Neuromuscular Blockers • Competitive Antagonists of the Nicotinic Receptor e.g. curare (d-tubocurarine), vecuronium, pancuronium, atracurium, etc… • Depolarizing Blockers e.g. succinylcholine, decamethonium
Decamethonium Depolarizing Blockers
Succinylcholine
Vecuronium
Competitive Blockers
D-tubocurarine
pancuronium
Neuromuscular blockers differ from each other in: • • • • •
Mechanism of action Duration of action Speed of onset and offset of action Selectivity of action and safety margin Adverse effects
Classification of Blockers Agent
Pharmacological Properties
Succinylcholine Ultrashort acting; Depolarizing D-tubocurarine
Long duration; Competitive
Atracurium
Intermediate duration; Competitive
Mivacurium
Short duration; Competitive
Pancuronium
Long duration; Competitive
Rocuronium
Intermediate duration; competitive
Onset time (min)
Duration (min)
1-1.5
6-8
4-6
80-120
Renal and liver
30-40
Plasma cholinesterase
12-18
Plasma cholinesterase
2-4 2-4 4-6 1-2
Elimination Plasma cholinesterase
4-6
Renal and liver
1-2
Renal and liver
Site of Action of d-Tubocurarine Nerve AP Muscle AP
Left Leg Muscle Stimulation
Right Leg Nerve Stimulation Right Leg Muscle Stimulation
Non-depolarizing Block
G: gallamine; TC: tubocurarine; NEO: neostigmine; S: succinylcholine.
Depolarizing Block
C10: TC: NEO: S:
decamethonium tubocurarine neostigmine succinylcholine
Comparison of Competitive and Depolarizing Blocking Agents Competitive
Depolarizing
Effect of previous dtubocurarine
Additive
Effect of previous decamethonium
None/antagonistic May be additive
Efect of cholinesterase inhibitors
Reverse
Effect on motor end plate
Elevated Partial, persisting threshold to Ach; depolarization no depolarization
Initial excitatory effect
None
Effect of KCl or tetatnus Transient on block reversal
Antagonistic
No antagonism
Transient fasciculations No antagonism
Dual Block by Depolarizing Agents
NEO reversed the blockade by C10.
C10: decamethonium; NEO: neostigmine; TC: tubocurarine
Changing Nature of Neuromuscular Blockade
Depolarizing Blocker
Competitive Blocker
Competitive Blockade Noncompetitive Blockade (desensitization) (electrogenic Na pump)
(direct channel block)
Sequence of Paralysis Fingers, orbit (small muscles)
limbs
Diaphragm
Trunk
neck
Intercostals
Recovery in Reverse
Other Effects of Neuromuscular Blockers • Action at Autonomic Ganglia e.g. d-tubocurarine blocks, succinylcholine may stimulate newer agents have less ganglionic effects
• Histamine Release e.g. d-tubocurarine bronchospasm, bronchial and salivary secretions
Adverse Effects/Toxicity • Hypotension • Decreased tone and motility in GI tract • Depolarizing agents can cause increased K efflux in patients with burns, trauma, or denervation and lead to hyperkalemia • Prolonged apnea (many reasons, check for pseudochlinesterase genetic polymorphism) • Malignant hyperthermia (succinylcholine + halothane especially) • Sinus bradycardia/junctional rhythm (with succinylcholine)
% Change in Systolic BP with d-Tubocurarine as a Function of Dose and Depth of Anesthesia Increasing Dose of d-tubocurarine
Increasing Depth (% Halothane) 0.25%
6 mg/m2 12 mg/m2
18 mg/m
2
Systolic BP
0.5%
0.75%
Systolic BP
Influence of Type of Anesthetic on Enhancement of Neuromuscular Blockade By d-Tubocurarine
Hemodynamic Effects of d-Tubocurarine and Pancuronium HR
SVR
CO
MAP
Drug Interactions • Cholinesterase Inhibitors (antagonize competitive and enhance depolarizing) • Inhalational Anesthetics (synergistic) • Aminoglycoside Antibiotics (synergistic) • Calcium Channel Blockers (synergistic)
Therapeutic Uses • Adjuvant in surgical anesthesia • Orthopedic procedures for alignment of fractures • To facilitate intubations – use one with a short duration of action • In electroshock treatment of psychiatric disorders