FIG. 23.1 Myoneural junction at resting state.
The nicotinic receptors are further classified as either N1 or N2 receptors. The N1 receptors are located at the presynaptic cleft and influence the release of acetylcholine. The N2 receptors are situated on the postsynaptic cleft in the neuromuscular junction and, when occupied by acetylcholine, open their channels to allow the flow of ions down the cell membrane, thus resulting in the skeletal muscle contraction. The nondepolarizing neuromuscular blocking agents such as pancuronium (Pavulon) produce a block of the N2 receptor and thus cause an inability of the channel to conduct ions, which results in skeletal muscle paralysis. Extrajunctional nicotinic receptors are located throughout the skeletal muscles. Their activity is normally suppressed by normal neural activity. However, when a patient has prolonged sepsis, inactivity, denervation, or burn trauma in the skeletal muscles, there is a proliferation of these extrajunctional nicotinic receptors. As a result, these patients usually have an exaggerated hyperkalemic response when succinylcholine is administered.1
The muscarinic receptors are also subdivided into M1 and M2 receptors. M1 receptors are located in the autonomic ganglia and the central nervous system, and M2 receptors are located in the heart and salivary glands. Atropine and glycopyrrolate (Robinul) block both the M1 and the M2 receptors.2
Acetylcholine is formed in the body of the nerve cell and cytoplasm of the nerve terminal and is stored in the small membrane-enclosed vesicles for subsequent release. A quantum is the amount of acetylcholine stored in each vesicle and represents approximately 10,000 molecules of acetylcholine. The presynaptic membrane contains discrete areas of specialization thought to be transmitter release sites. These presynaptic active zones lie directly opposite the N2 cholinergic receptors, which are located on the postsynaptic membrane. This alignment ensures that the acetylcholine quickly diffuses directly to the N2 receptors on the postsynaptic membrane and in a high concentration. The N2 receptor, which responds to the neurotransmitter acetylcholine, is a glycoprotein that is an integral part of the postsynaptic membrane of the neuromuscular junction (see Fig. 23.1). New evidence indicates that a positive feedback mechanism also exists at the neuromuscular junction. Acetylcholine has a presynaptic action; therefore, acetylcholine receptors are located on the presynaptic membrane. This positive feedback mechanism enhances the mobilization and release of acetylcholine. Finally, the enzyme that hydrolyzes acetylcholine is acetylcholinesterase, which is located in the neuromuscular junction.3
The initiation of skeletal muscle contraction occurs as a result of applying a threshold stimulus. An action potential travels down the axon, causing depolarization of the presynaptic membrane. As a result of this depolarization, the membrane permeability for calcium ions is increased, and the calcium enters or influxes into the presynaptic membrane. Calcium acts to unite the vesicle to the presynaptic membrane and causes the rupture of that coalesced membrane, thus releasing acetylcholine into the fluid of the synaptic cleft (Fig. 23.2).
The acetylcholine molecules released from the nerve terminal into the synaptic cleft are subject to two main processes: (1) attachment to N2 cholinergic receptors located on the postsynaptic membrane, which leads to an opening of calcium channels resulting in the movement of sodium into the region and generating an end plate potential (EPP), and (2) attachment of acetylcholine to the presynaptic nicotinic receptor, which enhances the release of more acetylcholine. When enough EPPs are generated, an action potential is propagated and spreads throughout the muscle. Causing a change in the ionic permeability of the muscle sarcolemma. This process results in the release of calcium from the sarcoplasmic reticulum with a resultant increase in free calcium concentration in the muscle fiber. The process of excitation-contraction (E-C) coupling then takes place within that skeletal muscle cell. The physiologic outcome of E-C coupling is the contraction of the skeletal muscle. The increased concentration of calcium in the muscle fiber leads to an interaction between troponin-tropomyosin and actin. This interaction causes the active sites on actin to be exposed interacting with myosin and sliding together, thus resulting in muscle contraction. This sliding of actin and myosin is sometimes called the ratchet effect.3 The contraction of the muscle fibers is terminated when calcium is pumped back into the sarcoplasmic reticulum of the muscle fibers. The calcium is stored in the sarcoplasmic reticulum for use when another action potential is generated.
Regulation and control of skeletal muscle contraction are also based on the enzymatic breakdown of acetylcholine. As previously discussed, the stimulus must be strong enough to release enough acetylcholine to bind to the postsynaptic N2 cholinergic receptor. This process of competition between the postsynaptic N2 receptor and acetylcholinesterase allows for some degree of regulation of the excitation process and for the recovery of the muscle cell membrane. The molecules of acetylcholine either diffuse in a random fashion to the N2 receptor or are destroyed by acetylcholinesterase. As the concentration gradient begins to decrease because of the destruction of acetylcholine by acetylcholinesterase, the N2 receptor gives up its acetylcholine, which is then destroyed, and the skeletal muscle relaxes. A small portion of the acetylcholine can escape the acetylcholinesterase in the synaptic cleft and migrate into the extracellular fluid and, from there, into the plasma. Acetylcholine within the plasma is then destroyed by plasma acetylcholinesterase or pseudocholinesterase, which is produced in the liver.1
Pharmacologic Overview of Commonly Used Muscle Relaxants
With the anatomy and physiology of neuromuscular transmission as background, the principal pharmacologic actions of the nondepolarizing and depolarizing skeletal muscle relaxants are discussed. Table 23.1 presents a pharmacologic overview of the commonly used skeletal muscle relaxants.
The prototypical nondepolarizing skeletal muscle relaxants are pancuronium and vecuronium (Norcuron). Pancuronium is an inhibitor of acetylcholine, is chemically viewed as two acetylcholine-like fragments, and has a bulky inflexible nucleus. This drug attaches to the N2 cholinergic receptors on the postsynaptic membrane and prevents depolarization. The skeletal muscle relaxant vecuronium has a chemical structure similar to a monoquaternary compound. The principal pharmacologic action of this drug is to block the postsynaptic N2 cholinergic receptor; in this way, it stops acetylcholine from binding to the receptor, which results in a competitive neuromuscular blockade. The nondepolarizing skeletal muscle relaxants also block the presynaptic cholinergic receptor and thus result in binding of the acetylcholine, preventing activation of the positive feedback mechanism.4
The pharmacologic actions of the nondepolarizing skeletal muscle relaxants can be reversed with anticholinesterase drugs such as neostigmine. In effect, these drugs increase the quantum of acetylcholine at the postsynaptic membrane by preventing destruction of the acetylcholine by acetylcholinesterase. This process promotes a more effective competition by the released acetylcholine with the nondepolarizing skeletal muscle relaxant occupying the N2 receptor. Because of the increased availability and mobilization of the acetylcholine, the concentration gradients favor acetylcholine and remove the nondepolarizing agents from the N2 receptor with the resultant return to normal contraction of the skeletal muscle.
The principal depolarizing skeletal muscle relaxant is succinylcholine (Anectine, Sucostrin). The molecular structure of this drug resembles two back-to-back acetylcholine molecules. Because of this structure, succinylcholine has the same effects as acetylcholine. Like acetylcholine, the succinylcholine molecule has a positively charged quaternary ammonium portion. This positively charged molecule is attracted by electrostatic action to the negatively charged N2 receptor. When the succinylcholine attaches to the receptor, a brief period of depolarization occurs manifested by transient muscular fasciculations. Succinylcholine also attaches to and activates the presynaptic acetylcholine receptor. This activation has an immediate effect of increased mobilization of acetylcholine in the motor nerve terminals, which explains why fasciculations are commonly observed after the administration of an intravenous bolus of succinylcholine. After the depolarization of the N2 receptor takes place, succinylcholine promotes and maintains the receptor in a depolarized state and prevents repolarization. Succinylcholine has a brief duration of action because of its rapid hydrolysis of the succinylcholine by the enzyme pseudocholinesterase, which is contained in the liver and plasma. The actions of succinylcholine cannot be pharmacologically reversed.5
Nondepolarizing Neuromuscular Blocking Agents
Long-Acting Nondepolarizing Skeletal Muscle Relaxants
Pancuronium Bromide
Pancuronium bromide (Pavulon) was introduced into clinical anesthesia in 1972. This drug has shown value (particularly in terms of its safety, cardiovascular stability, and skeletal muscle relaxant properties) and is still used today, particularly for cardiac anesthesia.
Chemically, pancuronium bromide is a biquaternary aminosteroid related to the androgens; however, it has no hormonal activities. Pancuronium is reversible with an anticholinesterase agent, such as neostigmine, administered in combination with an anticholinergic such as glycopyrrolate or atropine. This particular skeletal muscle relaxant has been shown clinically to be extremely difficult to reverse pharmacologically within the first 20 to 30 minutes after injection. In the PACU, if a skeletal muscle relaxant is needed for a short duration, another reversible skeletal muscle relaxant, such as vecuronium or atracurium, should be chosen. Approximately 30 to 40 minutes after injection, pancuronium is easily reversed with the combination of an anticholinesterase and anticholinergic drug preparation. Pancuronium is best suited for surgical procedures that last more than 1 hour; it is well suited for patients who need complete muscle relaxation with continuous mechanical ventilation. The dose for adults is approximately 0.08 to 0.1 mg/kg body weight. Relaxation lasts 60 to 85 minutes. If relaxation is necessary past this initial period, subsequent doses should be decreased to 0.02 to 0.04 mg/kg body weight.
Pancuronium bromide does not produce ganglionic blockade, but it does block the M2 cholinergic receptors in the heart. Consequently, when pancuronium bromide is administered, a slight 10% to 15% increase in heart rate is observed.6 Pancuronium activates the sympathetic nervous system by promoting the release of norepinephrine and blocking its uptake at the adrenergic nerve endings. After administration of this drug, a modest increase in mean arterial pressure and cardiac output is produced. Although isolated cases of histamine release have been reported, pancuronium can probably be used in patients who have a marginal allergy history. Pancu-ronium bromide is compatible with anesthetic agents used clinically and is safe for use in most patients when a nondepolarizing skeletal muscle relaxant is indicated. However, pancuronium bromide is not indicated when a nondepolarizing muscle relaxant is to be used with caution. In addition, pancuronium should not be used in patients who are undergoing chronic digitalis therapy because cardiac dysrhythmias have been reported. Finally, myocardial ischemia has been reported in patients with coronary artery disease when pancuronium is used. This ischemia is probably associated with the cardiac acceleration properties of the drug.
Pancuronium bromide should be avoided in patients with a history of myasthenia gravis. It is contraindicated in patients with true renal disease because a major portion of the drug is excreted unchanged in the urine. This agent is contraindicated in patients known to be hypersensitive to it or to the bromide ion.
Intermediate-Acting Nondepolarizing Skeletal Muscle Relaxants
Vecuronium Bromide
Vecuronium (Norcuron) is a nondepolarizing skeletal muscle relaxant with a more rapid onset of action and a shorter duration of action than pancuronium. Actually, vecuronium is pancu-ronium without the quaternary methyl group in the steroid nucleus. Because of this structural difference, vecuronium has no effect on heart rate, arterial pressure, autonomic ganglia, or the alpha and beta adrenal receptors. The potency of vecuronium is equal to or slightly greater than that of pancuronium. Vecuronium has little or no cumulative effect. Although a portion of vecuronium is metabolized, most of the drug is excreted unchanged in the urine and bile. However, the neuromuscular blockade produced by vecuronium is not prolonged by renal failure. The duration of neuromuscular blockade produced by vecuronium is increased in patients with impaired hepatic function. Of clinical interest is that vecuronium, like atracurium, is less influenced by general inhalation anesthetics than is pancuronium.7 The pharmacologic action of vecuronium is easily reversed with the combination of an anticholinesterase and an anticholinergic drug.
The onset of action of vecuronium is between 2.5 and 3 minutes, with the normal dose of 0.08 mg/kg intravenously. Because of the rapid onset of action, vecuronium can be used in certain circumstances for rapid sequence intubation. In this instance, a doubling of the dose of vecuronium to 0.2 mg/kg can be used to achieve intubation conditions within 45 seconds to 2 minutes. Vecuronium is primarily used for intraoperative skeletal muscle relaxation to improve surgical exposure and facilitation of mechanical ventilation in the critical care setting. Long-term infusions of this drug in the critical care setting can result in a prolonged recovery and an inability to pharmacologically reverse vecuronium because the metabolites are still in active form. If corticosteroid therapy is being used for patients with multiorgan failure, this prolonged effect can be exacerbated.
The dose is 0.05 to 0.2 mg/kg for skeletal muscle paralysis, and the onset is 1 to 3 minutes with a duration between 30 and 90 minutes. Prolonged skeletal muscle relaxing effects can be prolonged with patients with hepatic disease. No significant cardiac effects for this drug have been reported.
Atracurium Besylate
Atracurium (Tracrium) is a nondepolarizing skeletal muscle relaxant that offers an advantage over other skeletal muscle relaxants in that it does not depend on renal or hepatic mechanisms for its elimination. In fact, this quaternary ammonium compound breaks down in the absence of plasma enzymes through what is called Hofmann elimination and, to a lesser extent, through ester hydrolysis. Hofmann elimination is a nonbiologic method of degradation that occurs at a physiologic temperature and pH.
Atracurium is less potent than pancuronium and has a rapid onset of 1 to 3 minutes and a duration of action of 30 to 45 minutes. For endotracheal intubation in the PACU setting, 0.3 to 0.5 mg/kg of atracurium should provide adequate skeletal muscle relaxation for intubation in about 2.5 minutes. For maintenance of mechanical ventilation in the PACU setting, an infusion rate of 10 mcg/kg/min of atracurium may be used. When the infusion has been discontinued, spontaneous ventilation by the patient occurs in approximately 30 minutes.1 The effects can be reversed with a combination of anticholinesterase and antimuscarinic in 12 to 15 minutes after the discontinuation of the atracurium infusion.
Atracurium has many distinct advantages such as its neuromuscular blockade not being prolonged by renal failure or impaired hepatic function; it has little or no cumulative effect and is not influenced significantly by the specific general inhalation anesthetic dose or concentration. Finally, this drug has little or no cardiovascular effect and is easily antagonized with the combination of an anticholinesterase and an anticholinergic.
Cisatracurium Besylate
Cisatracurium (Nimbex) is a stereoisomer of atracurium that is approximately threefold more potent as atracurium but with fewer side effects; it is degraded by the same metabolic pathway as atracurium (i.e., the Hofmann elimination mechanism).
The average adult intubation dose of cisatracurium is 0.2 mg/kg and has an onset of approximately 90 seconds, a peak in 3 to 5 minutes, and a duration of action of 40 to 50 minutes. A supplemental dose of 0.03 mg/kg provides an additional 20 minutes of skeletal muscle relaxation. For maintenance of a stable state of skeletal muscle relaxation in the PACU, cisatracurium can be administered via infusion at a rate of 1 to 2 mcg/kg/min.8
This drug has all the assets of atracurium plus a great advantage over atracurium of less histamine release. It does not have any particular effect on the cardiovascular system, and because it undergoes an organ-independent clearance, it can be used in patients with hepatic or renal failure without a noticeable change in duration of action. It is well suited for many patients who undergo intermediate to long surgical procedures.
Short-Acting Nondepolarizing Skeletal Muscle Relaxants
Rocuronium Bromide
Rocuronium (Zemuron) is a nondepolarizing skeletal muscle relaxant with a chemical structure related to vecuronium. It has a rapid onset (1 to 1.5 minutes) and a short duration of action of 30 to 120 minutes depending on the total dose of the drug. The onset and duration of action are not altered in obese patients when the dose is based on the actual body weight. In patients older than 65 years, the duration of action is slightly prolonged. In pediatrics, the onset and duration are slightly faster.
Because rocuronium has such rapid effects and short duration of action, spontaneous recovery from neuromuscular blockade is possible. However, if a patient arrives to the PACU with spontaneous ventilation after rocuronium administration during surgery that was not reversed with anticholinesterase and an anticholinergic, the patient still should be monitored in the PACU for neuromuscular function with the use of a peripheral nerve stimulator (PNS). In addition to use of the PNS, the patient should be evaluated for adequate clinical evidence of an adequate return of neuromuscular function with evaluation of the 5-second head lift, adequate phonation, ventilation, and upper airway maintenance.1
Rocuronium can be used in patients with renal failure and has a low potential for histamine release. Although rare, its actions are prolonged in patients with cirrhosis of the liver. The muscle relaxant actions of rocuronium are potentiated by the inhalation anesthetics, which makes a prediction of a total recovery from neuromuscular blockade variable. Because rocuronium produces minimal cardiovascular effects, it does not have significant histamine-releasing effects.
Rocuronium can be used as an agent of choice for nondepolarizing rapid sequence intubation in the PACU when appropriate intubation doses are used because it has such a fast onset and short duration of action and therefore is useful in intraoperative and postoperative periods. At a dose of 0.6 to 1.0 mg/kg, rocuronium provides excellent intubating conditions in 60 to 90 seconds for both children and adults. Therefore, before the intubation is attempted, the patient should undergo ventilation with 100% oxygen until appropriate paralysis of the skeletal muscle occurs to facilitate the intubation. The maintenance dose for rocuronium for adults is between 0.1 and 0.2 mg/kg, and for children it is 0.08 to 0.12 mg/kg intravenously. If rocuronium is to be used for continuous infusion, the initial rate is 0.01 to 0.012 mg/kg/min; at the desired level of neuromuscular blockade, the infusion of this drug can be individualized according to the patient’s twitch response as monitored with the use of the PNS. The research indicates that infusion rates can range from 0.004 to 0.016 mg/kg/min. In assessment of the maintenance dosing of rocuronium, it should be administered at 25% of control T1, which is three twitches of the train-of-four. The infusion solutions for rocuronium can be prepared in solutions of 5% glucose and water or lactated Ringer solution. When the infusion is completed, the unused portions of the infusion solutions should be discarded.4
Reversal of Nondepolarizing Neuromuscular Blocking Agents
For restoration of neuromuscular transmission, the antagonist must displace the competitive neuromuscular blocking agent from the nicotinic receptor sites and open the way for depolarization of the postjunctional membrane. The antagonist is an antiacetylcholinesterase that blocks the enzymatic action of acetylcholinesterase located in the postsynaptic clefts so that acetylcholine is not hydrolyzed. The result is a buildup of acetylcholine at the end plate at the N2 cholinergic receptor. The accumulated acetylcholine displaces the competitive neuromuscular blocking agent, which diffuses back into the plasma and thus reestablishes neuromuscular transmission.
Neostigmine and pyridostigmine are usually the anticholinesterase drugs of choice because of their long duration of action and reliability compared with edrophonium chloride. However, research has shown that edrophonium chloride is an effective reversal agent of neuromuscular blockades produced by vecuronium and atracurium. Atropine or glycopyrrolate, both antimuscarinic (anticholinergic) drugs, can be administered immediately before or in conjunction with the anticholinesterase for minimization of the muscarinic effects of the anticholinesterase drug. The muscarinic effects include bradycardia, salivation, miosis, and hyperperistalsis. These effects are produced at lower concentrations of the anticholinesterase-type drug when administered (acetylcholine nicotinic effects are at the autonomic ganglia and the neuromuscular junction). Consequently, when an anticholinesterase drug is administered for reversal of the nondepolarizing neuromuscular blocking agent at the N2 receptor, an antimuscarinic drug is also given for prevention of the adverse muscarinic cholinergic effects associated with the high dose of anticholinesterase. Generally, 2.5 mg of neostigmine is the maximum dose necessary for reversal; however, the suggested limit is 5 mg. The method is administration of 0.4 mg atropine or 0.2 mg glycopyrrolate intravenously over a 1-minute period, observation for an increase in pulse rate, and then administration of 0.5 mg neostigmine intravenously and monitoring for the reversal. This procedure can be repeated until reversal has been achieved or until the limit of neostigmine that can be given is reached. If edrophonium chloride is indicated for reversal, the dose is 0.5 mg/kg with 0.007 mg/kg of atropine.
Neostigmine should be administered cautiously. Cardiac monitoring is essential, especially in elderly or debilitated patients and in patients with cardiac disease. Atrioventricular dissociation and other dysrhythmias can be initiated by the anticholinesterases.7
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