Neuromuscular Blocking Drugs Flashcards
What do NM blocking drugs deal with?
SOMATIC NS
NOT the ANS
Describe NM transmission
- Production of ACh using CAT
- AP propagation
- Ca2+ influx
- ACh exocytosis
- ACh binds to receptors
- Na+ influx
- ACh esterase breaks down ACh
- Recycling by uptake
3 most important NM-blocking drugs?
COMPETITIVE
• tubocurarine
• atracurium
DEPOLARISING
• suxamethonium
Why can we develop drugs that have some degree of selectivity for somatic nAChr?
The NMJ nAChR is DIFFERENT IN STRUCTURE to the ganglionic (ANS) nAChR
• so can develop selective drugs just for somatic NS
Describe the structure of the nAChR
5 subunits in the receptor • A1 • A2 • B • DELTA • GAMMA
ACh ONLY binds to the ALPHA-receptors
Large extracellular domain
Slightly smaller intracellular domain
Where is the density of the nAChR highest?
At the MOTOR-END PLATE
5 sites of drug action?
- Central Processes
- Conduction of nerve AP in motor neurone
- ACh release
- Depolarisation of motor end-plate AP initiation
- Propagation of AP along muscle fibre & muscle contraction
Drug that works for relaxant effect on the 1ST drug site?
- Central Processes
= SPASMOLYTICS
• e.g. Diazepam, Baclofen
They relieve spasm of the muscles
• reduce generation of AP around cell bodies (so before it enters the pre-synaptic neurone)
• work on SC so centrally acting
Drug that works for relaxant effect on the 2ND drug site?
- Conduction of nerve AP in motor neurone
= LOCAL ANAESTHETICS
• Inhibit influx of Na+
• so reduces the propagation of the AP along the nerve
• MORE effective around sensory fibres rather than motor fibres
Drug that works for relaxant effect on the 3RD drug site?
- ACh release
= Hemicholinium
= Ca2+-entry blockers
= Neurotoxins
• ALL inhibit re-uptake of Ca2+
Drug that works for relaxant effect on the 4TH drug site?
- Depolarisation of motor end-plate AP initation
= Tubocurarine
= Suxamethonium
• these react on the post-synpatic membrane
Drug that works for relaxant effect of the 5TH drug site?
- Propagation of AP along muscle fibre & muscle contraction
= Spasmolytics
• e.g. Dantrolene
Acts INSIDE the skeletal muscle (rather than the SC like the 1ST one does!)
• reduces Ca2+ release from sacroplasmic reticulum = relaxes muscles = reduces spascity
2 main groups of Post-synaptic NM-blocking drugs?
- Non-depolarising (competitive antagonists)
• e.g. tubocurarine & atracurium - Depolarising (agonist)
• e.g. suxamethonium (succinylcholine)
- good at stimulating due to its VERY SIMILAR STRUCTURE to ACh
What is special about the 2 main groups of post-synaptic NM-blocking drugs?
Do NOT affect consciousness OR pain sensation
• so NO analgesic properties - simply relax the muscles
• true for NM relaxants in general!
ALWAYS need to assist respiration
• until drug is inactive OR antagonised
Difference between antagonists & agonists in terms of structure?
Antagonists have a RIGID structure
• less free rotation
• bind onto receptor & block it
Agonists have MORE free rotation
• so can bind & allow for efficacy
Why is Suxamethonium an agonist?
Has 2 ACh groups on either side
MOA of Suxamethonium?
Causes an EXTENDED end-plate depolarising block
• takes a long time to break-down in synaptic cleft
• overstimulates the nAChR so shuts it down (compared to enzyme inhibitor which would not e.g. organophosphate)
Also causes fasciculations (brief twitches of muscle fibres)
• which turns into FLACCID PARALYSIS (loss of tone)
Pharmokinetics of Suxamethonium?
ROA = IV
• as it is highly-charged
Duration of paralysis is short
• ~5 mins
Metabolised by pseudo-cholinesterase
• in the liver & plasma
• remember, AChcholinesterase is SPECIFIC to ACh so cannot be used for this!
Uses of Suxamethonium?
Endotracheal intubation
• relaxes vocal chords
Muscle relaxant for ECT
• electro convulsive therapy - for severe clinical depression treatment
• across bi-temporal lobe
Unwanted effects of Suxamethonium?
Post-operative muscle pains
Bradycardia
• direct muscarinic action of the heart (as similar in shape to ACh)
BUT
• ATROPINE normally given as well so blocks it
Hyperkalaemia
• soft tissue injury or burns –> ventricular arrhythmias/MI
• if reduce cholinergic innervation, leads to denervation supersensitivity (as more nACHR = bigger Na+ influx = bigger K+ efflux)
Increase in IOP
• so avoid for eye injuries/glacucoma as causes constriction of extra-ocular muscles
If have glaucoma, what drug should be used?
NON-DEPOLARSING BLOCKER
as the DP agonist causes an increase in IOP
What is true about ALL Non-depolarising blockers?
Have similar MOA & side-effects
• BUT have DIFFERENT DOA
Where is Tubocurarine found?
Naturally occurring 4o ammonium compound found in S.ameria plants
MOA of Tubocurarine?
A COMPETITIVE nAChR antagonist
A block of 70-80% necessary
• to cause effect of skeletal muscle relaxation
• so EP potential is insufficient to fire an AP
