Mechanism of action

Nondepolarizing agents cause muscle paralysis by affecting the postsynaptic cholinergic receptors at the neuromuscular junction. By either blocking the channel externally, occupying the channel pore, or affecting the receptor from the internal side of the muscle membrane, these agents reduce the frequency of channel opening. Nondepolarizing agents compete against endogenous Ach for receptor occupancy. Muscle contraction does not occur if enough sites are blocked by these agents. This is illustrated in Figure 18-3, in which the drug (ND) occupies and then blocks the postsynaptic site at the neuromuscular junction. With nondepolarizing agents, depolarization of the postsynaptic membrane becomes a function of the amount of drug and the amount of Ach located around the receptor. In other words, because nondepolarizing agents act by competitive inhibition, their effect is dose related: Larger doses overcome the effects of Ach and block more receptors. The receptor blockade by nondepolarizing agents can be reversed by making more Ach available to compete for receptor sites. Inhibitors of AchE, an enzyme that breaks down Ach, can be used to reverse the competitive blockade. Neostigmine is an example of a cholinesterase inhibitor.

Pharmacokinetics of nondepolarizing agents

Nondepolarizing NMBAs chemically resemble Ach. These agents have a positively charged quaternary ammonium group (NH₄⁺) that binds to the negatively charged Ach receptor. Nondepolarizing agents are poorly lipophilic and do not penetrate well into fat tissue or across the blood-brain barrier. Also, these agents are poorly absorbed from the gastrointestinal tract and therefore must be given intravenously to allow for rapid onset of neuromuscular blockade.

The onset of paralysis and the duration of action of nondepolarizing blockers vary widely among members of this group of drugs. Tubocurarine, one of the first agents in this class, has a maximal paralyzing action that lasts 35 to 60 minutes, and complete recovery may take several hours. Pancuronium, pipecuronium, and doxacurium have durations of action similar to tubocurarine, and all of these agents are considered to be long-acting NMBAs. Atracurium, cisatracurium, vecuronium, and rocuronium are redistributed more rapidly and have shorter durations of action than tubocurarine. These agents are considered intermediate-acting NMBAs.¹

As previously noted, the magnitude of effect, rate of onset of maximum blockade, and duration of action of NMBAs is dose-dependent; this is illustrated in Table 18-2 for the drug rocuronium when used in adults. Factors such as advanced age generally increase the length of neuromuscular blockade activity. Hepatic or renal failure can cause decreased clearance, increased blood levels, and prolonged duration of action for agents metabolized and eliminated by the liver and kidney.

Metabolism

Neuromuscular blockade diminishes and transmission is restored after a single bolus dose once the agent is cleared off the receptor site via redistribution to the rest of the body. When normal conduction returns, 75% of Ach receptors may still be occupied by blocker; this explains why additional boluses of NMBA seem more potent and have a markedly prolonged duration of action. After prolonged infusion or repeated boluses, metabolism and excretion provide the mechanism for removal of the blocking agent from the neuromuscular junction.

Tubocurarine and doxacurium are minimally metabolized, and approximately 60% of an injected dose is excreted by the kidneys in urine. The remainder is excreted in bile. Pancuronium is also eliminated primarily by the kidneys. Pancuronium also undergoes some hepatic metabolism with production of an active metabolite that is eliminated by the kidneys.

Alternatively, vecuronium is an agent metabolized primarily by the liver. The metabolite of vecuronium also has activity and relies on the kidneys for excretion. All of these agents can accumulate in renal failure and cause prolonged paralysis when given in sufficient doses.

Atracurium and cisatracurium differ from other NMBAs regarding route of elimination. These agents are partly inactivated by a spontaneous degradation mechanism that is dependent on the pH of blood and temperature of the body. This nonenzymatic breakdown is termed Hofmann degradation. In addition to Hofmann degradation, these agents are rapidly converted to less active metabolites by circulating plasma esterases that cause hydrolysis of the compounds. Because of the lack of liver and kidney elimination, atracurium and cisatracurium are optimal choices for patients with hepatic or renal failure.

Atracurium further differs from cisatracurium because it has a breakdown product of Hofmann degradation called laudanosine. Laudanosine, which is eliminated primarily by the kidneys and is slowly metabolized by the liver, has a long half-life and can cross the blood-brain barrier. Laudanosine has been associated with neurostimulatory effects. CNS excitation and seizures should be considered as a possible complication, especially in patients receiving atracurium who have impaired renal function or liver failure.² Cisatracurium has less laudanosine production than atracurium and is considered more potent. The risk of further brain injury from seizures in patients with poor intracranial compliance (e.g., severe head injury) may make these drugs poor choices in these patients. Seizure activity might be masked by these agents, complicating assessment of the patient.

Mivacurium is one of the shortest acting NMBAs available (effect of 10 to 20 minutes in usual doses). It is unique among nondepolarizing agents in that it is eliminated by plasma cholinesterase, similar to succinylcholine, a depolarizing agent. Metabolism of mivacurium is independent of kidney or liver function.³ However, patients with renal failure or liver dysfunction may have decreased levels of plasma cholinesterase, prolonging the duration of action of mivacurium. The effects of organ failure on NMBA duration are illustrated in Table 18-3.

It is important to understand that the nondepolarizing NMBAs also competitively block Ach receptors at the autonomic ganglia, producing cardiovascular side effects on heart rate and blood pressure. They may cause a vagolytic effect, which produces tachycardia, and an increase in mean arterial pressure by promoting an increase in norepinephrine, a potent vasoconstrictor.³ Pancuronium has the greatest potential to cause cardiovascular side effects, especially tachycardia and hypertension. Agents such as vecuronium, doxacurium, and cisatracurium have minimal effects on heart rate and blood pressure.

Reversal of nondepolarizing blockade

Muscle paralysis caused by nondepolarizing NMBAs can be reversed by use of cholinesterase inhibitors such as neostigmine. Neostigmine inhibits the cholinesterase that would normally break down Ach. This action allows for more Ach to be available at the neuromuscular junction to compete with and displace the blocker from receptor sites. Other cholinesterase inhibitors include edrophonium and pyridostigmine. Edrophonium is rapid-acting but also has the shortest duration of action. Pyridostigmine has a slower onset and is the longest acting; it is often used to treat myasthenia gravis and can be given orally. Neostigmine is intermediate in onset and duration of action. Table 18-5 summarizes these agents with recommended doses to reverse neuromuscular blockage produced by the nondepolarizing agents.⁴

Because the reversing agents increase the levels of Ach, they also increase the effects of Ach at parasympathetic ganglia, producing cholinergic autonomic side effects. Major side effects of these agents include severe bradycardia and salivation. To reduce these adverse effects, agents such as atropine or glycopyrrolate are also given in conjunction with cholinesterase inhibitors. As vagolytic and anticholinergic agents, atropine and glycopyrrolate, respectively, prevent bradycardia, increased salivation, and hyperperistalsis associated with excessive Ach.⁵

Mechanism of action

The initial action of depolarizing NMBAs is to open sodium channels and depolarize the postsynaptic muscle membrane in the same manner as Ach. Depolarizing agents are resistant to the effects of AchE, allowing for a persistent and longer duration at the neuromuscular junction. Because depolarization lasts longer, the membrane is unable to repolarize, resulting in flaccid muscles.⁵ This is illustrated in Figure 18-4, in which molecules of succinylcholine (S) have occupied two Ach receptors, each opening a pore and allowing the local membrane to become permeable to sodium. If enough receptors are activated, depolarization occurs and is maintained until succinylcholine leaves the receptors. Further stimulation and contraction of the muscle fiber is impossible until the drug is removed by redistribution and metabolism.

In contrast to any agent discussed so far, succinylcholine has a unique feature of blockade activity. On initial bolus dose, succinylcholine depolarizes the membrane similar to Ach. The initial depolarization causes uncoordinated skeletal muscle contractions, referred to as fasciculations. Because succinylcholine remains at the neuromuscular junction longer than Ach, depolarization is prolonged, and flaccid paralysis occurs. This is referred to as phase I block. After prolonged use or large doses of succinylcholine, the type of blocking activity changes. Instead of showing depolarization characteristics, activity resembles the block produced by the nondepolarizing agents. This is referred to as phase II block or desensitization block. Phase II block involves a “fading” phenomenon in which stimulation of the motor neuron is poorly sustained and paralysis is prolonged. Although cholinesterase inhibitors can reverse phase II block, they may decrease the clearance of succinylcholine and enhance further blockade. The occurrence of a desensitization block must be considered as a possibility in patients with prolonged paralysis after succinylcholine administration. The fear of this “dual” mechanism limits the use of succinylcholine in repeated doses or as a continuous infusion.

Metabolism

Succinylcholine has a very short duration of action; this is mostly due to its rapid hydrolysis by plasma cholinesterase in blood. Succinylcholine is metabolized to succinylmonocholine, which provides weak nondepolarizing activity. Succinylmonocholine is thought to account for some of the reason why repeated doses of succinylcholine produce prolonged blockade.

Reversal

No agents are available for the reversal of succinylcholine. Use of cholinesterase inhibitors such as neostigmine may delay the elimination of succinylcholine, resulting in an even more prolonged depolarization and slower recovery of muscle activity.

Adverse effects

Succinylcholine produces many side effects, several of which can be life-threatening. The significance of these side effects may be of more concern in the ICU than during routine operating room use. Most adult patients have a sympathomimetic response causing tachycardia and an increase in blood pressure. Repeated bolus doses of succinylcholine may produce vagal responses, including bradycardia and hypotension. This side effect is seen more often in children. Succinylcholine also provokes histamine release, resulting in bronchospasm and hypotension in susceptible individuals.⁵

Muscle pain and soreness similar to myalgias are common after the administration of succinylcholine. A relationship between the pain and muscle fasciculations has been implicated but not confirmed. Some practitioners administer a small dose of a nondepolarizing blocker (e.g., 10% of the intubating dose) before giving succinylcholine to reduce fasciculations and pain.⁶ This pretreatment is often referred to as defasciculation. In patients receiving a nondepolarizing agent to prevent fasciculations, higher doses of succinylcholine are needed for complete paralysis because pretreatment reduces the effectiveness of succinylcholine. This practice is considered controversial because increased doses of succinylcholine are required, and pretreatment may cause partial paralysis, necessitating urgent intubation under nonideal conditions.⁷ Muscle fasciculations can also cause an increase in serum potassium and creatinine phosphokinase, an effect that is also reduced but not totally eliminated by pretreatment.

Succinylcholine can cause an efflux of potassium from muscle cells, causing serum potassium to increase by 0.5 to 1.0 mEq/L in normal individuals.⁶ Patients with spinal cord injury or upper motor neuron lesions, thermal injuries, and severe trauma, including closed head injury, are at a higher risk of developing life-threatening hyperkalemia if succinylcholine is administered. Effects of severe hyperkalemia include arrhythmias and cardiac arrest.

Succinylcholine-induced fasciculations can increase intraocular pressure and intragastric pressure. Patients are at risk of extrusion of intraocular contents and aspiration of gastric contents. These conditions may be partially prevented by defasciculation.

Succinylcholine can dangerously increase intracranial pressure in patients with cerebral edema and head trauma by a mechanism that is not well understood.⁶ One of the most serious complications that can occur with succinylcholine is malignant hyperthermia. Malignant hyperthermia is caused by a genetic defect of muscle metabolism. It is a potentially fatal hypermetabolic state of skeletal muscles. An uncontrolled release of calcium from the sarcoplasmic reticulum of muscles occurs, resulting in a host of harmful effects. The clinical features can manifest as intractable spasm of the jaw muscles, rigidity, increased oxygen demand, severe hyperthermia, metabolic acidosis, and tachycardia. Malignant hyperthermia is treated with dantrolene, an agent that blocks the release of intracellular calcium from the sarcoplasmic reticulum. Early recognition and treatment are key to ensuring a full recovery.⁸

Precautions and risks

All patients receiving NMBAs should receive additional care measures to decrease the negative effects that can be associated with the use of these agents. Proper eye care should be a standard of care for all patients receiving NMBAs. Normally, eye blinking lubricates and cleans the corneas. NMBAs cause paralysis of the eyelid muscles, which can result in corneal drying and ulceration. Appropriate eye lubrication and light taping of the eyes can prevent corneal abrasions. Eyes should be checked frequently.

With complete paralysis, the cough reflex is inhibited. Frequent suctioning along with appropriate sedation and analgesia to prevent pain and discomfort during suctioning is necessary. Retention of secretions is thought to increase the incidence of nosocomial pneumonia in patients receiving neuromuscular blockade for a prolonged period. Elevating the head can reduce the risk of aspiration, which is a risk factor for ventilator-associated pneumonia (VAP).

Support equipment must be closely monitored, including constant observation for extubation and ventilator malfunction. Alarm systems to detect hypoventilation and hypoxemia are the standard of care when NMBAs are used.

Patients receiving prolonged therapy with NMBAs are at risk for developing prolonged skeletal muscle weakness that persists long after the NMBA is discontinued. Myopathy, which may take months to resolve, may be associated more often with steroid-structured agents such as vecuronium and pancuronium (see Table 18-1 for classification), especially when they are combined with corticosteroids such as prednisone. Daily physical therapy with range of motion exercises may lessen the potential for muscle atrophy or wasting in patients receiving prolonged NMBA therapy. Patients given an NMBA should also be turned frequently to prevent the formation of pressure sores and decubitus ulcers. The risk of developing a deep vein thrombosis (DVT) is increased in these patients because of their immobility, making DVT prophylaxis imperative.

Use of sedation and analgesia

Of all adjunctive therapies patients may receive, it is essential to provide adequate sedation and analgesia for ventilated patients receiving a blocking agent. NMBAs cause muscle paralysis without affecting consciousness or the perception of pain. In 1947, a classic experiment that established this fact was performed by Smith and colleagues,¹⁰ in which Smith allowed himself to be paralyzed with tubocurarine. He reported full awareness during the paralysis, including sensations of choking while he was unable to swallow and shortness of breath even though he was being adequately ventilated. Neuromuscular blockade is unthinkable without proper sedation and pain control to prevent the nightmare of paralysis with full consciousness and sensory perception. Although many sedative and analgesia agents can cause hemodynamic instability, it is inappropriate to reduce or discontinue sedation and analgesia while a patient is paralyzed to address hemodynamic instability. Because clinical signs of restlessness, distress, and anxiety are lost with neuromuscular blockade, continuous cardiac monitoring is necessary, and vital signs should be assessed closely. Tachycardia, hypertension, diaphoresis, and lacrimation are physiologic responses that can indicate anxiety caused by inadequate sedation or lack of pain control.

For short procedures including endotracheal intubation, a sedative that has amnestic properties should be administered. In surgery, a sedative and an analgesic agent are recommended for all patients. For patients in the ICU, a sedative should be administered on a continuous basis before initiation of neuromuscular blockade. Continuous analgesia should also be used secondary to poor assessment capabilities for pain and the discomfort associated with the constant suctioning and the endotracheal tube itself. Sedatives that have amnestic effects include propofol (Diprivan), lorazepam (Ativan), and midazolam (Versed). It is important to realize that these agents do not provide pain control. Analgesics commonly used for pain control include fentanyl (Sublimaze), hydromorphone (Dilaudid), and morphine. In many situations, deep sedation with continuously infused sedatives and analgesics may prevent the need for a blocking agent in the ICU. Other suggestions for sedation and analgesia are presented in Chapter 20.

Interactions with neuromuscular blocking agents

Several clinical conditions and medications may alter the effect of an administered NMBA. Because different blocking drugs may act at different locations on the Ach receptor–pore complex (e.g., external, in the pore, intercellular), combination with certain agents may be synergistic and potentiate blockade. Advantage has been taken of this potential to produce a combination of relaxant drugs that gives adequate relaxation with fewer (cardiovascular) side effects. Examples include combining inhaled anesthetics, such as halothane or isoflurane, with a nondepolarizing NMBA. The inhaled anesthetics decrease the sensitivity of the neuromuscular junction to Ach, potentiating blockade. The dosage of the NMBA can be reduced, perhaps decreasing side effects. The problem with this approach has been the unpredictability of the duration of relaxation, which tends to be extremely prolonged, especially after repeated mixture administrations.

Some classes of drugs and other conditions have neuromuscular blocking effects themselves; these may be additive, antagonistic, or synergistic with NMBAs. Aminoglycoside antibiotics are often administered to critically ill patients in the ICU. Aminoglycosides produce blockade by inhibiting the release of Ach from presynaptic nerve endings and, to a lesser extent, by blocking the postsynaptic receptor. Agents such as phenytoin, azathioprine, and theophylline antagonize neuromuscular blockade.

Clinical factors such as acidosis, hypokalemia, hyponatremia, hypocalcemia, and hypermagnesemia all potentiate neuromuscular blockade. Alkalosis and hypercalcemia are known to inhibit the effects of blockade. Factors affecting the activity of NMBAs are listed in Table 18-6.