyltransferase

Question 6

How is the signal terminated?

Answer 6

ACh is broken down and a choline carrier reuptakes the choline

Question 7

What is the presynaptic nicotinic ACh receptor used for?

Answer 7

in a positive feedback mechanism it stimulates greater release of ACh

Question 8

What is a another mechanism that adds to the amount of ACh in the synaptic cleft?

Answer 8

ACh leak

Question 9

What drug blocks the carrier that transports ACh into the vesicle?

Answer 9

Vesamicol

Question 10

What drug blocks the choline transporter?

Answer 10

Hemicholinium

Question 11

What blocks the exocytosis of the vesicle?

Answer 11

toxins e.g botulinum

Question 12

How does the botulinum toxin work?

Answer 12

• the 1st subunit binds to presynaptic membrane
• 2nd subunit cleaves the proteins involved in exocytosis
• this blocks cholinergic synapses which causes muscle paralysis and can lead to death

Question 13

How do you treat botulinum poisoning pharmacologically?

Answer 13

Pharmacologically use 4-aminopyridine.

• blocks voltage gates K channels which prevents repolarisation of the membrane which prolongs the action potential
• this increases pre synaptic influx so calcium keeps coming in which triggers exocytosis

Question 14

How to you treat Botulinum poisoning immunologically?

Answer 14

use a antibody against the toxin. This prevents entry into the nerve terminal

Question 15

What are the two categories of neuromuscular blockers?

Answer 15

• non-depolarising blockers (antagonists)

- depolarising blokers (agonists)

Question 16

What are non-depolarising blockers?

Answer 16

they bind to the receptor but do no cause depolarisation, decrease endplate potential

Question 17

How are non-depolarising blockers involved in anaesthesia?

Answer 17

-cause muscle relaxation and mean that you can use smaller dose of anaesthetic (safer)

Question 18

How does the body recover from non-depolarising blockers?

Answer 18

liver metabolism or direct renal excretion

Question 19

What is an example of a depolarising blocker?

Answer 19

Suxamethonium (2 ACh molecules linked by an acetyl group)

Question 20

How do depolarising blockers work?

Answer 20

Act as agonist at nAChRs

• causes endplate depolarisation
• action potentials
• uncoordinated, fine contractions (fasciculations)
• causes failure of neuromuscular junction

Question 21

Why do depolarising blockers cause paralysis?

Answer 21

• not broken down by acetylcholinesterase in the synaptic cleft
• prolonged depolarisation
• paralysis due to inactivation of voltage gated sodium channels

Question 22

What breaks down suxamethonium?

Answer 22

plasma cholinesterase

Question 23

Is the recovery faster for depolarising blockers or non-depolarising blockers?

Answer 23

depolarising

Question 24

What are the unwanted effects of suxamethonium?

Answer 24

• brachycardia (activation of muscarinic ACh receptors in the heart)
• K+ release
• increased intraocular pressure

Question 25

What is the difference between phase 1 block and phase 2 block?

Answer 25

• phase 1 block is the inactivation of the sodium voltage gated channels
• phase 2 is due to inactivation of nAChRs

Question 26

What are the actions and effects of cholinesterase inhibitors?

Answer 26

• intereact with AChE and plasma cholinesterase
• prevent breakdown of ACh (enhance synaptic function)
• Affect other synapses where ACh is the transmitter (autonomic ganglia and postganglionic parasympathetic nerves)

Question 27

What are the different ways the drugs can interact with the enzyme?

Answer 27

• ionic (mins)
• covalent (hours)
• phosphorylation (irreversible)

Question 28

What can cholinesterase inhibitors reverse the effects of?

Answer 28

• non-polarising NMJ blockers
• end of operation
• increase ACh levels so it competes with antagonist, increasing endplate potential

Question 29

Why does cholinesterase inhibition make the effects of depolarising NMJ blocker worse?

Answer 29

-both act as agonist so effects increase