Neuromuscular Blocking Drugs
Michael H. Ossipov, Ph.D.
Department of Pharmacology
Neuromuscular blocking drugs
• Extract of vines (Strychnos toxifera; also
Chondrodendron species)
• Used by indegenous peoples of Amazon basin in
poison arrows (not orally active, so food is safe to
eat)
• Brought to Europe by Sir Walter Raleigh, others
• Curare-type drugs: Tubocurare (bamboo tubes),
Gourd curare, Pot curare
• Brody (1811) showed curare is not lethal is animal is
ventilated
• Harley (1850) used curare for tetanus and strychnine
poisoning
• Harold King (1935) isolates d-tubocurarine from a
museum sample – determines structure.
Neuromuscular blocking drugs
• Block synaptic transmission at the
neuromuscular junction
• Affect synaptic transmission only at skeletal
muscle
– Does not affect nerve transmission, action
potential generation
• Act at nicotinic acetylcholine receptor NII
Neuromuscular blocking drugs
(CH3)3N+-(CH2)6-N+(CH3)3
Hexamethonium
(ganglionic)
(CH3)3N+-(CH2)10-N+(CH3)3
Decamethonium
(motor endplate)
Neuromuscular blocking drugs
• Acetylcholine is released from motor neurons in
discrete quanta
• Causes “all-or-none” rapid opening of Na+/K+ channels
(duration 1 msec)
• Development of miniature end-plate potentials (mEPP)
• Summate to form EPP and muscle action potential –
results in muscle contraction
• ACh is rapidly hydrolyzed by acetylcholinesterase; no
rebinding to receptor occurs unless AChE inhibitor is
present
Non-depolarizing Neuromuscular blocking drugs
• Competetive antagonist of the nicotinic 2
receptor
• Blocks ACh from acting at motor end-plate
– Reduction to 70% of initial EPP needed to
prevent muscle action potential
• Muscle is insensitive to added Ach, but
reactive to K+ or electrical current
• AChE inhibitors increase presence of ACh,
shifting equilibrium to favor displacing the
antagonist from motor end-plate
Nondepolarizing drugs: Metabolism
• Important in patients with impaired organ
clearance or plasmacholinesterase deficiency
• Hepatic metabolism and renal excretion (most
common)
• Atracurium, cis-atracurium: nonenzymatic
(Hoffman elimination)
• Mivacurium: plasma cholinesterase
Depolarizing Neuromuscular blocking drugs
• Succinylcholine, decamethonium
• Bind to motor end-plate and cause
immediate and persistent depolarization
• Initial contraction, fasciculations
• Muscle is then in a depolarized, refractory
state
• Desensitization of Ach receptors
• Insensitive to K+, electrical stimulation
• Paralyzes skeletal more than respiratory
muscles
Succinlycholine: Pharmacokinetics
• Fast onset (1 min)
• Short duration of action (2 to 3 min)
• Rapidly hydrolyzed by plasma
cholinesterase
Succinlycholine: Clinical uses
• Tracheal intubation
• Indicated when rapid onset is desired
(patient with a full stomach)
• Indicated when a short duration is desired
(potentially difficult airway)
Succinylcholine: Side effects
• Prolonged neuromuscular blockade
– In patients lacking pseudocholinesterase
• Treat by maintaining ventilation until it wears off hours
later
Succinylcholine: Phase II block
•
•
•
•
Prolonged exposure to succinlycholine
Features of nondepolarizing blockade
May take several hours to resolve
May occur in patients unable to metabolize
succinylcholine (cholinesterase defects,
inhibitors)
• Harmless if recognized
Acetylcholinesterase inhibitors
• Acetylcholinesterase inhibitors have
muscarinic effects
–
–
–
–
Bronchospasm
Urination
Intestinal cramping
Bradycardia
• Prevented by muscarinic blocking agent
Selection of muscle relexant:
• Onset and duration
• Route of metabolism and elimination
Monitoring NM blockade
• Stimulate nerve
• Measure motor
response (twitch)
• Depolarizing
neuromuscular
blocker
– Strength of twitch
• Nondepolarizing
neuromuscular
blocker
– Strength of twitch
– Decrease in strength
of twitch with
repeated stimulation