DRUGS AFFECTING NMJ TRANSMISSION

Question 1

How can we block NMJ transmission?

Answer 1

Inhibit ACh (choline uptake) presynaptically
Inhibit ACh release presynaptically
Interfere with AChR postsynaptically

Question 2

What types of things can block nmj and what is their mechanism of action?

Answer 2

Anticholinesterases - affect AChE and affect choline reuptake presynaptically

Toxins/local anaesthetics which block ACh release

Depolarising and non-depolarising blockers which affect the postsynaptic ACh receptor

Question 3

Examples of inhibitors of ACh release

Answer 3

Local anaesthetic
General inhalation anaesthetics
Inhibitors/competitors of calcium such as magnesium and antibiotics (aminoglycosides gentamicin and tetracycline)
Neurotoxins such as botulinum and beta-bungarotoxin

Question 4

What are ACh release inhibitors used for

Answer 4

Endotrachael intubation
Surgical procedures as lessens concern of general anaesthetic needed
Allow mechanical ventilation in intensive care
Electroconvulsive therapy

Question 5

What types of ACh receptors are there

Answer 5

Muscarinic ACh

Nicotinic ACh

Question 6

What kind of receptor is muscarinic and what types are there?

Answer 6

G protein coupled
M1,3,5 excitatory
M2,4 inhibitory

Question 7

What kind of nicotinic receptors are there and what type of receptor are they

Answer 7

Ligand gated ion channels
N1 in MNJ
N2 in autonomic / parasympathetic nervous system

Excitatory only

Question 8

Where are muscarinic receptors not found

Answer 8

Sympathetic nervous system

Question 9

Where else are nicotinic ACh receptors found

Answer 9

Skeletal NMJ
Sympathetic and parasympathetic
Autonomic ganglia
CNS

Question 10

How do acetylcholine receptors work? What is their structure?

Answer 10

Chemically controlled sodium channel that opens when ACh binds- causes depolarisation

alpha, ACh, y, alpha, ACh, delta, beta

Question 11

Agonists of the AChR

Answer 11

Nicotine
Suxamethonium
Decamethonium

These are depolarising blockers

Question 12

Antagonists of the AChR

Answer 12

Tubocurarine
Atracurium

These are non-depolarising blockers

Question 13

How do antagonists/non-depolarising blockers work

Answer 13

Work by preventing ACh binding to site
Decrease motor EEP
Decrease depolarisation level of end plate
No activation of action potential

Question 14

How do agonists/depolarising blockers work

Answer 14

Attach to AChR and not metabolised by AChE

Long depolarisation of end plate
Prolonged EEP
Prolonged depolarisation of muscle membrane
Membrane pot above threshold for testing voltages gated sodium channels so channels remain refractory
No more action potential generated

Question 15

Non-depolarising blockers

Answer 15

Mivacurium 
Atracurium
Rocuronium
Vecuronium
Pancuronium

Question 16

Side effects of depolarising blocker suxamethonium and how are they caused

Answer 16

Bradycardia (muscarinic agonist effect)

Cardiac dysrhythmias inc k+ conc

Raised interoccular pressure (nicotinic agonist effect)

Postop myalgia (muscle fasciculations)

Malignant hypothermia (ryanodine receptor related)

Question 17

Examples of anticholinesterase drugs?

Answer 17

Neostigmine
Pyridostigmine
Dyflos
Parathion

Question 18

How do anticholinesterase drugs work

Answer 18

Inc availability of ACh by Dec segregation by AChE

Question 19

What are neostigmine and pyridostigmine and how do they work

Answer 19

Quaternary amines

Work by forming carbamylated enzyme complex which slows rate of hydrolysis

Question 20

What are dyflos and parathion and how do they work

Answer 20

Organophosphate anticholinesterase drugs
Work by irreversible inhibition by phosphorylation into highly stable complex

Can be coaxed off by pralidoxime

Question 21

What is pralidoxime and what is its function

Answer 21

Coaxes irreversible inhibiting anticholinesterase drugs dyflos and parathion from AChE

Question 22

Duration of cholinesterase degraded drugs are regulated by

Answer 22

Hydrolysis

Question 23

AChE vs. Plasma cholinesterases

Answer 23

AChE specific to hydrolysis of ACh
Found in conducting tissues and RBCs
Bound to plasma membrane in synaptic cleft

Broad spectrum of substrates wth widespread distribution and soluble in plasma

Question 24

Side effects of anticholinesterases

Answer 24

CNS
initial excitation with convulsions
Unconscious and respiratory failure

Autonomic nervous system
Salivation
Lacrimation
Urination
Defication
Gastrointestinal upset
Emesis 

Bradycardia
Hypotension
Bronchoconstruction
Construction Miosis of pupil

Question 25

Clinical use of anticholinesterases

Answer 25

Anaesthesia - to reverse non-polarising muscle blockade

Myasthenia gravis- inc NMJ transmission

Glaucoma - Dec interocc pressure

Alzheimer’s - enhance cholinergic transmission in CNS

Question 26

What are the 2 phases of depolarising blockers

Answer 26

Phase 1

Muscular fasciculations then blockage
Depolarisation inhibited causes K+ leak from cell causing hyperkalaemia
Voltage gated sodium channels kept inactive

Phase 2

Prolonged exposure increased exposure to drug causes desensitisation blockade where depolarisation cannot occur even in absence of drug

Question 27

What are SRBAs and what do they do?

Answer 27

SRBA are selective relaxant binding agents

Sugammadex

Reverses effect of rocuronium and vecuronium (nondepolarising)