Neuromuscular Blocking Agents copy.pptx

Neuromuscular blocker
(Muscle Relaxants)
Dr. P JABILI
1st yr DNB -DIPLOMA
Dept of Anaesthesiology
Thursday, March 16, 2023 Dr.Bimal Prasad Sahu

Neuromuscular Physiology
The neuromuscular junction consists of:
1.a motor nerve ending with mitochondria and
acetylcholine vesicles(prejunctional)
2.a synaptic cleft of 20-30nm in width containing
extracellular fluid .
3.a highly folded skeletal muscle membrane(post
junctional)
4.nicotinic cholinergic receptors located on both the
presynaptis and postsynaptic membranes.

Muscle Relaxants: Definition :
• Neuromuscular
blockers (NMB’s) :
Drugs that completely
paralyze skeletal
muscles (from normal
tone to zero) by
interfering with
acetylcholine at
neuromuscular jnx.
• Spasmolytics :
Drugs that used to relieve
skeletal muscle spasm &
bring them from
hypertonic state to
normal muscle tone.
>>> Drugs that decrease muscle tone
 IMPORTANT IN SURGERIES

Classification of Muscle Relaxants
According to Mechanism of Action
Depolarizing ,
Non competitive,
agonist.
Succinylcholine
Non depolarizing,
Competitive,
antagonist.
Tubocurarine

Classification of Muscle Relaxants
According to Mechanism of Action
Ultra-Short Short Intermediate Long
Succinylcholine Mivacurium
Vecuronium Pancuronium
Atracurium
Rocuronium
Cis-atracurium

Role of NMB ‘s in surgery:
• NMB’s are co-administrated with anasthetics in the induction
phase to induce muscle paralysis
facilitate the surgery, especially intra-abdominal and intra-
thoracic surgeries
 facilitate endotracheal intubation.
• BUT bcz NMB may paralyze muscles required for breathing,
mechanical ventilation should be available to maintain
adequate respiration.

Depolarizing Agents / structure :
• Only member = succinylcholine
(suxamethonium/ Anectine ®)
• succinylcholine
resembles two
acetylcholine
molecules linked end to end ,it has two
quaternary ammonium cations which interact
with the anionic sites on the muscle end plate
receptors.

Depolarizing Agents / MOA & Termination
In contrast to
Ach ,it resists
the hydrolysis
by Ach-estrase
enzyme so
remains
attached to
receptors for
longer time
succinylcholine
Bind nicotinic
cholinergic
receptors at end
plate lead to
depolarization
of muscle fibers
(so called
depolarizing)
constant,
continuous
stimulation of
receptors lead
to repeated
action potentials
& initial phase
of muscles
fasciculation
This continuous
stimulation of
receptors lead to
receptors
desensetization
(unresponsiveness)
then muscle
exhaustion &
paralysis
Drug remains
binding to Ach
receptors
causing
desensatization
till it diffuse
away from end
plate to plasma
In plasma it undergo
spontaneous
hydrolysis by
endogenous plasma
cholinesterase
(pseudocholieesteras
e), not
acetylcholinesterase
termination
NOTES :
•No drug to
antagonize it.
•It has shorter DOA
compared to
competitive blockers

Depolarizing Agents / Dosage & Kinetics
• Intubating dose : 1-2 mg/kg given IV
• It’s hydrolyzed in plasma & the metabolites are
excreted by kidneys.
• Peak effect reached within 60 sec, the blocking
effect dissipate over the next 5-10 min.

What factors increase DOA of suxamethonium ?
• 1- Quantitaive decrease in plasma choline-
esterase level : liver disease, cancer, pregnancy
& certain drugs like cyclophosphoamide,
phenylzine, monoamine oxidase inhibitors.
• 2- Qulitative decrease in plasma choline-
esterase level : geneticly inherited

• Usually there’s transient & brief increase in serum K+ of
about 0.5 meq/L following succinylcholine.
• Pts with K+ >=5.5 meq/L should not receive it.
• Pts having acute disruption of nerve activity of the skeletal
muscles if they take this drug they’ll have acute rise in serum
K+ to level as high as 13 meq/L  cardiac arrest.
Hyperkalemia following suxamethonium

Those pts who are at high risk of this dangerous
hyperkalemic response include :
- Extensive 3rd degree burns
- Severe intra-abdominal infection.
- Severe closed head injury
- UMN lesions
- Pts with nerve damage or neuromuscular diseases like
muscular dystrophy
- Pts with traumatic paralysis
Hyperkalemia following suxamethonium
continue

Succinylcholine
Side effects
Stimulation of muscarinic AChR
• Sinus bradycardia, even sinus arrest
• AV – node dysrhythmia, nodal rhythm
• Ventricular arrhythmia
• Usually with 2nd dose
Ganglionic stimulation
• Increased heart rate , hypertension
Allergic Reactions

Succinylcholine
Side effects
Depolarization of the endplate
Trigger for MH
Masseter spasm
Raised intracellular potassium
• No benefit with precurarization
Myalgia
• Prevented by precurarization, Benzo, Lido, Ca, Mg, repeated
Thio)

Succinylcholine
Side effects
Depolarization of the endplate
• Raised Intra Cranial Pressure
Due to increased cerebral perfusion.
• Raised Intra Ocular Pressure
4-8 mm, peaks 1-2 min. Due to Increase in choroid blood
vol., extra ocular muscle tone & aqueous outflow resistance
• Raised Intra Gastric Pressure
Due to fasciculations & increased vagal tone. Unaltered
barrier pressure). Prevented by precurarization

Depolarizing Agents / Pharmacodynamics
Dynamics
CNS :
- NO effect on
consciousness, pain
threshold & cerebral fnx
- ↑ intra-ocular pressure
- ↑ intracranial pressure
CVS :
-Bradycardia
-Dysarrythmia
-Sinus arrest
Resp:
-respiratory
muscles paralysis
MSS :
-skeletal muscles
paralysis
-myalagia
-myoglobinemia ,
myoglobinurea
-messeter muscle
spasm
GU:
-Coz metabolites
excreted by kidneys, pts
with RF may have
hyperkalemia

Succinylcholine
phase II block
• Repeated boluses (infusion) of SCh
• May occur with single dose in E1
a
• Fade, post tetanic facilitation
• Memb. potential returns to resting state
despite presence of the drug and the
transmission is blocked
• Possibly due to pre synaptic block, aggravated
by inhalational agents

Suxamethonium : Contra- indications /
absolute
1- inability to maintain airways
2- known allergy / hypersensetivity
3- positive Hx of malignant hyperthermia
4- myotonia (M. congenita, M.dystrophica,
paramyotonia congenita).
5- patient have risk of a hyperkalemic response
to succinylcoline, previously mentioned.
6-lack of resuscitative equipment

Suxamethonium : Contra- indications /
relative
1- known Hx of plasma cholinestrase
deficiency
2- myasthenia gravis & myasthenic
syndrome
3- familial periodic paralysis.
4- open eye injury

Suxamethonium : indications
1- Non Fasting Patients :i.e. Emergency,
cesarean section….., (full stomach)
2- predicted difficult intubation
3- prior to ECT
4- Operations of short duration where muscle
relaxation is needed.

Neuromuscular blocker
non depolarizing Muscle Relaxant

• These drugs combine with nicotinic
receptors and prevent binding of
acetylcholine so prevent depolarization of
the muscle cell membrane so inhibiting
muscle contraction.
Mechanism of action of
non depolarizing drugs

• these drugs competitively block the
receptors this means that you can
overcome their action by increase Ach
concentration by giving Ach esterase
inhibitors such as pyridostigmine or
neostigmine .
Mechanism of action of
non depolarizing drugs

 Skeletal muscles are paralyzed as follow:
Small rapidly contracting muscles of face and
eyes ,fingers, limbs, neck and trunk,
intercostals and lastly diaphragm.
Recovery is in reverse.
The sequence of skeletal muscle
paralysis

• All neuromuscular junction blocker are given
intravenously because oral absorption is poor
as they are highly polar.
• Don’t cross BBB or placenta.
Pharmacokinetics

1-PH: changes metabolic acidosis and to a lesser extent
respiratory acidosis extend the blockage duration
2-body temperature: Hypothermia potentiate the blockage
duration.
3-age: Older patients have prolonged effect also.
4-electrolytes changes: Decrease in serum potassium conc.
potentiate the blockage.Decrease in ionized calcium
conc. also potentiate the blockage
Note:
Concomitant administration of potent inhalational agents
potentiate the duration of blockage esp. with isoflurane,
enflurane and sevoflurane.
Factors that affect their duration of action:

Non-depolarizing agents
Altered response
Volatile Anesthetics
augment the neuromuscular blockade produced by
nondepolarizing muscle relaxants because
1) CNS depression
2) peripheral vasodilatation which allows a larger fraction of the
injected muscle relaxant to reach the neuromuscular junction
• Decreased sensitivity of post junctional memb. to depolarization
• No effect on Ach release or on receptors
• Change in pharmacodynamics than pharmacokinetics
• Longer acting NMB agents affected more

Altered response
Antibiotics
• Aminoglycosides: pre junctional effects like
magnesium (decreased release of Ach)
• Stabilize post junctional memb.
• Calcium improves Ach release but stabilize pos
tjunctional memb, so unpredictable effect

Altered response
Local Anesthetics
• Enhance the block by interfering Ach release,
stabilizing memb & depressing skeletal muscle
fibres.
• Esters compete with SCh for plasma
cholinesterase activity

Altered response
Anti dysrhythmic drugs
• IV lidocaine & quinidine potentiate the block
Diuretics
• Furosemide 1 mg/kg enhances the block (reduced
cAMP production) while large doses inhibit PDE
(increased cAMP) and antagonise the block
• Hypokalemia decreases doses of Pancuronium
• No effect of Mannitol

Altered response
Magnesium
• Enhanced block by reduced Ach release and
stabilizing the memb.
• SCh effect also enhanced (? Phase II block)
Lithium
• Enhanced block
Phenytoin
• Resistance to non-depolarizing NMBA

Altered response
Steroids
• IV steroids -- no effect
• In myasthenia, ACTH or cortisol improve NM
function
Hypothermia
• Prolonged duration of action (Panc, Vec)
• Reduced hepatic, renal & Hoffman clearance

Altered response
Potassium
• Acute fall in extra cellular K+  Increased
trans memb. potential  hyper polarization
 increased sensitivity to non-depolarizing &
resistance to SCh
Paresis / Hemiplegia
• Resistance to non-depolarizers plegic limb >
healthy limb > normal individual (Proliferation
of extra junctional receptors)

Differences between Depolarizing & Non-
depolarizing block
Depolarizing Nondepolarizing
Also called Phase I block -
Block preceded by muscle fasciculations No fasciculations
Depolarizing blocking drugs are called
Leptocurare
Called pachycurare
Does not require reversal rather
cholinesterase inhibitors (Neostigmine) can
prolong the depolarizing block ( because
these agents also inhibit the
pseudocholinesterase).
Reversed by cholinesterase inhibitors
like Neostigmine.

Neuromuscular block
Non-depolarizing Depolarizing
Action motor weakness, followed
by skeletal muscle
flaccidity and inexcitability
to electrical stimulation
fasciculations especially
over the chest and
abdomen followed by
complete paralysis
Order of muscle
involvement
1- smaller muscles (eg,
facial, foot, hand)
2- larger muscles (eg,
abdominal, trunk)
3- diaphragm
1- arm, neck, and leg
muscles
2- facial and pharyngeal
muscles.
3- respiratory
muscle weakness follows
rapidly, usually within 60
seconds
Recovery in reverse order, with the
diaphragm
regaining function firs
in reverse order

1. Short acting duration: Mivacurium (Mivacron)
2. Intermediate:
Vecuronium (Norcuron)
Rocuronium (Zemuron)
Cisatracurium (Nimbex)
3. long acting: Pancuronium (Pavulon)
Classification according to duration of action:

Aminosteroids
• Pancuronium
• Vecuronium
• Rocuronium
• Rapacuronium
Omium chlorofumarates
Gantacurium
Benzylisoquinolines
• Atracurium
• Cis-atracurium
• Mivacurium
• d - Tubocurarine

• Intermediate acting drug
• It is a popular agent because it does not
produce undesirable effects on CVS even
when administered rapidly in large doses
• Continuous infusions of 0.5-1.5 mcg/kg/min
have been used to maintain a stable
neuromuscular block during the procedure.
• ED95 is ( 0 . 0 5 mg/kg )
Vecuronium ( Norcuron)

New intermediate acting drug
Relaxant of choice for short and intermediate
procedures
Duration of action, route of metabolism and lack
of hemodynamic side effects all similar to
vecuronium.
It can quickly induce neuromuscular block make
it suitable for rapid induction and intubation
sequence.
–fast onset (< 1 min with 0.6 mg/kg)
–intermediate duration (44 min with 0.8
mg/kg)
Rocuronium bromide (Esmeron):

Nondepolarizing Muscle Relaxants
• Atracurium
– Metabolized by
• Ester hydrolysis
• Hofmann elimination
– Onset 3-5 minutes, duration 25-35 minutes
– Intubating dose 0.5 mg/kg
– Side effects :
• histamine release causing hypotension, tachycardia,
bronchospasm
• Laudanosine toxicity-CNS excitation,pptn of seizures.

• Is an intermediate acting drug
• Is one of the 10 isomers of atracurium and more
potent than atracurium
• The main advantage for this agent over atracurium is
that it lacks the possibility of histamine release.
• It is the ideal choice for a patient with renal or hepatic
insufficiency requiring muscle relaxation.
• eliminated by Hoffman degradation reaction.
• ED95 is ( 0.5 mg/kg )
Cisatracurium (Nimbex):

• Is a long acting drug
• Administration of pancuronium is associated with
a modest increase in heart rate, blood pressure and
cardiac output.
• Does not release histamine.
• Is much more dependant on renal excretion than
the other clinically used muscle relaxant, so a
prolonged block will result when it is
administered to a patient with renal failure.
• ED95 is 0.06 mg/kg
Pancuronium (Pavulon)

Mivacurium
Benzylisoquinoline
• Only non-depolarizer with short duration
• ED95 80 mcg/kg, onset 2 – 3 min, duration 12 – 20
min
• 2 X ED95 ok but 3 X ED95  histamine release and
hypotension
• Hydrolyzed by plasma cholinesterase (88 % rate of
SCh) 7% unchanged in urine
• Inactive metabolites
• Antagonism: Spontaneous recovery, ? Reversal with
neostigmine, Edrophonium for deep block

Newer Agents
Gantacurium (GW 280430 A)
• By GSK, similar to Mivacurium
• ED 95 = 0.18 mg/kg
• 3 x ED 95 (0.54 mg/kg): Onset 1.2 - 1.8 min &
duration of 15 min
• Higher doses cause histamine release without
change in onset time
• Alkaline hydrolysis in plasma + spontaneous
formation of cysteine adducts
• Very little genetic variability

ED95 Priming Intubati
ng dose
Onset Dur25 TOF>
0.9
Recov
ery
Rap
acu
1-1.2 1.5 1-1.5 15-20 25-50
Roc. 0.3 -- 0.6-1 1.5-2.5 35-50 55-80 60-120
Vec. 0.05 0.01 0.15-2 2-3 30-40 50-80 90-180
Pan. 0.07 3.5-6 70-120 130-
220
Miva 0.08 0.02 0.25 2.5-4.5 15-20 25-40 25-40
Atra. 0.25 0.05 .7-.8 2-3 35-50 55-80 60-90
Cis-
atra.
0.05 0.01 .2-.4 3-6 40-55 60-90 75-120
Nondepolarizing muscle relaxants

Consideration for choosing a muscle relaxant
include:
* Duration of action required
* Route of excretion
* Tendency to release histamine
* Cardiopulmonary side effects
* The ability to reverse the blockage
* Contraindication to any specific muscle
relaxant.
*Cost
Choice of muscle relaxants:

REVERSAL OF BLOCK
• Drugs used for reversal of block are cholinesterase inhibitors
(anticholinesterases).
• Reversal should be given only after some evidence of spontaneous
recovery appear.
Mechanism of Action
• It inactivate the enzyme acetylcholinesterase which is responsible for
break down of actetylcholine, thus increasing the amount of
acetylcholine available for competition with non depolarizing agent
thereby re-establishing neuromuscular transmission.
• Anticholinesterases used for reversal are:
• Neostigmine Edrophonium
• Physostigmine Pyridostigmine
•

• These agents except physostigmine are quarternary
ammonium compounds so they do not cross blood
brain barrier.
• The biggest disadvantage is that these agents also
increase the acetylcholine level at muscarinic
receptors producing muscarinic side effects like
bradycardia, bronchospasm.
• So, to prevent these muscarinic effects some anti
cholinergic like atropine or glycopyrrolate is to be
given with cholinesterase inhibitors.

Neostigmine : Anticholinergic preferred with it is
glycopyrrolate because both have same onset
of action (both are slow acting).
Edrophonium : Anticholinergic preferred with it
is atropine (both fast acting).
Pyridostigmine: It is preferred drug for renal
failure patients in whom a prolonged stay of
muscle relaxant is expected.

SIGNS OF ADEQUATE REVERSAL
• Regular respiration with adequate tidal volume
i.e. patient is able to maintain oxygen
saturation on room air.
• Spontaneous eye opening
• Spontaneous limb movement
• Able to protrude tongue
• Upper airway reflexes returns like patient is
able to cough & spit.
• Able to lift head for more than 5 seconds. This
is the best clinical sign.

CAUSES OF INADEQUATE REVERSAL
• Inadequate dose of neostigmine.
• Overdose of inhalational agents/opioids.
• Renal Failure,Hepatic failure
• Hypothermia
• Electrolyte abnormalities (Hypokalemia,
Hypocalcemia)
• Associated neuromuscular diseases.
• Shock
• Acid Base abnormalities especially acidosis. It
is impossible to reverse a patient with pCO2
more than 50mmHg.

Factors Prolonging the neuromuscular blocakde
• Neonates
• Old age
• Obesity
• Hepatic disease (both depolarizer & NMDR)
• Renal disease ( only NDMR)
• Inhalational agents : Prolong the block by both
depolarizers & NDMR. Inhalational agents decrease
the requirement of relaxant .The maximum
relaxation is by ether followed by desflurane
• Antibiotics: Both depolarizers & NMDR
– Aminoglycosides.
– Tetracyclines.

• Local Anaesthetics : Except procaine local anaesthetics
prolong the action by stabilizing post synaptic
membrane.
• Hypothermia : Decreases metabolism of muscle
relaxants.
• Hypocalcemia: Calcium is required for producing
action potential. Action of NDMR is enhanced.
• Hypokalemia : NMDR block is enhanced.
• Acid base imbalances especially acidosis.
• Calcium channel blockers
• Dantrolene
• Neuromuscular disease
• Hypermagnesemia.

Drugs which antagonise
Neuromuscular Blockade
• They reverse the block by NDMR only
• Phenytoin
• Carbamazepine
• Calcium
• Cholinesterase inhibitors
• Azathioprine
• Steroids.

Thank you
Thank you

Neuromuscular Blocking Agents copy.pptx

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