Fig. 13.1
Physiology of neuromuscular transmission. (a) At the neuromuscular junction, where calcium influx causes release of Ach. Ach then binds to the postsynaptic nicotinic Ach receptors at the motor end-plate. (b) Binding of two Ach molecules opens up the ion channel leading to an action potential, which causes muscle contraction (Ach-acetylcholine)
The nicotinic acetylcholine receptor on the postsynaptic membrane requires two acetylcholine molecules to bind to each alpha site prior to its activation. Once the two molecules are bound, a conformational change ensues resulting in activation of the associated ion channel. The resultant influx of sodium causes membrane depolarization and subsequent muscle contraction. The sodium channel closes and the acetylcholine molecules dissociate. Degradation of the remaining acetylcholine molecules occurs by acetylcholinesterase. When a neuromuscular blocker is given, the normal interaction of acetylcholine with the nicotinic receptor is attenuated, and muscle contraction is inhibited.
Classification of Muscle Relaxants
There are two main types of muscle relaxants: depolarizing and nondepolarizing. Depolarizing muscle relaxants physically resemble acetylcholine and are therefore direct agonists on the acetylcholine receptor (noncompetitive antagonism of acetylcholine). They cause initial depolarization of the skeletal muscle membrane and muscle contraction, followed by flaccid paralysis. This process is due to the higher affinity of the drug for the acetylcholine receptor as compared with acetylcholine. The depolarizing muscle relaxant remains bound after muscle contraction as it is metabolized slowly and not by acetylcholinesterase (which metabolizes acetylcholine). The bound drug blocks subsequent native acetylcholine stimulation. In addition, the postsynaptic membrane must repolarize before the sodium channels will open in response to another stimulus. The classic example of a depolarizing neuromuscular blocker is succinylcholine. It is the only clinically used depolarizing agent at present.
The second type of muscle relaxants is the nondepolarizing type. Nondepolarizing agents are competitive antagonists of acetylcholine at the postsynaptic membrane. The amount of acetylcholine present in the synaptic space, as well as number of acetylcholine receptors upregulated, will affect a nondepolarizing neuromuscular blockade. There are several nondepolarizing muscle relaxants that are routinely used for pharmacologic paralysis, and each can be subclassified by its chemical structure, duration of action, or potency. For each drug, an equivalent amount of receptors (approximately 500,000) need to be blocked to induce akinesia, which is easily obtained by doses that are routinely administered clinically. However, a less-potent drug administered in a higher relative dose produces a more rapid onset. Rocuronium, for example, is an intermediate-acting nondepolarizer that has the advantage of rapid onset.
Neuromuscular blocking agents do not cause unconsciousness, analgesia, or amnesia. Therefore, ensuring that a patient is appropriately anesthetized prior to drug administration is prudent to avoid patient awareness. In addition, all skeletal muscles throughout the body will be affected, including those involved in respiration. Therefore, the patient’s airway must be maintained at the time of administration either by bag-mask ventilation, laryngeal mask airway placement, or endotracheal intubation. Furthermore, standard monitors as defined by the American Society of Anesthesiologists (nerve stimulator) must be available and employed.
Specific Muscle Relaxants
Depolarizing Muscle Relaxant: Succinylcholine
Chemical structure: Succinylcholine is the only and most widely used and readily available depolarizing neuromuscular relaxant. Its molecular structure directly explains its mechanism of action in that it consists of two acetylcholine molecules joined through the acetate methyl group. The molecule is able to activate both alpha sites on the acetylcholine receptor and does so with greater affinity than acetylcholine. As a result, succinylcholine first induces muscle contraction and then blocks any further neurotransmitter–receptor interaction leaving the skeletal muscle in a state of flaccid paralysis. Visible contractions known as fasciculations are typically present prior to total pharmacologic paralysis.
Metabolism: Succinylcholine is rapidly cleared in the plasma by nonspecific plasma esterases. Only a small fraction of the administered dose reaches the neuromuscular junction. There are two ways in which the effects of succinylcholine can be prolonged: first, hypothermia and medications that affect plasma cholinesterase activity prolong the duration of succinylcholine (Table 13.1); second, patients who have a deficiency of butyrylcholinesterase (pseudocholinesterase), one of the nonspecific esterases, will also have prolonged paralysis after administration of succinylcholine. The butyrylcholinesterase enzyme activity can be determined clinically by calculating the dibucaine number. Dibucaine, an amide local anesthetic, selectively inhibits normal plasma cholinesterase with minimal effects on atypical cholinesterase. It causes 80 % inhibition of normal butyrylcholinesterase cholinesterase and 20 % inhibition of the abnormal enzyme. This response is predictable and can be used to determine whether a patient is homozygous for normal enzyme (80 %), heterozygous (60 %), or homozygous for abnormal enzyme (20 %). Patients with deficiency of this enzyme, who have received succinylcholine causing prolonged muscle relaxation, can be treated with mechanical ventilation (until muscle function returns to normal) and possible administration of fresh frozen plasma.
Table 13.1
Drugs that prolong duration of action of succinylcholine
Reduce plasma cholinesterase activity (prolong succinylcholine/mivacurium) | Oral contraceptives MAOIs Glucocorticoids Pancuronium |
Irreversibly inhibit plasma cholinesterase activity | Echothiophate Organophosphates |
Dosage and uses (Table 13.2 ): Muscle paresis occurs within 0.8–1.4 min following administration, which makes succinylcholine an ideal drug for rapid sequence induction (RSI). The duration of action is approximately 6–11 min. This rapid offset time is clinically useful for short case durations, potentially difficult airways, or patients who are prone to hypoxia. Other uses include electroconvulsive therapy, need for emergent intramuscular administration, and laryngospasm rescue.
Table 13.2
Dosing and administration of succinylcholine
Adult intubating dose | 0.5–1.5 mg/kg |
Short procedure | 0.3–1.1 mg/kg over 10–30 s |
Long procedure | 0.3–1.1 mg/kg followed by 0.04–0.07 mg/kg maintenance dose |
Pediatric intubating dose | 2.0 mg/kg |
Rapid sequence intubation | 1.5 mg/kg |
Intramuscular | 3–4 mg/kg (max dose 150 mg) |
Electroconvulsive therapy | 0.5–1.0 mg/kg |
Side effects: Common side effects of succinylcholine administration include elevation in plasma potassium concentration (ranging from 0.5 to 1 mEq/L), postoperative myalgias from muscle fasciculations, and transient increases in intragastric, intracranial, and intraocular pressures. With regard to intragastric and intracranial pressure, transient increases appear to be directly related to muscle fasciculations and can be reduced by pretreatment with a “defasciculating dose” of a nondepolarizing agent and intravenous lidocaine as appropriate. However, intraocular pressure and its transient increase with succinylcholine administration may occur independent of fasciculations. The significance of this minor pressure elevation is often debated, and avoiding succinylcholine in ophthalmologic trauma cases may minimize any further protrusion of vitreous humor from the eye. Less common side effects of succinylcholine include masseter muscle spasms, malignant hyperthermia, and anaphylaxis.
Contraindications to the use of succinylcholine include acute trauma, severe burns, myopathy, extensive degenerative neuropathy, hyperkalemia, prolonged paralysis with previous use, or family history of malignant hyperthermia. Succinylcholine has a black box warning due to acute hyperkalemic rhabdomyolysis leading to dysrhythmias in children with undiagnosed myopathies. It can also cause bradycardia, especially in the pediatric population.
Nondepolarizing Muscle Relaxants
Nondepolarizing muscle relaxants can be classified by their chemical structure: aminosteroids, benzylisoquinolines, and the new isoquinolines. This distinction can be used to explain their side effects. The aminosteroid agents have vagolytic properties causing an increase in heart rate, mean arterial pressure, and cardiac output upon administration. The benzylisoquinolines stimulate the release of histamine and have secondary cardiovascular effects including hypotension, tachycardia, and facial flushing. More recently, the isoquinoline compounds have also shown histamine release in early trials comparable to the benzylisoquinoliniums.
Newer nondepolarizing muscle relaxants within the aminosteroid class have been developed that have reduced side effect profiles. With the exception of cisatracurium, the benzylisoquinolines have not shown a similar improvement in side effect profiles.
Rocuronium (Aminosteroid)
Rocuronium is an intermediate acting aminosteroid nondepolarizing muscle relaxant. It is less potent than other intermediate acting agents and has a rapid onset of 0.9–1.7 min. These properties allow it to be used as an alternative to succinylcholine when RSI is desired (Table 13.3). Duration of action is 36–73 min making it more useful for cases that are of medium to long duration.
Table 13.3
Dosing and administration of rocuronium
Intubating dose | 0.6–1 mg/kg |
RSI | 0.6–1.2 mg/kg |
Defasciculating dose | 0.06 mg/kg or 1/10 the intubating dose |
Maintenance dose | 0.1–0.2 mg/kg |
Continuous infusion | 10–12 mcg/kg/min initially followed by 4–16 mcg/kg/min titrated to desired level of paralysis (1 twitch) |
Rocuronium has few side effects, although hypersensitivity reactions and anaphylaxis have been reported. Vagolysis is minimal, and hemodynamic stability is maintained at doses up to four times the ED95 (0.3 mg/kg). Rocuronium is excreted unchanged through the biliary system with a small percentage excreted unchanged in urine. The duration of action is prolonged in the presence of hepatic impairment.
Vecuronium (Aminosteroid)
Vecuronium is an intermediate acting aminosteroid nondepolarizing muscle relaxant. It has a higher potency than rocuronium with an onset time of 2–3 min. Its duration of action is 40–45 min, making it useful for cases of medium to long duration (Table 13.4). Vecuronium has a few side effects, including hypersensitivity and rare anaphylactic reactions. Similar to rocuronium, it has minimal cardiovascular effects at clinically used doses.
Table 13.4
Dosing and administration of vecuronium
Intubating dose | 0.08–0.1 mg/kg |
Maintenance dose | 0.01–0.015 mg/kg |
Continuous infusion | 0.8–1.2 mcg/kg/min |
Vecuronium is metabolized in the liver and excreted through the biliary system. Therefore, hepatic disease will prolong its duration of action. Additionally, during metabolism, deacetylation produces a partially active metabolite. This active metabolite has less clinical impact in the operating room than with prolonged administration in the intensive care unit (ICU). Studies that examine ICU patients paralyzed long term with vecuronium suggest a higher incidence of prolonged blockade and critical illness polyneuropathy. Prolonged effects for typical use in the operating room are seen only with severe renal impairment (creatinine clearance < 10 mL/min).
Pancuronium (Aminosteroid)
Pancuronium is a long acting aminosteroid nondepolarizing muscle relaxant with high potency. Its onset time is 3–4 min and the duration of action is 85–100 min. Pancuronium exhibits the vagolytic effects characteristic of the aminosteroid class. Patients develop tachycardia and mild increases in cardiac output. It also has the potential to cause hypersensitivity reactions. It is deacetylated to a limited extent in the liver. It can be used in cases of long duration (cardiac bypass) in the absence of renal failure, but its use has been largely replaced by the intermediate acting agents. Pancuronium is excreted unchanged in the urine. Its use should be avoided for prolonged administration or in the setting of renal impairment. Dosage: 0.06–0.1 mg/kg (intubating dose), 0.01 mg/kg (maintenance).
Atracurium (Benzylisoquinoline)
Atracurium is a benzylisoquinoline compound that consists of 10 stereoisomers. It has an intermediate onset (3 min) and duration of action (45 min). In clinical practice, it has been replaced by cisatracurium, due to the same favorable traits and fewer side effects (Table 13.6). Atracurium is metabolized by Hoffman elimination and plasma esterases. Hoffman elimination is an enzyme-independent hydrolysis that relies on physiologic pH and temperature. Laudanosine is a byproduct of this metabolic process and can cross the blood brain barrier. In animal studies, this metabolite has been shown to induce epileptiform activity in high concentrations. Atracurium can stimulate histamine release and cause associated tachycardia, hypotension, or bronchospasm. Dosage: 0.2–0.3 mg/kg (intubating dose), 0.08–0.1 mg/kg (maintenance).
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