Drugs acting on the Neuromuscular Junction

Question 1

Name the three ways to block neuromuscular transmissions

Answer 1

• Presynaptically by inhibiting ACh synthesis
• Presynaptically by inhibiting ACh release
• Postsynaptically (interfering with the actions of ACh on the receptor)

Question 2

Name some of the ways you can inhibit ACh release

Answer 2

Local Anaesthetics - Blocks propagation of an action potential
General inhalation anaesthetics
Magnesium - It competes for calcium but when inside the cell it won’t trigger the release of NTs
Some antibiotics - Aminoglycosides and tetracyclins (as these bind to calcium)
Neurotoxins - e.g. Botulinum toxin

Question 3

Name some of the clinical uses of neuromuscular blocking drugs

Answer 3

• Endotracheal intubation
• During surgical procedures ( to allow for surgical access to abdominal cavity, to ensure immobility, allow for relaxation to reduce displaced fracture/dislocation and to decrease the concentration of general anaesthetics needed)
• Infrequently in intensive care (for mechanical ventilation)
• During electroconvulsive therapy

Question 4

What does an antagonist and agonist do to the nicotinic acetylcholine receptor?

Answer 4

Antagonist - occupies the channel but does not induce the conformational change
Agonist - Binds to the receptor and causes the conformational change

Question 5

Describe how non-depolarising blockers work (competitive antagonists)

Answer 5

Prevents ACh from binding by occupying the site. Decreases the motor end plate potential (EPP). Decreases depolarisation of the motor end plate region. So no activation of the muscle action potential.

Question 6

Describe how depolarising drugs work

Answer 6

Persistent depolarisation of the motor end plate (because ACh receptor kept open) leading to prolonged EPP. Prolonged depolarisation of the muscle membrane. The membrane potential remains above the threshold for the resetting of the voltage-gated sodium channels. Sodium channels remain refractory and so no more muscle action potentials are generated

Question 7

Depolarisation block can occur in two phases; Describe these two phases

Answer 7

Phase 1 - Muscular fasciculations observes then blocked. Repolarisation is blocked. Potassium leaks from cells leading to hyperkalemia and voltage-gated sodium channels kept inactive.
Phase 2 - Prolonged or increased exposure to the drug leads to ‘desensitisation blockade’ which is where depolarisation cannot occur even when the drug is absent

Question 8

Name some of the non-depolarising blocking drugs

Answer 8

Pancuronium
Vecuronium
Rocuronium

Atracurium
Mivacurium

Question 9

Describe the onset, duration and side effects of pancuronium

Answer 9

Onset - Medium
Duration - Long
Side effects Tachycardia

Question 10

Describe the onset, duration and side effects of Vecuronium

Answer 10

Onset - medium
Duration - medium
Side effects - very few

Question 11

Describe the onset, duration and side effects of Rocuronium

Answer 11

Onset - Fast
Duration - Medium
Side effects tachycardia

Question 12

Describe the onset, duration and side effects of Atracurium

Answer 12

Onset - Medium
Duration - Medium
Side effects - Hypotension and bronchospasm

Question 13

Describe the onset, duration and side effects of Mivacurium

Answer 13

Onset - fast
Duration - Short
Side effects - Hypotension and bronchospasm

Question 14

Describe the onset, duration and side effects of Suxamethonium

Answer 14

Onset - Fast
Duration - Short
Side Effects- Bradycardia, Cardiac disrhythmias, Raised intraocular pressure, postoperative myalgia (flu like feelings of muscle aches) and Malignant Hypothermia

Question 15

How is Atracurium metabolised?

Answer 15

Ester hydrolysis and hofmann elimination

Question 16

How are mivacurium and suxamethonium metabolised? and what can be an issue with this metabolism?

Answer 16

Via plasma cholinesterases. However genetic variation in the population means that there can be a prolonged block meaning it takes some people longer to metabolise the drug

Question 17

How are pancuronium and Vecuronium metabolised?

Answer 17

Via hepatic metabloism

Question 18

How is Rocuronium metabolised?

Answer 18

Its unchanged in bile and urine

Question 19

Name the two cholinesterases

Answer 19

Acetylcholinesterase and Plasma cholinesterase

Question 20

Describe some of the features of acetylcholinesterase

Answer 20

Specific for the hydrolysis of ACh.
Present in conducting tissue and red blood cells.
Bound to the basement membrane in the synaptic cleft

Question 21

Describe some of the features of plasma cholinesterase

Answer 21

Pseudocholinesterase.
Broad spectrum of substrates.
Widespread distribution.
Soluble in plasma.

Question 22

Describe the features of anticholinesterase drugs

Answer 22

They increase the availability and duration of ACh at the NMJ by decreasing degradation. It means there is more ACh to compete with non-depolarising blockers

Question 23

Name some of the anticholinesterase drugs

Answer 23

Most commonly used in clinical practice -Neostigmine and Pyridostigmine
Not used clinically - Dyflos and Parathion

Question 24

What is the duration and mechanism of neosigmine and pyridostigmine

Answer 24

Duration - medium

Action - Formation of carbamylated enzyme complex

Question 25

What is the duration and mechanism of action of Dyflos and Parathion

Answer 25

Duration - long

Action - irreversable inhibition

Question 26

What will prevent dyflos and parathion from dystroying the enzyme?

Answer 26

A drug called pralidoxime. It can ‘coax’ the drugs off the enzyme

Question 27

Name some of the effects of anticholinesterases on the CNS

Answer 27

• Initiate excitation with convulsions

- Unconsciousness and respiratory failure

Question 28

Name some of the effects of anticholinesterases on the autonomic NS

Answer 28

SLUDGE + PHBB (Puppy Had a Big Ball)
Salivation
Lacrimation (flow of tears)
Urination
Defecation (discharge of faeces from body)
GI upset
Emesis (vomiting)

Pupillary constriction
Hypotension
Bradycardia
Bronchoconstriction

Question 29

Name some of the clinical uses of anticholinesterases

Answer 29

In anaesthesia - To reverse non-depolarising muscle blockade however it is given atropine or glycopyrrolate to counteract the parasympathetic effects
Myasthenia Gravis - increase neuromuscular transmission
Glaucome - Decrease intraocular pressure
Alzheimer’s disease - enhance the cholinergic transmission in the CNS

Question 30

What class of drug is Sugammadex and what does it do?

Answer 30

Class - Selective Relaxant Binding Agent (SRBA)

Does - reverses the effects of rocuronium and vecuronium by engulfing them