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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) 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. The synapse b/w axon of motor neuron and Skeletal fibre is called NMJ. The nerve end makes a junction with the muscle fibre.. Motor end plate - The entire structure, the nerve terminal and muscle fibre is called motor end plate. Synaptic space Synaptic cleft/gutter Definition space b/w nerve terminal and fibre membrane. 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. 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 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, Approx 50-100 vesicles of Ach are released Approx 12000 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. Two molecules of Ach binds with single Ach receptor Action of Ach on the post synaptic membrane 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 Out 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 510msec 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 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 Acetylcholine synthesis and choline recycling 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. Some of choline is also formed by the liver. ANIMATION NEURO MUSCULAR BLOCKS Neuromuscular blocking agents (drugs) provide Skeletal muscle relaxation to facilitate Endotreacheal Intubation Mechanical Ventilation Optimizing surgical operating conditions HISTORY OF NEUROMUSCULAR DRUGS HISTORY 1494 - Tales of travelers killed by poison darts 1551 - Ourari” or “cururu” meaning “bird killer” 1812 - Curarized cat kept alive by artificial respiration 1912 - Curare used to prevent fractures during ECT 1941 - Initial use by Griffith, Culler, and Rovenstine 1951 - Succinylcholine chloride first used in Stockholm INTRODUCTION OF NEW DRUGS 1494 - 1942 1947 - 1951 1960’s 1970’s 1980’s 1990 1991 1992 1994 1999 Curare Succinylcholine chloride, Gallamine, Metocurine, Decamethonium Alcuronium Pancuronium bromide, Fazadinium Vecuronium bromide, Atracurium besylate Pipecuronium bromide Doxacurium chloride Mivacurium chloride Rocuronium bromide Rapacuronium bromide STRUCTURAL CLASSES OF NONDEPOL.ARIZING RELAXANTS Amino Steroids: Rocuronium bromide, Vecuronium bromide, Pancuronium bromide, Pipecuronium bromide. Benzylisoquinoliniums: Atracurium besylate, Mivacurium chloride, Doxacurium chloride, Tubocurarine, Gallamine, Metocurine NEUROMUSCULAR DRUGS Depolarizing agents Non-depolarizing Depolarizing agents (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 High doses of depolarizing agent b/w (317mg/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 Fast dissociation from receptor Block is not reversed by neostigmine Potentiate by hypothermia,resp.alkalosis. Repeated/continuous use leads to phase 2 block. Non–depolarizing agents Competitive antagonist at Ach 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 Have slow onset(1-5) mins and slow dissociation from receptors. Are reversed by anticholinesterases. Relaxed muscle remains responsive to other mechanical or electrical stimuli.. Effect potentiate by volatile agents, acidosis and hypokalemia. Differences bw Dep/ NDMR block SUXAMETHONIUM Introduced in 1952 Depolarizing neuromuscular blocker PRESENTATION 50 mg/ml (2 ml amp) Mode of Action Nicotinic receptors Metabolism degraded not by acetylcholinesterase but by butyrylcholinesterase, a plasma cholinesterase SUXAMETHONIUM Indication Rapid sequence Induction Electroconvulsive therapy Onset Of Action 30 sec (highly lipid soluble) Effect may last up to 10 min Dose 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 CVS Bradycardia (2nd dose +children) Metabolic Increase potassium level Raised intracranial and intraocular pressure Prolonged paralysis (absent or atypical plasma cholinestrase) Anaphylaxis Muscle pains ATRCURIUM Nondepolarizing neuromuscular blocking agent Benzyl isoquinolinium compound PRESENTATION 10mg/ml (2.5 -5 ml) METABOLISM Ester Hydrolysis (non specific esterases) Hofmann Elimination ATRACURIUM DOSAGE 0.3-0.5 mg/kg body wt (intubation dose) duration 30-40 min 0.1mg/kg body wt (maintenance dose) duration 10-20min Average infusion rates of 11 to 13 mcg/kg per minute in ICU SENSITIVITY stored at 2-8 C use within 14 days if at room temp ATRCURIUM SIDE EFFECTS Hypotension and tachycardia Histamine release Bronchospasm Laudanosine toxicity (excitation of cns ,increasing mac, --- seziures) Allergic reactions MIVACURIUM Nondepolarizing neuromuscular blocking agent (short acting 10 min) Benzylisoquinoline derivative METABOLISM Metabolised by cholinesterase Duration of action prolong if plasma cholenestrase minimum or absent Hepatic or renal dysfunction prolong action Edrophonium a better reversal than neostigmine in this case MIVACURIUM DOSAGE 0.15-0.2 mg/kg b wt intubating dose 4-10 micro gm/kg b wt maintainace by infusion Sensitivity Unlike atracurium its shelf life is 18 months at room temp MIVACURIUM Side Effects Histamine release (Slow IV induction) CVS Manifestations may Occur Pancuronium can markedly prolong its effect (SMITH) PANCURONIUM Nondepolarizing neuromuscular blocking agent DOSAGE 0.08-0.12 mg/kg/bw intubation dose 0.01 mg/kg/bw maintenance dose every 20-40 min SENSITIVITY upto 6 months at room temp PRESENTATION 2 mg/ml clear solution PANCURONIUM METABOLISM Renal 40% Liver 10% Effect of this drug may be prolonged in renal diseases PANCURONIUM SIDE EFFECTS Hypertension and Tachycardia (vagal bockade+sympathetic stimulation) Caution in CAD Arrhythmias (especially if combined with halothane) Allergic reaction (bromide) vecuronium Nondepolarizing neuromuscular blocking agent Monoquaternary compound DOSAGE 0.08-0.12 mg/kg/bw intubation dose 0.01 mg/kg/bw maintainace dose (15-20) or 1-2 mic/kg/min infusion vecuronium METABOLISM Renal 25% Biliary 40% PREDESPOSING FACTORS (prolong effect) Female gender Renal Failure Corticosteroid therapy (Critical illness myopathy/ polyneuropathy) Sepsis vecuronium PRESENTATION 4mg and 10 mg powder form should be discarded after 24 hrs ADVANTAGE Safe in cardiac patients ROCURONIUM Provides rapid onset of action ( similar to suxamethonium) Onset 45-60 sec Monoquaternary steroid DOSAGE 0.45-0.9 mg/kg. intubation dose 0.15 mg/kg/ maintainace dose or 5-12 micro gm/kg/min in infusion form Increase dosage in infants 1mg/kg and 2 mg/kg in children ROCURONIUM METABOLISM Liver (mostly) Kidneys (To some extent) Effect may be prolonged in liver disease and pregnancy ROCURONIUM ADVANTAGE suitable alternate for suxamethonium in RSI DISADVANTAGE Much longer duration of action even more than atracurium SIDE EFFECTS Vagolytic properties Cis Atracurium Purified form of one of the 10 isomers of actracurium besylate. Three times more potent than atracurium 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 Amount of laudanosine is produced less due to its high potency hence less chances of toxicity Dose not effect blood pressure and HR No release of Histamine Elimination through Hoffmann so safe in renal and liver diseases Cis Atracurium DOSAGE 0.1-0.15 mg/kg intubation dose (2 min) 1-2 mcg/kg maintainace dose in infusion form Duration of action of drug is like of intermediate acting Pipecuronium Bisquaternary Steroid compound Similar structure as Pancuronium More potent than pancuronium DOSAGE 0.06-0.1 mg/kg intubation dose Children require less dosage than adults Pipecuronium EXCRETION Renal mainly 70% Biliary 20% CONTRAINDICATION Increase duration in Hepatic diseases on other hand do not effect duration of action COMPARISON OF NMB IN SIDE EFFECTS