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MD2002 > Pharmacology of the Neuromuscular Junction > Flashcards

Pharmacology of the Neuromuscular Junction Flashcards

1
Q

What are the different ways in which to block neuromuscular transmission ?

A
  1. Presynaptically, by inhibiting ACh synthesis
    – Rate-limiting step is choline uptake
  2. Presynaptically, by inhibiting ACh release
  3. Postsynaptically
    – By interfering with the actions of ACh on the receptor (e.g. drugs acting as antagonists)
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2
Q

What are substances used to inhibit ACh release ?

A

LOCAL ANAESTHETICS

GENERAL INHALATIONAL ANAESTHETICS

INHIBITORS/COMPETITORS OF CALCIUM

NEUROTOXINS

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3
Q

What are examples of inhibitors/competitors of Calcium used to inhibit ACh release ?

A

Magnesium ions

Some antibiotics
• Aminoglycosides(e.g.gentamicin)
• Tetracycline

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4
Q

What are examples of neurotoxins, used to inhibit ACh release ?

A 
Botulinum toxin (clostridium botulinum) 
β-Bungarotoxin (Taiwanese banded krait)
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5
Q

What are some clinical situations which may involve use of neuromuscular- blocking drugs ?

A

Endotracheal intubation

During surgical procedures

Infrequently in intensive care

During electroconvulsive therapy

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6
Q

What may be the role of neuromuscular-blocking drugs during surgical procedures ?

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
– Allows ↓ concentration of general anaesthetic needed

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7
Q

What is a situation in intensive care in which neuromuscular-blocking drugs may be used ?

A

Mechanical ventilation at extremes of hypoxia

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8
Q

What is the structure of the nicotinic acetylcholine receptor ? How does this structure change upon ACh binding ?

A

2 receptor binding sites for ACh
Alpha helices forming gate

Upon ACh binding, conformational change to the gate, allow opening of gates and flooding in of ions)

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9
Q

What is the name of the receptor for ACh in muscles ?

A

Nicotinic Acetylcholine receptor

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10
Q

What are some agonists of the nicotinic acetylcholine receptor ? What is their effect on the receptor ?

A

Nicotine, suxamethonium

Causes receptor to open, resulting in depolarisation which will spread across the muscle

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11
Q

What are some antagonists of the nicotinic acetylcholine receptor ?

A

Tubocurarine, atracurium

Prevents receptor from opening (occupy binding site for ACh)

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12
Q

Are nicotinic receptors only found in the neuromuscular junction ? If not, are all nicotinic ACh receptors the same?

A

No

No, the type found in neuromuscular junction, has specific arrangement of subunits

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13
Q

What are non-depolarising blockers ? Give examples of non-depolarising blockers.

A

Competitive antagonists of Nicotinic ACh receptors at the NMJ.
E.g. Tubocurarine, atracurium

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14
Q

Explain the mechanism of non-depolarising blockers.

A
  1. Prevents ACh binding to receptor by occupying site
  2. Decreases the motor end plate potential (EPP)
  3. Decreases depolarisation of the motor end plate region 4. No activation of the muscle action potential
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15
Q

What are depolarising blockers ? Give examples of non-depolarising blockers.

A

Agonists of Nicotinic ACh receptors at the NMJ

E.g. Suxamethonium

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16
Q

What property of suxamethonium allows it to yield prolonged depolarisation of the muscle membrane ?

A

Because it it not metabolised by Acetylcholinesterase in plasma membrane of the synaptic cleft (only metabolised by plasma cholinesterase), so remains there and causes overstimulation

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17
Q

Explain the mechanism of depolarising blockers.

A
  1. Persistent depolarisation of the motor end plate
  2. Prolonged EPP
  3. Prolonged depolarisation of the muscle membrane
  4. Membrane potential above the threshold for the resetting of the voltage-gated sodium channels
  5. Sodium channels remain refractory
  6. No more muscle action potentials generated
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18
Q

What are the two phases of 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

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19
Q

What are the two main groups of neuromuscular blocking drugs ?

A

Depolarising and non-depolarising blockers

20
Q

What are the two main types of non-depolarising blockers ?

A

Aminosteroidal and Benzylisoquiolinium drugs

21
Q

List the names, onset, duration, and side effects of Aminosteroidal drugs.

A

PANCURONIUM: Medium onset / Long duration / Tachycardia

VECURONIUM: Medium onset / Medium duration / Few side effects

ROCURONIUM: Fast onset / Medium duration / Tachycardia

22
Q

List the names, onset, duration, and side effects of Benzylisoquiolinium drugs.

A

ATRACURIUM: Medium onset / Medium duration / Hypotension and bronchospasm (histamine release)

MIVACURIUM: Fast onset / short duration / Hypotension / bronchospasm (histamine release)

23
Q

List the name, onset, and duration of a depolarising blocker drug.

A

SUXAMETHONIUM: Fast onset / short duration

24
Q

What are the side effects of suxamethonium ?

A
  • Bradycardia (muscarinic agonist effect)
  • Cardiac dysrhythmias (increased plasma K+ concentration)
  • Raised intraocular pressure (nicotinic agonist effect)
  • Postoperative myalgia (muscle fasciculations)
  • Malignant hyperthermia (ryanodine receptor related)
25
Q

How are Suxamethonium, Veruconium, Mivacurium, Rocuronium, Atracurium, and Pancuronium metabolised/eliminated ?

A

ATRACURIUM:
Ester hydrolysis and Hofmann elimination

MIVACURIUM and SUXAMETHONIUM:
Plasma cholinesterases

PANCURONIUM and VERUCONIUM: 
Hepatic metabolism (liver and kidneys)

ROCURONIUM:
Unchanged in bile/urine

26
Q

Will the status of of plasma cholinesterase or liver and kidney function affect the duration of effect of Atracurium ? Why or why not ?

A

No, because it is unstable and will therefore be degraded rapidly (without need of plasma cholinesterases or liver/kidneys)

27
Q

Will the status of of plasma cholinesterase or liver and kidney function affect the duration of effect of mivacurium and suxamethonium ? Why or why not ?

A

The status of plasma cholinesterase will affect the duration of their effect. There exists two polymorphisms, one in which the blockage lasts 10 minutes rather than 2-3 minutes (in 4% of the population) and another polymorphism in which the blockage lasts hours (in 0.04% of the population).

28
Q

What is the main difference between mivacurium and suxamethonium, besides side effects and the fact that the first is non-depolarising whilst the second one is depolarising.

A

Suxamethonium will cause muscle fasciculations while mivacurium will not

29
Q

Will the status of of plasma cholinesterase or liver and kidney function affect the duration of effect of Pancuronium and Vecuronium ? Why or why not ?

A

The status of liver/kidney function will affect the duration of their effect. For instance in the case of liver failure or kidney disease, the blocker will not be metabolised so fast and the block will therefore last longer.

30
Q

What is the duration of action of ACh regulated by ?

A

Hydrolysis by ACh.E and plasma cholinesterase

31
Q

What are the main differences between acetylcholinesterases and plasma cholinesterases in terms of substrate, distribution, and location in the NMJ ?

A

Substrate: ACh.E is specific for hydrolysis of ACh whilst plasma cholinesterases have a broad spectrum of substrates

Distribution: ACh.E is present in conducting tissue and red blood cells whilst plasma cholinesterase is widespread

Location in NMJ: ACh.E is bound to basement membrane in the synaptic cleft, whilst plasma cholinesterase is soluble in plasma

32
Q

How do Anticholinesterase drugs work ?

A

Inhibit cholinesterase enzymes –> Increase availability of ACh at NMJ by ↓ degrada on –> Increases duration of activity of ACh at NMJ –> More ACh to compete with non-depolarising blockers

33
Q

What are the main 2 groups of Anticholinesterase drugs ?

A

Quaternary amines and organophosphates

34
Q

Give examples of quaternary amine anticholinesterase drugs, as well their duration and mechanism of action.

A

Neostigmine:

  • Medium duration
  • Formation of carbamylated enzyme complex

Pyridostigmine

  • Medium duration
  • Formation of carbamylated enzyme complex
35
Q

Give examples of organophosphate anticholinesterase drugs, as well their duration and mechanism of action.

A

Dyflos:

  • Long duration
  • Irreversible inhibition

Parathion:

  • Long
  • Irreversible inhibition
36
Q

How does carbamylation work ?

A

Neostigmine or Pyridostigmine bind to enzymatic site of cholinesterase and get carbamyl group onto esteratic site of achetylcholinesterase reversibly (so only slow down hydrolysis)

37
Q

How do Dyflos and Parathion irreversibly inhibit cholinesterases ?

A

Phosphorylate cholinesterases permanently (in esteratic site)

38
Q

What does recovery from irreversible inhibition of cholinesterases by Dyflos and Parathion depend on ?

A

Synthesis of new enzyme

39
Q

What substance may coax off Dyflos and Parathion from cholinesterase ?

A

Pralidoxime

40
Q

What are the effects of anticholinesterases on CNS ?

A

– Initial excitation with convulsions

– Unconsciousness and respiratory failure

41
Q

What are the effects of anticholinesterases on Autonomic nervous system ?

A 
SLUDGE
– Salivation
– Lacrimation
– Urination
– Defecation
– Gastrointestinal upset 
– Emesis

– Bradycardia
– Hypotension
– Bronchoconstriction
– Pupillary constriction (miosis)

42
Q

What are some clinical uses of anticholinesterases ?

A

Anaesthesia:
-reversing non-depolarising muscle blockade
-given with atropine or glycopyrrolate to counteract
parasympathetic effects

Myasthenia Gravis
-Increase neuromuscular transmission

Glaucoma
– Decrease intraocular pressure

Alzheimer’s disease
– Enhance the cholinergic transmission in the CNS

43
Q

What is sugammadex ? What is its role ?

A

Selective Relaxant Binding Agent (SRBA)

Reverses effect of rocuronium and vecuronium

44
Q

What is the advantage of sugammadex over inhibitors of cholinesterases ?

A

It does not have the side effects that they have

45
Q

What are the main groups of chemicals used to block neuromuscular transmission ? Give examples for each.

A
  1. Pre-synaptic toxins (Botulinum)
  2. Non-depolarising blocking agents (Tubocurarine)
  3. Depolarising blocking agentst (Suxamethonium)
  4. Anticholinesterases (Neostigmine)
46
Q

What is the width of the synpase at the neuromuscular junction ?

A

50 nm

MD2002 (77 decks)

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