Pharmacology of the NMJ

Question 1

what are the three ways to block neuromuscular transmission

Answer 1

presynaptically, by inhibiting ACh synthesis
-rate-limiting step is choline uptake
presynpatically, by inhibiting ACh release
Postsynaptically
- by interfering with the actions of ACh on the receptor

Question 2

What are the ways of blocking ACh release

Answer 2

Local anaesthetics
General inhalation anaesthetics
Inhibitors/competitors of calcium
- magnesium ions (compete with calcium)
- some antibiotics (bind to ca2+)(ahminoglycosides (gentamicin) and tetracycline)
Neurotoxins
- botulinum toxin (clostridium botulinum)
- beta bungarotoxin (botox, stops the triggering of ACh)

Question 3

Name some clinical uses of neuromuscular blocking drugs

Answer 3

endotracheal intubation
During surgical procedures
- to allow surgical access to abdominal cavity
- to ensure immobility
- allow relaxation to reduce displaced fracture or dislocation
- decrease in concentration of general anaesthetic needed
Infrequently used in intensive care
- mechanical ventilation at extremes of hypoxia
During electroconvulsive therapy

Question 4

what is the structure of the nicotinic acetylcholine receptor

Answer 4

found in the NMJ but also in the brain and autonomic nervous system.
has a central pore of 0.7nm in diameter
two alpha helices forming the gate
two ACh receptors

Question 5

nicotinic acetylcholine receptor agonist

Answer 5

this causes ACh to bind and causes a conformational change but then eventually leads to loss of control

Question 6

nicotinic acetylcholine receptor antagonist

Answer 6

This channel is simply closed

Question 7

what is the action of non-depolarising blockers = competitive antagonists of Nicotinic ACh receptors at the NMJ
TUBOCURARINE

Answer 7

prevents ACh binding to receptor by occupying site
Decreases the motor end plate potential (EPP)
decreases depolarisation of the motor end plate region
No activation of the muscle potential

Question 8

What is the action of depolarising blockers = agonists of nicotinic acetylcholine receptor at the NMJJ = NOT METABALISED BY ACETYLCHOLINE ESTERASE
SUXAMETHONIUM

Answer 8

This initially causes a twitch due to a small AP which immediately goes away so does cause an initial conformational change.
Persistent depolarisation of the motor endplate
prolonged EPP
Prolonged depolarisation of the muscle membrane
Membrane potential above the threshold for the resting of the voltage-gated sodium channels
sodium channels remain refractory
no more muscle action potentials generated

Question 9

Phase 1, in a depolarising block

Answer 9

Phase 1:
muscle fasciculations observed, then blocked
depolarisation inhibited (K+ leaks from the cells as sodium enters (hyperkalemia)
voltage gated na+ channels kept inactivated

Question 10

Phase 2, in a depolarising block

Answer 10

prolonged/increased exposure to drug
‘desensitisation blockade’ - tissue desensitisation due to prolonged exposure -depolarisation cannot occur, even in the absence of the drug

Question 11

the side effects of non-depolarising blockers

Answer 11

normally result in tachycardia responses and hypotension (AM) which leads to bronchospasm due to histamine release

Question 12

the side effects of depolarising blockers include

Answer 12

brachycardia 
cardiac dysrhythmias 
raised intraocular pressure
postoperative myalgia - feeling of flu or space
malignant hyperthermia

Question 13

What blocker can be used for ester hydrolysis and Hofmann elimination

Answer 13

atracurium

Question 14

what blockers can be used for plasma cholinesterases

Answer 14

these provide a prolonged block

• mivacurium
• suxamethonium

Question 15

what blockers can be used for hepatic metabolism

Answer 15

pancuronium

vecuronium

Question 16

what blocker is unchanged in bile and urine

Answer 16

recuronium

Question 17

what is the action of ACh regulated by

Answer 17

hydrolysis

Question 18

acetylcholinesterase (synaptic cleft NMJ and is readily available)

Answer 18

true cholinesterase, specific for hydrolysis of ACh
present in conducting tissue and red blood cells
bound to basement membrane in the synaptic cleft

Question 19

plasma cholinesterase

Answer 19

pseudocholinesterase, broad spectrum of substrates
widespread distribution
soluble in plasma
(prevents breakdown of ACh)

Question 20

tell me more about anticholinesterases

Answer 20

they are all inhibitors of cholinesterases which result in:

• increase in availability of ACh at NMJ
• increases duration of activity of ACh at NMJ
• More ACh to compete with non-depolarising blockers

Question 21

pancuronium

Answer 21

medium onset and long duration, non depolarising so tachycardia

Question 22

vecuronium

Answer 22

medium onset and medium duration non depolarising with few side effects

Question 23

rocuronium

Answer 23

fast onset and medium duration non-depolarising with tachycardia side effects

Question 24

atracurium

Answer 24

medium onset with medium duration, non-depolarising with hypotension/bronchospasm side effects

Question 25

mivacurium

Answer 25

fast onset with short duration, non-depolarising with hypotension/bronchospasm side effects

Question 26

neostigmine and pyridostigmine

Answer 26

medium duration, anticholinesterase, formation of carbamylated enzyme complex

Question 27

dyflos and marathon

Answer 27

long onset and act by irreversible inhibition

Question 28

what slows the rate of hydrolysis

Answer 28

carbamylation

Question 29

phosphorylation by dyflos/parathion irreversibly changes the enzyme unless

Answer 29

coaxed out by pralidoxime so there can be synthesis of a new enzyme

Question 30

Effects of anticholinesterases on the CNS

Answer 30

Initial excitation with convulsions | unconsciousness and respiratory failure

Question 31

Effects of anticholinesterases on the ANS

Answer 31

``` SLUDGE SALIVATION LACRIMATION URINATION DEFACATION GASTROINTESTINAL UPSET EMESIS (vomit) ```

Question 32

what are the clinical uses of anticholinesterases

Answer 32

In anaesthesia – Reverse non-depolarising muscle blockade – Given with atropine or glycopyrrolate to counteract parasympathetic effects Myasthenia Gravis – Increase neuromuscular transmission Glaucoma – Decrease intraocular pressure Alzheimer’s disease – Enhance the cholinergic transmission in the CNS

Question 33

Myasthenia gravis

Answer 33

autoantibodies may be produced against the acetylcholine receptor blocking the interaction of the acetylcholine receptor with its ligand (acetylcholine) and leading to increased muscle weakness and death.

Question 34

Sugammadex

Answer 34

Selective relaxant binding agent (SRBA) | • Reverses effects of rocuronium and vecuronium