Skeletal muscle relaxants

Skeletal muscle relaxants are drugs that block the neuromuscular junction (NMJ) by binding to acetylcholine (ACh) receptors located on it. This process leads to paralysis of all skeletal muscles, starting with the small muscles of the face and paralyzing the diaphragm last. Succinylcholine, the only depolarizing NMJ-blocking drug, binds to ACh receptors and causes a prolonged depolarization of the motor end plate, resulting in flaccid paralysis. Nondepolarizing NMJ-blocking drugs bind to the ACh receptors and prevent depolarization of the motor end plate (depolarization block). These drugs are subdivided into short-acting, intermediate-acting, and long-acting agents. Based on the duration of action, NMJ-blocking drugs are useful adjuncts to anesthetic agents and are, therefore, used for laryngeal intubation, artificial ventilation, or intraoperative skeletal muscle relaxation. All NMJ-blocking drugs cause respiratory arrest (apnea) by paralyzing the diaphragm and intercostal muscles, requiring patients to be artificially ventilated. Succinylcholine is a known trigger of malignant hyperthermia and can also cause hyperkalemia, postoperative muscle pain, and cardiac arrhythmias. Nondepolarizing drugs that cause histamine release (atracurium) or have sympathomimetic properties (pancuronium) can cause bronchospasms and tachycardia. Patients who have received NMJ-blocking drugs must be monitored either clinically (e.g., ability to lift head/legs or open eyes) or with a peripheral nerve stimulator to assess the degree of skeletal muscle paralysis. Antagonists to nondepolarizing drugs (neostigmine, pyridostigmine, sugammadex) are used to reverse the NMJ block. Inadequate reversal can cause respiratory complications. Succinylcholine does not have a specific antagonist.

Depolarizing and nondepolarizing muscle relaxants only target Nm nicotinic receptors at the NMJ; they do not target autonomic Nn receptors.

Depolarizing muscle relaxants

• Succinylcholine (suxamethonium)
  • Binds to ACh receptors → depolarization of cell membrane at motor end plate → skeletal muscle fasciculations
  • Acetylcholinesterase cannot break down succinylcholine → persistent depolarization of the motor end plate → unresponsiveness of the motor end plate to subsequent nerve impulses (depolarized block) → flaccid paralysis of the skeletal muscles
  • Within 5–10 minutes, plasma cholinesterases metabolize succinylcholine (a short-acting muscle relaxant).
    • A family of enzymes that catalyze the breakdown of choline esters (e.g., acetylcholine, succinylcholine).
    • Includes acetylcholinesterase and butyrylcholinesterase.
    • Patients with atypical plasma cholinesterase: prolonged paralysis
  • Succinylcholine has no antagonist.
  • Neuromuscular monitoring
    • Phase I blockade
      • Persistent depolarization of the acetylcholine receptors of the neuromuscular junction
      • There is currently no antidote.
      • Phase I blockade is potentiated by the effects of cholinesterase inhibitors.
      • Train-of-four stimulation shows an equal decrease in the amplitude of all 4 muscle twitches.
    • Phase II blockade
      • Despite continued depolarization by succinylcholine, the postsynaptic membrane repolarizes and becomes desensitized,; (i.e., resistant to depolarization by acetylcholine) leading to prolonged muscle relaxation.
      • Cholinesterase inhibitors may reverse the effects of phase II blockade.
      • Train-of-four stimulation shows a fade-off in the amplitude of the muscle twitch.

Nondepolarizing muscle relaxants

• Compete with ACh to bind with the (nicotinic) ACh receptors at the motor end plate (competitive antagonists) → prevents depolarization of the motor end plate (nondepolarization block)
• Antagonists
  • Neostigmine, pyridostigmine, and edrophonium are usually coadministered with anticholinergics, such as atropine or glycopyrrolate, to counter muscarinic effects like bradycardia, nausea, and bronchospasm.
  • Sugammadex: a selective relaxant binding agent and rapid-acting antidote for rocuronium and vecuronium
• Assessment of anesthetic depth and possible continued postsurgical effect requires neuromuscular monitoring.
  • Train-of-four stimulation shows a fade-off in the amplitude of the muscle twitch

Paralysis affects the small muscles of the face first, progresses to the extremities and trunk, and affects the intercostal muscles and diaphragm last.
References:^{[8][9][10][11]}

Depolarizing NMJ blocker (succinylcholine)

• Hyperkalemia
  • Mechanism: depolarization of large muscle groups → efflux of potassium ions into the extracellular space
  • Succinylcholine is contraindicated in case of hyperkalemia or in conditions associated with a high-risk of hyperkalemia, including:
    • Burn injuries
    • Rhabdomyolysis
    • Demyelinating disorders (e.g., Guillain-Barré syndrome, multiple sclerosis, ALS) ^[12][13]
    • Stroke
    • Spinal cord injury
• Hypercalcemia
• Postoperative muscle pain due to muscle fasciculations (see “Effects” above)
• Prolonged muscle paralysis, respiratory depression and/or apnea in patients with a congenital deficiency of plasma cholinesterase
• Malignant hyperthermia
• Cardiac arrhythmias
• Raised intragastric pressure → emesis

Nondepolarizing NMJ blockers

• Adverse effects due to histamine release (atracurium, mivacurium): rash, bronchospasm, hypotension
• Tachycardia (pancuronium)
• Respiratory depression or apnea
• Critical illness myopathy

References:^{[8][9][11][14][15][16][17][18][19]}

We list the most important adverse effects. The selection is not exhaustive.

• Skeletal muscle relaxants are used as adjuncts to anesthetic agents:
  • Laryngeal intubation and rapid sequence induction of anesthesia : drugs with fast onset of action (e.g., succinylcholine, rocuronium)
  • Artificial ventilation (during anesthesia or in intubated ICU patients)
  • Abdominal muscle relaxation during laparotomy
    • Prevents the patient from moving during surgery
    • Facilitates physical manipulation (e.g., surgical incisions, moving the patient)

References:^[20]

• Patients who have been given NMJ blockers should be monitored.
• Clinical assessment: ability of the patient to spontaneously open the eyes, lift the head/legs, or the presence of spontaneous ventilation help determine the degree of paralysis
• Neuromuscular monitoring: objectively determines degree of muscle paralysis with the help of a peripheral nerve stimulator
  • Method: train-of-four (TOF) response
    • Four electric stimuli are administered at intervals of 0.5 seconds (2 Hz).
    • The number of twitches of the adductor pollicis muscle is counted.
    • The test can be repeated as needed but no less than 10 seconds after the previous one to allow recovery of the motor endplate.
  • Interpretation
    • 0 twitches indicates profound NMJ block
    • 1–2 twitches indicate a partial block.
    • 1 twitch per electric stimulus indicates no NMJ block.
  • Inadequate reversal (postoperative residual neuromuscular weakness) can lead to upper airway obstruction (pharyngeal muscle weakness) and inadequate ventilation