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Neuromuscular disorders and the Acetylcholine receptor

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Diseases that Increase AChRs in Skeletal Muscle. Disease that decreases ... Congenital conditions do not seem to be a risk for hyperkalemia (CP/ syringomyelia) ... – PowerPoint PPT presentation

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Title: Neuromuscular disorders and the Acetylcholine receptor


1
Neuro-muscular disorders and the Acetylcholine
receptor
  • Joseph M. Caiati, MD
  • Department of Anesthesiology

2
Overview
  • The Neuromuscular Junction
  • Diseases that Increase AChRs in Skeletal Muscle
  • Disease that decreases AChRs in Skeletal Muscle
  • Succinylcholine and other NDMRs
  • Sugammadex

3
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

4
Normal
5
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)

6
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

7
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

8
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9
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

10
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

11
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

12
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

13
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

14
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15
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.

16
CNS/ upper motor neuron disorders that do NOT
cause upregulation of AChRs
  • Cerebral Palsey
  • Spina Bifida/Meningomyelocele
  • Both are congenital
  • Succinylcholine not contraindicated

17
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

18
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

19
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

20
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

21
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22
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

23
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

24
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

25
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26
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

27
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)

28
Diseases that Decrease AChRs in Skeletal
Musclea.k.a. down-regulation
  • Myasthenia Gravis
  • Chronic Anti-cholinesterase use
  • Heavy chronic conditioning exercise?

29
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?)

30
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.

31
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

32
Sugammadex neutralizing Rocuronium molecule
33
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.
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