Neuromuscular blocking drugs are used induce temporary muscle paralysis in various medical and surgical settings. Most commonly, these drugs facilitate endotracheal intubation and mechanical ventilation, as they are instrumental in preventing vomiting and in helping medical professionals visualize the throat. They can also decrease the likelihood of vocal cord injuries during intubation.1 Neuromuscular blocking agents do not induce anesthesia, amnesia, or analgesia (pain relief), and therefore must be used in conjunction with agents that do.2 An uncommon but important potential complication is evolution into a phase 2 neuromuscular block.
Neuromuscular blocking agents are classified according to two categories, depending on their mechanism of action. Non-depolarizing agents, such as rocuronium, vecuronium, and atracurium, are antagonists for the neurotransmitter acetylcholine, preventing the propagation of nerve signals and therefore the contraction of muscle cells.
Depolarizing agents, on the other hand, are agonists for acetylcholine—they bind to acetylcholine receptors but mimic the effects of the neurotransmitter. When acetylcholine is released into the synapse and binds to its receptors, it causes an influx of sodium ions into the muscle cell, leading to depolarization and, subsequently, muscle contraction. Depolarizing agents, the most common of which is succinylcholine, generate this action potential in the same way. However, unlike acetylcholine, they are not broken down by the enzyme acetylcholinesterase—a process that happens in milliseconds for acetylcholine—and therefore the nerve and muscle cells cannot repolarize. As a result, further transmission of nerve impulses and muscle contractions are prevented, leading to paralysis.3 This process is known as a phase 1 neuromuscular block. During this phase, patients initially experience muscle fasciculations (twitching) followed by flaccid paralysis.4
However, depolarizing neuromuscular blockade can enter a phase 2 block, during which it begins to resemble a non-depolarizing block. Typically caused by prolonged administration of a depolarizing blocker or by using large doses, the phase 2 block resembles a non-depolarizing block in that there is a fade on the train of four test. Additionally, a phase 2 block can be partially reversed with the administration of anticholinesterase inhibitors like neostigmine, which is not the case for a phase 1 block.
Although the phase 2 neuromuscular block has been recognized since the 1970s,5 it is still not understood exactly why or how it occurs. One possible explanation is that the gradual repolarization of muscle cells causes it, despite the depolarizing drug still being bound to acetylcholine receptors. Another is that the presynaptic acetylcholine receptors are blocked, reducing the synthesis of acetylcholine.4 There are few case reports of patients experiencing a phase 2 block, suggesting it is rare. Nevertheless, a better understanding of how a depolarizing neuromuscular block can unfold would enable the medical community to improve patient care.
References
1. Clinical use of neuromuscular blocking agents in anesthesia – UpToDate. https://www.uptodate.com/contents/clinical-use-of-neuromuscular-blocking-agents-in-anesthesia.
2. Cook, D. & Simons, D. J. Neuromuscular Blockade. in StatPearls (StatPearls Publishing, Treasure Island (FL), 2025).
3. Themes, U. F. O. Neuromuscular Blocking Agents. Anesthesia Key https://aneskey.com/neuromuscular-blocking-agents-2/ (2016).
4. Appiah-Ankam, J. & Hunter, J. M. Pharmacology of neuromuscular blocking drugs. Continuing Education in Anaesthesia, Critical Care and Pain 4, 2–7 (2004), https://doi.org/10.1093/bjaceaccp/mkh002
5. LEE, C. DOSE RELATIONSHIPS OF PHASE II, TACHYPHYLAXIS AND TRAIN-OF-FOUR FADE IN SUXAMETHONIUM-INDUCED DUAL NEUROMUSCULAR BLOCK IN MAN. Br J Anaesth 47, 841–845 (1975), https://doi.org/10.1093/bja/47.8.841