Pharmacology of the Neuromuscular Junction

Question 1

What are the 3 ways to block neuromuscular transmission?

Answer 1

+ Presynaptically, by inhibiting ACh synthesis (rate-limiting step in choline uptake)

+ Presynaptically, by inhibiting Ach release

+ Postsynaptically (by interfering with the actions of ACh on the receptor)

Question 2

What can inhibit ACh release?

Answer 2

+ Local anaesthetics
+ General inhalation anaesthetics
+ Inhibitors/competitors of calcium
+ Neurotoxins

Question 3

What are examples of inhibitors/competitors of calcium?

Answer 3

+ Magnesium ions

+ Some antibiotics

• aminoglycosides (gentamicin)
• tetracycline

Question 4

What are some examples of neurotoxins that inhibit ACh release presynaptically?

Answer 4

+ Botulinum toxin (clostridium botulinum)

+ β-Bungarotoxin (Taiwanese banded krait)

Question 5

What are some clinical uses of neuromuscular-blocking drugs?

Answer 5

+ Endotracheal intubation

+ During surgical procedures: ↓ concentration of general anaesthetic needed

+ In intensive care: during mechanical ventilation at extremes of hypoxia

+ During electroconvulsive therapy

Question 6

what are examples of nicotinic Ach receptor agonists?

Answer 6

+ nicotine

+ suxamethonium

Question 7

what are examples of nicotinic Ach receptor antagonists?

Answer 7

+ tubocurarine

+ atracurium

Question 8

what are non-depolarising blockers?

Answer 8

competitive ANTAGONISTS of nicotinic Ach receptors at the NMJ

Question 9

how do non-depolarising blockeres/competitive antagonists work?

Answer 9

1. prevent Ach binding to receptor by occupying site
2. decreases motor end plate potential (EPP)
3. decreases depolarisation of motor end plate region
4. no activation of the muscle action potential

Question 10

what are depolarising blockers?

Answer 10

AGONISTS of nicotinic Ach receptors at NMJ

- not metabolised by Ach esterase

Question 11

how do depolarising blockers/agonists work?

Answer 11

1. persistent depolarisation of motor end plate
2. prolonged EPP
3. prolonged depolarisation of muscle membrane
4. membrane potenial above the threshold for resetting of voltage-gated sodium channels
5. sodium channels remain refractory
6. no more muscle action potentials generated

Question 12

how many phases does a depolarising block occur in?

Answer 12

2 phases

Question 13

what is phase 1 of a depolarising block?

Answer 13

+ muscle fasciculations observed, then blocked

+ repolarisation inhibited
- K+ leaks from cells (hyperkalemia)

+ voltage-gated Na+ channels kept inactivated

Question 14

what is phase 2 of a depolarising block?

Answer 14

+ prolonged/increased exposure to drug

+ “desensitisation blockade”
- depolarisation cannot occur, even in absence of drug

Question 15

which neuromuscular blocking drug is unchanged in bile/urine?

Answer 15

rocuronium

Question 16

which neuromuscular blocking drug is affected by hepatic metabolism?

Answer 16

• pancuronium

- vecuronium

Question 17

which neuromuscular blocking drug is affected by plasma cholinesterases?

Answer 17

• mivacurium

- suxamethonium

Question 18

which neuromuscular blocking drug is affected by ester hydrolysis and hofmann elimination?

Answer 18

atracurium

Question 19

what type of onset does suxamethonium have?

Answer 19

fast

Question 20

what type of duration does suxamethonium have?

Answer 20

short

Question 21

which neuromuscular blocking drugs have a medium onset?

Answer 21

• pancuronium
• vecuronium
• atracurium

Question 22

which neuromuscular blocking drugs have a fast onset?

Answer 22

• rocuronium
• mivacurium
• suxamethonium

Question 23

which neuromuscular blocking drugs have a long duration?

Answer 23

pancuronium

Question 24

which neuromuscular blocking drugs have a medium duration?

Answer 24

• vecuronium
• rocuronium
• atracurium

Question 25

which neuromuscular blocking drugs have a short duration?

Answer 25

- mivacurium | suxamethonium

Question 26

what are the main side effects of suxamethonium?

Answer 26

- bradycardia (muscarinic agonist effect) - cardiac dysrhymias (increased plasma K+ concentration) - raised intraocular pressure (nicotinic agonist effect) - postoperative myalgia (muscle fasciculations) - malignant hyperthermia (ryanodine receptor related)

Question 27

what are features of acetylcholinesterase (Ach.E)?

Answer 27

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

Question 28

what are features of plasma cholinesterase?

Answer 28

- pseudocholinesterase, broad spectrum of substrates - widespread distribution - soluble in plasma

Question 29

what is the main role of anticholinesterase drugs?

Answer 29

inhibit cholinesterase

Question 30

what is the effect of inhibiting cholinesterase enzymes?

Answer 30

- ↑ availability of ACh at NMJ by ↓ degradation - increases duration of activity of ACh at NMJ - more ACh to compete with non-depolarising blockers

Question 31

what are some anticholinesterase drugs?

Answer 31

- neostigmine - pyridostigmine - dyflos - parathion

Question 32

what is the mechanism of action employed by anticholinesterase drugs, neostigmine and pyridostigmine?

Answer 32

formation of carbamylated enzyme complex

Question 33

what is the mechanism of action employed by anticholinesterase drugs, dyflos and parathion?

Answer 33

irreversible inhibition (by phosphorylation)

Question 34

what is the effect of carbamylation?

Answer 34

slows rate of hydrolysis

Question 35

what are the effects of anticholinesterases on the central nervous system?

Answer 35

- initial excitation with convulsions | - unconscious and respiratory failure

Question 36

what are the effects of anticholinesterases on the autonomic nervous system?

Answer 36

- Salivation - Lacrimation - Urination - Defecation - Gastrointestinal upset - Emesis - Bradycardia - Bronchoconstriction - Hypotension - Pupillary constriction (miosis)

Question 37

what are some clinical uses of anticholinesterases?

Answer 37

- in anaesthesia - myasthenia gravis - glaucoma - alzheimer's disease

Question 38

what is the effect of anticholinesterases in anaesthesia?

Answer 38

- reverse non-depolarising muscle blockade | - given with atropine or glycopyrrolate to counteract parasympathetic effects

Question 39

what is the effect of anticholinesterases in myasthenia gravis?

Answer 39

increase neuromuscular transmission

Question 40

what is the effect of anticholinesterases in glaucoma?

Answer 40

decrease intraocular pressure

Question 41

what is the effect of anticholinesterases in alzheimer's disease?

Answer 41

enhance cholinergic transmission in CNS

Question 42

what is sugammadex?

Answer 42

selective relaxant binding agent (SRBA) | - reverses effects of rocuronium and vecuronium (very specific)