Lecture 10 - Neuromuscular Blocking Drugs Flashcards
What is a neuromuscular junction?
Synapse of the axon terminal of a motor neuron with a motor end plate
What is a motor end plate?
A highly excitable region of muscle fibre plasma membrane responsible for initiation of action potentials across the muscle’s surface leading to muscle contraction
What happens at neuromuscular junctions (NMJs) and what is the neurotransmitter involved?
NMJ is the location where the neurone activates muscle to contract
- Acetylcholine
What is a neuromuscular junction?
The junction between an motor neuron axon terminal and a motor end plate
Describe the events in the process required to make the muscle contract starting from the arrival of an action potential at the axon terminal of a motor neurone.
1) An action potential propagates along the motor neurone of a muscle fibre to the axon terminal
2) The AP depolarises the neuronal membrane, this stimulates voltage gated Ca2+ channels to open
3) Ca2+ ions diffuse into the axon terminal. This triggers acetylcholine-containing vesicles to move to and fuse with the presynaptic membrane
4) ACh is released into synaptic cleft by exocytosis and diffuses from presynaptic terminal to motor end plate
5) (KEY PART) ACh binds to nicotinic receptors on motor end plate, this opens Na+ and K+ channels. More Na+ ions move into the muscle fibre than K+ ions out, this depolarises the membrane of the muscle fibre and generates an END PLATE POTENTIAL (EPP)
6) Local currents depolarise the plasma membrane of the muscle fibre adjacent to the motor end plate. This generates an action potential which spreads along the rest of the muscle membrane
7) Action of ACh is terminated by acetylcholinesterase. Choline produced by the breakdown of ACh is recycled by reuptake back into the presynaptic terminal for new synthesis of ACh
What type of proteins are nicotinic receptors, what are the 5 subunits of these receptors, and what is the combination of subunits in muscular nicotinic receptors?
- Ligand gated ion channels
- alpha, beta, gamma, delta, epsilon
- 2a, 1b, 1d, 1e (2 alpha subunits are where ligand binds)
What kind of potential is an End Plate Potential?
It is a GRADED POTENTIAL - dependent on how much acetylcholine is released and how many receptors are stimulated
How does an End Plate Potential propagate an action potential?
The grading is dependent on the stimulation of the receptors on the end plate. If enough receptors are stimulated, the end plate potential reaches a threshold and propagates an action potential along the muscle fibre
What are the 3 main neuromuscular blocking drugs?
Suxamethonium
Tubocurarine
Atracurium
What are the two types of neuromuscular blocking drugs and which of tubocurarine and suxamethonium is which?
Non-depolarising (competitive antagonist) - Tubocurarine
Depolarising (agonist) - Suxamethonium
How do both types of drug interact with consciousness, pain sensation and respiratory?
Both do NOT affect consciousness or pain sensation
Both ALWAYS assist respiratory until drug is inactive or antagonised
Where is the location of action of neuromuscular blocking drugs and how does each type affect this?
Post-synaptic, act on the nicotinic receptors on the motor end plate
- Non-depolarising are competitive antagonistic molecules, they bind with no efficacy and prevent agonist molecules from binding
- Depolarising are agonist molecules, they bind and cause overstimulation resulting in depolarisation block of the NMJ (a.k.a phase 1 block)
What type of neuromuscular blocking drug is suxamethonium and what is its mechanism of action?
Depolarising NM blocking drug, agonist molecule for nicotinic receptors
- Stimulates the nicotinic receptors on the end plate
- Isn’t metabolised as quickly as ACh so remains bound to the receptor and continually stimulates it
- Very quickly the receptors will switch off
- This is a depolarisation block caused by overstimulation (phase 1 block)
What does suxamethonium cause as it diffuses into the muscle fibre and what kind of paralysis does it cause after it has acted?
Causes fasciculations - individual fibre twitches as the suxamethonium begins to stimulate the nicotinic receptors but haven’t switched them off yet
Flaccid paralysis, no muscle tone
Regarding the pharmacokinetics of suxamethonium, by what route is it administered, what is the duration of paralysis and what enzymes metabolise it and where?
- Administered intravenously (highly charged)
- 5 minutes paralysis
- Metabolised by pseudocholinesterase in liver and plasma
What are the uses of suxamethonium?
Endotracheal intubation - relaxes skeletal muscle of the airways
Muscle relaxant for electroconvulsive therapy - treatment for severe clinical depression
What are the unwanted effects of suxamethonium?
Post-operative muscle pains
Bradycardia - direct muscarinic action on the heart
Hyperkalaemia - soft tissue injury or burns lead to ventricular arrhythmias/cardiac arrest
Raised intraocular pressure - avoid using in patients with eye injuries or glaucoma
What type of NM blocking drug is Tubocurarine?
Competitive nicotinic acetylcholine receptor antagonist - non-depolarising NM blocker
Do competitive nicotinic receptor antagonists cause complete or incomplete block?
Incomplete as competitive so cannot 100% outcompete endogenous agonist
What % of block does tubocurarine require for full relaxation of the muscles and why is this?
Need 70-80% block for full relaxation
- If this proportion of receptors are blocked then even if the remaining proportion are stimulated, the end plate potential won’t reach the threshold required for initiation of action potentials in the muscle fibre
What type of paralysis does it produce, which 3 sets of skeletal muscles are paralysed and which order do they relax and return to normal?
Flaccid paralysis (same as suxamethonium)
- Extrinsic eye muscles (relaxes first, returns to normal last)
- Small muscles of the face, limbs, pharynx
- Respiratory muscles (relax last, return to normal first)
You must be able to recognise a log dose-response curve showing the response of skeletal muscle to increasing concentrations of ACh and additionally how this would be altered in the presence of tubocurarine. What is the effect of tubocurarine on neuromuscular transmission?
Reduces amplitude of the End Plate Potential so no action potential is generated in the muscle fibre
- In a normal log D-R curve there is a large EPP and a corresponding action potential
- In a tubocurarine-affected D-R curve there is a small EPP and no corresponding action potential
What are the uses of tubocurarine and other drugs like it and why are they used in these ways?
- Relaxation of skeletal muscles during surgery - less anaesthesia required
- Permits artificial ventilation
How are the effects of tubocurarine and other NM blockers like it reversed?
Administration of ANTOCHOLINESTERASES - neostigmine (+atropine)
- Increases concentration of ACh at all NMJs to outcompete tubocurarine, atropine acts as a muscarinic antagonist and prevent unwanted stimulation of parasympathetic NS by the new high levels of ACh
Why is tubocurarine ineffective if administered orally, what is the preferred administration route, and why does it not act centrally (on CNS)?
- Highly charged molecule so not easily absorbed enterally (in the gut) so little reaches systemic circulation
- Doesn’t act centrally as unable to cross BBB (again, highly charged and not lipid soluble)
Regarding tubocurarine, what is the route of administration, the onset of action, the duration of action and the path of elimination?
- Intravenous administration
- Onset 2-3minutes
- Duration of paralysis 40-60minutes (long effect and slow metabolism)
- Is not metabolised so excretion is 70% in urine and 30% in bile (so care using if renal/hepatic function impaired)
What are the unwanted effects of tubocurarine?
These are mainly due to ganglion blockade and histamine release from mast cells
- Hypotension - BP drops due to ganglion blockade and vasodilation caused by histamine
- Tachycardia - Reflex in response to hypotension, may lead to arrhythmias
- Bronchospasm - caused by histamine release
- Excessive secretions - caused by histamine release
- Apnoea - This is why respiration is always assisted in someone taking tubocurarine
What is atracurium and what are its effects?
Another nicotinic antagonist acting at the NMJ, non-depolarising blocker like tubocurarine
- Has the same effects as tubocurarine but these last for a shorter duration
When is atracurium used and why is this?
Used in patients needing tubocurarine but that have renal or hepatic impairment preventing safe removal of tubocurarine from their body
- Atracurium is useful here as it is a highly unstable molecule - due to the pH of the plasma, it gets hydrolysed into two inactive fragments
What is the structure of suxamethonium and why is this important for its function?
Two ACh molecules joined together basically
- Allows one molecule of suxamethonium to bind to both alpha subunits on the nicotinic receptor so allows one molecule of suxamethonium to stimulate the nicotinic receptor where it would have taken two ACh molecules, also allows easier outcompeting of ACh
