Neuromuscular Disorders and the Acetylcholine Receptor

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

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

The Neuromuscular Junction
Normal

• AChRs at NMJ are nicotinic
• AChRs only in Neuromuscular Junction
• 75% blocked=weakness 95%=paralysis
• 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

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)

The Neuro-Muscular Junctionup-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

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

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
 
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

Diseases that Increase AChRs in Skeletal Muscle
a.k.a “up-regulation”

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

Upper Motor Neuron Disorders
Stroke/ 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

Motor Neuron Disorders
Amyotrophic Lateral Sclerosis
“Lou Gerhig’s 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 

Multiple Sclerosis (MS)

• Women: Men 2:1
• 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.

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

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

Lower Motor Neuron Disorders
Guillain-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

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

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

Muscle Disorders
Duchenne’s 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

Muscle Disorders
Muscle Trauma/ Burns/ immobilization
Burns:
% and degree not always proportional to susceptibility to hyperkalemia
Hyperkalemic arrest reported in 8% BSA burn
no reports of hyperkalemia < 24hrs
NDMR resistant proportional to BSA burned
Immobilization:
Upregulation within 6-12 hours
Clinically relevant within 24-72 hours

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- don’t wait for K+ levels
• If there are EKG changes- TREAT

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- don’t wait for K+ levels
• If there are EKG changes- TREAT

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

Recommendations

• Avoid SCh after 48-72 hours of denervation/immobilization 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)

Diseases that Decrease AChRs in Skeletal Muscle
a.k.a. “down-regulation”

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

Diseases of the Neuromuscular Junction
Myasthenia 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 stress> exacerbation
• Resistant to SCh*,Sensitive to NDMRs (avoid?)

Sugammadex-the holy grail?
Reverses NM blockade by ENCAPSULATION

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

Sugammadex-the holy grail?
Reverses NM blockade by ENCAPSULATION

• 45 patients TIVA
• 1.2mg/kg rocuronium
• 5 min. after roc. 12 mg/kg Sugam. Given
• TOF >0.9 mean 1.4min (1.0-1.9)
• NO EVIDENCE OF BLOCK RECURRENCE/ SIDE EFFECTS

Sugammadex neutralizing Rocuronium molecule
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.