Neuromuscular Blocking Drugs Flashcards
What part of the nervous system do NM blocking drugs affect?
- the somatic NS
- alpha motor neurones innervating skeletal muscle
- NMJ with ACh receptors
What happens at the NMJ?
- Acetyl Coa + Choline -> acetylcholine via CAT and ACh is packaged into vesicles
- AP at presynaptic cell
- Ca2+ influx
- vesicles move towards the nerve terminal -> exocytosis of ACh
- ACh binds to AChR (alpha subunits) on postsynaptic cell
- Na+ influx and depolarisation (end plate potential)
- ACh is broken down to Acetic Acid and Choline vie Ash-Esterase
- Choline is taken up by the presynaptic cell (pump?)
CAT
Cholineacetyl Transferase
What are the subunits of the AChR?
2 alpha (ACh binds here)
1 beta
1 gamma
1 delta
How many molecules of ACh have to bind to the receptor to cause a response?
2
What are the 5 steps in the neuromuscular pathway?
- Central porcesses
- Conduction of nerve AP in Motor neurone
- ACh release
- Depolarisation of motor end-plate -> AP initiation
- propagation of AP along muscle fibre and muscle contraction
What drugs can affect central processes in the NM pathway?
- spasmolytics
- e.g. diazepam, baclofen (-> GABAergic drugs)
reduce NM transition in spinal cord
What drugs can affect conduction of AP in motor neurone in the NM pathway?
- local anaesthetics
- blocks Na+ channels -> stops/limits APs to the brain
- can cause skeletal muscle weakness
What drugs can affect ACh release in the NM pathway?
- HEMICHOLINIUM
- Ca2+ ENTRY BLOCKERS
- NEUROTOXINS (e.g. botulinum toxin)
Botulinum toxin
- disrupts release of ACh
- Botox paralyses skeletal msucles of forehead and causes the skin to look smoother -> also same muscles that are responsinbel for facial expression -> flat looking faces.
What drugs affect the depolarisation of motor end-plate -> AP initiation in the NM pathway?
- tubocurarine
- suxamethonium
What drugs affect the propagation of AP along muscle fibre and muscle contraction in the NM pathway?
- spasmolytics
- e.g. dantrolene
- redeces Ca2+ release
What is some general info about NM blocking drugs?
- POSTsynaptic action
- relax skeletal muscles
- 2 types: depolarising and non-depolarising
- they do not affect consciousness
- they do not affect pain sensation
- they are used in surgery
- ALWAYS assist respiration until the drug is inactive or antagonised
Non-Depolarising NM blocking drugs
= competitive antagnosists
- e.g. tubocurarine, atracurium
Depolarising NM blocking drugs
- agonists
- e.g. suxamethonium (=succinylcholine)
Molecular structures of NM blocking drugs?
- Tubocurarine: can bind to AChR but has no efficacy; quaternary ammonium groups -> similarity to ACh
- Suxamethonium: essentially 2 ACh molecules -> agonist
- in general antagonists have a rigid, bulky structure with relatively little free rotation -> bind and block receptor
- agonists e.g. suxamethonium: much more rotation around free bonds -> have better efficacy
MoA of suxamethonium
- extended end-plate depolarisation -> depolarisation block
- fasciculations -> flaccid paralysis
- depolarises the end-plate
- does not dissociate rapidly from receptors -> prolonged receptor activation
- this causes a brief train of muscle APs and muscle fibre twitches
- NM block occurs because:
a) voltage sensitive Na+ channels are inactivated in the surrounding muscle fibre membrane -> APs are no longer generated.
b) activated receptors are transformed into a desensitised state and are unresponsive to ACh
Pharmacokinetics
- rapid onset
- RoA: i.v. (highly charged)
- duration of action ~5 minutes (2-6 minutes)
- usually hydrolysed rapidly by (plasma) pseudocholinesterase -> in liver or plasma
Why do some people react differently to Suxamethonium?
- about 1 in 3000 people inherit an atypical pseudocholinesterase
- in those individuals the NM block can last for hours
What are the clinical uses of suxamethonium?
- endotracheal intubation
- muscle relaxant for ECT (electrocompulsive therapy - last resort treatment in depression)
Why is suxamethonium used in ECT?
- prevents movements
- this decreases the likelihood that there will be damage to the brain as the patient does not move.
What are unwanted effects of suxamethonium?
- post op muscle pains -> due to fasciculations which cause damage
- Bradycardia: direct muscarinic action on the heart (atropine can block this effect)
- Hyperkalaemia: deinnervation supersensitivity post soft tissue injury such as burns -> more nicotinic receptors added to the end plate region; Such patients there would be a massively enhanced response: big Na+ influx and K+ efflux which can lead to hyperkalaemia. This may lead to ventricular arrhythmia or cardiac arrest
- increased intra-ocular pressure
In what patients would you avoid the use of suxamethonium?
- burn injury patients
- patients with soft tissue damage
=> due to deinnervation supersensitivity: ascending innervation reduced after injury but more nicotinic receptors added onto the end-plate region there. In those patients there would be a more profound effect due to the increased number of channels with more Na+ influx and K+ efflux which could cause ventricular arrhythmia or even cardiac arrest due to HYPERKALAEMIA.
- also Glaucoma and eye-injury patients as suxamethonium increases intra-ocular pressure
- in those patient groups use a non-depolarising blocker
Tubocurarine general information
- non-depolarising NM blocking drug
- Naturally occurring 4° AMMONIUM COMPOUND (ALKALOID) FOUND IN S. AMERICAN PLANT (ARROW POISON)
- RANGE OF SYNTHETIC DRUGS NOW AVAILABLE
What is the mode of action of tubocurarine?
- competitive nAChR antagonist
- 70 - 80% block necessary to achieve flaccid paralysis
What are the effects of tubocurarine?
- flaccid paralysis
- extrinsic eye muscles (double vision if the patient is concious)
- small muscles of face, limbs and pharynx (difficulty swallowing)
- respiratory muscles
Recovery: 3 -> 2 -> 1
What are the clinical uses of tubocurarine?
- relaxation of skeletal muscle during surgical operations -> you need less general anaesthetic which makes the patient come around from the surgery quicker
- to permit artificial ventilation -> the patient is not working against the ventilator.
How can actions of non-depolarising NM blockers be reversed?
- by anticholinesterases
- e.g. neostigmine (+atropine)
Pharmacokinetics of tubocurarine
- RoA: i.v. (highly charged)
- does not cross BBB or placenta
- duration of paralysis: 1-2 h(-> long)
- NOT metabolised
- Excretion: 70% urine, 30% bile -> care if renal or hepatic function is impaired.
Atracurium
- 15 min duration
- chemically unstable - breaks down spontaneously in 15 minutes
What are unwanted effects of tubocurarine?
Ganglion block + histamine release
- Hypotension (ganglion blockade causes reduction in TPR, so does histamine (=vasodilator) release from mast cells)
- Tachycardia: Reflex to hypotension, may give rise to arrhythmias; blockade of vagal ganglia.
- Bronchospasm
- excessive secretions (bronchial and salivary)
- these 2 are due to histamine release
- apnoea (ALWAYS assist reparation)
SBA 1: The clinical use of neuromuscular blocking drugs will most likely involve interference with which of following physiological processes?
A: Kidney function B: Consciousness C: Body temperature regulation D: Pain sensation E: Respiration
E
SBA 2: Which of the following effects would be observed with a non-depolarising neuromuscular block?
A: Initial muscle fasciculations B: Irreversible nAChR blockade C: The block would be enhanced by anti-cholinesterase drugs D: A flaccid paralysis E: Increased arterial pressure
D
