Ach released from the nerve endings does not combine with Nicotinic (NM) receptor to generate action potential
Most of these skeletal muscle relaxants release histamine and cause ganglion blockade. Succinlycholine cause ganglionic stimulation. Mivacurium is one of the shortest acting ( duration ~ 20 mins ) competitive muscle relaxants. Not used commonly anymore.
This is a “take home” summary table. There is not much on the new agent so it is not included.
In renal failure patients, the elimination kinetics were slightly decreased for Rocuronium
POST OPERATIVE RESIDUAL CURIZATION OR PARALYSIS Is a common problem especially with long acting agents Until recently the standard was TOF &gt; 0.7 . This value was derived from “awake unanesthetized volunteers who had sign. decreases in measured FVC and max inspiratory pressures. It now appears that a TOF of &gt;0.9 is needed to assure complete recovery from NMB, since we now know that even small degrees of block may modify respiratory response to hypoxia and predispose to aspiration!
It is going to be difficult to reverse a block induced with Doxacurium in “cold”and hypokalemic 80 year old on an aminoglycoside with barely one twitch with O.3 mg/kg of Edrophonium Factors prolonging NMB: Deficiency or atypical pseudocholinesterase, Hypermagnesemia,Hypothermia,Respiratory acidosis, Hypokalemia, Antibiotics
Dr Pranav Bansal
BPS GMC, Khanpur kalan, Sonipat
What are neuromuscular blocking drugs ?
These are agents that act peripherally at
neuromuscular junction/muscle fibre itself to
block neuromuscular transmission.
Why do we need them ?
In order to facilitate muscle relaxation for
surgery & for mechanical ventilation during
surgery or in ICU
What are SMRs ?
Definition: SMRs are the drugs that act
peripherally at neuromuscular junction or
muscle fibre itself or in cerebrospinal axis to
reduce muscle tone and /cause muscle
In 1942 Griffith & Johnson suggested
that d-tubocuranine is a safe drug to
use during surgery.
Succinycholine for the first time
introduced by Thesleff & by Foldes &
In 1962 Baird & reid first administered
Vecoronium, a amino steroid &
atracurium, a benzylisoquinolinium
introduced in 1980 and
Mivacurium introduced in 1990.
All modern agents are entirely
Site of action of neuromuscular
Site of action
neuromuscular blocking agents
Post junctional receptor
containing five subunits-
Fetal post junctional
receptor consists of
Skeletal muscle relaxants
Skeletal muscle relaxants block peripherally at the
neuromuscular junction (Nicotinic receptor of Ach –
Types of Skeletal muscle relaxants:
Directly acting Muscle relaxants
Miscellaneous : Aminoglycosides
Skeletal muscle relaxants
Most peripheral NM blockers are quaternary
compounds – not absorbed orally.
Do not cross blood brain barrier or placenta
No analgesia /loss of consciousness
Volatile anes potentiate effect by dec tone of skeletal
muscle and dec sensitivity of post synaptic memb to
SCh is metabolized by Pseudocholinesterase.
Atracurium is inactivated in plasma by spontaneous
non-enzymatic degradation (Hoffman elimination).
Mechanism of action
(non depolarizing agents)
a) At low doses:
These drugs combine with nicotinic receptors and prevent
acetylcholine binding.as they compete with acetycholine for
receptor binding they are called competitive blockers
Thus prevent depolarization at end-plate.
Hence inhibit muscle contraction, relaxation of skeletal muscle
Their action can be overcome by increasing conc. of
acetylcholine in the synaptic gap (by ihibition of
acetyle choline estrase enzyme) e.g.: Neostigmine
Anesthetist can apply this strategy to shorten the
duration of blockage or over come the overdosage.
At high doses
These drugs block ion channels of the end plate.
Leads to further weakening of the transmission and
reduces the ability of Ach-esterase inhibitors to
reverse the action.
All the muscles are not equally sensitive to blockade.
Small and rapidly contracting muscles are paralyzed
Respiratory muscles are last to be affected and first to
Cross blood brain barrier poorly (they are poorly lipid
Some are not metabolized in liver, their action is
terminated by redistribution, excreted slowly and
excreted in urine unchanged (tubocurarine,
They have limited volume of distribution as they are
Atracurium is degraded spontaneously in plasma by
ester hydrolysis ,it releases histamine and can
produce a fall in blood pressure ,flushing and
bronchoconstriction. is metabolized to
laudanosine( which can provoke
seizures),Cisatracurium with similar
pharmacokinetics is more safer.
non depolarizers are excreted via kidney ,have long
half life and duration of action than those which are
excreted by liver.
Some (vecuronium, rocuronium) are acetylated in liver.( there
clearance can be prolonged in hepatic impairment)
Can also be excreted unchanged in bile.
They differ in onset, duration and recovery (see table)
Uses: as adjuvant to anesthesia during surgery.
Control of ventilation (Endotracheal intubation)
Treatment of convulsion
Choline esterase inhibitors such as neostigmine,
pyridostimine and edrophonium reduces or overcome
their activity but with high doses they can cause
depolarizing block due to elevated acetylcholine
concentration at the end plate.
Halogenated hydrocarbons ,aminoglycosides
,calcium channel blockers synergize their effect.
Fall in arterial pressure chiefly a result to ganglion
block , may also be due to histamine release this may
give rise to bronchospasm (especially with
tubocurarine ,mivacurium ,and atracurium)
Gallamine and pancuronium block, muscarinic
receptors also, particularly in heart which may
results in to tachycardia.
DRUGS Suxamethonium ( succinylecholine)
Mechanism of action:
These drugs act like acetylcholine but persist at the synapse at
high concentration and for longer duration and constantly
stimulate the receptor.
First, opening of the Na+ channel occurs resulting in
depolarization, this leads to transient twitching of the muscle,
continued binding of drugs make the receptor incapable to
transmit the impulses, paralysis occurs.
The continued depolarization makes the receptor incapable of
transmitting further impulses.
When rapid endotracheal intubations is required.
Electroconvulsive shock therapy.
Due to rapid inactivation by plasma cholinestrase,
given by continued infusion.
• It causes paralysis of skeletal muscle.
Sequence of paralysis may be different from that of
non depolarizing drugs but respiratory muscles are
Produces a transient twitching of skeletal muscle
before causing block
It causes maintained depolarization at the end plate,
which leads to a loss of electrical excitability.
It has shorter duration of action.
It stimulate ganglion sympathetic and para
In low dose it produces negative ionotropic and
In high dose it produces positive ionotropic and
It act like acetylcholine but diffuse slowly to the
end plate and remain there for long enough that
the depolarization causes loss of electrical
If cholinestrase is inhibited ,it is possible for
circulating acetylcholine to reach a level sufficient
to cause depolarization block.
Bradycardia preventable by atropine.
Hyperkalemia in patients with trauma or burns
this may cause dysrhythmia or even cardiac arrest.
Increase intraocular pressure due to contracture of
extra ocular muscles .
increase intragastric pressure which may lead to
emesis and aspiration of gastric content.
Malignant hyperthermia: rare inherited condition
probably caused by a mutation of Ca++
of sarcoplasmic reticulum, which results muscle
spasm and dramatic rise in body temperature. (This is
treated by cooling the body and administration of Dantrolene)
Prolonged paralysis: due to factors which reduce the
activity of plasma cholinesterase
genetic variants as abnormal cholinesterase, its severe deficiency.
anti -cholinesterase drugs
Depolarizing block ( Non-competitive ) :
Succinylcholine have affinity and sub maximal intrinsic
activity at NM receptors.
They open Na channels which cause initial twitching
and fasciculation. (fasciculation or "muscle twitch", is
a small, local, involuntary muscle contraction and
relaxation visible under the skin arising from the
spontaneous discharge of a bundle of skeletal muscle
fibers (muscle fascicle).)
It does not dissociate rapidly from the receptors
resulting in prolonged depolarization and inactivation of
the Na + channels
A.A. Non-depolarizing agents (CompetitiveNon-depolarizing agents (Competitive
Mechanism of action :
• These have an affinity for the Nicotinic (NM) receptors
at the muscle end plates but have no intrinsic activity.
• The antagonism is surmountable by increasing the
conc. of Ach.
Neuromuscular blocking agents :
Skeletal muscle relaxants
USES OF NEUROMUSCULAR BLOCKERS :
Adjuvant in general anesthesia
Intubation and endoscopies
Skeletal muscle relaxants
Directly acting muscle relaxants :
Depolarization triggered release of calcium
from the sarcoplasmic contraction is blocked /
Dantrolene is used orally/ i.v to reduces
spasticity in hemiplegia and cerebral palsy.
It is the drug of choice – malignant
It acts directly
It reduces skeletal muscle strength by interfering with
excitation-contraction coupling into the muscle fiber, by
inhibiting the release of activator calcium from the
It is very useful in the treatment of malignant hyperthermia
caused by depolarizing relaxants.
This drug can be administered orally as well as intravenously.
Oral absorption is only one third.
Half life of the drug is 8-9 hours.
Depolarising or non-competitive type
Non-depolarising or competitive type
Depolarising or non-competitive
Sccinylcholine -consists of two acetylcholine
molecule linked back to back by acetate methyl
Mechanism of action-
it stimulates cholinergic receptor at NMJ &
Nicotinic (ganglionic) & muscarinic autonomic sites to
open ionic channel leading to depolarisation.
Metabolism of succinylcholine
Onset of action-30-60sec.
Duration of action-9-13 min.
Shortest acting neuromuscular blocking agent.
Metabolised by- butrycholinesterase or
- plasma cholinesterase or
Metabolism of succinylcholine
Scuccinycholine on breakdown by
1- succinylmonocholine - succinic acid & choline
At neuromuscular junction effect of succinylcholine
terminated by diffusion.
Factors affecting metabolism
As succinylcholine enter the circulation, its rapidly
metabolized by pseudocholinesterase.
This process is so efficient that only a fraction of
injected dose ever reaches neuromuscular junction.
The duration of action is prolonged by high dose or
by abnormal metabolism.
Abnormal metabolism may result from hypothermia,
low enzyme levels or genetically aberrant enzyme.
Factors affecting metabolism
Hypothermia decreases rate of hydrolysis.
Low levels of pseudocholinesterase accompany
pregnancy, liver dz, renal failure ,neostigmine, perinorm,
advanced age, bruns, oral contraceptives.
Obese and m. gravis resistant to s.choline
1 in 50 pts has one normal & abnormal gene, resulting in
a slightly prolonged block(20-30 min).
1 in 3000 pts have 2 abnormal genes (homozygus
atypical) which will have a very long blockade (eg 6-8 h).
Prolonged paralysis caused by atypical cholinesterase
should be treated with cont mechanical ventilation until
muscle function returns to normal.
Qualitative analysis of
it is a amide based local anesthetic that inhibits
normal butrycholinesterase by 80%.
Abnormal enzyme by 20%.
can increase or decrease blood pressure and
heart rate (due to stimulation at parasympathetic
and sympathetic ganglia)
dt stimulation at SA node by
succinylmonocholine.More common in;
Digitalised and beta-blocked patient
normal short lasting rise in K+ (0.5-1.0 mmol/L).
Life threatening K+ elevation possible in burn
injury,massive trauma,neurologic or muscular
4. Muscle pains
5. Intragastric pressure elevation
6. Intraocular pressure elevation
7. Malignant hyperthermia
-potent trigerring agent in patient
susceptible to MH.
8. Prolonged paralysis
9. Intracranial pressure
-slight increase in cerebral blood flow
and intracranial pressure in some
-can be prevented by pretreating with
NDMR and IV Lignocaine (1.5-2mg/kg)
2-3 minutes prior intubation.
Indication of use of succinylcholine- rapid sequence
Recommendations for use:
use Peripheral Nerve Stimulator
maximal dose 1-1.5 mg/kg
look for recovery before admin of NDMR’s
Do not treat with anti AChE unless:
proper N-M monitoring is available
spont. recovery of TOF is documented or
ChE is administered first
Non depolarising neuromuscular blocking
drugs classification (on basis of chemical
Classification of Non-Depolarising
Ultra short Short Intermediate Long
Rapacuronium Mivacurium Vecuronium Pancuronium
GW 280430 Atracurium d-Tubocurare
Bis-quaternary Aminosteroid NMJ blocking agent.
Onset of action-3-5min / Duration-60-90 min.
No or slight increase on blood pressure, HR (Vagolytic)
Hepatic metabolism & Renal clearance ( dose reduction in
Onset of action-3-5min/Duration-20-35min
Depends primarily on biliary excretion and secondarily on renal
excretion (no dose reduction required)
Active metabolites- 3 cis vecuronium responsible for prolonged
Prolonged effect in old age, obesity, renal failure, AIDS, obesity
Non-organ dependent elimination
Non specific estererase: 60% of elimination
Hofmann elimination : spontaneous nonenzymatic
chemical breakdown occurs at physiologic pH and T.
Histamine release at higher clinical dose in 30% of
-breakdown product from Hofmann elimination, assoc. with
central nervous system excitation resulting in elevation of
MAC and precipitation of seizures.
Temperature and pH sensitivity-action markedly prolonged
in hypo- thermic or acidotic patients.
3x more potent than atracurium.
No ester hydrolysis.
dosage: 0.1-0.15mg/kg (within 2 min)
1.0-2.0 mcg/kg/min (infusion rate)
Minimal histamine release
potency, 1/3 that of atracurium
slow onset 1.5 min with 0.25 mg/kg
short duration 12-18 min with 0.25 mg/kg
histamine release with doses 3-4X ED95
hydrolyzed by pChE, recovery may be prolonged in some
populations (e.g. atypical pChE)
potency, approx 1/6 that of Vecuronium
fast onset (< I min with 0.8 mg/kg)
intermediate duration (44 min with 0.8 mg/kg)
minimal CV side effects
onset and duration prolonged in elderly
slight decrease in elimination in RF
monoquaternary aminosteroid, analogue of
low potency, fast onset, short to intermediate duration
1.5-2.0 mg/kg doses give good intubating conditions at
duration of action, dependent on dosage and age of
20 % decrease in aBP observed with 2-3 mg/kg doses
principle route of elimination may be liver as 22% is renal
introduced in 2000 in US and removed from market 19
mos. later, after paediatric deaths (bronchospasm),
never available in Canada)
POSTOPERATIVE RESIDUAL CURARIZATION
common after NDMRs
long acting > intermediate > short acting
Assoc with respir. morbidity
not observed in children
monitoring decreases incidence
CHOLINESTERASE INHIBITORS (ANTICHOLINESTERASE INHIBITORS (ANTI
Primary clinical use is to reverse
nondepolarising muscle blockade
Neuromuscular transmission is blocked when
NDMR compete with Ach to bind to nicotinic
The cholinesterase inhibitors indirectly increase
amount of Ach available to compete with NDMR,
thereby re-establish NM transmission.
In excessive doses, Achse inhibitors can
paradoxically potentiate a nondepolarizing NM
It also prolong the depolarization blockade of
Quaternary ammonium group
Dosage : 0.04-0.08 mg/kg
Effects apparent in 5-10 min and last more than
Muscarinic side effects are minimized by prior or
concomitant administration of anticholinergic
Also used to treat myasthaenia gravis, urinary
bladder atonyand paralytic ileus.
Dosage : 0.1-0.4 mg/kg
Onset slower (10-15 min) and duration slightly
longer (>2 hours)
Equivalent dose of anticholinergic are required
to prevent bradycardia.
Dosage : 0.5-1.0mg/kg
Most rapid onset (1-2 min )
Shortest duration of action
Higher dose prolong duration of action to > than
More effective at reversing mivacurium
Difficulty reversing block
Intensity of block to be reversed?
Choice of relaxant?
Age of patient?
Acid-base and electrolyte status?
Dosage : 0.01-0.02 mg/kg up to usual adult
dose of 0.4-0.6 mg.
Potent effects on heart and brochial smooth
Dose is same as atropine and usually given
More potent antisialagogue than atropine and
cause greater central nervous system effects.
Can cause drowsiness and amnesia.
Prevent motion sickness
Avoided in patient with close-angle glaucoma
Dosage : 0.005-0.01 mg/kg up to 0.2-0.3 mg in
Cannot cross blood-brain barrier and almost
always devoid of central nervous system and
Potent inhibition of salivary gland and respiratory
Longer duration than atropine (2-4 hours)