Chapter 9 Neuromuscular Blocking Drugs
Clinical uses
2. What are some clinical situations in which skeletal muscle relaxation is desired?
3. What are some methods by which skeletal muscle relaxation can be achieved without the administration of neuromuscular blocking drugs?
4. What analgesic effects do neuromuscular blocking drugs have?
5. What are some characteristics of neuromuscular blocking drugs that may influence the choice of which drug is administered for clinical use for a given patient?
Neuromuscular junction
6. What is the neuromuscular junction?
7. What events lead to the release of neurotransmitter at the neuromuscular junction? What is the neurotransmitter that is released?
8. What class of receptors is located on postjunctional membranes? What clinical effect results from the stimulation of these receptors?
9. How, and in what time course, is the action of acetylcholine terminated in the synaptic cleft? What is the clinical relevance of this?
10. With respect to the neuromuscular junction, what are the three sites at which nicotinic cholinergic receptors are located?
11. What is the role of prejunctional receptors?
12. What is the role of extrajunctional receptors? What is their effect when stimulated?
13. What is the structure of nicotinic cholinergic receptors? How is the junction of the cholinergic receptor related to its structure?
14. What is the binding site for an agonist at the nicotinic cholinergic receptor?
Depolarizing neuromuscular blocking drugs
16. What is the intubating dose of succinylcholine? What are its approximate time of onset and duration of action when administered at this dose?
17. What is the mechanism of action of succinylcholine?
18. What is phase I neuromuscular blockade?
19. What is phase II neuromuscular blockade? What is the mechanism by which it occurs? When is phase II neuromuscular blockade most likely to occur clinically?
20. What occurs clinically as a result of the opening of the nicotinic cholinergic receptor ion channel that occurs with the administration of succinylcholine?
21. How efficiently does plasma cholinesterase hydrolyze succinylcholine? Where is plasma cholinesterase produced?
22. How is the effect of succinylcholine at the cholinergic receptor terminated?
23. How is the duration of action of succinylcholine influenced by plasma cholinesterase?
24. What are some drugs, chemicals, or clinical diseases that may affect the activity of plasma cholinesterase?
25. What is atypical plasma cholinesterase? What is its clinical significance?
26. What is dibucaine? What is its clinical use?
27. What is the normal dibucaine number? For heterozygous and homozygous atypical cholinesterase patients, what is their associated dibucaine number, duration of action of an intubating dose of succinylcholine, and incidence in the population?
28. Why is succinylcholine usually not administered to children under nonemergent conditions?
29. What are some adverse cardiac rhythms that may result from the administration of succinylcholine? When and why are they likely to occur?
30. How can the potential risk of adverse cardiac rhythms associated with the administration of succinylcholine be minimized?
31. What is the mechanism by which succinylcholine may induce a hyperkalemic response with its administration? Which patients are especially at risk for this effect of succinylcholine?
32. Are renal failure patients at greater risk for a hyperkalemic response to the administration of succinylcholine?
33. What is the mechanism by which succinylcholine may induce postoperative myalgias with its administration? Which muscles are typically affected? Which patients are especially at risk for this effect of succinylcholine?
34. How might the fasciculations associated with the administration of succinylcholine be blunted?
35. What effect does the administration of succinylcholine have on intraocular pressure? What is the clinical significance of this?
36. What effect does the administration of succinylcholine have on intragastric pressure? What is the clinical significance of this?
37. What effect does the administration of succinylcholine have on masseter muscle tension? What is the clinical significance of this?
Nondepolarizing neuromuscular blocking drugs
38. What is the mechanism of action of nondepolarizing neuromuscular blocking drugs?
39. Describe the lipid solubility of nondepolarizing neuromuscular blocking drugs. How does this influence its volume of distribution and clinical effect?
40. What are some of the methods by which nondepolarizing neuromuscular blocking drugs are cleared? How does this influence its duration of action?
41. What are some drugs and physiologic states that may enhance the neuromuscular blockade produced by nondepolarizing neuromuscular blocking drugs?
42. What is the mechanism by which volatile anesthetics are believed to enhance the neuromuscular blockade produced by nondepolarizing neuromuscular blocking drugs?
43. What are some of the methods by which nondepolarizing neuromuscular blocking drugs are able to exert cardiovascular effects?
44. What is a concern regarding patients receiving long-term nondepolarizing neuromuscular blocking drugs in the intensive care unit?
45. Which patients are at risk for developing a myopathy after the administration of nondepolarizing neuromuscular blocking drugs in the intensive care unit? How might they present clinically?
Intermediate-acting nondepolarizing neuromuscular blocking drugs
48. Name some intermediate-acting nondepolarizing neuromuscular blocking drugs. What is their approximate time of onset and duration of action?
49. How is vecuronium excreted from the body? How does renal failure affect the clearance of vecuronium?
50. How does the time of onset of rocuronium compare with the time of onset of succinylcholine?
51. How is rocuronium excreted from the body? How does renal failure affect the clearance of rocuronium?
52. How are cisatracurium and atracurium structurally related?
53. How are atracurium and cisatracurium cleared from the plasma? How does renal failure affect the clearance of these drugs?
54. What is the principal metabolite of atracurium and its potential adverse physiologic effect? Which patients are especially at risk for this adverse effect?
55. What are some of the cardiovascular effects of atracurium?
56. What are some differences between cisatracurium and atracurium that make cisatracurium more desirable for clinical use?
Short-acting nondepolarizing neuromuscular blocking drugs
57. Name a short-acting nondepolarizing neuromuscular blocking drug. What is its approximate time of onset and duration of action?
58. How is mivacurium cleared from the plasma? How is the duration of action of mivacurium altered in patients who have deficiencies in plasma cholinesterase enzyme, liver disease, or renal disease?
59. Does the administration of neostigmine reverse the neuromuscular blockade produced by mivacurium?
60. What are some of the cardiovascular effects of mivacurium?
Monitoring the effects of nondepolarizing neuromuscular blocking drugs
61. What is the most common method for monitoring the effects of neuromuscular blocking drugs during general anesthesia?
62. What are two ways in which a peripheral nerve stimulator may be useful during the administration of neuromuscular blocking drugs during general anesthesia?
63. Which nerve and muscle are most commonly used to evaluate the neuromuscular blockade produced by neuromuscular blocking drugs?
64. Which nerves may be used for the evaluation of the neuromuscular blockade produced by neuromuscular blocking drugs through the use of a peripheral nerve stimulator when the arm is not available to the anesthesiologist?
65. How do the neuromuscular blocking drugs vary with regard to their time of onset at the adductor pollicis muscle, orbicularis oculi muscle, laryngeal muscles, and diaphragm?
66. What are some of the mechanical responses evoked by a peripheral nerve stimulator that are used to monitor the effects of neuromuscular blocking drugs? What are the methods to evaluate the mechanically evoked response?
67. What percent of depression of a mechanically evoked single twitch response from its control height correlates with adequate neuromuscular blockade for intubation of the trachea or for the performance of intraabdominal surgery? What approximate percent of nicotinic cholinergic receptors must be occupied by a nondepolarizing neuromuscular blocking drug to achieve this effect?
68. What is the train-of-four stimulus delivered by a peripheral nerve stimulator? What is its clinical use?
69. What is the train-of-four ratio? What is its clinical use?
70. What train-of-four ratio correlates with the complete return to control height of a single twitch response?
71. What is the train-of-four ratio during phase I neuromuscular blockade resulting from the administration of a depolarizing neuromuscular blocking drug such as succinylcholine?
72. How accurate is the estimation of the train-of-four ratio by clinicians evaluating the response visually and manually? What percent of the first twitch control height must be present before the fourth twitch is detectable?
73. What is the double burst suppression stimulus delivered by a peripheral nerve stimulator? What is its clinical use?
74. What is tetany? How might it be mechanically produced by a peripheral nerve stimulator?
75. How is the normal response to tetany altered by the administration of depolarizing and nondepolarizing neuromuscular blocking drugs?
76. What is posttetanic stimulation? What is its clinical use?
Antagonism of nondepolarizing neuromuscular blocking drugs
77. What is the mechanism by which the neuromuscular blockade produced by nondepolarizing neuromuscular blocking drugs is antagonized?
78. How are the cardiac muscarinic effects of anticholinesterases attenuated?
79. Name two factors that influence the choice of anticholinesterase drug to be administered to antagonize the neuromuscular blockade produced by nondepolarizing neuromuscular blocking drugs.
80. When might neostigmine or edrophonium be an appropriate choice of anticholinesterase drug to administer to antagonize neuromuscular blockade? What anticholinergic drug is often paired with each?
81. What are some tests that can be done to evaluate the adequacy of the recovery from the effects of neuromuscular blockade?
82. How might the residual effects of neuromuscular blockers be manifest clinically in the awake patient?
83. What are some pharmacologic or physiologic factors that may interfere with the antagonism of the neuromuscular blockade produced by neuromuscular blocking drugs?
Adverse outcomes from inadequate antagonism of neuromuscular blockade
84. What risk factors contribute to adverse respiratory events in the first hour postoperative in the postanesthetic care unit (PACU)?
85. In addition to induction of anesthesia, what is the most dangerous time for anesthetic complications in the postoperative period?
86. What is sugammadex? What is the mechanism of action of sugammadex?
87. What are the major clinical differences between sugammadex and neostigmine?
88. What are some advantages of sugammadex for the antagonism of neuromuscular blockade?
Answers*
1. Neuromuscular blocking drugs interrupt transmission of nerve impulses at the neuromuscular junction and thereby produce paresis or paralysis of skeletal muscles. (144)
Clinical uses
2. Skeletal muscle relaxation (i.e., paralysis) is desired most frequently to facilitate intubation of the trachea and provide excellent surgical conditions. Other clinical situations in which skeletal muscle relaxation is desired include to facilitate mechanical ventilation of the lungs either intraoperatively, in the intensive care unit, or during cardiopulmonary resuscitation. (144)
3. Skeletal muscle relaxation can be achieved without the administration of neuromuscular blocking drugs by the administration of high concentrations of volatile anesthetics, regional anesthesia, and by proper patient positioning on the operating table. (81, 252, 300)
4. Neuromuscular blocking drugs do not have any anesthetic or analgesic effects. The potential therefore exists for the patient to be rendered paralyzed without adequate anesthesia and subsequent unrecognized awareness during anesthesia. (144, 737)
5. Neuromuscular blocking drugs vary in their mechanism of action, speed of onset, duration of action, route of elimination, and associated side effects. These characteristics of a neuromuscular blocking drug may influence whether a specific neuromuscular blocking drug is chosen for administration to a given patient. (144)
Neuromuscular junction
6. The neuromuscular junction is the location where the transmission of neural impulses at the nerve terminal becomes translated into skeletal muscle contraction at the motor endplate. The highly specialized neuromuscular junction consists of the prejunctional motor nerve ending, a highly folded postjunctional skeletal muscle membrane, and the synaptic cleft in between. (144-146, Figure 12-1)
7. A nerve impulse conducted down the motor nerve fiber, or axon, ends in the prejunctional motor nerve ending. The resulting stimulation of the motor nerve terminal causes an influx of calcium into the nerve terminal. The influx of calcium results in a release of the neurotransmitter acetylcholine into the synaptic cleft. This is why administration of calcium briefly improves neuromuscular function. The nerve synthesizes and stores acetylcholine in vesicles in the motor nerve terminals, which is available for release with the influx of calcium. Acetylcholine released into the synaptic cleft binds to receptors in the postjunctional skeletal muscle membrane, leading to skeletal muscle contraction. (145-146, Figure 12-1)
8. Nicotinic cholinergic receptors are located on the skeletal muscle membrane, or postjunctional membrane. When acetylcholine binds to the nicotinic cholinergic receptor, there is a change in the permeability of the skeletal muscle membrane to sodium and potassium ions. The resultant movement of these ions down their concentration gradients causes a decrease in the membrane potential of the skeletal muscle cell from the resting membrane potential to the threshold potential. The resting membrane potential is the electrical potential of the skeletal muscle cell at rest, usually about − 90 mV. The threshold potential is about − 45 mV. When the threshold potential is reached, an action potential becomes propagated over the surfaces of skeletal muscle fibers. This leads to the contraction of these skeletal muscle fibers. (146, Figure 12-2)
9. Acetylcholine is hydrolyzed in the synaptic cleft by the enzyme acetylcholinesterase, or true cholinesterase. This occurs rapidly, within 15 ms. Clinically, this allows for the restoration of the membrane to its resting membrane potential. The metabolism of acetylcholine also prevents sustained depolarization of the skeletal muscle cells, and thus prevents tetany from occurring. (145, Figure 12-1)
10. Nicotinic cholinergic receptors are located in three separate sites relative to the neuromuscular junction and are referred to by their varied locations. Each of these receptors also has a different functional capacity with regard to its role in skeletal muscle contraction. The three types of nicotinic cholinergic receptors are prejunctional, postjunctional, and extrajunctional. Prejunctional receptors are located at the motor nerve terminal. Postjunctional receptors are located just opposite the prejunctional receptors in the endplate and are the most important receptors for the action of neuromuscular blocking drugs. Extrajunctional receptors are immature in form and are located throughout the skeletal muscle membrane. They are located in areas other than the endplate region of the muscle membrane as well as at the motor endplate region. (145-146, Figure 12-1)
11. Prejunctional receptors are located on the motor nerve terminal and influence the release and replenishment of acetylcholine from the nerve terminal. (145-146, Figure 12-1)
12. Extrajunctional receptors are located throughout the skeletal muscle membrane. They differ from the other two types of nicotinic cholinergic receptors both in their location and by their molecular structure. Under normal circumstances, the synthesis of extrajunctional receptors is suppressed by neural activity and has minimal contribution to skeletal muscle action. Extrajunctional receptors may proliferate under conditions of denervation, trauma, strokes, or burn injury. Conversely, when neuromuscular activity returns to normal, extrajunctional receptors quickly lose their activity. Extrajunctional receptors are stimulated more by lower concentrations of acetylcholine and depolarizing neuromuscular blocking drugs than are prejunctional or postjunctional receptors. In addition, extrajunctional receptors remain open longer and permit more ions to flow across the skeletal muscle cell membrane once activated. Clinically, this may manifest as an exaggerated hyperkalemic response when succinylcholine is administered to patients with denervation injuries. (146)
13. Nicotinic cholinergic receptors are made up of glycoproteins divided into five subunits. There are two α subunits and one each of β, γ, and δ subunits. The subunits are arranged in such a way that they form a channel in the membrane, with the binding site for the agonist being the α subunits. When the receptor becomes stimulated by the binding of an agonist or acetylcholine, the channel changes conformation such that it allows the flow of ions through the cell membrane along their concentration gradient. Extrajunctional receptors differ slightly from postjunctional nicotinic cholinergic receptors in that the γ and δ subunits of these receptors are altered from those of the postjunctional receptors. The two α subunits, however, are identical. (146, Figure 12-2)
14. The binding site for agonists at the nicotinic cholinergic receptor is the α subunit. Acetylcholine must bind to both of the two α subunits of the receptor to stimulate the receptor to change conformation and allow the flow of ions through the resulting ion channel. Nondepolarizing neuromuscular blocking drugs also bind to the α subunits of the receptor but only require that one α subunit be bound to exert their pharmacologic effect. With the binding of a nondepolarizing neuromuscular blocking drug to an α subunit on the receptor, acetylcholine is unable to bind to the receptor, the flow of ions across the channel does not occur, and the physiologic effect of skeletal muscle contraction becomes blocked. The binding of a depolarizing neuromuscular blocking drug, like acetylcholine, requires that both α subunits be bound before stimulating the receptor to change conformation and the resulting skeletal muscle contraction. Succinylcholine, a depolarizing neuromuscular blocking drug, exerts its effect in this manner. The elimination of succinylcholine is through its clearance from the plasma and requires a few minutes to occur. This accounts for its prolonged binding period on the nicotinic cholinergic receptor and subsequent skeletal muscle paralysis for the minutes after its administration. (146-148)
