9. Neuromuscular blocking drugs Flashcards
Where is choline acetyltransferase found and what does it do?
- Only found in cholinergic nerve terminals (motor)
* Synthesises ACh from Acetyl CoA and Choline
How does an action potential lead to vesicle exocytosis in motor neurones?
- Depolarisation of membrane
- Opening of voltage sensitive calcium channels
- Calcium influx
- Vesicle exocytosis
What are the targets for the ACh at neuromuscular junctions?
Nicotinic acetylcholine receptors on the end plate
Describe how ACh stimulates the receptors on at the neuromuscular junction
• Nictonic receptors are ion channel linked
• Stimulation => conformation change + influx of sodium ions
• Depolarisation of membrane
- graded potential: depends on how much ACh and how many receptors stimulated
• Once end plate potential reaches threshold => action potential
• AP propagates in both directions
• Acetylcholinesterase is bound to the basement membrane in the synaptic cleft - it breaks down ACh to acetate and choline
Name 3 of the main neuromuscular blockers
- Tubocurarine
- Atracurium
- Suxamethonium
What are the 2 main subtypes of nicotinic receptors?
- Ganglionic (neuronal)
* Muscle (on skeletal muscle)
How many subunits make up the nicotinic ACh receptor?
- 5 subunits
* 2 α subunits - must bind to ACh for receptor to be activated (so 2 ACh needed)
Name a spasmolytic that facilitates GABA transmission
Diazepam
Name a GABA receptor agonist
Baclofen
What is the site of action for local anaesthetics?
Conduction of action potentials down a motor neurone
Where do neuromuscular blocking drugs act?
Motor end plate (post-synaptic)
How does dantrolene work?
- Spasmolytic
- Works in muscle fibres themselves
- Inhibits Ca2+ release
What is the difference between depolarising and non-depolarising neuromuscular blocking drugs?
- Depolarising - nicotinic receptor agonists e.g. suxamethonium
- Non-depolarising - competitive nicotinic receptor antagonists e.g. tubocurarine, atracurium
Do neuromuscular blocking drugs affect the following:
- consciousness
- respiration
- pain sensation
Only can affect respiration, so assistance needed
How does the structure of a depolarising drug differ from non-depolarising?
Depolarising
• more flexible and allows rotation
• made up of 2 ACh molecules linked together - therefore only one needed to stimulate receptor
Non-depolarising
• big, bulky molecules
• restricted movement around the bonds
Outline the mechanism of action of suxamethonium
• Extended end plate depolarisation => depolarisation block of the NMJ
• Phase 1 block
• Slowly seeps into muscle fibres
• Stimulates nicotinic receptors (agonist)
- isn’t metabolised rapidly
- remains bound => receptors switch off by overstimulation
Suxamethonium causes fasciculations, what is this?
- Individual fibre twitches as it begins to stimulate nicotinic receptors
- Leads to flaccid paralysis - no muscle tone
How is suxamethonium administered, what is the duration of paralysis and how is it metabolised?
- IV (highly charged)
- Paralysis for 5 minutes
- Metabolised by pseudocholinesterase in the liver and plasma
What is suxamethonium used for?
- Endotracheal intubation - relaxes skeletal muscle of airways
- Relaxant for electroconvulsive therapy
What are the unwanted effects of suxamethonium?
• Post-operative muscle pains (due to initial fasciculations)
• Bradycardia (muscarinic action) - but tends to be prevented by atropine in general anaesthetic
• Hyperkalaemia if there is a soft tissue injury
- loss of neurones innervating the muscle
- upregulation of receptors, deinnervation supersensitivity
- exaggerated response to drug
- bigger efflux of potassium
• Raised intraocular pressure
What is the mechanism of action of tubocurarine?
- Competitive nicotinic ACh receptor antagonist
- 70-80% block for full relaxation
- End plate potential can’t reach threshold
What are the effects of tubocurarine?
• Same as suxamethonium • Flaccid paralysis • Muscles relax in the following order: - extrinsic eye muscles - small muscles of the face, limbs, pharynx - respiratory muscles • Recovery in the opposite order
What is tubocurarine used for?
- Relaxation of skeletal muscles during surgical operations - therefore less general anaesthetic needed
- Permit artificial ventilation
How can you reverse the effects of non-depolarising blockers?
• Neostigmine (reversible anticholinesterase)
• Increases [ACh] in all other cholinergic synapses
- so give some atropine to block muscarinic receptor over stimulation
How is tubocurarine administered, what is the duration of paralysis and how is it metabolised?
• IV (highly charged)
• Paralysis for 40-60 minutes
(• doesn’t cross BBB or placenta)
• Not metabolised - excreted in urine (70%) and bile (30%)
- hepatic or renal function impairment increases duration of action
What do you administer if someone with hepatic or renal impairment is given tubocurarine?
- Atracurium
- Duration of action - 15 mins
- Chemically unstable - plasma pH causes hydrolysis into 2 inactive fragments
What are the unwanted affects of tubocurarine?
- Could block some nicotinic receptors in ganglia
- Histamine release from mast cells
- Hypotension - ganglion blockade and histamine causing vasodilation
- Tachycardia => arrhythmias - due to reflex to hypotension, vagal ganglia blockade
- Bronchospasm - from histamine release
- Apnoea
