Nondepolarizing Neuromuscular Blockers

Mechanism of Action

nNMBs function as competitive antagonists of acetylcholine (ACh) by binding to the alpha subunits of nicotinic receptors on the postsynaptic membrane. Under normal circumstances, the transmission of impulses from the primary motor cortex to motor endplates occurs via ACh release from the presynaptic terminal, diffusion across the synaptic membrane, and binding to nicotinic receptors on the postsynaptic membrane. The binding of the receptor activates its sodium (Na⁺) channel domain, allowing Na⁺ influx and depolarizing the motor endplate from a resting membrane potential of −100 mV to +40 mV. This depolarization signal then reaches the sarcoplasmic membrane, triggering the release of calcium ions (Ca²⁺) that facilitate muscle contraction.[5] 

nNMBs play a crucial role in this metabolic process by blocking ACh binding to the alpha subunits on nicotinic receptors, thus maintaining the polarized state of the motor endplate. This mechanism results in muscle paralysis, which is beneficial for patients undergoing perioperative procedures. These agents are classified into 2 subcategories based on their structure and clinical reversal patterns:[6]

• Steroidal: Rocuronium, vecuronium, and pancuronium 
• Benzylisoquinolinium: Atracurium, cisatracurium, and mivacurium

Although there are slight differences in clinical effects, such as steroidal agents exhibiting greater vagolytic activity and benzylisoquinolines causing more histamine reactions, both subtypes share the same mechanism of action. However, clinical reversal algorithms have evolved due to the recent introduction of sugammadex.[7]

Administration

nNMBs are primarily administered via the IV route, with individualized dosing for each agent, although intramuscular (IM) injections may be feasible for some. The 95% effective dose (ED95) of nNMBs refers to the amount required to achieve 95% twitch suppression in 50% of individuals. For intubation, 1 to 2 times the ED95 dose is typically administered. Weight-based dosing is crucial, as using total body weight can result in overdose, while relying on ideal body weight may be subtherapeutic. To prevent prolonged paralysis, nNMBs are generally dosed based on ideal body weight.[8][9][10]

Adult Dosages

The selection of a nondepolarizing NMB depends on factors such as the desired onset speed, duration of action, route of elimination, and potential adverse effects (see Table below). For example, rocuronium’s rapid onset and short duration make it ideal for endotracheal intubation. In contrast, pancuronium’s longer duration and potential to cause significant tachycardia make it less favorable in cases requiring quick reversal due to the risk of prolonged paralysis and postoperative complications.[1]

Table. Dosage Guidelines for Common Nondepolarizing Neuromuscular Blockers 

Table reference [11].

Adverse Effects

The common adverse reaction to monitor with nNMBs is histamine release. Studies show that benzylisoquinolinium nNMBs (atracurium and mivacurium) have the highest incidence of histamine-induced reactions in the perioperative setting. These reactions can lead to hemodynamic instability (tachycardia and hypotension), bronchospasm, and urticaria.[6] Slow injection rates and pretreatment with antihistamines can reduce the severity or incidence of these reactions. Please see StatPearls' companion resource, "General Anesthesia for Surgeons," for more information.

Drug-Drug Interactions

The primary drug interaction to monitor involves the coadministration of nNMBs with inhaled anesthetics (desflurane, sevoflurane, isoflurane, enflurane, halothane, or nitrous oxide). Inhaled anesthetics enhance the effect of nNMBs, requiring dose adjustments to prevent overdose. Failure to reduce the nNMB dose increases the risk of residual neuromuscular blockade and pulmonary complications.[1] 

Other categories of drug interactions can be classified as either enhancing or inducing resistance to activity:

• Augmenting agents: Antibiotics (aminoglycosides, clindamycin, and tetracycline), antiarrhythmics (quinidine and calcium channel blockers), dantrolene, ketamine, local anesthetics, and magnesium sulfate.
• Resistance-inducing agents: Anticonvulsants (phenytoin, valproic acid, and carbamazepine) and cholinesterase inhibitors (neostigmine and pyridostigmine).

Please see StatPearls' companion resource, "General Anesthesia for Surgeons," for more information.

Contraindications

Contraindications 

• Conditions exhibiting resistance: Cerebral palsy, burn injuries, hemiplegia (on the affected side), peripheral nerve injury, severe chronic infections such as botulism or tetanus.
• Conditions exhibiting hypersensitivity: Amyotrophic lateral sclerosis (ALS), autoimmune disorders (systemic lupus erythematosus (SLE), polymyositis, and dermatomyositis), Guillain-Barré syndrome, Duchenne muscular dystrophy, and myasthenia gravis.

Please see StatPearls' companion resource, "General Anesthesia for Surgeons," for more information.

Cautions 

• Hypothermia: This condition can prolong neuromuscular blockade by reducing metabolism and elimination.
• Respiratory acidosis: This condition can potentiate neuromuscular blockade and antagonize reversal.
• Electrolyte abnormalities: Hypokalemia and hypocalcemia can enhance neuromuscular blockade. Additionally, preeclamptic patients receiving magnesium sulfate may develop hypermagnesemia, which also potentiates the blockade.
• Hepatic disease or failure: This condition reduces clearance and increases the volume of distribution.
• Renal failure: This condition decreases clearance, although the extent of blockade prolongation varies.

Please see StatPearls' companion resource, "General Anesthesia for Surgeons," for more information.

Monitoring

Train-of-four (TOF) is the standard method for monitoring a patient’s blockade status during the perioperative and postoperative periods. TOF consists of 4 2-Hz stimulations applied to specific muscle groups to assess the extent of the blockade and, in a prognostic sense, to predict how the patient will respond when maintenance of the blockade is withdrawn. Typically, TOF is performed on the adductor pollicis muscle by stimulating the ulnar nerve, with the desired response being a twitch that indicates muscle contraction. The 4 twitches are quantified, and a normal TOF value is greater than or equal to 1, indicating that the muscle demonstrates improved contraction with each stimulation, such that the fourth twitch is significantly stronger than the first.[12] 

This reaction indicates that no additional nNMB is needed and that reversal should proceed with a standard dose. However, if the TOF is less than 0.9, there is an increased risk of post-residual blockade and postoperative complications. The primary concern is respiratory distress resulting from the residual blockade of the diaphragm and laryngeal muscles. If TOF is less than 0.7, this would indicate persistent blockade.[6] In both scenarios, the nNMB should be discontinued, or a higher dose of a reversal agent may be required. Additionally, the patient may need to remain on mechanical ventilation until the blockade sufficiently reverses to allow for spontaneous respiration.[11]

Toxicity

Signs and Symptoms of Overdose

Most nNMBs are metabolized and eliminated through either an ester hydrolysis process conducted by nonspecific esterases at the synaptic cleft or through Hoffman elimination—a spontaneous nonenzymatic breakdown that occurs at physiological pH. For atracurium and cisatracurium, Hoffman elimination generates the metabolite laudanosine. If allowed to accumulate, particularly in cases of hepatic failure, this metabolite can lead to central nervous system excitation, potentially resulting in seizure activity.[13] 

Pancuronium, typically eliminated through deacetylation by hepatocytes, can lead to an increased volume of distribution in patients with cirrhosis or renal failure. Due to pancuronium's action of inducing high vagal blockade activity, it can lead to hypertension and tachycardia in excess, increasing the risk of ventricular arrhythmias in individuals predisposed to such conditions or those already taking tricyclic antidepressants.[14] In contrast, both vecuronium and rocuronium are relatively less concerning regarding toxic effects. Vecuronium may potentiate opioid-induced bradycardia in some cases, while rocuronium exhibits only mild vagal blockade effects. Please see StatPearls' companion resource, "General Anesthesia for Surgeons," for more information.

Management of Overdose 

In the event of overdose or perioperative reversal of nNMB activity: Initially, all neuromuscular blockers were reversed via acetylcholinesterase inhibitors (neostigmine, edrophonium, and pyridostigmine).[15] The reversal occurs when these agents block acetylcholinesterase enzymes in the synaptic cleft that normally break down ACh. With these enzymes inhibited, the concentration of ACh at the postsynaptic membrane increases, allowing it to outcompete the antagonists and restore the function of sodium channels, resulting in muscle contraction. Administering neostigmine alone, the most clinically relevant acetylcholinesterase inhibitor, can increase parasympathetic activity, with bronchospasm and laryngeal collapse being the most concerning effects. To mitigate these risks, glycopyrrolate, an antimuscarinic agent, is added to the regimen. Please see StatPearls' companion resource, "General Anesthesia for Surgeons," for more information.

Sugammadex, a steroidal nNMB binder, is now integrated into reversal protocols due to its effectiveness in reversing nNMB effects with a lower incidence of laryngeal collapse. Sugammadex functions by binding to nNMB molecules in a 1:1 ratio, creating a concentration gradient in the synaptic cleft that facilitates the diffusion of these molecules away from the postsynaptic membrane.[6] Although sugammadex was initially developed to reverse steroidal nNMBs, the neostigmine/glycopyrrolate combination remains in use for reversing benzylisoquinolinium nNMBs.[15]

Enhancing Healthcare Team Outcomes

nNMBs are often administered to assist with endotracheal intubations and provide adjuvant therapy during the perioperative maintenance of anesthesia and the care of critically ill patients. These drugs cause paralysis of the muscles, making it difficult for patients to breathe. Therefore, no alert patient should ever receive these agents. To ensure the safety of these drugs, the physician, nurse anesthetist, and nursing staff must collaborate as a team to guarantee safe intubations and achieve the best possible patient outcomes. When administering nondepolarizing agents, resuscitative equipment must be readily available at the bedside for immediate intubation.

Nurses taking care of patients in the intensive care unit should be familiar with the dosage and potential adverse effects of nNMBs. Additionally, pharmacists should always double-check the drug dosage and possible drug-drug interactions before dispensing it to the nursing staff. Only through open communication and interprofessional teamwork among healthcare providers can patient safety be ensured when using nNMBs.[16]