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 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

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

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 Muscle a.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 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

13. 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

15. 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.

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 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

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 rhabdomyolysis Duchenne’s 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

22. 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

23. 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

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

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/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)

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

29. 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?)

30. 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. 3 min5 min15 min No Sug52.151.735.6 Sug.1.81.51.4 Sparr et al. Anesthesiology 2007; 106(5):935-943

31. 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 De Boer et al. Anesthesiology 2007; 107(2)239-244

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.