Skeletal Muscle Relaxants and

Reversal Agents

Dr Pranav Bansal
Professor & HeaD
DePartment of anaestHesiology
BPs gmC, KHanPur Kalan, soniPat
 Learning Objectives

 PY3.4 Describe the structure of neuro-muscular junction and

transmission of impulses
 PY3.5 Discuss the action of neuro-muscular blocking agents
 PH1.15 Describe mechanism/s of action, types, doses, side
effects, indications and contraindications of skeletal muscle
relaxants
 AS4.1 Describe and discuss the pharmacology of drugs used in
induction and maintenance of general anaesthesia (including
depolarising and non-depolarising muscle relaxants,
anticholinesterases. Part 2/2)
 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,
Optimize surgical working conditions & for mechanical
ventilation during surgery or in ICU
HISTORY
How skeletal muscle
relaxation can be achieved
Intra-operatively?
 High doses of volatile anesthetics
 Regional anesthesia
 Administration of neuromuscular blocking
agents
Muscle Relaxants
 How do they work?
 Neuromuscular junction
 Nerve terminal
 Motor endplate of a muscle
 Synaptic cleft
 Nerve stimulation
 Release of Acetylcholine (Ach)
 Postsynaptic events
Neuromuscular Junction
(NMJ)
 Skeletal Muscle Relaxants

 Drugs that act peripherally at the neuromuscular

junction (Nicotinic receptor of Ach – Muscle).

 Types of Skeletal muscle relaxants:


Competitive (Non-depolarizing)
 Non-competitive (Depolarizing)

 Miscellaneous : Aminoglycosides
Muscle Relaxants
 Depolarizing muscle relaxant
 Succinylcholine, Decamethonium
 Nondepolarizing muscle relaxants
 Ultrashort acting
 Short acting
 Intermediate acting
 Long acting
 Depolarizing Muscle
Relaxant
 Succinylcholine
 What is the mechanism of action?
 Physically resemble Ach
 Act as acetylcholine receptor agonist
 Not metabolized locally at NMJ
 Metabolized by pseudocholinesterase in plasma
 Depolarizing action persists > Ach
 Continuous end-plate depolarization causes muscle
relaxation
 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.
 DEPOLARIZING AGENTS
 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.
12
Depolarizing Muscle
Relaxant
 Succinylcholine
 What is the clinical use of
succinylcholine?
 Most often used to facilitate intubation

 What is intubating dose of

succinylcholine?
 1-1.5 mg/kg

 Onset 30-60 seconds, duration 5-10

minutes
Depolarizing Muscle
Relaxant
 Succinylcholine
 What is phase I neuromuscular

blockade?

 What is phase II neuromuscular

blockade?
 Resemble blockade produced by
nondepolarizing muscle relaxant

Succinylcholine infusion or dose >5-7 mg/kg
 Succinylcholine Side effects:
 Cardiovascular

Fasciculation

Muscle pain
 Increase intraocular pressure
 Increase intragastric pressure
 Increase intracranial pressure

Hyperkalemia
 Prolonged Paralysis: Succinylcholine-induced neuromuscular
blockade can be significantly prolonged if a patient has an abnormal
genetic variant of butyrylcholinesterase (Atypical
Pseudocholinesterase).

Malignant hyperthermia
 Prolonged paralysis: due to factors which reduce the activity of
plasma cholinesterase:

genetic variants as abnormal cholinesterase, its severe
deficiency.

anti -cholinesterase drugs

liver disease
 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)
Signs of MH
 Specific  Non-specific
 Muscle rigidity  Tachycardia
 Increased CO2  Tachypnea
production  Acidosis
 Rhabdomyolysis  Hyperkalemia
 Marked temperature
elevation
 Immediate Therapy of MH
 Discontinue triggering agents
 Hyperventilate with oxygen
 Get help
 Dantrolene 2.5 mg/kg push. Must dilute 20 mg bottle with
60 ml DW. Continue for 24-48 hours
 Cooling the patient
 Do not give calcium channel blockers
 Labs as necessary for K+, myoglobin
 Succinylcholine
 Therapeutic uses:
 When rapid endotracheal intubations is required.
 Electroconvulsive shock therapy.

Pharmacokinetics:
 Administered intravenously.

 Metabolised to succinyl-monocholine and choline. Succinyl-

monocholine is metabolized much more slowly to succinic acid

and choline. The elimination half-life of succinylcholine is
estimated to be 47 seconds.

19
 Non depolarising neuromuscular blocking
drugs classification (on basis of chemical
strucure)

Benzylisoquinolinium Aminosteroid Asymmetri

D-tubocurare Pancuronium c mixed-
onium
Metocurine Vecuronium
fumarates
Doxacurium Rocuronium
Atracurium Rapacuronium
Gantacurium
Cisatracurium
Mivacurium
 Classification of Non-Depolarising Muscle
Relaxants according to Duration of Action

Ultra short Short Intermediate Long

Gantacurium
Rapacuronium Mivacurium Vecuronium Pancuronium
GW 280430 Atracurium d-Tubocurare
Cis-atracurium Gallamine
Rocuronium Metocurine
Doxacurium
Pipecuronium
 Nondepolarizing Muscle
Relaxants
 What is the mechanism of action?
 Compete with Ach at the binding sites
 Do not depolarize the motor endplate
 Act as competitive antagonist
 Excessive concentration causing channel
blockade
 Act at presynaptic sites, prevent movement of
Ach to release sites
 Competitive Non-Competitive
Non-depolarizing Depolarizing

Paralysis Flaccid Fasciculations---›

Flaccid
Neostigmine Antagonizes Exaggerate /
no effect.
Examples Pancuronium Succinylcholine
Nondepolarizing Muscle
Relaxants
 Pancuronium
 Aminosteroid compound
 Onset 3-5 minutes, duration 60-90 minutes
 Intubating dose 0.08-0.12 mg/kg
 Elimination mainly by kidney (85%), liver
(15%)
 Side effects : hypertension, tachycrdia,
dysrhythmia
Nondepolarizing Muscle
Relaxants
 Vecuronium
 Analogue of pancuronium
 much less vagolytic effect and shorter duration
than pancuronium
 Onset 3-5 minutes duration 20-35 minutes
 Intubating dose 0.08-0.12 mg/kg
 Elimination 40% by kidney, 60% by liver
 Atracurium
 Non-organ dependent elimination
 Non specific estererase: 60% of elimination

 Hofmann elimination : spontaneous nonenzymatic

chemical breakdown occurs at physiologic pH and Temp.

 Onset 3-5 minutes, duration 25-35 minutes

 Intubating dose 0.5 mg/kg

 Side effects : histamine release causing 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.
Nondepolarizing Muscle
Relaxants
 Cisatracurium
 Isomer of atracurium
 Metabolized by Hofmann elimination
 Onset 3-5 minutes, duration 20-35 minutes
 Intubating dose 0.1-0.2 mg/kg
 Minimal cardiovascular side effects
 Much less laudanosine produced
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 3-4 X ED95
 hydrolyzed by AChE, recovery may be prolonged in
some populations (e.g. atypical AChE)
 Nondepolarizing Muscle
Relaxants
 Rocuronium
 Analogue of vecuronium
 Rapid onset 1-2 minutes, duration 20-35
minutes
 Onset of action similar to that of
succinylcholine
 Intubating dose 0.6 mg/kg
 Elimination primarily by liver, slightly by kidney
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
Alteration of responses
 Temperature
 Acid-base balance
 Electrolyte abnormality
 Age
 Concurrent diseases
 Drug interactions
Alteration of responses
 Concurrent diseases
 Neurologic diseases
 Muscular diseases

Myasthenia gravis

Myasthenic syndrome (Eaton-Lambert synrome)
 Liver diseases
 Kidney diseases
Alteration of responses
 Drug interactions
 Inhalation agents
 Intravenous anesthetics
 Local anesthetics
 Antibiotics
 Anticonvulsants
 Magnesium
Muscle Relaxants
 Muscle relaxants must not be given without
adequate dosage of analgesic and hypnotic
drugs

 Inappropriately given : a patient is

paralyzed but not anesthetized
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).
Reversal of
Neuromuscular Blockade

 Goal : re-establishment of spontaneous

respiration and the ability to protect
airway from aspiration
 CHOLINESTERASE INHIBITORS (ANTI
CHOLINESTERASE)

 Primary clinical use is to reverse non-depolarising

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.
 Antagonism of
Neuromuscular Blockade
 What is the mechanism of action?
 Inhibiting activity of acetylcholineesterase
 More Ach available at NMJ, compete for sites
on nicotinic cholinergic receptors
 Action at muscarinic cholinergic receptor
 Bradycardia

Hypersecretion

Increased intestinal tone
Antagonism of
Neuromuscular Blockade
Effectiveness of anticholinesterases depends on the
degree of recovery present when they are
administered

 Anticholinesterases
 Neostigmine
 Onset 3-5 minutes, elimination half life 77 minutes

 Dose 0.04-0.07 mg/kg

 Pyridostigmine
 Edrophonium
Antagonism of
Neuromuscular Blockade
 Muscarinic side effects are minimized
by anticholinergic agents
 Atropine
 Dose 0.01-0.02 mg/kg
 Scopolamine
 Glycopyrrolate
 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 urinary bladder atony and
paralytic ileus.
 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)
Postoperative Residual Curarization
(PORC)

 Common after NDMRs

 Long acting > intermediate > short acting
 Associated with respiratory morbidity
 Not observed in children
 Monitoring decreases incidence
Monitoring
Neuromuscular Function

 What are the purposes of

monitoring?
 Administer additional relaxant as
indicated
 Demonstrate recovery
Monitoring Neuromuscular Function

How to monitor?
 Clinical signs
 Use of nerve stimulator
 Monitoring
Neuromuscular Function
 Clinical signs
 Signs of adequate recovery

 Sustained head lift for 5 seconds

 Lift the leg (child)

Ability to generate negative inspiratory pressure at least
25 cmH2O, able to swallow and maintain a patent airway
 Other crude tests : tongue protrusion, arm lift, hand grip
strength