nondepolarizing neuromuscular blocker

MECHANISM: NDMBs competitively bind the alpha subunits of postsynaptic nicotinic (NM) receptors at the neuromuscular junction, preventing ACh from opening the ligand-gated Na+ channel. No end-plate depolarization occurs, so there are no fasciculations. Paralysis is surmountable by increasing ACh at the synapse (e.g., AChE inhibitors).

ONSET OF PARALYSIS: Small, rapidly moving muscles (extraocular, facial, fingers) are affected first, then limbs and trunk, then intercostals and finally the diaphragm. Recovery occurs in reverse order (diaphragm recovers first).

KEY DRUGS & PHARMACOKINETICS: - Benzylisoquinolines (names often end in -curium or -curine): tubocurarine, atracurium, cisatracurium, mivacurium. Atracurium and cisatracurium undergo Hofmann elimination (spontaneous, organ-independent, pH/temperature dependent), so they are preferred in renal or hepatic failure. Mivacurium is metabolized by plasma pseudocholinesterase. Atracurium, mivacurium, and tubocurarine release histamine, causing hypotension, flushing, and bronchospasm. Atracurium's metabolite laudanosine can cause seizures. - Aminosteroids (names often end in -onium): rocuronium, vecuronium, pancuronium. Metabolized hepatically and/or excreted renally. Rocuronium has the fastest onset among NDMBs, making it an alternative to succinylcholine for rapid sequence intubation. Pancuronium is vagolytic (blocks muscarinic M2 receptors), causing tachycardia and hypertension, and is contraindicated in some cardiac patients.

REVERSAL: - Acetylcholinesterase inhibitors (neostigmine, edrophonium, pyridostigmine) raise synaptic ACh to outcompete the blocker. They are given with an antimuscarinic (glycopyrrolate or atropine) to prevent bradycardia, salivation, and bronchospasm from muscarinic stimulation. - Sugammadex: a modified gamma-cyclodextrin that encapsulates and inactivates aminosteroid NDMBs (rocuronium > vecuronium). It rapidly reverses even deep blockade and has no muscarinic side effects. It does not reverse benzylisoquinolines. Adverse effects: anaphylaxis, bradycardia; it can reduce the effectiveness of hormonal contraceptives (counsel patients to use backup contraception).

POTENTIATORS OF BLOCKADE (high-yield): inhaled volatile anesthetics (isoflurane, sevoflurane, desflurane), aminoglycosides, clindamycin, polymyxins, Mg2+ sulfate, calcium channel blockers, local anesthetics, hypokalemia, hypocalcemia, hypermagnesemia, acidosis, hypothermia, and dantrolene. Neuromuscular junction diseases markedly increase sensitivity: myasthenia gravis (very sensitive to NDMBs) and Lambert-Eaton syndrome. Conversely, patients with MG are resistant to succinylcholine (depolarizing).

COMPARISON WITH DEPOLARIZING BLOCKER (succinylcholine): - Succinylcholine: nicotinic receptor agonist; Phase I block shows fasciculations, is NOT reversed (potentiated) by AChE inhibitors; Phase II block resembles nondepolarizing block. Adverse effects: hyperkalemia, malignant hyperthermia, bradycardia, increased intraocular/intragastric pressure; prolonged paralysis in pseudocholinesterase deficiency. - NDMBs: competitive antagonists, no fasciculations, reversible with neostigmine/sugammadex, do not trigger malignant hyperthermia.

MONITORING: Train-of-four (TOF) stimulation. With NDMBs, there is fade (decreasing twitch height with repeated stimulation) and post-tetanic potentiation. Phase I depolarizing block shows no fade. Reversal is adequate when TOF ratio is ≥0.9.

CLINICAL USES: Skeletal muscle relaxation during surgery and mechanical ventilation, facilitation of endotracheal intubation, and ICU use (e.g., ARDS ventilator synchrony). Patients are not sedated or analgesed by these drugs, so adequate anesthesia/sedation is essential to avoid awareness under paralysis.

OTHER ADVERSE EFFECTS: Prolonged ICU use (especially aminosteroids with corticosteroids) can cause critical illness myopathy/polyneuropathy. Residual blockade postoperatively can cause hypoventilation, aspiration, and airway obstruction. Anaphylaxis is possible (rocuronium is a notable cause among NDMBs).

BOARD PEARL: A competitive antagonist's effect can be overcome by raising agonist concentration. This is why neostigmine reverses NDMBs but worsens (prolongs) succinylcholine Phase I block.