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Semester 2 Pharmacology > Pharmacology of the Neuromuscular junction > Flashcards

Pharmacology of the Neuromuscular junction Flashcards

1
Q

What are the three ways in which a neuromuscular blocking drug can work?

A

1) PRESYNAPTICALLY: Inhibiting Acetylcholine synthesis by limiting choline uptake
2) PRESYNAPTICALLY: Inhibiting the release of acetylcholine
3) POSTSYNAPTICALLY: Interfering with the actions of acetylcholine on the receptor

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2
Q

How can you inhibit the release of acetylcholine?

A
  • Local anaesthetics
  • General inhalation anaesthetics: Interacts with the fluidity of the membrane and stops the flow of excitable transmission
  • Neurotoxins: Botulinum toxin or B-Bungarotoxin
  • Inhibitors or competitors of calcium e.g. magnesium ions, some antibiotics (Amino glycosides or Tetracycline)
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3
Q

What neurotoxins can be used to inhibit acetylcholine release (and how do they work)?

A
  • Botulinum toxin (Clostridium botulinum): acts on snare proteins
  • β-Bungarotoxin
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4
Q

What is the role of a snare protein?

A

They mediate vesicle fusion with the target membrane

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5
Q

Which antibiotics can be used to inhibit the release of acetylcholine and how?

A
  • Aminoglycosides e.g. gentamicin

* Tetracycline: binds to calcium so it cannot enter

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6
Q

Which ion can cause the inhibition of the release of acetylcholine and how?

A

Magnesium ions, competes with the influx of calcium and also doesn’t cause the release of vesicles

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7
Q

What are the clinical uses of neuromuscular blocking?

A

• Endotracheal intubation: Relax the airways so tube can be introduces
• During surgical procedures:
- Surgical access to the abdominal cavity
- Ensure immobility e.g. preventing a cough during head + neck surgery
- Allow relaxation to reduce displaced fracture or dislocation
• Means a lower concentration of general anaesthetic can be used
• In intensive care (infrequently) in mechanical ventilation at extremes of hypoxia
• During electroconvulsive therapy (as it can cause seizures which could lead to damage e.g. biting of tongue)

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8
Q

Describe the structure of the acetylcholine receptor

A
  • 0.7nm in diameter
  • 5 subunits with 2 binding sites for acetylcholine (2α, 1β, 1δ, 1γ)
  • Opens when two molecules of acetylcholine have bound
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9
Q

What happens when there are 2 molecules of acetylcholine bound to the acetylcholine receptor?

A
  • The pore opens
  • Influx of sodium
  • Leakage of potassium
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10
Q

What forms the gate of the acetylcholine receptor?

A

• Alpha helices

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11
Q

What is an agonist?

A

Anything that binds to a receptor and causes a change

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12
Q

What is an antagonist?

A

Anything that binds to a receptor but does not cause a change

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13
Q

What are two agonists of the nicotinic acetylcholine receptor?

A
  • Nicotine

* Suxamethonium

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14
Q

What are the antagonists of the nicotinic acetylcholine receptor?

A
  • Tubocuraine

* Atracurium

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15
Q

Where are the nicotinic acetylcholine receptors found in the body?

A
  • Neuromuscular junction

* Autonomic nervous system

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16
Q

What are the types of acetylcholine receptor and how is their mechanism different?

A
  • Nicotinic acetylcholine: Ligand gated

* Muscarinic acetylcholine receptor: G coupled receptor

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17
Q

How do non-depolarising blockers work?

A
  1. Prevents ACh binding to receptor by occupying the binding 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
    (They are competitive antagonists of the receptor)
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18
Q

Describe why suxamethonium can block

A

Depolarising blocker
• Looks at 2 ACh molecules stuck together
• Binds to the receptor and causes the sodium channels to open causing the influx of sodium and the efflux of potassium
• Not metabolised by ACh.E so remains bound and the channels remain open
• Causes twitches which summate to nothing

19
Q

Describe how depolarising blockers work

A
  1. Persistant depolarisation of the motor end plate
  2. Prolonged EPP - depolarisation
  3. Membrane potential above the threshold for the resetting of the voltage gated sodium channels
  4. Sodium channels remain refractory
  5. No more muscle action potentials generated
20
Q

Describe Phase 1 of the 2 phases that can occur with depolarising blockers

A

Phase 1:
• Muscle fasciculations observed and then blocked
• Repolarisation is inhibited and K+ leaks from the cell (hyperkalemia)
• Voltage gated Na+ channels are kept inactivated until removed and degraded by plasma esterases

21
Q

Describe phase 2 of the 2 phases that can occur with depolarising blockers

A

Phase 2:
• Prolonged/increased exposure to the drug
• ‘Desensitisation blockage’ Depolarisation cannot occur even after the drug has been removed due to a conformational change which doesn’t revert back to normal

22
Q

What are the 2 classes of non depolarising drugs?

A
  • Aminosteroidal

* Benzylisoquiolinium

23
Q

What are the aminosteroidal non-depolarising drugs?

A
  • Pancuronium
  • Vecuronium
  • Rocuronium
24
Q

What are the benzylquiolinium non-depolarising drugs?

A
  • Atracurium

* Mivacurium

25
Q

What are the depolarising blocking drugs?

A

Suxamethonium

26
Q

Pancuronium

A
  • Aminosteroidal non-depolarising drug
  • Medium onset
  • Long duration
  • Side effect: Tachycardia
  • Hepatic metabolism
27
Q

Vecuronium

A
  • Aminosteroidal non-depolarising drug
  • Medium onset
  • Medium duration
  • Few side effects
  • Hepatic metabolism
28
Q

Rocuronium

A
  • Aminosteroidal non-depolarising drug
  • Fast onset
  • Medium duration
  • Side effect: Tachycardia
  • Unchanged, mostly excreted in bile or urine
29
Q

Atracurium

A
  • Benzylisoquiolinium non-depolarising drug
  • Medium onset
  • Medium duration
  • Side effect: Hypotension/bronchospasm (histamine release)
  • Ester hydrolysis and Hofmann elimination (degrades spontaneously dependent on pH of plasma)
30
Q

Mivacurium

A
  • Benzylisoquiolinium non-depolarising drug
  • Fast onset
  • Short duration
  • Side effect: Hyoptension/bronchospasm (histamine release)
  • Plasma cholinesterases
31
Q

Suxamethonium

A

• Depolarising drug
• Fast onset
• Short duration
• Side effects:
- Bradycardia (acts as an agonist at the musculoronic ACh receptor)
- Cardiac dysrhythmias (increased K+ plasma conc)
- Raised intraocular pressure (nicotinic agonist effect)
- Postoperative myalgia (muscle fasciculations)
- Malignant hypothermia (related to the ryanodine receptor)
• Plasma cholinesterases

32
Q

What are the two types of Cholinesterases?

A
  • Acetylcholinesterases

* Plasma cholinesterase

33
Q

Compare Acetylcholinesterases and Plasma esterases

A
  • ACh.E is a true cholinesterase (ACh. only substrate) but Plasma esterase is a pseudocholinestares (broad spectrum of substrates
  • ACh.E is present in conducting tissue and red blood cells, Plasma cholinesterase has widespread distribution
  • ACh.E is bound to basement membrane in the synaptic cleft, Plasma cholinesterase is soluble in plasma
34
Q

How do anti cholinesterase drugs work?

A
  • They are all inhibitors of cholinesterase enzymes
  • Increase the availability of ACh at the neuromuscular junction by decreasing degradation
  • More ACh is available to compete with the non-depolarising blocker
35
Q

What are the 4 Anticholinesterase drugs?

A
  • Neostigmine
  • Pyridostigmine
  • Dyflos
  • Parathion
36
Q

Neostigmine

A
  • Anticholinesterase drug
  • Quaternary amine
  • Medium duration
  • Mechanism of action: Formation of carbamylated enzyme complex
  • Reversible
37
Q

Pyridostigmine

A
  • Anticholinesterase drug
  • Quaternary amine
  • Medium duration
  • Mechanism of action: Formation of carbamylated enzyme complex
  • Reversible
38
Q

Dyflos

A
  • Anticholinesterase drug
  • Organophosphate
  • Long duration
  • Mechanism: Irreversible inhibition
39
Q

Parathion

A
  • Anticholinesterase drug
  • Organophosphate
  • Long duration
  • Mechanism: Irreversible inhibiton
40
Q

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

A
  • Initial excitation with convulsions

* Unconsciousness and respiratory failure

41
Q

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

A 
• Salivation
• Lacrimation
• Urination
• Defecation
• Gastrointestinal upset
• Emesis (SLUDGE)
- Bradycardia 
- Hypotension
- Bronchoconstriction 
- Pupillary constriction (mitosis)
42
Q

What are the clinical uses of anticholinesterases?

A 
• In anaesthesia
-Reverse non-depolarising muscle blockade
• Myasthenia Gravis
-increase neuromuscular transmission 
• Glaucoma 
-Decrease introcular pressure
• Alzheimer's disease 
- Enhance the cholinergic transmission in the CNS
43
Q

What are anticholinesterases given with in anaesthesia and why?

A
  • Atropine or glycopyrrolate to counteract parasympathetic effects
  • They are antagonists of the musculorinic acetylcholine receptors
44
Q

What is Sugammadex?

A

Selective relaxant binding agent (SRBA) which reverses the effect of rocuronium and vecuronium
• Way to get rid of non-depolarising blockers, curls and coats the drug and stops it from acting on the receptor

Semester 2 Pharmacology (11 decks)

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