Table 9–1 summarizes the pharmacological properties of various neuromuscular blocking agents.
The anatomy, physiology, and pharmacology of the motor end plate are shown in Figure 9–3.
SKELETAL MUSCLE Competitive antagonists competitively block the binding of ACh to the nicotinic ACh receptor at the end plate. The depolarizing agents, such as succinylcholine, act by a different mechanism: initially, they depolarize the membrane by opening channels in the same manner as ACh. However, they persist for longer durations at the neuromuscular junction because of their resistance to AChE. The depolarization is thus longer-lasting, resulting in a brief period of repetitive excitation (fasciculations), followed by block of neuromuscular transmission (and flaccid paralysis). Paralysis occurs because released ACh binds to receptors on an already depolarized end
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plate (an end plate depolarized from –80 to –55 mV by a depolarizing blocking agent is resistant to fur-ther depolarization by ACh). The exact sequence from fasciculations to paralysis is influenced by such factors as the anesthetic agent used concurrently, the type of muscle, and the rate of drug adminis- tra-tion. The characteristics of depolarization and competitive blockade are contrasted in Table 9–2.
SEQUENCE AND CHARACTERISTICS OF PARALYSIS Following intravenous adminis-tration of an appropriate dose of a competitive antagonist, motor weakness progresses to a total flaccid paralysis. Small, rapidly moving muscles (e.g., those of the eyes, jaw, and larynx) relax before those of the limbs and trunk. Ultimately, intercostal muscles and finally the diaphragm are paralyzed, and respiration then ceases. Recovery of muscles usually occurs in the reverse order to that of their paralysis, and thus the diaphragm ordinarily is the first muscle to regain function.
After a single intravenous dose of 10–30 mg of a depolarizing agent such as succinylcholine, muscle fasciculations, particularly over the chest and abdomen, occur briefly; relaxation occurs within 1 minute, becomes maximal within 2 minutes, and generally disappears within 5 minutes.
Transient apnea usually occurs at the time of maximal effect. Muscle relaxation of longer duration is achieved by continuous intravenous infusion. After infusion is discontinued, the effects of the drug usually disappear rapidly because of its rapid hydrolysis by plasma and hepatic butyryl-cholinesterase. Muscle soreness may follow the administration of succinylcholine. Small prior doses of competitive blocking agents have been employed to minimize fasciculations and muscle pain caused by succinylcholine, but this procedure is controversial because it increases the require-ment for the depolarizing drug.
During prolonged depolarization, muscle cells may lose significant quantities of K+and gain Na+, Cl–, and Ca2+. In patients in whom there has been extensive injury to soft tissues, the efflux of K+ following continued administration of succinylcholine can be life-threatening. Thus, there are many conditions for which succinylcholine administration is contraindicated or should be undertaken with great caution. Under clinical conditions, with increasing concentrations of succinylcholine and over time, the block may convert slowly from a depolarizing to a nondepolarizing type (termed phase I and phase II blocks). This change in the nature of the blockade produced by succinylcholine (from phase I to phase II) presents an additional complication with long-term infusions (see Table 9–3).
Central Nervous System
Tubocurarine and other quaternary neuromuscular blocking agents are virtually devoid of central effects following ordinary clinical doses because of their inability to penetrate the blood–brain barrier.
AUTONOMIC GANGLIA AND MUSCARINIC SITES Neuromuscular blocking agents show variable potencies in producing ganglionic blockade. Clinical doses of tubocurarine produce partial blockade both at autonomic ganglia and at the adrenal medulla, resulting in a fall in blood pressure and tachycardia. Pancuronium shows less ganglionic blockade at standard clinical doses.
FIGURE 9–1 Subunit organization of the nicotinic ACh receptor and related pentameric ligand-gated ion channels.
For each subunit (MW∼40–60 kDa), the amino terminal region (∼210 amino acids) is at the extracellular surface, followed by 4 transmembrane domains (TM1–TM4), with a small carboxyl terminus at the extracellular surface. Five subunits aggregate to form the receptor/pore/ion channel; the a-helical TM2regions from each subunit of the pentameric receptor line the internal pore of the receptor. One disulfide motif is conserved throughout the family of receptors.
CHAPTER 9 Agents Acting at the Neuromuscular Junction and Autonomic Ganglia
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FIGURE 9–2 Neuromuscular blocking agents. (* This methyl group is absent in vecuronium.)
Classification of Neuromuscular Blocking Agents
Time of Clinical
Agent (TRADE NAME) Chemical Class Pharmacological Properties Onset, min Duration, min Mode of Elimination
Succinylcholine Dicholine ester Ultrashort duration; 1–1.5 5–8 Hydrolysis by plasma cholinesterases
(ANECTINE, others) depolarizing
D-Tubocurarine Natural alkaloid (cyclic Long duration; competitive 4–6 80–120 Renal elimination; liver clearance benzylisoquinoline)
Atracurium (TRACRIUM) Benzylisoquinoline Intermediate duration; competitive 2–4 30–60 Hofmann degradation; hydrolysis by plasma esterases; renal elimination Doxacurium (NUROMAX) Benzylisoquinoline Long duration; competitive 4–6 90–120 Renal elimination
Mivacurium (MIVACRON) Benzylisoquinoline Short duration; competitive 2–4 12–18 Hydrolysis by plasma cholinesterases Pancuronium (PAVULON) Ammonio steroid Long duration; competitive 4–6 120–180 Renal elimination
Pipecuronium (ARDUAN) Ammonio steroid Long duration; competitive 2–4 80–100 Renal elimination; liver metabolism and clearance
Rocuronium (ZEMURON) Ammonio steroid Intermediate duration; competitive 1–2 30–60 Liver metabolism
Vecuronium (NORCURON) Ammonio steroid Intermediate duration; competitive 2–4 60–90 Liver metabolism and clearance; renal elimination
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Atracurium, vecuronium, doxacurium, pipecuronium (no longer marketed in the U.S.), mivac-urium, and rocuronium are even more selective. The maintenance of cardiovascular reflex responses usually is desired during anesthesia.
Pancuronium has a vagolytic action, presumably from blockade of muscarinic receptors, that leads to tachycardia. Of the depolarizing agents, succinylcholine, at doses producing skeletal muscle relaxation, rarely causes effects attributable to ganglionic blockade. However, cardiovascu-lar effects are sometimes observed, probably owing to the successive stimulation of vagal ganglia (manifested by bradycardia) and sympathetic ganglia (resulting in hypertension and tachycardia).
HISTAMINE RELEASE Tubocurarine produces typical histamine-like wheals when injected intracutaneously or intra-arterially in humans; some clinical responses to neuromuscular FIGURE 9–3 Pharmacology of the neuromuscular junction. The modification of excitation-ACh secretion and nicotinic receptor activation-contraction coupling by various agents is shown on the right; an arrow marked with an X indicates inhibition or block; a plain arrow indicates enhancement or activation.
Table 9–2
Comparison of Competitive (D-Tubocurarine) and Depolarizing (Decamethonium) Blocking Agents
D-Tubocurarine Decamethonium
Effect of D-tubocurarine administered Additive Antagonistic previously
Effect of decamethonium administered No effect, or Some tachyphylaxis,
previously antagonistic but may be additive
Effect of anticholinesterase agents Reversal of block No reversal on block
Effect on motor end plate Elevated threshold to Partial, persisting acetylcholine; no depolarization depolarization
Initial excitatory effect on striated muscle None Transient fasciculations Character of muscle response to indirect Poorly sustained Well-sustained
tetanic stimulation during partial block contraction contraction
blocking agents (e.g., bronchospasm, hypotension, excessive bronchial and salivary secretion) appear to be caused by the release of histamine. Succinylcholine, mivacurium, doxacurium, and atracurium also cause histamine release, but to a lesser extent unless administered rapidly. The ammonio steroids, pancuronium, vecuronium, pipecuronium, and rocuronium, have even less ten-dency to release histamine after intradermal or systemic injection. Histamine release typically is a direct action of the muscle relaxant on the mast cell rather than IgE-mediated anaphylaxis.
ACTIONS OF NEUROMUSCULAR BLOCKING AGENTS WITH LIFE-THREATEN-ING IMPLICATIONS Depolarizing agents can release K+rapidly from intracellular sites; this may be a causative factor in production of the prolonged apnea in patients who receive these drugs while in electrolyte imbalance.
Succinylcholine-induced hyperkalemia is a life-threatening complication of that drug (e.g., in patients with congestive heart failure who are receiving digoxin or diuretics). Likewise, caution should be used or depolarizing blocking agents should be avoided in patients with extensive soft tissue trauma or burns. A higher dose of a competitive blocking agent often is indicated in these patients. In addition, succinylcholine administration is contraindicated or should be given with great caution in patients with nontraumatic rhabdomyolysis, ocular lacerations, spinal cord injuries with paraplegia or quadriplegia, or muscular dystrophies. Succinylcholine no longer is indicated for children≤8 years of age unless emergency intubation or securing an airway is necessary. Hyper-kalemia, rhabdomyolysis, and cardiac arrest have been reported; a subclinical dystrophy frequently is associated with these adverse responses. Neonates also may have an enhanced sensitivity to com-petitive neuromuscular blocking agents.
DRUG INTERACTIONS From a clinical viewpoint, important pharmacological interactions of these drugs occur with certain general anesthetics, certain antibiotics, Ca2+channel blockers, and anti-ChE compounds. Since the anti-ChE agents neostigmine, pyridostigmine, and edrophonium preserve endogenous ACh and also act directly on the neuromuscular junction, they can be used in the treatment of overdosage with competitive blocking agents. Similarly, on completion of the sur-gical procedure, many anesthesiologists employ neostigmine or edrophonium to reverse and decrease the duration of competitive neuromuscular blockade. Succinylcholine should never be administered after reversal of competitive blockade with neostigmine; in this circumstance, a pro-longed and intense blockade often results (see Table 9–2). A muscarinic antagonist (atropine or glycopyrrolate) is used concomitantly to prevent stimulation of muscarinic receptors and thereby to avoid slowing of the heart rate. Many inhalational anesthetics (e.g., halothane, isoflurane, enflu-rane) “stabilize” the postjunctional membrane and act synergistically with the competitive block-ing agents; this requires a reduction in the dose of the nicotinic receptor blockblock-ing drugs.
Aminoglycoside antibiotics produce neuromuscular blockade by inhibiting ACh release from the preganglionic terminal (through competition with Ca2+) and to a lesser extent by noncompetitively blocking the receptor. Tetracyclines also can produce neuromuscular blockade, possibly by chelation of Ca2+. Additional antibiotics that have neuromuscular blocking action, through both presynaptic Table 9–3
Clinical Responses and Monitoring of Phase I and Phase II Neuromuscular Blockade by Succinylcholine Infusion
Response Phase I Phase II
End-plate membrane potential Depolarized to –55 mV Repolarization toward –80 mV
Onset Immediate Slow transition
Dose-dependence Lower Usually higher or
follows prolonged infusion
Recovery Rapid More prolonged
Train of four and tetanic stimulation No fade Fade*
Acetylcholinesterase inhibition Augments Reverses or antagonizes Muscle response Fasciculations → flaccid paralysis Flaccid paralysis
*Post-tetanic potentiation follows fade.
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and postsynaptic actions, include polymyxin B, colistin, clindamycin, and lincomycin. Ca2+ chan-nel blockers enhance neuromuscular blockade produced by both competitive and depolarizing antagonists. When neuromuscular blocking agents are administered to patients receiving these agents, dose adjustments should be considered; if recovery of spontaneous respiration is delayed, Ca2+salts may facilitate recovery.
Miscellaneous drugs that may have significant interactions with either competitive or depo-larizing neuromuscular blocking agents include trimethaphan (no longer marketed in the U.S.), opioid analgesics, procaine, lidocaine, quinidine, phenelzine, phenytoin, propranolol, magnesium salts, corticosteroids, digitalis glycosides, chloroquine, catecholamines, and diuretics.
TOXICOLOGY The important untoward responses of the neuromuscular blocking agents include prolonged apnea, cardiovascular collapse, those resulting from histamine release, and, rarely, anaphylaxis. Related factors may include alterations in body temperature; electrolyte imbal-ance, particularly of K+(discussed earlier); low plasma butyrylcholinesterase levels, resulting in a reduction in the rate of destruction of succinylcholine; the presence of latent myasthenia gravis or of malignant disease such as small cell carcinoma of the lung (Eaton-Lambert myasthenic syn-drome); reduced blood flow to skeletal muscles, causing delayed removal of the blocking drugs;
and decreased elimination of the muscle relaxants secondary to reduced renal function. Great care should be taken when administering these agents to dehydrated or severely ill patients.
MALIGNANT HYPERTHERMIA Malignant hyperthermia is a potentially life-threatening event triggered by certain anesthetics and neuromuscular blocking agents. Clinical features include contracture, rigidity, and heat production from skeletal muscle resulting in severe hyperthermia, accelerated muscle metabolism, metabolic acidosis, and tachycardia. Uncontrolled release of Ca2+
from the sarcoplasmic reticulum of skeletal muscle is the initiating event. Although the halogenated hydrocarbon anesthetics (e.g., halothane, isoflurane, and sevoflurane) and succinylcholine alone reportedly precipitate the response, most incidents arise from the combination of depolarizing blocking agent and anesthetic.
Susceptibility to malignant hyperthermia, an autosomal dominant trait, is associated with cer-tain congenital myopathies such as central core disease. In the majority of cases, however, no clin-ical signs are visible in the absence of anesthetic intervention.
Susceptibility relates to a mutation in RyR-1, the gene encoding the skeletal muscle ryanodine receptor (RYR-1); other loci have been identified on the L-type Ca2+channel and on associated proteins.
Treatment entails intravenous administration of dantrolene (DANTRIUM), which blocks Ca2+
release and its sequelae in skeletal muscle. Rapid cooling, inhalation of 100% oxygen, and control of acidosis should be considered adjunct therapy in malignant hyperthermia.
Central core disease has five allelic variants of RyR-1; patients with central core disease are highly susceptible to malignant hyperthermia with the combination of an anesthetic and a depolar-izing neuromuscular blocker. Patients with other muscle syndromes or dystonias also have an increased frequency of contracture and hyperthermia in the anesthesia setting.
RESPIRATORY PARALYSIS Treatment of respiratory paralysis arising from an adverse reaction or overdose of a neuromuscular blocking agent includes positive-pressure artificial respira-tion with oxygen and maintenance of a patent airway until recovery of normal respirarespira-tion is ensured.
With the competitive blocking agents, this may be hastened by the administration of neostigmine methylsulfate (0.5–2 mg intravenously) or edrophonium (10 mg intravenously, repeated as required).
INTERVENTIONAL STRATEGIES FOR OTHER TOXIC EFFECTS Neostigmine effectively antagonizes only the skeletal muscular blocking action of the competitive blocking agents and may aggravate side effects (e.g., hypotension) or induce bronchospasm. In such cir-cumstances,sympathomimetic amines may be given to support the blood pressure. Atropine or gly-copyrrolate is administered to counteract muscarinic stimulation. Antihistamines will counteract the responses that follow the release of histamine, particularly when administered before the neuro-muscular blocking agent.
ABSORPTION, FATE, AND EXCRETION Quaternary ammonium neuromuscular blocking agents are poorly and irregularly absorbed from the gastrointestinal (GI) tract. Absorption is adequate from intramuscular sites. Rapid onset is achieved with intravenous administration. The more potent agents must be given in lower concentrations, and diffusional requirements slow their rate of onset.
With long-acting competitive blocking agents (e.g., D-tubocurarine, pancuronium), blockade may diminish after 30 minutes owing to redistribution of the drug, yet residual blockade and plasma levels of the drug persist. Subsequent doses show diminished redistribution. Long-acting agents may accumulate with multiple doses.
The ammonio steroids contain ester groups that are hydrolyzed in the liver. Typically, the metabo-lites have about half the activity of the parent compound and contribute to the total relaxation pro-file. Ammonio steroids of intermediate duration of action (e.g., vecuronium, rocuronium; see Table 9–1) are cleared more rapidly by the liver than is pancuronium. The more rapid decay of neu-romuscular blockade with compounds of intermediate duration argues for sequential dosing of these agents rather than administering a single dose of a long duration neuromuscular blocking agent.
Atracurium is converted to less active metabolites by plasma esterases and spontaneous degra-dation. Because of these alternative routes of metabolism, atracurium does not exhibit an increased t1/2in patients with impaired renal function and therefore is the agent of choice in this setting.
Mivacurium shows an even greater susceptibility to butyrylcholinesterases, and thus has the short-est duration among nondepolarizing blockers. The extremely brief duration of action of succinyl-choline also is due largely to its rapid hydrolysis by the butyrylsuccinyl-cholinesterase of liver and plasma.
Among the occasional patients who exhibit prolonged apnea following the administration of suc-cinylcholine or mivacurium, most (but not all) have atypical or deficient plasma cholinesterase, hepatic or renal disease, or a nutritional disturbance.