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Michael H. Ossipov, Ph.D.Department of Pharmacology
Neuromuscular Blocking Drugs
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