Chapter 4 Autonomic Nervous System
1. What are the two principal branches of the autonomic nervous system (ANS), and what is the primary function of each?
The sympathetic nervous system
2. Where do the preganglionic fibers of the sympathetic nervous system (SNS) originate?
3. Where are the ganglia of the SNS located?
4. How are sympathetic signals amplified to broaden the sympathetic response?
5. What neurotransmitter and receptor are involved in the autonomic ganglia?
6. What is the most common neurotransmitter released by the postganglionic sympathetic neurons when they synapse with their target organs?
7. What are the other neurotransmitters of the SNS?
8. What are some of the common cotransmitters released at the terminal of the postganglionic sympathetic fibers, and what do they do?
9. What receptor types do the various classic sympathetic neurotransmitters bind to at the target organ?
10. Where are α2 receptors located, and what happens when they are stimulated?
11. What are the chemical intermediates in the synthesis of norepinephrine from tyrosine substrate, and where does this process occur?
12. What is the rate limiting step in the synthesis of norepinephrine, and what enzyme catalyzes this step?
13. Where is epinephrine synthesized?
14. What percent of the norepinephrine reserve stored in vesicles at the sympathetic nerve terminal is released with each depolarization of the postganglionic nerve?
15. How is the action of norepinephrine at the synapse terminated?
The parasympathetic nervous system
16. Where do the preganglionic fibers of the parasympathetic nervous system (PNS) originate?
17. Where are the ganglia of the PNS located?
18. How are the postganglionic neurons of the PNS different from the postganglionic neurons of the SNS?
19. What happens to ACh after it is released into the synaptic cleft?
Adrenergic pharmacology
20. Which adrenergic effect of norepinephrine predominates, the α or the β? What are the usual clinical responses seen to administration of norepinephrine?
21. What risks are associated with the administration of norepinephrine?
22. What receptors does epinephrine stimulate?
23. What life-threatening events are treated with epinephrine?
24. Name two ways that the local vasoconstrictive effects of epinephrine are used clinically.
25. What are the therapeutic effects of intravenous epinephrine?
26. Which response, sympathetic or parasympathetic, predominates in the following organs? The heart, the vasculature, the bronchial tree, the uterus, the gastrointestinal tract, and the pancreas.
27. What are the usual infusion rates for the catecholamines dopamine, norepinephrine, epinephrine, and dobutamine?
28. What are the primary endocrine and metabolic effects of epinephrine administration?
29. In what circumstances is an intravenous bolus of 1.0 mg of epinephrine appropriate?
30. What are epinephrine’s primary effects at low, medium, and high infusion rates?
31. What are the mechanisms of action of epinephrine for the treatment of bronchospasm? How is the epinephrine administered? What is the dosing?
32. What is the concern when giving epinephrine to a patient during a halothane-based anesthetic?
33. What receptors bind dopamine?
34. In what two ways does dopamine exert its sympathomimetic effects?
35. Which vascular beds are uniquely dilated by dopamine?
36. How is dopamine metabolized?
37. How does the dose of dopamine administered affect its clinical response?
38. How does dopamine affect renal function in shocklike states?
Synthetic catecholamines
39. What receptors are stimulated by isoproterenol?
40. Why has isoproterenol fallen into disuse?
41. Which adrenergic receptors are stimulated by dobutamine?
42. What patients are most likely to benefit from treatment with dobutamine?
43. What is the problem with prolonged administration of dobutamine?
44. Which receptors are stimulated by fenoldopam?
Noncatecholamine sympathomimetic amines
47. Through what two mechanisms do most noncatecholamine sympathomimetic amines exert their effects?
48. Name three noncatecholamine sympathomimetic amines.
49. What are the advantages and disadvantages of using ephedrine to treat hypotension in pregnancy?
50. What is the cause of tachyphylaxis after repeat doses of ephedrine?
51. Should ephedrine be used to treat life-threatening events?
α2-Adrenergic agonists
55. What is the mechanism of action of the α2-adrenergic agonists?
56. What are the clinical effects of administering α2 agonists?
57. What is “clonidine withdrawal”?
58. What drug is commonly used to treat clonidine withdrawal?
59. How does the administration of an α2 agonist affect a patient’s anesthetic requirements?
60. What effect do the α2 agonists have on perioperative mortality?
61. How is clonidine used in the treatment of chronic pain syndromes?
62. What is the context-specific half-life of dexmedetomidine?
63. What is the dosing for a dexmedetomidine infusion?
64. What makes dexmedetomidine an attractive agent for use in awake intubations?
65. What makes dexmedetomidine an attractive agent for use in patients with sleep apnea?
α-Adrenergic receptor antagonists
67. What side effects are commonly associated with the use of α1 antagonists as antihypertensive therapies?
68. What must happen before there is complete recovery from α1-blockade with phenoxybenzamine?
69. What are the primary clinical effects of treatment with phenoxybenzamine?
70. Phenoxybenzamine is most often used to treat what disease?
β-Adrenergic antagonists
73. What are some of the clinic indications for β-blocker therapy?
74. What benefit has been demonstrated for the use of perioperative β-blockers in patients at risk for coronary artery disease?
75. What are the risks of giving perioperative β-blockers?
76. What are the current recommendations for initiating β-blockade perioperatively?
77. What are the significant characteristics that differentiate the intravenous β-blockers commonly used in anesthetic practice?
78. What are the primary effects of the cardioselective (β1 selective) β-blockers?
79. What are the cardiac side effects of β-blockade?
80. What are the risks of treating diabetics with β-blockers?
81. Can β-blockers be used in patients who have pheochromocytomas?
82. How should a β-blocker overdose be treated?
83. Which drug-drug interactions are particularly concerning when a patient is on β-blockers?
84. How is propranolol metabolized?
85. What effect does propranolol have on the oxyhemoglobin dissociation curve?
86. What is the intravenous dosing for the cardioselective β-blocker metoprolol?
87. What adrenergic receptors are antagonized by labetalol?
88. What is the dosing for labetalol?
89. Why is labetalol used to treat hypertension during pregnancy?
90. What accounts for the short half-life of esmolol?
91. When is esmolol an especially good choice for β-blockade?
Cholinergic pharmacology
92. What are the pharmacologic effects of the muscarinic antagonists?
93. How does the quaternary structure of glycopyrrolate affect its clinical actions?
94. In what kinds of cases are muscarinic antagonists still commonly given as premedications?
95. Why is glycopyrrolate given when neuromuscular blockade is reversed with the anticholinesterase drugs?
96. What are the common uses and side effects of a scopolamine patch?
97. What is the central anticholinergic syndrome and how is it treated?
98. What is the mechanism of action of the cholinesterase inhibitors (anticholinesterases)?
99. What is the clinical use for the cholinesterase inhibitors in the perioperative period?
100. What is the anesthetic risk for patients who use echothiophate eye drops?
Answers*
1. The two principal branches of the ANS are the sympathetic and parasympathetic nervous systems. The sympathetic nervous system (SNS) is responsible for increasing cardiac output and shunting blood to the skeletal muscles to enable the “fight or flight” response necessary when an organism is threatened. The parasympathetic nervous system (PNS), on the other hand, is responsible for the body’s maintenance functions such as digestion and genitourinary function. (66)
The sympathetic nervous system
2. The preganglionic neurons of the SNS originate from the thoracic and lumbar regions of the spinal cord. (66)
3. Most of the ganglia of the SNS are distributed along the paired sympathetic chains that are immediately lateral to the left and right borders of the vertebral column. Other sympathetic fibers extend to ganglia along the midline in the celiac or mesenteric plexuses. (66)
4. The initial sympathetic signal is amplified as the preganglionic fibers do not synapse at the ganglion of the level of their origin alone; rather they course up and down the sympathetic chain activating ganglia of the adjacent spinal levels thereby widening the body’s response to the sympathetic signal. (66-68)
5. The neurotransmitter released at both sympathetic and parasympathetic ganglia is acetylcholine (ACh) and the postganglionic receptors that bind the ACh in both the SNS and the PNS are nicotinic receptors. (68)
6. While preganglionic sympathetic fibers are short (traveling only from the spinal column to the adjacent sympathetic chains before they synapse at the sympathetic ganglia), the postganglionic sympathetic neurons are relatively long as they must travel from the sympathetic chain to the target organ. The neurotransmitter released at the terminal end of the postganglionic sympathetic fiber at the synapse with its target organ is usually norepinephrine. (68)
7. Besides norepinephrine, the other classic neurotransmitters of the SNS are epinephrine and dopamine. (68)
8. Identified sympathetic cotransmitters include adenosine triphosphate (ATP) and neuropeptide Y. These molecules are released into the sympathetic synapse with the target organ and modulate the sympathetic activity. (68)
9. Norepinephrine and epinephrine bind to adrenergic receptors located postsynaptically on the target organ. These receptors include α1, β1, β2, and β3 receptors. Dopamine binds postsynaptically to dopamine-1 (D-1) receptors. (68)
10. α2 Receptors are located presynaptically on the terminal end of the postganglionic nerve fiber. When norepinephrine binds to the α2 receptor, subsequent norepinephrine release is decreased (negative feedback). (68)
11. Tyrosine is converted to dihydroxyphenylalanine (DOPA), DOPA is converted to dopamine, and dopamine is converted to norepinephrine. These transformations occur in the postganglionic sympathetic nerve ending. (69)
12. The rate limiting step in the synthesis of norepinephrine is the conversion of tyrosine to DOPA. The enzyme that catalyzes this reaction is tyrosine hydroxylase. (69)
13. Norepinephrine is converted to epinephrine in the adrenal medulla. The enzyme that catalyzes the methylation of norepinephrine to epinephrine is phenylethanolamine N-methyltransferase. (69)
14. Approximately 1% of the stored norepinephrine is released with each depolarization, so there is a tremendous functional reserve of norepinephrine at the nerve ending. (69)
15. After being released from the adrenergic receptor(s), most of the norepinephrine in the synaptic cleft is actively taken up at the presynaptic nerve terminal and transported to vesicles for reuse. Norepinephrine that escapes reuptake and makes its way into the bloodstream is metabolized by either the monoamine oxidase (MAO) or catechol-O-methyltransferase enzyme in the blood, liver, or kidney. (69)
The parasympathetic nervous system
16. The preganglionic fibers of the PNS arise from cranial nerves III, VII, IX, and X and from sacral nerve roots. (69)
17. Unlike the ganglia of the SNS that are located in ganglionic chains on either side of the vertebral column, the ganglia of the PNS are located close to or within their target organs. (70)
18. The postganglionic neurons of the PNS are short (since the PNS ganglia are close to or within the target organs), and they release acetylcholine (ACh) from their terminal end when the postganglionic neuron depolarizes. (70)
19. ACh released from the parasympathetic neuron binds to postsynaptic muscarinic receptors on the target cell. Upon release from these receptors, ACh is rapidly metabolized within the synapse by the cholinesterase enzyme. (70)
Adrenergic pharmacology
20. Norepinephrine’s stimulatory effects on α1-adrenergic receptors predominate. This leads to an increase in peripheral vascular resistance and a resultant increase in diastolic, systolic, and mean arterial pressure. The increase in systemic vascular resistance can also lead to a reflex bradycardia. (70)
21. Besides the acute risks associated with severe hypertension that can occur with the administration of norepinephrine, the vasoconstriction caused by norepinephrine can decrease the blood flow to the pulmonary, renal, and mesenteric circulations so infusions must be carefully monitored to decrease the risk of injury to these vital organs. Additionally, prolonged norepinephrine infusions can cause ischemia of the fingers because of the marked peripheral vasoconstriction. (70)
22. Epinephrine binds to α- and β-adrenergic receptors. (70)
23. Exogenous epinephrine is given intravenously to treat cardiac arrest, circulatory collapse, and anaphylaxis. (70)
24. Epinephrine is commonly added to local anesthetics to decrease the spread of the local anesthetic. It can also be injected locally to decrease surgical blood loss from the soft tissue (as in tumescent anesthesia for liposuction). (70)
25. Among the therapeutic effects of intravenous epinephrine are: positive inotropy, chronotropy, and enhanced conduction through the heart (β1 mediated); smooth muscle relaxation in the vasculature and bronchial tree (β2 mediated); and vasoconstriction (α1 mediated). The predominant effect depends on the dose of epinephrine administered. (70)
26. Most organs receive dual innervation from the SNS and PNS. When an organ receives these dual inputs one or the other normally predominates. In the heart, the rate and force of the contraction are mainly determined by the cholinergic (PNS) response. Vascular tone is determined solely by adrenergic (SNS) inputs. The tone of the smooth muscle of the bronchial tree is predominantly controlled by PNS inputs. Uterine tone is primarily controlled by adrenergic inputs. The gastrointestinal tract’s primary inputs are from the PNS. The pancreas’ insulin release is controlled exclusively by the SNS. (70-72)
27. All the exogenous catecholamines have short half-lives so they are administered as continuous infusions. The usual dose for dopamine is 2 to 20 μg/kg/min. The usual dose of norepinephrine is 0.01 to 0.1 μg/kg/min. The usual dose of epinephrine is 0.03 to 0.15 μg/kg/min. The usual dose of dobutamine is 2 to 20 μg/kg/min. (72)
28. Epinephrine’s endocrine and metabolic effects result in increased blood glucose (via decreased insulin release), increased lactate, and increased free fatty acids. (72)
29. An intravenous dose of 1.0 mg of epinephrine is given for cardiovascular collapse, asystole, ventricular fibrillation, electromechanical dissociation, or anaphylactic shock. This dose of epinephrine is chosen because it constricts the peripheral vasculature while maintaining myocardial and cerebral perfusion. (72)
30. At low infusion rates (1 to 2 μg/min), epinephrine’s primary action is a β2-mediated decrease in airway resistance and vascular tone. At medium doses (2 to 10 μg/min) of epinephrine one usually sees an increase in heart rate, an increase in myocardial contractility, and increased conduction through the AV node. At high doses (> 10 μg/min), the α1 effects predominate and there is a generalized vasoconstriction with a reflex bradycardic response. (72)
31. Epinephrine is effective therapy for bronchospasm both because of its direct effect as a bronchodilator (via relaxation of the bronchial smooth muscle) and because it decreases antigen-induced release of bronchospastic substances (as may occur during anaphylaxis) by stabilizing the mast cells that release these substances. When using epinephrine to treat bronchospasm, it can be given subcutaneously. The usual SQ dose is 300 μg every 20 minutes with a maximum of three doses. (72)
32. Epinephrine decreases the myocardial refractory period, so giving epinephrine during a halothane-based anesthetic increases the risk of cardiac arrhythmias associated with the administration of halothane. This risk seems to be lower in pediatric cases (the population in which halothane is still used) and the arrhythmic risk increases with hypocapnia. (72)
33. Dopamine is bound by α, β, and dopaminergic receptors. (72)
34. Dopamine binds to the adrenergic receptors on target cells to cause a direct adrenergic effect. Dopamine also causes the release of endogenous norepinephrine from storage vesicles. This is referred to as dopamine’s indirect sympathomimetic effect. (72)
35. Dopamine is unique in its ability to selectively improve blood flow through the renal and mesenteric beds in shocklike states by binding to postjunctional dopamine-1 receptors. (72)
36. Dopamine, like the other endogenous catecholamines, is rapidly metabolized by MAO and COMT. The rapid metabolism by these enzymes results in dopamine’s half-life of 1 minute. (72)
37. At doses between 0.5 to 2 μg/kg/min the dopamine-1 receptors are stimulated resulting in renal and mesenteric vascular dilation. At doses between 2 to 10 μg/kg/min, the β1 effects predominate with increases in cardiac contractility and cardiac output. At doses greater than 10 μg/kg/min, the α1 effects predominate, and there is generalized vasoconstriction negating any benefit to renal perfusion. (72)
38. Whereas previous literature suggested that low-dose dopamine infusions protected the kidneys and aided in diuresis, recent studies have shown no renal protection when dopamine is administered during periods of global hypoperfusion, and the use of dopamine under these circumstances has been called into question. (72)
Synthetic catecholamines
39. Isoproterenol is bound by the β1– and β2-adrenergic receptors, with its β1 effects predominating. Because it is not taken up into the adrenergic nerve ending like the endogenous catecholamines, its half-life is longer than the endogenous catecholamines. (72)
40. Administration of isoproterenol is associated with marked tachycardia and arrhythmias. As a result, it has been removed from the ACLS resuscitation protocols. Its one remaining use is as a chronotropic agent after cardiac transplantation. (72)
41. Dobutamine stimulates β1-adrenergic receptors without significant effects on β2, α, or dopaminergic receptors. (72)
42. Dobutamine is particularly useful in patients with congestive heart failure (CHF) or myocardial infarction complicated by low cardiac output. Doses lower than 20 μg/kg/min usually do not cause tachycardia. Because dobutamine has no indirect adrenergic action, it is effective even in catecholamine-depleted states such as chronic CHF. While dobutamine treatments have improved exercise tolerance in chronic CHF, they have not been shown to improve survival. (72)
43. Prolonged treatment with dobutamine causes down-regulation of β receptors, and tolerance to its hemodynamic effects is significant after 3 days. To avoid the problem of tachyphylaxis, intermittent infusions of dobutamine have been used in the long-term treatment of heart failure. (72)
44. Fenoldopam is a selective dopamine-1 agonist. (72)
45. Fenoldopam is a potent vasodilator that increases renal blood flow and diuresis. It is usually administered as a continuous infusion at 0.1 to 0.8 μg/kg/min. (72)
46. Because of unconvincing data from clinical trials, fenoldopam is no longer used to treat CHF or chronic hypertension. It is still used as an alternative to sodium nitroprusside to treat severe acute hypertension. Its peak effects occur in 15 minutes. (72)
Noncatecholamine sympathomimetic amines
47. Noncatecholamine sympathomimetic amines exert their effects on the α and β receptors via both direct and indirect actions. The direct effects result from the binding of these compounds to the adrenergic receptors like other sympathomimetic agents. The indirect effects result from the release of endogenous norepinephrine stores that these compounds induce. (73)
48. Mephentermine, metaraminol, and ephedrine. (73)
49. Animal models suggest that ephedrine does not decrease uterine blood flow significantly and, as a result, it has been the drug of choice for treating hypotension in the parturient for many years. Recent studies, however, suggest that phenylephrine causes less fetal acidosis than ephedrine and so the use of phenylephrine to treat hypotension in these laboring patients is on the rise. (73)
50. The response to the indirect sympathomimetic effects of ephedrine wanes as the body’s stores of norepinephrine available for release become depleted. (73)
51. While ephedrine is widely used as a first-line drug to treat intraoperative hypotension, data from the closed-claims database suggest that relying on ephedrine in situations where there is life-threatening hypotension rather than switching early on to epinephrine leads to an increase in morbidity from these events. (73)
α1 Agonists
52. The primary effect of the α1 agonists is to cause vasoconstriction. The rise in blood pressure that results leads to a reflex slowing of the heart rate. These agents are used when blood pressure is low and cardiac output is adequate (e.g., to treat the hypotension that can accompany the delivery of a spinal anesthetic). Phenylephrine is also used when a decrease in afterload compromises coronary perfusion in the context of aortic stenosis. (73)
53. Phenylephrine has a rapid onset of action and a short duration of action (5 to 10 minutes). It can be given as a bolus of 40 to 100 μg or as an infusion starting at 10 to 20 μg/min. (73)
54. Phenylephrine is also a mydriatic and nasal decongestant. It can be applied topically to the nostril to prepare the nose for nasotracheal intubation. (73)
α2-Adrenergic agonists
55. The α2 agonists bind the presynaptic α2 receptor on the postganglionic sympathetic neuron and decrease the release of norepinephrine. This results in a decrease in the overall sympathetic tone of the patient. (73)
56. Besides the decrease in blood pressure, the α2 agonists have sedative, anxiolytic, and analgesic effects. (73)
57. Acute stoppage of chronic clonidine therapy can lead to a rebound hypertensive crisis, so clonidine should be continued throughout the perioperative period. If a patient is unable to take clonidine orally, administration can be topical via a transdermal patch. (73)
58. Labetalol is commonly used to treat clonidine withdrawal syndrome. (73)
59. α2 Agonists reduce the requirements for other intravenous or inhaled anesthetics as part of a general or regional anesthetic technique. (73)
60. Like the β-blockers, the α2 agonists decrease the incidence of myocardial infarction and perioperative mortality in patients undergoing vascular surgeries. (73)
61. Clonidine is used to treat patients with reflex sympathetic dystrophy and other neuropathic pain syndromes. Epidural clonidine has orphan drug approval from the U.S. Food and Drug Administration (FDA) for the treatment of intractable pain. (73)
62. The distribution half-life of dexmedetomidine is less than 5 minutes, making its clinical effect quite short. (73)
63. Because of its short clinical effect dexmedetomidine is run as a continuous infusion of 0.3 to 0.7 μg/kg/hr either with or without a 1 μg/kg loading dose given over 10 minutes. (73)
64. The relatively minor impact of α2 induced sedation on respiratory function combined with its short duration of action has made dexmedetomidine a popular sedative agent for awake fiber-optic intubations. (73)
65. Infusions of dexmedetomidine in the perioperative period in obese patients with sleep apnea minimize the need for narcotics while providing adequate analgesia. (73)
α-Adrenergic receptor antagonists
67. The common side effects of α1-blockers are orthostatic hypotension, fluid retention, and nasal stuffiness. (74)
68. Because phenoxybenzamine irreversibly binds α1 receptors, new receptors must synthesized before complete recovery can occur. (74)
69. The primary clinical effects of phenoxybenzamine are decreased blood pressure and increased cardiac output (both are the result of decreased peripheral vascular resistance). (74)
70. Phenoxybenzamine is most often used to create a “chemical sympathectomy” ahead of resection of a pheochromocytoma (a catecholamine secreting tumor). Effective α-adrenergic blockade in these patients makes arterial pressure less labile intraoperatively and has decreased surgical mortality dramatically. (74)
71. When exogenous sympathomimetic drugs are given following α-blockade, their effects are inhibited. Nevertheless, a phenoxybenzamine overdose is treated with an infusion of norepinephrine. Presumably, this is effective because some of the α receptors remain free of the phenoxybenzamine. (74)
72. Prazosin lowers low-density lipid levels and raises high-density lipid levels. (74)
β-Adrenergic antagonists
73. β-blockers are used in ischemic heart disease, postinfarction management, arrhythmias, hypertrophic cardiomyopathy, hypertension, heart failure, migraine prophylaxis, thyrotoxicosis, and glaucoma. (74)
74. In the 1990s, the Perioperative Ischemia Research Group showed that patients going for surgery who were at risk for coronary artery disease and who were given perioperative β-blockers had a decrease in all cause mortality up to 2 years after surgery. (74)
75. The POBBLE and DIPOM studies showed no survival benefit to initiating β-blockers in patients undergoing vascular surgery or patients with diabetes (two of the “at-risk” groups for coronary artery disease). Furthermore, a large retrospective study showed an increased risk of morbidity in patients started on β-blockers who did not have clear-cut evidence of coronary artery disease. (74)
76. At this point, the only strong indication for initiating β-blockade perioperatively is for patients who need vascular surgery and have evidence of coronary ischemia on preoperative testing. While these are the only indications for initiating β-blockade immediately ahead of surgery, it is important to remember that patients on chronic β-blocker therapy for angina, arrhythmias, or hypertension should continue their β-blockers because acute β-blocker withdrawal can lead to life-threatening events. (74)
77. The β-blockers commonly used during anesthesia are propranolol, metoprolol, labetalol, and esmolol. These intravenous agents are differentiated based on their duration of action and cardioselectivity. (74)
78. With β1 selective blockade, velocity of atrioventricular conduction, heart rate, and cardiac contractility all decrease. Renin release and lipolysis also decrease with β1-blockade. At higher doses, the cardioselectivity of the β1-blockers is lost and β2 receptors are also blocked, which can lead to bronchoconstriction, vasoconstriction, and decreased glycogenolysis. (74)
79. Life-threatening bradycardia or asystole may occur with β-blockade. In addition, β-blockade can precipitate heart failure in patients with compromised cardiac contractility. (75)
80. Diabetes mellitus is a relative contraindication to the long-term use of β-blockers because warning signs of hypoglycemia (tachycardia and tremor) can be masked and because compensatory glycogenolysis is inhibited. (75)
81. To avoid worsening the hypertension in patients with pheochromocytomas, β-blockers should only be given after the patient is fully α blocked. (75)
82. A β-blocker overdose may be treated with atropine. Isoproterenol, dobutamine, glucagon, or cardiac pacing may also be necessary depending on the patient’s symptoms and response to initial therapy. (75)
83. The combination of a β-blocker with either verapamil or digoxin can lead to life-threatening effects on heart rate (verapamil or digoxin) and contractility (verapamil) or conduction (digoxin). (75)
84. Propranolol is highly lipid soluble and extensively metabolized in the liver, so changes in liver function or hepatic blood flow can profoundly affect propranolol’s clinical response and duration of action. (75)
85. Propranolol shifts the oxyhemoglobin dissociation curve to the right. (75)
86. Intravenous dosing for metoprolol is 2.5 to 5 mg every 2 to 5 minutes up to a total dose of 15 mg. The doses are titrated to the patient’s heart rate and blood pressure. (75)
87. Labetalol is a competitive antagonist of the α1– and β-adrenergic receptors. (75)
88. Five to 10 mg of labetalol can be given intravenously every 5 minutes. Because, like propranolol, it is metabolized in the liver, changes in hepatic blood flow affect its clearance. (75)
89. Labetalol is used acutely and chronically to treat hypertension during pregnancy because uterine blood flow is not affected by labetalol therapy, even with significant reductions in blood pressure. (75)
90. Esmolol is hydrolyzed by blood-borne esterases, resulting in a half-life for the drug of only 9 to 10 minutes. (75)
91. Because of its short half-life, esmolol is particularly useful when the duration of β-blockade desired is short or in critically ill patients in whom the adverse effects of bradycardia, heart failure, or hypotension may require rapid discontinuation of the drug. (75)
Cholinergic pharmacology
92. The muscarinic antagonists cause an increase in heart rate, sedation, and dry mouth. (75)
93. The quaternary structure of glycopyrrolate (as opposed to the tertiary structure of atropine and scopolamine) makes it impossible for this larger compound to cross the blood-brain barrier. As a result, glycopyrrolate has fewer CNS effects than the other two muscarinic antagonists. (75-76)
94. Preoperative use of muscarinic antagonists continues in some pediatric and otorhinolaryngologic cases or when planning fiber-optic intubation to dry the oral secretions. (76)
95. Glycopyrrolate is given along with the reversal agent to block the adverse effects (bradycardia) of the anticholinesterase. Glycopyrrolate is used because it has a longer duration of action than atropine and because unlike atropine or scopolamine it does not cross the blood-brain barrier, so there are fewer CNS side effects (sedation or delirium). (76)
96. A scopolamine patch is used prophylactically to protect against postoperative nausea and vomiting. It can be associated with adverse eye, bladder, skin, and psychological effects. (76)
97. The distortion of mentation (delusions and/or delirium) that can result from atropine or scopolamine’s effects on the CNS has been labeled the “central anticholinergic syndrome.” It is treated with physostigmine, a cholinesterase inhibitor that has a tertiary structure that allows it to cross the blood-brain barrier. (76)
98. The cholinesterase inhibitors inhibit the cholinesterase enzyme that normally catalyzes the inactivation of acetylcholine at the nicotinic and muscarinic receptors. As a result, these drugs sustain cholinergic agonism at the cholinergic receptors. (76)
99. The cholinesterase inhibitors are used clinically in the reversal of muscle relaxation produced by nondepolarizing neuromuscular blocking drugs. The accumulation of acetylcholine that results from the administration of the anticholinesterases allows acetylcholine to more effectively compete with nondepolarizing neuromuscular blocking drugs for sites on the nicotinic receptor, thereby overcoming the effects of the paralytic agents. (76)
100. Echothiophate iodine irreversibly binds the cholinesterase enzyme and can interfere with the metabolism of succinylcholine (as the anticholinesterases impair the function of the pseudocholinesterase enzyme as well) leading to a marked prolongation of succinylcholine’s paralytic effects. (76)
