Neuromuscular Blocking Agents

Neuromuscular Blocking Agents

Uses

Neuromuscular blocking agents are one of the most commonly used classes of drugs in the OR. They are used primarily as an adjunct to general anesthesia to facilitate endotracheal intubation and to relax skeletal muscle during surgery under general anesthesia.⁶⁶ Skeletal muscle relaxation optimizes the surgical field for the surgeon and prevents patient movement as a reflex response to surgical stimulation. Neuromuscular blocking agents are also used in the ICU to paralyze mechanically ventilated patients.⁶⁷ An important point to remember is that neuromuscular blocking agents have no known effect on consciousness or pain threshold. Consequently, adequate sedation and analgesia must be ensured when neuromuscular blocking agents are administered to ICU patients.

Mechanism of Action

When two molecules of Ach bind to the Ach subunits of the nicotinic cholinergic receptors located on the motor nerve end plate, the Ach receptor undergoes a conformational change that allows the influx of sodium and potassium into the muscle cell, the membrane depolarizes, and the muscle contracts. Neuromuscular blocking agents bind to these subunits and effectively block normal neuromuscular transmission. Two classes of neuromuscular blocking agents exist based on their mechanism of action: depolarizing and nondepolarizing. Succinylcholine, the only depolarizing neuromuscular blocking agent in clinical use today, acts like Ach to depolarize the membrane. Because succinylcholine is not metabolized as quickly as Ach at the neuromuscular junction, its action at the nicotinic receptor persists longer than Ach. Succinylcholine causes a persistent depolarization of the motor end plate because the sodium channels cannot reopen until the motor end plate repolarizes. As a result, sustained skeletal muscle paralysis occurs. The paralysis produced by depolarizing agents is preceded initially by fasciculations (transient twitching of skeletal muscle). The nondepolarizing neuromuscular blocking agents act as competitive antagonists to Ach at the Ach subunits of the nicotinic cholinergic receptors, thereby preventing Ach from binding and causing depolarization of the muscle membrane and muscle contraction.^66,68

Table 9-7 Classification of Neuromuscular Blocking Agents

Agent Type of Block Clinical Duration of Actiona Structure Atracurium (Tracrium) – Intermediate Benzylisoquinolinium Cisatracurium (Nimbex) – Intermediate Benzylisoquinolinium Pancuronium (Pavulon) – Long Steroidal Rocuronium (Zemuron) – Intermediate Steroidal Succinylcholine (Anectine, Quelicin) + Ultrashort Acetylcholine-like Vecuronium (Norcuron) – Intermediate Steroidal aTime from injection of agent to return to twitch height to 25% of control (time at which another dose of agent will need to be administered to maintain paralysis); in general, clinical duration of a standard intubating dose of ultrashort agents ranges from 3 to 5 minutes, intermediate agents from 30 to 40 minutes, and long agents from 60 to 120 minutes. +, depolarizing; –, nondepolarizing. Adapted from reference 69.

Monitoring Neuromuscular Blockade

In addition to clinical assessment (e.g., lack of movement) by the anesthesia provider and the surgeon, the degree of neuromuscular blockade produced by neuromuscular blocking agents is monitored by nerve stimulation with a peripheral nerve stimulator. Most commonly, the ulnar nerve is electrically stimulated, and the response of the innervated muscle, the adductor pollicis in the thumb, is visually assessed. Adequate neuromuscular blockade is present when the train-of-four (four electrical stimulations of 2 Hz delivered every 0.5 seconds) count is 1/4 or 2/4 (one or two visible muscle twitches out of a possible four twitches).⁶⁷

Classification

Neuromuscular blocking agents are commonly classified by the type of blockade produced (depolarizing vs. nondepolarizing), chemical structure (steroidal compound, Ach-like, benzylisoquinolinium compound), or duration of action (ultrashort, intermediate, long), as listed in Table 9-7.⁶⁹

Adverse Effects

The underlying mechanisms for the cardiovascular adverse effects of neuromuscular blocking agents are listed in Table 9-8 and include blockade of autonomic ganglia (hypotension), blockade of muscarinic receptors (tachycardia), and/or release of histamine from circulating mast cells (hypotension).^68,69,70 In general, the steroidal compounds exhibit varying degrees of vagolytic effect, whereas the benzylisoquinolinium compounds are associated with varying degrees of histamine release. Although not reported as a problem when used short term in the OR, the use of neuromuscular blocking agents in ICU patients for extended periods can result in prolonged neuromuscular blockade or acute quadriplegic myopathy syndrome, albeit infrequently.⁶⁸ Of the currently available neuromuscular blocking agents, cisatracurium (Nimbex) and vecuronium (Norcuron) are devoid of clinically significant cardiovascular effects and are the agents of choice for patients with unstable cardiovascular profiles.^66,68,69 Succinylcholine (Anectine, Quelicin) is associated with a significant number of adverse effects, including hyperkalemia; arrhythmias; fasciculations; muscle pain; myoglobinuria; trismus; phase II block; and increased intraocular, intragastric, and intracranial pressures.^69,70 Succinylcholine, like inhalational anesthetics, can trigger MH.⁶⁸ Of these adverse effects, bradycardia, hyperkalemia (which can trigger arrhythmias and cardiac arrest in patients at risk), and MH crisis are severe and potentially life-threatening reactions. Nevertheless, succinylcholine is still used today because of its rapid onset and ultrashort duration of action as well as its ability to be administered intramuscularly in children in an emergent situation when IV access has not been established.

Table 9-8 Causes of Cardiovascular Adverse Effects of Neuromuscular Blocking Agents

Agent Histamine Releasea Autonomic Ganglia Vagolytic Activity Sympathetic Stimulation Atracuriuma (Tracrium) ++ – – – Cisatracurium (Nimbex) – – – – Pancuronium (Pavulon) – Weak block ++ ++ Rocuroniumb (Zemuron) – – + – Succinylcholine (Anectine, Quelicin) + Stimulates – – Vecuronium (Norcuron) – – – – aHistamine release is dose and rate related; cardiovascular changes can be lessened by minimizing dose and injecting agent slowly. bProduces an increase in heart rate of approximately 18% with intubating dose of 0.6 mg/kg; effect usually transient and resolves spontaneously. + – ++, likelihood of developing the cardiovascular adverse effect relative to the other agents; –, no effect. Adapted from references 68, 69, 70.

Drug Interactions

Several drugs interact with neuromuscular blocking agents. The volatile inhalation agents potentiate the neuromuscular

blockade produced by nondepolarizing agents, thereby allowing a lower dose of the latter to be used when administered concomitantly. Other agents reported to potentiate the effects of neuromuscular blocking agents include the aminoglycosides, clindamycin, magnesium sulfate, quinidine, furosemide, lidocaine, amphotericin B, and dantrolene. Carbamazepine, phenytoin, corticosteroids (chronic administration), and theophylline antagonize the effects of neuromuscular blocking agents.^68,69 By appropriately monitoring the patient and dosing the neuromuscular blocking agent to effect, significant problems from drug interactions can be minimized.

Reversal of Neuromuscular Blockade

The action of neuromuscular blocking agents ceases spontaneously as plasma concentrations decline or when anticholinesterases (e.g., neostigmine, edrophonium, pyridostigmine) are administered. Anticholinesterases inhibit the enzyme acetylcholinesterase, which degrades Ach, and are used to reverse paralysis produced by nondepolarizing agents. Anticholinergic agents are coadministered (in same syringe) with the anticholinesterases to minimize other cholinergic effects (e.g., bradycardia, bronchoconstriction, salivation, increased peristalsis, nausea, vomiting) caused by the increase in Ach concentration. Atropine is routinely administered with edrophonium, and glycopyrrolate with neostigmine or pyridostigmine, to take advantage of similar onset times and durations of action.^66,67,69 Reversal of neuromuscular blockade, as a general rule, is not attempted until spontaneous recovery is well established. Before extubation, adequacy of reversal is assessed with the use of a peripheral nerve stimulator and by clinical assessment of the patient (e.g., ability to sustain head lift for 5 seconds).^69,70

A new reversal agent, sugammadex, is currently under development that may eliminate some of the issues currently seen with the anticholinesterases. Sugammadex, a modified cyclodextrin, encapsulates steroidal (e.g., rocuronium) neuromuscular blocking agents, thereby preventing them from acting at the neuromuscular junction. It produces a rapid recovery from neuromuscular blockade, even when administered during profound blockade, and does not appear to have any serious adverse effects.⁷¹

Table 9-9 Pharmacokinetic and Pharmacodynamic Parameters of Action of Neuromuscular Blocking Agents

Agent Cl (mL/kg/min) Vdss (L/kg) Half-Life (minutes) ED95 (mg/kg) Intubating Dosea,b (mg/kg) Onsetc (minutes) Clinical Duration of Action of Initial Dose (minutes) Atracuriumd (Tracrium) 5–7 0.2 20 0.2–0.25 0.4–0.5 2–3 25–30 Cisatracurium (Nimbex) 4.6 0.15 22 0.05 0.15–0.2 2–2.5 50–60 Pancuronium (Pavulon) 1–2 0.3 80–120 0.07 0.04–0.1 3–5 80–100 Rocuroniumd (Zemuron) 4.0 0.3 60–70 0.3 0.6–1.2 1–1.5 30–60 Succinylcholined (Anectine, Quelicin) 37 0.04 0.65 0.25 1.5 1 5–10 Vecuroniumd (Norcuron) 4.5 0.4 50–70 0.05–0.06 0.1 2–3 25–30 aDose when nitrous oxide-opioid technique is used. bIntermittent maintenance doses to maintain paralysis, as a general rule, will be approximately 20% to 25% of the initial dose. cTime to intubation. dAlso can be administered as a continuous infusion to maintain paralysis. Suggested infusion ranges under balanced anesthesia are atracurium, 4-12 mcg/kg/min; cisatracurium, 1-2 mcg/kg/min; rocuronium, 6-14 mcg/kg/min; succinylcholine, 50-100 mcg/kg/min; vecuronium, 0.8-2 mcg/kg/min. Cl, clearance; ED95, effective dose causing 95% muscle paralysis; Vdss, steady-state volume of distribution. Adapted from references 67, 68, 69, 70.

Pharmacokinetics and Pharmacodynamics

Rapid Sequence Induction

10. R.D., a 36-year-old man, ASA-I, is admitted through the ED for an emergency appendectomy. R.D. is otherwise healthy, has no drug allergies, and is currently taking no medications. All laboratory values are normal. Admission notes reveal that R.D. ate dinner approximately 2 hours earlier. Because of this, the anesthesia provider plans to perform a rapid sequence induction using the Sellick maneuver. Which neuromuscular blocking agent would be most appropriate for R.D.?

Rapid sequence induction is indicated for patients at risk for aspiration of gastric contents should regurgitation occur. Patients who have recently eaten (with a full stomach), morbidly obese patients, or patients with a history of gastroesophageal reflux are at risk for aspiration, as is the case for R.D. The goal of rapid sequence induction is to minimize the time during which the airway is unprotected by intubating the patient as fast as possible (e.g., within 60 seconds). In this technique, the patient is preoxygenated, after which an IV induction agent is administered, followed immediately by a neuromuscular blocking agent. Manual ventilation of the patient is not attempted after administration of these agents. Apnea occurs as the neuromuscular blocking agent takes effect; therefore, a neuromuscular blocking agent with as rapid an onset as possible is required to produce adequate intubating conditions as quickly as possible. The Sellick maneuver is often used during rapid sequence induction. It is performed by placing downward pressure on the cricoid cartilage, which compresses and occludes the esophagus and helps prevent passive regurgitation of gastric contents into the trachea. Intubation is then performed within 60 seconds.

Table 9-9 lists the onset times of normal intubating doses and other information pertaining to the use of neuromuscular blocking agents.^67,68,69,70 Succinylcholine has the fastest onset time, which makes it an appropriate agent to use in rapid sequence induction.⁷²

Because R.D. is an otherwise healthy man with no contraindications to the use of succinylcholine, this agent should be used.

Depolarizing Agent Contraindications

11. What would be your choice of a neuromuscular blocking agent if R.D. presents with a history of susceptibility to MH, and why?

Succinylcholine is contraindicated in patients with skeletal muscle myopathies; after the acute phase of injury (i.e., 5-70 days after injury) following major burns, multiple trauma, extensive denervation of skeletal muscle, or upper motor neuron injury; in children and adolescents (except when used for emergency tracheal intubation or when the immediate securing of the airway is necessary); and in patients with a hypersensitivity to the drug.^66,69 Succinylcholine can also trigger MH and is absolutely contraindicated in MH-susceptible patients.⁷³

The nondepolarizing neuromuscular blocking agents are safe to use in MH-susceptible patients.⁷⁴ Rocuronium (Zemuron) has the fastest onset time of the nondepolarizing agents, although it is slightly slower than succinylcholine.⁷⁰ The onsets of the remaining intermediate and long duration agents can be shortened by increasing the dose, which not only results in a faster onset of action but also prolongs the duration of action. Rocuronium's time to maximum blockade, for example, can be reduced to 60 seconds with an initial dose of 1.2 mg/kg (vs. a normal initial dose of 0.6 mg/kg). Increasing the dose from 0.6 mg/kg to 1.2 mg/kg, however, will prolong the clinical duration from approximately 30 minutes to at least 60 minutes.⁷⁵ Rocuronium, with its rapid onset of action, would be a suitable alternative to succinylcholine in R.D.'s case. Its longer clinical duration of action could be a concern if the airway cannot be secured immediately or if the procedure is shorter than the duration of an intubating dose of rocuronium. Because this procedure will last longer than the duration of muscle relaxation provided by the intubating dose of rocuronium, this is not a concern.

Routes of Elimination

12. M.M., a 70-year-old woman, ASA-IV, is scheduled to undergo a 2-hour GI procedure. Pertinent laboratory findings are aspartate aminotransferase (AST), 272 U/L (normal, 5-45 U/L); alanine aminotransferase (ALT), 150 U/L (normal, 5-37 U/L); BUN, 40 mg/dL (normal, 8-21 mg/dL); serum creatinine (SrCr), 1.8 mg/dL (normal, 0.5-1.1 mg/dL); albumin, 2.6 g/dL (normal, 3.5-5.0 g/dL); and bilirubin, 0.74 mg/dL (normal, 2-18 mg/dL). Which neuromuscular blocking agent would you recommend for M.M.?

Table 9-10 Elimination of Neuromuscular Blocking Agents

Agent Renal Hepatic Biliary Plasma Atracurium (Tracrium) 10%   NS Hofmann elimination, ester hydrolysis Cisatracurium (Nimbex) NS   NS Hofmann elimination Pancuronium (Pavulon) 80% 10% 5%–10%   Rocuronium (Zemuron) 10%–25% 10%–20% 50%–70%   Succinylcholine (Anectine, Quelicin)       Plasma cholinesterase Vecuronium (Norcuron) 15%–25% 20%–30% 40%–75%   NS, not significant. Adapted from references 66, 67, and 70.

[SI units: AST, 4.5 µkat/L; ALT, 2.5 µkat/L; BUN, 14.28 mmol/L; SrCr, 159 µmol/L; albumin, 26 g/L; bilirubin, 12.7 mol/L]

When selecting a neuromuscular blocking agent, one of the factors that must be considered is the patient's renal and hepatic function. Neuromuscular blocking agents often depend on the kidneys and liver for varying amounts of their metabolism and excretion (Table 9-10).^66,67,70 Some agents, however, are primarily metabolized by plasma cholinesterase (pseudocholinesterase), Hofmann elimination (a nonbiological process that does not require renal, hepatic, or enzymatic function), and/or nonspecific esterases.

Hofmann elimination is a pH- and temperature-dependent process unique to atracurium (Tracrium) and cisatracurium (Nimbex). One of the products produced by Hofmann elimination is laudanosine, a CNS stimulant in high concentrations. Laudanosine undergoes renal and hepatic elimination. Due to the short-term use of atracurium and cisatracurium in the OR, accumulation of laudanosine with resultant seizure activity is not a concern, even in patients with end-stage renal failure.⁷⁶ Because plasma cholinesterase levels may be decreased in patients with renal or hepatic dysfunction, the duration of action of succinylcholine could be prolonged. The increased duration of action of succinylcholine in patients with low levels of normal plasma cholinesterase is not clinically significant. Atypical plasma cholinesterase can increase the duration of action of succinylcholine significantly.⁷⁷

Unchanged neuromuscular blocking agents and their metabolites are excreted by the renal or biliary routes. The duration of action of the renally eliminated agent, pancuronium, will be increased in patients with renal failure. Vecuronium's duration of action can be increased in patients with liver disease, particularly when larger doses (0.2 mg/kg) are administered, reflecting impaired metabolism or excretion rather than termination of effect by redistribution.⁷⁸ Although the main route of elimination of rocuronium is hepatobiliary, the duration of action of rocuronium can be significantly prolonged in chronic renal failure.⁷⁹

Because M.M. has evidence of both significant renal and hepatic impairment, cisatracurium or atracurium would be appropriate choices for a neuromuscular blocking agent because their properties are not altered significantly by renal and hepatic failure. Furthermore, because these agents have an intermediate duration of action, they can easily be used in a 2-hour procedure. The availability of generic atracurium makes this agent a more economic choice; however, the greater propensity of atracurium to cause histamine release with resultant hypotension makes cisatracurium the most appropriate choice in this 70-year-old, ASA-IV patient.

Posted in: General Care,Perioperative Care