Anesthesia Pharmacology:  Neuromuscular Blocking Agents and Muscle Relaxants

Pharmacodynamics

• Neuromuscular blocking drug pharmacodynamic characteristics determined by measuring

  •  Speed of onset.

  •  Duration of neuromuscular blockade.

• Clinical method of determining neuromuscular-blockade properties

  •  Determine skeletal muscle response evoked by supramaximal electrical stimulation using a peripheral nerve stimulator.

  •  Typically: single twitch response to 1Hz (adductor pollicis muscle - ulnar nerve stimulation).

• Potency determination comparing neuromuscular-blocking drugs

  •  Dose required to suppress 95% of the single twitch response (ED₉₅).

    •  Potency determined in the presence of nitrous oxide-barbiturate-opioid anesthesia.

    •  Volatile anesthetics will significantly decreased ED₉₅.

• Neuromuscular blocking drugs: sequence of muscles affected

  •  Small, rapidly moving muscles (fingers, eyes) before diaphragm.

    •  Recovery in reverse order.

  •  IV neuromuscular blocker injection (nondepolarizing) to an awake patient:

    1.  Initial difficulty in focusing & weakness in mandibular muscles.

    2.  Then ptosis, diplopia and dysphagia.

  •  Consciousness and sensorium: unaffected, even with complete neuromuscular block.

• Blockade onset

  •  More rapid, less intense effect at laryngeal muscles (vocal cords) then at adductor pollicis (peripheral muscle example).

    •  More rapid laryngeal muscle onset is probably due to a more rapid drug plasma: drug muscle equilibration.

    •  Reduced initial intensity of effect at laryngeal muscle (fast fibers) follows from the requirement for more complete receptor blockade for effect then for muscles mainly composed of slow fibers, e.g. adductor pollicis.

  •  Neuromuscular diaphragm blockade:

    • Requires 2 times the dose required for adductor pollicis muscle blockade.

    • Adductor pollicis monitoring: poor indicator of cricothyroid muscle (laryngeal) relaxation.

    • Facial nerve stimulation with orbicularis oculi muscle response monitoring is a better reflection of neuromuscular diaphragm blockade onset.

    • Orbicularis oculi muscle monitoring is preferable to monitoring adductor pollicis as indicator of laryngeal muscle blockade.

      •  

        orbicularis oculi

        "The orbicularis oculi is the thin sphincter muscle of the eyelids. It is innervated by temporal and zygomatic branches of the facial nerve.", Image courtesy of Vesalius, used with permission

      •  

        Adductor Pollicis

        Image courtesy of EatonHand

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        Cricothyroid Muscle

        Cricothyroid Muscle: Vesalius Site, used with permission

Clinical Uses

• Primary uses of neuromuscular-blocking drugs

  1. Skeletal muscle relaxation facilitating tracheal intubation.

  2. Skeletal muscle relaxation to improve intraoperative surgical conditions.

• Dose guidelines

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

    • Laryngospasm: effectively treated with succinylcholine (Anectine).

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

• Neuromuscular-blocking drugs:  no CNS depression; no analgesia therefore they do not substitute for anesthetic agents.

• Other clinical uses

  • In managing patients requiring mechanical ventilation (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.

• Rationale for Monitoring Neuromuscular Blockade

  1. NMJ blocking drugs are dangerous in that they interfere with respiration.

  2. Depression of ventilation is a significant cause of anesthesia-related morbidity/mortality which is an important factor is the extent of residual neuromuscular blockade.

  3. Narrow drug safety margin which in molecular terms may correspond to a narrow range of receptor occupancy.

  4. Significant patient-to-patient response variabilty to the same dosage.

  5. Interactions between NMJ blocking drugs with other agents.