Md (surg) part1 nmj 2011 student

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Md (surg) part1 nmj 2011 student

  1. 1. Neuromuscular Physiology Prof. Vajira Weerasinghe Department of Physiology Faculty of Medicine University of Peradeniya
  2. 2. <ul><li>Nerve conduction </li></ul><ul><li>NMJ </li></ul><ul><li>Muscle contraction </li></ul>
  3. 3. Nerve conduction <ul><li>Electrochemical basis </li></ul><ul><ul><ul><li>concentration gradient, membrane permeability ionic channels </li></ul></ul></ul><ul><li>Resting membrane potential (RMP) </li></ul><ul><ul><ul><li>K+ efflux, Na/K pump </li></ul></ul></ul><ul><ul><ul><li>Leaky channels </li></ul></ul></ul><ul><li>Action potential (AP) </li></ul><ul><ul><ul><li>depolarisation, repolarisation </li></ul></ul></ul><ul><ul><ul><li>Voltage-gated channels </li></ul></ul></ul><ul><li>Propagation of AP </li></ul><ul><ul><ul><li>Local current flow </li></ul></ul></ul>
  4. 4. Membrane potential <ul><li>A potential difference exists across all cell membranes </li></ul><ul><ul><li>This is referred to as “Resting Membrane Potential” (RMP) </li></ul></ul><ul><ul><li>Inside is negative with respect to the outside </li></ul></ul>
  5. 5. What are excitable tissues? <ul><li>They are capable of generating electrochemical impulses and transmitting them along the membrane </li></ul>
  6. 6. <ul><li>Excitability of a tissue depends on its membrane potential </li></ul><ul><ul><li>Excitable tissues have more negative RMP ( - 70 to - 90 mV) </li></ul></ul><ul><ul><li>Non-excitable tissues have less negative RMP ( - 40 mV) </li></ul></ul>excitable neuron muscle Non-excitable Red cell GIT
  7. 7. Resting Membrane Potential <ul><li>This depends on following factors </li></ul><ul><ul><li>Ionic distribution across the membrane </li></ul></ul><ul><ul><li>Membrane permeability </li></ul></ul><ul><ul><li>Other factors </li></ul></ul><ul><ul><ul><li>Na + /K + pump </li></ul></ul></ul>
  8. 8. Factors contributing to RMP <ul><li>One of the main factors is K+ efflux (Nernst Potential: -94mV) </li></ul><ul><li>Contribution of Na influx is little (Nernst Potential: +61mV) </li></ul><ul><li>Na/K pump causes more negativity inside the membrane </li></ul><ul><li>Negatively charged protein remaining inside due to impermeability contributes to the negativity </li></ul><ul><li>Net result: -90 mV inside </li></ul>
  9. 9. Ionic channels <ul><li>Leaky channels (K-Na leak channel) </li></ul><ul><ul><li>More permeable to K </li></ul></ul><ul><ul><li>Allows free flow of ions </li></ul></ul>K + Na +
  10. 10. Na/K pump <ul><li>Active transport system for Na-K exchange using energy </li></ul><ul><li>It is an electrogenic pump since 3 Na influx coupled with 2 K efflux </li></ul><ul><li>Net effect of causing negative charge inside the membrane </li></ul>3 Na + 2 K + ATP ADP
  11. 11. Action Potential (A.P.) <ul><li>When an impulse is generated </li></ul><ul><ul><li>Inside becomes positive </li></ul></ul><ul><ul><li>Causes depolarisation </li></ul></ul><ul><ul><li>Nerve impulses are transmitted as AP </li></ul></ul>
  12. 12. Depolarisation Repolarisation RMP Hyperpolarisation -90 +35
  13. 13. Physiological basis of AP <ul><li>When the threshold level is reached </li></ul><ul><ul><li>Voltage-gated Na channels open up </li></ul></ul><ul><ul><li>Since Na conc outside is more than the inside </li></ul></ul><ul><ul><li>Na influx will occur </li></ul></ul><ul><ul><li>Positive ion coming inside increases the positivity of the membrane potential and causes depolarisation </li></ul></ul><ul><ul><li>When it reaches +35, Na channels closes </li></ul></ul><ul><ul><li>Then Voltage-gated K channels open up </li></ul></ul><ul><ul><li>K efflux occurs </li></ul></ul><ul><ul><li>Positive ion leaving the inside causes more negativity inside the membrane </li></ul></ul><ul><ul><li>Repolarisation occurs </li></ul></ul>
  14. 14. Physiological basis of AP <ul><li>Since Na has come in and K has gone out </li></ul><ul><li>Membrane has become negative </li></ul><ul><li>But ionic distribution has become unequal </li></ul><ul><li>Na/K pump restores Na and K conc slowly </li></ul><ul><ul><li>By pumping 3 Na ions outward and 2 K ions inward </li></ul></ul>
  15. 15. <ul><li>At rest: the activation gate is closed </li></ul><ul><li>At threshold level: activation gate opens </li></ul><ul><ul><li>Na influx will occur </li></ul></ul><ul><ul><li>Na permeability increases to 500 fold </li></ul></ul><ul><li>when reaching +35, inactivation gate closes </li></ul><ul><ul><li>Na influx stops </li></ul></ul><ul><li>Inactivation gate will not reopen until resting membrane potential is reached </li></ul>outside inside outside inside -90 Threshold level +35 Na+ Na+ Na+ m gate h gate outside inside
  16. 16. <ul><ul><li>At rest: K channel is closed </li></ul></ul><ul><ul><li>At +35 </li></ul></ul><ul><ul><ul><li>K channel open up slowly </li></ul></ul></ul><ul><ul><ul><li>This slow activation causes K efflux </li></ul></ul></ul><ul><ul><li>After reaching the resting still slow K channels may remain open: causing further hyperpolarisation </li></ul></ul>outside inside outside inside -90 At +35 K+ K+ n gate
  17. 17. Propagation of AP <ul><li>When one area is depolarised </li></ul><ul><li>A potential difference exists between that site and the adjacent membrane </li></ul><ul><li>A local current flow is initiated </li></ul><ul><li>Local circuit is completed by extra cellular fluid </li></ul>
  18. 18. Propagation of AP <ul><li>This local current flow will cause opening of voltage-gated Na channel in the adjacent membrane </li></ul><ul><li>Na influx will occur </li></ul><ul><li>Membrane is deloparised </li></ul>
  19. 19. Propagation of AP <ul><li>Then the previous area become repolarised </li></ul><ul><li>This process continue to work </li></ul><ul><li>Resulting in propagation of AP </li></ul>
  20. 20. AP propagation along myelinated nerves <ul><li>Na channels are conc around nodes </li></ul><ul><li>Therefore depolarisation mainly occurs at nodes </li></ul>
  21. 21. AP propagation along myelinated nerves <ul><li>Local current will flow one node to another </li></ul><ul><li>Thus propagation of A.P. is faster. Conduction through myelinated fibres also faster. </li></ul><ul><li>Known as Saltatory Conduction </li></ul>
  22. 22. Membrane stabilisers <ul><li>Membrane stabilisers (these decrease excitability) </li></ul><ul><ul><ul><li>Increased serum Ca++ </li></ul></ul></ul><ul><ul><ul><ul><li>Hypocalcaemia causes membrane instability and spontaneous activation of nerve membrane </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Reduced Ca level facilitates Na entry </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Spontaneous activation </li></ul></ul></ul></ul><ul><ul><ul><li>Decreased serum K+ </li></ul></ul></ul><ul><ul><ul><li>Local anaesthetics </li></ul></ul></ul><ul><ul><ul><li>Acidosis </li></ul></ul></ul><ul><ul><ul><li>Hypoxia </li></ul></ul></ul><ul><li>Membrane destabilisers (these increase excitability) </li></ul><ul><ul><ul><li>Decreased serum Ca++ </li></ul></ul></ul><ul><ul><ul><li>Increased serum K+ </li></ul></ul></ul><ul><ul><ul><li>Alkalosis </li></ul></ul></ul><ul><ul><ul><li>Caffeine </li></ul></ul></ul><ul><ul><ul><li>strychnine </li></ul></ul></ul>
  23. 23. NMJ function <ul><li>Pre-synaptic membrane </li></ul><ul><ul><ul><li>Ca channels </li></ul></ul></ul><ul><ul><ul><li>Acetycholine release </li></ul></ul></ul><ul><li>Postsynaptic membrane </li></ul><ul><ul><ul><li>Acetylcholine receptors </li></ul></ul></ul><ul><ul><ul><li>Ligand-gated channels </li></ul></ul></ul><ul><li>Synaptic cleft </li></ul><ul><ul><ul><li>cholinesterase </li></ul></ul></ul>
  24. 24. Synapse <ul><li>A gap between two neurons </li></ul><ul><li>More commonly chemical </li></ul><ul><li>Rarely they could be electrical (with gap junctions) </li></ul>
  25. 25. <ul><li>Although an axon conducts bothways, conduction through synapse is oneway </li></ul><ul><li>presynaptic neuron to postsynaptic neuron </li></ul><ul><li>A neurone receives more than 10000 synapses. Postsynaptic activity is an integrated function </li></ul>
  26. 26. Presynaptic terminal (terminal knob, boutons, end-feet or synaptic knobs) <ul><ul><li>Terminal has synaptic vesicles and mitochondria </li></ul></ul><ul><ul><li>Mitochondria (ATP) are present inside the presynaptic terminal </li></ul></ul>Vesicles containing neurotransmitter (Ach)
  27. 27. Presynaptic terminal (terminal knob, boutons, end-feet or synaptic knobs) <ul><ul><li>Presynaptic membrane contain voltage-gated Ca channels </li></ul></ul><ul><ul><li>The quantity of neurotransmitter released is proportional to the number of Ca entering the terminal </li></ul></ul><ul><ul><li>Ca ions binds to the protein molecules on the inner surface of the synaptic membrane called release sites </li></ul></ul><ul><ul><li>Neurotransmitter binds to these sites and exocytosis occur </li></ul></ul>
  28. 28. Ca 2+ Ca 2+
  29. 29. <ul><li>Postsynaptic membrane contain receptors for the neurotransmitter released </li></ul><ul><li>eg: Acetylcholine receptor </li></ul>Ach Na+ <ul><li>This receptor is Ach-gated Na+ channel </li></ul><ul><li>When Ach binds to this, Na+ channel opens up </li></ul><ul><li>Na+ influx occurs </li></ul>
  30. 30. <ul><li>Na+ influx causes depolarisation of the membrane </li></ul><ul><ul><li>End Plate Potential (EPP) </li></ul></ul><ul><ul><ul><li>This is a graded potential </li></ul></ul></ul><ul><ul><ul><li>Once this reaches the threshold level </li></ul></ul></ul><ul><ul><ul><li>AP is generated at the postsynaptic membrane </li></ul></ul></ul>
  31. 31. Ach release <ul><li>An average human end plate contains 15-40 million Ach receptors </li></ul><ul><li>Each nerve impulse release 60 Ach vesicles </li></ul><ul><li>Each vesicle contains about 10,000 molecules of Ach </li></ul><ul><li>Ach is released in quanta (small packets) </li></ul><ul><li>Even at rest small quanta are released </li></ul><ul><li>Which creates a minute depolarising spike called Miniature End Plate Potential (MEPP) </li></ul><ul><li>When an impulse arrives at the NMJ quanta released are increased in several times causing EPP </li></ul>
  32. 32. Ach vesicle docking <ul><li>With the help of Ca entering the presynaptic terminal </li></ul><ul><li>Docking of Ach vesicles occur </li></ul><ul><li>Docking: </li></ul><ul><ul><li>Vesicles move toward & interact with membrane of presynaptic terminal </li></ul></ul><ul><li>There are many proteins necessary for this purpose </li></ul><ul><li>These are called SNARE proteins </li></ul><ul><li>eg. Syntaxin, synaptobrevin etc </li></ul>
  33. 33. Axoplasmic transport <ul><li>The process by which mitochondria, synaptic vesicles and other cytoplasmic constituents travel to and from the cell body </li></ul><ul><li>axon contains 100 times the volume of the cell body </li></ul><ul><li>proteins for neurotransmitters and membrane repair are constantly transported anterogradely </li></ul><ul><ul><li>to maintain normal axonal function </li></ul></ul><ul><li>If the axon is deprived of proteins because it is severed or crushed </li></ul><ul><ul><li>the segment that is distal to the injury cannot support itself and will degenerate </li></ul></ul>
  34. 34. NMJ blocking <ul><li>Useful in general anaesthesia to facilitate inserting tubes </li></ul><ul><li>Muscle paralysis is useful in performing surgery </li></ul>
  35. 35. Earliest known NMJ blocker - Curare <ul><li>Curare has long been used in South America as an extremely potent arrow poison </li></ul><ul><li>Darts were tipped with curare and then accurately fired through blowguns made of bamboo </li></ul><ul><li>Death for birds would take one to two minutes, small mammals up to ten minutes, and large mammals up to 20 minutes </li></ul><ul><li>NMJ blocker used in patients is tubocurarine </li></ul><ul><li>Atracurium is now used </li></ul>
  36. 36. Neuromuscular blocking agents <ul><li>Non-depolarising type (competitive) </li></ul><ul><ul><li>Act by competing with Ach for the Ach receptors </li></ul></ul><ul><ul><li>Binds to Ach receptors and blocks </li></ul></ul><ul><ul><li>Prevent Ach from attaching to its receptors </li></ul></ul><ul><ul><li>No depolarisation </li></ul></ul><ul><ul><li>Prolonged action (30 min) </li></ul></ul><ul><ul><li>Ach can compete & the effect overcomes by an excess Ach </li></ul></ul><ul><ul><li>Anticholinesterases can reverse the action </li></ul></ul><ul><ul><li>eg. </li></ul></ul><ul><ul><ul><li>Curare </li></ul></ul></ul><ul><ul><ul><li>Tubocurarine </li></ul></ul></ul><ul><ul><ul><li>Gallamine </li></ul></ul></ul><ul><ul><ul><li>Atracurium </li></ul></ul></ul>
  37. 37. Neuromuscular blocking agents <ul><li>Depolarising type (non-competitive) </li></ul><ul><ul><li>Act like Ach, but resistant to AchE action </li></ul></ul><ul><ul><li>Bind to motor end plate and once depolarises </li></ul></ul><ul><ul><li>Persistent depolarisation leads to a block </li></ul></ul><ul><ul><ul><li>Due to inactivation of Na channels </li></ul></ul></ul><ul><ul><li>Two phases </li></ul></ul><ul><ul><ul><li>Phase I – depolarisation phase – fasciculations </li></ul></ul></ul><ul><ul><ul><li>Phase II – paralysis phase </li></ul></ul></ul><ul><ul><li>Ach cannot compete </li></ul></ul><ul><ul><li>Quick action (30 sec), short duration (10 min) </li></ul></ul><ul><ul><li>Anticholinesterases cannot reverse the action </li></ul></ul><ul><ul><li>eg. </li></ul></ul><ul><ul><ul><li>suxamethonium </li></ul></ul></ul><ul><ul><ul><li>Ach in large doses </li></ul></ul></ul><ul><ul><ul><li>nicotine </li></ul></ul></ul>
  38. 38. Neuromuscular blocking agents <ul><li>AchE inhibitors </li></ul><ul><ul><li>Inhibit AchE so that Ach accumulates and causes depolarising block </li></ul></ul><ul><li>Reversible </li></ul><ul><ul><li>Competitive inhibitors of AChE </li></ul></ul><ul><ul><li>Block can be overcome by curare </li></ul></ul><ul><ul><ul><li>physostigmine, neostigmine, edrophonium </li></ul></ul></ul><ul><li>Irreversible </li></ul><ul><ul><li>Binds to AChE irreversibly </li></ul></ul><ul><ul><ul><li>, insecticides, nerve gases </li></ul></ul></ul>
  39. 39. NMJ disorders <ul><li>Myasthenia gravis </li></ul><ul><ul><li>Antibodies to Ach receptors </li></ul></ul><ul><ul><li>Post synaptic disorder </li></ul></ul><ul><li>Lambert Eaton Syndrome (myasthenic syndrome) </li></ul><ul><ul><li>Presynaptic disorder (antibodies against Ca channels) </li></ul></ul><ul><li>Botulism </li></ul><ul><ul><li>Presynaptic disorder </li></ul></ul><ul><ul><li>Binds to the presynatic region and prevent release of Ach </li></ul></ul>
  40. 40. NMJ disorders <ul><li>Snake venom (Presynaptic or postsynaptic disorder) </li></ul><ul><ul><li>Krait (bungarotoxin) </li></ul></ul><ul><ul><ul><li>Postsynaptic disorder </li></ul></ul></ul><ul><ul><li>Cobra </li></ul></ul><ul><ul><ul><li>Postsynaptic disorder </li></ul></ul></ul><ul><ul><li>Russell’s viper </li></ul></ul><ul><ul><ul><li>Presynaptic disorder </li></ul></ul></ul>
  41. 41. Botulinum toxin <ul><li>Most potent neurotoxin known </li></ul><ul><li>Produced by bacterium Clostridium botulinum </li></ul><ul><li>Causes severe diarrhoeal disease called botulism </li></ul><ul><li>Action: </li></ul><ul><ul><li>enters into the presynaptic terminal </li></ul></ul><ul><ul><li>cleaves proteins (syntaxin, synaptobrevin) necessary for Ach vesicle release with Ca2+ </li></ul></ul><ul><li>Chemical extract is useful for reducing muscle spasms, muscle spasticity and even removing wrinkles (in plastic surgery) </li></ul>
  42. 42. Video clip
  43. 43. Organophosphates <ul><li>Phosphates used as insecticides </li></ul><ul><li>Action </li></ul><ul><ul><li>AchE inhibitors </li></ul></ul><ul><ul><li>Therefore there is an excess Ach accumulation </li></ul></ul><ul><ul><li>Depolarising type of postsynaptic block </li></ul></ul><ul><li>Used as a suicidal poison </li></ul><ul><ul><ul><li>Causes muscle paralysis and death </li></ul></ul></ul><ul><li>Nerve gas (sarin) </li></ul>
  44. 44. Snake venom <ul><li>Common Krait ( bungarus caeruleus) </li></ul><ul><ul><li>Produces neurotoxin known as bungarotoxin </li></ul></ul><ul><ul><li>Very potent </li></ul></ul><ul><ul><ul><li>Causes muscle paralysis and death if not treated </li></ul></ul></ul><ul><li>Cobra </li></ul><ul><ul><li>venom contain neurotoxin </li></ul></ul>
  45. 45. Myasthenia gravis <ul><li>Serious neuromuscular disease </li></ul><ul><li>Antibodies form against acetylcholine nicotinic postsynaptic receptors at the NMJ </li></ul><ul><li>Characteristic pattern of progressively reduced muscle strength with repeated use of the muscle and recovery of muscle strength following a period of rest </li></ul><ul><li>Present with ptosis, fatiguability, speech difficulty, respiratory difficulty </li></ul><ul><li>Treated with cholinesterase inhibitors </li></ul>
  46. 46. Muscle contraction <ul><li>T tubules </li></ul><ul><li>Voltage-gated Ca channels </li></ul><ul><li>Actin-myosin cross bridges </li></ul><ul><li>Muscle contraction </li></ul><ul><li>ATP release </li></ul><ul><li>Reversal of the process </li></ul>
  47. 47. Muscle contraction <ul><li>Depolarisation of the muscle membrane spreads through the muscle </li></ul><ul><li>Causes muscle contraction </li></ul>
  48. 48. Muscle contraction <ul><li>Excitation - contraction coupling </li></ul><ul><ul><li>Excitation : electrical event </li></ul></ul><ul><ul><li>Contraction : mechanical event </li></ul></ul>
  49. 49. Ca++ Ca++
  50. 50. <ul><li>AP spreads through t tubule into the muscle tissue </li></ul><ul><li>Close to the sarcoplasmic reticulum, AP activates a receptor (votage-gated Ca++ channel) </li></ul><ul><li>Ca flows to the myoplasm in the vicinity of actin & myosin </li></ul>
  51. 51. <ul><li>Ca ++ binds to troponin </li></ul><ul><li>Troponin shifts tropomyosin </li></ul><ul><li>Myosin binding sites in actin filament uncovered </li></ul><ul><li>Myosin head binds with actin </li></ul><ul><li>Cross bridges form </li></ul><ul><li>Filaments slide with ATP being broken down </li></ul><ul><li>Muscle shortens </li></ul><ul><li>New ATP occupies myosin head </li></ul><ul><li>Myosin head detaches </li></ul><ul><li>Filaments slide back </li></ul><ul><li>Cycling continues as long as Ca is available </li></ul>Troponin Actin Myosin Tropomyosin ATP
  52. 52. Detachment Sliding Binding Ca 2+ Troponin Actin Myosin Tropomyosin Ca 2+ Myosin binding sites Ca 2+ Ca 2+
  53. 53. <ul><li>Relaxation </li></ul><ul><ul><li>This occurs when Ca++ is removed from myoplasm by Ca++ pump located in the sarcoplasmic reticulum </li></ul></ul><ul><ul><li>When Ca++ conc is decreased </li></ul></ul><ul><ul><li>Troponin returns to original state </li></ul></ul><ul><ul><li>Trpomyosin covers myosin binding sites </li></ul></ul><ul><ul><li>Cross-bridge cycling stops </li></ul></ul>
  54. 54. slow & fast fibres <ul><li>Slow twitch fibre (type I fibre) </li></ul><ul><li>Fast twitch fibre (type II fibre) </li></ul>
  55. 55. Slow twitch fibre (type I fibre) <ul><ul><li>Slow cross-bridge cycling </li></ul></ul><ul><ul><li>slow rate of shortening (eg. soleus muscle in calf) </li></ul></ul><ul><ul><li>high resistance to fatigue </li></ul></ul><ul><ul><li>high myoglobin content </li></ul></ul><ul><ul><li>high capillary density </li></ul></ul><ul><ul><li>many mitochondria </li></ul></ul><ul><ul><li>low glycolytic enzyme content </li></ul></ul><ul><ul><li>They are red muscle fibres </li></ul></ul>
  56. 56. Fast twitch fibre (type II fibre) <ul><ul><li>rapid cross-bridge cycling, </li></ul></ul><ul><ul><li>rapid rate of shortening (eg. extra-ocular muscles) </li></ul></ul><ul><ul><li>low resistance to fatigue </li></ul></ul><ul><ul><li>low myoglobin content </li></ul></ul><ul><ul><li>low capillary density </li></ul></ul><ul><ul><li>few mitochondria </li></ul></ul><ul><ul><li>high glycolytic enzyme content </li></ul></ul><ul><ul><li>fast twitch fibers use anaerobic metabolism to create fuel, they are much better at generating short bursts of strength or speed than slow muscles </li></ul></ul>

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