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Year 3 nmj
- 1. An overview of NMJ physiology and pharmacology Amare H.
- 2. What is the neuromuscular junction? Physiologically • Junction between motor nerve end-plate and muscle fibre • Allows action potential in neurone to activate muscle fibre • A neurone may supply one or many muscle fibres • Muscle fibres are activated in “on-or-off” manner Pharmacologically • Target for suxamethonium (depolarising) and non-depolarising blockers (pancuronium / vecuronium / atracurium) • Site of action of neostigmine
- 3. The NMJ: what we’ll cover Physiology Pharmacology Suxamethonium
- 4. (1) The nicotinic acetylcholine receptor (nACh-r) How does the NMJ function physiologically? Na-channel within nACh-r protein Cell membrane ACh Na+ influx The “receptor” is a protein in the cell membrane of the muscle fibre Binding of ACh molecules causes the protein to change shape This opens a channel for Na+ ions, and allows their influx
- 5. (2) The motor neurone (“α neurone”) How does the NMJ function physiologically? Action potential Ca2+ Ca2+ ACh ACh ACh Na+ K+ Na channel K channel Ca channel then breaks down to give choline ACh acts on nACh-r + ACh vesicles Ca influx causes ACh release
- 6. (3) The muscle end-plate How does the NMJ function physiologically? Na influx through channels of nACh-r Na influx ACh binds the nACh- r and opens them Acetylcholine-esterase in the folds breaks down ACh (“turns off signal”) intracellularextracellular If enough receptors activate enough Na→ + influxes → membrane depolarises → muscle fibre activates There are “spare” receptors; in some muscles only 30% occupancy is required nACh-r NMJ cleft
- 7. (4) The whole NMJ How does the NMJ function physiologically? AP Ca influx Na influx Na influxNa influx Na influx ACh choline recycled MEMBRANE DEPOLARISES + MUSCLE CONTRACTS When ACh leaves receptor, channels close, allowing repolarisation ACh broken down by AChE
- 9. What is suxamethonium? CH3-C-O-CH2-CH2-N+ CH3 CH3 CH3 O CH2-C-O-CH2-CH2-N+ CH2-C-O-CH2-CH2-N+ CH3 CH3 CH3 CH3 CH3 CH3 O O Suxamethonium (succinylcholine) Acetylcholine • Suxamethonium (“sux”) is 2 ACh molecules linked together • It binds nACh-r and opens the channel • Unlike ACh it remains bound to the nACh-r for several minutes All drugs acting at nACh-r have this N+
- 10. (1) At the nACh-r What does Suxamethonium do? • Suxamethonium remains bound to the nACh-r for several minutes • This allows ongoing Na influx and continued depolarisation of the muscle membrane • Initially, the muscle fibre is activated fasciculations are seen→ • Rapidly, muscle activity is replaced by relaxation, since the muscle cannot reactivate without repolarising (NOTE: this relaxation occurs even whilst the channels are open)
- 11. (2) How it affects the whole NMJ What does Suxamethonium do? Na influx Na influxNa influx Na influx ACh Sux Sux keeps channels open INITIAL ACTIVATION, THEN MUSCLE RELAXES Extra ACh will NOT alter the block (since ACh opens channels) ACh
- 12. (3) How does it wear off? What does Suxamethonium do? • After leaving the nACh-r, sux can be broken down • Sux is not broken down by acetylcholinesterase (AChE) • Sux is broken down by plasma cholinesterase; a less specific enzyme NOTE: • Some people are deficient in plasma cholinesterase • In these, sux paralysis lasts a lot longer – maybe many hours • This is “SUX APNOEA” • These cases must be re-sedated and ventilated until the paralysis wears off
- 13. (4) Side effects What does Suxamethonium do? • increase in plasma K • muscle pain post-op (myalgia) • raised intra-cranial and intra-ocular pressure Repeated doses • bradycardia (atropine should be given / available) • development of Type II block acts like non-depolarising block, but neostigmine NOT→ advised (5) Adverse reactions • anaphylaxis (sux is the most common cause in hospital) • “sux” apnoea • malignant hyperthermia
- 14. Who is particularly at risk of increased K and why?? What does Suxamethonium do? (1) Patients prone to higher increases in K (2) Patients for whom an increase in K is particularly dangerous • burns > 10% area (from 24 hr to 18 months) • post-trauma immobility • neuromuscular disorders (eg paraplegia) • those with an already raised K Normal muscle fibre: Fibre from at risk groups: these have abnormal nACh-r distribution
- 15. (1) At the nACh-r What do non-depolarising blockers* do? • They bind the nACh-r • They do NOT open the channel • They block activation by ACh molecules • As they wear off, a “higher than normal” concentration of ACh can partially overcome the block (* NDMBs for short)
- 16. What do non-depolarising blockers do? (2) How they affect the whole NMJ Na influx ACh NDMB NDMB blocks channels MUSCLE CANNOT ACTIVATE Even extra ACh could not open enough channels to activate muscle Some channels open – but not enough to activate cell ACh
- 17. What do non-depolarising blockers do? (3) How do they wear off? • Atracurium; spontaneous breakdown at 37°C (50%) plasma cholinesterase (50%) • Vecuronium; liver metabolism • Pancuronium; urinary excretion (60%) liver metabolism and bile excretion (40%) As the plasma concentration decreases, fewer of the NDMB molecules bind nACh-r and the block wears off
- 18. What does neostigmine do? (1) To ACh levels (2) Systemically • Acetylcholinesterase (AChE) breaks down ACh • AChE is found in the NMJ cleft • Neostigmine inhibits AChE • Using neostigmine increases ACh concentration in the NMJ cleft • AChE also breaks down ACh in parasympathetic system • Neostigmine blocks this AChE, too • Neostigmine alone causes increases parasympathetic activity → bradycardia, increased gut motility (rarely bronchospasm) For this reason, neostigmine is generally given with glycopyrolate (or atropine)
- 19. What does neostigmine do? (3) To the action of non-depolarising blockers Na influx ACh NDMB NDMB block some channels Extra ACh can open enough channels to activate muscle once NMBD starts to wear off neostigmine inhibits AChE Na influx Na influx
- 20. What does neostigmine do? (3) To the action of non-depolarising blockers (cont.) Initially, so many nACh-r are blocked that no amount of ACh will cause muscle activation neostigmine will not reverse NMBD effect Later, 80% of nACh-r are still blocked (but 2 twitches can be seen with nerve stimulator ) neostigmine would give incomplete reversal Finally, <75% of nACh-r are blocked (and 3-4 twitches can be seen with nerve stimulator) neostigmine → ACh levels↑ → ACh will occupy enough nACh-r → effective reversal of NMDB effect Full reversal requires enough nACh-r to be unoccupied by the NDMB
- 21. What does neostigmine do? (4) Why you do NOT use it to reverse Suxamethonium Na influx Na influxNa influx Na influx ACh Sux Sux keeps channels open Extra ACh will NOT improve the block neostigmine inhibits AChE SO NEOSTIGMINE MAY MAKE PARALYSIS WORSE Since ACh opens channels (for paralysis to recover, the muscle must be able to repolarise)