10.1 Depolarizing Muscle Relaxants: Succinylcholine

10.1 Depolarizing Muscle Relaxants: Succinylcholine

Neuromuscular blocking agents (NMBAs) are essential pharmaceuticals in modern anesthesia practice, utilized to facilitate tracheal intubation, optimize surgical operating conditions, and manage patient-ventilator synchrony. Neuromuscular blockers are divided into two distinct pharmacodynamic classes: depolarizing and non-depolarizing agents. Succinylcholine chloride (Anectine, Quelicin) remains the sole depolarizing muscle relaxant in widespread clinical use worldwide.

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Chemical Structure & Mechanism of Action

Molecular Architecture: Diacetylcholine

The chemical structure of succinylcholine consists of two acetylcholine (ACh) molecules linked together end-to-end through their acetate methyl groups, forming a symmetrical diacetylcholine molecule. Because of this structural homology with endogenous acetylcholine, succinylcholine exhibits a high affinity for nicotinic acetylcholine receptors (nAChRs) situated at the motor endplate of the neuromuscular junction (NMJ).

   Acetylcholine:    (CH3)3N+ - CH2 - CH2 - O - C(=O) - CH3

   Succinylcholine:  (CH3)3N+ - CH2 - CH2 - O - C(=O) - CH2 - CH2 - C(=O) - O - CH2 - CH2 - N+(CH3)3
                     |_________________Acetylcholine #1__________________| |_________________Acetylcholine #2________________|

Depolarization and the Phase I Block

At the skeletal muscle motor endplate, the post-synaptic nicotinic receptor is a pentameric ligand-gated ion channel composed of five glycoprotein subunits: two alpha-1 (α1), one beta-1 (β1), one delta (δ), and one epsilon (ε) in mature adult junctional tissue. For channel activation to occur under normal physiological conditions, two molecules of acetylcholine must bind simultaneously to the two α1 subunits, triggering a conformational shift that opens the central aqueous ion pore to sodium (Na+) and calcium (Ca2+) influx, alongside potassium (K+) efflux.

When succinylcholine is administered intravenously:

1. Receptor Activation: Succinylcholine binds to one or both α1 subunits of the post-synaptic nicotinic receptor, mimicking acetylcholine and opening the ion channel.
2. Sustained Endplate Depolarization: Unlike acetylcholine, which is hydrolyzed within microseconds by acetylcholinesterase (AChE) in the synaptic cleft, succinylcholine is not metabolized by acetylcholinesterase. It remains bound to the post-synaptic receptor for a prolonged period, causing persistent depolarization of the motor endplate.
3. Initial Fasciculations: The initial sustained depolarization generates disorganized, asynchronous muscle contractions across motor units throughout the body, clinically observed as muscle fasciculations (fine twitching visible in the eyelids, face, neck, trunk, and extremities).
4. Flaccid Paralysis via Voltage-Gated Channel Inactivation: Persistent endplate depolarization prevents the adjacent perijunctional muscle membrane from repolarizing. The voltage-gated sodium channels in the perijunctional zone transition into an inactive, closed state. Because repolarization is required to reset these channels into an activatable resting state, the muscle becomes completely refractory to subsequent nerve impulses, resulting in profound flaccid paralysis.

Train-of-Four (TOF) Dynamics in Phase I Blockade

When evaluating neuromuscular blockade using a peripheral nerve stimulator (typically stimulating the ulnar nerve while monitoring the adductor pollicis muscle):

• Uniform Twitch Reduction: During a classic Phase I block, all four twitches of the train-of-four (TOF) stimulus (2 Hz delivered over 2 seconds) are diminished in amplitude to an equal extent.
• Absence of Fade: There is no progressive decline in twitch height from the first twitch (T1) to the fourth twitch (T4). The train-of-four ratio (TOFR = T4/T1) remains equal to 1.0 (or >0.7 during partial onset/recovery).
• Absence of Post-Tetanic Potentiation: High-frequency tetanic stimulation (50 Hz for 5 seconds) does not elicit post-tetanic potentiation (facilitation). The post-tetanic twitch response remains suppressed without an augmented burst of contraction.
• Post-Tetanic Count: A post-tetanic count (PTC) is absent; there is no post-tetanic recruitment of twitches.

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The Phase II Block Transition (Desensitization Block)

Under specific clinical conditions, prolonged or excessive exposure of the motor endplate to succinylcholine causes the nature of the blockade to alter fundamentally, transitioning from a depolarizing Phase I block to a non-depolarizing-like Phase II block (also termed a desensitization block or dual block).

Mechanisms and Etiology

A Phase II block develops when the motor endplate becomes desensitized to acetylcholine and succinylcholine. The post-synaptic membrane repolarizes, but the receptor conformation changes such that the channel pore remains closed or refractory to further stimulation. Intracellular sodium accumulates, and uncoupling of receptor activation from downstream intracellular excitation occurs.

Clinical risk factors for transitioning into a Phase II block include:

• High Cumulative Dosing: Cumulative doses of succinylcholine exceeding 4 to 5 mg/kg (or >500 mg in adults).
• Continuous Infusions: Infusions of succinylcholine administered over prolonged operative durations.
• Repeated Boluses: Frequent, repeated intermittent boluses administered during lengthy procedures.
• Atypical Pseudocholinesterase: In patients who cannot metabolize succinylcholine normally, a standard single intubating dose (1.0 mg/kg) remains in the NMJ for hours, precipitating a Phase II block.

Peripheral Nerve Stimulator Characteristics: Phase I vs. Phase II

[!WARNING] Although a Phase II block exhibits non-depolarizing characteristics, administering an anticholinesterase (such as neostigmine) to reverse it is unpredictable and clinically hazardous. Neostigmine inhibits both acetylcholinesterase and pseudocholinesterase; if significant circulating succinylcholine remains, neostigmine will block its metabolic breakdown, paradoxically intensifying and prolonging neuromuscular paralysis. The patient must remain intubated, sedated, and mechanically ventilated until spontaneous recovery occurs.

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Pharmacokinetics & Pseudocholinesterase Hydrolysis

Metabolism and Clearance Pathway

Succinylcholine has the most rapid onset and the shortest duration of action of all clinical neuromuscular blocking agents:

• Intubation Dose: 1.0 to 1.5 mg/kg IV (in adults; up to 2.0 mg/kg in infants and small children due to their larger extracellular fluid volume).
• Onset of Intubating Conditions: 30 to 60 seconds.
• Duration of Clinical Action: 5 to 10 minutes; full recovery of twitch height occurs within 10 to 15 minutes.

Following intravenous injection, the vast majority of succinylcholine (approximately 90%) is rapidly metabolized in the bloodstream and liver before ever reaching the neuromuscular junction. This breakdown is mediated by plasma cholinesterase (also designated pseudocholinesterase, butyrylcholinesterase [BChE], or serum cholinesterase), an enzyme synthesized exclusively by hepatocytes.

Hydrolysis proceeds in a two-stage enzymatic reaction:

1. Primary Cleavage: Pseudocholinesterase cleaves succinylcholine into succinylmonocholine and free choline.
   • Clinical Note: Succinylmonocholine has extremely weak neuromuscular blocking properties (approximately 1/20th to 1/80th the potency of succinylcholine).
2. Secondary Cleavage: Succinylmonocholine is subsequently hydrolyzed very slowly by pseudocholinesterase and non-specific esterases into succinic acid and choline.

Importantly, true acetylcholinesterase present in the synaptic cleft does not hydrolyze succinylcholine. The termination of action at the motor endplate occurs purely by passive diffusion of succinylcholine out of the synaptic cleft down a concentration gradient back into the extracellular fluid and plasma, where it is promptly degraded by circulating pseudocholinesterase.

Clinical Factors Altering Pseudocholinesterase Activity

Pseudocholinesterase levels or enzymatic function can be suppressed by acquired physiological states, pathological diseases, and pharmacological inhibitors:

• Hepatic Disease: Severe liver dysfunction, cirrhosis, and acute hepatic failure decrease enzymatic synthesis.
• Pregnancy & Postpartum: Enzymatic activity falls by 20% to 30% in the third trimester and remains low for up to 6 weeks postpartum.
• Severe Thermal Burns: Extensive burns depress pseudocholinesterase synthesis starting several days post-injury.
• Malnutrition & Cachexia: Severe protein-calorie deficit impairs hepatic protein synthesis.
• Pharmacological Inhibitors:
  • Anticholinesterase drugs: Neostigmine, pyridostigmine, and echothiophate eye drops.
  • Organophosphate poisoning: Irreversible organophosphate insecticides or nerve agents.
  • Chemotherapeutic agents: Alkylating agents like cyclophosphamide.
  • Cardiovascular and GI drugs: Esmolol (metabolized by RBC esterases, competing for esterase pathways), metoclopramide (Reglan), oral contraceptive pills, and MAO inhibitors.

In patients with acquired pseudocholinesterase deficiency, succinylcholine duration is moderately prolonged (e.g., 15 to 30 minutes rather than 5 to 10 minutes), but rarely causes multi-hour paralysis unless combined with genetic defects.

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Atypical Pseudocholinesterase & The Dibucaine Test

Genetic Polymorphisms

Inherited abnormalities of pseudocholinesterase result from mutations on the BCHE gene located on chromosome 3. The most clinically significant genetic variants include:

1. Usual / Normal Allele (Eᵘ or U): Codes for normal, fully functional enzyme.
2. Atypical Allele (Eᵃ or A): Codes for an abnormal enzyme with markedly reduced substrate affinity for succinylcholine.
3. Fluoride-Resistant Allele (Eᶠ or F): Codes for an enzyme resistant to inhibition by sodium fluoride.
4. Silent Allele (Eˢ or S): Produces no detectable, functional pseudocholinesterase enzyme.

The Dibucaine Number: Mechanism and Clinical Interpretation

Because quantitative laboratory measurements of pseudocholinesterase activity can be misleading (an atypical enzyme may be present in normal numerical quantities but lack catalytic function), the Dibucaine Number Test is the definitive laboratory assay.

Dibucaine is an amide local anesthetic that inhibits normal pseudocholinesterase activity by approximately 80%, but inhibits atypical pseudocholinesterase by only 20%. The dibucaine number represents the percentage of pseudocholinesterase enzyme activity inhibited by dibucaine under standardized laboratory conditions; it reflects enzymatic quality, not total quantity.

Clinical Management of Prolonged Apnea

When a patient fails to resume spontaneous ventilation following succinylcholine administration, the anesthesia technologist and care team must execute a structured supportive protocol:

1. Maintain Mechanical Ventilation & Oxygenation: The primary treatment is purely supportive. Continue controlled mechanical ventilation to maintain normocarbia and normoxemia.
2. Ensure Amnesia & Sedation: Flaccid paralysis without sedation is terrifying. Titrate intravenous sedatives (e.g., propofol infusion) and analgesics to guarantee patient comfort and amnesia while paralyzed.
3. Do NOT Administer Neostigmine: Anticholinesterases inhibit pseudocholinesterase, further delaying enzymatic recovery. Neostigmine is strictly contraindicated.
4. Avoid Routine FFP Transfusion: While fresh frozen plasma (FFP) or whole blood contains donor pseudocholinesterase and can accelerate recovery, transfusing allogeneic blood products carries risks of transfusion-related acute lung injury (TRALI), transfusion reactions, and bloodborne pathogen transmission. Because mechanical ventilation is safe and definitive, blood transfusion for atypical pseudocholinesterase is clinically inappropriate in routine practice.
5. Neuromuscular Monitoring: Monitor peripheral nerve stimulation continuously until spontaneous recovery to a TOFR ≥ 0.9 is documented before attempting tracheal extubation.
6. Post-Recovery Workup: Send blood for dibucaine number and pseudocholinesterase genotypic testing. Counsel the patient and provide a medical alert bracelet to protect against future exposures.

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Clinical Complications & Adverse Effects

Fasciculations and Postoperative Myalgia

• Postoperative Myalgia: Occurs in up to 50% of patients receiving succinylcholine, predominantly affecting young, muscular, ambulatory patients undergoing minor procedures. Pain is localized to the neck, shoulders, back, and upper abdomen, often described as resembling intense unaccustomed exercise.
• Defasciculating Doses: Administering a sub-paralyzing dose of a non-depolarizing relaxant (typically 10% of the ED95, such as rocuronium 0.03 to 0.06 mg/kg or vecuronium 0.01 mg/kg) approximately 3 minutes prior to succinylcholine blunts visible fasciculations and reduces the incidence and severity of postoperative myalgias.
• Clinical Dosing Adjustment: Because the defasciculating agent competitively occupies a portion of the post-synaptic receptors, the intubating dose of succinylcholine must be increased to 1.5 to 2.0 mg/kg to ensure rapid, reliable intubating conditions.

Hyperkalemic Cardiac Arrest & Extrajunctional Receptors

In healthy patients, the normal depolarization of motor endplates causes a transient, clinically benign rise in serum potassium (K⁺) of +0.5 mEq/L (rarely exceeding 1.0 mEq/L).

However, in patients with specific underlying clinical conditions, succinylcholine produces a catastrophic, massive efflux of potassium that can drive serum potassium to 8.0 to 10.0+ mEq/L within minutes, precipitating peaked T waves, widening QRS complexes, ventricular tachycardia, ventricular fibrillation, and cardiac asystole.

   Normal Adult Junctional nAChR:        Immature Extrajunctional nAChR (Fetal Type):
   - 2 α1, 1 β1, 1 δ, 1 ε                - 2 α1, 1 β1, 1 δ, 1 γ  (gamma replaces epsilon)
   - Localized strictly to NMJ           - Spreads across entire muscle sarcolemma
   - Brief open channel time (~1 ms)     - Prolonged open channel time (2-10x longer)
   - Normal K+ efflux (+0.5 mEq/L)       - Massive, unchecked systemic K+ efflux

The Extrajunctional Receptor Mechanism

In mature skeletal muscle, neuromuscular receptors are restricted entirely to the post-junctional endplate and contain the epsilon (ε) subunit. When skeletal muscle is deprived of normal motor nerve innervation or subjected to severe trauma, inflammation, or disuse, the muscle reverts to an embryonic state, proliferating immature extrajunctional receptors across the entire sarcolemma outside the NMJ:

1. Fetal Pentamers (α₁β₁δγ): The adult ε subunit is replaced by the fetal gamma (γ) subunit.
2. Alpha-7 Homopentamers ((α₇)₅): Receptors composed entirely of five α₇ subunits.

These extrajunctional receptors possess distinct electrophysiological properties:

• They are exquisitely sensitive to depolarizing agonists (activated by minute agonist concentrations).
• Their ion channels remain open significantly longer than mature junctional receptors.
• Because they cover the entire surface area of massive skeletal muscle beds rather than being confined to the microscopic NMJ, their simultaneous activation dumps intracellular potassium into the systemic circulation at lethal rates.

High-Risk Clinical Conditions (Absolute Contraindications)

[!CAUTION] FDA Boxed Warning: Because of the risk of hyperkalemic cardiac arrest in children with undiagnosed myopathies, succinylcholine use in children should be reserved for emergency tracheal intubation or situations requiring immediate airway control. Undiagnosed Duchenne or Becker muscular dystrophy in apparently healthy young males exposed to succinylcholine can trigger acute rhabdomyolysis, intractable hyperkalemic cardiac arrest, and death.

Autonomic and Cardiac Dysrhythmias

Succinylcholine stimulates all autonomic cholinergic receptors, including cardiac muscarinic M₂ receptors in the sinus node and AV node, and sympathetic and parasympathetic autonomic ganglia:

• Sinus Bradycardia & Asystole: Muscarinic stimulation can precipitate severe sinus bradycardia, nodal/junctional escape rhythms, and asystole. Bradycardia is most common in:
  • Pediatric patients after the first dose of succinylcholine (high resting parasympathetic tone).
  • Adult patients receiving a second dose within 5 to 10 minutes of the first dose.
• Prevention: Prophylactic administration of intravenous atropine (0.01 to 0.02 mg/kg in children; 0.4 to 0.6 mg in adults) or glycopyrrolate effectively prevents muscarinic-mediated bradycardia.

Increased Pressures: Intraocular, Intragastric, and Intracranial

• Intraocular Pressure (IOP): Succinylcholine causes a transient increase in IOP of 5 to 10 mmHg, peaking at 2 to 4 minutes and resolving within 6 to 10 minutes. The primary mechanism is tonic contracture of the extraocular muscles coupled with choroidal vascular engorgement. In patients with an open globe injury (penetrating eye trauma), sudden IOP elevation poses a theoretical risk of extruding intraocular contents (vitreous humor) leading to permanent blindness. High-dose rocuronium (1.2 mg/kg) is frequently selected as an alternative for rapid sequence intubation in open globe cases.
• Intragastric Pressure (IGP): Abdominal wall fasciculations increase intragastric pressure by 15 to 20 cmH2O. However, succinylcholine also increases lower esophageal sphincter (LES) tone via cholinergic stimulation, which generally preserves the physiological barrier pressure (Barrier Pressure = LES Pressure - Intragastric Pressure) in fasting patients.
• Intracranial Pressure (ICP): Succinylcholine induces a transient rise in ICP of 5 to 10 mmHg, thought to result from muscle spindle afferent stimulation transiently increasing cerebral blood flow. This elevation can be blunted by prior defasciculation or an adequate depth of hypnotic induction agent (e.g., propofol).

Masseter Muscle Rigidity & Malignant Hyperthermia

• Masseter Muscle Rigidity (MMR): Characterized by sustained, jaw-clenching contracture ("jaws of steel") that severely hinders opening the mouth for direct laryngoscopy. While mild masseter tone increases can occur normally, true severe MMR is considered a herald sign of susceptibility to Malignant Hyperthermia (MH) in approximately 50% of cases.
• MH Trigger: Succinylcholine is a potent pharmacological trigger of Malignant Hyperthermia (alongside all halogenated volatile anesthetics: sevoflurane, desflurane, isoflurane). It causes uncontrolled intracellular calcium release from the sarcoplasmic reticulum via defective ryanodine receptors (RYR1) in genetically susceptible individuals.