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Neuromuscular Blocking Agents (Non-Depolarizing Type (antagonizing) (Drugs…
Neuromuscular Blocking Agents
Non-Depolarizing Type (antagonizing)
Pharmacokinetics
Absorption
All NMBs are highly polar
usually administered thru IV or IM
Distribution
rapid initial distribution
presence of 1/2 quaternary nitrogens make them highly ionized, thus poor membrane penetration
do not enter cells or cross BBB
Metabolism & Excretion
most are not metabolized, action is terminated via redistribution
pathway of excretion varies
Adverse Effects
Tubocurarine, Atracurium, Mivacurium = fall BP, skin flushing, bronchospasm
Pancuronium = slight tachycardia
Atracurium = metabolized to laudanosine which can provoke seizure
Mechanism of Action
prevents binding of ACh
at low dose, can be reversed by increasing ACh conc thru AChE inhibitors
at high dose, produce more intense blockage leads to weakening of neuromuscular transmission
Drugs Interactions
Cholinisterase inhibitors (antagonizing) = drugs can reverse action of non-depolarizing NMB
Halogenated hydrocarbon anesthetics (synergistic) = drugs such as halothane enhance blockade at NMJ by sensitizing the NMJ to effects of NMBs
Aminoglycoside antibiotics (synergistic) = drugs such as gentamicin inhibit ACh release by competing with Ca2+
Calcium channel blockers (synergistic) = these agents increase neuro-muscular block of competitive, non-depolarizing NMBs
Example
pancuronium, doxacurium, pipecurium, atracurium
Therapeutic Use
Used to facilitate intubation in mechanical artificial ventilation
Used in orthopedic surgery (fracture alignment)
Adjuvant drugs in anesthesia to relax skeletal muscle
Depolarizing Type (agonizing)
Pharmacokinetics
injected thru IV
short duration of action
effects rapidly disappear upon discontinuation
Therapeutic Use
useful for rapid endotracheal intubation
used during electroconvulsive shock treatment
Mechanism of Action
attaches to nicotinic receptor & acts like ACh to depolarize the junction (agonist)
more resistant to degradation by AChE
Phase I (depolarizing)
cause opening of Na channel associated with nicotinic receptor, results in depolarization of receptor
leads to transient contraction or twitching of muscle (fasciculation)
Phase ii (desensitization)
continuous depolarization gives way to gradual repolarization
however, membrane cannot easily depolarized again since it is desensitized to the effect of ACh as Na channel closed/blocked
Desensitization --> resistance to depolarization --> flaccid paralysis (muscles no longer contract)
Adverse Effects
Malignant Hyperthermia = abnormal ryanodine receptor that cause Ca buildup result in massive metabolic reactions (hyperpyrexia, tachycardia). treat with dantrolene
Prolong Apnea (shallow breathing during sleep) = administration of drug to patient with genetic deficiency in plasma pseudocholinisterase can prolong apnea due to paralysis of diaphragm
Hyperkalemia = increase K+ release from intracellular store, may result in cardiac arrest. Dangerous in patients wth burn & massive tissue damage
Others = raise intra-ocular pressure, cause myalgia
Example
Succinylcholine (suxamethonium)