Neuromuscular blocking agents (NMBAs or “paralytics”) are categorized as depolarizing (classically succinylcholine) and nondepolarizing. They’re important drugs to know because we routinely use them in the operating room, intensive care unit, and during elective endotracheal intubations. They have potential life threatening complications like malignant hyperthermia and anaphylaxis as well as different metabolic profiles.
Succinylcholine (“sux”) is structurally composed of two acetylcholine (ACh) molecules linked together. It binds the post-synaptic neuromuscular junction (NMJ) motor end plate to cause depolarization at the acetylcholine receptor (AChR). This is exactly what normal ACh neurotransmitter molecules do as they leave the active zone, traverse the synaptic cleft, and bind the AChR. Initially, this depolarizing effect stimulates muscle contraction which we see as diffuse fasciculations. Unlike ACh which is rapidly hydrolyzed by acetylcholinesterase (AChE), sux remains on the AChR causing continued depolarization and profound muscular relaxation as calcium is reuptaken into the sarcoplasmic reticulum. This phase 1 block explains why we see fasciculations (contractions) followed by relaxation.
With higher doses of sux (typically > 4 mg/kg), continuous binding to the acetylcholine receptors causes an ongoing influx of sodium and efflux of potassium. The sodium-potassium ATPase’s activity is upregulated bringing ion concentrations back towards their resting states. The receptor no longer responds appropriately to acetylcholine, and the NMJ blockade is prolonged. This phase 2 block has features similar to non-depolarizing blockers (ie, rocuronium, vecuronium) such as a fade with train-of-four (TOF) peripheral nerve stimulation. If a phase 2 block develops, supportive care is often the best management until the block wears off.
As an anesthesiologist, whenever I’m called for a stat intubation, I’m looking for reasons NOT to use sux.
- Known familial or prior history of malignant hyperthermia
- Known hypersensitivity reactions
- Skeletal muscle myopathies
- Acute burn injury, extensive denervation injury, and upper motor neuron injury
- Extrajunctional AchR proliferation will peak at 7-10 days after injury
- Severe hyperkalemia
A standard induction dose of sux will raise one’s potassium by 0.5 mEq. This usually is insignificant unless you’re already hyperkalemic and have evidence of end-organ involvement (EKG with peaked T waves and/or widened QRS complexes… think about ESRD patients). In fact, cardiac arrest minutes after sux administration is due to hyperkalemia until proven otherwise and should be treated accordingly with hyperventilation, bicarbonate, glucose/insulin, albuterol, etc.
Burn and denervation injuries cause an upregulation of NMJ acetylcholine receptors, so giving these patients a dose of sux will result in the depolarization of a LOT more receptors and subsequent release of MORE potassium. Ultimately, sux will diffuse out of the synaptic cleft and undergo metabolism by pseudocholinesterase in the plasma.
Now let’s move on to nondepolarizing NMBAs. These drugs are subdivided into aminosteroids (ie, rocuronium, vecuronium) and benzylisoquinoliniums (ie, atracurium, cisatracurium, mivacurium). Onset, duration, and metabolism differ among the aforementioned, but they’ve all competitive antagonists at the AChR. In other words, they prevent ACh from binding its receptor. As with all competitive antagonists, they can be overcome by increasing the amount of normal substrate. In this case, if we could boost Ach, more of it would find its way to AChR before a nondepolarizing NMBA. This is the premise behind “reversing” nondepolarizers with drugs like neostigmine or edrophonium – two AChE inhibitors. By inhibiting AchE, the enzyme that normally degrades ACh, you create a net surplus of ACh substrate to bind AChR.
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