Nursing Pharmacology Chapter 20:  Neuromuscular Blockers

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

    •  Other drugs' presence

  • 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 + duration of neuromuscular-blockade {nondepolarizing agents}-- decreasing neuromuscular blocker dose requirement

  •  Most prominent with:

    • Isoflurane (Forane)

    • Desflurane (Suprane)

    • Sevoflurane (Sevorane, Ultane)

  •  Intermediate effects with:

    • halothane (Fluothane)

  •  Least effect with:

    • Initrous 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 and 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: 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-blockade} recovery.

  • Quinidine gluconate (Quinaglute, Quinalan)

    • Increased blockade {for both nondepolarizing and depolarizing drugs}

      • Probable mechanism: attenuation of 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 (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) may enhanced neuromuscular-blockade by both depolarizing and nondepolarizing drugs

• Cyclosporine (Sandimmune, Neoral) administration may result in 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 in addition

  • 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.