Depolarizing Neuromuscular Blocking Drugs

Mechanism of Action

There are 2 categories of neuromuscular blocking agents found at the neuromuscular junction: depolarizing and non-depolarizing agents. Depolarizing muscle relaxants act as acetylcholine (ACh) receptor agonists by binding to the ACh receptors of the motor endplate and generating an action potential. However, they are resistant to (and not metabolized by) acetylcholinesterase, leading to persistent depolarization of the muscle fibers, resulting in the patient's well-recognized muscle fasciculations and paralysis. This contrasts with non-depolarizing muscle relaxants, which act as competitive antagonists. Non-depolarizing agents bind (ACh) receptors but do not produce an action potential; these agents prevent the generation of action potentials at the neural endplate, disrupting neuromuscular transmission.[5][6]

After a depolarizing agent binds to the motor endplate receptor, the agent remains bound, and thus, the endplate cannot repolarize. This is also known as a phase I block. During this depolarizing phase, transient muscle fasciculation occurs. After adequate depolarization, phase II (desensitizing phase) sets in, and the muscles are no longer receptive to acetylcholine released by the motor neurons. At this point, the depolarizing agent has fully achieved paralysis.[6] Importantly, these muscle relaxants target both nicotinic and muscarinic receptors.[7]

Pharmacokinetics

Absorption: Succinylcholine has a rapid onset (30 seconds) and a short duration of action (4 to 6 minutes) because of the degradation by cholinesterases.[6]

Distribution: At IV doses of 1 mg/kg and 2 mg/kg, the mean apparent volumes of distribution are 16.4 (±14.7) and 5.6 (±6.8) mL/kg, respectively.

Metabolism: Succinylcholine is rapidly metabolized by plasma cholinesterase (pseudocholinesterase/butyrylcholinesterase) to succinic acid and choline.[8]

Elimination: The mean plasma clearance of succinylcholine following an IV dose of 1 mg/kg is approximately 4.17 (±2.37) L/min. Approximately 10% of succinylcholine is excreted unchanged in the urine.

Administration

Available Dosage Forms and Strengths

Succinylcholine is available in formulations of 20 mg/mL and 100 mg/5 mL in single-dose, prefilled syringes.

Adult Dosing

Short surgical procedures: The intravenous dose for neuromuscular blockade to facilitate endotracheal intubation is 0.6 mg/kg. The dose can vary among patients, ranging from 0.3 mg/kg to 1.1 mg/kg. Neuromuscular blockade develops in about 1 minute. The maximum effect may persist for about 2 minutes. The recovery phase lasts about 4 to 6 minutes. However, substantial doses may result in a prolonged blockade. A test dose between 5 and 10 mg may help determine the individual patient's sensitivity and recovery time.

Lengthy surgical procedures: The average rate for adult surgical procedures is between 2.5 and 4.3 mg/min. An IV injection of 0.3 mg/kg to 1.1 mg/kg may be administered, followed by additional injections of 0.04 mg/kg to 0.07 mg/kg at appropriate intervals to maintain the required level of muscle relaxation.

Specific Patient Populations

Hepatic impairment: The product labeling does not include dosage adjustments for hepatic impairment; use with caution.

Renal impairment: The product labeling does not include dosage adjustments for renal impairment; use with caution.

Pregnancy considerations: According to the American College of Obstetricians and Gynecologists, general anesthesia is seldom used for vaginal or cesarean deliveries in modern obstetrics and is usually reserved for emergency cesarean sections or situations in which neuraxial anesthesia is contraindicated or has failed. The parturient faces the risk of gastric content aspiration and altered anesthetic requirements before and after delivery. The standard protocol for administering general anesthesia includes preoxygenation, followed by an induction agent and a muscle relaxant (succinylcholine/rocuronium), with subsequent intubation and cricoid pressure.[9] Plasma cholinesterase levels are reduced by approximately 24% during pregnancy and postpartum, which may extend the effects of succinylcholine and lead to prolonged apnea in some women who are pregnant. Apnea and flaccidity in the newborn can occur after repeated high doses or in the presence of atypical plasma cholinesterase in the mother. Succinylcholine is commonly administered for muscle relaxation during cesarean delivery and crosses the placental barrier in amounts dependent on the concentration gradient between the maternal and fetal circulations.

Breastfeeding considerations: Succinylcholine is rapidly hydrolyzed in maternal plasma, with a short half-life of approximately 3 to 5 minutes. Succinylcholine is a highly polar compound; it is unlikely to be excreted into breast milk or absorbed orally by the infant. While general anesthetic regimens involving succinylcholine for cesarean sections have been linked to a delay in the time to first breastfeeding, it is still uncertain how much succinylcholine contributes to this delay. Given its rapid elimination and low oral absorption, the risk of succinylcholine having adverse effects on breastfed infants is considered minimal.[10] According to product labeling, the developmental/health benefits must be carefully considered, including the mother's requirement for succinylcholine and any potential risks posed to the breastfed infant by succinylcholine or the maternal condition.

Pediatric patients: For emergency tracheal intubation or when immediate airway management is required, the intravenous dose of succinylcholine is 2 mg/kg for infants and small pediatric patients. The recommended dose for older children and adolescents is 1 mg/kg. However, the effective dose of succinylcholine in the pediatric population may be higher than that predicted by body weight alone. The standard adult intravenous dose of 0.6 mg/kg corresponds to a 2 mg/kg to 3 mg/kg dose for neonates and infants younger than 6 months and 1 mg/kg to 2 mg/kg for infants younger than 2 years. This discrepancy is due to the larger volume of distribution in children compared to adults. Rarely, IV succinylcholine in pediatric patients may cause ventricular arrhythmias and cardiac arrest due to hyperkalemia, a common complication in patients with undiagnosed myopathies. A meticulous history, physical exam, and preoperative creatine kinase levels can help identify at-risk patients. Due to the associated risks, succinylcholine should only be used in pediatric patients for emergency airway management.

Older patients: Dose selection for older patients should start low, considering decreased organ function, potential comorbidities, and polypharmacy.

Adverse Effects

Since these drugs cause paralysis of the diaphragm, mechanical ventilation should be at hand to provide respiratory support. These drugs may produce cardiovascular effects, including dysrhythmias since they have effects on muscarinic receptors.[7] When nicotinic receptors of the autonomic ganglia or adrenal medulla are blocked, these drugs cause autonomic symptoms. Additionally, neuromuscular blockers result in a histamine release, leading to hypotension, flushing, and tachycardia.[7] The depolarizing effect on the muscle fibers may momentarily release a large amount of potassium. This places the patient at risk for life-threatening complications such as hyperkalemia and cardiac arrhythmias.[6][7]

More commonly reported adverse drug reactions are listed below.[6][7]

• Muscle fasciculation, which may result in postoperative pain [11]
• Jaw rigidity
• Apnea
• Respiratory depression
• Bradycardia
• Hypotension
• Sinus tachycardia
• Excessive salivation
• Hypersensitivity reactions
• Myoglobinuria/myoglobinemia
• Malignant hyperthermia [12]
• Increased IOP [13][14]

Drug-Drug Interactions

Drugs that may enhance the neuromuscular blocking action of succinylcholine include oxytocin, quinidine, β-blockers, lidocaine, lithium, magnesium, quinine, chloroquine, desflurane, isoflurane, metoclopramide, and terbutaline. Additionally, medications that reduce plasma cholinesterase activity, such as long-term use of oral contraceptives and glucocorticoids, can increase the neuromuscular blocking effect of succinylcholine.

Contraindications

Depolarizing muscle agents are contraindicated in cases of neurologic injuries, such as a cerebral vascular accident, spinal cord injury, or severe tissue injury, including trauma or burns. This results from post-synaptic receptor up-regulation that typically occurs within 3 to 5 days. These injuries place the patient at risk for life-threatening hyperkalemia. The risk of hyperkalemia is not associated with decreased potassium clearance; however, attention should be given to chronically elevated potassium levels, such as in patients with renal failure.[7]

Depolarizing agents are contraindicated in patients with degenerative neuromuscular disorders or a history of malignant hyperthermia. Undiagnosed children with skeletal muscle myopathy, such as Duchenne muscular dystrophy, are at risk for rhabdomyolysis with hyperkalemia.[7][15] This is followed by ventricular dysrhythmias, cardiac arrest, and death.

Other contraindications are listed below.[6][7]

• Hypersensitivity to drug
• Malignant hyperthermia
• Lack of ventilatory support
• History of ocular surgery, penetrating eye injuries, or closed-angle glaucoma 
• Disorders of plasma pseudocholinesterase (these patients will have prolonged paralysis)
• Myopathies associated with elevated serum creatine kinase
• Extensive denervation of skeletal muscle or upper motor neuron injury

Box Warnings

Rare cases of rhabdomyolysis with hyperkalemia, resulting in ventricular dysrhythmias, cardiac arrest, and mortality, have been reported after succinylcholine administration in otherwise healthy pediatric patients. These cases often involve undiagnosed skeletal muscle myopathy, especially Duchenne muscular dystrophy.[16] They typically present with peaked T-waves and sudden cardiac arrest, usually within minutes of succinylcholine administration. If a previously healthy child experiences cardiac arrest shortly after receiving succinylcholine, and this is not due to inadequate ventilation/oxygenation or anesthetic agent overdose, rapid treatment for hyperkalemia should be initiated. This includes intravenous calcium, bicarbonate, glucose with insulin, and hyperventilation. Resuscitative efforts may often be ineffective, but prolonged and extraordinary measures have sometimes led to successful outcomes. If signs of malignant hyperthermia are present, appropriate treatment should be started immediately. Given the lack of warning signs in at-risk patients, succinylcholine should only be used in children for emergency intubation or situations requiring rapid airway management (eg, laryngospasm, difficult airway, full stomach) or intramuscular use when a vein is inaccessible.

Warning and Precautions

• Bradycardia: As mentioned above, depolarizing muscle agents bind to all acetylcholine receptors of the autonomic nervous system, and when targeting cardiac muscarinic receptors, patients may develop bradycardia, especially in repeat doses. There is a relative contraindication in a patient with bradycardia. Additionally, the defasciculations result in a large amount of potassium release and oxygen depletion.[7][17]

• Aspiration risk: Succinylcholine can increase intragastric pressure, raising the risk of regurgitation and aspiration. Monitor patients for signs of vomiting or aspiration during anesthesia induction.

• Prolonged neuromuscular block: Neuromuscular blockade may be prolonged in patients with hypokalemia or hypocalcemia. Correct electrolyte imbalances and monitor neuromuscular transmission to prevent prolonged blockade.

• Increased intracranial pressure: Succinylcholine may transiently raise intracranial pressure, but proper anesthetic induction can minimize this effect. There is no strong evidence, but caution is advised.[18][19]

Monitoring

The proper precautions are necessary because of the potential severity of these agents. The immediate availability of appropriate emergency treatment is unquestionable. These agents should be administered by trained personnel with a facility equipped to monitor, assist, and control respiration. The American Society of Anesthesiologists (ASA) states that it is essential to measure a single twitch baseline and use the percentage of that twitch to track the return of strength. If the rate of block regression is abnormal, it may indicate abnormal pseudocholinesterase activity. While this monitoring may be impractical for clinicians who administer only a single dose of succinylcholine without subsequent nondepolarizing blockers, the task force advises using neuromuscular monitoring to guide extubation in delayed recovery from succinylcholine. The ASA suggests confirming a "train-of-four" ratio of ≥0.90 before extubation when using quantitative neuromuscular monitoring to reduce the risk of residual neuromuscular blockade.[20][21]

Toxicity

Signs and Symptoms of Overdose

Malignant hyperthermia is a life-threatening clinical syndrome of hypermetabolism involving the skeletal muscle and is triggered in susceptible individuals primarily by inhalational anesthetic agents and the muscle relaxant succinylcholine, although other drugs have also been considered potential triggers. This condition is not an allergy but an inherited disorder. A typical presentation involves tachycardia, dysrhythmias, rigidity, rapidly increasing temperature, hyperkalemia, sympathetic hyperactivity, disseminated intravascular coagulopathy (DIC), and multi-organ failure.[22] Another concern is the Phase II block due to prolonged administration, which is characterized by respiratory muscle paralysis or weakness. The hallmark sign is the "fade" phenomenon observed during peripheral nerve stimulation, particularly with the "train of four" (TOF) method. Delayed recovery of muscle function should be expected.

Management of Overdose

Dantrolene is the primary drug used for the treatment and prevention of malignant hyperthermia.[23] To manage Phase II block, use peripheral nerve stimulation and observe the fade in response to TOF stimulation. Reversal of Phase II block with anticholinesterase agents, like neostigmine, should only be attempted after confirming Phase II block with TOF and ensuring that spontaneous muscle twitches have plateaued for at least 20 minutes. The anticholinesterase drug should be accompanied by an anticholinergic agent (eg, atropine) to prevent bradycardia.[24] In accidental ingestion, ensure oxygenation while monitoring heart rate, blood pressure, and temperature. A patent airway should be established, with ventilation support provided if necessary. Hemodynamic monitoring is critical, particularly for bradycardia and hypotension, with atropine administration for resuscitation if needed. Fluid resuscitation and inotropic support should be provided to maintain adequate organ perfusion.[24]

Enhancing Healthcare Team Outcomes

Several controversies persist regarding RSI. The most prominent debate centers on using rocuronium versus succinylcholine for standard RSI paralysis. Advocates of rocuronium cite its lack of contraindications and avoidance of depolarization in the middle of an intubation attempt. Advocates for succinylcholine argue that its rapid onset and rapid recovery time are potentially helpful in a critically ill patient with difficulty intubating and oxygenating. One of the main differences between these types of neuromuscular-blocking drugs is their reversal and pharmacokinetics. Acetylcholinesterase inhibitor drugs reverse non-depolarizing blockers since they are competitive antagonists at the ACh receptor site and, thus, reverse by increasing ACh levels. On the other hand, the depolarizing blockers are more resistant to acetylcholinesterase, resulting in a prolonged effect when acetylcholinesterase inhibitors are administered. The argument is mostly academic. Both agents are excellent and, when dosed properly, result in comparable intubating conditions.[25][26]

Neuromuscular blocking agents (NMBAs) are vital in surgical and critical care settings. Anesthesiologists select the appropriate NMBA based on the patient's needs, while nurse anesthetists (CRNAs) administer and monitor these agents, adjusting dosages as needed. Nurses ensure the safe preparation, administration, and monitoring of NMBAs, watching for adverse effects. Pharmacists offer guidance on drug selection and dosing to promote safe use. In cases of malignant hyperthermia or toxicity, critical care professionals quickly diagnose and provide necessary interventions along with supportive care to stabilize the patient. When using depolarizing neuromuscular blockade drugs, involving an interprofessional team, including clinicians and specialists, anesthesiologists and/or nurse anesthetists, pharmacists, nurses, and EMT personnel, is essential.