Download Muscle relaxant

Muscle Relaxant
DR NAJWA MANSOR
2013
reversal
Muscle relaxant
Depolarizing
Non-depolarizing
Aminosteroid Benzyl isoquinoline
“-uronium”
“-urium”
Short: rapicuronium
Short: mivacurium
Intermediate:
Vecuronium
rocuronium
Intermediate:
Atracurium
cisatracurium
Long:
Pancuronium
pipecuronium
Long:
Curare, metocurine
doxacurium
Factors
General considerations in the
use of muscle relaxants


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

Always be certain that you will able to maintain airway
before paralyzing them.
allow time for relaxation to develop before attempting
intubation.
The supplemental dose should be about 25% of the
initial dose.
Never attempt to reverse the relaxation until at least
15-20 minutes after the last dose of relaxant was given.
Never extubate a patient until you are certain that the
paralysis has been reversed and they have adequate
muscle strength to protect their airway and breathe.
ensure that the depth of anaesthesia is adequate
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 JUNCTION
• 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.
Acethylcholinesterase
• 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.
INTRODUCTION



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 analgesia
BRIEF HISTORY OF NMBAs
•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
•1938- Antagonism of curare by physostigmine (AChE).
(Fetler et al)  limited used d/t central effect
•1950
– Gallamine
•1961
– Alcuronium
•1967
– Pancuronium
•1972
– Fazadinium
•1980’s
– Atracurium
– Vecuronium
Gallamine


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 MUSCLE
RELAXANT

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
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
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
Rapid onset (1 min)
 To avoid hypoxia & aspiration of gastric content
Nondepolarizing
Predictable duration
Easily antagonized, fully reversed
No drug interaction
Non-toxic
Free of side effect eg. CVS, respiratory
Stable pharmacokinetic and pharmacodynamic in the present
of renal or hepatic disease
No accumulation
Safe in pregnancy
INDICATION 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
Thumb
orbicularis oculit
limbs
Diaphragm
Trunk
Laryngeal muscle
Intercostals
Recovery in Reverse
DEPOLARIZING ACTION AT NMJ ( agonist )
Suxamethonium

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 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 ®
Opening of ion
channel
depolarization
not
hydrolyzed
Sustained
depolarization
paralysis

Dose


Onset



1 – 1.5 mg/kg
30 – 60 s
Duration
- 5 – 10 min
Half life


Metabolism
succinylcholine
plasma
Pseudo
cholinesterases
succinylmonocholine + choline.
5 – 12 days
hydolyzed
succinic acid and choline

plasma Pseudocholinesterases



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
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 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

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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

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Contraction of extraocular muscle
2 – 4 min after admin.
open eye inj

Increase in intragastric pressure
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Fasciculation of abdominal skeletal muscle
Risk of aspiration
Transient increase ICP
Masseter muscle spasm

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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
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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:
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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
DEPOLARIZING MUSCLE RELAXANT



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.
NONDEPOLARIZING MUSCLE RELAXANT



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
Patterns of Neuromuscular Blockade
Depolarising Block
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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



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Phase I
Membrane 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 Relaxants
2 CLASSIFICATION
By chemical structure
Steroidal Compounds
Pancuronium
Pipecuronium
Vecuronium
Rocuronium
Benzylisoquinolinium Compounds
d-Tubocurarine
Metocurine
Doxacurium
Atracurium
Mivacurium
Trisquaternary ether
Gallamine
duration of action
Long-acting
–Pancuronium
–Doxacurium
–Pipecuronium
Intermediate-acting
–Atracurium
–Vecuronium
–Rocuronium
–Cisatracurium
Short-acting
–Mivacurium
Rapid onset, short acting
–Rapacuronium
NON DEPOLARIZING
M. 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
Non-depolarising m.relaxants general
•
•
•
-
Slower time of onset
Longer duration of action
Used
following Suxamethanium to maintain
relaxation during surgery
- to facilitate tracheal intubation in nonurgent situation
• Onset decreased by
– Large dose
– Priming principle
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
Molecular Features &
Physicochemical Properties…


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
PHARMACOKINETICS
Because 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 acting
Tubocurarine (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 STRUCTURE
PANCURONIUM
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
Pharmacokinetic and hepatic dysfunction
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
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
INTERMEDIATE ACTING NONDEPOLARISING NMB
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)
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:
3x ED95:
SBP and heart rate do not change.
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.
<1/10 potent
- 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.
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
agents
a.
b.
c.
d.
dTC
atracurium
mivacurium
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 M2receptors and result in a tachycardia
• vagolytic activity is seen with all
steroidal based agents
Summary of the pharmacology of NDMR
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
ASSESSEMENT OF NEUROMUSCULAR BLOCKADE
Monitoring of Blockade
Assessment of response
Observing or palpating
• Simplest method
Mechanical
Force Transducer
• Inaccurate
Accelerometer
• Costly & complex
Measure
muscle
tension
••The
transducer
consist
of a piezo- electric ceramic wafer with
Intergrated
EMG
electrodes on both sides
• Register the EMG response via 2 surface/needle
• Following
electrodes.changes in velocity, an electrical voltage proportional
to acceleration is generated between the electrodes.
• Only monitors transmission across the NMJ.
• Force=mass x acceleration,thus the muscle tension response
• More
specific
than mech. assessment
may be
evaluated.
Monitoring of Blockade
Stimulation pattern
Single twitch response
Train Of Four
Tetanic Stimulation
Dual Burst Stimulation
Post Tetanic Stimulation
Post Tetanic Count
Monitoring of Blockade
Stimulation pattern
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
Time
0.2 msec duration
Monitoring of Blockade
Stimulation pattern
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
Time
0.2 msec
500 msec
Monitoring of Blockade
Stimulation pattern
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
Time
0.2 msec
20 msec
Monitoring of Blockade
Stimulation pattern
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
Time
0.2 msec 750 msec
Monitoring of Blockade
Stimulation pattern
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.
Monitoring of Blockade
Fade
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.
Monitoring of Blockade
Post Tetanic potentiation
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
Monitoring of Blockade
Stimulation pattern
EVOKED STIM
TOF
DEP
NON DEP
PH I
PH II
Constant &
Fade
Fade
fade
fade
Fade
Fade
Present
Present
amplitude
TETANY
Constant &
 amplitude
DBS
Constant &
 amplitude
PTF
Absent
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;



Non depolarizing muscle relaxant.




Frequent phase II block even with single dose.
Increase plasma [K+] concentration.
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 relaxant




Succinylcholine : normal response.
NDMRs : increase sensitivity.
NDMRs of intermediate duration of action
pyrido-stigmine is not effective.
TABLE 19-5. Comparison of Myasthenia Gravis and Myasthenic Syndrome
Myasthenia Gravis
Myasthenic Syndrome
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
Manifestations
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
OF NDMRs
SPONTANEOUS REVERSAL
Gradual diffusion
Redistribution
Metabolism
PHARMACOLOGIC REVERSAL
Excreation
Indirectly increase the amount of Ach
available to compete with NDMRs
Reestablishing
neuromuscular
transmission
Anticholinesterase
ANTICHOLINESTERASE

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 determine the choice &
dose of anticholinergic.


Only the nicotinic effect of antiAChE
are disired
the muscarinic effect must be block.
Reversal agent should be routinely given to
a patients who have received NDMRs unless
Full reversal can be demonstrated
Postoperative plan includes
continued intubation & ventilation
Organ System
Muscarinic Side Effect
Cardiovascular
 HR, dysrhythmias
Pulmonary
Bronchospasm,bronchial
secreation
Cerebral
Diffuse excitation
( Physostigmine )
GIT
Intestinal spasm,
 salivation
G/urinary
 Bladder tone
Ophthalmologic
Pupillary constriction
Cholinester Usual Dose
ase Inhibitor of
Cholinester
ase
Inhibitor
(mg/kg)
Recommen
ded
Anticholiner
gic
Usual Dose of
Anticholinergic
per mg of
Cholinesterase
Inhibitor
Neostigmine
0.04-0.08
Glycopyrrolat
e
0.2 mg
Pyridostigmi
ne
0.1-0.4
Glycopyrrolat
e
0.05 mg
Edrophoniu
m
0.5-1.0
Atropine
0.014 mg
0.01-0.03
Usually not
necessary
NA
Physostigmin
e
Atropine
Scopolamine
Glycopyrrolate
Atropine
Scopolamine
Glycopyrrolate
Sedation
Antisiolagogue
↑ HR
Relax
smooth
muscle
+
+
+++
++
+++
+++
+
+
0
++
++
++
Mydriasis
cyloplegia
Prevent
motioninduced
nausea
↓ gastric
H+
secretion
Alter fetal
HR
+
+
+
0
+++
+++
+
?
0
0
+
0