What is the mechanism of action of atracurium (besylate)?

Mechanism of Action of Atracurium Besylate

Atracurium besylate is a nondepolarizing neuromuscular blocking agent that works by competitively binding to cholinergic receptor sites on the motor end-plate, antagonizing the neurotransmitter action of acetylcholine. 1

Primary Mechanism

• Acts as a competitive antagonist at nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction
• Binds to acetylcholine receptors but does not activate them, preventing acetylcholine from binding 2
• Blocks the conversion of chemical signals (acetylcholine binding) into electrical signals that would normally cause muscle contraction 2
• Has been shown to have high affinity for embryonic-type nicotinic acetylcholine receptors with a KB of approximately 1 μM 3

Pharmacological Classification

• Belongs to the benzylisoquinolinium class of neuromuscular blocking agents 2
• Intermediate-acting neuromuscular blocker with clinical duration of approximately 20-35 minutes after initial dose 1
• Unlike steroidal neuromuscular blockers (e.g., pancuronium, vecuronium), atracurium has a different chemical structure that influences its metabolism and side effect profile 2

Unique Metabolic Properties

• Undergoes metabolism via two pathways independent of renal or hepatic function:
  1. Ester hydrolysis
  2. Hofmann elimination (spontaneous non-enzymatic degradation) 2, 4
• This unique metabolism makes it particularly useful in patients with renal or hepatic dysfunction 2
• Hofmann elimination is enhanced at higher pH, which can affect the duration of neuromuscular blockade 5

Pharmacodynamic Effects

• Initial dose of 0.4-0.5 mg/kg produces maximum neuromuscular block within 3-5 minutes 1
• Recovery begins approximately 20-35 minutes after injection 1
• Recovery to 95% of control typically occurs within 60-70 minutes after injection 1
• Potency is enhanced by potent inhalation anesthetics:
  • Isoflurane and enflurane increase potency by approximately 35%
  • Halothane increases potency by approximately 20% 1

Secondary Effects on Other Receptors

• At higher doses (>0.5 mg/kg), atracurium can cause histamine release, which may lead to cardiovascular effects 4
• Studies have shown that atracurium can also interact with neuronal nicotinic receptors (α4β2, α3β4, α3α5β4, and α7) in the micromolar range 6
• This interaction with neuronal nicotinic receptors may explain some of the adverse effects occasionally observed during administration 6

Reversal of Action

• The neuromuscular blockade produced by atracurium can be reversed by acetylcholinesterase inhibitors such as:
  • Neostigmine
  • Edrophonium
  • Pyridostigmine 1
• These agents increase acetylcholine concentration at the neuromuscular junction, allowing it to compete with atracurium for receptor binding 1
• Reversal can typically be attempted 20-35 minutes after initial dose 1

Clinical Implications

• Monitoring with peripheral nerve stimulation (train-of-four) is recommended to guide dosing and prevent overdosage 4
• Unlike pancuronium, atracurium has minimal vagolytic effects at clinical doses 2
• Laudanosine, a breakdown product of atracurium, has been associated with CNS excitation at extremely high doses or in patients with hepatic failure 2, 4
• Cisatracurium, an isomer of atracurium, has similar mechanism of action but with less histamine release and is approximately 3-fold more potent 7

Understanding atracurium's competitive antagonism at the neuromuscular junction and its unique metabolism pathways is essential for its safe and effective clinical use, particularly in patients with organ dysfunction.