Muscle Relaxants

Januari 2020
Outline
• Neuromuscular Junction
• Neuromuscular Transmission
• Muscle Relaxants
• Depolarizing
• Succinylcholine
• Non Depolarizing
• Atracurium
• Vecuronium
• Rocuronium
• Anticholinesterase Drug
Neuromuscular Junction
Synaptic vesicles
 Calcium influx Exocytosis
Pre-synapse

Choline acetyltransferase
 catalyze choline + acetyl
co A  Ach

Ca2+

Ca2+

Ca2+
Post-synapse

• Acetylcholine undergo rapid (1ms) hydrolysis by acetylcholinesterase 

choline + acetate
• Acetylcholine have to bind to two alpha receptor
Muscle Relaxants
Depolarizing muscle relaxant
• Succinylcholine is composed of two molecules of acetylcholine linked
through the acetate methyl groups
• Bind to Nicotinic Acetylcholine receptors (NAchR)
• Acetylcholine  rapid degradation by acetylcholinesterase
• Succinylcholine 
• Not susceptible to hydrolysis by acetylcholinesterase
• Hydrolyzed by butyryl-cholinesterase
• Not eliminated from the junctional cleft until after they are eliminated from
plasma
• The depolarizing relaxants characteristically have a biphasic action on
muscle
• An initial contraction
• Followed by relaxation lasting from minutes to hours.
• The quick shift from excitation of muscle contraction to block of
transmission by depolarizing relaxants occurs because the end plate is
continuously depolarized.
• This mechanism results in
(1)desensitization of the nAChR
(2)inactivation of voltage-gated Na+ channels at the neuromuscular junction
(3)increases in K+ permeability in the surrounding membrane
• The end results are failure of action potential generation and
neuromuscular blockade.
SCh
Phase II Block
• May occur with increasing doses of succinylcholine
• IAChRs are blocked by higher-than-usual concentrations of
succinylcholine
• The receptor does not respond appropriately to acetylcholine, and
neuromuscular blockade is prolonged
Pharmakokinetic and Pharmacodynamic of
Succinylcholine
• Rapid onset of action and short duration
• 1 mg/kg of succinylcholine results in complete suppression of
response to neuromuscular stimulation in approximately 60 seconds.
• Recovery to 90% muscle strength following administration of 1 mg/
kg succinylcholine requires 9 to 13 minutes
• Rapid hydrolysis by butyrylcholinesterase (plasma cholinesterase or
pseudocholinesterase)  succinylmonocholine and choline (not in
the NMJ)
• Elimination half-life  47 seconds
Side Effects of Succinylcholine
• Fasciculation
• Cardiovascular Effects
• Sinus Bradycardia  after second dose
• Junctional rhythm  after second dose
• Ventricular dysrhythmia
• Hyperkalemia
• Increased Intra Ocular Pressure
• Increased Intragastric Pressure
• Increased Intra Cranial Pressure
• Myalgia
• Masseter muscle rigidity
• Malignant Hyperthermia
Dosage
• Intubation : recommended dose 1–1.5 mg/kg IV, but 0.5 – 0.6 mg/kg
is adequate
• Repeated small boluses (10 mg) or a succinylcholine drip (1 g in 500
or 1000 mL, titrated to effect) can be used during surgical procedures
that require brief but intense paralysis
• Increase in children  4–5 mg/kg does not always produce complete
paralysis
Non-Depolarizing Muscle Relaxants (NDMR)
• Origin in the arrow poisons or curares of South American Indians
• NMBDs pancuronium, vecuronium, pipecuronium, rocuronium,
rapacuronium, atracurium, doxacurium, mivacurium, cisatracurium,
gantacurium, and gallamine are all synthetic compounds
• All NDMRs impair or block neurotransmission by competitively
preventing the binding of acetylcholine to the muscle AChR
• A single molecule of antagonist is adequate to prevent depolarization
of that receptor
• Normally, acetylcholinesterase destroys acetylcholine and removes it
from competition for a receptor
NDMR : Suitability for intubation
• None of the currently available nondepolarizing muscle relaxants equals
succinylcholine’s rapid onset of action or short duration.
• Timing Technique
• Priming Technique
• Large-Dose Regimen for Rapid Tracheal Intubation.
• Usually recommended when intubation must be accomplished in less than 90
seconds.
• Consider exacerbation of side effects and prolong duration of blockade.
• Small-Dose Relaxants for Tracheal Intubation
• Advantages :
• Shortens the time to recovery from neuromuscular blockade
• Reduces the requirement for anticholinesterase drugs
• Rocuronium has the shortest onset time of all the nondepolarizing NMBDs
currently available
NDMR : Suitability for Preventing Fasciculations
• 10% to 15% of a non-depolarizer intubating dose can be
administered 5 min before succinylcholine.

NDMR : Maintenance Relaxation

• Achieved by bolus or infusion
• Monitor neuromuscular function with a nerve stimulator and
clinical signs
Atracurium
• Metabolism & Excretion
• Extensively metabolized
• Pharmacokinetics are independent of renal and hepatic function, and less
than 10% is excreted unchanged by renal and biliary routes
• Side Effects and Clinical Consideration
• Hypotension and tachycardia : in excess of 0.5 mg/kg
• Bronchospasm : should be avoided in asthma patients
• Duration prolonged in hypothermia and acidosis
Vecuronium
• Metabolism & Excretion
• Depends primarily on biliary excretion and secondarily (25%) on renal
excretion
• Long term administration  prolonged neuromuscular blockade
• Accumulation of its active 3-hydroxy metabolite
• Side Effects and Clinical Consideration
• Cardiovascular : potentiation of opioid – induced bradycardia in some patient
• Liver failure : duration of action is not significantly prolonged in patient with
cirrhosis unless doses greater than 0.15 mg/kg
Rocuronium
• Metabolism & Excretion
• Undergoes no metabolism
• Eliminated primarily by the liver and slightly by the kidneys
• Duration of action is not significantly affected by renal disease, but it is
modestly prolonged by severe hepatic failure and pregnancy
• Side Effects and Clinical Consideration
• Rocuronium (at a dose of 0.9–1.2 mg/kg) has an onset of action that
approaches succinylcholine (60–90 s)  suitable alternative for rapid-
sequence inductions  much longer duration of action.
• Effective agent of precurarization
Cholinesterase Inhibitor
• Incomplete reversal of neuromuscular blocking agents and residual
post-procedure paralysis are associated with morbidity
• Cholinesterase inhibitors indirectly increase the amount of
acetylcholine available to compete with the nondepolarizing agent,
thereby reestablishing normal neuromuscular transmission.
• Cholinesterase inhibitors inactivate acetylcholinesterase by reversibly
binding to the enzyme.
• Factors influencing the success of antagonism of NMBDs
• The intensity of the neuromuscular blockade at the time that the
pharmacologic antagonist is administered
• The choice of antagonist drug
• The dose of antagonist drug
• The rate of spontaneous recovery from the NMBD
• The concentration of the inhaled anesthetic.
Neostigmine
• Neostigmine consists of a carbamate moiety (binds to
acetylcholinesterase) and a quaternary ammonium group
• Effects of neostigmine (0.04 mg/kg) are usually apparent in 5min,
peak at 10 min, and last more than 1 hr.
• Clinical Considerations :
• Duration of action is prolonged in geriatric patients.
• Crosses the placenta, resulting in fetal bradycardia
Pyridostigmine
• Structurally similar to neostigmine
• Clinical consideration
• Onset of action of pyridostigmine is slower (10–15 min) than that of
neostigmine
• Glycopyrrolate (0.05 mg per 1 mg of pyridostigmine) or atropine (0.1 mg per 1
mg of pyridostigmine) must also be administered to prevent bradycardia.
Sugammadex : A New Antagonist of
Neuromuscular Blocking Drugs
• A γ-cyclodextrin (sugammadex) is a relatively new antagonist
• Antagonizes steroidal NMBDs especially rocuronium and vecuronium,
by encapsulating and inactivating them.
• Sugammadex transports rocuronium or vecuronium away from the
NMJ
• Reversal by this novel mechanism can therefore be achieved at any
level of neuromuscular block provided the amount of cyclodextrin
(sugammadex) is large enough