NEURO MUSCULAR PHYSIOLOGY AND BLOCK

NEURO MUSCULAR NEURO MUSCULAR PHYSIOLOGY AND BLOCKPHYSIOLOGY AND BLOCK

DR IMRAN SHAUKATDR IMRAN SHAUKATDR JAHANZAIBDR JAHANZAIBSUPERVISORSUPERVISOR

DR ZIA DR ZIA

NEUROMUSCULAR NEUROMUSCULAR PHYSIOLOGYPHYSIOLOGY

Deals with structure and function of Deals with structure and function of muscles and motor neuron supplying muscles and motor neuron supplying these fibres (muscles)these fibres (muscles)

The basic unit of neuromuscular The basic unit of neuromuscular junction is known as motor unitjunction is known as motor unit

Motor unit

Motor unit = a motor neuron + all muscle fibers it controls

Axon of a motor neuron divides into many branches

Each muscle fiber is controlled by a branch from only one motor neuron

Single motor unit consisting of one motor neuron and the muscle fibers it innervates

Motor unit

NEUROMUSCULAR NEUROMUSCULAR JUNCTIONJUNCTION

Definition. Definition. The synapse b/w axon of motor neuron The synapse b/w axon of motor neuron

and Skeletal fibre is called NMJ.and Skeletal fibre is called NMJ. The nerve end makes a junction with the The nerve end makes a junction with the

muscle fibre..muscle fibre.. Motor end plateMotor end plate - - The entire structure, the nerve terminal The entire structure, the nerve terminal

and muscle fibre is called motor end and muscle fibre is called motor end plate. plate.

Synaptic spaceSynaptic space

Synaptic cleft/gutter Synaptic cleft/gutter Definition Definition

space b/w nerve terminal and fibre membranespace b/w nerve terminal and fibre membrane.. 20-30nm wide 20-30nm wide Bottom of cleft there are numerous folds of Bottom of cleft there are numerous folds of

muscle membrane called sub-neural folds muscle membrane called sub-neural folds which increases the surface area at which which increases the surface area at which synaptic transmitter can act. synaptic transmitter can act.

EVENTS OCCURING DURING EVENTS OCCURING DURING NM TRANSMISSIONNM TRANSMISSION

At rest transmembrane potential is about -At rest transmembrane potential is about -90mv (-ve inside) Normally depolarization of 90mv (-ve inside) Normally depolarization of about 40 mv occurs bringing the about 40 mv occurs bringing the transmembrane potential to -50mvtransmembrane potential to -50mv

Action potential spreads over the nerve Action potential spreads over the nerve terminal, terminal, It opens voltage gated calcium channels.It opens voltage gated calcium channels. Calcium diffuses interacellular of the nerve Calcium diffuses interacellular of the nerve

terminal terminal Intracellular Ca influences on the Ach Intracellular Ca influences on the Ach

vesicles.vesicles.

EVENTS OCCURING DURING EVENTS OCCURING DURING NM TRANSMISSIONNM TRANSMISSION

When nerve impulse reaches the NMJ, When nerve impulse reaches the NMJ, Approx 50-100 vesicles of Ach are released Approx 50-100 vesicles of Ach are released

Approx 12000 molecules of Ach are present in Approx 12000 molecules of Ach are present in

each vesicles.each vesicles. Vesicles fuse with plasma membrane and Vesicles fuse with plasma membrane and

empty their Ach into the synaptic space by empty their Ach into the synaptic space by the process of exocytosis.the process of exocytosis.

Two molecules of Ach binds with single Two molecules of Ach binds with single Ach receptor Ach receptor

Action of Ach on the post Action of Ach on the post synaptic membranesynaptic membrane

Ach receptors are gated ion channels Ach receptors are gated ion channels Located near the sub-neural folds on post Located near the sub-neural folds on post

synaptic membranesynaptic membrane Two alpha, and one each beta, delta, Two alpha, and one each beta, delta,

epsilon sub unitsepsilon sub units OOut of which only alpha unit constitute the ut of which only alpha unit constitute the

binding site for Achbinding site for Ach..

Ach gated ion channelAch gated ion channel Remain constricted until two Remain constricted until two

molecules of Ach binds with single molecules of Ach binds with single Ach receptorAch receptor

conformational change, will cause conformational change, will cause opening of the channel.opening of the channel.

Brings a potential change at muscle Brings a potential change at muscle fibre membrane called End plate fibre membrane called End plate potential,potential,

Generates action potential at the muscle Generates action potential at the muscle membranemembrane

Depolarization will occur that causes Depolarization will occur that causes muscle contraction by the help of actin muscle contraction by the help of actin and myosine filamentsand myosine filaments

Ach gated ion channelAch gated ion channel Whole sequence of events occurs Whole sequence of events occurs

in 5-10msecin 5-10msec Repolarisation will occur when Ach Repolarisation will occur when Ach

receptors are inactived and K+ receptors are inactived and K+ moves out. moves out.

Ach once released into the synaptic Ach once released into the synaptic space continues to activate Ach space continues to activate Ach receptors as long as it persists in receptors as long as it persists in the spacethe space

Rapidly removed by enzyme Rapidly removed by enzyme AcetylcholinesterasesAcetylcholinesterases into acetyl co into acetyl co and cholineand choline

Acetylcholine synthesis and Acetylcholine synthesis and choline recyclingcholine recycling

Synthesis takes place in cytoplasm of Synthesis takes place in cytoplasm of nerve terminalnerve terminal

With the help of enzyme (CAT), With the help of enzyme (CAT), mitochondria provides energy for the mitochondria provides energy for the synthesissynthesis

Ach is then taken up into the Ach is then taken up into the synaptic vesicles by an active synaptic vesicles by an active vesicular transport, where it is storedvesicular transport, where it is stored

Acetylcholine synthesis and Acetylcholine synthesis and choline recyclingcholine recycling

Ach is splitted by enzyme Ach is splitted by enzyme Acetycholinesterases into acetate Acetycholinesterases into acetate and choline at the postsynaptic and choline at the postsynaptic membrane.membrane.

Choline is then actively re-absorbed Choline is then actively re-absorbed into the nerve terminal to be re-used into the nerve terminal to be re-used in the forming of new Ach.in the forming of new Ach.

Some of choline is also formed by the Some of choline is also formed by the liver.liver.

ANIMATIONANIMATION

NEURO MUSCULAR BLOCKSNEURO MUSCULAR BLOCKS

Neuromuscular blocking agents Neuromuscular blocking agents (drugs) provide Skeletal muscle (drugs) provide Skeletal muscle relaxation to facilitate relaxation to facilitate

Endotreacheal IntubationEndotreacheal Intubation

Mechanical VentilationMechanical Ventilation

Optimizing surgical operating Optimizing surgical operating conditionsconditions

HISTORY OF NEUROMUSCULARHISTORY OF NEUROMUSCULARDRUGSDRUGS

HISTORYHISTORY 1494 - Tales of travelers killed by poison darts1494 - Tales of travelers killed by poison darts

1551 - Ourari” or “cururu” meaning “bird killer”1551 - Ourari” or “cururu” meaning “bird killer”

1812 - Curarized cat kept alive by artificial respiration1812 - Curarized cat kept alive by artificial respiration

1912 - Curare used to prevent fractures during ECT1912 - Curare used to prevent fractures during ECT

1941 - Initial use by Griffith, Culler, and Rovenstine1941 - Initial use by Griffith, Culler, and Rovenstine

1951 - Succinylcholine chloride first used in Stockholm1951 - Succinylcholine chloride first used in Stockholm

INTRODUCTION OF NEW INTRODUCTION OF NEW DRUGSDRUGS

1494 - 1942 1494 - 1942 CurareCurare1947 - 1951 1947 - 1951 Succinylcholine chloride, Gallamine, Succinylcholine chloride, Gallamine,

Metocurine, DecamethoniumMetocurine, Decamethonium1960’s1960’s AlcuroniumAlcuronium1970’s1970’s Pancuronium bromide, FazadiniumPancuronium bromide, Fazadinium1980’s1980’s Vecuronium bromide, Atracurium besylateVecuronium bromide, Atracurium besylate19901990 Pipecuronium bromidePipecuronium bromide19911991 Doxacurium chlorideDoxacurium chloride19921992 Mivacurium chlorideMivacurium chloride19941994 Rocuronium bromideRocuronium bromide19991999 Rapacuronium bromideRapacuronium bromide

STRUCTURAL CLASSES OF STRUCTURAL CLASSES OF NONDEPOL.ARIZING NONDEPOL.ARIZING

RELAXANTSRELAXANTS Amino Steroids: Rocuronium Amino Steroids: Rocuronium

bromide, Vecuronium bromide, bromide, Vecuronium bromide, Pancuronium bromide, Pipecuronium Pancuronium bromide, Pipecuronium bromide.bromide.

Benzylisoquinoliniums: Atracurium Benzylisoquinoliniums: Atracurium besylate, Mivacurium chloride, besylate, Mivacurium chloride, Doxacurium chloride, Tubocurarine, Doxacurium chloride, Tubocurarine, Gallamine, MetocurineGallamine, Metocurine

NEUROMUSCULARNEUROMUSCULARDRUGSDRUGS

Depolarizing agentsDepolarizing agents Non-depolarizingNon-depolarizing Depolarizing agents Depolarizing agents

(phase 1) block(phase 1) block agents have agonist action on Ach receptors agents have agonist action on Ach receptors These agents resemble Ach, so mimic the These agents resemble Ach, so mimic the

action Ach action Ach Bind with Ach receptorsBind with Ach receptors Generating action potential in similar way of Generating action potential in similar way of

Ach Ach


These agents are not metabolised by These agents are not metabolised by acetylcholinesterases so their concentration acetylcholinesterases so their concentration in the synaptic cleft does not fall rapidly in the synaptic cleft does not fall rapidly

Continuous end plate potential depolarization Continuous end plate potential depolarization will leads to muscle relaxation will leads to muscle relaxation

End plate cannot repolarized as long as End plate cannot repolarized as long as depolarizing agent binds to Ach receptorsdepolarizing agent binds to Ach receptors

Recovery only occur when drug diffuses away Recovery only occur when drug diffuses away from the receptor and its plasma level falls.from the receptor and its plasma level falls.

SC is metabolized by plasma cholinesterase.SC is metabolized by plasma cholinesterase.


Phase 2 blockPhase 2 block

High doses of depolarizing agent b/w (3-High doses of depolarizing agent b/w (3-17mg/kg) generates phenomena known as 17mg/kg) generates phenomena known as phase 2 block, previously called dual phase 2 block, previously called dual block, in this features of short lived block, in this features of short lived depolarizing block changes into non depolarizing block changes into non depolarizing block characterized by fade of depolarizing block characterized by fade of train of four, which may be reversed by train of four, which may be reversed by anticholinesterasesanticholinesterases

Salient Features of NM Salient Features of NM Blocking (depolarizing) DrugsBlocking (depolarizing) Drugs

Muscle fasciculation followed by Muscle fasciculation followed by relaxationrelaxation

Fast dissociation from receptorFast dissociation from receptor Block is not reversed by neostigmineBlock is not reversed by neostigmine Potentiate by Potentiate by

hypothermia,resp.alkalosis.hypothermia,resp.alkalosis. Repeated/continuous use leads to Repeated/continuous use leads to

phase 2 block.phase 2 block.

Non–depolarizing agentsNon–depolarizing agents

Competitive antagonist at Ach Competitive antagonist at Ach receptorsreceptors

Non-depolarizing drugs compete with Non-depolarizing drugs compete with the alpha subunits binding sites of the alpha subunits binding sites of nicotinic receptors nicotinic receptors

Incapable to produce conformational Incapable to produce conformational change in Ion channelchange in Ion channel

As the receptors are bound by NDMR, As the receptors are bound by NDMR, Ach is prevented to bind it’s receptorsAch is prevented to bind it’s receptors

No End plate potentialNo End plate potential

Features of non-depolarizing Features of non-depolarizing neuromuscular blocking drugsneuromuscular blocking drugs

No muscular fasciculationNo muscular fasciculation Have slow onset(1-5) mins and slow Have slow onset(1-5) mins and slow

dissociation from receptors.dissociation from receptors. Are reversed by anticholinesterases.Are reversed by anticholinesterases. Relaxed muscle remains responsive Relaxed muscle remains responsive

to other mechanical or electrical to other mechanical or electrical stimuli..stimuli..

Effect potentiate by volatile agents, Effect potentiate by volatile agents, acidosis and hypokalemia.acidosis and hypokalemia.

Differences bw Dep/ NDMR Differences bw Dep/ NDMR blockblock

SUXAMETHONIUMSUXAMETHONIUM

Introduced in 1952Introduced in 1952 Depolarizing neuromuscular blockerDepolarizing neuromuscular blocker PRESENTATIONPRESENTATION 50 mg/ml (2 ml amp)50 mg/ml (2 ml amp) Mode of ActionMode of Action Nicotinic receptorsNicotinic receptors MetabolismMetabolism degraded not by acetylcholinesterase but degraded not by acetylcholinesterase but

by butyrylcholinesterase, a plasma by butyrylcholinesterase, a plasma cholinesterase cholinesterase


IndicationIndication Rapid sequence InductionRapid sequence Induction Electroconvulsive therapy Electroconvulsive therapy Onset Of ActionOnset Of Action 30 sec (highly lipid soluble)30 sec (highly lipid soluble) Effect may last up to 10 minEffect may last up to 10 min DoseDose Intravenous 1-2 mg/kgIntravenous 1-2 mg/kg


ContraindicationsContraindications

recent burns (24 hrs after uptil 6 recent burns (24 hrs after uptil 6 months)months)

spinal cord trauma causing paraplegia spinal cord trauma causing paraplegia

raised potassium levels (> 5.5mg%) raised potassium levels (> 5.5mg%)

severe muscle trauma severe muscle trauma

history of malignant hyperpyrexia history of malignant hyperpyrexia


Adverse effectsAdverse effects CVSCVS Bradycardia (2Bradycardia (2ndnd dose +children) dose +children) MetabolicMetabolic Increase potassium level Increase potassium level Raised intracranial and intraocular pressureRaised intracranial and intraocular pressure Prolonged paralysis (absent or atypical Prolonged paralysis (absent or atypical

plasma cholinestrase)plasma cholinestrase) AnaphylaxisAnaphylaxis Muscle painsMuscle pains

ATRCURIUMATRCURIUM

Nondepolarizing neuromuscular blocking Nondepolarizing neuromuscular blocking agent agent

Benzyl isoquinolinium compoundBenzyl isoquinolinium compound PRESENTATIONPRESENTATION

10mg/ml (2.5 -5 ml)10mg/ml (2.5 -5 ml) METABOLISMMETABOLISM

Ester Hydrolysis (non specific esterases)Ester Hydrolysis (non specific esterases)

Hofmann EliminationHofmann Elimination

ATRACURIUMATRACURIUM

DOSAGEDOSAGE 0.3-0.5 mg/kg body wt (intubation dose) 0.3-0.5 mg/kg body wt (intubation dose)

duration 30-40 minduration 30-40 min 0.1mg/kg body wt (maintenance dose) 0.1mg/kg body wt (maintenance dose)

duration 10-20minduration 10-20min Average infusion rates of 11 to 13 mcg/kg Average infusion rates of 11 to 13 mcg/kg

per minute in ICUper minute in ICU SENSITIVITYSENSITIVITY stored at 2-8 C stored at 2-8 C use within 14 days if at room tempuse within 14 days if at room temp

ATRCURIUMATRCURIUM

SIDE EFFECTSSIDE EFFECTS

Hypotension and tachycardiaHypotension and tachycardia

Histamine releaseHistamine release

BronchospasmBronchospasm

Laudanosine toxicity (excitation of Laudanosine toxicity (excitation of cns ,increasing mac, --- seziures) cns ,increasing mac, --- seziures)

Allergic reactionsAllergic reactions

MIVACURIUMMIVACURIUM

Nondepolarizing neuromuscular blocking Nondepolarizing neuromuscular blocking agent (short acting 10 min)agent (short acting 10 min)

Benzylisoquinoline derivativeBenzylisoquinoline derivative METABOLISMMETABOLISM Metabolised by cholinesteraseMetabolised by cholinesterase Duration of action prolong if plasma Duration of action prolong if plasma

cholenestrase minimum or absent cholenestrase minimum or absent Hepatic or renal dysfunction prolong actionHepatic or renal dysfunction prolong action Edrophonium a better reversal than Edrophonium a better reversal than

neostigmine in this caseneostigmine in this case


DOSAGEDOSAGE 0.15-0.2 mg/kg b wt intubating dose0.15-0.2 mg/kg b wt intubating dose 4-10 micro gm/kg b wt maintainace 4-10 micro gm/kg b wt maintainace

by infusionby infusion SensitivitySensitivity Unlike atracurium its shelf life is 18 Unlike atracurium its shelf life is 18

months at room tempmonths at room temp


Side EffectsSide Effects

Histamine release (Slow IV induction)Histamine release (Slow IV induction)

CVS Manifestations may OccurCVS Manifestations may Occur

Pancuronium can markedly prolong Pancuronium can markedly prolong its effect (SMITH)its effect (SMITH)

PANCURONIUMPANCURONIUM

Nondepolarizing neuromuscular blocking Nondepolarizing neuromuscular blocking agent agent

DOSAGEDOSAGE 0.08-0.12 mg/kg/bw intubation dose0.08-0.12 mg/kg/bw intubation dose 0.01 mg/kg/bw maintenance dose every 0.01 mg/kg/bw maintenance dose every

20-40 min20-40 min SENSITIVITYSENSITIVITY upto 6 months at room tempupto 6 months at room temp PRESENTATIONPRESENTATION 2 mg/ml clear solution2 mg/ml clear solution


METABOLISMMETABOLISM

Renal 40%Renal 40%

Liver 10%Liver 10%

Effect of this drug may be prolonged Effect of this drug may be prolonged in renal diseasesin renal diseases



Hypertension and Tachycardia (vagal Hypertension and Tachycardia (vagal bockade+sympathetic stimulation)bockade+sympathetic stimulation)

Caution in CADCaution in CAD

Arrhythmias (especially if combined Arrhythmias (especially if combined with halothane)with halothane)

Allergic reaction (bromide)Allergic reaction (bromide)

vecuroniumvecuronium

Nondepolarizing neuromuscular Nondepolarizing neuromuscular blocking agentblocking agent

Monoquaternary compoundMonoquaternary compound DOSAGEDOSAGE 0.08-0.12 mg/kg/bw intubation dose0.08-0.12 mg/kg/bw intubation dose 0.01 mg/kg/bw maintainace dose 0.01 mg/kg/bw maintainace dose

(15-20)(15-20) oror 1-2 mic/kg/min infusion1-2 mic/kg/min infusion


METABOLISMMETABOLISM Renal 25%Renal 25% Biliary 40%Biliary 40% PREDESPOSING FACTORS (prolong effect)PREDESPOSING FACTORS (prolong effect) Female genderFemale gender Renal FailureRenal Failure Corticosteroid therapy (Critical illness Corticosteroid therapy (Critical illness

myopathy/ polyneuropathy)myopathy/ polyneuropathy) Sepsis Sepsis


PRESENTATIONPRESENTATION

4mg and 10 mg powder form4mg and 10 mg powder form

should be discarded after 24 hrsshould be discarded after 24 hrs

ADVANTAGEADVANTAGE

Safe in cardiac patientsSafe in cardiac patients

ROCURONIUMROCURONIUM

Provides rapid onset of action ( similar to Provides rapid onset of action ( similar to suxamethonium) Onset 45-60 sec suxamethonium) Onset 45-60 sec

Monoquaternary steroidMonoquaternary steroid DOSAGEDOSAGE 0.45-0.9 mg/kg. intubation dose0.45-0.9 mg/kg. intubation dose 0.15 mg/kg/ maintainace dose0.15 mg/kg/ maintainace dose oror 5-12 micro gm/kg/min in infusion form5-12 micro gm/kg/min in infusion form Increase dosage in infants 1mg/kg and 2 Increase dosage in infants 1mg/kg and 2

mg/kg in childrenmg/kg in children


METABOLISMMETABOLISM

Liver (mostly)Liver (mostly)

Kidneys (To some extent)Kidneys (To some extent)

Effect may be prolonged in liver Effect may be prolonged in liver disease and pregnancydisease and pregnancy


ADVANTAGEADVANTAGE

suitable alternate for suxamethonium in RSIsuitable alternate for suxamethonium in RSI DISADVANTAGEDISADVANTAGE

Much longer duration of action even more Much longer duration of action even more than atracuriumthan atracurium


Vagolytic propertiesVagolytic properties

Cis AtracuriumCis Atracurium

Purified form of one of the 10 isomers of actracurium besylate.

Three times more potent than atracurium MODE OF ACTIONMODE OF ACTION

Binds to cholinergic receptors on the motor end-plate to antagonize the action of acetylcholine, resulting in a competitive block of neuromuscular transmission


ADVANTAGESADVANTAGES

Amount of laudanosine is produced less due Amount of laudanosine is produced less due to its high potency hence less chances of to its high potency hence less chances of toxicitytoxicity

Dose not effect blood pressure and HRDose not effect blood pressure and HR

No release of HistamineNo release of Histamine

Elimination through Hoffmann so safe in Elimination through Hoffmann so safe in renal and liver diseasesrenal and liver diseases


DOSAGEDOSAGE

0.1-0.15 mg/kg intubation dose (2 0.1-0.15 mg/kg intubation dose (2 min)min)

1-2 mcg/kg maintainace dose in 1-2 mcg/kg maintainace dose in infusion form infusion form

Duration of action of drug is like of Duration of action of drug is like of intermediate actingintermediate acting

PipecuroniumPipecuronium

Bisquaternary Steroid compoundBisquaternary Steroid compound Similar structure as PancuroniumSimilar structure as Pancuronium More potent than pancuroniumMore potent than pancuronium DOSAGEDOSAGE

0.06-0.1 mg/kg intubation dose0.06-0.1 mg/kg intubation dose

Children require less dosage than adults Children require less dosage than adults

PipecuroniumPipecuronium

EXCRETIONEXCRETION

Renal mainly 70%Renal mainly 70%

Biliary 20%Biliary 20%

CONTRAINDICATIONCONTRAINDICATION

Increase duration in Increase duration in

Hepatic diseases on other hand do Hepatic diseases on other hand do not effect duration of actionnot effect duration of action

COMPARISON OF NMB IN SIDE COMPARISON OF NMB IN SIDE EFFECTSEFFECTS

NEURO MUSCULAR PHYSIOLOGY AND BLOCK

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