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 Motor neurons : are the nerves that innervate muscle fibers Motor unit : single motor neuron and the muscle fibers it innervate

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

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

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

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

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

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

Sequence Of Events At Neuromuscular Junction (continued)

Sequence Of Events At Neuromuscular Junction (continued)

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

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

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

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.

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.

Objectives Mechanism of action Monitoring Pharmacology Reversal non-depolarizers depolarizers Reversal

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

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

Smith CE, Peerless JR: ITACCS Monograph 1996 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

TOF Monitoring TOF: Loss of all 4 twitches: Return of 1-2 twitches: 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

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

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

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

Prielipp et al: Anesth Analg 1995;81:3-12 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

Succinylcholine Maintenance dose: no longer used 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

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

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

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

Bevan DR, Bevan JC, Donati F: 1988 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

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

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

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

Savarese JJ, Caldwell JE, Lien CA, Miller RD: 2000 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

Reversal of NM Block Clinical practice: Rule of thumb: 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!

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

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