NEUROMUSCULAR JUNCTION

BLOCKING AGENTS

Dr Pranav Bansal
Associate Professor
BPS GMC, Khanpur kalan, Sonipat
Introduction

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
paralysis.
HISTORY
HISTORY
 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 &
colleagues in1952.
 In 1962 Baird & reid first administered
pancuronium
 Vecoronium, a amino steroid &
atracurium, a benzylisoquinolinium
introduced in 1980 and
 Mivacurium introduced in 1990.
 All modern agents are entirely
synthetic
Site of action of neuromuscular
blocking agents
 Two types
 Pre junctional
recceptor

 Post junctional
recceptor
Site of action
neuromuscular blocking agents
 Post junctional receptor

Pentameric structure
containing five subunits-
2α,β,δ,Є(adult).

Fetal post junctional

receptor consists of
2α,β,δ,γ.
Skeletal muscle relaxants
A. Nicotinic (Muscle) receptor blockers – Skeletal
muscle relaxants.
B. Nicotinic (Nerve) receptor blockers – Ganglion
blockers
Skeletal muscle relaxants
 Skeletal muscle relaxants block peripherally at the
neuromuscular junction (Nicotinic receptor of Ach –
Muscle).

 Types of Skeletal muscle relaxants:

 Competitive (Non-depolarizing)

 Non-competitive (Depolarizing)

 Directly acting Muscle relaxants

 Miscellaneous : Aminoglycosides
Skeletal muscle relaxants
Pharmacokinetics :
 Most peripheral NM blockers are quaternary
compounds – not absorbed orally.
 Administered intravenously.
 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
depolarisation
 SCh is metabolized by Pseudocholinesterase.
 Atracurium is inactivated in plasma by spontaneous
non-enzymatic degradation (Hoffman elimination).
Skeletal muscle relaxants
 Neuromuscular blockers

 Depolarizing blockers : (Non-competitive)

 Succinylcholine (Suxamethonium)

 Non - depolarizing ( competitive )

 Long acting : Pancuronium, Pipecuronium,

 Intermediate : Vecuronium, Rocuronium, Atracurium

 Short acting : Mivacurium

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

occurs.

12 11/01/15
 Their action can be overcome by increasing conc. of
acetylcholine in the synaptic gap (by ihibition of
acetyle choline estrase enzyme) e.g.: Neostigmine
,physostigmine, edrophonium
 Anesthetist can apply this strategy to shorten the
duration of blockage or over come the overdosage.

13 11/01/15
 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.

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 ACTIONS
 All the muscles are not equally sensitive to blockade.

 Small and rapidly contracting muscles are paralyzed

first.

 Respiratory muscles are last to be affected and first to

recover.

15 11/01/15
Pharmacokinetics:
 Administered intravenously

 Cross blood brain barrier poorly (they are poorly lipid

soluble)

 Some are not metabolized in liver, their action is

terminated by redistribution, excreted slowly and
excreted in urine unchanged (tubocurarine,
mivacurium, metocurine).

 They have limited volume of distribution as they are

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highly ionized. 11/01/15
 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.

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 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

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Drug interactions
 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.

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Unwanted effects
 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.
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DEPOLARIZING AGENTS
 DRUGS Suxamethonium ( succinylecholine)
 Decamethonium
 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.


21 The continued depolarization11/01/15
makes the receptor incapable of
transmitting further impulses.
 Therapeutic uses:
 When rapid endotracheal intubations is required.

 Electroconvulsive shock therapy.

Pharmacokinetics:
 Administered intravenously.

 Due to rapid inactivation by plasma cholinestrase,

given by continued infusion.
22 11/01/15
SUCCINYLCHOLINE
• It causes paralysis of skeletal muscle.
 Sequence of paralysis may be different from that of
non depolarizing drugs but respiratory muscles are
paralyzed last

 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.
23 11/01/15
 It stimulate ganglion sympathetic and para
sympathetic both.

 In low dose it produces negative ionotropic and

chronotropic effect

 In high dose it produces positive ionotropic and

chronotropic effect.
24 11/01/15
 It act like acetylcholine but diffuse slowly to the
end plate and remain there for long enough that
the depolarization causes loss of electrical
excitability

 If cholinestrase is inhibited ,it is possible for

circulating acetylcholine to reach a level sufficient
to cause depolarization block.
25 11/01/15
 Unwanted effects:
 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.
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 Malignant hyperthermia: rare inherited condition
probably caused by a mutation of Ca++ release channel
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
 neonates
 liver disease
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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
Neuromuscular blocking agents :

A. Non-depolarizing agents (Competitive

blockers).

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.
Skeletal muscle Duration (mins.)
relaxants
Pancuronium 40-80

Pipecuronium 50-100
Vecuronium 20-40
Atracurium 20-40
Rocuronium 20-40
Succinyl choline 3-6
Skeletal muscle relaxants

Depolarizing block (Non-competitive) :

Succinylcholine
 It causes muscle pain.
 It causes hyperkalemia.

 Malignant Hyperthermia.
Competitive Non-Competitive
Non-depolarizing Depolarizing
Paralysis Flaccid Fasciculations---›
Flaccid

Neostigmine Antagonizes Exaggerate /

no effect.
Examples Pancuronium Succinylcholine
Skeletal muscle relaxants

USES OF NEUROMUSCULAR BLOCKERS :

 Adjuvant in general anesthesia
 Intubation and endoscopies
 Brief procedure
Skeletal muscle relaxants
Directly acting muscle relaxants :
Dantrolene :
Depolarization triggered release of calcium
from the sarcoplasmic contraction is blocked /
reduced.
 Dantrolene is used orally/ i.v to reduces
spasticity in hemiplegia and cerebral palsy.
 It is the drug of choice – malignant
hyperthermia
DANTROLENE

 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
sarcoplasmic stores.
 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.

35
Classification
 Two groups

 Depolarising or non-competitive type

 Non-depolarising or competitive type

Depolarising or non-competitive
type
 Sccinylcholine -consists of two acetylcholine
molecule linked back to back by acetate methyl
group.

 Mechanism of action-

like acetylcholine
 it stimulates cholinergic receptor at NMJ &
 Nicotinic (ganglionic) & muscarinic autonomic sites to

open ionic channel leading to depolarisation.

Metabolism of succinylcholine
 ED950.51-0.63mg/kg.

 Onset of action-30-60sec.

 Duration of action-9-13 min.

 Shortest acting neuromuscular blocking agent.

 Metabolised by- butrycholinesterase or

- plasma cholinesterase or
- pseudocholinesterase
Metabolism of succinylcholine
 Scuccinycholine on breakdown by
butrycholinesterase produces

1- succinylmonocholine - succinic acid & choline

2-choline.

 At neuromuscular junction effect of succinylcholine

terminated by diffusion.
Factors affecting metabolism
of succinylcholine
 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
of succinylcholine
 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
Butrycholinesterase

 Dibucain number-
 it is a amide based local anesthetic that inhibits
normal butrycholinesterase by 80%.
Abnormal enzyme by 20%.

 Flouride number
Side effects
1. Cardiovascular:
 can increase or decrease blood pressure and
heart rate (due to stimulation at parasympathetic
and sympathetic ganglia)
 Bradycardia-
 dt stimulation at SA node by
succinylmonocholine.More common in;
 Unatropinised children
 Digitalised and beta-blocked patient
Side effects
2. Hyperkalemia
 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
disorder.
Side effects
3. Fasciculation
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
Side effects
9. Intracranial pressure
-slight increase in cerebral blood flow
and intracranial pressure in some
patients.
-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
induction.
Succinylcholine
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
strucure)

Benzylisoquinolinium Aminosteroid
D-tubocurare Pancuronium
Metocurine Vecuronium
Doxacurium Rocuronium
Atracurium Rapacuronium
Cisatracurium
mivacurium
Classification of Non-Depolarising
Muscle Relaxants
Ultra short Short Intermediate Long

Rapacuronium Mivacurium Vecuronium Pancuronium

GW 280430 Atracurium d-Tubocurare
Cis-atracurium Gallamine
Rocuronium Metocurine
Doxacurium
Pipecuronium
Pancuronium
 Bis-quaternary Aminosteroid NMJ blocking agent.
 ED95 B-70µg/kg
 Onset of action-3-5min / Duration-60-90 min.
 Dosage-intubation-0.08-0.12mg/kg
maintenance-0.04mg/kg

 Long acting
 No or slight increase on blood pressure, HR (Vagolytic)
 Hepatic metabolism & Renal clearance ( dose reduction in
failure)
 Histamine release
Vecuronium
 aminosteriod
 ED95 B-50µg/kg
 Onset of action-3-5min/Duration-20-35min
 Dosage-intubation-0.08-0.12mg/kg
maintenance-0.04mg/kg
infusion-1-2µg/kg/min
 Depends primarily on biliary excretion and secondarily on renal
excretion (no dose reduction required)
 Intermediate acting
 Active metabolites- 3 cis vecuronium responsible for prolonged
effect
 Prolonged effect in old age, obesity, renal failure, AIDS, obesity
Atracurium
 Benzoisoquinoline derivative
 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
patients(Hypotension,tachycardia,Bronchospasm)
 Laudanosine toxicity
-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.
Cis-atracurium

 Benzoisoquinoline derivative

 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

.
Mivacurium
 Bisquaternary benzylisoquinoline
 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)

Rocuronium

Mono-quaternary aminosteroid
 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
Rapacuronium
monoquaternary aminosteroid, analogue of
Vecuronium
 low potency, fast onset, short to intermediate duration
 1.5-2.0 mg/kg doses give good intubating conditions at
60 sec
 duration of action, dependent on dosage and age of
patient
 20 % decrease in aBP observed with 2-3 mg/kg doses
 principle route of elimination may be liver as 22% is renal
excretion.
 introduced in 2000 in US and removed from market 19
mos. later, after paediatric deaths (bronchospasm),
never available in Canada)
Comparative Pharmacology of Muscle
Relaxants

Agent ED95 Int Dose Onset Duration Elim/Met

(mg/kg) (mg/kg) (min) (min)

Succinylcholine 0.3 1-1.5 <1 12 pChE

Rapacuronium (1.0) 1.3 1.5 9 nonenzym./Hep.
Rocuronium 0.3 0.6 1 60 Hep./Renal
Mivacurium 0.08 0.2 2 25 PChE
Atracurium 0.2 0.6 2-3 60 Hoff/hydrol.
Cis-atracurium 0.05 0.15 3-4 60 Hoff/hydrol.
Vecuronium 0.05 0.10 2-3 60 Hep./Renal
Pancuronium 0.07 0.10 3-5 100 Renal/Hepatic
Pipecuronium 0.05 0.15 2-5 190 Renal
Doxacurium 0.025 0.08 3-5 200 Renal/ChE
Percent of Dose Dependant
on Renal Elimination

> 90% 60-90% 40-60% <25%

Gallamine (97) Pancuronium (80) d-TC (45) Succinylcholine

Pipecuronium (70) Vecuronium (20)
Doxacurium (70) Atracurium (NS)
Metocurine (60) Mivacurium (NS)
Rocuronium
POSTOPERATIVE RESIDUAL CURARIZATION
PORC)

 common after NDMRs

 long acting > intermediate > short acting

 Assoc with respir. morbidity

 not observed in children

 monitoring decreases incidence

CHOLINESTERASE INHIBITORS (ANTI
CHOLINESTERASE)
 Primary clinical use is to reverse
nondepolarising muscle blockade
 Neuromuscular transmission is blocked when
NDMR compete with Ach to bind to nicotinic
cholinergic receptors.
 The cholinesterase inhibitors indirectly increase
amount of Ach available to compete with NDMR,
thereby re-establish NM transmission.
Cholinesterase inhibitors
 In excessive doses, Achse inhibitors can
paradoxically potentiate a nondepolarizing NM
blockade.

 It also prolong the depolarization blockade of

succinylcholine.
ANTICHOLINESTERASE AGENTS
1. Neostigmine

2. Pyridostigmine

3. Edrophonium

4. Physostigmine
Neostigmine
 Quaternary ammonium group
 Dosage : 0.04-0.08 mg/kg

 Effects apparent in 5-10 min and last more than

1 hour.
 Muscarinic side effects are minimized by prior or
concomitant administration of anticholinergic
agent.
 Also used to treat myasthaenia gravis, urinary

bladder atonyand paralytic ileus.

Pyridostigmine
 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.
Edrophonium
 Dosage : 0.5-1.0mg/kg
 Less potent

 Most rapid onset (1-2 min )

 Shortest duration of action

 Higher dose prolong duration of action to > than

1 hour.
 More effective at reversing mivacurium
blockade.
Difficulty reversing block
 Right dose?
 Intensity of block to be reversed?
 Choice of relaxant?
 Age of patient?
 Acid-base and electrolyte status?
 Temperature?
 Other drugs?
Atropine
 Tertiaryamine
 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
muscle.
Scopolamine
 Dose is same as atropine and usually given
intramuscularly.
 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

Glycopyrrolate
 Dosage : 0.005-0.01 mg/kg up to 0.2-0.3 mg in
adults.
 Cannot cross blood-brain barrier and almost
always devoid of central nervous system and
ophthalmic activity.
 Potent inhibition of salivary gland and respiratory
tract secretions.
 Longer duration than atropine (2-4 hours)