10 - Neuromuscular Blocking Drugs Flashcards
What are alpha motor neurones?
Where are they located?
What do they innervate?
Large, multipolar lower motor neurones of the brainstem and spinal cord.
Their cell body is in the ventral horn of the spinal chord.
They innervate extrafusal muscle fibres of skeletal muscle and are directly responsible for initiating their contraction
In terms of motor neurones, how does the somatic system differ from the autonomic?
in the somatic nervous system, only a single axonal cell is involved in the innervation of the skeletal muscle (one 1 neurone - no ganglion)
What type of transmission occurs in the neuromuscular junctions of the somatic system?
cholinergic
What type of receptor is found at the neuromuscular junction?
Action potential propagates along the presynaptic neurone —–> depolarisation of presynaptic membrane —–> opening of voltage gated calcium channels —–> calcium influx —–> vesicle exocytosis
Where are these (nACh) receptors found on the muscle fibre?
Motor end plate (usually in the middle of the muscle fibres)
What does depolarisation of this membrane cause? Describe the character of this depolarisation.
This causes a change in end plate potential
This is a graded potential meaning that it is dependent on the amount of acetylcholine released and the number of receptors stimulated
Once the end plate potential reaches a threshold, it generates an action potential that propagates in both directions along the muscle fibre
Where is acetylcholinesterase found?
It is bound to the basement membrane in the synaptic cleft
State the three main neuromuscule blockers.
Tubocurarine
Atracurium
Suxamethonium
State the two main types of nicotinic acetylcholine receptor.
Ganglionic
Muscle
NOTE: they are slightly different in structure, so more selective drugs can be developed against
Describe the structure of nicotinic acetylcholine receptors.
They consist of 5 subunits (subunits can be alpha, beta, gamma, delta, epsilon)
There are always 2 alpha subunits, which bind to acetylcholine and activate the receptor
How many molecules of acetylcholine are required to activate one nicotinic acetylcholine receptor?
2
Name two drugs that are used as spasmolytics
What site do they act upon and describe their action.
Diazepam
Baclofen (GABA receptor agonist)
Act on the CNS
They both facilitate GABA transmission
Give some examples of conditions in which spasmolytics may be used.
They are both useful in some forms of cerebral palsy and spasticity following strokes
What do local anaesthetics have their effect on?
Conduction of action potentials in sensory neurones - decreases stimulation to the sensory cortex
What can be the result of injecting local anaesthetic into a motor neurone?
may see some muscle weakness
Describe the action of neurotoxins.
Neurotoxins inhibit the release of acetylcholine and hence block the contraction of respiratory skeletal muscle causing death
What are the two types of neuromuscular blocker?
Depolarising
Non-depolarising (competitive)
What type of drug is dantrolene and what is its mechanism of action?
a spasmolytic
it works in the muscle fibres themselves by inhibiting calcium release in the muscle fibre
(NM blocking drugs act nicotinic receptors on the motor end plate)
Describe the difference in mechanism of action between depolarising and non-depolarising NM blockers.
Name NM blockers fall into each category?
Depolarising = suxamethonium = nicotinic acetylcholine receptor AGONIST
Non-depolarising = tubocurarine + atracurium = nicotinic acetylcholine receptor antagonist
How do NM blockers affect consciousness and pain sensation?
They do NOT
NOT GENERAL ANAESTHETICS OR ANALGESICS
What must you always do when giving NM blockers?
Assist respiration because of their effect on respiratory muscle action
Describe the difference in structure between non-depolarising and depolarising NM blockers?
Non-depolarising = big, bulky molecules with limited movement around their bonds
have affinity and no efficacy (are antagonists)
(depolarising) Suxamethonium = made up of two acetylcholine molecules - more flexible and allows rotation. As it is made up of two acetylcholine molecules it can binds to the two alpha subunits and activate the receptor.
possesses affinity and efficacy - very effective agonist
Describe the mechanism of action suxamethonium.
Suxamethonium is a nicotinic receptor agonist.
It causes an extended end plate depolarisation leading to a depolarising block of the NMJ (caused by overstimulation)
This is a phase 1 block
What are the impacts of suxamethonium?
Initially fasciculations – individual fibre twitches as the suxamethonium begins to stimulate the nicotinic receptor (remember it is an agonist)
This leads to flaccid paralysis
What is the duration of paralysis of suxamethonium?
5 mins
How is suxamethonium metabolised?
It is metabolised by pseudocholinesterase (butyrylcholinesterase) in the liver and plasma
What are the 2 main uses of suxamethonium?
Endotracheal intubation – relaxes the muscles of the airways
Muscle relaxant for electroconvulsive therapy (treatment for severe clinical depression)
State and explain four unwanted effects of suxamethonium.
Post-operative muscle pains
• Due to initial fasciculations
Hyperkalaemia
• if there is soft tissue injury (e.g. burns), there is loss of some neurones innervating the tissues
• (deinnervation supersensitivity) - upregulation of receptors in the skeletal muscle
• suxamethonium administration - exaggerated response with a bigger influx of sodium and bigger efflux of potassium
• This can lead to ventricular arrhythmias/cardiac arrest
Bradycardia
• due to the direct muscarinic action on the heart
• usually prevented because suxamethonium is usually given after GA and hence following administration of atropine (muscarinic antagonist)
Raised intraocular pressure
• AVOID for eye injuries and glaucoma
Describe the mechanism of action of tubocurarine.
a competitive nicotinic acetylcholine receptor antagonist.
Blocking this proportion means the end-plate potential generated will NOT reach the threshold. Only 70-80% block is required to achieve full relaxation of the muscles
What are the effects of tubocurarine?
(same as suxamethonium)
Initially fasciculations
causes flaccid paralysis
Describe the order of relaxation of skeletal muscles and the order in which they return back to normal when given tubocurarine.
Order:
• Extrinsic eye muscles (first to relax, last to go back to normal)
• Small muscles of the face, limbs and pharynx
• Respiratory muscles
State two uses of tubocurarine.
Relaxation of muscles during surgical operations (this means that less general anaesthetic is needed)
Permit artificial ventilation
How can the actions of non-depolarising NM blockers be reversed?
Give an anti-cholinesterase (e.g. physostigmine)
What else must you give with physostigmine (anti-cholinesterase) when trying to reverse the actions of (non-depolarising) NM blockers?
Atropine
Giving physostigmine will raise the synaptic concentration of acetylcholine at ALL cholinergic synapses (not just the neuromuscular junctions) so you need some atropine to block these unwanted effects
How are all NM blockers administered?
Intravenously
What is the duration of paralysis of tubocurarine?
40 mins
Describe the metabolism and excretion of tubocurarine?
It is NOT metabolised at all
It is excreted in the urine (70%) and bile (30%)
Under which conditions would you get an increased duration of action of tubocurarine?
What would you change under these conditions?
Impairment of hepatic or renal function increases the duration of action of tubocurarine
Under these conditions you would use ATRACURIUM (15 min duration) and is NOT affected by liver or kidney function
State some unwanted effects of tubocurarine.
MAIN EFFECTS: ganglion block + histamine release from mast cells cause most of the unwanted effects
• HYPOTENSION
• TACHYCARDIA – reflex tachycardia in response to hypotension
• BRONCHOSPASM
• EXCESSIVE SECRETIONS
• APNOEA
