Neuromuscular disorders and the Acetylcholine receptor

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Neuro-muscular disorders and the Acetylcholine
receptor

• Joseph M. Caiati, MD
• Department of Anesthesiology

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Overview

• The Neuromuscular Junction
• Diseases that Increase AChRs in Skeletal Muscle
• Disease that decreases AChRs in Skeletal Muscle
• Succinylcholine and other NDMRs
• Sugammadex

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The Neuromuscular JunctionNormal

• AChRs at NMJ are nicotinic
• AChRs only in Neuromuscular Junction
• 75 blockedweakness 95paralysis
• Depolarization with SCh leads to increase in
  serum K of 0.5-1.0meq/L
• ACh and SCh act briefly at NMJ due to rapid
  metabolism by ACh esterase

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Normal
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Classic receptor theory

• Lack of receptor stimulation causes receptor
  proliferation
• Heavy receptor stimulation causes receptor number
  to decrease
• If there is a proliferation of AChRs
• There will be increased sensitivity to agonists
  (SCh)
• There will be decreased sensitivity to
  competitive antagonists (NDMR)

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The Neuro-Muscular Junction up-regulated

• AChRs spread throughout the muscle membrane - up
  to 100X more receptors
• Additional Isoforms of AChRs expressed when lack
  of NM transmission
• Metabolites of ACh and SCh (choline) will also
  strongly and persistently open (2-10X) the AChRs
  exaggerating the K flow

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The Neuro-Muscular Junction up-regulated

• ACh from nerve terminal in upregulated state does
  not cause hyperkalemia- ACh esterase prevents
  spread beyond NMJ
• Systemic SCh reaches all AChRs and depolarizes
  all virtually simultaneously many far from ACh
  esterase of nerve terminal- metabolites as well
  continue to open channels causing hyperkalemia

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Pharmacologic Basis for Agonist (SCh) Sensitivity

• Upregulated AChRs stay open longer in response to
  agonist
• Metabolites of both ACh and SCh (choline) also
  can open the upregulated (immature) AChRs

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Pharmacologic Basis for Resistance to NDMRs

• More AChRs- upregulation
• Same amount of NDMR
• ACh can still find many available AChRs to cause
  depolarization and muscle twitch

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Diseases that Increase AChRs in Skeletal
Musclea.k.a up-regulation

• Motor Neuron Disorders
• Upper, lower or both
• Disorders of the Neuro-Muscular Junction
• Muscle Disorders
• Other disorders

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Upper Motor Neuron DisordersStroke/ Traumatic
spinal cord injury

• After stroke, weak/paretic side resistant to
  NDMRs (monitor twitches elsewhere)
• After cord injury, diffuse AChR proliferation
  within 3-5 days (fastest)
• SCh safe for first 24 hours after event

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Motor Neuron DisordersAmyotrophic Lateral
Sclerosis Lou Gerhigs disease

• Typically affects men 40-60 years old
• Progressive weakness leading to respiratory
  failure and death after mean 3-5 years
• Upper and lower motor neurons spontaneously
  degenerate
• Only FDA approved Rx may prolong life by 3-6
  months
• SCh may produce hyperkalemia
• Usually NMB resistant
• High risk for resp failure and aspiration periop

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Multiple Sclerosis (MS)

• Women Men 21
• Autoimmune demyelinating disease of CNS
• Motor and sensory paths involved
• Spares peripheral nerves
• Vision problems, limb paresthesias, incontinence
• Characterized by relapses/flairs and remissions
• Rx Corticosteroids/ immunosuppressants
• Global resistance to NDMRs
• Hyperkalemia has been reported
• Avoid regional- demyelinated nerves more
  vulnerable to neurotoxic effects of local anes.

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CNS/ upper motor neuron disorders that do NOT
cause upregulation of AChRs

• Cerebral Palsey
• Spina Bifida/Meningomyelocele
• Both are congenital
• Succinylcholine not contraindicated

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Lower Motor Neuron DisordersGuillain-Barre

• Autoimmune-mediated LMN polyneuropathy
• Often preceded by viral or bacterial infection
• Rapidly progressive
• Variable severity
• May lead to respiratory failure or paralysis
• Autonomic nerves affected- labile BP
• Often recovery after supportive care
• SCh hyperkalemia- NMB sensitivity
• Autonomic involvement-HD monitoring
• High risk for resp failure and aspiration

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Hyperkalemia in ICU patients after SCh

• Multifactorial sensory and motor neuropathy of
  critically ill patients
• Steroid neuropathy
• Nutritional neuropathy
• Neuro-trauma
• Chronic neuro-muscular blockers
• chemical denervation
• Disuse atrophy/immobilization

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Traumatic peripheral nerve injury

• AChR upregulation in muscles begins in 3-4 days
• Resistance to NDMRs
• Depending on extent of denervation, SCh induced
  hyperkalemia possible within 5-7 days
• Do not monitor twitches on affected limb
• Immobilization of a limb and PVD with atrophy-
  slower upregulation than after nerve injury but
  still a risk

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Muscle Disorders-upregulation and
rhabdomyolysisDuchennes Muscular Dystrophy

• Inherited sex linked recessive (X chrom.)
• 1/3500 male births
• Dystrophin- important in myocyte structure
• Poorly anchored muscle cells degenerate and are
  replaced by fat cells
• Smooth, cardiac and skeletal muscle cells all
  affected
• Appears age 2-6 card/ resp failure by 20
• Corticosteroids slow process a bit

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Muscle DisordersDuchennes Muscular Dystrophy

• Aspiration, respiratory failure and dilated
  cardiomyopathy are periop concerns
• Hyperkalemia and rhabdomyolysis in response to
  SCh- avoid esp in young boys
• Volatile agents may cause rhabdomyolysis
• Very sensitive to NDMRs- monitor
• Association with MH? clean technique suggested

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Muscle DisordersMuscle Trauma/ Burns/
immobilization

• Burns
• and degree not always proportional to
  susceptibility to hyperkalemia
• Hyperkalemic arrest reported in 8 BSA burn
• no reports of hyperkalemia lt 24hrs
• NDMR resistant proportional to BSA burned
• Immobilization
• Upregulation within 6-12 hours
• Clinically relevant within 24-72 hours

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Diagnosis and treatment of hyperkalemia from SCh

• Hyperkalemia is dose dependent
• Treatment is initiated based on history
• SCh administration and susceptible pathologic
  state
• Treatment based on EKG due to acuity- dont wait
  for K levels
• If there are EKG changes- TREAT

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Diagnosis and treatment of hyperkalemia from SCh

• CPR
• Antagonize effect of hyperkalemia
• Calcium Chloride (1-2gm over 2-3min.)
• Move potassium out of plasma
• Into cells
• D50 regular insulin
• Epinephrine
• Out of body
• GI resins not helpful in acute setting

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Recommendations

• Avoid SCh after 48-72 hours of denervation/immobil
  ization or any pathologic state where AChRs are
  known to upregulate
• Pre-curarization does not affect susceptibility
• Upregulation lasts far beyond recovery
  (hyperkalemic arrest 8 weeks after full recovery
  from stroke, years after long ICU stay or major
  burns)
• Multiple risk factors dramatically increase risk
  of hyperkalemic response
• Congenital conditions do not seem to be a risk
  for hyperkalemia (CP/ syringomyelia)

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Diseases that Decrease AChRs in Skeletal
Musclea.k.a. down-regulation

• Myasthenia Gravis
• Chronic Anti-cholinesterase use
• Heavy chronic conditioning exercise?

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Diseases of the Neuromuscular JunctionMyasthenia
Gravis

• Autoimmune disease
• Antibodies against AChR
• Characterized by fatigable weakness
• Improved by rest or ACh esterase drugs
• Ocular or generalized (resp/crisis)
• Rx cholinesterase inhibitors, immunosuppressants,
  thymectomy (96)
• Physiologic stressgt exacerbation
• Resistant to SCh,Sensitive to NDMRs (avoid?)

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Sugammadex-the holy grail?Reverses NM blockade
by ENCAPSULATION
Sparr et al. Anesthesiology 2007 106(5)935-943

• 98 healthy male volunteers
• 0.6mg/kg rocuroniumTIVA
• Time to TOF 0.9 after 8mg/kg Sugamm.

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Sugammadex-the holy grail?Reverses NM blockade
by ENCAPSULATION
De Boer et al. Anesthesiology 2007 107(2)239-244

• 45 patients TIVA
• 1.2mg/kg rocuronium
• 5 min. after roc. 12 mg/kg Sugam. Given
• TOF gt0.9 mean 1.4min (1.0-1.9)
• NO EVIDENCE OF BLOCK RECURRENCE/ SIDE EFFECTS

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Sugammadex neutralizing Rocuronium molecule
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Bibliography

• Stevens RD. Neuromuscular Disorders and
  Anesthesia. Current Opinions in Anesthesiolgy
  2001 14 693-698
• Martyn JA et al. Succinylcholine-induced
  Hyperkalemia in Acquired Pathologic States.
  Anesthesiology 2006 104(1) 158-169
• Martyn JA et al. Up-and-down regulation of
  skeletal muscle acetylcholine receptors.
  Anesthesiology 1992 76 822-843.