Muscle RelaxantMuscle Relaxant

DR NAJWA MANSORDR NAJWA MANSOR20132013

Muscle Muscle relaxant

Depolarizing Non-depolarizing

Aminosteroid“-uronium”

Benzyl isoquinoline“-urium”

Short: mivacurium

Intermediate: Atracurium

cisatracurium

Long:Curare, metocurine

doxacurium

Short: rapicuronium

Intermediate:Vecuroniumrocuronium

Long:Pancuroniumpipecuronium

reversalreversal

Factors

General considerations in General considerations in the use of muscle relaxantsthe use of muscle relaxants

Always be certain that you will able to maintain Always be certain that you will able to maintain airway before paralyzing them. airway before paralyzing them.

allow time for relaxation to develop before attempting allow time for relaxation to develop before attempting intubation. intubation.

The supplemental dose should be about 25% of the The supplemental dose should be about 25% of the initial dose.initial dose.

Never attempt to reverse the relaxation until at least Never attempt to reverse the relaxation until at least 15-20 minutes after the last dose of relaxant was 15-20 minutes after the last dose of relaxant was given. given.

Never extubate a patient until you are certain that the Never extubate a patient until you are certain that the paralysis has been reversed and they have adequate paralysis has been reversed and they have adequate muscle strength to protect their airway and breathe. muscle strength to protect their airway and breathe.

ensure that the depth of anaesthesia is adequateensure that the depth of anaesthesia is adequate

Thank you Thank you

PYSIOLOGY OF NEUROMUSCULAR

TRANSMISSION

NMJ

• Transmission of neural impulse at the nerve terminal translated into skeletal muscle contraction at motor end plate

Junction between the terminal of a motor neuron and a muscle fiber.

One kind of synapse. Also called myoneural

junction.

NEUROMUSCULAR NEUROMUSCULAR JUNCTIONJUNCTION

• When 2 Ach molecules bind simultaneously to 2 subunits – a channel opens thru the

center. • Allowing Na+ & Ca2+ tp

move into the muscle & K+ to move out.

AcethylcholinesteraseAcethylcholinesterase

• Synthesis in the muscle, under the end plate• Secreted from the muscle but remains attached

to it via thin stalk of collagen fastened to the basement membrane

• Destroy Ach that do not react immediately with receptor & that are released from binding sites.

• Ach is destroyed in < 1 ms after it is released.

Prevent sustained depolarization

Prevent tetany

• Most efficient enzyme known.– A single molecule has the capacity to

hydrolyze an estimated 300 000 molecules of Ach per minute.

INTRODUCTIONINTRODUCTION

BRIEF HISTORY PRINCIPLES OF

NEUROMUSCULAR TRANSMISSION

MUSCLE RELAXANT Ideal properties Indications & Contraindication Mechanism of action Side effect

Before neuromuscular blocking introduce: High concentration of inhalational anesthetic

agent Regional anesthesia

1942 curare (tubocurarine) introduce Less anesthetic administered

block neuromuscular transmission paralysis

presynaptically via the inhibition of acetylcholine (ACh) synthesis or release

postsynaptically at the acetylcholine receptor. adjunct to anesthesia to induce paralysis

not fully selective for the nicotinic ® and hence may have effects on muscarinic ®

Histamine release hypotension, flushing, and tachycardia.

! Important to realize that relaxant does not ensure unconsciousness, amnesia or analgesiaunconsciousness, amnesia or analgesia

BRIEF HISTORY OF BRIEF HISTORY OF NMBAsNMBAs •Curare- arrow poison by South American

Indian.

• 1932 – used in tetanus & spastic disorders (West)

• 1942 –1st used as muscle relaxant (Griffith & Johnson)

•Metocurine – few yrs later; 3x potency of dTC

•1949 - Sch independently described in

Italy, UK,USA

•1950 – Gallamine

•1961 – Alcuronium

•1967 – Pancuronium

•1972 – Fazadinium

•1980’s – Atracurium

– Vecuronium

•1938- Antagonism of curare by physostigmine (AChE). (Fetler et al) limited used d/t central effect

GallamineGallamine 1st synthetic NDMR after dTC. popularity d/t :

Mark CVS effect Potent vagal blockade Direct stimulating effect on ß1-receptor of

myocardium Both above lead to tachycardia + hypertension

Mainly excreated via kidney Contraindicated in ESRF & compromised renal f(x)

eg. Hypovolemia. Fat soluble++ Cross placenta

Contraindicated for LSCS

IDEAL PROPERTIES OF IDEAL PROPERTIES OF MUSCLE RELAXANT MUSCLE RELAXANT

Rapid onset (1 min)Rapid onset (1 min) To avoid hypoxia & aspiration of gastric contentTo avoid hypoxia & aspiration of gastric content

NondepolarizingNondepolarizing Predictable durationPredictable duration Easily antagonized, fully reversedEasily antagonized, fully reversed No drug interactionNo drug interaction Non-toxicNon-toxic Free of side effect eg. CVS, respiratoryFree of side effect eg. CVS, respiratory Stable pharmacokinetic and pharmacodynamic in Stable pharmacokinetic and pharmacodynamic in

the present of renal or hepatic diseasethe present of renal or hepatic disease No accumulationNo accumulation Safe in pregnancySafe in pregnancy

INDICATION OF NBAINDICATION OF NBA

To facilitate tracheal intubation Presence of residual

gastric content. Sch, rocuronium

To provide surgical relaxation To enable positive pressure

ventilation during & after

anesthesia Intensive care

unit

Sequence of Paralysis

orbicularis oculit

limbs Trunk Laryngeal muscle

IntercostalsDiaphragm

Recovery in Reverse

Thumb

DEPOLARIZING ACTION AT NMJ ( agonist )DEPOLARIZING ACTION AT NMJ ( agonist )

SuxamethoniumSuxamethonium

Suxamethonium chloride (also known as succinylcholine, or scoline) is a white crystalline substance, it is odourless and highly soluble in water. The compound consists of two acetylcholine molecules that are linked by their acetyl groups.

Administered IV, IM or SC agonists at nicotinic receptors activates prejunctional and endplate

receptors, resulting in depolarisation Causes muscle twitching and fasciculation,

which are followed by the onset of blockade Neuromuscular blockade is not complete until

~ 95% receptors occupied

Suxamethonium actionSuxamethonium action

2 succinylcholine molecules bind to the receptors in postsynaptic membrane

Depolarization- Fasciculation

Remains active at the endplate maintaining the depolarization

Preventing further muscle activity(paralysis)

Scoline –N ®

Sustained depolarization

depolarization

Opening of ion channel

hydrolyzed

paralysis

not

Dose 1 – 1.5 mg/kg

Onset 30 – 60 s

Duration

- 5 – 10 min

Half life 5 – 12 days

Metabolism

succinylcholine

plasma Pseudocholinesterases

succinylmonocholine + choline.

hydolyzed

succinic acid and choline

plasma Pseudocholinesterases Hydrolysis of scoline Rapid ate Extremely efficient

produce – liver Succinylcholine degraded in the serum but not in the

NMJ termination of action is then by dissociation &

diffusion, as there is no pseudocholinesterase at the endplate

Metabolism of SCh:

Elimination 10% is excreted unchanged in the urine. impaired renal function - prolonged apnoea

accumulation of succinylmonocholine

DNMB-SCh-duration of action

PLASMA CHOLINESTERASE ACTIVITY Elimination ½ life: 8-16 hours. Levels < 75% necessary for prolongation of Sch effect. Reduce/absent plasma cholinesterase in :

- Severe hepatic disease.- Drug induced – e.g: neostigmine, insecticides (anticholinesterase drugs), drugs for glaucoma and MG, nitrogen mustard & cyclophosphamide metoclopramide, high estrogen level.- Genetically determined.

Increase plasma cholinesterase in: - Obese pt. - Myasthenia Gravis (MG). - genetic inherited C5 isoenzyme - juvenile hyaline fibromatosis

SCh-duration of action

ATYPICAL PLASMA CHOLINESTERASE

Healthy patient who experiences prolonged NM blockade (1-3 hours) after conventional dose of SCh.

Dibucaine –related variant:

- Reflects quality of cholinesterase enzyme

- Patient with liver disease has normal dibucaine number.

Dibucaine test : a local anesthetic with amide linkage - inhibit activation of normal plasma cholinesterase enzyme –

If 80% atypical enzyme is 20%

NM blockade after SCh 1mg/kg iv persist >3 Hrs or longer

Dibucaine no. Plasma

cholinesterase

Neuromuscular

recovery

Incidence

80% Normal Normal 96%

40-60% Heterozygous

atypical

Moderate increase

1:480

20% Homozygous

atypical

Prolonged by hours

1:3200

Cardiac dysrhythmias cholinomimetic actions, acting at,

a. parasympathetic & sympathetic autonomic ganglia b. M2 receptors of the heart

Stimulate cardiac post gangflionic M ® Sinus brady, junctional rhythm,ventricular arrythmia

effects are variable, a. adults premedication with antimuscarinic drugs

® tachycardia and increased BP b. children

bradycardia or sinus arrest,

sinus bradycardia or a junctional rhythm

>> after a second dose ( after 5 minute first dose )

Pretreatment Atropine Subparalyzing dose of NDM

Muscle Pains

Fasciculations transient, generalized, unsynchronized

muscle contraction Skeletal muscle damage and myalgias neck, shoulder girdle and chest Reduce the incidence with a “precurarization” Young muscular adult, minor procedure with

early ambulation

Hyperkalaemia

increase in serum [K+] ~ 0.5 mmol/l Hyperkalaemic response secondary to

proliferation of extrajunctional R More ion channels being open More site for pottasium leakage R remain open longer

No benefit of priming

a. denervation

b. burns -most common causes

c. major trauma

d. neurologic disease & trauma

e. severe sepsis

f. renal failure‡

g. cerebrovascular accidents

Extra Junctional Cholinergic ReceptorExtra Junctional Cholinergic Receptor Located throughout skeletal muscle membrane Normally not present in large number Synthesis is suppressed by neural activity Min. involvement in neural act-y proliferate rapidly

motor less active due to trauma ms denervation

Highly responsive to agonist – Ach/Sch

Within 24 h

it may persist for 2-3 months following burns up to 6 months following neurological lesions

renal failure- normokalaemic safely received scoline (lack of reliance on renal excretion)

Transient increase of IOP Contraction of extraocular muscle 2 – 4 min after admin. open eye inj

Increase in intragastric pressure Fasciculation of abdominal skeletal muscle Risk of aspiration

Transient increase ICP Masseter muscle spasm

Trismus ?? Malignant hyperthermia

Suxamethonium Apnoea prolonged apnoea may result from,

a. plasma cholinesterase deficiency

- acquired

- congenital

b. phase II block

c. drug interactions

Acquired Enzyme Deficiency

a. patients with acute or chronic liver diseases

b. malnutrition

c. pregnancy

d. collagen diseases

e. chronic anaemia

f. uraemia

g. myxedema

h. other chronic debilitating diseases

i. severe burns

j. chronic pesticide exposure & accidental poisoning

k. drugs

- chlorpromazine

- pancuronium, neostigmine

m.increased levels are found in obesity, type IV hyperlipoproteinaemia, nephrosis & toxic goitre

Malignant Hyperpyrexia

in genetically susceptible individuals ~ 70% elevated creatine phosphokinase

levels in the resting, fasted state determined by muscle biopsy studies masseter spasm occurs mainly in children

Malignant hyperthermia Presentation

Unexplained tachycardia

Tachypnoea in spont breathing pt

unresponsive to increased depth of anaesthesia

Ms rigidity Cardiac dysrhythmias ↓SpO2 and cyanosis end-tidal CO2 Labile blood pressure Metabolic acidosis

Immediate mx: Airway secured Hyperventilation with

100% oxygen All anaesthetic agents

stopped lowering of temperature sodium bicarbonate restoration of fluids,

adequate urinary output electrolyte balance IV Dantrolene Monitor vital signs Patient to be transfered

to ICU for continued monitoring

CONTRAINDICATION TO SUX

Drug interactions

2-Non depolarizing muscle relaxant Small doses of NDM antagonize DMR phase I block

by occupy some Ach R prevent depolarization by Succinylchol.

Except pancuronium,augment scoline block by inhibiting pseudocholenesterase.

NDM will potentiate phase II block Similarly succinylchol reduces NDM requirement for

at least 30 minutes

Bind to subunit in the same way that Ach does.

If bind to a pair of subunits stimulate an initial opening of ion channel producing a contraction known as fasciculation.

H/ever, this drugs are not broken down by acethylcholinesterase, they bind for longer period than Ach persistent depolarization of the end plate & neuromuscular block.

NDMRs compete with Ach to bind to subunit.

Attachment to subunit doesn’t open the ion channel so no current will flow thru the channel.

Membrane will not depolarize muscle become flaccid

DEPOLARIZING MUSCLE RELAXANTDEPOLARIZING MUSCLE RELAXANT NONDEPOLARIZING MUSCLE RELAXANT

Patterns of Neuromuscular Blockade

Depolarising Block

fasciculations preceding paralysis

absence of tetanic fade at slow and fast rates

no post-tetanic potentiation potentiation by anti-AChE

agents potentiation by depolarising

relaxants antagonism by

nondepolarising relaxants

Nondepolarising Block

no muscle fasciculation

tetanic fade, with train of four (0.5-2 Hz)

post-tetanic potentiation antagonism by anti-AChE

agents antagonism by depolarising

relaxants potentiation by

nondepolarising relaxants

Phase IMembrane depolarizes resulting in an initial discharge which produces transient fasciculations followed by flaccid paralysis

Phase II Membrane repolarizes

but receptor is desensitized

Phase II or Dual Block

phase II blockade occurs more commonly in patients either

a. given repeated doses of depolarising agents

b. with atypical plasma cholinesterase activity

c. with myasthenia gravis, or myasthenia-like syndromes

Muscle RelaxantsMuscle Relaxants

2 CLASSIFICATION

Steroidal CompoundsPancuroniumPipecuroniumVecuroniumRocuronium

Benzylisoquinolinium Compoundsd-TubocurarineMetocurineDoxacuriumAtracuriumMivacurium

Trisquaternary etherGallamine

duration of action

Long-acting–Pancuronium–Doxacurium –Pipecuronium

Intermediate-acting–Atracurium–Vecuronium–Rocuronium–Cisatracurium

Short-acting–Mivacurium

Rapid onset, short acting–Rapacuronium

By chemical structure

NON DEPOLARIZING NON DEPOLARIZING M. RELAXANTSM. RELAXANTS

- Do not cause depolarization

- Competes with Ach for postsynaptic receptors

- Competitively inhibit Ach stimulating the receptors at the motor end plate

- Block prejunctional Ach receptors: decrease Ach release

• Slower time of onset• Longer duration of action• Used- following Suxamethanium to maintain

relaxation during surgery- to facilitate tracheal intubation in non-

urgent situation• Onset decreased by

– Large dose– Priming principle

Non-depolarising m.relaxants generalNon-depolarising m.relaxants general

Priming principle

• Admin 10-20 % intubation dose of NDM 5 min before induction

• Not lead to clinically significant paralysis (safety margin for transmission and blockade is not

seen until > 70% receptor occupancy)– Some pt do

• Dyspnea or dysphagia

• Significant decrease resp fx ( FVC)– Desaturation---marginal pulmonary reserve

• Small dose binds a certain no. of spare ®

• Second larger dose----speed of onset

Generally not actively metabolized by the liver (although some of the steroidal muscle relaxants are an exception).

Reasons:

i. Water solubility of relaxants inhibits uptake into hepatocytes

ii. Cytochrome P-450 oxidative enzyme system in liver microsomes requires lipophilic substrates, generally excluding the relatively hydrophilic muscle relaxants.

All muscle relaxants are highly water soluble and hydrophilic.

Reason:i. +ve charges, which give muscle

relaxants the physicochemical properties of cations in watery media such as the plasma and urine

ii. Various oxygen-bearing groups Ester linkages of Sch &

atracurium Acetate groups of

pancuronium, vecuronium & rocuronium

Molecular Features & Molecular Features & Physicochemical Properties…Physicochemical Properties…

PHARMACOKINETICSPHARMACOKINETICSBecause of their quaternary ammonium groups, these agents:

almost completely ionized at physiological pH highly water soluble very low lipid soluble

They tend to be, poor GIT absorption

Oral absorption is not effective. resistant to hepatic metabolism (steroids excluded) low volumes of distribution

Similar to ECV ~ 200 mls/kg If Vd ↓, the same dose of drug produces a higher plasma [ ] &

apparent potensy of the drugs augmented. Dehydration Acute haemorrhage

poor BBB penetration (CNS) No CNS effects

Placenta – fetus not affected

Long actingTubocurarine (Curare, d-tubocurarine)

South American plant genus Strychnos

• 3-5 minutes to act • lasts for 30-40 minutes. • 0.3-0.6 mg/kg• hypotension - histamine

- blocking autonomic ganglia

• Bronchospasm

• Route of excretion in the urine.

LONG-ACTING NONDEPOLARIZING NMB

PANCURONIUM

INTRODUCTION• Bisquaternary aminosteroid.

• ED95: 0.07mg/kg.

• Onset: 3 – 5 min.• Duration: 60 – 90 min.

MOLECULAR STRUCTUREPANCURONIUM

PANCURONIUM –clearance

• 10 – 40% of dose of pancuronium undergoes hepatic diacetylation produce:i. 3 – desacetylpancuronium – 50% potent as pancuronium.ii. 17 – desacetylpancuronium.iii. 3,17 – desacetylpancuronium. minimal activity

• Pt with total biliary obstruction, hepatic obstruction : will have- Increase Vd ( Large initial dose required but prolonged action because of decrease plasma clearance)- Prolonged elimination ½ time of pancuronium.

Aging: in elderly, decreased in plasma clearance (reduce renal fn) – prolonged elimination half time of drug hence duration of neuromuscular blockade prolonged.

PANCURONIUM

CLEARANCE

• 80% of single dose of pancuronium is eliminated unchanged in urine.

• Renal failure: plasma clearance is decreased 33 – 55%. As a result-prolonged elimination half time

Normal hepatic fn

cirrhosis

Vol.of distribution (Vd)-ml/kg 279 416

Clearance –ml/kg/min 1.9 1.5

Elimination half time-min 114 208

Pharmacokinetic and hepatic dysfunction

PANCURONIUM

CVS EFFECTS• 10 – 15% increase in heart rate, cardiac o/put due to:

- Selective cardiac vagal blockade.- Activation of sympathetic nervous system.Mechanism:

i. Release of NE from adrenergic nerve endings.ii. Blockade of uptake of NE back into postganglionic nerve endings.

iii. Release of NE from muscarinic receptor inhibition • Increase plasma concentration of catecholamines.

PANCURONIUM –cvs effect

• increased in BP due to effect of increased heart rate on cardiac output.

• increase incidence of cardiac dysrhythmias - in pt with digitalis

• may increase MI incidence in patient with CAD.• No histamine release.• No autonomic ganglion blockade

Doxacurium

• a new benzylisoquinoline ester

• very potent, long lasting relaxant

• ~ 2x as potent as pancuronium

• no histamine release / CVS effects

• excreted - kidney & bile

Pipercuronium

• similar potency & duration to pancuronium

• excreted principally through the kidney & bile

• duration of action is similarly prolonged in renal and hepatic insufficiency, and in the elderly

• elimination half life, t½ ~ 100 min

• Intermediate-acting– Atracurium– Vecuronium– Rocuronium– Cisatracurium

• Minimal cumulative effects as infusion d2 rapid clearance

• Lack of CV effects• Higher cost

ATRACURIUM

INTRODUCTION• Bisquaternary benzylisoquinolones

• ED95 : 0.2 mg/kg

• Onset: 3 – 5 min

• Duration: 20 – 35 min

• 82 % bound to plasma proteins, presumably albumin

• Undergo spontaneous Hoffmann elimination at normal body temperature and pH

• Iodide salt besylate:

- Provides water solubility

- Adjust the pH of 3.25 – 3.65, minimizes the likelihood of

spontaneous degradation

Should not mixed with alkaline drugs (barbiturates)

INTERMEDIATE ACTING NONDEPOLARISING NMB

ATRACURIUM

CLEARANCE

• 2 processes:i. base-catalysed reaction: Hofmann elimination.ii. hydrolysis by non specific plasma esterases : ester hydrolisis

• Major metabolites of both pathways: - Laudanosine – not active at NMJ. - electrophilic acrylate – from Hoffman degradation• Routes of metabolism independent of:

- Hepatic function. - Renal function.- Plasma cholinesterase activity.

• Efficient clearance mechanism minimize cumulative effects.

METABOLISM OF ATRACURIUM

ATRACURIUM - clearance

LAUDANOSINE• Major metabolite. Each molecule of atracurium produce:

- Hofmann elimination: 2 molecules

- Ester hydrolysis: 1 molecule

• Peak plasma concentration: after 2 min

• Depends on liver for clearance, 70% excreted via bile

- Hepatic cirrhosis: clearance unaltered

- Biliary obstruction: impaired metabolite excretion

• CNS stimulant in animal studies (epileptiform)

ATRACURIUM -

ACID BASE CHANGES• pH alter rate of Hofmann elimination (accelerate by alkalosis, slowed

by acidosis)

• pH changes influence the rate of ester hydrolysis in a reduction opposite to the changes in the rate of Hofmann elimination.

CUMULATIVE EFFECT• Absence of significant cumulative drug is due to rapid clearance of

atracurium from plasma, that is independent of renal and hepatic function.

ATRACURIUM

CVS EFFECTS• 2X ED95: SBP and heart rate do not change.

3x ED95: Increase HR by 8.3%.

Reduce MAP by 21.5%

The effects is:

- Transient.

- Occuring 60 – 90 sec after administration.

- Disappear within 5 min.

Due to release of histamine.

Plasma histamine concentration must double before CVS changes

• Histamine release evoked by atracurium and mivacurium does not occur repeatedly because tissue histamine stores are not replenished for several days.

ATRACURIUM

PEDIATRIC PATIENT• Children (2 – 16 years old): ED95 as adult.

• Infants (1-6/12 old): One ½ dose given to older children.

• Recovery: infants is more rapid than adolescent.

ELDERLY PATIENT• Rate of recovery and duration of neuromuscular blockade is similar in

young adults and elderly.

• Changes in Vd that occur with aging will not influence clearance of atracurium from plasma.

INTERMEDIATE NONDEPOLARISING NMB

VECURONIUM

INTRODUCTION• Monoquaternary aminosteroid

• ED95: 0.05mg/kg

• Onset: 3 – 5 min

• Duration: 20 – 35 min

• Vecuronium = pancuronium w/out quaternary methyl group

• Absence of quaternary methyl group decreases the Ach-like character of pancuronium – reduce vagolytic property by 20 fold

• Increased lipid solubility due to monoquaternary structure

• Unstable in solution

MOLECULAR STRUCTURE

VECURONIUM

VECURONIUM

CLEARANCE• Hepatic metabolism and renal excretion.• Deacetylation (in liver) produce:

- 3-desacetylvecuronium: ½ potent as parent component.

- 17-desacetylvecuronium.

- 3,17-desacetylvecuronium.• 40% of drug excreted unchanged in bile in 1st 24 hours.• 30% of administered dose appeared in urine as unchanged drugs and

metabolites in 1st 24 hours.

<1/10 potent

VECURONIUM -clearance

RENAL DYSFUNCTION• Prolonged elimination half time – decrease clearance.

• Increase plasma concentration of 3-desacetylvecuronium may contribute to persistent skeletal muscle paralysis after prolonged infusion.

HEPATIC DYSFUNCTION• Smaller dose (0.1mg/kg) – elimination ½ time have no difference due to:

- Renal clearance.

- Diffusion of drug into inactive tissue.

• 0.2mg/kg – prolonged duration of action.

VECURONIUM

ACID BASE CHANGES• Depends on the changes in blood pH precede or follow the administration of

vecuronium.

eg: Changes in PaCO2 - before administration: no effect.

- after administration: enhance vecuronium effect.

CUMULATIVE EFFECTS• Less than pancuronium and greater from atracurium.

• Occur in renal failure patient:

- Gradual saturation of peripheral storage site.

- Accumulation of 3-desacetylvecuronium especially after repeated

doses.

VECURONIUM

CVS EFFECTS• No circulatory effects even with rapid IV administration of doses that exceed

ED95 x 3 - lack of vagolitic effect/histamine release

• Modest vagotonic effect

• Other effects that has been described: sinus node exit block and cardiac arrest

PEDIATRIC PATIENT• Potency of vecuronium is similar in all age group

• Onset rapid in infants – increase COP

• Duration of action:

Longest in infant due to: - Immature enzyme system of liver

- Increase Vd.

- Age related changes in biliary clearance

VECURONIUM

ELDERLY PATIENT• Age related decreased in liver blood flow and microsomal enzyme activity.

Age related decreased in renal blood flow.

*decrease plasma clearance - prolonged duration of action

• Delayed rate of recovery

OBSTETRIC PATIENT• Insufficient amount cross the placenta to produce clinical significant effect in the

fetus eg : maternal to fetal ratio of vecuronium 0.11

• Clearance of vecuronium may accelerated during late pregnancy:

- Stimulation of hepatic microsomal enzymes by progesterone.

- CVS changes.

- Fluid shift.

INTERMEDIATE NONDEPOLARISING NMB

ROCURONIUM

INTRODUCTION• Monoquaternary aminosteroid

• ED95: 0.3 mg/kg

• Onset: 1 – 2 min• Duration: 20 – 35 min• Structurally resembles vecuronium except for the presence of a

hydroxyl group

• 3 – 4x ED95 resembles the onset of action of SCh 1mg/kg IV – alternative of SCh if contraindicated

Disadvantages:i. Large doses may resembles long acting NDNMB (pancuronium) action.ii. Laryngeal adductor muscle & diaphram are more resistant to

Rocuronium compared to adductor pollicis as with other NDNMB.- Onset will be delayed compared to SCh.- Risk of pulmonary aspiration if diaphragm & laryngeal

muscles are not fully relaxed.

MOLECULAR STRUCTURE

ROCURONIUM

ROCURONIUM

CLEARANCE• Largely excreted unchange in the bile (~50% in 2Hr)• No deacetylation• Renal excretion > 30% in 24 hours• Renal failure patient – modestly prolonged duration of action• Liver failure patient – increased Vd: longer duration of action especially

after repeated dose/infusion• Elderly:

- Similar speed of onset- Prolonged duration of action

CVS EFFECT• May produce slight vagolytic effect• Useful in surgery that associated with vagal stimulation• Absence of histamine release

Short-acting

Mivacurium

• Onset 3 - 5 min

• Duration 10 – 20 min

• hydrolysed by plasma cholinesterase– slightly slower than succinylcholine

• cardiovascular effects are minimal

• rapid bolus injection of larger doses results in histamine release with,

i. transient facial erythema

ii. a brief fall in mean arterial pressure

Rapid onset, short acting

Rapacuronium

• Rapid onset and offset• Being withdrawn by manufacture due to

several reports of serious bronchospasm including unexplained fatalities

Histamine Release & Anaphylaxis

• Generic side-effect of the benzoisoquinoline ester agentsa. dTCb. atracuriumc. mivacurium d. doxacurium

• NB: most drugs administered IV release small amounts of histamine, which are pharmacologically insignificant 1ng/ml

• increases of 5-10 fold are required for significant systemic effects

a. 2-3 ng/ml - no clinical significance

b. < 10 ng/ml - urticaria, flushing, tachycardia

c. > 10 ng/ml - ± life threatening bronchospasm, hypotension & arrest

Cardiac Vagus Effects

• Pancuronium & gallamine block M2-receptors and result in a tachycardia

• vagolytic activity is seen with all steroidal based agents

relaxant Met. excretion onset duration histamine Vagal blockade

cost

Tubocurarine Insignificant Renal + + + + + + + + 0 Low

Metocurine Insignificant Renal + + + + + + + 0 Mod

Atracurium + + + Insignificant + + + + + 0 High

Cisatracurium + + + Insignificant + + + + - 0 High

Mivacurium + + + Insignificant + + + 0 Mod

Pancuronium + Renal + + + + + - + + Low

Vecuronium + + Biliary + + + + - 0 High

Rocuronium Insignificant Biliary + + + + - + High

rapacuronium + Renal + + + 0 high

Summary of the pharmacology of NDMR

ASSESSEMENT OF NEUROMUSCULAR BLOCKADEASSESSEMENT OF NEUROMUSCULAR BLOCKADE

Mechanical Force

TransducerAcceleromete

r Intergrated EMG

Assessment of response

Monitoring of BlockadeMonitoring of Blockade

Observing or palpating

• Costly & complex

• Measure muscle tension

• Costly & complex

• Measure muscle tension

• Simplest method

• Inaccurate

• Simplest method

• Inaccurate

• The transducer consist of a piezo- electric ceramic wafer with electrodes on both sides

• Following changes in velocity, an electrical voltage proportional to acceleration is generated between the electrodes.

• Force=mass x acceleration,thus the muscle tension response may be evaluated.

• The transducer consist of a piezo- electric ceramic wafer with electrodes on both sides

• Following changes in velocity, an electrical voltage proportional to acceleration is generated between the electrodes.

• Force=mass x acceleration,thus the muscle tension response may be evaluated.

• Register the EMG response via 2 surface/needle electrodes.

• Only monitors transmission across the NMJ.

• More specific than mech. assessment

• Register the EMG response via 2 surface/needle electrodes.

• Only monitors transmission across the NMJ.

• More specific than mech. assessment

Stimulation pattern

Monitoring of BlockadeMonitoring of Blockade

Single twitch response

Train Of Four

Tetanic Stimulation

Dual Burst Stimulation

Post Tetanic Stimulation

Post Tetanic Count

Stimulation pattern

Monitoring of BlockadeMonitoring of Blockade

Single twitch response

• A single pulse that is delivered from every second to every 10

second (1-0.1Hz)

• Increasing blockade results in decreased evoked response to

twitch stimulation

0.2 msec duration

Time

Stimulation pattern

Monitoring of BlockadeMonitoring of Blockade

Train of Four• 4 successive twitch in 2 seconds (2Hz)

• The twitches progressively fade as relaxation .• TOF ratio –between the 1st & 4th twitch – indicator for non dep. NMB

• Also by observation – disappearance of the 4th twitch – 75% block, the 3rd –

80% block & the 2nd – 90% block

0.2 msec

Time

500 msec

Stimulation pattern

Monitoring of BlockadeMonitoring of Blockade

Tetany• Continuous stimulation at 50 -100Hz

• Sensitive test for neuromuscular function

• Sustained contraction for 5 sec indicate adequate reversal from NMB

• Painful in conscious patient

0.2 msec

Time

20 msec

Stimulation pattern

Monitoring of BlockadeMonitoring of Blockade

Double-Burst Stimulation

• 2 variation of tetany DBS3,3 or DBS3,2

• 3 short (200 sec) high frequency burst at 50Hz followed 750msec

later by another 3/2 such burst

• Less painful & > sensitive than TOF for evaluation of fade

0.2 msec

Time

750 msec

Stimulation pattern

Monitoring of BlockadeMonitoring of Blockade

Post Tetanic Count• To assess intense blockade

• A single twitch 1 Hz for 1 minute than followed by 5 sec tetanus at 50Hz ,

and after 3 sec the no. of twitches at 1Hz is counted.

• A PTC of 2 suggest no twitch response for 20-30minutes, PTC of 5 10-15

minutes.

Fade

Monitoring of BlockadeMonitoring of Blockade

Indicative of Non dep. NMBA

Gradual decrease in strength of muscle contraction during

prolonged / repeated stimulation

Due to pre junctional effect of NMBA that reduce Ach in

the nerve terminal for release during stimulation.

Adequate clinical recovery absence of fade.

Post Tetanic potentiation

Monitoring of BlockadeMonitoring of Blockade

Indicative of Non dep. NMBA

Also indicative for dep.( MBA phase II)

The ability of tetanic stimulation to increase evoke

response to a subsequent twitch

Due to increase presynaptic mobilization & release of Ach

following tetanic stimulation

Stimulation patternMonitoring of BlockadeMonitoring of Blockade

EVOKED STIMEVOKED STIM DEPDEP NON DEPNON DEP

PH IPH I PH IIPH II

TOFTOF Constant &

amplitude

Fade Fade

TETANYTETANY Constant &

amplitude

fade fade

DBSDBS Constant &

amplitude

Fade Fade

PTFPTF Absent Present Present

MYASTHENIA GRAVIS (MG)

Myasthenia gravis (my: muscle, asthenia: weakness, gravis: severe)

Autoimmune disorder antibodies directed against acetylcholine

receptors.

Characterised by weakness or exaggerated fatiguability on sustained effort.

Depolarizing muscle relaxant; Frequent phase II block even with single dose. Increase plasma [K+] concentration.

Non depolarizing muscle relaxant. Resistance, required higher dose for rapid sequence

intubation. Sensitivity and duration increased. Monitoring neuromuscular blocker is

necessary. Controlled factor which increase

neuromuscular block.

The Lambert-Eaton syndrome

Proximal fatiguability, which is relieved by exercise.

Association; Malignancy : pulmonary, gastric,

kidney or bowel tumours in (old patients)

Autoimmune diseases in (young patients).

Muscle relaxantMuscle relaxant Succinylcholine : normal response.Succinylcholine : normal response. NDMRs : increase sensitivity.NDMRs : increase sensitivity. NDMRs of intermediate duration of NDMRs of intermediate duration of

action action pyrido-stigmine is not effective.pyrido-stigmine is not effective.

TABLE 19-5. Comparison of Myasthenia Gravis and Myasthenic Syndrome

Myasthenia Gravis Myasthenic Syndrome

Manifestations Extraocular, bulbar, and facial muscle weakness Proximal limb weakness (legs > arms)

Fatigue with exercise Exercise improves strength

Muscle pain uncommon Muscle pain common

Reflexes normal or decreased Reflexes absent

Gender Female > male Male > female

Coexisting pathology

Thymoma Cancer (especially small cancer of the lung)

Response to muscle relaxants

Resistant to succinylcholine and sensitive to nondepolarizing muscle relaxants

Sensitive to succinylcholine and nondepolarizing muscle relaxants

ANTICHOLINESTERASE DRUGS AND CHOLINERGIC AGONIST

• Introduction.• Molecular structure.• Mechanism of action.• Classification.• Pharmacokinetic of anticholinesterases.• Pharmacologic effects of anticholinesterases.• Antagonist-assisted reversal of neuromuscular

blockade.

REVERSAL OF BLOCKADE REVERSAL OF BLOCKADE OF NDMRsOF NDMRs

SPONTANEOUS REVERSALSPONTANEOUS REVERSAL PHARMACOLOGIC REVERSALPHARMACOLOGIC REVERSAL

Gradual diffusionGradual diffusion RedistributionRedistribution MetabolismMetabolismMetabolismMetabolism ExcreationExcreationExcreationExcreation AnticholinesteraseAnticholinesterase

Indirectly increase the amount of Achavailable to compete with NDMRs

Reestablishing neuromuscular transmission

ANTICHOLINESTERASEANTICHOLINESTERASE

Drugs inhibit AChE (truecholinesterase) which responsible for hydrolysis of Ach. Prolong depolarizing blockade of Sch by possible

mechanism: Ach Inhibition of pseudocholinesterase activity.

glycopyrrolate + edrophonium = bradycardia "standard" reversal combination,

i. atropine 1.2 mg ~ 17 µg / kg x 70 ii. neostigmine 2.5 mg ~ 35 µg / kg x 70

atropine + neostigmine induce an initial tachycardia, followed by a late bradycardia

The choice & dose of cholinesterase inhibitor The choice & dose of cholinesterase inhibitor determine the choice & dose of anticholinergic.determine the choice & dose of anticholinergic.

Only the nicotinic effect of antiAChE Only the nicotinic effect of antiAChE are disiredare disired

the muscarinic effect must be block.the muscarinic effect must be block.

Reversal agent should be routinely given to a patients who have received NDMRs unless

Full reversal can be demonstratedPostoperative plan includes continued intubation & ventilation

Organ System Muscarinic Side Effect

Cardiovascular HR, dysrhythmias

PulmonaryBronchospasm,bronchial secreation

CerebralDiffuse excitation ( Physostigmine )

GITIntestinal spasm, salivation

G/urinary Bladder tone

Ophthalmologic Pupillary constriction

Cholinesterase Inhibitor

Usual Dose of Cholinesterase Inhibitor (mg/kg)

Recommended Anticholinergic

Usual Dose of Anticholinergic per mg of Cholinesterase Inhibitor

Neostigmine 0.04-0.08Glycopyrrolat

e0.2 mg

Pyridostigmine

0.1-0.4Glycopyrrolat

e0.05 mg

Edrophonium 0.5-1.0 Atropine 0.014 mg

Physostigmine

0.01-0.03Usually not necessary

NA

Sedation Antisiolagogue ↑ HR Relax smooth muscle

Atropine + + +++ ++

Scopolamine +++ +++ + +

Glycopyrrolate 0 ++ ++ ++

Mydriasis

cyloplegia

Prevent motion-induced nausea

↓ gastric H+

secretionAlter fetal

HR

Atropine + + + 0

Scopolamine +++ +++ + ?

Glycopyrrolate 0 0 + 0