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Semester 2 Year 1 > Pharmacology of the Neuromuscular Junction > Flashcards

Pharmacology of the Neuromuscular Junction Flashcards

1
Q

What are the 3 ways to block neuromuscular transmission?

A

Presynaptically, by inhibiting ACh synthesis

Presynaptically, by inhibiting ACh release

Postsynaptically by interfering with the actions of ACh on the receptor

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2
Q

When blocking neuromuscular transmission presynaptically by inhibiting ACh synthesis, what is the rate limiting step?

A

Choline uptake

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3
Q

What TYPES of substances may inhibit ACh release?

A

Local anaesthetics
General inhalational anaesthetics
Inhibitors/competitors of calcium
Neurotoxins

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4
Q

What inhibitors/competitors of calcium can inhibit ACh release?

A

– Magnesium ions
– Some antibiotics
—-• Aminoglycosides (e.g. gentamicin)
—-• Tetracycline

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5
Q

What neurotoxins may inhibit ACh release?

A

– Botulinum toxin (clostridium botulinum)

– β-Bungarotoxin (Taiwanese banded krait)

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6
Q

What is botulinum toxin (clostridium botulinum) more commonly known as?

A

Botox

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7
Q

What can botox be used to treat?

A
  • Muscle spasticity (overactive muscles)
  • Hyperhydrosis (lotsa sweat)
  • Is used cosmetically
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8
Q

What are some clinical uses of neuromuscular- blocking drugs?

A

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

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9
Q

During surgical procedures when may neuromuscular- blocking drugs be used?

A

– To allow surgical access to abdominal cavity
– To ensure immobility
—-• (e.g.prevent cough during head and neck surgery)
– Allow relaxation to reduce displaced fracture or dislocation
– ↓ concentration of general anaesthetic needed

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10
Q

When may neuromuscular- blocking drugs be used in intensive care?

A

– In mechanical ventilation at extremes of hypoxia

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11
Q

What is the structure of the nicotinic acetylcholine receptor?

A

It is made of five subunits: a beta, a delta, a gamma and two alpha. The delta is replaced with an epsilon in the adult form
Forming the gate of the pore are alpha-helices

Like any ligand gated ion channels opening of the nAChR channel pore requires the binding of a chemical messenger

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12
Q

What are the effects of an agonist on the nicotonic ACh Receptor and provide two examples?

A
  • They cause the channel to open

- nicotine, suxamethonium

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13
Q

What are the effects of an antagonist on the nicotonic ACh Receptor and provide two examples?

A
  • They keep the channel closed

- tubocurarine, atracurium

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14
Q

What are non-depolarising blockers of the nicotinic ACh receptors?

A

Competitive antagonists of Nicotinic ACh receptors at the NMJ.
e.g. tubocurarine, atracurium

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15
Q

What do non-depolarising blockers of the nicotinic ACh receptor do?

A

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 action potential

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16
Q

What are depolarising blockers of the nicotinic ACh receptors?

A

Agonists of Nicotinic ACh receptors at the NMJ

e.g. suxamethonium

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17
Q

What is the difference between a depolarising blocker and acetylcholine in regards to their binding to nicotinic ACh receptors?

A

Depolarising blockers are not metabolised by Acetylcholine esterase

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18
Q

What do depolarising blockers do?

A

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

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19
Q

In how many phases may a depolarising block occur?

A

Two

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20
Q

What are the two phases of a depolarising block?

A

Phase 1
– Muscle fasciculations observed, then blocked
– Repolarisation inhibited
• K+ leaks from cells (hyperkalemia)
– Voltage-gated Na+ channels kept inactivated

Phase 2
– Prolonged / increased exposure to drug
– “Desensitisation blockade”
• Depolarisation cannot occur, even in absence of drug

21
Q

How does the body eliminate/metabolise atracurium?

A

(Non-depolarising blocker - muscle relaxant)

Ester hydrolysis and Hofmann elimination

22
Q

How does the body eliminate/metabolise mivacurium?

A

(Non-depolarising blocker - muscle relaxant)

Plasma cholinesterases

23
Q

How does the body eliminate/metabolise suxamethonium?

A

(depolarising blocker - muscular relaxant)

Plasma cholinesterases

24
Q

How does the body eliminate/metabolise pancuronium?

A

(depolarising blocker - aminosteroid muscle relaxant)

Hepatic metabolism

25
Q

How does the body eliminate/metabolise vercuronium?

A

(depolarising blocker - aminosteroid muscle relaxant)

Hepatic metabolism

26
Q

How does the body eliminate/metabolise rocuronium?

A

(depolarising blocker - aminosteroid muscle relaxant)

It doesn’t really, - unchanged in bile/urine

27
Q

What is the duration of action of ACh regulated by?

A

Hydrolysis

28
Q

What enzymes hydrolyse ACh?

A

Acetylcholinesterase (ACh.E)

Plasma cholinesterase

29
Q

How does acetylcholinesterase (ACh.E) act on ACh and where is it found?

A

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

30
Q

How does plasma cholinesterase act on ACh and where is it found?

A

– Pseudocholinesterase, broad spectrum of substrates
– Widespread distribution
– Soluble in plasma

31
Q

What are anticholinesterase drugs?

A

inhibitors of cholinesterase enzymes

32
Q

What is the effect of anticholinesterase drugs?

A

As they inhibit cholinesterase enzymes, they therefore increase availability of ACh at NMJ by decreasing ACh degradation
So
– Increases duration of activity of ACh at NMJ
– More ACh to compete with non-depolarising blockers

33
Q

Spit some anticholinesterase drugs dog 😎

A

(quartenary amines - med duration)
Neostigmine Pyridostigmine

(organophosphates - long duration)
Dyflos
Parathion

34
Q

Describe the action of anticholinesterase drugs

A

Carbamylation slows rate of hydrolysis
Phosphorylation by dyflos/parathion is highly stable
– Recovery depends on synthesis of new enzyme
– Can be ‘coaxed’ off by pralidoxime

35
Q

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

A

– Initial excitation with convulsions

– Unconsciousness and respiratory failure

36
Q

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

A

SLUDGE, Hi BP!

– Salivation
– Lacrimation
– Urination
– Defecation
– Gastrointestinal upset 
– Emesis (vomiting)
– Bradycardia (Brachy=low)
– Hypotension
– Bronchoconstriction
– Pupillary constriction (miosis)
37
Q

What are the clinical uses of anticholinesterase?

A

In anaesthesia
For Myasthenia Gravis
For Glaucoma
For Alzheimer’s disease

38
Q

How may anticholinesterases be used in anaesthesia?

A

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

39
Q

How may anticholinesterases be used in myasthenia gravis?

A

– Increase neuromuscular transmission

40
Q

How may anticholinesterases be used in glaucoma?

A

– Decrease intraocular pressure

41
Q

How may anticholinesterases be used in Alzheimer’s disease?

A

– Enhance the cholinergic transmission in the CNS

42
Q

What is myasthenia gravis?

A

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.

43
Q

What is sugammadex

A

Selective relaxant binding agent (SRBA)
• Reverses effects of rocuronium and vecuronium
A potential origin for the sugandese?

44
Q

How many binding sites for acetylcholine do nicotinic acetylcholine receptors have?

A

2

45
Q

How wide is the pore of nicotinic acetylcholine receptors?

A

~0.7nm

46
Q

What enzyme normally degrades Acetylcholine?

A

Acetylcholine esterase

47
Q

What is Hofmann elimination?

A

Pretty much spontaneous elimination of a drug in the plasma

48
Q

Sludge?

A 
Salivation
Lacrimation
Urination
Defecation
Gastrointestinal upset
Emesis 
All effects of anticholinesterases

Semester 2 Year 1 (82 decks)

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