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Neuromuscular Blocking Agents

Neuromuscular Blocking Agents. David Hirsch MD CA-1. Disclosures. Key Concepts. 1) PARALYTICS DO NOT CAUSE AMNESIA, ANALGESIA OR UNCONSCIOUSNESS 2) Depolarizing = Ach receptor agonists Non-depolarizing=competitive antagonists. History. 1942 Harold Griffith

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Neuromuscular Blocking Agents

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  1. Neuromuscular Blocking Agents David Hirsch MD CA-1

  2. Disclosures

  3. Key Concepts • 1) • PARALYTICS DO NOT CAUSE AMNESIA, ANALGESIA OR UNCONSCIOUSNESS • 2) • Depolarizing = Ach receptor agonists • Non-depolarizing=competitive antagonists

  4. History • 1942 • Harold Griffith • Studied a refined extract of curare • “South American Arrow Poison” • Noted that they produced paralysis not anesthesia

  5. Introduction • Skeletal muscle relaxation can be caused by • Deep inhalational anesthesia • Regional nerve block • Neuromuscular blocking agents

  6. Neuromuscular Transmission • Neuromuscular Junction • Between motor neuron and muscle cell • AP depolarizes terminal, influx of calcium ions through voltage gated Ca channels =release of ach • Diffuse along synaptic cleft • Bind with nicotinic cholinergic receptors on motor end plate • Each NM junction = 5 million receptors • Activation requires around 500k

  7. Neuromuscular Transmission

  8. Structure • Ach receptor • 5 protein subunits • 2 alpha, 1 beta, 1 delta, 1 epsilon • Only alpha bind ach • If both binding sites occupied by Ach, conformational change occurs • Fetal muscle • Gamma subunit instead of epsilon

  9. Neuromuscular Transmission • Cations flow through open ach • Na/Ca in; K out • Generates end plate potential • 1 vesicle = quanta of ach (104) • usually 200 per nerve impulse released • Depend on extracellular ionized calcium (higher calcium concentration = increased quanta release • When enough receptors occupied by ach, end plate potential strong enough to depolarize peri-junctional membrane • Sodium channels open when threshold voltage reached, as opposed to end-plate receptors that open to Ach.

  10. Sodium Channel • Trans-membrane protein with two functional gates • Sodium ions pass only when both gates are open • At rest, lower gate open, upper gate closed • Muscle membrane reaches voltage depolarization, upper gate opens and • sodium can pass • Shortly after upper gate opens, time dependent lower gate closes • When membrane repolarizes to its resting voltage , upper gate closes and lower gate opens

  11. Action Potential • The resulting action propagates down muscle membrane and T tubule system. • Opens sodium channels • Releases calcium into sarcoplasmic reticulum • Allows contractile proteins myosin and actin to interact • Amount of ach released and number of receptors far exceed minimum required • Except for • Lambert-Eaton Syndrome (decreased release of ach) • Myasthenia gravis (decreased number of receptors

  12. Neuromuscular Blockade: Mechanism • Depolarizing Muscle Relaxants • Closely resemble Ach • Bind to receptors • NOT metabolized by acetylcholinesterase therefore concentration in synaptic cleft does not fall as rapidly • Results in prolonged depolarization of muscle-end plate

  13. Neuromuscular Blockade: Mechanism • Depolarizing Muscle relaxant • Prolonged depolarization causes relaxation due to the time limited lower gate on the sodium channel. • Gate cannot reopen until end plate repolarization • End plate cannot repolarize as long as muscle relaxant bind to ach receptor (Phase 1 block) • Prolonged end-plate depolarization can cause ionic and conformational changes in ach receptor that result in phase II block • similar to non depolarizing muscle relaxants

  14. Neuromuscular Blockade: Mechanism • Non-depolarizing muscle relaxants • Bind to ach receptors • Incapable of inducing conformational changes • Ach prevented from binding to receptors • No end-plate potential • NM blockade even if only one alpha subunit blocked • *Depolarizing=agonist • *Non-depolarizing = competitive antagonists

  15. Acetylcholinesterase • Substrate-specific enzyme • Rapidly hydrolyzes acetylcholine into acetate and choline • Embedded into motor end-plate immediately adjacent to ach receptors

  16. Depolarizing and non-depolarizing Muscle Relaxants

  17. Non-classical Blockade • Some drugs interfere without agonist or antagonist properties • Include inhaled anesthetic, local anesthetic or ketamine • Interfere with normal functioning of ach binding site and/or opening and closing of receptor channel • Closed channel blockade • Open channel blockade • Drug enters and obstructs ach receptor channel after opened • Use dependent • Occurs with antibiotics, cocaine and quinidine • Interferes with blockade reversal

  18. Reversal • Jake Hummel’s wonderful lecture to follow

  19. Succinylcholine • Only depolarizing in clinical use • Copycat Ach structure • Rapid onset (30-60s) • Low lipid solubility as well as relative overdose given • Short duration of action (< 10 min) • As it enters the system, most is metabolized by pseudocholinesterase • Only small fraction of injected dose reach NMJ

  20. Duration of Action: Succinylcholine • Prolonged by high dose or abnormal metabolism • Hypothermia • Decreased rate of hydrolysis • Low pseudo-cholinesterase levels • Pregnancy, liver disease, renal failure and drugs • Esmolol, metoclopramide, OCP among others • Genetically variable enzyme • 1 in 50 = one normal and one abnormal gene • Slightly prolonged block (20-30 min) • 1 in 3000 • 2 abnormal genes, up to 4-8 hour blockade • Dibucaine resistant –most common abnormal pseudocholinesterase

  21. Q • How should prolonged paralysis from succinylcholine caused by abnormal pseudo cholinesterase be treated? • A. Page Dr Friedman and ask for help • B. Give Neostigimine • C. Mechanical ventilate until muscle function returns to normal • D. Give cholinesterase substitute

  22. C

  23. Drug Interactions: Succinylcholine • Cholinesterase inhibitors • Prolong phase 1 block • Inhibit acetylcholinesterase=higher ach concentration which increase depolarization • Reduce hydrolysis of succinylcholine • Inhibit pseudocholinestrase

  24. Drug Interactions: Succinylcholine • Non-depolarizing muscle relaxant • Small dose • Occupy some ach receptors, blocking succinylcholine depolarization • Exception: Pancuronium: augments by inhibiting pseudocholinestrase • Intubating dose • Reduced dose needed • Atracurium and rocuronium • No effect • Mivacurium, pancuronium, pipercuronium

  25. Dosage: Succinylcholine • Adult • Intubation • 1-1.5 mg/kg IV *(possibly excessive) • .5 mg/kg acceptable if defasciculating dose of non-depolarizer is not used • Maintenance • Repeated small bolus (10mg) or drip (1g in 500-1000ml titrated to effect) • Children • Intubation • Infants/Small kids: 2mg/kg • Older children and Adolescents 1mg/kg

  26. Side Effects • Cardiovascular • Variable • Secondary to possible stimulation of nicotinic receptors in parasympathetic and sympathetic ganglia, as well as muscarinic receptors in SA node • Low doses • Can produce negative chronotropic/inotropic effects • Higher doses • Tend to increase heart rate and contractility as well as elevate circulating catecholamine • Children • Particularly susceptible to bradycardia • Often treated prophylactically with atropine

  27. Side effects cont. • Fasciculation • Signals onset of paralysis • Prevented by non-depolarizing relaxant • Muscle Pains • Increased post-op myalgia • Possibly from unsynchronized contraction of muscle groups • Increased CK and myoglobinemia can be found after succinylcholine given • Reduced by NSAID preoperatively

  28. Side Effects • Hyperkalemia • Intubating dose • Normal muscle releases enough potassium to raise serum .5 meq • Concerning in cases of • Preexisting hyperkalemia (renal failure) • Burn Injury • Massive Trauma • Neurological disorders • Many more • Cardiac arrest can prove to be quite refractory to routine cardiopulmonary resuscitation

  29. Side effects • Malignant Hyperthermia • Potent triggering agent in patients susceptible to MH • Intracranial pressure • May lead to increase in cerebral blood flow and ICP • Attenuated with hyperventilation/good airway control • Pre-treat with non-depolarizing muscle relaxant and IV lidocaine 2-3 minutes prior to intubation

  30. Side effects • Intragastric pressure elevation • Abdominal wall fasciculations increase pressure • Offset by increase LES tone • No increase reflux/aspiration • Abolished by pretreatment • Intraocular pressure elevation • Extra-ocular muscle • multiple motor-end plates each cell • Prolonged depolarization and contraction of muscle transiently raise IOP • Worrisome in patient’s with injured eye

  31. Which non-depolarizer has the slowest onset (at proper intubating dose)? • A. Rocuronium • B. Pancuronium • C. Vecuronium • D. Doxacurium • E. Atracurium

  32. D

  33. Which non-depolarizer causes the most vagal blockade? • A. Rocuronium • B. Pancuronium • C. Vecuronium • D. Doxacurium • E. Atracurium

  34. B

  35. Non-Depolarizers

  36. Non-depolarizers • Two types • Benzylisoquinolines • Release histamine • Steroids • Vagolytic • Related allergic history

  37. Non-depolarizers • Intubation • None as rapid onset as succinylcholine • Quickened by larger dose or priming dose • Prolongs duration of blockade and exacerbates SE • Priming dose • 10-15 % of intubating dose 5 minutes before induction will occupy enough receptors so that paralysis quickly follows full dose • Intubation conditions at 60s (Rocuronium) • 90s with other intermediate-acting depolarizers • Does not usually lead to clinically significant paralysis • (75-80% of receptors blocked) • Can cause dyspnea, dysphagia and diplopia

  38. Non-depolarizers • Maintenance relaxation • LARGE VARIABLE IN DOSE RESPONSES • Requires Close monitoring with Neuro-stimulator • Bolus or infusion should be guided by stimulator as well as clinical signs • Movement • Spontaneous ventilation • Some return of neuromuscular transmission should be evident prior to bolus dose • Infusion should be titrated at or just above rate that allows return of neuromuscular transmission

  39. Non-depolarizers • Potentiated by inhalational anesthetics • Volatile agents decrease dosage requirements by at least 15 % • Depends on agent • Des> Sevo > Iso and Enflurane > Halothane > N202 • Muscle relaxant • Pancuronium > vecuronium and atracurium • Hypothetically due to volatile induced enhanced affinity for non-depolarizing muscle relaxants

  40. Autonomic side Effects • Older agents (tubocurarine/metocurine) • Blocked autonomic ganglia • Decreased contractility/response to hypotension • Pancuronium • Blocks vagal muscarinic receptors • Tachycardia • Newer agents • Devoid of significant autonomic effects

  41. Excretion • Hepatic • Pancuronium\Vecuronium metabolized mostly by liver • Liver failure • Prolongs pancuronium as well as rocuronium blockade • Less effect on vecuronium • No effect on Cisatracurium or atracurium • Renal • Doxacurium/Pancuronium/Vecuronium and pipecuronium excreted by kidneys • Prolonged action in patients with renal failure

  42. Characteristics • Greater Potency=slower onset • Temperature • Hypothermia prolongs blockade • Decreased metabolism and excretion • Acid-Base • Respiratory acidosis • Potentiates blockade • Hypokalemia/Hypocalcemia • Prolong blockade • Hypermagesemia • Prolongs blockade by competing with Ca++ at motor-end plate • Seen in preeclampsia

  43. Atracurium • Benzylisoquinoline • Metabolized independent of renal and biliary routes • Hoffman elimination • Triggers dose –dependent histamine release above .5mg/kg (intubating dose) • Hypotension/reflex tachycardia/cutaneous flush • Laudanosine toxicity • Product of breakdown of atracurium • CNS excitation: possibly seizures • Only relevant at extremely high doses or hepatic failure • Precipitate as free acid if placed in IV line with alkaline solution (thiopental)

  44. Cisatracurium • Stereoisomer of atracurium • 4 times more potent • Hoffman elimination • *Does not produce a dose-dependent increase in histamine • Also lower laudaonsine toxicity • PH/Temperature sensitive • Secondary to unique metabolism • Prolonged action by hypothermia/acidosis

  45. Mivacurium • Metabolized by pseudocholinesterase • Also prolonged by low pseudocholinesterase levels • Also causes histamine release • Brief duration of action • About half of atracurium/vec/rocuronium • Markedly prolonged by prior administration of pancuronium

  46. Doxacuronium • Benzylisoquinoline • Renal excretion • Similar to other long acting non-depolarizers • Slow onset (4-6 minutes) • .05mg/kg for tracheal intubation within 5 min • No cardiac or histamine-release side effects • Duration:60-90 minutes

  47. Pancuronium • Steroid base • Primarily renal excretion • Slowed by renal failure • Some excretion by bile • Cirrhotic patients require higher initial dose • Side Effects: • HTN and tachycardia • Combination of vagal blockade and sympathetic stimulation • Caution with CAD, aortic stenosis • Arrhythmias • Increases AV conduction and catecholamine release • Worsened in patients using TCA and halothane • Allergic reaction possible in patients hypersensitive to bromide

  48. Pipecuronium • Steroid base (similar to Pancuronium) • Renal excretion • No cardiovascular side effects • Advantage over pancuronium

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