1. NEUROMUSCULAR JUNCTION PHYSIOLOGY & BLOCKING AGENTS
PROF V K BHATIA
DEPT OF ANAESTHESIOLOGY
KGMU

2. Neuromuscular junction (example of chemical synapse)
Neuromuscular junction : the synapse between motor neuron and muscle fiber is called the neuromuscular junction
Motor neurons : are the nerves that innervate muscle fibers
Motor unit : single motor neuron and the muscle fibers it innervate

3. Physiologic anatomy of N.M junction (continued)
As axon approaches muscle , it divides into many terminal branches and loses its myelin sheath
Each of these axon terminal forms special junction ,a neuromuscular junction with one or more muscle fiber

5. Physiologic anatomy of N.M junction (continued)
The axon terminal is enlarged into a knoblike structure ,the terminal botton,which fits into shallow depression in underlying muscle fiber

7. Sequence Of Events At Neuromuscular Junction
Action potentials arriving at the presynaptic terminal cause voltage-gated Ca2+ channels to open.

8. Sequence Of Events At Neuromuscular Junction (continued)
Ca2+ uptake into the terminal causes release of the neurotransmitter acetylcholine into synaptic cleft , which has been synthesized and stored into synaptic vesicles

9. Sequence Of Events At Neuromuscular Junction (continued)
Ach travels across the synaptic cleft to postsynaptic membrane which is also known as motor end plate.

10. Sequence Of Events At Neuromuscular Junction (continued)
Motor end plate contains nicotinic receptors for Ach , which r ligand gated ion channels
Ach binds to the alpha subunits of nicotinic receptors and causes conformational change.
When conformational changes occurs ,the central core of channels opens & permeability of motor end plate to Na+ & K+ increases

11. Sequence Of Events At Neuromuscular Junction (continued)

12. Sequence Of Events At Neuromuscular Junction (continued)

13. End plate potential
When the ion channel on post synaptic membrane opens both Na+ & K+ flow down their concentration gradient.
At resting potential net driving force for Na+ is much greater than K+ ,when Ach triggers opening of these channels more Na+ moves inwards than K+ out wards, depolarizing the end plate.this potential change is called end plate potential (EPP).
EPP is not an action potential but it is simply depolarization of specialized motor end plate

14. End plate potential (continued)
Small quanta (packets) of Ach are released randomly from nerve cell at rest, each producing smallest possible change in membrane potential of motor end plate, the MINIATURE EPP.
When nerve impulse reaches the ending, the number of quanta release increases by several folds and result in large EPP.
EPP than spread by local current to adjacent muscle fibers which r depolarized to threshold & fire action potential

15. Acetyl cholinesterase ends Ach activity at N.M junction
To ensure purposeful movement ,muscle cell electrical response is turned off by acetylcholinestrase(AchE), which degrade Ach to choline & acetate
About 50%of choline is returned to the presynaptic terminal by Na+choline transport to be reused for Ach synthesis.
Now muscle fiber can relax ,if sustained contraction is needed for the desired movement another motor neuron AP leads to release of more Ach

16. Myasthenia gravis
A disease involving N.M junction is characterized by the extreme muscular weakness (myasthenia=muscular & gravis=severe)
It is an auto immune condition (auto immune means immunity against self) in which the body erroneously produces antibodies against its own motor end plate ach receptors.
Thus not all Ach molecules can find functioning receptors site with which to bind.
As a results ,AchE destroys much of Ach before it ever has a chance to interact with receptor site & contribute to EPP.

17. Treatment :
it is treated with long acting anticholinesterase inhibitor pyridostigmine or neostigmine. Which maintains the Ach levels at N.M junction at high levels thus prolonging the time available for Ach to activate its receptors.

18. Objectives Mechanism of action Monitoring Pharmacology Reversal
non-depolarizers
depolarizers
Reversal

20. Classical Mechanism of Action
Non-depolarizers:
bind to AchR, post junctional nicotinic receptor
competitively prevent binding of Ach to receptor
ion channel closed, no current can flow
Depolarizers- succinylcholine:
mimic action of Ach
excitation of muscle contraction followed by blockade of neuromuscular transmission

21. Margin of Safety Wide margin of safety of neuromuscular transmission
70% receptor occupancy before twitch depression

22. Smith CE, Peerless JR: ITACCS Monograph 1996
Clinical Use
Anesthesia:
facilitate tracheal intubation
paralysis for surgery + mechanical ventilation
ICU:
 VO2
tetanus
status epilepticus
 ICP
 shivering
Smith CE, Peerless JR: ITACCS Monograph 1996

23. TOF Monitoring TOF: Loss of all 4 twitches: Return of 1-2 twitches:
4 supramaximal stimuli at 2 Hz, every 0.5 sec
observe ratio of 4rth twitch to first
Loss of all 4 twitches:
profound block
Return of 1-2 twitches:
sufficient for most surgeries
Return of all 4 twitches:
easily “reversible”
Viby-Mogensen, 1984

24. Onset + Recovery of NM Block
A-Nondepolarizing. B- Sux. Viby-Mogensen: BJA 1982;54:209

25. Vecuronium
ED90: 0.04 mg/kg
intubating dose: mg/kg
onset: 2-4 min, clinical duration: min
Maintenance dose: mg/kg, duration: min
Metabolized by liver, 75-80%
Excreted by kidney, 20-25%
½ life : 60 minutes
Prolonged duration in elderly + liver disease
No CV effects, no histamine release, no vagolysis
May precipitate after thiopental

26. Rocuronium
ED90: 0.3 mg/kg
intubating dose: mg/kg
onset: minutes, clinical duration: min
Maintenance dose: mg/kg, duration: min
Metabolized by liver, 75-80%
Excreted by kidney, 20-25%
½ life : ~ 60 minutes
Mild CV effects- vagolysis, no histamine release,
Prolonged duration in elderly + liver disease
Only non-depolarizer approved for RSI

27. Prielipp et al: Anesth Analg 1995;81:3-12
Cisatracurium
ED90: 0.05 mg/kg
intubating dose: 0.2 mg/kg
onset: 2-4 minutes, clinical duration: 60 min
Hofmann elimination: not dependent on liver or kidney for elimination
Predictable spontaneous recovery regardless of dose
½ life : ~ 60 minutes
No histamine release
CV stability
Agent of choice for infusion in ICU
Prielipp et al: Anesth Analg 1995;81:3-12

28. Succinylcholine Maintenance dose: no longer used
ED90: 0.3 mg/kg
intubating dose: mg/kg
onset: sec, clinical duration: 5-10 min
can be given IM or sublingual
dose to relieve laryngospasm: 0.3 mg/kg
Maintenance dose: no longer used
Metabolized by pseudocholinesterase
prolonged duration if abnormal pc (dibucaine # 20)
Prolonged effect if given after neostigmine

29. Succinylcholine: Key Concepts
Bradycardia + nodal rhythms after “2nd dose” in adults + after initial dose in children
Hyperkalemia + cardiac arrest likely 1 week after major burns, or in children with Duchenne’s muscular dystrophy
Not contraindicated in patients with head injury
May cause malignant hyperthermia or masseter spasm
Duration increased by prior administration of neostigmine

30. Succinylcholine Adverse Effects
Hyperkalemia + cardiac arrest in “at risk patients”
denervation, burns, myopathy
Malignant hyperthermia, masseter spasm
 IOP- blood flow mechanism
Myalgias,  intragastric pressure
 dose requirement for non-depolarizers after sux
 ICP- blood flow mechanism; clinically irrelevant
Bevan DR: Semin Anesth 1995;14:63-70

31. Kovarik, Mayberg, Lam: Anesth Analg 1994;78:469-73
Head Injury + Sux
Kovarik, Mayberg, Lam: Anesth Analg 1994;78:469-73

32. Bevan DR, Bevan JC, Donati F: 1988
Sux + Hyperkalemia
Burns, Hemiplegia, Paraplegia, Quadraplegia:
 extrajunctional receptors after burn or denervation
Danger of hyperkalemia with sux: 48 hrs post injury until …?
Muscular Dystrophy
Miscellaneous
severe infections, closed head injury, crush, rhabdo, wound botulism, necrotizing pancreatitis
Renal failure: pre-existing hyperkalemia
Acidosis:  extracellular K
Bevan DR, Bevan JC, Donati F: 1988

33. Cholinesterase Inhibitors
↑ Ach at nicotinic + muscarinic receptors to antagonize NMB
Full reversal depends on diffusion, redistribution, metabolism + excretion

34. Key Concepts of NMBA Reversal
Cholinesterase inhibitors indirectly reverse NMB
Head lift x 5 sec- reliable sign of reversal
Teeth clenching x 5 sec- reliable sign of reversal
Usually not difficult to reverse block if 2 twitches are visible in response to TOF
Neostigmine is a minor risk factor for PONV
Anticholinergic agents should never be omitted with reversal

35. Double Burst TOF fade: difficult to detect clinically until < 0.2
Use double burst:
2 short bursts of tetanic stimulation separated by 750 ms
Easier to detect fade + residual block,
Viby-Mogensen, 2000

36. Savarese JJ, Caldwell JE, Lien CA, Miller RD: 2000
Clinical Evaluation
Reliable signs of adequate NM transmission
Head lift x 5 s
Leg lift x 5 s
Hand grip as strong as preop x 5 s
Sustained bite
Helpful, but unreliable
Normal Vt , Vc, + cough
Savarese JJ, Caldwell JE, Lien CA, Miller RD: 2000

37. Reversal of NM Block Clinical practice: Rule of thumb:
if no evidence block + 4 half-lives: omit reversal
if still evidence block: give reversal
if unsure: give reversal
Rule of thumb:
if 2 twitches of TOF visible, block is usually reversible
if no twitches visible, best to wait (check battery)
Neostigmine 2.5 mg/Glycopyrolate 0.5 mg
do not omit anti-cholinergic!

38. Suggamadex (Org 25969): Safer way to reverse NMB
Gijsenbergh et al, Anesthesiology 2005;103; Belgium. Phase 1 study
Modified cyclodextrin
Encapsulates roc
Promotes dissociation of roc from AchR
No recurarization

39. Summary Indications: tracheal intubation, surgery, mech ventilation
Choice of drug: pharmacology + other factors (histamine)
Onset of action:
sux is fastest
roc is suitable alternative
Duration:
non-depolarizing block easily reversible if 2 twitches
residual block:  incidence with intermediate rx
Monitoring + Reversal: TOF, double burst, clinical signs
Suggmadex: will likely replace neostigmine for reversal