Anesthesia Pharmacology:  Neuromuscular Blocking Agents and Muscle Relaxants

Non-depolarizing Blocking Drugs

• Mechanism of Action: Nondepolarizing neuromuscular-blocking drugs

  •  Combination with nicotinic, cholinergic receptors.

  •  Greater than 80%-90% receptor blockade required for neuromuscular transmission failure.

    •  Reflects wide safety margin as well as basis for neuromuscular blockade clinical monitoring.

• Cardiovascular Effects:  nondepolarizing neuromuscular blockers:

  • Secondary to:

    •  Histamine/other vasoactive substance release.

      • Effects mediated by cardiac muscarinic cholinergic receptors.

      •  Effects mediated by autonomic nicotinic cholinergic receptors.

  • Factors responsible for cardiovascular effect variation between patients:

    •  Basal autonomic state.

    •  Preoperative medications.

    •  Choice of agent for anesthesia maintenance.

    •  Presence of other drugs.

  • Clinical Significance:  Cardiovascular effects of nondepolarizing agents are usually not significant

  • "Autonomic Margin of Safety": difference between dosage producing neuromuscular-blockade and dosage producing circulatory effects

    •   Relatively low autonomic safety margin.

      • Pancuronium (Pavulon): e.g. ED₉₅ pancuronium (Pavulon) dosage which produces neuromuscular-blockade highly likely to produce cardiovascular effects (particularly chronotropic changes).

    •  Relatively high autonomic safety margin.

      •  Vecuronium (Norcuron), rocuronium (Zemuron), cisatracurium (Nimbex): wide safety margins, i.e. neuromuscular-blocking doses are much less than doses required to influence cardiovascular status.

  • Myopathy associated with Critical Illness

    •  Definition: patients on nondepolarizing neuromuscular blockers to facilitate mechanical ventilation during prolonged illness may show skeletal muscle weakness following recovery

      •  Critical illness may be associated with acute injury (multi-organ failure), or asthma.

      •  Moderate to severe quadriparesis (+/- areflexia) may be exhibited.

      •  Weakness time-course: unpredictable.

      •  Duration: weeks/months following discontinuation of nondepolarizing agent.

      •  Probably more common with aminosteroid agent (e.g. pancuronium (Pavulon) or vecuronium (Norcuron)); has also been observed with atracurium (Tracrium).

        •  Possible increased risk: pre-treatment with glucocorticoids.

Factors which alter patient responses to nondepolarizing agents

Gender may also influence duration of action;  combinations of nondepolarizing neuromuscular-blocking agents may result in different effects than agents used separately

• Volatile Anesthetics: interactions with neuromuscular, nondepolarizing agents

  • Dose-dependent increases in magnitude and duration of neuromuscular-blockade (nondepolarizing agents) thus decreasing neuromuscular blocker dose requirement.

    •  Most prominent with:

      • Isoflurane (Forane).

      • Desflurane (Suprane).

      • Sevoflurane (Sevorane, Ultane).

    •  Intermediate effects with:

      • halothane (Fluothane).

    •  Least effect with:

      • nitrous oxide-opioid combinations.

  • Differential effects based on duration of action of neuromuscular blocking drug:

    • Less reduction in blocker dosage as a result of volatile anesthetic use with intermediate-duration agents:

      • Atracurium (Tracrium).

      • Vecuronium (Norcuron).

      • Rocuronium (Zemuron).

      • Cisatracurium (Nimbex).

    • Greater reduction in blocker dosage as a result of volatile anesthetic use are required with long acting agents:

      • Pancuronium (Pavulon).

      • Doxacurium (Nuromax).

      • Pipecuronium (Arduan).

    •  Advantage of using intermediate-duration neuromuscular-blocking agents:

      • Reduced effects on dosage by volatile anesthetics allows "more predictable degree" of skeletal muscle block (in the absence of exact information about brain anesthetic partial pressures)

    •  Mechanism of volatile anesthetic effect on nondepolarizing neuromuscular-blocking drugs:possible causes  

      1.  Anesthetic-induced CNS depression -- with secondary decrease in skeletal muscle tone

      2.  Decreased postjunctional synaptic membrane sensitivity to depolarization

         • Volatile anesthetics decreased twitch response (50% reduction) at higher MAC values, i.e. {1.25-1.75 MAC enflurane (Ethrane); 2.8-3.7 MAC halothane (Fluothane)}

• Antibiotic effects on neuromuscular-blockade (nondepolarizing agents)

  • Some antibiotics increase the effect of nondepolarizing neuromuscular blockers.

  • Aminoglycoside antibiotics are most likely to produce this increased blocking effect.

• Local Anesthetics (low-dose): enhancement of blockade by nondepolarizing agents

  • Higher local anesthetic doses may cause complete neuromuscular blockade.

  • Local anesthetics may:

    • Inhibit acetylcholine release

    • "Stabilize" postsynaptic membrane (making depolarization more difficult)

    • Direct muscle fiber depression.

• Cardiac antiarrhythmic agents/nondepolarizing neuromuscular blocker interactions

  • Lidocaine (Xylocaine) (IV): may increase preexisting blockade.

    • Clinical context: lidocaine (Xylocaine) administration during general anesthesia (protocol includes neuromuscular-blockad) recovery.

  • Quinidine gluconate (Quinaglute, Quinalan)

    • Increased blockade  for both nondepolarizing and depolarizing drugs

      • Probable mechanism: reduced acetylcholine release.

      • Clinical Context: quinidine gluconate (Quinaglute, Quinalan) administration during recovery from general anesthesia (protocol includes neuromuscular blockers).

• Diuretics:  furosemide (Lasix)

  • Increases neuromuscular-blocking by nondepolarizing agents

  • Probably due to reduced acetylcholine release.

  • Related issues:

    • Hypokalemia associated with chronic diuretic use:

      • Decreases pancuronium (Pavulon) dose requirements.

      • Increases neostigmine (Prostigmin) dosage required for neuromuscular blockade antagonism.

• Magnesium

  • Accentuates neuromuscular-blockade by nondepolarizing drugs; to a lesser degree also accentuates blockade by succinylcholine (Anectine).

  • Interaction may be more pronounced with magnesium and vecuronium (Norcuron) than with other agents.

  • Clinical Context:

    • Observed as enhancement of neuromuscular blockade (nondepolarizing agent mediated) when magnesium is administered to patients treated with magnesium for pregnancy-caused hypertension (e.g. toxemia of pregnancy).

• Phenytoin (Dilantin)

  • Patients chronically treated with phenytoin (Dilantin) are resistant to neuromuscular-blockade produced by nondepolarizing agents.

  • Mechanism: pharmacodynamic (higher neuromuscular blocker-plasma concentration are required to produce a given level blockade in patients treated with phenytoin (Dilantin) than to produce same level of blockade in untreated patients).

• Lithium: (used to treat bipolar disorder):possible enhanced neuromuscular-blockade by both depolarizing and nondepolarizing drugs

• Cyclosporine (Sandimmune, Neoral):  possible prolongation of neuromuscular-blockade by nondepolarizing drugs

• Ganglionic blocking drugs (e.g., mecamylamine (Inversine)) may affect duration of neuromuscular-blockade by

  • Reduced skeletal muscle blood flow.

  • Plasma cholinesterase activity.

  • Reduced post-junctional, nicotinic cholinergic receptor sensitivity.

• Hypothermia

  • Increased neuromuscular-blockade duration (pancuronium (Pavulon) and vecuronium (Norcuron)).

    • Mechanism: decreased hepatic inactivating enzyme activity (temperature dependency); decreased biliary and renal drug clearance.

  •  Increased neuromuscular junctional sensitivity to pancuronium.

  •  Increased duration of atracurium (Tracrium) action (also reduces infusion rate necessary to maintain stable neuromuscular-blockade).

    • Atracurium (Tracrium) effect: probably caused by decreased rate of Hoffmann elimination and reduced ester hydrolysis.

• Burns

  •  Prolonged resistance to nondepolarizing neuromuscular blockers:

    • Starts about 10 days following injury.

    • Peaks about 40 days later.

    • Declines after about two months (may last considerably longer > one-year).

  • Mechanism:  probably pharmacodynamic (higher plasma drug concentration required to cause a given extent of twitch suppression compared to similar extent in non--burn patients)

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; Miller, R.D., Skeletal Muscle Relaxants, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 434-449.