NEUROMUSCULAR BLOCKING AGENTS

NEUROMUSCULAR TRANSMISSION

Neuromuscular junction
Motor neuron muscle cell region of approximation

Cell membrane of neuron muscle 20nm narrow gap synaptic cleft Nerve action potential terminal depolarizing calcium ion voltagegated clacium chnnel influx cytoplasm storage vesicles terminal membrane release their contents (Ach) Ach molecule synaptic cleft diffusion muscle membrane nicoticinc receptor (mortor end plate)

neuromuscular junction , 500,000 muscle contracture   2  Ach receptor alpha, 2 alpha subunit 5

500 activation subunit

Ach receptor , normal

beta, delta, epsilon subunits Ach molecule occupy , , receptor core influx,

2 alpha subunit , binding site receptor conformational change ion channel open

Ach receptor channel sodium calcium potassium outflux end-plate potential

 single vesicle Ach quantum (100,000 ) miniature end-plate potential nerve impulse 200 Ach quantum release extracellular calcium , calcium , relasese quantum

 recepor Ach perijunctional membrane  sodium channel

, end-plate potential threshold voltage across

Muscle

perijunctional area

sodium channel

Action potential muscle membrane propagation , T-tubule systme sodium channel open sarcoplasmic reticulum cytoplasm calcium ion Intracelluar calcium Ach hydrolize action myosin

into acetate, choline

By the acetylcholineesterase in motor end-plate Receptors ion channel close repolarize

Action potential cease , calcium ion sarcoplasmic reticulum

DISTICTIONS BETWEEN DEPOLARIZING & NONDEPOLARIZING BLOCKCADE

MECHANISM OF ACTION
Ach neuromuscular blocking agents quaternary ammonium compound  1 Depolarizing agent   Ach receptor , agent ,synaptic cleft Ach action potential acetylcholinesterase 2 quaternary ammonium compound,

Prolonged depolarization Continuous end-plate depolarization muscle relax sodium channel lower gate open (time limited) initial excitation & opening upper gate close , closing repolarization open .

MECHANISM OF ACTION

MECHANISM OF ACTION
 depolarizing muscle relaxant end-plate repolarizing Phase I block  receptor , prolonged end-plate depolarization ionic and conformational change Ach Ach receptor

Phase II block  nondepolarizing mescle relaxant

Nondepolarizing muscle relaxant Ach receptor chonformational change Ach receptor , depolarizing agent end-plate potential

MECHANISM OF ACTION
Depolarizing agent Ach receptor agonist , nondepolarzing agent competitive antagonist Chronic decrease in Ach release (eg, muscle denervation injury)  , Ach receptor induction ,nondepolarzing

Immature isoform of the Ach receptor  agent depolarzing agent resistance

Fewer Ach receptors Down-regulation in Myasthenia gravis Nondepolarzing agent

NONCLASSICAL MECHANISMS OF NEUROMUSCULAR BLOCKADE

 drug agonist antagonist effect Ach receptor closing,

Receptor binding site, receptor channel opening function 
,
, ketamine

Channel blocking agent Neostigmine, antibiotics, cocaine, quinidine

REVERSAL OF NEUROMUSCULAR BLOCKADE

Depolarizing agent acetylcholinesterase hydrolyzed , NM junction diffuse , plasma liver Pseudocholinesterase hydrolyzed  Mivacurium , reversal excretion  reverse agent , nodepolarzing agent redistribution, gradual metabolism,

reversal agent (cholinesterase inhibitors) Ach

Acetylcholinesterase , NM junction nondepolarizing agent  depolarizing agent pseudocholinesterase prolong,

RESPONSE TO PERIPHERAL NERVE STIMULATION

Pph nerve stimulator neuromuscular function monitor Tetany : sustained stimulus of 50-100 Hz, lasting 5s. Twitch : A single pulse 0.2ms duration Train-of-four : A series of four twitches in 2s (2Hz frequency, duration 0.2 ms Double burst stimulation (DBS) : Three short (0.2 ms) highfrequency (50Hz) and followed 750 ms later by two or three additional impulse Polonged or repeated nerve stimulation Fade, gradual diminution of evoked response nondepolarizing block Fade Ach amount nondepolarizing agent prejunctional effect , nerve terminal available for release

RESPONSE TO PERIPHERAL NERVE STIMULATION

Adequate clinical revery fade sustained tetanic adequacy

Fade TOF repeated twitch stimulation. DBS

 sustained tetacic stimulation, DBS of recovery Posttetanic potentiation

Partial nondepolarizing block , tetanic stimulation twitch , increased evoked potential Transient increase in Ach mobilization Phase I depolarization block Posttetanic potentiation  , dose nondepolarizing agent phase II blockade , tetanus, TOF, fade

RESPONSE TO PERIPHERAL NERVE STIMULATION

DEPOLARIZING MUSCLE RELAXANT

SUCINYLCHOLINE
Physical Structure
Diacetylcholine or suxamethonium Two joined Ach molecule

SUCINYLCHOLINE

SUCINYLCHOLINE
Metabolism & Excretion
Rapid onset of action(30-60s), short duration of action Low lipid solubility Circulation Succynylmonocholine  small fraction of the injected dose , NM junction succinylcholine diffuse NM junction (pseudocholinesterase)

 blood stream

SUCINYLCHOLINE
Metabolism & Excretion
Duration of action High dose Abnormal metabolism Hypothermia : decrease hydrolysis Low level of pseudocholinesterase (modest prolongation2-20 min)  , liver dz, renal failure, certain drug therapy

Pseudocholinesterase gene defect Dibucaine number  proportional to pseudocholinesterase function Abnormal pseudocholinesterase prolonged paralysis continued mechanical ventilation q

SUCINYLCHOLINE
Metabolism & Excretion

SUCINYLCHOLINE
Drug interactions
Cholinesterase inhibitors Markdly prolong a depolarizing phase I block Acetylcholinesterase inhibition Ach , depolarization Pseudocholinesterase inhibition Eg, organophosphate acetylcholinesterase activity action prolongation Nondepolarizing relaxants Small dose phase I block antagonize (pancuronium ) nerve terminal hydrolysis succinylcholine

Same Ach receptor

Intubation dose succinylcholine atracurium dose

rocuronium,

SUCINYLCHOLINE
Drug interactions

SUCINYLCHOLINE
Dosage
Good choice for routine intubation Rapid onset, short duration, low cost Usual intubation dose : 1-1.5mg iv
 0.5 mg / kg dose acceptable defasciculating dose nondepolarizer Intense drip paralysis intubation bolus nerve

repeated small dose

 , overdosing phase II block stimulator monitoring

 ) technique

short acting nondepolarizing agent (mivacurium

Distribution : lipid solubility ECF infant

, neonate

ECF dosage

SUCINYLCHOLINE
Side Effects & Clinical Consideration
Relatively safe drug  potential complication ,

Hyperkalemia, rhabdomyolysis, cardiac arrest in children Routine management of children and adolescent pt  clinician difficult intubation full stomach , adult ruotine use  rapid onset nondepolarizing agnet short duration succinylcholine

SUCINYLCHOLINE
Side Effects & Clinical Consideration
Cardiovascular
Ach : NM junction cholinergic receptor

Ach parasympathetic n. sympathetic gg, adrenal medulla, sweat gl neurotransmitter Succinylacholine  receptor Low dose High dose HR NM junction nicotinic receptor , SA node muscarinic

nicotinic receptor, BP HR

negative chronotropic, inotropic effects circulating catecholamine level

contractility bradycardia 3-8 2nd dose , brady cardia SA node

Children

Adult : first dose

 first dose muscarinic receptor

metabolite sensitization

SUCINYLCHOLINE
Side Effects & Clinical Consideration
Fasciculation
Onset of paralysis  Pretreatment succinylcholine Fasciculation visible muscle contraction

small dose pretreatment , depolarizing (1.5mg/kg) children antagonize, elderly

Hyperkalemia
Succinylcholine induced depolarization pottasium serum level 0.5 mEq/l normal m.

 normal baseline level , preexisting hyperkalemia, burn, massive trauma, neurological disorder life threatening

SUCINYLCHOLINE
Side Effects & Clinical Consideration
Hyperkalemia

SUCINYLCHOLINE
Side Effects & Clinical Consideration
Hyperkalemia
 severe hyperkalemia routine CPR , calciem, insulin, glucose, bicarbonate, cation-exchange resins, dantrolene Dennervation injury , immature isoform of Ach receptor NM junction site induce (up-regulation) wide spread depolarization , extensive potassium release  life-threatening potassium release pretreatment

SUCINYLCHOLINE
Side Effects & Clinical Consideration
Muscle Pains
Unsynchronized muscle contraction Increase incidence of postoperative myalgia M/C in female and outpatient,  clinician pretreatment , controversial , , fasciculation report

Rocuronium 0.06-0.1 mg/kg postoperative myalgia

Perioperative NSAIDs : reduce the incidence and severity

Intragastric pressure elevation

Abdominal wall muscle fasciculation intragastric pressure , lower esophageal sphincter tone aspiration, reflux

SUCINYLCHOLINE
Side Effects & Clinical Consideration
Intraocular Pressure Elevation
Extraocular m. :  striated m. q multiple end-plate intraocular pressure

Masseter Muscle Rigidity

Masster m. tone Intubation mouth openning difficult

Marked increase in masster m. tone laryngoscope use difficul : malignant hyperthermia premonitory sign

Malignant hyperthermia
Hypermetabolic disorder of skeletal m. NMS (neuroleptic malignant syndrome) Malignant hyperthermia succinylcholine , pathogenesis

SUCINYLCHOLINE
Side Effects & Clinical Consideration
Prolonged paralysis Intracranial pressure
Slight increase in cerebral blood flow Muscle fasciculation activity ICP  stretch receptor cerebral

good airway control, hyperventilation q lidocaine iv preventing

Histamine release

NONDEPOLARIZING MUSCLE RELAXANT

UNIQUE PHARMACOLOGICAL CHARACTERISTICS

UNIQUE PHARMACOLOGICAL CHARACTERISTICS

Suitability For Intubation
Succcinyl choline Rapid onset ED
95

rapid onset, short duration , large dose, priming dose intubation dose ,

1-2

Larger intubation dose onset speed prolonged blockade, side effect

 large dose reversing ( More potent drug

duration of action , completely , postoperative pulmonary complication ) onset speed

Priming dose : short or intermediate acting agent, usual intubating dose 10-15% (induction 5 )
Rocuronium , 60 , intubation suitable

UNIQUE PHARMACOLOGICAL CHARACTERISTICS

Suitability For Intubation
Priming dose
 priming dose ,  Priming , clinically significant paralysis , distressing dyspnea, diplopia, dysphagia , induction

significant deteriotaion in respiratory function

UNIQUE PHARMACOLOGICAL CHARACTERISTICS

Suitability For Preventing Fasciculation
Intubationg dose , fasciculation 10-15 % succinylcholine 5 ( tubocurarine, rocuronium)

UNIQUE PHARMACOLOGICAL CHARACTERISTICS

Maintenance relaxation
Intubation , muscle paralysis
, clinical sign , Abd. Surgery, anesthetic management for mechnical ventilation Nerve stimulator monitoring

UNIQUE PHARMACOLOGICAL CHARACTERISTICS

Potentiation By Other Nondepolarizer
Some combination (eq, mivacurium + pancuronium)
Greater potency Closely related compound ( )  mechanism drug , potency potency

UNIQUE PHARMACOLOGICAL CHARACTERISTICS

Autonomic Side Effects
 receptor , clinical dose effect , nicotinic or muscarinic Ach

 older agent (eg, tubocurarine, metocurarine ) autonomic ganglia block, sympathetic nervous system compromise
Hypotension, intraoperative steress

Pancuronium SA node block tachycardia

vagal muscarinic receptor

Atracurium, cisatracurium, mivacurium, vecuronium newer agent dosage significant autonomic side effects

UNIQUE PHARMACOLOGICAL CHARACTERISTICS

Hepatic clearance
Pancuronium liver Vecuronium
Liver cirrhosis

vecuronium

significantly metabolized in

Active metabolite

clinical effect

rocuronium
blockade effect

bile

excretion

Atracurium, cisatracurium depend on extrahepatic mechanism

 liver disease

UNIQUE PHARMACOLOGICAL CHARACTERISTICS

Renal Excretion
Doxacurium, pancuronium, vecuronium, pipecuronium kidney partially excreted
Renal failure prolonged action

GENERAL PHARMACOLOGICAL CHARACTERISTICS

Temperature
Hypotermia prolongs blockade by decreasing metabolism (mivacurium, atracurium, cisatacurium), and delaying excretion ( pancuronium, vecuronium)

Acid-base balance
Respiratory acidosis reversal antagonize  hypoventilating postoperative potency

Electrolyte abnormality
Hypokalemia, hypocalcemia effect Preeclampsia pt , motor end-plate , magnesium sulfate calcium block magnesium blockade

GENERAL PHARMACOLOGICAL CHARACTERISTICS

AGE
Neonate , immature NM junction sensitivity , ECF volume drug Vd

Drug interactions

GENERAL PHARMACOLOGICAL CHARACTERISTICS

Concurrent disease
LC, CRF (dosage Vd ) water soluble drug plasma conc. drug

 hepatic clearance renal excretion prolonged effects ( dosage ) 

, greater initial dose, smaller maintenece dose

GENERAL PHARMACOLOGICAL CHARACTERISTICS

Muscle Groups Muscle group , onset intensity of blockade

Blood flow, distance, different fiber types Choice of m. relaxant  m. group sensitivity thumb m.

, diaphragm, jaw, larynx, facial muscle recover blockade ED95 adductor pollicis

Glottic m.

Laryngeal m. orbicularis oculi m.  

twitch response

good intubation condition duration response magnitude indibidual Pt ,

Text dosage recommend modification

ATRACURIUM
Physical Structure Quaternary group, benzylisoquinoline 10 stereoisomer Metabolism & Excretion Extensively metabolized, independent of renal, hepatic function Ester hydrolysis : nonspecific esterase Hofmann elimination : physiologic pH nonenzymatic chemical breakdown Dosage For intubation : 0.5 mg/kg iv (30-60 inject0

Intraoperative relaxation : initial 0.25 mg/kg, 10-20 0.1mg/kg iv, infusion 5-10 microgram /kg/min Age : insignificant effects, , short acting

ATRACURIUM
Side effects & clinical considerations Dose dependent histamine release : 0.5mg/kg Hypotension and tachycardia 0.5mg/kg dose

Transient drop in systemic vascular resistance, increase acrdiac index Slow rateof injection Bronchospasm Avoided in asthmatic pt Severe bronchospasm Laudanosine toxicity Atracurium MAC Hofmann elimination product asthma Hx minimize this effects

, CNS excitation

ATRACURIUM
Side effects & clinical considerations Temperature and pH sensitivity Hypothermia, acidosis Thiopental Allergic reaction Rare anaphylactoid reaction duration ,

alkaline solution

CISATRACURIUM
Hofmann elimination : end product neuromuscular blocking effect Laudanosine Age Dosage 0.1-0.15 mg/kg 2 good intubataion condition aracurium no intrinsic

pharmacokinetic change

Average infusion rate : 1.0-2.0 microgram/kg Atracurium cisatracurium 2-8 14 (atracurium) 21 (cisatracurium) Side effects & clinical consideration Dose not produce histamine release Dose not affect HR, BP, autonomic effects Ph, temperature, chemical incompatibility atracurium ,

MIVACURIUM
Metaboliosm & Excretion Metabolized by pseudocholinesterase Prolonged action in pt with low pseudocholinesterase  revese (neostigmine ) edrophonium neostigmine , plasma cholinesterase activity

Renal failure, hepatic failure, pregnancy, postpartum Duration of action Dosage Intubating dose : 0.15-2 mg/kg Intraoperative relaxation dose : 4-10 microgram/kg/min Children  18 dose

MIVACURIUM
Side effects & clinical consideration Atracurium Cardiovascular side effect minimized Cardiac dx significant ABP histamine release slow injection (over 1min) , 0.15mg/kg 0 dose

Onset time : 2-3 min (atracurium

Principal advantage : brief duration of action (20-30min) Succinyl choline phase I block 2-3 duration

Atracurium, vecuronium, rocuronium  recovery q

, pharmacological recovery monitoring duration

Pancuronium

DOXACURIUM
Physical structure Mivacurium, atracurium compound Metabolism & Excretion Long acting relaxant, hydrolyzed by plasma cholinesterase ( long acting relaxant Primary Elimination route : renal excretion Renal dz Dosage Intubating dose : 0.05 mg/kg, 5 adequate condition prolonged ) denzylquinoline

Intraoperative relaxation : initial 0.02mg/kg, followed by 0.005mg/kg Age action dose , prolonged

DOXACURIUM
Side effects & clinical considerations Cardiovascular effects & histamine release Onset long acting drug (4-6 )

Prolonged action

PANCURONIUM
Physical structure Bisquaternary relaxant (tow modified Ach molecule + steroid ring) Metabolism & Excretion Liver  40% (deacetylated) some blocking effect kidney excretion prolonged action , initial dose , maintenance

Renal failure

Liver cirrhosis , Vd , plasma clearance dose

PANCURONIUM
Dosage Intubation dose : 0.08-0.12 mg/kg , 2-3 Intraoperative relaxation dose : 0.04 mg/kg 0.01 mg/kg injection  2-8 moderately higher dose ,6 stable , 20-40

Side effects & clinical considerations Hypertension & tachycardia Vagal blockade Sympathetic stimulation : ganglionic stimulation, catecholamine release from adrenergic nerve endings, decreased catecholamine reuptake Increased HR (coronary aretery dz, idiopathic hypertrophic subaortic stenosis ) monitoring

PANCURONIUM
Side effects & clinical considerations Arrhythmias Atrioventricular conduction release predisposed pt dysfunction Pancuronium arrhythmogenic Allergic reactions Bromide reaction hypersensitive allergic (eg, pancuronium bromide) TCA, halothane , catecholamine ventricular

PIPECURONIUM
Physical structure Bisquaternary steroidal structure, pancuronium Metabolism & excretion Metabolism minor role, elimination excretion

Renal 70%, biliary 20% Renal failure insufficiency Dosage Pancuronium slightly potent duration , hepatic

Intubating dose 0.06-0.1 mg/kg Maintenance relaxation dose 20% Infants , kg dose pancuronium ,

PIPECURONIUM
Side effects & Clinical considerations Principal advantage over pancuronium : lack of cardiovascular side effects (cardiac muscarine receptor binding ) Onset of action duration pancuronium

VECURONIUM
Physical structure Pancuronium  side effects quaternary methyl group pnacuronium potency ,

Metabolism & Excretion  small extent, excretion Renal failure duration biliary excretion, 25% , satisfactory, renal

Pancuronium , brief duration, rapid clearance, due to shorter elimination half life ICU long term administration prolonged blockade , active metabolite accumulation, drug clearance ,poly neuropathy  female,renal failure, high dose , long term steroid therapy, sepsis risk factor

VECURONIUM
Metabolism & Excretion Long-term relaxant prolonged lack of Ach binding at the post synaptic nicotinic Ach receptors chr. Denervation state lasting receptor dysfunction, paralysis Long term use of nondepolarizing m. relaxant toleranace Dosage Pancuronium potent

Intubating dose : 0.08-0.12 mg/kg Intraoperative relaxation dose : 0.04 mg/kg (initial)  15-20 0.01 mg/kg

Infusion : 1-2 micro grams/kg/min Age :initial dose neonate infant not affected , subsequent dose less frequent

VECURONIUM
Dosage  duration 30 % sensitive (blockade )

Fat & muscle mass, protein binding,Vd Postpartum pt Liver uptake duration of action hepatic blood flow water

10mg of powder : 5-10 ml  Thiopental 24 line

VECURONIUM
Side effects & clinical considerations Cardiovascular : 0.28 mg/kg cardiovacular effects  , opioid induced bradycardia significant potentiation

Liver failure 0.15 mg dose prolongation Liver transplantation cirrhosis anhepatic phase ,

ROCURONIUM
Physical structure Vecuronium analogue Metabolism & Excretion No metabolism, liver Renal dz , duration hepatic failure pregnancy excretion , severe , modest prolongation , active metabolite duration rapid onset of action

Prolonged infusion , rocuronium vecuronium  ,liver mass

ROCURONIUM
Dosage Induction dose (0.9-1.2 mg /kg ) succinycholine (60-90s) Rapid-sequence induction dose duration  clinician (succinylcholine thiopental 20  administration rocuronium ) , rocuronium induction agent onset of action , ,

longer action , pofol : timing principle delayed paralyzed

Rocuronium 0.1mg/kg precurarization

succinylcholine