neuromuscular junction physiology & blocking agents prof v k bhatia dept of anaesthesiology kgmu...

NEUROMUSCULAR JUNCTION PHYSIOLOGY &BLOCKING AGENTS

PROF V K BHATIADEPT OF ANAESTHESIOLOGY

KGMU

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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

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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

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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

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Sequence Of Events At Neuromuscular Junction

Action potentialAction potential

Ca2+Ca2+

PresynapticterminalPresynapticterminal

Voltage-gatedCa2+ channelVoltage-gatedCa2+ channel

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Action potentials arriving at the presynaptic terminal cause voltage-gated Ca2+ channels to open.

Sequence Of Events At Neuromuscular Junction (continued)

Ca2+ diffuse into the cell and cause synaptic vesicles to releaseacetylcholine, a neurotransmitter molecule.

Ca2+Ca2+

SynapticvesicleSynapticvesicle

AcetylcholineAcetylcholine

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Ca2+ uptake into the terminal causes release of the neurotransmitter acetylcholine into synaptic cleft , which has been synthesized and stored into synaptic vesicles


Ach travels across the synaptic cleft to postsynaptic membrane which is also known as motor end plate.Acetylcholine diffuses from the presynaptic terminal across the

synaptic cleft.

Synaptic cleftSynaptic cleft



Ca2+Ca2+

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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

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Acetylcholine boundto receptor site opensligand-gated Na+

channel


channel

Ca2+Ca2+

Voltage-gatedCa2+ channelVoltage-gatedCa2+ channel

SynapticvesicleSynapticvesicle

PostsynapticmembranePostsynapticmembrane


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Synaptic cleftSynaptic cleft

Action potentialAction potential


Na+Na+

1

2

3

1

2

3

1

2

3

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2

3

4


Acetylcholine molecules combine with their receptor sites andcause ligand-gated Na+ channels to open.

Na+Na+


channel


channel

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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

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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

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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 15

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.

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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.

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Objectives

Mechanism of action Monitoring Pharmacology

non-depolarizers depolarizers

Reversal

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

Margin of Safety Wide margin of

safety of neuromuscular transmission 70% receptor

occupancy before twitch depression

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

Viby-Mogensen, 1984

TOF Monitoring TOF:

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”

A-Nondepolarizing. B- Sux. Viby-Mogensen: BJA

1982;54:209

Onset + Recovery of NM Block

Vecuronium ED90: 0.04 mg/kg

intubating dose: 0.1-0.2 mg/kg onset: 2-4 min, clinical duration: 30-60 min

Maintenance dose: 0.01-0.02 mg/kg, duration: 15-30 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

Rocuronium ED90: 0.3 mg/kg

intubating dose: 0.6-1.0 mg/kg onset: 1-1.5 minutes, clinical duration: 30-60 min

Maintenance dose: 0.1-0.15 mg/kg, duration: 15-30 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

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

Succinylcholine

ED90: 0.3 mg/kg intubating dose: 1.0-1.5 mg/kg onset: 30-45 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

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

Bevan DR: Semin Anesth 1995;14:63-70

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

Kovarik, Mayberg, Lam: Anesth Analg 1994;78:469-73

Head Injury + Sux

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

Cholinesterase Inhibitors

•↑ Ach at nicotinic + muscarinic receptors to antagonize NMB •Full reversal depends on diffusion, redistribution, metabolism + excretion

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

Viby-Mogensen, 2000

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, 0.2-0.7

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

Reversal of NM Block Clinical practice:

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!

Suggamadex (Org 25969): Safer way to reverse

NMB Gijsenbergh et al, Anesthesiology

2005;103;695-703. Belgium. Phase 1 study

Modified cyclodextrin Encapsulates roc Promotes dissociation of roc from

AchR No recurarization

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

neuromuscular junction physiology & blocking agents prof v k bhatia dept of anaesthesiology kgmu...

Documents

end plate potentialwhen

muscle fibers motor

potential change

underlying muscle fiber

adjacent muscle fibers

single motor neuron

motor neuron ap

terminal botton