Succinylcholine, also known by its alternative name suxamethonium, is a depolarizing neuromuscular blocking agent that has been widely used in anesthesia practice for decades. Its rapid onset and short duration of action make it an ideal choice for rapid sequence intubation and other clinical settings where immediate paralysis is necessary. Despite being one of the oldest neuromuscular blocking drugs in clinical use, succinylcholine remains a key player in modern anesthesiology and critical care.
This in-depth article will explore the pharmacology of succinylcholine by examining its history, classification, mechanism of action, pharmacodynamics, pharmacokinetics, clinical uses, side effects, potential adverse reactions, contraindications, drug interactions, and ongoing research. While this information is intended for educational purposes, always remember to consult a qualified healthcare professional for individualized medical advice.
Historical Background and Discovery
From Curare to Synthetic Compounds
Before succinylcholine became the neuromuscular blocking agent of choice for rapid sequence intubation, anesthesiologists primarily relied on curare-derived non-depolarizing muscle relaxants. Curare was derived from certain plant extracts in South America and used by indigenous populations as arrow poisons. Early anesthesiologists discovered the potential for these compounds to induce muscle relaxation necessary for surgery. Over time, however, researchers sought more improved agents with rapid onset of action and shorter duration to reduce complications, such as residual neuromuscular blockade.
Development of Succinylcholine
In the 1940s, pharmacologists investigating synthetic molecules as safer alternatives to curare-based products discovered succinylcholine. One of the key figures in its discovery is Nobel Prize–winning pharmacologist Daniel Bovet, who worked on muscle relaxants and contributed to the broader field of anesthesia. Initially introduced in the 1950s, succinylcholine quickly became popular for endotracheal intubation because of its remarkably fast onset.
Modern-Day Significance
Although newer non-depolarizing muscle relaxants have come onto the market—such as rocuronium and vecuronium—succinylcholine has remained clinically significant. Its short duration of action, normally lasting only several minutes in most patients, underpins its continued usage. Moreover, succinylcholine’s ability to facilitate rapid intubation has made it a cornerstone in trauma cases, emergency surgeries, and full-stomach anesthesia, where minimizing aspiration risk is crucial.
Classification of Succinylcholine
Depolarizing vs. Non-Depolarizing Neuromuscular Blockers
Neuromuscular blocking agents are broadly classified into two categories:
- Non-depolarizing neuromuscular blockers: These agents (e.g., rocuronium, vecuronium, pancuronium) compete with acetylcholine for nicotinic receptors at the neuromuscular junction (NMJ), preventing depolarization and hindering muscle contraction.
- Depolarizing neuromuscular blockers: Succinylcholine is the prime example in this category. Instead of simply blocking the receptor, it mimics the action of acetylcholine by binding to nicotinic receptors and generating a depolarization—a process that leads to brief fasciculations followed by paralysis.
Because succinylcholine causes an initial depolarization, it is referred to as a depolarizing muscle relaxant. The prolonged depolarization of the muscle endplate makes the muscle temporarily refractory to further stimulation. This unique characteristic sets it apart from the more common non-depolarizing neuromuscular blockers.
Succinylcholine is composed of two acetylcholine molecules linked together, essentially functioning as a double molecule of acetylcholine. This unique structure confers its potent ability to bind and activate nicotinic receptors in skeletal muscle. Nonetheless, while structurally similar to acetylcholine, succinylcholine has distinct pharmacokinetic and pharmacodynamic profiles that give it clinical utility.
Mechanism of Action
Depolarizing the Neuromuscular Junction
Succinylcholine exerts its main effect through activation of nicotinic acetylcholine receptors on the motor endplate of skeletal muscles. Upon administration, succinylcholine binds to these receptors, causing an inward flow of sodium ions and an outward flow of potassium ions. This ion flux results in the depolarization of the muscle membrane, leading to a transient phase of muscle fasciculations (small, uncontrolled muscle twitches).Phase I and Phase II Block
The blockade produced by succinylcholine is typically categorized as a Phase I block, which is characterized by:
- Persistent Depolarization: More prolonged than that caused by acetylcholine, the depolarized membrane is unable to reset and cannot respond to subsequent nervous impulses.
- Fasciculations: A brief period of muscle twitches often observed in the initial moments of succinylcholine’s action.
- No Fade Phenomenon: Unlike non-depolarizing blockers, train-of-four (TOF) stimulation typically does not show fade in a pure Phase I block; instead, all responses are equally reduced.
With repeated or prolonged exposure to succinylcholine, the blockade may transition into a Phase II block, which can mimic the characteristics of a non-depolarizing block. This occurs when the neuromuscular junction becomes repolarized but remains desensitized to acetylcholine. Clinically, higher or repeated doses of succinylcholine can induce this transitional state, meaning the anesthesiologist must monitor neuromuscular blockade carefully if multiple doses are given.
Metabolism by Plasma Cholinesterase
One crucial factor that influences succinylcholine’s mechanism is its rapid metabolism by the enzyme plasma cholinesterase (also known as pseudocholinesterase or butyrylcholinesterase). This enzyme is produced primarily in the liver and is present in the plasma, rapidly hydrolyzing succinylcholine into inactive metabolites, succinylmonocholine and choline. This quick breakdown leads to succinylcholine’s very short duration of action under normal conditions.
Pharmacodynamics
Dynamics of Muscle Paralysis
Following intravenous administration, succinylcholine begins to act within 30 to 60 seconds, causing a complete neuromuscular blockade that typically lasts about 5 to 10 minutes in individuals with normal levels of plasma cholinesterase. The initial muscle fasciculations might be visible and can be uncomfortable if the patient is awake—or can lead to postoperative myalgias if sedation or anesthesia is not sufficiently deep prior to administration.
Dose-Response Relationship
A typical intubating dose of succinylcholine used clinically is around 1 to 1.5 mg/kg IV
. This dose is chosen to guarantee rapid and thorough onset of neuromuscular paralysis, ideal for securing the airway promptly in scenarios like emergency intubation. Smaller doses (e.g., 0.5 mg/kg IV
) may not reliably produce favorable intubating conditions.
Cardiac Effects
Succinylcholine may produce transient bradycardia, especially in pediatric populations and in adults after a second dose. This bradycardia may be attributed to succinylcholine’s similarity to acetylcholine, which can stimulate muscarinic receptors in the heart, reducing heart rate. Pretreatment with an anticholinergic agent such as atropine often mitigates this effect.
Increased Intraocular and Intracranial Pressure
Depolarization of skeletal muscles can transiently raise intraocular pressure (IOP) and possibly intracranial pressure (ICP). While the clinical significance of raised IOP is somewhat controversial, it remains a consideration in patients with penetrating eye injuries. The increase in ICP usually resolves quickly, but it warrants attention in neurosurgical contexts.
Pharmacokinetics
Absorption and Distribution
Succinylcholine is typically administered intravenously for rapid and consistent onset of action. When given through an IV route, it is quickly distributed throughout the extracellular fluid compartment. The onset of action is notably faster in well-perfused tissues, such as the brain and lungs. However, since the primary target is the neuromuscular junction of skeletal muscles, distribution to these sites ensures effective paralysis.
Metabolism by Plasma Cholinesterase
The hallmark of succinylcholine’s pharmacokinetic profile is its dependence on plasma cholinesterase for metabolism. Normally, this enzyme hydrolyzes succinylcholine within minutes, ensuring that the blockade is short-lived. The resulting metabolites—choline and succinylmonocholine—are less potent and typically cleared by the kidneys and liver.
Halflife
Because of extensive and rapid metabolism, the effective clinical half-life of succinylcholine is only a few minutes. The plasma elimination half-life, if measured precisely, might range around 2 to 4 minutes. This short half-life contributes prominently to the agent’s favorable profile for rapid sequence induction, allowing patients to recover neuromuscular function quickly—often faster than if alternative non-depolarizing muscle relaxants were used.
Prolonged Block in Atypical Cholinesterase
Certain genetic variants or acquired deficiencies in plasma cholinesterase can increase succinylcholine’s duration of action from the usual 5 to 10 minutes to as long as several hours. These atypical enzymes have diminished capacity to hydrolyze succinylcholine, leading to prolonged apnea and paralysis. Identifying patients at risk for this complication involves a combination of patient history (e.g., prior prolonged block) and laboratory testing, including the dibucaine number—which gauges enzyme activity.
Clinical Uses
Rapid Sequence Intubation (RSI): Perhaps the most common and critical use of succinylcholine is rapid sequence induction in patients who are at high risk for aspiration. In such situations, its swift onset and short duration allow anesthesiologists to secure the airway under optimal conditions, minimizing the time for potential aspiration events.
Electroconvulsive Therapy (ECT): Succinylcholine is often used to provide muscle relaxation during ECT to prevent excessive muscle contractions and reduce the risk of fractures or musculoskeletal injuries.
Short, Outpatient Procedures: In some short diagnostic or therapeutic procedures requiring brief paralysis—like laryngoscopy or bronchoscopy—succinylcholine may be employed for convenience.
Facilitation of Ventilation in Intensive Care: In certain ICU scenarios, succinylcholine can help with procedures like bronchoscopy or emergent airway management. However, repeated dosing in the ICU must be performed cautiously due to the risk of Phase II block and hyperkalemia.
Adverse Effects
In the field of anesthesiology, succinylcholine is notoriously linked to various potential side effects. Understanding these reactions is essential for safe clinical use:
Prolonged Paralysis: In patients with atypical or deficient plasma cholinesterase, succinylcholine’s paralysis effect can last far beyond normal durations, prompting extended mechanical ventilation and ICU monitoring.
Hyperkalemia: Succinylcholine administration leads to a small but significant efflux of potassium from cells during depolarization. While serum potassium typically rises by about 0.5 mEq/L in most individuals, certain patient populations are at high risk for dangerous hyperkalemia. Examples include burn patients (especially those with burns older than 72 hours), patients with denervation injuries (like spinal cord injury or stroke), and individuals with severe muscle trauma or prolonged immobilization. In these patients, succinylcholine can cause life-threatening potassium spikes.
Malignant Hyperthermia (MH): This is a rare, genetically predetermined condition triggered by succinylcholine (and volatile anesthetic agents) leading to an uncontrolled hypermetabolic state. Classic signs include rapidly rising body temperature, tachycardia, tachypnea, rigidity (often involving the masseter muscle), and eventual rhabdomyolysis. Dantrolene is the essential antidote for malignant hyperthermia.
Fasciculations and Myalgias: As succinylcholine depolarizes skeletal muscles, patients may experience muscle fasciculations, often described as “twitching.” Postoperative muscle aches, or myalgias, are relatively common but can be attenuated by giving small doses of non-depolarizing muscle relaxants before succinylcholine (a process known as “defasciculation”).
Bradycardia: Particularly seen in children or after a second dose in adults, succinylcholine can stimulate muscarinic receptors in the heart, leading to bradycardia. Prophylactic administration of atropine is often recommended for pediatric patients.
Increased Intragastric, Intraocular, and Intracranial Pressures: While these rises tend to be transient, they can be clinically relevant in vulnerable populations. For instance, in someone with a penetrating eye injury, the temporary increase in intraocular pressure might theoretically worsen the injury.
Contraindications
Because of its potential adverse effects, succinylcholine is not always the recommended agent in every scenario. Common contraindications include:
- History of Malignant Hyperthermia: Patients with known susceptibility should avoid succinylcholine due to the life-threatening nature of malignant hyperthermia.
- High-Risk Hyperkalemia: Patients with extensive burns (post-72 hours), severe crush injuries, upper or lower motor neuron lesions, denervation, or significant muscle wasting are at risk for abrupt, fatal hyperkalemia.
- Atypical Plasma Cholinesterase: Known or suspected deficiency in pseudocholinesterase function is a red flag for prolonged block.
- Penetrating Eye Injuries: Increased intraocular pressure might be detrimental to patients with open globe injuries, although this remains controversial.
- Neurological Injuries: In chronic spinal cord injury or neuromuscular disease, succinylcholine can trigger excessive potassium release.
Drug Interactions
- Volatile Anesthetic Agents: Succinylcholine, sometimes used in conjunction with inhalational anesthetics, can increase the likelihood of malignant hyperthermia. Anesthesiologists need to maintain a heightened vigilance for early recognition of MH signs.
- Aminoglycosides and Other Antibiotics: Certain antibiotics can potentiate neuromuscular blockade, although this effect is more pronounced with non-depolarizing agents.
- Acetylcholinesterase Inhibitors: Agents like neostigmine, used to reverse non-depolarizing neuromuscular blockade, may prolong or enhance the depolarizing blockade if given prematurely, as they increase acetylcholine levels, maintaining the depolarized state.
- Lithium and Calcium Channel Blockers: Some evidence suggests these drugs can alter neuromuscular transmission and potentiate block. Clinicians must be cautious with patients on multiple medications that could affect muscle relaxant handling.
Special Considerations in Different Populations
- Pediatric Population: Succinylcholine is associated with increased bradycardia in children. Hence, atropine pretreatment is often used. Additionally, the risk of hyperkalemia is elevated in children with undiagnosed muscular dystrophies, making the use of succinylcholine more controversial unless it is an emergency.
- Geriatric Population: In older adults, distribution may be altered due to decreased muscle mass and changes in total body water. Although succinylcholine is typically well-tolerated, anesthesiologists must remain vigilant for side effects like bradycardia and hyperkalemia, especially in those with comorbidities.
- Obstetric Patients: Pregnant individuals often require rapid sequence induction to prevent aspiration (particularly in emergent C-sections). Succinylcholine’s rapid onset makes it advantageous in obstetric anesthesia; however, pregnancy-related changes in plasma cholinesterase activity can slightly prolong its duration, although usually not significantly enough to change clinical practice.
- Patients with Burns or Spinal Cord Injury: As emphasized previously, these patient groups have a high risk of dangerous hyperkalemia after succinylcholine administration. Careful evaluation and alternative muscle relaxants—like rocuronium with sugammadex reversal—are often preferred.
Comparison with Non-Depolarizing Agents
Rocuronium vs. Succinylcholine
Rocuronium is a non-depolarizing neuromuscular blocker often compared to succinylcholine, especially since rapid-onset rocuronium (e.g., using doses of 0.9 to 1.2 mg/kg) plus sugammadex for reversal offers an alternative for rapid sequence intubation (RSI). However, succinylcholine still outperforms rocuronium in terms of onset speed—generally guaranteeing optimal intubating conditions around 45-60 seconds.
Vecuronium vs. Succinylcholine
Vecuronium is another non-depolarizing agent with a somewhat intermediate onset that is slower compared to succinylcholine. While it enjoys a more predictable duration and fewer adverse effects like hyperkalemia, vecuronium does not match succinylcholine’s ultra-fast onset, making it less ideal for emergencies requiring immediate intubation.
In contemporary practice, clinicians weigh pros and cons: succinylcholine stands out for short duration and swift onset but poses potential for severe hyperkalemia in susceptible patients. Non-depolarizing alternatives have fewer serious side effects but lack the unique speed of onset that remains succinylcholine’s hallmark.
Monitoring Neuromuscular Blockade
Peripheral Nerve Stimulator
Anesthesiologists frequently use a peripheral nerve stimulator (PNS) to assess the degree of neuromuscular blockade and recovery. For succinylcholine-induced blockade, the primary pattern in a classic Phase I block is an equal reduction in all four twitches, with no fade. Over time, if a Phase II block ensues (due to repeated or prolonged administration), the pattern may paradoxically shift to mimic a non-depolarizing blockade, showing fade and post-tetanic facilitation.
Clinical Signs
Aside from objective nerve stimulation, clinical signs of paralysis—such as the loss of muscle tone, inability to breathe spontaneously, and absence of gag reflex—are important indicators of adequate blockade. As succinylcholine’s short duration wanes, spontaneous respirations usually resume quickly, albeit the time frame can be extended in patients with pseudocholinesterase deficits.
Management of Succinylcholine-Induced Complications
- Hyperkalemia: Sudden, life-threatening hyperkalemia can provoke cardiac arrhythmias and cardiac arrest. Management involves typical hyperkalemia treatments such as intravenous calcium, albuterol nebulization, IV insulin with glucose, and possibly sodium bicarbonate. Avoiding succinylcholine in high-risk patients is the best preventive measure.
- Malignant Hyperthermia: Rapid detection and treatment with intravenous dantrolene is critical. Supportive measures like active cooling and correcting acid-base and electrolyte abnormalities are equally important.
- Prolonged Paralysis: Anticipating potential pseudocholinesterase deficiencies allows the anesthesiologist to plan alternatives. If unexpected prolonged blockade occurs, supportive mechanical ventilation and sedation must be continued until neuromuscular function recovers.
Succinylcholine Apnea and Its Treatment
A rare but serious adverse effect is succinylcholine-induced apnea, which is commonly associated with an inherited deficiency of plasma cholinesterase. The normal treatment for succinylcholine apnea is to maintain sedation and ventilate the patient in an intensive care unit until muscle function has returned. All anaesthetists are trained to recognize succinylcholine apnea and will use a machine (a ventilator) to help the patient’s breathing until the drug wears off. Recombinant plant-derived butyrylcholinesterase was capable of counteracting and reversing apnea in two complementary models of lethal succinylcholine toxicity, completely preventing mortality.
Future Developments and Research
Phase II Block Insights
Ongoing research aims to better characterize the transition from a Phase I to a Phase II block. Understanding the exact molecular mechanisms may lead to refined dosing practices and potentially new agents that avoid this phenomenon.
Safer Agents or Reversal Strategies
As the field of anesthesia continues to evolve, scientists and clinicians continuously evaluate muscle relaxants that can replace or improve upon succinylcholine’s profile. One main impetus is reducing the risk of hyperkalemia while maintaining the rapid onset. Approaches like using high-dose rocuronium plus sugammadex or exploring novel depolarizing agents with reduced hyperkalemic risk are under investigation.
Molecular Genetics of Pseudocholinesterase
Research into genetic variants of pseudocholinesterase may advance screening methods. Rapid, precision-based genetic testing might help identify patients at risk for prolonged apnea. This could significantly enhance patient safety by guiding clinicians to alternative muscle relaxants when needed.
Prevention of Myalgia
Further evidence-based protocols addressing postoperative myalgia—for instance, prophylactic NSAIDs, magnesium, or small-dose non-depolarizing relaxants—are areas of continued clinical interest. If standardized guidelines for prophylaxis become widely accepted, the incidence of postoperative myalgias after succinylcholine could decline.
Practical Tips for Clinicians
- Always Analyze Patient-Specific Risks: Patients with burns, neuromuscular disorders, or prolonged immobilization are highly vulnerable to fatal hyperkalemia after succinylcholine. Screening for any red flags is essential before administration.
- Be Prepared for Possible Bradycardia: Particularly in pediatric patients or with repeat doses. Having atropine on hand is a prudent practice.
- Monitor Neuromuscular Function: Use of a peripheral nerve stimulator facilitates accurate assessment of blockade depth and speed of recovery.
- Plan for Unexpected Prolonged Apnea: Patient factors such as pseudocholinesterase deficiency can catch practitioners off-guard. Have backup airway and ventilatory management plans ready.
- Have a Malignant Hyperthermia Plan: When using succinylcholine, remain prepared to recognize and treat MH promptly. Ensure dantrolene is readily available and the anesthesia team is well-trained in MH crisis management.
Summary of Key Points
- Succinylcholine is a depolarizing neuromuscular blocker primarily used to facilitate rapid sequence intubation and brief surgical or procedural muscle relaxation.
- It works by binding to nicotinic acetylcholine receptors and causing persistent depolarization, leading to muscle fasciculations followed by paralysis.
- The rapid onset and short duration are due to its efficient metabolism via plasma cholinesterase.
- Major side effects include hyperkalemia, malignant hyperthermia, bradycardia, increased intraocular pressure, and myalgias.
- Contraindications cover those at high risk of hyperkalemia (burns, denervation), malignant hyperthermia susceptibility, and individuals with known atypical pseudocholinesterase.
- Alternative muscle relaxants like rocuronium are often considered, but succinylcholine’s unmatched speed of onset continues to make it favored in urgent clinical scenarios.
- Ongoing research on pseudocholinesterase genetics and novel neuromuscular blockers aims to refine anesthesia safety and effectiveness.
Conclusion
Succinylcholine (suxamethonium) stands out as a cornerstone of modern anesthesia, cherished for its ultra-rapid onset and short-acting neuromuscular blockade. Its unique function as a depolarizing muscle relaxant enables anesthesiologists to secure airways quickly and reliably, especially in emergency and full-stomach patients. However, clinicians should be aware of the potential for severe complications such as hyperkalemia and malignant hyperthermia, along with the issue of prolonged paralysis in patients with atypical plasma cholinesterase.
By recognizing the pharmacological, physiological, and genetic factors at play, healthcare providers can harness succinylcholine’s benefits while mitigating its risks. In practice, this means meticulously assessing individual patient factors, staying vigilant for early signs of adverse reactions, and preparing contingency plans for emergencies like malignant hyperthermia. The availability of newer agents and reversal drugs (e.g., sugammadex) has expanded the toolkit for rapid sequence intubation, but succinylcholine remains unparalleled in many respects for its rapid onset.
Though the future may bring more refined neuromuscular blocking agents or even gene-based customizations, succinylcholine endures as a pivotal drug in the anesthesiologist’s armamentarium. Continued research into optimizing dosing regimens, preventing complications, and identifying genetic vulnerabilities will likely refine its use further. For now, succinylcholine continues to serve its indispensable role in anesthesia practice, standing as both a benchmark for rapid, brief neuromuscular blockade and a cautionary tale of the potent adverse effects of neuromuscular blocking drugs.
Disclaimer
This article provides general information on the pharmacology of succinylcholine and its clinical aspects. It is intended for educational purposes only and should not replace professional medical advice, diagnosis, or treatment. Always seek the guidance of a qualified healthcare professional with any questions regarding a medical condition or treatment, and never disregard professional advice or delay in seeking it because of something you have read here.