Anesthesia Pharmacology:  Neuromuscular Blocking Agents and Muscle Relaxants

Clinical Pharmacology

• Primary uses of neuromuscular-blocking drugs

  1. Skeletal muscle relaxation facilitates tracheal intubation.

  2. Skeletal muscle relaxation improves intraoperative surgical conditions.

  • Dose guidelines:

    •  Facilitation of tracheal intubation may require 2 x ED₉₅ dose of nondepolarizing muscle relaxant.

      • Laryngospasm can be effectively treated with succinylcholine (Anectine).

    •  Optimal intraoperative conditions include 95% single twitch response suppression.

  • Neuromuscular-blocking drugs are not associated with CNS depression;

    • These drugs do not provide analgesia; therefore, they do not substitute for anesthetic agents

  • Other clinical uses:

    • Managing patients who require mechanical ventilation, typically in the intensive care environment.

      •  Adult respiratory distress syndrome.

      •  Tetanus.

      •  Suppression of spontaneous respiration.

  Miller, R.D., Skeletal Muscle Relaxants, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 434-449. Stoelting, R.K., "Neuromuscular-Blocking Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 182-219. White, P. F. "Anesthesia Drug Manual", W.B. Saunders Company, 1996.

Reversal of non-depolarizing blockers: Antagonist-assisted reversal of neuromuscular blockade produced by nondepolarizing neuromuscular-blocking agents

• Antagonist-assisted neuromuscular-blockade reversal:

  • Edrophonium (Tensilon), neostigmine (Prostigmin), or pyridostigmine (Mestinon). 

    • These agents are effective because they increase acetylcholine availability at the neuromuscular junction, following  acetylcholinesterase inhibition.

      • Physostigmine (Antilirium) is not used because dosage requirement is excessive.

  • Anticholinesterase agents are usually administered during spontaneous neuromuscular-blockade recovery

    • Recovery rate is the sum of:

      • (1) Spontaneous recovery from the blocking drug and

      • (2) Activity of the pharmacologic antagonist (anticholinesterase drugs).

    • Therefore: pharmacologic antagonism is more effective for short-or intermediate-acting neuromuscular-blocking drugs (undergoing plasma hydrolysis or Hofmann elimination) compared to long-acting nondepolarizing neuromuscular-blocking agents

  • Special Considerations: use of muscarinic antagonists with anticholinesterases in Reversal of Neuromuscular Blockade

    • Reversal of nondepolarizing neuromuscular-blockade depends only on nicotinic cholinergic effects of anticholinesterases agents

      • Minimizing muscarinic receptor-mediated effects of anticholinesterase drugs is beneficial and accomplished by a concurrent administration of atropine or glycopyrrolate (Robinul) (antimuscarinics)

    •  Antimuscarinic agent should have a more rapid onset than the anticholinesterase drugs thus reducing drug-induced bradycardia

      •  If edrophonium (Tensilon) (0.5 mg/kg) is used; atropine 7 μg/kg is appropriate

      •  A higher dose atropine (10-15 μg/kg) has been recommended, particularly if opioid-based maintenance anesthetic has been used

      •  If neostigmine is used (slower onset of action compared edrophonium (Tensilon)), then atropine or glycopyrrolate (Robinul) and may be administered as the antimuscarinic agent.

        • Concurrent administration of these drugs results in an initial tachycardia because of atropine's more rapid onset

  • Factors influencing the speed and extent of neuromuscular blockade reversal by anticholinesterase agents:

    •  Intensity neuromuscular-blockade when reversal is initiated (train-of-four visible twitches).

    •  Which nondepolarizing neuromuscular-blocking drug is being reversed is a factor.

      • Edrophonium (Tensilon) is less effective than neostigmine in reversing deep neuromuscular blockade (twitch height < 10% of control) produced by continuous atracurium (Tracrium), vecuronium (Norcuron), or pancuronium (Pavulon) infusions.

      • Edrophonium (Tensilon), probably better than neostigmine (Prostigmine for reversing atracurium (Tracrium) blockade.

      • Neostigmine (Prostigmin), probably better than edrophonium (Tensilon) for reversing vecuronium (Norcuron) blockade.

    •   Prevention/inhibition of anticholinesterase-mediated antagonism of neuromuscular-blockade

      •  Possible factors favoring this effect include:

        • Certain antibiotics.

        • Hypothermia.

        • Respiratory acidosis (PaCO2 >50 mm Hg.

        • Hypokalemia/metabolic acidosis.

    • Reversal of phase II block (following prolonged/repeated succinylcholine (Anectine)): may be reversed with edrophonium (Tensilon) or neostigmine (Prostigmin) in patients with normal plasma cholinesterase.

      •  In patients with atypical plasma cholinesterase, phase II block reversal may not be reliable, requiring mechanical ventilation until blockade subsides.

Stoelting, R.K., "Anticholinesterase Drugs and Cholinergic Agonists", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 224-237.

• Neuromuscular blockade: depolarizing agent followed by nondepolarizing agent (Succinylcholine (Anectine), then nondepolarizing agent)

  • Clinical Context

    1. Initial administration of succinylcholine (Anectine){1 mg/kg, IV} supports tracheal intubation.

    2. Subsequent administration nondepolarizing agent.

    • Greater neuromuscular-blockade in this case (even if evidence of succinylcholine (Anectine) effect has significantly diminished) .

      • Counterintuitive effect: since the drug effects should be antagonistic.

    • Duration of action of nondepolarizing agents (atracurium (Tracrium) or vecuronium (Norcuron))is not affected; just the initial increased response

    • At lower succinylcholine (Anectine) doses (0.5 mg/kg) there is no initial enhancement of vecuronium (Norcuron) mediated neuromuscular-blockade.

Stoelting, R.K., "Neuromuscular-Blocking Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 182-219

• Combinations of Neuromuscular-blocking agents

  • Neuromuscular-blockade enhancement due to drug combinations:

    •  Example-- Different major site of action (postsynaptic vs. presynaptic).

      •  Pancuronium (Pavulon) + metocurine (Metubine Iodide) or tubocurarine.

        • Shorter duration than with pancuronium (Pavulon) alone.

      •  Vecuronium (Norcuron) + tubocurarine.

    •  Combinations of nondepolarizing agents results in the same degree of blockade with smaller dose of each drug.

      • Benefit includes fewer dose-related side effects.

        •  Example: BP/heart rate effects of pancuronium (Pavulon) + metocurine (Metubine Iodide) < with pancuronium (Pavulon) monotherapy.

Stoelting, R.K., "Neuromuscular-Blocking Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 182-219

• Gender and neuromuscular-blockade

  • Differential drug sensitivity due to gender:

    •  Pancuronium (Pavulon).

    •  Vecuronium (Norcuron).

    •  Rocuronium (Zemuron).

  • Women:

    •  Require 22% less vecuronium (Norcuron) than men to obtain the same degree of neuromuscular junctional blockade.

    •  30% more sensitive to rocuronium (Zemuron) than men.

  • Clinical significance:

    • Normal rocuronium (Zemuron) dose should be reduced in women compared to men.

  • Possible mechanism: men have a greater skeletal muscle mass percentage, thus requiring a higher neuromuscular-blocking dosage.

Stoelting, R.K., "Neuromuscular-Blocking Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 182-219