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Pharmacology > Drugs Acting on the Neuromuscular Junction > Flashcards

Drugs Acting on the Neuromuscular Junction Flashcards

1
Q

List the 3 ways of blocking neuromuscular transmission.

A
  • Presynaptically, by inhibiting ACh synthesis.
    • Rate limiting step is choline uptake - blocking of the choline transporter stops it from being taken up by the cell.
  • Presynaptically, by inhibiting ACh release.
  • Postsynaptically, by interfering with the actions of ACh on the receptor.
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2
Q

List substances which can inhibit ACh release.

A
  • Local anaesthetics
  • General inhalational anaesthetics
  • Inhibitors / competitors of calcium
    • Magnesium ions
    • Some antibiotics
      • Aminoglycosides (e.g. gentamicin)
      • Tetracycline
  • Neurotoxins
    • Botulinum toxin
    • β-bungarotoxin
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3
Q

How do local anaesthetics work to inhibit ACh release?

A

They block voltage-gated sodium channels.

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4
Q

What are the clinical uses of neuromuscular blocking agents?

A
  • Endotracheal intubation
  • During surgical procedures
    • To allow surgical access to abdominal cavity.
    • To ensure immobility
      • E.g. to prevent cough during head and neck surgery.
    • Allow relaxation to reduce displaced fracture dislocation.
    • To decrease the concentration of general anaesthetic needed.
  • Infrequently in intensive care
    • Mechanical ventilation at extremes of hypoxia
  • During ECT
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5
Q

Give examples of nicotinic ACh receptor agonists.

A
  • Nicotine
  • Suxamethonium - depolarising blocker of the NMJ.
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6
Q

Give examples of nicotinic ACh receptor antagonists.

A
  • Tubocurarine
  • Atracurium - non-depolarising blocker of the NMJ. It does not cause a conformational change.
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7
Q

Describe the action of non-depolarising blockers (competative antagonists of nicotinic ACh receptors at the NMJ).

For example: tubocurarine or atracurium.

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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8
Q

Describe the action of depolarising blockers (agonists of nicotinic ACh receptors at the NMJ).

For example: suxamethonium.

A
  • Persistent depolarisation of the motor end plate.
  • Prolonged EPP.
  • 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 are generated.
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9
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 are kept inactivated
  • Phase 2
    • Prolonged / increased exposure to drug
    • ‘Desensitisation blockade’
      • Depolarisation cannot occur, even in the absence of the drug.
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10
Q

Give 3 examples of aminosteroidal non-depolarising neuromuscular blockers.

A
  • Pancuronium
  • Vecuronium
  • Rocuronium
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11
Q

Give 2 examples of benzylisoquiolinium non-depolarising neuromuscular blockers.

A
  • Atracurium
  • Mivacurium
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12
Q

What is the primary depolarising neuromuscular blocker?

A

Suxamethonium

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13
Q

What are the properties of pancuronium?

A
  • Onset - medium
  • Duration - long
  • Side effects - tachycardia
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14
Q

What are the properties of vecuronium?

A
  • Onset - medium
  • Duration - medium
  • Few side effects
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15
Q

What are the properties of rocuronium?

A
  • Onset - fast
  • Duration - medium
  • Side effects - tachycardia
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16
Q

What are the properties of atracurium?

A
  • Onset - medium
  • Duration - medium
  • Side effects - hypotension / bronchospasm
    • (Histamine release)
17
Q

What are the properties of mivacurium?

A
  • Onset - fast
  • Duration - short
  • Side effects - hypotension / bronchospasm
    • (Histamine release)
18
Q

What are the properties of suxamethonium?

A
  • Onset - fast
  • Duration - short
  • Side effects:
    • 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)
19
Q

Which neuromuscular blockers are metabolised and eliminated by ester hydrolysis and Hofmann elimination?

A

Atracurium

20
Q

Which neuromuscular blockers are metabolised and eliminated by plasma cholinesterases?

A
  • Mivacurium
  • Suxamethonium

NB - Plasma cholinesterase defficiency means that it is not so able to break down suxamethonium causing a very long prolonged block.

21
Q

Which neuromuscular blockers are metabolised and eliminated by hepatic metabolism?

A
  • Pancuronium
  • Vecuronium
22
Q

Which neuromuscular blocker is unchanged in bile / urine?

A

Rocuronium

23
Q

What regulates the duration of the action of ACh?

A

Hydrolysis

24
Q

Describe the properties of acetylcholinesterase (ACh.E).

A
  • True cholinesterase, specific for hydrolysis of ACh.
  • Present in conducting tissue and RBCs.
  • Bound to basement membrane in the synaptic cleft.

NB - acetylcholinesterase can be used in myesthenia gravis (autoimmune disease) which (basically) blocks ACh. So anticholinesterases prevent the degradation of ACh so can restore transmission.

25
Q

Describe the properties of plasma cholinesterase.

A
  • Pseudocholinesterase, broad spectrum of substrates
  • Widespread distribution
  • Soluble in plasma
26
Q

What are the properties of anticholinesterase drugs?

A
  • Are all inhibitors of cholinesterase enzymes
    • Therefore, there is an increased availability of ACh at the NMJ by decreased degradation.
    • Increases duration of activity of ACh at NMJ.
    • More ACh to compete with non-depolarising blockers.
27
Q

Give 2 examples of anticholinesterase drugs which are quaternary amines.

A
  • Neostigmine
  • Pyridostigmine
28
Q

Give 2 examples of anticholinesterase drugs which are organophosphates.

A
  • Dyflos
  • Parathion
29
Q

What are the properties of neostigmine?

A
  • Duration - medium
  • Mechanism of action - formation of carbamylated enzyme complex.
30
Q

What are the properties of pyridostigmine?

A
  • Duration - medium
  • Mechanism of action - formation of carbamylated enzyme complex
31
Q

What are the properties of dyflos?

A
  • Duration - long
  • Mechanism of action - irreversible inhibition
32
Q

What are the properties of parathion?

A
  • Duration - long
  • Mechanism of action - irreversible inhibition
33
Q

What is the effect of carbamylation?

A

Slow the rate of hydrolysis

34
Q

Describe phosphorylation by dyflos / parathion.

A
  • 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 CNS?

A
  • Initial excitation with convulsions
  • Unconsciousness and respiratory failure
36
Q

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

A
  • Salivation
  • Lacrimation
  • Urination
  • Defacation
  • Gastrointestinal upset
  • Emesis
  • Bradycardia
  • Hypotension
  • Bronchoconstriction
  • Pupillary constriction
37
Q

What are the clinical uses of anticholinesterases?

A
  • In anaesthesia
    • ​Reverse non-depolarising muscle blockade
    • Given with atropine or glycopyrrolate to counteract parasympathetic effects
  • Myasthenia gravis
    • ​Increase neuromuscular transmission
  • Glaucoma
    • ​Decrease intraoccular pressure
  • Alzheimer’s disease
    • ​Enhance the cholinergic transmission in the CNS
38
Q

What is sugammadex?

A
  • Selective relaxant binding agent (SRBA)
  • Reverses the effects of rocuronium and vecuronium

Pharmacology (7 decks)

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