n-mBlockers
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Neuromuscular Blockers
• Competitive Antagonists of the Nicotinic Receptore.g. curare (d-tubocurarine), vecuronium, pancuronium, atracurium, etc…
• Depolarizing Blockerse.g. succinylcholine, decamethonium
D-tubocurarine pancuronium
Vecuronium
Decamethonium
SuccinylcholineDepolarizing
Blockers
CompetitiveBlockers
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
Agent PharmacologicalProperties
Onset time (min)
Duration(min)
Elimination
Succinylcholine Ultrashort acting;Depolarizing
1-1.5 6-8Plasma cholinesterase
D-tubocurarine Long duration;Competitive
4-6 80-120Renal and liver
Atracurium Intermediate duration;Competitive
2-4 30-40Plasma cholinesterase
Mivacurium Short duration;Competitive
2-4 12-18Plasma cholinesterase
Pancuronium Long duration;Competitive
4-6 4-6Renal and liver
Rocuronium Intermediate duration;competitive
1-2 1-2Renal and liver
Classification of Blockers
Muscle AP
Nerve AP
Left Leg Muscle Stimulation
Right Leg Nerve Stimulation
Right Leg Muscle Stimulation
Site of Action of d-Tubocurarine
Competitive Depolarizing
Effect of previous d-tubocurarine
Additive Antagonistic
Effect of previous decamethonium
None/antagonistic May be additive
Efect of cholinesterase inhibitors
Reverse No antagonism
Effect on motor end plate
Elevated threshold to Ach; no depolarization
Partial, persisting depolarization
Initial excitatory effect None Transient fasciculations
Effect of KCl or tetatnus on block
Transient reversal
No antagonism
Comparison of Competitive and Depolarizing Blocking Agents
Dual Block by Depolarizing Agents
C10: decamethonium; NEO: neostigmine; TC: tubocurarine
NEO reversedthe blockadeby C10.
Depolarizing Blocker
Competitive Blockade
Competitive Blocker
Noncompetitive Blockade
(desensitization)(electrogenic Na pump)
(direct channel block)
Changing Nature of Neuromuscular Blockade
Sequence of Paralysis
Fingers, orbit (small muscles)
limbs Trunk neck
IntercostalsDiaphragm
Recovery in Reverse
Other Effects of Neuromuscular Blockers
• Action at Autonomic Ganglia e.g. d-tubocurarine blocks, succinylcholine may stimulatenewer agents have less ganglionic effects
• Histamine Release e.g. d-tubocurarinebronchospasm, 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)
Systolic BP Systolic BP
% Change in Systolic BP with d-Tubocurarine as a Function of Dose and Depth of Anesthesia
Increasing Doseof d-tubocurarine
Increasing Depth(% Halothane)
0.25%
0.5%
0.75%
6 mg/m2
12 mg/m2
18 mg/m2
Drug Interactions
• Cholinesterase Inhibitors (antagonize competitive and enhance depolarizing)
• Inhalational Anesthetics (synergistic)• Aminoglycoside Antibiotics (synergistic)• Calcium Channel Blockers (synergistic)