Nondepolarizing NMBDs bind to postsynaptic to postsynaptic receptors (they must bind to one of the αsubunits) in a competitive fashion to produce neuromuscular blockade.

1. Characteristics of Nondepolarizing Blockade (see Table 20-3: Characteristics of The Nondepolarizing Neuromuscular Blockade). The fade observed in response to high-frequency stimulation is characteristic of nondepolarizing blockade.
2. Pharmacokinetics (Table 20-5: Typical Pharmacokinetic Data for Nondepolarizing Muscle Relaxants)
   1. The pharmacokinetic variables derived from measurements of plasma concentrations of nondepolarizing muscle relaxants depend on the dose administered, the sampling schedule used, and the accuracy of the assay.
   2. All nondepolarizing muscle relaxants have a volume of distribution that is approximately equal to extracellular fluid volume.
3. Onset and Duration of Action (Table 20-6: Comparative Pharmacology of Nondepolarizing Muscle Relaxants)
   1. Although peak plasma concentrations of nondepolarizing NMBDs occur within 1 minute of injection, the onset of maximum blockade is reached only after 2 to 7 minutes, reflecting the time required for drug transfer between plasma and NMJ.
   2. The duration of action of nondepolarizing NMBDs is determined by the time required for drug concentration at site of action to decrease below a certain level, usually corresponding to 25% first-twitch blockade
4. Individual Nondepolarizing Relaxants (Table 20-5: Typical Pharmacokinetic Data for Nondepolarizing Muscle Relaxants to Table 20-8: Mechanisms for Clearance of Nondepolarizing Muscle Relaxants)
   1. Atracurium is an intermediate-acting benzylisoquinolinium-type nondepolarizing NMDB. Metabolism is by nonspecific ester hydrolysis (group of tissue esterases that are distinct from plasma or acetyl cholinesterases with the same tissue esterases that are responsible for degradation of esmolol and remifentanil) and the Hofmann reaction (nonenzymatic degradation at body temperature and pH). Subjects with abnormal plasma cholinesterase have a normal response to atracurium. An end product of degradation of atracurium is laudanosine. (High doses in animals cause seizures, but no deleterious effect has been conclusively documented in humans.)
      1. Cardiovascular Effects. Atracurium releases histamine in a dose-related manner.
      2. Clinical Uses. Atracurium has fallen into disfavor because of its cardiovascular effects.
   2. Cisatracurium. In an attempt to increase the gap between the neuromuscular blocking dose and the histamine-releasing dose, a potent isomer of atracurium, cisatracurium was identified. (It is devoid of histamine-releasing properties even at high doses.)
   3. Pancuronium is a long-acting nondepolarizing NMBD with a steroid structure but lacking any endocrine effects.
      1. Cardiovascular Effects. Pancuronium is associated with increases in heart rate, blood pressure, and cardiac output, especially at doses >2 × ED₉₅. Pancuronium does not release histamine.
      2. Clinical Use. The slow onset of action of pancuronium limits its usefulness in facilitating tracheal intubation. In cardiac anesthesia, this drug has enjoyed popularity because it counters the bradycardic effects of high doses of opioids. Pancuronium neuromuscular blockade is more difficult to reverse than blockade of the intermediate-acting nondepolarizing NMBDs.
   4. Rocuronium is an aminosteroid NMBD that has a more rapid onset (intubating conditions 60 seconds after administration of 1 mg/kg IV resemble conditions after administration of 1 mg/kg IV of SCh) but similar duration of action and pharmacokinetic characteristics as vecuronium.
      1. Pharmacology. As for other short- and intermediate-acting NMBDs, the onset of action of rocuronium is more rapid at the diaphragm and laryngeal muscle than at the adductor pollicis, and about twice as much drug is required to produce the same degree of paralysis.
      2. Allergy. The incidence of anaphylactic reactions to rocuronium is unclear, and current data suggest marked variations in the geographical incidence (higher in France than the United States), perhaps reflecting sensitization to pholcodine, an antitussive in cough syrups.
      3. Rapid Sequence Induction. Rocuronium is the drug of choice for rapid sequence induction (>1 mg/kg resulting in prolonged duration of action) and tracheal intubation if SCh is contraindicated (children with undiagnosed muscle dystrophy).
   5. Vecuronium is an intermediate-acting aminosteroid NMBD that is devoid of histamine-releasing and cardiovascular side effects. (It has been largely replaced by rocuronium.)

Neuromuscular Blocking Agents

1. Physiology and Pharmacology
2. Neuromuscular Blocking Agents
3. Depolarizing Blocking Drugs: Succinylcholine
4. Nondepolarizing Drugs
5. Drug Interactions
6. Altered Responses to Neuromuscular Blocking Agents
7. Monitoring Neuromuscular Blockade
8. Reversal of Neuromuscular Blockade