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

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