How do depolarizing neuromuscular blocking agents (NMBAs) like succinylcholine depolarize at the neuromuscular junction?

Mechanism of Depolarizing Neuromuscular Blocking Agents at the Synapse

Succinylcholine acts as an agonist at nicotinic acetylcholine receptors, causing the ion-gated channels to open and remain open, resulting in initial depolarization (seen as fasciculations) followed by paralysis due to persistent depolarization of the neuromuscular junction. 1, 2

Neuromuscular Junction Structure and Function

The neuromuscular junction consists of:

• Presynaptic motor axon terminals containing acetylcholine-filled vesicles
• A 30-nm synaptic cleft
• Muscle sarcolemma with specialized folds containing approximately 10,000 acetylcholine receptors/μm² 1

Under normal conditions:

• Acetylcholine is released from nerve terminals
• Binds to nicotinic acetylcholine receptors on muscle
• When two acetylcholine molecules bind, they open ion channels
• This creates an electrical signal leading to muscle contraction
• Acetylcholinesterase quickly breaks down acetylcholine, terminating the action 3

Mechanism of Succinylcholine (Depolarizing NMBA)

Unlike normal acetylcholine function, succinylcholine:

1. Initial Action: Binds to nicotinic receptors at the motor end plate 2

   • Structurally resembles acetylcholine
   • Acts as an agonist at these receptors

2. Depolarization Phase:

   • Opens ion channels similar to acetylcholine
   • Causes initial depolarization of the muscle membrane
   • Clinically manifests as visible fasciculations 1, 2

3. Persistent Effect:

   • Unlike acetylcholine, which is rapidly hydrolyzed by acetylcholinesterase
   • Succinylcholine remains bound to receptors longer
   • Keeps the channels open, maintaining depolarization
   • Prevents repolarization of the muscle membrane 2

4. Resulting Paralysis:

   • The persistent depolarization prevents new action potentials
   • Neuromuscular transmission is inhibited as long as adequate concentration remains at receptor sites
   • Results in flaccid paralysis within less than one minute of IV administration 2

5. Duration and Metabolism:

   • Effect typically lasts 4-6 minutes with single administration
   • Rapidly hydrolyzed by plasma cholinesterase to succinylmonocholine
   • Further broken down to succinic acid and choline
   • Approximately 10% excreted unchanged in urine 2

Clinical Implications and Considerations

• Progressive Paralysis: Different muscle groups have different sensitivities, with paralysis typically affecting facial muscles first, then glottic muscles, and finally intercostal muscles and diaphragm 2

• Phase II Block: With prolonged or repeated administration, the characteristic depolarizing block (Phase I) may change to a block resembling non-depolarizing block (Phase II), which can lead to prolonged paralysis 2

• Hyperkalemia Risk: In certain pathologic states (denervation, immobilization, burns, trauma), there is up-regulation of acetylcholine receptors throughout the muscle membrane. Depolarization of these widespread receptors by succinylcholine can cause significant potassium efflux, potentially leading to dangerous hyperkalemia 4

• Cardiovascular Effects: Succinylcholine stimulates both autonomic ganglia and muscarinic receptors, which may cause changes in cardiac rhythm including cardiac arrest 2

• Other Effects:

  • Increases intraocular pressure
  • May slightly increase intracranial pressure
  • Potential for histamine release (though uncommon in normal clinical use) 2

Contrast with Non-depolarizing NMBAs

Unlike succinylcholine, non-depolarizing NMBAs:

• Act as competitive antagonists at nicotinic receptors
• Prevent acetylcholine from binding to receptors
• Do not cause initial depolarization or fasciculations
• Generally have longer duration of action 1, 5

Understanding this mechanism is crucial for appropriate clinical use and anticipation of potential complications associated with succinylcholine administration.