Neuromuscular Blocking Drugs

Skeletal muscles are innervated by somatic motor nerves, which originate in the spinal cord, terminate at muscle cells, and release ACh as their neurotransmitter (see Chapters 9 10). Upon arrival of an action potential, ACh is released from synaptic vesicles by exocytosis, crosses the synapse, and interacts with skeletal muscle nicotinic cholinergic receptors to depolarize the postsynaptic membrane (see Chapter 1). When the membrane reaches threshold, a muscle action potential is generated and propagates along the fiber to initiate excitation-contraction coupling. The action of ACh is terminated very rapidly by hydrolysis by acetylcholinesterase (AChE) located in the synaptic junction. Neuromuscular transmission is depicted in Figure 12-1.

FIGURE 12–1 Neuromuscular transmission and sites of drug action. (1) The action potential is conducted down the motor nerve axon and can be blocked by Na⁺ channel blockers, such as local anesthetics or tetrodotoxin. (2) When the action potential reaches the nerve terminal, Ca⁺⁺-mediated vesicular acetylcholine (ACh) release occurs by exocytosis, a process blocked by botulinum toxin or hemicholinium. (3) After release, ACh diffuses across the synaptic cleft and binds to nicotinic receptors in the motor endplate. The binding can be blocked competitively by nondepolarizing neuromuscular blockers such as curare or noncompetitively by depolarizing neuromuscular blockers, such as succinylcholine. (4) ACh is very rapidly hydrolyzed by acetylcholinesterase (AChE), which can be inhibited by cholinesterase inhibitors, such as neostigmine. (5) ACh-activated nicotinic receptors in the motor endplate generate a muscle action potential, which leads to Ca⁺⁺ release mediated by ryanodine receptors, initiating excitation-contraction coupling and muscle contraction; this Ca⁺⁺ release can be blocked by the antispasticity drug dantrolene.

Neuromuscular blocking agents interfere with neurotransmission by either: (1) occupying and activating the nicotinic receptor for a prolonged period of time, leading to blockade, which occurs with the depolarizing agents; or (2) competitively antagonizing the actions of ACh at nicotinic acetylcholine receptors, which occurs with the nondepolarizing agents. Not surprisingly, the structures of the depolarizing agents resemble that of ACh, whereas the nondepolarizing agents are bulky, rigid molecules. A comparison of the structure of ACh with prototypical depolarizing (succinylcholine) and nondepolarizing (tubocurarine and pancuronium) neuromuscular blockers is shown in Figure 12-2.

FIGURE 12–2 Structures of acetylcholine, a depolarizing neuromuscular blocker (succinylcholine), and several chemical types of nondepolarizing (competitive) neuromuscular blocking agents.

As mentioned, the nondepolarizing blockers are competitive antagonists at nicotinic receptors. They have little or no agonist activity but competitively occupy the receptor binding site. The first compound, d-tubocurarine, was extracted from plants by native South Americans to coat their darts and rapidly paralyze their prey. This led to the development of synthetic compounds including the benzylisoquinolines such as atracurium and the aminosteroids such as pancuronium.

Nondepolarizing neuromuscular blocking drugs decrease the ability of ACh to open the ligand-gated cation channels in skeletal muscle, producing flaccid paralysis. Muscle contraction is partially impaired when 75% to 80% of receptors are occupied and inhibited totally when 90% to 95% are occupied. Required concentrations vary with the drug, the muscle and its location, and the patient.

Because nondepolarizing blockers compete with ACh, the blockade can be reversed by increasing the concentration of ACh. This is done by inhibiting AChE, which hydrolyzes ACh (Chapter 9 10). Neostigmine, edrophonium, and pyridostigmine are AChE inhibitors used clinically to reverse neuromuscular block caused by nondepolarizing blockers. However, if the concentration of the competitive blocking agent is greater than that needed for blockade of 95% of the receptors, AChE inhibitors will be unable to increase ACh sufficiently to reverse the block.

There is only one depolarizing agent currently in clinical use, succinylcholine (see Fig. 12-2). This compound binds to and activates muscle nicotinic receptors in the same manner as ACh. However, succinylcholine is not metabolized by AChE, resulting in receptor occupation for a prolonged period. Succinylcholine is hydrolyzed primarily by butyrylcholinesterase, which is present in the plasma but not in high concentrations at the neuromuscular junction, resulting in continuing muscle depolarization. The neuromuscular block resulting from succinylcholine is characterized by two phases. The first, termed phase I block, is a consequence of prolonged depolarization, rendering the membrane unresponsive to further stimuli. It is characterized by initial muscle fasciculations followed by a flaccid paralysis that is not reversed, but intensified, by administration of AChE inhibitors. With continued exposure to succinylcholine, phase II block occurs, during which the membrane repolarizes but is still unresponsive, reflecting a desensitized state of the nicotinic cholinergic receptor. This phase progresses to a state in which the block appears similar to that produced by nondepolarizing agents, that is, it becomes responsive to high concentrations of ACh and can be reversed by AChE inhibitors.

Spasmolytics

Antispasticity Drugs

The antispasticity agents include baclofen, which is a structural analog of γ-aminobutyric acid (GABA). Baclofen decreases spasticity by binding to GABA_B receptors on presynaptic terminals of spinal interneurons (Fig. 12-3). Binding to presynaptic GABA_B receptors results in hyperpolarization of the membrane, which reduces Ca⁺⁺ influx and decreases the release of the excitatory neurotransmitters, glutamate, and aspartate. Postsynaptic interactions with sensory afferent terminals cause membrane hyperpolarization via a G-protein-coupled receptor that leads to increases in K⁺ conductance, enhancing inhibition. Baclofen may also inhibit γ-motor neuron activity and reduce muscle spindle sensitivity, leading to inhibition of monosynaptic and polysynaptic spinal reflexes.

FIGURE 12–3 Sites of spasmolytic drug action on the spinal cord and muscle. Baclofen acts presynaptically at GABA_B receptors in the spinal cord to reduce transmitter release. Tizanidine also acts presynaptically at α₂ adrenergic receptors to inhibit spinal motorneurons. Diazepam enhances the action of GABA at GABA_A receptors to enhance inhibition at presynaptic and postsynaptic sites in the spinal cord; it also acts in the brain (not shown). Botulinum toxin produces a long-lasting paralysis of “spastic” muscles by preventing ACh release. Dantrolene reduces spasticity by reducing Ca⁺⁺-mediated excitation-contraction coupling through block of ryanodine receptor channels.

Benzodiazepines such as diazepam have an antispasticity effect by acting on GABA_A receptors to increase their affinity for GABA in the brain and in the spinal cord (see Chapter 31 and Fig. 12-3).

Tizanidine is a clonidine derivative with short-acting presynaptic α₂ adrenergic receptor agonist actions. The ability of tizanidine to affect spinal motor neurons via presynaptic inhibition is believed to mediate its antispasticity effects.

Dantrolene has direct effects on skeletal muscle to inhibit ryanodine receptor Ca⁺⁺ release channels on the sarcoplasmic reticulum of skeletal muscle, thereby uncoupling motor nerve excitation and muscle contraction (see Fig. 12-3). Dantrolene may also have actions on the CNS that contribute to its antispasticity effects, although the cellular mechanisms have not been elucidated.

Neuromuscular Blocking Drugs

The neuromuscular blocking drugs differ considerably in their pharmacokinetic properties, and the choice of a particular compound is determined in part by the duration of action of the agent needed for the particular procedure (Table 12-1). Because these drugs are positively charged, they cross membranes poorly and are generally limited in distribution to the extracellular space. However, small amounts of pancuronium, vecuronium, and pipecuronium cross membranes. Pancuronium also crosses the placenta but not in sufficient amounts to cause problems in the fetus when used during a cesarean section.

The use of pancuronium or tubocurarine is discouraged in patients with impaired renal function, because appreciable fractions of these drugs are cleared by renal filtration. Atracurium is inactivated almost entirely by metabolism, two thirds enzymatic and one third by spontaneous nonenzymatic breakdown. Vecuronium and pancuronium undergo significant hepatic metabolism, and their 3-hydroxy metabolites have much less neuromuscular blocking activity than do the parent drugs. Succinylcholine and mivacurium are metabolized by plasma butyrylcholinesterase, with minimal hydrolysis by AChE.

Spasmolytics

Neuromuscular Blocking Drugs

The choice of neuromuscular blocking agent is based primarily on the speed of onset, the duration of neuromuscular block required, and the severity of side effects. The duration of blockade required is, in turn, influenced by the anatomical location of the surgery and the condition of the patient. Relative potency is not a principal consideration, despite a 100-fold variation in the doses of different drugs needed to attain 95% neuromuscular blockade.

Several factors such as patient age, weight, renal function, and genetic makeup can influence the choice of a particular compound used; also, the electrolyte content of body fluids can influence the degree of blockade achieved with a given dose of a particular muscle relaxant. The actions of tubocurarine and atracurium, for example, are potentiated in neonates as compared with children and adults, but succinylcholine is less potent in neonates. Such pharmacokinetic considerations can explain some differences in effectiveness between patients of different ages.

The actions of nondepolarizing blocking agents are often potentiated by inhalational anesthetics (see Chapter 35) and also by low concentrations of extracellular K⁺ or Ca⁺⁺, as may occur after use of diuretics or in renal dysfunction. Elevated K⁺ or Ca⁺⁺ and reduced Mg⁺⁺ concentrations, however, may counteract drug actions through changes in ACh release in response to depolarization or changes in membrane potential at the muscle endplate.

In most surgical procedures in which neuromuscular blocking agents are used, the drugs enter the systemic circulation and are distributed widely. Spontaneous respiration is usually inhibited, and ventilatory support must be available. The rate of neuromuscular block and recovery varies with different muscles. Muscles of respiration are usually among the last to be paralyzed and the first to recover. It is not practical to attempt selective blockade of one anatomical area for prolonged periods because of the widespread distribution of these drugs.

In patients with burns, denervated muscles, spinal cord injury, or other trauma, sensitivity to neuromuscular blocking drugs may vary. In some patients with burns, for example, doses of atracurium may need to be two to three times greater than normal. Succinylcholine use may pose an unacceptable risk in these patients, because the rise of K⁺ in denervated muscle can lead to severe hyperkalemia, which can result in cardiac arrest. Because of its rapid onset and short duration of action, succinylcholine is used primarily for facilitation of endotracheal intubation and for relaxation during extremely short surgical procedures.

Spasmolytics

Neuromuscular Blocking Drugs

The major side effects of the neuromuscular blocking drugs are cardiovascular effects and histamine release. Their significance varies, with the older compounds exhibiting greater effects and the newer drugs having fewer effects.

Although nondepolarizing neuromuscular blocking drugs are generally selective for nicotinic cholinergic receptors in skeletal muscle, cholinergically innervated parasympathetic and sympathetic ganglia and cardiac parasympathetic neuroeffector junctions can all be affected if drug concentrations are sufficiently high. At normal doses most agents do not exhibit these effects except for tubocurarine, which produces a significant degree of ganglionic blockade. Because of the structural similarity of succinylcholine to ACh, succinylcholine binds to ganglionic nicotinic and cardiac muscarinic receptors and stimulates cholinergic transmission. Pancuronium exerts a direct blocking effect on muscarinic M₂ receptors at doses used for neuromuscular blockade, but tubocurarine and atracurium produce muscarinic blockade only at much higher concentrations. Pancuronium and succinylcholine also produce direct muscarinic effects that result in cardiac dysrhythmias. Pancuronium also causes tachycardia and hypertension by blocking norepinephrine reuptake. The reduced cardiac effects of the newer agents greatly increase their safety margins.

Histamine release is a major problem with tubocurarine and a lesser problem with succinylcholine and mivacurium. Because of its marked histamine release and ganglionic blockade leading to hypotension and reflex tachycardia, tubocurarine is now seldom used, except as a pre-curarizing agent before the administration of succinylcholine.

The main disadvantage of atracurium is histamine release, which occurs in approximately 30% of patients. Pancuronium does not release histamine or block ganglia, but it does cause moderate increases in heart rate, blood pressure, and cardiac output as a consequence of sympathomimetic and anticholinergic effects. Histamine release may also occur with cisatracurium and mivacurium, but there are no cardiovascular effects at clinical doses. Doxacurium, rocuronium, and vecuronium are essentially free of cardiovascular and histamine effects.

Long-term use of several neuromuscular blockers in the intensive care unit to maintain controlled ventilation has resulted in prolonged periods of paralysis. Indications for reversal of neuromuscular block are postoperative residual curarization—that is, the inability of the patient to breathe adequately after discontinuation of anesthesia, or when it is impossible to artificially ventilate the patient after administration of a muscle relaxant. Although many criteria, such as the ability of the patient to sustain voluntary activities (adequate swallowing, coughing, eye opening, and head lifting), are used to evaluate the return of muscle function immediately after the use of muscle relaxants, monitoring the response to electrical stimulation is one of the most accurate methods to detect residual neuromuscular blockade. Other methods include electroencephalography, electromyography, mechanomyography, and accelerography.

The K⁺ efflux elicited by succinylcholine is dangerous in patients with neurological diseases such as hemiplegia, paraplegia, intracranial lesion, peripheral neuropathy, and in patients with extensive soft-tissue damage such as burns. Plasma K⁺ concentrations ≥13 mM produce cardiac arrhythmias and arrest. In these patients a marked resistance to nondepolarizing neuromuscular agents called extrajunctional chemosensitivity is present, probably because of an increased number of extrajunctional receptors. In addition, a combination of succinylcholine and halothane or other volatile anesthetics may result in a malignant hyperthermia syndrome in patients, which is a pharmacogenomic disorder of skeletal muscle that presents as a hypermetabolic response that can be fatal. This disorder involves an uncontrolled rise of muscle Ca⁺⁺, which is treated with dantrolene.

Neuromuscular blocking agents must be used with caution in patients with underlying neuromuscular, hepatic, or renal disease or electrolyte imbalance. Patients with neuromuscular disorders such as myasthenia gravis may be resistant to succinylcholine because of a decrease in the number of ACh receptors; the dose of muscle relaxants must be reduced by 50% to 75% in such patients. Patients with myasthenia gravis are also more likely than healthy patients to develop a phase II block in response to succinylcholine, particularly when repeated doses have been administered. Patients with myasthenia gravis exhibit much greater sensitivity to nondepolarizing agents, and the use of long-acting muscle relaxants such as pancuronium, pipecuronium, and doxacurium must be avoided in these patients. Intermediate- and short-acting nondepolarizing drugs can be administered carefully in lower doses with close monitoring of neuromuscular transmission. Lambert-Eaton Myasthenic syndrome, an autoimmune presynaptic neuromuscular disorder in which the stimulated release of ACh is reduced at the neuromuscular junction, is another disease in which patients are very sensitive to muscle relaxants.

Special consideration is required for use of neuromuscular blockers in patients with renal or hepatic disease. Prolonged neuromuscular block has been reported in these patients with pancuronium, vecuronium, rocuronium, and tubocurarine. These drugs are all H₂O-soluble compounds that depend on glomerular filtration, tubular excretion, and tubular reabsorption for clearance. The larger volume of distribution in the edematous renal patient, a reduced renal clearance, and decreased plasma protein binding can cause prolonged elimination. The drug of choice in patients with renal disease is atracurium because of its unique degradation that is unaffected by renal or hepatic dysfunction.

Hepatic disease also prolongs the duration of neuromuscular blockade. The liver is especially important in the metabolism of steroid-type relaxants such as vecuronium and rocuronium. In patients with cholestasis or cirrhosis, uptake of drug into the liver is decreased; thus plasma clearance is also decreased, leading to a prolonged effect. Because butyrylcholinesterase is produced in the liver, in patients with hepatic disease a decrease in enzyme production may prolong the effect of succinylcholine. Again, because the liver is not involved in the elimination of atracurium, it is the drug of choice in patients with hepatic failure.

Drug interactions occur between neuromuscular blockers, anesthetics, Ca⁺⁺ channel blockers, and some antibiotics. Many volatile anesthetic agents enhance the action of the nondepolarizing neuromuscular blockers by decreasing the open time of the ACh receptor, which increases ACh binding affinity. Enflurane has the strongest effect, followed by halothane. The local anesthetic bupivacaine potentiates blockade by nondepolarizing and depolarizing agents, and lidocaine and procaine prolong the duration of action of succinylcholine by inhibiting butyrylcholinesterase.

Ca⁺⁺ channel blockers, and to a lesser extent β adrenergic blockers, potentiate neuromuscular blocking drugs. Antibiotics that interact with neuromuscular blocking agents are aminoglycosides, tetracyclines, polymyxin, and clindamycin. Aminoglycosides decrease ACh release and lower postjunctional sensitivity to ACh. Tetracyclines chelate Ca⁺⁺ and reduce ACh release. Lincomycin and clindamycin block nicotinic receptors and depress muscle contractility, enhancing neuromuscular blockade. The duration of action of vecuronium, pancuronium, doxacurium, and pipecuronium is also reduced in patients taking phenytoin or carbamazepine. These anticonvulsants decrease the affinity of nicotinic receptors for neuromuscular blockers and increase the number of receptors on muscle fibers. The duration of action of vecuronium is also prolonged in patients treated with cimetidine, and magnesium sulfate, used to treat preeclampsia, prolongs the effect of nondepolarizing relaxants and inhibits the effect of succinylcholine.

A source of acute pharmacovigilance in the use of neuromuscular blocking drugs has surfaced lately, because these drugs are widely used as adjuncts during surgery. It has been known for more than 60 years that these agents have essentially no effect on brain activity and consciousness. The patient’s respiration is often completely controlled externally during surgery. It is known that a patient could experience pain from the surgical procedures if the anesthetic level is or becomes insufficient during the procedure, but the patient is unable to communicate this because they are unable to move or speak. This can lead to unacceptable infliction of pain, which can be avoided if physiological parameters, such as electroencephalographic activity described previously, are monitored; procedures should be used to prevent this from occurring.

Genetic variations in butyrylcholinesterase activity result in either lower concentrations of normal enzyme or an abnormal enzyme. A dose of 1 to 2 mg/kg succinylcholine in healthy patients produces neuromuscular blockade lasting <15 minutes; in a patient with a variant of this enzyme with decreased effectiveness, the same dose may last much longer. This is illustrated in Figure 12-4, with block defined as the duration of apnea. Trauma, alcoholism, pregnancy, use of oral contraceptives, and other conditions in which butyrylcholinesterase activity is changed can alter the duration of neuromuscular block produced by succinylcholine.

FIGURE 12–4 Dose-related succinylcholine-induced neuromuscular block (duration of apnea) after intravenous administration to a normal and deficient ChE population, the latter representing individuals with a genetic variant in plasma butyrylcholinesterase activity.

Spasmolytics