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NEUROMUSCULAR JUNCTION PHYSIOLOGY & BLOCKING AGENTS

NEUROMUSCULAR JUNCTION PHYSIOLOGY & BLOCKING AGENTS. PROF V K BHATIA DEPT OF ANAESTHESIOLOGY KGMU. Neuromuscular junction (example of chemical synapse). Neuromuscular junction : the synapse between motor neuron and muscle fiber is called the neuromuscular junction

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NEUROMUSCULAR JUNCTION PHYSIOLOGY & BLOCKING AGENTS

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  1. NEUROMUSCULAR JUNCTION PHYSIOLOGY &BLOCKING AGENTS PROF V K BHATIA DEPT OF ANAESTHESIOLOGY KGMU

  2. Neuromuscular junction(example of chemical synapse) • Neuromuscular junction : the synapse between motor neuron and muscle fiber is called the neuromuscular junction • Motor neurons : are the nerves that innervate muscle fibers • Motor unit : single motor neuron and the muscle fibers it innervate

  3. Physiologic anatomy of N.M junction (continued) • As axon approaches muscle , it divides into many terminal branches and loses its myelin sheath • Each of these axon terminal forms special junction ,a neuromuscular junction with one or more muscle fiber

  4. Physiologic anatomy of N.M junction (continued) • The axon terminal is enlarged into a knoblike structure ,the terminal botton,which fits into shallow depression in underlying muscle fiber

  5. Sequence Of Events At Neuromuscular Junction Action potentials arriving at the presynaptic terminal cause voltage-gated Ca2+ channels to open.

  6. Sequence Of Events At Neuromuscular Junction (continued) Ca2+ uptake into the terminal causes release of the neurotransmitter acetylcholine into synaptic cleft , which has been synthesized and stored into synaptic vesicles

  7. Sequence Of Events At Neuromuscular Junction (continued) • Ach travels across the synaptic cleft to postsynaptic membrane which is also known as motor end plate.

  8. Sequence Of Events At Neuromuscular Junction (continued) • Motor end plate contains nicotinic receptors for Ach , which r ligand gated ion channels • Ach binds to the alpha subunits of nicotinic receptors and causes conformational change. • When conformational changes occurs ,the central core of channels opens & permeability of motor end plate to Na+ & K+ increases

  9. Sequence Of Events At Neuromuscular Junction (continued)

  10. Sequence Of Events At Neuromuscular Junction (continued)

  11. End plate potential • When the ion channel on post synaptic membrane opens both Na+ & K+ flow down their concentration gradient. • At resting potential net driving force for Na+ is much greater than K+ ,when Ach triggers opening of these channels more Na+ moves inwards than K+ out wards, depolarizing the end plate.this potential change is called end plate potential (EPP). • EPP is not an action potential but it is simply depolarization of specialized motor end plate

  12. End plate potential (continued) • Small quanta (packets) of Ach are released randomly from nerve cell at rest, each producing smallest possible change in membrane potential of motor end plate, the MINIATURE EPP. • When nerve impulse reaches the ending, the number of quanta release increases by several folds and result in large EPP. • EPP than spread by local current to adjacent muscle fibers which r depolarized to threshold & fire action potential

  13. Acetyl cholinesterase ends Ach activity at N.M junction • To ensure purposeful movement ,muscle cell electrical response is turned off by acetylcholinestrase(AchE), which degrade Ach to choline & acetate • About 50%of choline is returned to the presynaptic terminal by Na+choline transport to be reused for Ach synthesis. • Now muscle fiber can relax ,if sustained contraction is needed for the desired movement another motor neuron AP leads to release of more Ach

  14. Myasthenia gravis • A disease involving N.M junction is characterized by the extreme muscular weakness (myasthenia=muscular & gravis=severe) • It is an auto immune condition (auto immune means immunity against self) in which the body erroneously produces antibodies against its own motor end plate ach receptors. • Thus not all Ach molecules can find functioning receptors site with which to bind. • As a results ,AchE destroys much of Ach before it ever has a chance to interact with receptor site & contribute to EPP.

  15. Treatment : it is treated with long acting anticholinesterase inhibitor pyridostigmine or neostigmine. Which maintains the Ach levels at N.M junction at high levels thus prolonging the time available for Ach to activate its receptors.

  16. Objectives • Mechanism of action • Monitoring • Pharmacology • non-depolarizers • depolarizers • Reversal

  17. Classical Mechanism of Action • Non-depolarizers: • bind to AchR, post junctional nicotinic receptor • competitively prevent binding of Ach to receptor • ion channel closed, no current can flow • Depolarizers- succinylcholine: • mimic action of Ach • excitation of muscle contraction followed by blockade of neuromuscular transmission

  18. Margin of Safety • Wide margin of safety of neuromuscular transmission • 70% receptor occupancy before twitch depression

  19. Clinical Use • Anesthesia: • facilitate tracheal intubation • paralysis for surgery + mechanical ventilation • ICU: •  VO2 • tetanus • status epilepticus •  ICP •  shivering Smith CE, Peerless JR: ITACCS Monograph 1996

  20. TOF Monitoring • TOF: • 4 supramaximal stimuli at 2 Hz, every 0.5 sec • observe ratio of 4rth twitch to first • Loss of all 4 twitches: • profound block • Return of 1-2 twitches: • sufficient for most surgeries • Return of all 4 twitches: • easily “reversible” Viby-Mogensen, 1984

  21. Onset + Recovery of NM Block A-Nondepolarizing. B- Sux. Viby-Mogensen: BJA 1982;54:209

  22. Vecuronium • ED90: 0.04 mg/kg • intubating dose: 0.1-0.2 mg/kg • onset: 2-4 min, clinical duration: 30-60 min • Maintenance dose: 0.01-0.02 mg/kg, duration: 15-30 min • Metabolized by liver, 75-80% • Excreted by kidney, 20-25% • ½ life : 60 minutes • Prolonged duration in elderly + liver disease • No CV effects, no histamine release, no vagolysis • May precipitate after thiopental

  23. Rocuronium • ED90: 0.3 mg/kg • intubating dose: 0.6-1.0 mg/kg • onset: 1-1.5 minutes, clinical duration: 30-60 min • Maintenance dose: 0.1-0.15 mg/kg, duration: 15-30 min • Metabolized by liver, 75-80% • Excreted by kidney, 20-25% • ½ life : ~ 60 minutes • Mild CV effects- vagolysis, no histamine release, • Prolonged duration in elderly + liver disease • Only non-depolarizer approved for RSI

  24. Cisatracurium • ED90: 0.05 mg/kg • intubating dose: 0.2 mg/kg • onset: 2-4 minutes, clinical duration: 60 min • Hofmann elimination: not dependent on liver or kidney for elimination • Predictable spontaneous recovery regardless of dose • ½ life : ~ 60 minutes • No histamine release • CV stability • Agent of choice for infusion in ICU Prielipp et al: Anesth Analg 1995;81:3-12

  25. Succinylcholine • ED90: 0.3 mg/kg • intubating dose: 1.0-1.5 mg/kg • onset: 30-45 sec, clinical duration: 5-10 min • can be given IM or sublingual • dose to relieve laryngospasm: 0.3 mg/kg • Maintenance dose: no longer used • Metabolized by pseudocholinesterase • prolonged duration if abnormal pc (dibucaine # 20) • Prolonged effect if given after neostigmine

  26. Succinylcholine: Key Concepts • Bradycardia + nodal rhythms after “2nd dose” in adults + after initial dose in children • Hyperkalemia + cardiac arrest likely 1 week after major burns, or in children with Duchenne’s muscular dystrophy • Not contraindicated in patients with head injury • May cause malignant hyperthermia or masseter spasm • Duration increased by prior administration of neostigmine

  27. Succinylcholine Adverse Effects • Hyperkalemia + cardiac arrest in “at risk patients” • denervation, burns, myopathy • Malignant hyperthermia, masseter spasm •  IOP- blood flow mechanism • Myalgias,  intragastric pressure •  dose requirement for non-depolarizers after sux •  ICP- blood flow mechanism; clinically irrelevant Bevan DR: Semin Anesth 1995;14:63-70

  28. Head Injury + Sux Kovarik, Mayberg, Lam: Anesth Analg 1994;78:469-73

  29. Sux + Hyperkalemia • Burns, Hemiplegia, Paraplegia, Quadraplegia: •  extrajunctional receptors after burn or denervation • Danger of hyperkalemia with sux: 48 hrs post injury until …? • Muscular Dystrophy • Miscellaneous • severe infections, closed head injury, crush, rhabdo, wound botulism, necrotizing pancreatitis • Renal failure: pre-existing hyperkalemia • Acidosis:  extracellular K Bevan DR, Bevan JC, Donati F: 1988

  30. Cholinesterase Inhibitors • ↑ Ach at nicotinic + muscarinic receptors to antagonize NMB • Full reversal depends on diffusion, redistribution, metabolism + excretion

  31. Key Concepts of NMBA Reversal • Cholinesterase inhibitors indirectly reverse NMB • Head lift x 5 sec- reliable sign of reversal • Teeth clenching x 5 sec- reliable sign of reversal • Usually not difficult to reverse block if 2 twitches are visible in response to TOF • Neostigmine is a minor risk factor for PONV • Anticholinergic agents should never be omitted with reversal

  32. Double Burst • TOF fade: difficult to detect clinically until < 0.2 • Use double burst: • 2 short bursts of tetanic stimulation separated by 750 ms • Easier to detect fade + residual block, 0.2-0.7 Viby-Mogensen, 2000

  33. Clinical Evaluation • Reliable signs of adequate NM transmission • Head lift x 5 s • Leg lift x 5 s • Hand grip as strong as preop x 5 s • Sustained bite • Helpful, but unreliable • Normal Vt , Vc, + cough Savarese JJ, Caldwell JE, Lien CA, Miller RD: 2000

  34. Reversal of NM Block • Clinical practice: • if no evidence block + 4 half-lives: omit reversal • if still evidence block: give reversal • if unsure: give reversal • Rule of thumb: • if 2 twitches of TOF visible, block is usually reversible • if no twitches visible, best to wait (check battery) • Neostigmine 2.5 mg/Glycopyrolate 0.5 mg • do not omit anti-cholinergic!

  35. Suggamadex (Org 25969): Safer way to reverse NMB • Gijsenbergh et al, Anesthesiology 2005;103;695-703. Belgium. Phase 1 study • Modified cyclodextrin • Encapsulates roc • Promotes dissociation of roc from AchR • No recurarization

  36. Summary • Indications: tracheal intubation, surgery, mech ventilation • Choice of drug: pharmacology + other factors (histamine) • Onset of action: • sux is fastest • roc is suitable alternative • Duration: • non-depolarizing block easily reversible if 2 twitches • residual block:  incidence with intermediate rx • Monitoring + Reversal: TOF, double burst, clinical signs • Suggmadex: will likely replace neostigmine for reversal

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