Monograph of Succinylcholine

Introduction

Succinylcholine chloride is a synthetic, short‑acting depolarizing neuromuscular blocker employed predominantly to facilitate tracheal intubation and to provide skeletal muscle relaxation during surgical procedures. The compound serves as a prototype for depolarizing agents, illustrating key pharmacological principles such as receptor activation, ion channel modulation, and rapid metabolic clearance. This monograph addresses the pharmacological profile of succinylcholine comprehensively, with emphasis on its therapeutic use, safety concerns, and clinical decision making.

Historically, succinylcholine was first synthesized in the early 1940s and introduced into clinical practice during the 1950s. Its adoption was driven by the need for a muscle relaxant that could rapidly induce intubation and permit short surgical interventions without the prolonged paralysis associated with non‑depolarizing agents. The development of succinylcholine represented a significant advancement in anesthetic science, providing a tool that could be titrated to the minimal effective dose and rapidly reversed by endogenous acetylcholinesterase activity.

The significance of succinylcholine in contemporary practice remains notable. Although newer agents have supplanted it in many settings, succinylcholine continues to be favored in rapid‑sequence intubation, emergency airway management, and situations requiring short‑duration muscle relaxation. Understanding its pharmacodynamics, pharmacokinetics, and safety profile is essential for clinicians and pharmacists involved in perioperative care and critical‑care settings.

Learning Objectives

• Describe the chemical structure and mechanism of action of succinylcholine.
• Explain the pharmacokinetic parameters influencing onset, duration, and elimination.
• Identify the major clinical indications and contraindications for succinylcholine use.
• Recognize common adverse effects and strategies for mitigation.
• Apply evidence‑based decision making to dosing and monitoring in diverse patient populations.

Fundamental Principles

Core Concepts and Definitions

Succinylcholine is a non‑selective, non‑depolarizing cholinergic agonist that functions as a pseudo‑cholinergic agonist at nicotinic acetylcholine receptors (nAChRs) present at the motor endplate. Its structure comprises two choline moieties linked by a disulfide bond, conferring amphiphilic properties that enable rapid membrane association.

The drug elicits a depolarization response, generating a brief, sustained muscle contraction followed by inexorable flaccid paralysis. This phenomenon is referred to as the “phase I block.” Subsequent exposure can lead to a “phase II block,” characterized by a gradual loss of depolarization and a more prolonged, non‑depolarizing blockade.

Theoretical Foundations

At the neuromuscular junction, succinylcholine competitively binds to the nicotinic acetylcholine receptor (α₁β₁γδ), mimicking acetylcholine (ACh) but resisting hydrolysis. This binding leads to persistent opening of the associated ligand‑gated ion channel, allowing an influx of Na⁺ and a transient efflux of K⁺. The resulting depolarization initiates an action potential, thereby producing muscle contraction. However, the persistent presence of the drug in the channel prevents repolarization, culminating in a block of further action potentials.

The depolarizing effect is short‑lived because succinylcholine is rapidly hydrolyzed by plasma cholinesterase (pseudo‑cholinesterase). The enzymatic activity is crucial for determining the drug’s duration; polymorphisms in the BCHE gene can lead to markedly prolonged blockade in individuals with atypical or deficient cholinesterase activity.

Key Terminology

• Phase I block – Initial depolarizing block with muscle fasciculations.
• Phase II block – Secondary, longer‑lasting non‑depolarizing blockade.
• Plasma cholinesterase (pseudo‑cholinesterase) – Enzyme responsible for succinylcholine hydrolysis.
• Endplate potential (EPP) – Depolarization at the motor endplate following acetylcholine release.
• Muscle relaxation index (MRI) – Quantitative assessment of neuromuscular blockade severity.

Detailed Explanation

Mechanisms and Processes

The pharmacodynamic action of succinylcholine is governed by its interaction with nAChRs. Upon intravenous administration, the drug reaches the neuromuscular junction within seconds. By occupying the ligand‑binding sites, succinylcholine induces a conformational change that opens the ion channel, permitting Na⁺ influx and K⁺ efflux. The resulting depolarization is transient; the channel remains open until the drug is hydrolyzed or unbound. Because succinylcholine is not removed by the cholinergic synaptic cleft’s acetylcholinesterase, the depolarization persists, inactivating the voltage‑gated Na⁺ channels responsible for action potential propagation. The net effect is a rapid, profound muscle paralysis with a typical onset of 30–60 seconds and a duration of 3–5 minutes in normal individuals.

Pharmacokinetics: Mathematical Relationships

The disposition of succinylcholine follows a two‑compartment model. The initial distribution phase (t½α ≈ 15–30 seconds) reflects rapid equilibration between plasma and the central compartment (muscle). The elimination phase (t½β ≈ 5–8 minutes) is governed by hydrolysis by plasma cholinesterase. The following simplified equations describe the plasma concentration (C) over time (t):

• Distribution phase: C(t) = C₀ × e^(–kαt)
• Elimination phase: C(t) = C₀ × e^(–kβt)

where kα and kβ are the respective rate constants for distribution and elimination. The area under the concentration–time curve (AUC) correlates strongly with the severity and duration of the neuromuscular block, providing a quantitative basis for dose adjustment.

Factors Affecting the Process

Several physiological and pathological variables influence succinylcholine’s effect:

• Plasma cholinesterase activity – Genetic variants (e.g., atypical pseudo‑cholinesterase) reduce hydrolysis, prolonging blockade.
• Age – Neonates and infants exhibit lower cholinesterase activity; elderly patients may have altered distribution volumes.
• Renal and hepatic impairment – Limited impact on metabolism, but may alter distribution due to fluid shifts.
• Concurrent medications – Agents that inhibit cholinesterase (e.g., organophosphates) or potentiate neuromuscular blockade (e.g., magnesium) can extend duration.
• Electrolyte imbalances – Hypokalemia or hyperkalemia can influence the magnitude of fasciculations and the risk of hyperkalemia‑induced cardiac arrhythmia.

Clinical Significance

Relevance to Drug Therapy

Succinylcholine’s rapid onset and short duration make it ideal for situations requiring immediate muscle relaxation without prolonged paralysis. Its use is integral to rapid‑sequence intubation (RSI) protocols, where airway protection must be secured promptly in patients with a high aspiration risk. Additionally, succinylcholine is employed in the operating room for short procedures or when rapid reversal is desired, as its effects dissipate quickly once plasma cholinesterase activity resumes.

Practical Applications

In practice, succinylcholine is administered as a single bolus dose ranging from 0.5 to 1.5 mg/kg, depending on the desired intensity of relaxation and patient factors. The dose may be titrated incrementally to achieve adequate intubation conditions while minimizing the risk of prolonged blockade. Monitoring with train‑of‑four (TOF) or double‑twitch stimulation assists in assessing neuromuscular function and determining readiness for extubation or further dosing.

Clinical Examples

1. **Emergency airway management** – In a trauma patient with a suspected cervical spine injury, succinylcholine facilitates intubation while maintaining spontaneous ventilation until the airway is secured.

2. **Short surgical procedures** – During a minor tonsillectomy, a single 1 mg/kg dose provides sufficient relaxation for the 15‑minute operation, obviating the need for continuous infusion.

3. **Diagnostic neuromuscular studies** – Succinylcholine is used to provoke a phase I block in nerve conduction studies, aiding in the differentiation between myasthenia gravis and Lambert–Eaton syndrome.

Clinical Applications/Examples

Case Scenarios

**Scenario A – Rapid‑Sequence Intubation**: A 45‑year‑old woman presents with a severe upper‑GI bleed and is hemodynamically unstable. RSI is indicated to prevent aspiration. A 1.0 mg/kg bolus of succinylcholine is administered, achieving intubation conditions within 45 seconds. Post‑intubation, the patient is placed on a ventilator with continuous monitoring of neuromuscular function to detect any residual blockade.

**Scenario B – Atypical Cholinesterase**: A 30‑year‑old man with a family history of prolonged neuromuscular blockade undergoes a laparoscopic cholecystectomy. Pre‑operative testing reveals reduced plasma cholinesterase activity. Instead of succinylcholine, a non‑depolarizing agent (e.g., rocuronium) is selected to avoid prolonged paralysis. The anesthetic plan includes a reversal agent (sugammadex) upon completion of the procedure.

Application to Specific Drug Classes

Succinylcholine is a member of the depolarizing neuromuscular blocker class. Its pharmacological profile contrasts with non‑depolarizing agents such as rocuronium, vecuronium, and atracurium, which bind to the same receptor but induce a reversible blockade without depolarization. Comparative studies indicate that succinylcholine provides faster onset and shorter duration, whereas non‑depolarizing agents allow for more controlled titration and longer windows for reversal if needed.

Problem‑Solving Approaches

• Identify contraindications (e.g., myasthenia gravis, Eaton–Lambert syndrome, hyperkalemia, long QT syndrome).
• Screen for atypical cholinesterase via serum esterase activity if prolonged paralysis is suspected.
• Employ dose titration guided by TOF monitoring to achieve desired blockade while minimizing exposure.
• Prepare reversal strategies: anticholinesterases for non‑depolarizing agents; readiness for spontaneous recovery for succinylcholine.

Summary/Key Points

• Succinylcholine is a short‑acting depolarizing neuromuscular blocker with rapid onset (30–60 s) and brief duration (3–5 min).
• Pharmacodynamics involve competitive binding to nAChRs, inducing a phase I block characterized by fasciculations and subsequent paralysis.
• Plasma cholinesterase activity determines the drug’s elimination; genetic variants can prolong blockade.
• Clinical indications include rapid‑sequence intubation, short procedures, and neuromuscular diagnostic testing.
• Contraindications encompass conditions that predispose to prolonged blockade or severe hyperkalemia.
• Monitoring with TOF or double‑twitch stimulation guides dosing and ensures timely recovery.
• Key relationships: C(t) = C₀ e^(–kαt) for distribution and C(t) = C₀ e^(–kβt) for elimination; AUC correlates with blockade severity.
• Clinical pearls: use the minimal effective dose, consider pre‑operative cholinesterase screening in at-risk patients, and remain vigilant for hyperkalemia in patients with burns or severe muscle injury.

References

1. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
2. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
3. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
4. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
5. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
6. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
7. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
8. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.