Pharmacology of the Neuromuscular Junction

Question 1

Briefly describe what happens at the NMJ (refer to ACh)

Answer 1

ACh is created and packaged into vesicles, so that when we have excitation of that motor neuron, that stimulates the release of the vesicle.

ACh is released and acts on the post-synaptic nicotinic receptor.

This action is degraded rapidly by the presence of acetylcholine esterase enzymes.

Question 2

State 3 ways to block the neuromuscular junction

Answer 2

Presynaptically by INHIBITING ACh synthesis

Presynaptically by INHIBITING ACh release

Postsynaptically by interfering with the actions of ACh on the receptor

Question 3

State ways of achieving presynaptic blockade

Answer 3

By inhibiting ACh release :

• Local anaesthetics
• General inhalational anaesthetics
• Inhibitors/competitors of calcium
• Neurotoxins

Question 4

How do local anaesthetics work ?

Answer 4

They bind and block the voltage gated sodium channels.

Question 5

State some inhibitors of calcium release

Answer 5

Antibiotics :

• Aminoglycosides (e.g. gentamicin)
• Tetracycline

Question 6

State a competitor of calcium

Answer 6

Magnesium ions

Question 7

Name some neurotoxins

Answer 7

Boutilin toxin
Beta-Bungarotoxin

Question 8

Boutilin toxin cause

Answer 8

clostridium botulinum

Question 9

Uses of botox

Answer 9

Prevents muscle spasticity
Cosmetic reasons
Prevents hyperhydrosis (sweating)

Question 10

How does botox work ?

Answer 10

Prevents the release of ACh, but also influences other neurons, not specific to inhibit the control of muscle.

Question 11

State ways of achieving postsynaptic blockade

Answer 11

Endotracheal intubation
During surgical procedures
Infrequently in intensive care
During electroconvulsive therapy

Question 12

Why are neuromuscular blocking drugs used during surgical procedures ?

Answer 12

To allow access to abdominal cavity

To ensure immobility

To allow relaxation to reduce displaced fracture or dislocation

Question 13

Advantage of using neuromuscular blocking drugs during surgical procedures

Answer 13

Lowers the concentration of general anaesthetic needed

Question 14

Describe the structure of the nicotinic acetylcholine receptor

Answer 14

Alpha2Beta1Gamma1Delta1
Has 2 ACh gates

The ACh gates require the binding of 2 molecules of ACh to the receptor to cause a conformational change that allows it to open.

Question 15

What are agonists ?

Answer 15

Things that open the channel and act as the endogenous ligand would on that system.

Question 16

What are antagonists ?

Answer 16

They block the action of ACh on the receptor, so they prevent ACh from opening the channel and having its effect.

Question 17

Name some nicotinic ACh receptor agonists

Answer 17

ACh
Nicotine
Suxamethonium

Question 18

Name some nicotinic ACh receptor antagonists

Answer 18

Tubocurarine
Atracurium

Question 19

What are non-depolarising blockers ?

Answer 19

They act as competitive antagonists of nicotinic ACh receptors at the NMJ.

Question 20

Name some non-depolarising blockers

Answer 20

Tubocurarine
Atracurium

Question 21

Describe the action of non-depolarising blockers

Answer 21

Prevents ACh binding to the receptor by occupying site

Decreases the motor end plate potential (EPP)

Decreases depolarisation of the motor end plate region

No activation of the muscle action potential

Question 22

What happens at the end-plate ?

Answer 22

The end plate is where you get the synapse between your motor neuron and the muscle fibre that’s controlling.

Question 23

What are depolarising blockers ?

Answer 23

They are agonists of nicotinic ACh receptors at the NMJ.

Question 24

Name a depolarising blocker

Answer 24

Suxamethonium

-> opens nicotinic ACh receptors

Question 25

Describe the action of suxamethonium

Answer 25

Suxamethonium will activate nicotinic acetylcholine receptors and open them. This allows sodium to come into the cell, which would cause an action potential. This results in contraction of the muscle. Initial contraction, relaxation and no further ability to cause contraction. (overstimulation of cell) Suxamethonium is not degraded as rapidly as ACh. It is only degraded by the acetylcholine esterase found in the patients plasma.

Question 26

Describe the action of depolarising blockers

Answer 26

Persistent depolarisation of the motor end plate Prolonged EPP Prolonged depolarisation of the muscle membrane Membrane potential above the threshold for resetting of voltage gated sodium channels. Sodium channels remain refractory No more muscle action potentials generated

Question 27

Describe phase 1 of the depolarising block

Answer 27

Muscle fasciculations observed, then blocked Repolarisation inhibited - K+ leaks from cells (hyperkalaemia) Voltage gated Na+ channels kept inactivated

Question 28

Describe phase 2 of the depolarising block

Answer 28

Occurs when prolonged/ increased exposure to drug "Desensitisation blockade" - Depolarisation cannot occur, even in absence of drug

Question 29

List the drugs that affect NMJ neurotransmission

Answer 29

Pancuronium Vecuronium Rocuronium Atacurium Mivacurium Suxamethonium

Question 30

Describe the drug : Pancuronium

Answer 30

Onset : Medium Duration : Long Main side effect(s) : Tachycardia

Question 31

Describe the drug : Vecuronium

Answer 31

Onset : Medium Duration : Medium Main side effect(s) : Few side effects

Question 32

Describe the drug : Rocuronium

Answer 32

Onset : Fast Duration : Medium Main side effect(s) :Tachycardia

Question 33

Describe the drug : Atacurium

Answer 33

Onset : Medium Duration : Medium Main side effect(s) : Hypotension / Bronchospasm

Question 34

Describe the drug : Mivacurium

Answer 34

Onset : Fast Duration : Short Main side effect(s) : Hypotension / Bronchospasm

Question 35

Describe the drug : Suxamethonium

Answer 35

Onset : Fast Duration : Short Main side effect(s) : - Bradycardia - Cardiac dysrhythmias - Malignant hypothermia etc.

Question 36

Describe the action of atracurium

Answer 36

Atracurium undergoes ester hydrolysis and Hofmann elimination

Question 37

Describe the action of mivacurium and suxamethonium

Answer 37

These drugs are metabolised by plasma cholinesterases This breaks down ACh which is present in plasma.

Question 38

Describe the action of pancuronium and vecuronium

Answer 38

These drugs undergo hepatic metabolism and are dependent on liver function.

Question 39

Describe the action of rocuronium

Answer 39

Unchanged in bile/urine

Question 40

State ways to reverse neuromuscular blockade

Answer 40

Cholinesterases : the duration of action of ACh is regulated by hydrolysis

Question 41

Describe acetylcholinesterase

Answer 41

True cholinesterase, specific for hydrolysis of ACh Present in conducting tissue and red blood cells Bound to the basement membrane in the synaptic cleft

Question 42

Describe plasma cholinesterase

Answer 42

Pseudocholinesterase, broad spectrum of substrates Widespread distribution Soluble in plasma

Question 43

Describe how cholinesterases act

Answer 43

If you inhibit the activity of acetylcholinesterase, in the synaptic region, the concentration of ACh present in the synaptic region increases. As the concentration of ACh released increases, this increases the amount able to bind to the nicotinic receptors. Restoration of transmission

Question 44

What are anti-cholinesterase drugs ?

Answer 44

They are all inhibitors of cholinesterase enzymes.

Question 45

How do anti cholinesterase drugs act ?

Answer 45

They increase the availability of ACh @ the NMJ by decreasing degradation. This increases the duration of activity of ACh @ NMJ More ACh to compete with non-depolarising blockers

Question 46

Name some anti cholinesterase drugs

Answer 46

Neostigimine Pyridostigmine

Question 47

Function of carbamylation

Answer 47

Slows the rate of hydrolysis

Question 48

Describe some effects of anticholinesterases on the CNS

Answer 48

Initial excitation with convulsions Unconsciousness and respiratory failure

Question 49

Describe some effects of anticholinesterases on the ANS

Answer 49

Salivation Lacrimation Urination Defecation Gastrointestinal upset Emesis Bradycardia Hypotension Bronchoconstriction Pupillary constriction

Question 50

State some clinical uses of anticholinesterases

Answer 50

In anaesthesia Myasthenia Gravis Glaucoma Alzheimer's disease

Question 51

How do anticholinesterases work in anaesthesia ?

Answer 51

Reverse non-depolarising muscle blockade Given with atropine or glycopyrrolate to counteract parasympathetic effects

Question 52

How do anticholinesterases work in myasthenia gravis ?

Answer 52

Increase neuromuscular transmission

Question 53

How do anticholinesterases work in glaucoma ?

Answer 53

Decrease intraocular pressure

Question 54

How do anticholinesterases work in Alzheimer's disease ?

Answer 54

Enhances the cholinergic transmission in the CNS

Question 55

Myasthenia Gravis

Answer 55

Autoantibodies may be produced against the acetylcholine receptor, blocking the interaction of the acetylcholine receptor with its ligand. This leads to increased muscle stiffness and weakness.