Neuromuscular Blockers

(2)

• Neuromuscular blockers cause skeletal muscle relaxation by interfering with signal transmission at the neuromuscular junction.
• They are used as adjuncts to anesthesia, to facilitate endotracheal intubation and mechanical ventilation, and in the intensive care units for patients requiring paralysis.

Extra-junctionalAchR Proliferation

Causes

(3)

• The only depolarizing agent in clinical use in the US
• Metabolized by pseudocholinesterase
• Rapid Onset/Short Duration
• Malignant Hyperthermia Trigger
• Hyperkalemia Risk
• Succinylcholine should be avoided in patients susceptible to malignant hyperthermia (e.g. family or personal history), patients at risk for hyperkalemia
  (e.g. renal failure, burn trauma, bed ridden, muscular dystrophy, upper motor neuron disease), and patients with known or suspected pseudocholinesterase
  abnormality or deficiency.
  

• Non-Enzymatic degradation in the plasma by Hofmann Elimination
• Laudanosine Breakdown Product that may accumulate with excessively large doses or liver failure; causes CNS excitation and seizures
• Histamine Release
• An intermediate duration benzyl isoquinolone derivative that undergoes nonenzymatic breakdown in the plasma by Hofmann elimination.
  
• Atracurium does not rely on the hepatic or renal systems for termination of effects. Its administration is associated with histamine release.
  
• Laudanosine is a breakdown product that, under circumstances of hepatic failure or extremely high atracurium doses, could cause central nervous system excitation or seizures.
  

• Hofmann Elimination
• Laudanosine Breakdown Product
• NO Histamine Release
• An intermediate duration benzyl isoquinolone derivative that,like atracurium, undergoes Hofmann elimination with laudanosine as a breakdown product.
• Cisatracurium also does not rely on the hepatic or renal systems for termination of effects.
  
• Unlike atracurium, cisatracurium is not associated with histamine release.
  

• Long acting
• Vagolytic and Catecholamine releasing side effects
• Renal Elimination
• A long acting steroid derivative associated with significant vagolytic effects and catecholamine release.
  

• Rapid Onset suitable for Rapid Sequence Intubation
• An intermediate duration steroid derivative with rapid onset suitable for rapid sequence induction;
  
• it has less vagolytic effects than pancuronium.
  

• Active 3-OH metabolite that may cause prolonged paralysis after prolonged administration
• An intermediate duration steroid derivative with no vagolytic effects; its active 3-hydroxy metabolite is associated with prolonged neuromuscular blockade and polyneuropathy after long-term administration to patients in intensive care units.
  

General Points

(5)

• NMB’s cause PARALYSIS(i.e. patients will stop breathing!)
• NMB’s have NO Intrinsic Anesthetic Properties
• NMB’s are used to facilitate intubation and mechanical ventilation, to provide immobility during surgical procedures,and as adjuncts in the ICU.
  
• Succinylcholine may cause hyperkalemia
• Succinylcholine is a Malignant Hyperthermia trigger

Neuromuscular blockers

(3)

• Neuromuscular blockers cause skeletal muscle relaxation by interfering with signal transmission at the neuromuscular junction;
• they are used as adjuncts to anesthesia, to facilitate endotracheal intubation and mechanical ventilation, and in intensive care units to cause skeletal muscle paralysis.
  
• Development of neuromuscular blocking agents is aimed at improving specificity for the nicotinic receptors at the neuromuscular junction, decreasing onset time, and eliminating cumulative dosing effects.

Neuromuscular signal transmission

Mechanism

(7)

• Neuromuscular signal transmission at the neuromuscular junction begins with arrival of an impulse at the motor nerve terminal which results in calcium influx and subsequent release of acetylcholine into the synaptic cleft.
• Motor end plate depolarization results from binding of two acetylcholine molecules to the nicotinic cholinergic receptor;
• if the end plate depolarization is sufficient to cause adjacent muscle membrane depolarization, an action potential is propagated along the entire muscle fiber and excitation-contraction coupling causes muscle contraction.
• Acetylcholine at the neuromuscular junction is either metabolized by acetylcholinesterase or diffuses away from the motor end plate.
• In addition to the acetylcholine receptors at the end plate, there are two additional types of acetylcholine receptors involved in neuromuscular transmission:
• prejunctional receptors that are involved in mobilization of additional acetylcholine vesicles for subsequent release of acetylcholine, and
• extrajunctional/perijunctional receptors that may proliferate during periods of prolonged immobilization or after burn injury

• prejunctional receptors that are involved in mobilization of additional acetylcholine vesicles for subsequent release of acetylcholine, and
• extrajunctional/perijunctional receptors that may proliferate during periods of prolonged immobilization or after burn injury

Pharmacodynamics of Neuromuscular Blocking Agents

Structure-Activity Characteristics

• All of the neuromuscular blocking agents bear a structural resemblance to acetylcholine

• Succinylcholine is two acetylcholine molecules linked together.
• [image]

• In nondepolarizing neuromuscular blocking agents the double acetylcholine structure is concealed within either a benzyl isoquinolone or steroid ring system.
• Benzyl isoquinolone agents have an “urium”
  ending. Steroid derivative agents have
  an “onium” ending.
• Nondepolarizing agents also contain quaternary nitrogens that make them poorly lipid soluble.