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 Fetal muscle
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

10. 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.

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
Short-acting
Succinylcholine
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
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 ml titrated to effect)
Children
Infants/Small kids: 2mg/kg
Older children and Adolescents 1mg/kg

27. Side Effects Cardiovascular Variable Low doses Higher doses Children
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 Muscle Pains
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 Concerning in cases of
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 Intracranial pressure
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 Drug Structure Metabolism Primary Excretion Onset
Duration
Hist.
Release
Vagal Blockade
Atracurium B
+++ x ++ +
Cisatracurium
Mivacurium
Doxacurium
Insignificant
Renal
Pancuronium S
Pipercuronium
Vecuronium
Biliary
Rocuronium
insignificant

37. Drug
Intubation dose
(mg/kg)
Onset of action for Intubating dose
Duration of Intubating dose
(min)
Maintenance dosing by boluses
Maintenance dosing by infusion
(ug/kg/min)
Succinylcholine 1 .5
5-10
.15
2-15 mg/min
Rocuronium .8
1.5
35-75
9-12
Mivacurium .2
15-20
.05
4-15
Atracurium
30-45 ,1
5-12
Cisatracurium
2-3
40-75
.02
1-2
Vecuronium
.12
45-90
.01
Pancuronium
60-120 x
Pipercuronium .1
80-120
Doxacurium
.07
4-5
90-150

38. Non-depolarizers Two types Benzylisoquinolines Steroids
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
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

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 Renal
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 Acid-Base
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 Side effects
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. 6th ed. Philadelphia, PA: Elsevier Saunders; 2011.
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; 2006.
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.