NEURO MUSCULAR PHYSIOLOGY AND BLOCK DR IMRAN SHAUKAT DR JAHANZAIB SUPERVISOR DR ZIA

NEUROMUSCULAR PHYSIOLOGY Deals with structure and function of muscles and motor neuron supplying these fibres (muscles) Deals with structure and function of muscles and motor neuron supplying these fibres (muscles) The basic unit of neuromuscular junction is known as motor unit The basic unit of neuromuscular junction 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 JUNCTION Definition. Definition. The synapse b/w axon of motor neuron and Skeletal fibre is called NMJ. The synapse b/w axon of motor neuron and Skeletal fibre is called NMJ. The nerve end makes a junction with the muscle fibre.. The nerve end makes a junction with the muscle fibre.. Motor end plate Motor end plate - The entire structure, the nerve terminal and muscle fibre is called motor end plate. - The entire structure, the nerve terminal and muscle fibre is called motor end plate.

Synaptic space Synaptic cleft/gutter Synaptic cleft/gutter Definition Definition space b/w nerve terminal and fibre membrane. space b/w nerve terminal and fibre membrane nm wide 20-30nm wide Bottom of cleft there are numerous folds of muscle membrane called sub-neural folds which increases the surface area at which synaptic transmitter can act. Bottom of cleft there are numerous folds of muscle membrane called sub-neural folds which increases the surface area at which synaptic transmitter can act.

EVENTS OCCURING DURING NM TRANSMISSION At rest transmembrane potential is about -90mv (-ve inside) Normally depolarization of about 40 mv occurs bringing the transmembrane potential to -50mv At rest transmembrane potential is about -90mv (-ve inside) Normally depolarization of about 40 mv occurs bringing the transmembrane potential to -50mv Action potential spreads over the nerve terminal, Action potential spreads over the nerve terminal,  It opens voltage gated calcium channels.  Calcium diffuses interacellular of the nerve terminal  Intracellular Ca influences on the Ach vesicles.

EVENTS OCCURING DURING NM TRANSMISSION When nerve impulse reaches the NMJ, When nerve impulse reaches the NMJ,  Approx vesicles of Ach are released  Approx molecules of Ach are present in each vesicles. Vesicles fuse with plasma membrane and empty their Ach into the synaptic space by the process of exocytosis. Vesicles fuse with plasma membrane and empty their Ach into the synaptic space by the process of exocytosis. Two molecules of Ach binds with single Ach receptor Two molecules of Ach binds with single Ach receptor

Action of Ach on the post synaptic membrane Ach receptors are gated ion channels Ach receptors are gated ion channels  Located near the sub-neural folds on post synaptic membrane  Two alpha, and one each beta, delta, epsilon sub units  O ut of which only alpha unit constitute the binding site for Ach.

Ach gated ion channel  Remain constricted until two molecules of Ach binds with single Ach receptor  conformational change, will cause opening of the channel.  Brings a potential change at muscle fibre membrane called End plate potential,  Generates action potential at the muscle membrane  Depolarization will occur that causes muscle contraction by the help of actin and myosine filaments

Ach gated ion channel  Whole sequence of events occurs in 5- 10msec  Repolarisation will occur when Ach receptors are inactived and K+ moves out.  Ach once released into the synaptic space continues to activate Ach receptors as long as it persists in the space  Rapidly removed by enzyme Acetylcholinesterases into acetyl co and choline

Acetylcholine synthesis and choline recycling Synthesis takes place in cytoplasm of nerve terminal Synthesis takes place in cytoplasm of nerve terminal With the help of enzyme (CAT), mitochondria provides energy for the synthesis With the help of enzyme (CAT), mitochondria provides energy for the synthesis Ach is then taken up into the synaptic vesicles by an active vesicular transport, where it is stored Ach is then taken up into the synaptic vesicles by an active vesicular transport, where it is stored

Acetylcholine synthesis and choline recycling Ach is splitted by enzyme Acetycholinesterases into acetate and choline at the postsynaptic membrane. Ach is splitted by enzyme Acetycholinesterases into acetate and choline at the postsynaptic membrane. Choline is then actively re-absorbed into the nerve terminal to be re-used in the forming of new Ach. Choline is then actively re-absorbed into the nerve terminal to be re-used in the forming of new Ach. Some of choline is also formed by the liver. Some of choline is also formed by the liver.

ANIMATION ANIMATION

NEURO MUSCULAR BLOCKS Neuromuscular blocking agents (drugs) provide Skeletal muscle relaxation to facilitate Neuromuscular blocking agents (drugs) provide Skeletal muscle relaxation to facilitate Endotreacheal Intubation Endotreacheal Intubation Mechanical Ventilation Mechanical Ventilation Optimizing surgical operating conditions Optimizing surgical operating conditions

HISTORY OF NEUROMUSCULAR DRUGS HISTORY HISTORY Tales of travelers killed by poison darts Tales of travelers killed by poison darts Ourari” or “cururu” meaning “bird killer” Ourari” or “cururu” meaning “bird killer” Curarized cat kept alive by artificial respiration Curarized cat kept alive by artificial respiration Curare used to prevent fractures during ECT Curare used to prevent fractures during ECT Initial use by Griffith, Culler, and Rovenstine Initial use by Griffith, Culler, and Rovenstine Succinylcholine chloride first used in Stockholm Succinylcholine chloride first used in Stockholm

INTRODUCTION OF NEW DRUGS Curare Succinylcholine chloride, Gallamine, Metocurine, Decamethonium 1960’sAlcuronium 1970’sPancuronium bromide, Fazadinium 1980’sVecuronium bromide, Atracurium besylate 1990Pipecuronium bromide 1991Doxacurium chloride 1992Mivacurium chloride 1994Rocuronium bromide 1999Rapacuronium bromide

STRUCTURAL CLASSES OF NONDEPOL.ARIZING RELAXANTS Amino Steroids: Rocuronium bromide, Vecuronium bromide, Pancuronium bromide, Pipecuronium bromide. Amino Steroids: Rocuronium bromide, Vecuronium bromide, Pancuronium bromide, Pipecuronium bromide. Benzylisoquinoliniums: Atracurium besylate, Mivacurium chloride, Doxacurium chloride, Tubocurarine, Gallamine, Metocurine Benzylisoquinoliniums: Atracurium besylate, Mivacurium chloride, Doxacurium chloride, Tubocurarine, Gallamine, Metocurine

NEUROMUSCULAR DRUGS Depolarizing agents Depolarizing agents Non-depolarizing Non-depolarizing Depolarizing agents Depolarizing agents (phase 1) block (phase 1) block  agents have agonist action on Ach receptors  These agents resemble Ach, so mimic the action Ach  Bind with Ach receptors  Generating action potential in similar way of Ach

NEUROMUSCULAR DRUGS  These agents are not metabolised by acetylcholinesterases so their concentration in the synaptic cleft does not fall rapidly  Continuous end plate potential depolarization will leads to muscle relaxation  End plate cannot repolarized as long as depolarizing agent binds to Ach receptors  Recovery only occur when drug diffuses away from the receptor and its plasma level falls.  SC is metabolized by plasma cholinesterase.

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

Salient Features of NM Blocking (depolarizing) Drugs Muscle fasciculation followed by relaxation Muscle fasciculation followed by relaxation Fast dissociation from receptor Fast dissociation from receptor Block is not reversed by neostigmine Block is not reversed by neostigmine Potentiate by hypothermia,resp.alkalosis. Potentiate by hypothermia,resp.alkalosis. Repeated/continuous use leads to phase 2 block. Repeated/continuous use leads to phase 2 block.

Non–depolarizing agents Competitive antagonist at Ach receptors Competitive antagonist at Ach receptors Non-depolarizing drugs compete with the alpha subunits binding sites of nicotinic receptors Non-depolarizing drugs compete with the alpha subunits binding sites of nicotinic receptors  Incapable to produce conformational change in Ion channel  As the receptors are bound by NDMR, Ach is prevented to bind it’s receptors  No End plate potential

Features of non-depolarizing neuromuscular blocking drugs No muscular fasciculation No muscular fasciculation Have slow onset(1-5) mins and slow dissociation from receptors. Have slow onset(1-5) mins and slow dissociation from receptors. Are reversed by anticholinesterases. Are reversed by anticholinesterases. Relaxed muscle remains responsive to other mechanical or electrical stimuli.. Relaxed muscle remains responsive to other mechanical or electrical stimuli.. Effect potentiate by volatile agents, acidosis and hypokalemia. Effect potentiate by volatile agents, acidosis and hypokalemia.

Differences bw Dep/ NDMR block

SUXAMETHONIUM Introduced in 1952 Introduced in 1952 Depolarizing neuromuscular blocker Depolarizing neuromuscular blocker PRESENTATION PRESENTATION 50 mg/ml (2 ml amp) 50 mg/ml (2 ml amp) Mode of Action Mode of Action Nicotinic receptors Nicotinic receptors Metabolism Metabolism degraded not by acetylcholinesterase but by butyrylcholinesterase, a plasma cholinesterase degraded not by acetylcholinesterase but by butyrylcholinesterase, a plasma cholinesterase

SUXAMETHONIUM Indication Indication Rapid sequence Induction Rapid sequence Induction Electroconvulsive therapy Electroconvulsive therapy Onset Of Action Onset Of Action 30 sec (highly lipid soluble) 30 sec (highly lipid soluble) Effect may last up to 10 min Effect may last up to 10 min Dose Dose Intravenous 1-2 mg/kg Intravenous 1-2 mg/kg

SUXAMETHONIUM Contraindications recent burns (24 hrs after uptil 6 months) spinal cord trauma causing paraplegia raised potassium levels (> 5.5mg%) severe muscle trauma history of malignant hyperpyrexia

SUXAMETHONIUM Adverse effects Adverse effects CVS CVS Bradycardia (2 nd dose +children) Bradycardia (2 nd dose +children) Metabolic Metabolic Increase potassium level Increase potassium level Raised intracranial and intraocular pressure Raised intracranial and intraocular pressure Prolonged paralysis (absent or atypical plasma cholinestrase) Prolonged paralysis (absent or atypical plasma cholinestrase) Anaphylaxis Anaphylaxis Muscle pains Muscle pains

ATRCURIUM Nondepolarizing neuromuscular blocking agent Nondepolarizing neuromuscular blocking agent Benzyl isoquinolinium compound Benzyl isoquinolinium compound PRESENTATION PRESENTATION 10mg/ml ( ml) 10mg/ml ( ml) METABOLISM METABOLISM Ester Hydrolysis (non specific esterases) Ester Hydrolysis (non specific esterases) Hofmann Elimination Hofmann Elimination

ATRACURIUM DOSAGE DOSAGE mg/kg body wt (intubation dose) duration min mg/kg body wt (intubation dose) duration min 0.1mg/kg body wt (maintenance dose) duration 10-20min 0.1mg/kg body wt (maintenance dose) duration 10-20min Average infusion rates of 11 to 13 mcg/kg per minute in ICU Average infusion rates of 11 to 13 mcg/kg per minute in ICU SENSITIVITY SENSITIVITY stored at 2-8 C stored at 2-8 C use within 14 days if at room temp use within 14 days if at room temp

ATRCURIUM SIDE EFFECTS SIDE EFFECTS Hypotension and tachycardia Hypotension and tachycardia Histamine release Histamine release Bronchospasm Bronchospasm Laudanosine toxicity (excitation of cns,increasing mac, --- seziures) Laudanosine toxicity (excitation of cns,increasing mac, --- seziures) Allergic reactions Allergic reactions

MIVACURIUM Nondepolarizing neuromuscular blocking agent (short acting 10 min) Nondepolarizing neuromuscular blocking agent (short acting 10 min) Benzylisoquinoline derivative Benzylisoquinoline derivative METABOLISM METABOLISM Metabolised by cholinesterase Metabolised by cholinesterase Duration of action prolong if plasma cholenestrase minimum or absent Duration of action prolong if plasma cholenestrase minimum or absent Hepatic or renal dysfunction prolong action Hepatic or renal dysfunction prolong action Edrophonium a better reversal than neostigmine in this case Edrophonium a better reversal than neostigmine in this case

MIVACURIUM DOSAGE DOSAGE mg/kg b wt intubating dose mg/kg b wt intubating dose 4-10 micro gm/kg b wt maintainace by infusion 4-10 micro gm/kg b wt maintainace by infusion Sensitivity Unlike atracurium its shelf life is 18 months at room temp Unlike atracurium its shelf life is 18 months at room temp

MIVACURIUM Side Effects Side Effects Histamine release (Slow IV induction) Histamine release (Slow IV induction) CVS Manifestations may Occur CVS Manifestations may Occur Pancuronium can markedly prolong its effect (SMITH) Pancuronium can markedly prolong its effect (SMITH)

PANCURONIUM Nondepolarizing neuromuscular blocking agent Nondepolarizing neuromuscular blocking agent DOSAGE DOSAGE mg/kg/bw intubation dose mg/kg/bw intubation dose 0.01 mg/kg/bw maintenance dose every min 0.01 mg/kg/bw maintenance dose every min SENSITIVITY SENSITIVITY upto 6 months at room temp upto 6 months at room temp PRESENTATION PRESENTATION 2 mg/ml clear solution 2 mg/ml clear solution

PANCURONIUM METABOLISM METABOLISM Renal 40% Renal 40% Liver 10% Liver 10% Effect of this drug may be prolonged in renal diseases Effect of this drug may be prolonged in renal diseases

PANCURONIUM SIDE EFFECTS SIDE EFFECTS Hypertension and Tachycardia (vagal bockade+sympathetic stimulation) Hypertension and Tachycardia (vagal bockade+sympathetic stimulation) Caution in CAD Caution in CAD Arrhythmias (especially if combined with halothane) Arrhythmias (especially if combined with halothane) Allergic reaction (bromide) Allergic reaction (bromide)

vecuronium Nondepolarizing neuromuscular blocking agent Nondepolarizing neuromuscular blocking agent Monoquaternary compound Monoquaternary compound DOSAGE DOSAGE mg/kg/bw intubation dose mg/kg/bw intubation dose 0.01 mg/kg/bw maintainace dose (15-20) 0.01 mg/kg/bw maintainace dose (15-20) or or 1-2 mic/kg/min infusion 1-2 mic/kg/min infusion

vecuronium METABOLISM METABOLISM Renal 25% Renal 25% Biliary 40% Biliary 40% PREDESPOSING FACTORS (prolong effect) PREDESPOSING FACTORS (prolong effect) Female gender Female gender Renal Failure Renal Failure Corticosteroid therapy (Critical illness myopathy/ polyneuropathy) Corticosteroid therapy (Critical illness myopathy/ polyneuropathy) Sepsis Sepsis

vecuronium PRESENTATION PRESENTATION 4mg and 10 mg powder form 4mg and 10 mg powder form should be discarded after 24 hrs should be discarded after 24 hrs ADVANTAGE ADVANTAGE Safe in cardiac patients Safe in cardiac patients

ROCURONIUM Provides rapid onset of action ( similar to suxamethonium) Onset sec Provides rapid onset of action ( similar to suxamethonium) Onset sec Monoquaternary steroid Monoquaternary steroid DOSAGE DOSAGE mg/kg. intubation dose mg/kg. intubation dose 0.15 mg/kg/ maintainace dose 0.15 mg/kg/ maintainace dose or or 5-12 micro gm/kg/min in infusion form 5-12 micro gm/kg/min in infusion form Increase dosage in infants 1mg/kg and 2 mg/kg in children Increase dosage in infants 1mg/kg and 2 mg/kg in children

ROCURONIUM METABOLISM METABOLISM Liver (mostly) Liver (mostly) Kidneys (To some extent) Kidneys (To some extent) Effect may be prolonged in liver disease and pregnancy Effect may be prolonged in liver disease and pregnancy

ROCURONIUM ADVANTAGE ADVANTAGE suitable alternate for suxamethonium in RSI suitable alternate for suxamethonium in RSI DISADVANTAGE DISADVANTAGE Much longer duration of action even more than atracurium Much longer duration of action even more than atracurium SIDE EFFECTS Vagolytic properties Vagolytic properties

Cis Atracurium Purified form of one of the 10 isomers of actracurium besylate. Three times more potent than atracurium MODE OF ACTION MODE 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

Cis Atracurium ADVANTAGES ADVANTAGES Amount of laudanosine is produced less due to its high potency hence less chances of toxicity Amount of laudanosine is produced less due to its high potency hence less chances of toxicity Dose not effect blood pressure and HR Dose not effect blood pressure and HR No release of Histamine No release of Histamine Elimination through Hoffmann so safe in renal and liver diseases Elimination through Hoffmann so safe in renal and liver diseases

Cis Atracurium DOSAGE DOSAGE mg/kg intubation dose (2 min) mg/kg intubation dose (2 min) 1-2 mcg/kg maintainace dose in infusion form 1-2 mcg/kg maintainace dose in infusion form Duration of action of drug is like of intermediate acting Duration of action of drug is like of intermediate acting

Pipecuronium Bisquaternary Steroid compound Bisquaternary Steroid compound Similar structure as Pancuronium Similar structure as Pancuronium More potent than pancuronium More potent than pancuronium DOSAGE DOSAGE mg/kg intubation dose mg/kg intubation dose Children require less dosage than adults Children require less dosage than adults

Pipecuronium EXCRETION Renal mainly 70% Renal mainly 70% Biliary 20% Biliary 20%CONTRAINDICATION Increase duration in Increase duration in Hepatic diseases on other hand do not effect duration of action Hepatic diseases on other hand do not effect duration of action

COMPARISON OF NMB IN SIDE EFFECTS