Lect 24

• Neuromuscular blocking agents (NMBAs) are agents used in clinical medicine that act by interfering with the action of endogenous neurotransmitter ACh on the nicotinic cholinergic receptor at the neuromuscular junction (NMJ).
• Neuromuscular blocking drugs originated with the discovery of curare.
• In 1856, Claude Bernard demonstrated that curare causes paralysis by blocking neuromuscular transmission.
• During the 16th century, European explorers found that natives in the Amazon Basin of South America were using curare, an arrow poison that produced skeletal muscle paralysis, to kill animals.
• The introduction of NMBAs into anesthesiology is a relatively recent event in medical practice, occurring in the 1940s.
• Neuromuscular blocking agents are used in clinical medicine for various purposes such as muscle relaxation during surgery, intubation, and mechanical ventilation.
• Neuromuscular blocking agents work by blocking the action of acetylcholine (ACh) on the nicotinic cholinergic receptor at the neuromuscular junction (NMJ).
• A single synaptic vesicle contains 7,000 - 12,000 molecules of ACh.
• A single action potential may trigger the fusion of 40 - 300 vesicles.
• The relative ratio of binding site for ACh on the nicotinic cholinergic receptor to AChE binding sites at the NMJ is approximately 10:1.
• Tetrodotoxin and saxitoxin (fish and shellfish poisons) block the permeability of excitable membranes to Na+ (but not to K+), resulting in muscle paralysis.
• Local anesthetics inactivate Na+/K+ channels, halting the propagation of action potentials.
• Rocuronium undergoes hepatic uptake and biliary excretion with a half-life of 20-30 minutes.
• The onset of action for Pancuronium is 5 minutes and its duration is 30-60 minutes.
• The onset of action for Doxacurium is 40 minutes and its duration is 100-120 minutes.
• The onset of action for Vecuronium is 5 minutes and its duration is 30-40 minutes.
• Pancuronium has an onset of 5 minutes and a duration of 30-60 minutes.
• Gantacurium has an onset of 1-2 minutes and a duration of 5 minutes.
• Three groups of synthetic pachycurares contain the drugs in common use in medicine today: Benzylisoquinoliniums, Aminosteroids, and Asymetric mixed-onium chlorofumarates.
• The onset of action for Gantacurium is 1-2 minutes and its duration is 5 minutes.
• Rocuronium has an onset of 1-2 minutes and a duration of 20-30 minutes.
• Atracurium, Cisatracurium, Mivacurium, Doxacurium, and Vecuronium are examples of NMBA.
• Gantacurium undergoes pH-sensitive hydrolysis in plasma and cysteine binding with a half-life of 5 minutes.
• The onset of action for Cisatracurium is 5 minutes and its duration is 30-40 minutes.
• Nondepolarizing NMB agents are classified as pachycurares or bulky molecules.
• The onset of action for Atracurium is 5 minutes and its duration is 30-40 minutes.
• Pancuronium undergoes hepatic metabolism with a half-life of 30-60 minutes.
• Hemicholinium interferes with the choline reuptake into cholinergic neurons, preventing the generation of acetylcholine (ACh).
• In Phase II block, the nonselective cation channel closes and repolarization occurs, rendering the neuromuscular junction resistant to depolarization, leading to flaccid paralysis.
• In Phase I block, the nonselective cation channel associated with the NMJ is opened, depolarizing the receptor and causing it to be more permeable to Na+ and K+ ions.
• It has been estimated that a relatively large percentage of the cholinergic receptors must be occupied by a NMBA before muscle twitch fails, for example, in the cat diaphragm, muscle twitch is not affected until about 80% of the receptors are blocked by d-tubocurarine.
• When NMBAs are used, it is imperative that apparatus for administering mechanical ventilation is available.
• Succinylcholine causes a persistent alteration because it is not hydrolyzed and must slowly diffuse away from the NMJ.
• Onset of action and recovery of NMBAs can be affected by the dose administered, with doses adequate to paralyze ambulatory muscle but insufficient to affect the diaphragm potentially leading to respiratory insufficiency.
• NMBAs can cause muscle paralysis to proceed at different rates in different body regions, with extraocular muscles, facial muscles, and those of the head and neck being affected first, followed by muscles of the limbs, deglutition and laryngeal muscles (glottis), abdominal muscles, intercostal muscles, and the diaphragm.
• The mechanism of depolarizing has been described as biphasic.
• Clinical use of NMBAs includes facilitating tracheal intubation prior to administration of sedation or tranquilization, increasing muscle relaxation to facilitate surgical access to difficult anatomic regions, evoking muscle relaxation to facilitate orthopedic manipulations, and helping improve ocular positioning for surgery.
• Hemicholinium has no current clinical application but is used in research applications.
• Gantacurium has an ultrashort duration of action and is degraded in plasma by pH-sensitive chemical hydrolysis.
• At clinical doses, cats and dogs do not appear to have appreciable cardiovascular effects and recovery is accelerated with AChE inhibitors.