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Neuromuscular Blocking Agents David Hirsch MD CA-1.

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Presentation on theme: "Neuromuscular Blocking Agents David Hirsch MD CA-1."— Presentation transcript:

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

10 Neuromuscular Transmission Cations flow through open ach – Na/Ca in; K out – Generates end plate potential – 1 vesicle = quanta of ach (10 4 ) 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.

11 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

12 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

13 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

14 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

15 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

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

17 Depolarizing and non-depolarizing Muscle Relaxants DepolarizingNon-depolarizing Short-acting Succinylcholine Short-acting Mivacurium Intermediate-acting Atracurium; Cisatracurium Rocuronium; Vecuronium Long-Acting Doxacurium Pancuronium; Pipecuronium

18 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

19 Reversal Jake Hummel’s wonderful lecture to follow

20 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

21 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

22 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

23 C

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

25 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

26 Dosage: Succinylcholine Adult – Intubation 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 ml titrated to effect) Children – Intubation Infants/Small kids: 2mg/kg Older children and Adolescents 1mg/kg

27 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

28 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

29 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

30 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

31 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

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

33 D

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

35 B

36 Non-Depolarizers DrugStructureMetabolismPrimary Excretion OnsetDurationHist. Release Vagal Blockade AtracuriumB+++x++ +0 CisatracuriumB+++x++ 00 MivacuriumB+++x++++0 DoxacuriumBInsignificantRenal PancuroniumS+Renal PipercuroniumS+Renal VecuroniumS+Biliary++ 00 RocuroniumSinsignificantBiliary

37 DrugIntubation dose (mg/kg) Onset of action for Intubating dose (mg/kg) Duration of Intubatin g dose (min) Maintenance dosing by boluses (mg/kg) Maintenance dosing by infusion (ug/kg/min) Succinylcholine mg/min Rocuronium Mivacurium Atracurium ,15-12 Cisatracurium Vecuronium Pancuronium x Pipercuronium x Doxacurium x

38 Non-depolarizers Two types – Benzylisoquinolines Release histamine – Steroids Vagolytic – Related allergic history

39 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 % 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

40 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

41 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

42 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

43 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

44 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

45 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)

46 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

47 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

48 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

49 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

50 Pipecuronium Steroid base (similar to Pancuronium) Renal excretion No cardiovascular side effects – Advantage over pancuronium

51 Vecuronium Biliary and renal excretion Satisfactory in renal failure however some prolongation occurs Side effects – No significant CV effects Can cause potentiation of opioid-induced bradycardia – *Long term administration causes buildup of active 3-hydroxy metabolite: elongates drug clearance and can cause polyneuropathy

52 Rocuronium Analogue of vecuronium designed for rapid onset No active metabolite – Better choice for long term infusion Can cause prolonged duration of action in elderly Primary hepatic and renal elimination – Duration of action prolonged by hepatic disease and pregnancy – Not Significantly affected by renal failure

53 Rocuronium Useful for quick onset of action – Closest non-depolarizer to succinylcholine.1 mg/kg shown to be rapid and effective agent (decreased fasciculations and post-op myalgias for precurarization administration of succinylcholine Slight vagolytic tendencies

54 The Future? Want better control over onset/duration/off Replacement for succinylcholine – 430a Supposedly coming soon Similar onset, duration and offset to succinylcholine First non-depolarizer with these futures Quicker/more efficient reversal – Cysteine? Reversal of still-developing drugs in 1-2 minutes at 100%

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

56 Sources Feldman S: Neuromuscular Blockade. Butterworth-Heinemann, Excellent chapters on neuromuscular transmission, acetylcholine pharmacology, and mechanisms of muscle relaxant actions. Miller, Ronald D, Pardojr, Manuel C. Chapter 12. Neuromuscular Blocking Agents, IN: Miller: Basics of Anesthesia. 6 th ed. Philadelphia, PA: Elsevier Saunders; Morgan, Jr. GE, Mikhail MS, Murray MJ. Chapter 9. Neuromuscular Blocking Agents. In: Morgan, Jr. GE, Mikhail MS, Murray MJ, eds. Clinical Anesthesiology. 4th ed. New York: McGraw-Hill; Naguib M, Flood P, McArdle JJ, Brenner HR: Advances in the neurobiology of the neuromuscular junction. Anesthesiology 2002;96:202. Naguib M, Samarkandi A, Riad W, Alharby SW: Optimal dose of succinylcholine revisited. Anesthesiology 2003;99:1045.


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