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CHAPTER 196: Antihypertensives 1279 controlled trial of pigs poisoned by propranolol showed a dose response over time, with improvements of cardiac output with increasing HDI doses up to 10 units/kg per hour. No ceiling dose has yet been established. Page et al 50 showed no significant increase in complications between use of lower- and higher-dose insulin in a retrospective study. The hemodynamic response to HDI is usually seen in 15 to 45 minutes, so begin the infusion at 1 unit/kg per hour, and increase the infusion rate if there is no clinical improvement within 30 minutes. Monitor the serum glucose concentrations and adjust the dextrose infusion to maintain an acceptable glucose range. Maintain the HDI infusion until toxicity has resolved; durations of 9 to 49 hours may be necessary. The insulin infusion may be reinstituted if toxicity recurs. Due to persistent elevated insulin concentrations, dextrose supplementation may be required for up to 24 hours after the infusion is discontinued.  GLUCAGON Glucagon, a hormone synthesized by the pancreas, is the therapy of choice for β-adrenergic blocker poisoning because of its ability to bypass the β-adrenergic receptor and stimulate cardiac activity via activation of adenylate cyclase (see Chapter 194, “Beta-Blockers”). In CCB poisoning, the inhibition is downstream from glucagon’s binding site; therefore, glucagon theoretically offers no advantage over other agents. Nevertheless, glucagon administration improves blood pressure in animal models, and several case reports have also noted improvement in hemodynamics after glucagon therapy. 53-56 However, failure to respond has also been reported.43 The recommended glucagon dose is an initial IV bolus of 5 milligrams in adults and 0.03 milligram/kg in children given over 1 to 2 minutes (Figure 195-1). A response is usually seen within 15 minutes. If there is no response, the bolus dose may be repeated. If there is hemodynamic improvement, a maintenance infusion should be initiated at 5 milligrams/kg per hour in adults and 0.05 milligram/kg per hour in children. The main adverse effects of glucagon are vomiting and hyperglyce mia; empirically give ondansetron, once it is determined that there is no QT c prolongation, hypokalemia, or hypomagnesemia. Because of the large amounts of glucagon required, hospital supplies of the drug are often rapidly depleted; plan ahead and consider making arrangements (e.g., with nearby centers) for additional glucagon.  IV LIPID EMULSION THERAPY Lipid emulsion therapy was first described in the management of local anesthetic toxicity. Lipid emulsions appear to create a pharma cologic sink for fat-soluble drugs. 57 Therapy may also provide fatty acid substrate for cardiac energy supply and improve myocyte func tion by increasing intracellular calcium levels. Lipid emulsion therapy prolonged survival in an animal model of verapamil poisoning, 58 and several case reports described benefit in CCB ingestions unresponsive to standard therapy. 59,60 There are many different commercial lipid emulsion preparations, with the major components typically being soybean oil, egg yolk phospholipids, and glycerin. The recommended dose is a 20% lipid emulsion given as a 1.5 mL/kg bolus over 2 to 3 minutes, followed by a 0.25 mL/kg per minute infusion. If the blood pressure remains low, an additional 1.5 mL/kg bolus may be repeated followed by an increase in the infusion rate to 0.5 mL/kg per minute.

k phospholipids, and glycerin. The recommended dose is a 20% lipid emulsion given as a 1.5 mL/kg bolus over 2 to 3 minutes, followed by a 0.25 mL/kg per minute infusion. If the blood pressure remains low, an additional 1.5 mL/kg bolus may be repeated followed by an increase in the infusion rate to 0.5 mL/kg per minute. The recommended upper limit for lipid emulsion infusion is about 10 mL/kg over the initial 30 minutes. If the patient’s hemody namic stability is dependent on continued lipid infusion, the treatment may be continued. 61 Case reports suggest that if sudden cardiac arrest occurs in the setting of overdose, a bolus can be given in the hope of restoring spontaneous circulation. In addition to interference with laboratory parameters (e.g., blood cell count, electrolytes, liver trans aminases), there are rare adverse effects such as hypertriglyceridemia, hypoxemia (with high doses), and hyponatremia.  EXTRACORPOREAL CIRCULATORY SUPPORT With lack of response to aggressive medical therapy, consider circulatory support measures, such as the placement of intra-aortic balloon pumps, the use of left ventricular assist devices, and even extracorporeal mem brane oxygenation, which may provide adequate blood pressure to allow clearance of the drug and resolution of symptoms. 23,62,63 Lipid emulsion therapy can cause complications with extracorporeal membrane oxy genation.64 Contact the extracorporeal membrane oxygenation team before starting lipid emulsion, if extracorporeal membrane oxygenation is to be used. Due to CCB’s large volume of distribution and high affinity for protein binding, hemodialysis and hemoperfusion are not beneficial in the treatment of CCB overdoses. DISPOSITION AND FOLLOW-UP In general, patients usually manifest toxicity within 6 hours of ingestion of IR products. Therefore, those who are asymptomatic and who have normal vital signs and normal ECG after a 6-hour observation period can be discharged after appropriate psychiatric evaluation. 24 Toxicity may be delayed for up to 12 hours after ingestion of ER products. 8,9 As a rule, patients who ingest potentially toxic amounts of ER products should be monitored for at least 24 hours. Contact the regional poison control center for assistance with management. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Antihypertensives Frank LoVecchio Dan Quan INTRODUCTION An estimated 29% of adults in the United States have hypertension; thus, antihypertensives are commonly found in patient homes. 1 Several classes of drugs used to treat hypertension are discussed in this chapter: diuretics, sympatholytic agents, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and vasodilators (Table 196-1). Calcium channel blockers and β-blockers, also used in the treatment of hypertension, are discussed elsewhere (see Chapter 195, “Calcium Channel Blockers, ” and Chapter 194, “Beta-Blockers”). For most of these agents, life-threatening toxicity is not expected in acute overdose. 2 In nearly all cases, good supportive care is adequate. The initial approach to the patient with potential overdose of an anti hypertensive drug is fairly uniform. Secure the airway as necessary, establish IV access, provide continuous cardiac monitoring, and obtain an ECG. A bolus of crystalloid solution is first-line treatment for hypo tension. If a vasopressor is required, a direct-acting drug such as norepinephrine is preferred. If pulmonary aspiration is not a concern, activated charcoal can be given within the first hour. Although there is usually no specific therapy for initial management of these drugs in overdose, the different classes of antihypertensives are distinct in their potential for causing metabolic derangements and adverse effects.

ulmonary aspiration is not a concern, activated charcoal can be given within the first hour. Although there is usually no specific therapy for initial management of these drugs in overdose, the different classes of antihypertensives are distinct in their potential for causing metabolic derangements and adverse effects. DIURETICS Diuretics initially control hypertension by increasing elimination of salts, but their mechanism of action in long-term blood pressure control is not clear. All diuretics cause increased sodium elimination, which results in the potential for hyponatremia, hypokalemia, hyperkalemia, hypomagnesaemia, and hypovolemia. Thiazides, like hydrochlorothiazide, inhibit sodium chloride reabsorption in the renal distal convoluted tubule. Decreased sodium reabsorption leads to increased excretion of potassium and the possibility of hypokalemia. Calcium regulation is also affected by thiazide diuretics via two separate mechanisms: (1) inhibition of vitamin D synthesis and thus decreased calcium absorption from the GI tract, and (2) increased CHAPTER Tintinalli_Sec15_p1187-1332.indd 1279 8/2/19 8:40 PM 1280 SECTION 15: Toxicology TABLE 196-1 Summary of Antihypertensive Drugs Class Drug Mechanism of Action Clinical Presentation With Toxicity Comments Diuretics Chlorothiazide Chlorthalidone Hydrochlorothiazide Indapamide Metolazone Inhibition of distal tubule sodium chloride absorption Hypovolemia Hypokalemia Hypercalcemia Metabolic complications, such as hypokalemia, glucose intolerance, and hyperuricemia seen with increased therapeutic thiazide doses. Bumetanide Furosemide Inhibition of sodium-potassium-chloride symporter in renal loop of Henle Hypovolemia Hypocalcemia Hypokalemia Hypomagnesemia Amiloride Triamterene Inhibition of sodium absorption and potassium elimination in renal distal collecting duct Hypovolemia Hyperkalemia Eplerenone Spironolactone Mineralocorticoid antagonist Hypovolemia Hyperkalemia Sympatholytics Doxazosin Prazosin Tamsulosin Terazosin 1-Adrenergic receptor antagonist Hypotension Phenylephrine may be used for refractory hypotension.

Amiloride Triamterene Inhibition of sodium absorption and potassium elimination in renal distal collecting duct Hypovolemia Hyperkalemia Eplerenone Spironolactone Mineralocorticoid antagonist Hypovolemia Hyperkalemia Sympatholytics Doxazosin Prazosin Tamsulosin Terazosin 1-Adrenergic receptor antagonist Hypotension Phenylephrine may be used for refractory hypotension. Clonidine Guanabenz Guanfacine 2-Adrenergic receptor agonist Imidazoline receptor agonist µ-Receptor opioid agonist Hypotension Bradycardia Neurologic depression Dopamine considered agent of choice for hypotension. Phenylephrine may be used for refractory hypotension. Oxymetazoline Tetrahydrozoline Imidazoline receptor agonist Hypotension Bradycardia Neurologic depression Guanadrel Decreased norepinephrine release Hypotension Methyldopa   Bradycardia Reserpine   Hemolytic anemia (idiosyncratic reaction to methyldopa) Angiotensinconverting enzyme inhibitors Benazepril Captopril Enalapril Fosinopril Moexipril Perindopril Quinapril Trandolapril Inhibition of ACE Inhibition of bradykininase Hypotension Hyperkalemia Angioedema (idiosyncratic) Cough (idiosyncratic) Epinephrine, corticosteroids, and antihistamines have no proven benefit in ACEI-induced angioedema. Icatibant 30 milligrams SC or C1 esterase inhibitor [human] 1000 U IV appear effective in ACEI-induced angioedema. Angiotensin receptor blockers Candesartan Eprosartan Irbesartan Losartan Telmisartan Valsartan Angiotensin II receptor antagonist Hypotension Hyperkalemia Angioedema (less common than with ACE inhibitors) Epinephrine, corticosteroids, or antihistamines have no proven benefit in ARB-induced angioedema. Vasodilators Hydralazine Arteriolar vasodilation Hypotension Lupus-like syndrome (idiosyncratic reaction to hydralazine) Minoxidil Arteriolar vasodilation Tachycardia Increased myocardial oxygen demand Sodium nitroprusside Arteriolar and venous vasodilation (via nitric oxide release) Hypotension Tachycardia Thiocyanate toxicity (after prolonged infusion) Cyanide toxicity (very rare) Thiosulfate should be administered if cyanide toxicity is considered. Many pharmacies mix sodium nitroprusside and thiosulfate to avert cyanide toxicity. Abbreviations: ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; ACEI = angiotensin-converting enzyme inhibitors. Tintinalli_Sec15_p1187-1332.indd 1280 8/2/19 8:40 PM

Sodium nitroprusside Arteriolar and venous vasodilation (via nitric oxide release) Hypotension Tachycardia Thiocyanate toxicity (after prolonged infusion) Cyanide toxicity (very rare) Thiosulfate should be administered if cyanide toxicity is considered. Many pharmacies mix sodium nitroprusside and thiosulfate to avert cyanide toxicity. Abbreviations: ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; ACEI = angiotensin-converting enzyme inhibitors. Tintinalli_Sec15_p1187-1332.indd 1280 8/2/19 8:40 PM CHAPTER 196: Antihypertensives 1281 renal absorption of calcium. The net result, however, is calcium reten tion and potentially hypercalcemia. 3 Glucose intolerance is noted at higher doses. Loop diuretics, such as furosemide and bumetanide , are used more frequently for control of edema and pulmonary congestion than for hypertension. Loop diuretics inhibit the activity of the sodiumpotassium-chloride symporter (a type of cotransporter that facilitates transport across a plasma membrane) in the renal loop of Henle, where 25% of the filtered sodium load is typically reabsorbed. A secondary effect of the inhibition of this symporter is decreased calcium and mag nesium reabsorption, which results in hypocalcemia, hypokalemia, and hypomagnesemia. Triamterene, amiloride , spironolactone , and eplerenone are referred to as potassium-sparing diuretics for their ability to cause a sodium chloride diuresis without increased potassium secretion. Triamterene and amiloride inhibit sodium channels in the distal renal tubule and collecting duct, which play a role in both reabsorbing sodium and secreting potassium. These drugs may be used in conjunction with other stronger diuretics for management of hypertension. Triamterene has been associated with rare cases of crystalline nephropathy. Spironolactone and eplerenone are antagonists of mineralocorticoids such as aldosterone. Mineralocorticoid antagonists increase elimination of sodium and retention of hydrogen and potassium. Spironolactone is typically used to treat heart failure and hepatic cirrhosis. In the acute overdose setting, hyperkalemia and hypotension are the most serious clinical manifestations of these drugs. Clinical manifestations of excessive diuresis include tachycardia, hypotension (orthostatic or supine), electrolyte abnormalities, and generalized weakness. The ECG may show changes caused by these electrolyte abnormalities (see Chapter 17, “Fluids and Electrolytes”). A widened QRS interval or peaked T waves may suggest hyperkalemia, such as from a potassium-sparing diuretic. A prolonged QT interval may indicate hypokalemia, hypomagnesemia, or hypocalcemia, which may be caused by a loop diuretic. The first priority of therapy is restoration of plasma volume. Administer an isotonic crystalloid solution bolus, such as 0.9% saline. Treat electrolyte abnormalities, such as hyperkalemia, hypokalemia or hypocalcemia, with standard management and fluid resuscitation (see Chapter 17, “Fluids and Electrolytes”). In addition to causing direct toxicity, diuretics may potentiate toxicity from other medications. Mechanisms include decreased renal clearance of drugs or creation of a metabolic state that changes a particular drug’s effect. Diuretics and ACEIs can increase the risk of lithium toxicity by reducing lithium elimination (see Chapter 181, “Lithium”). 5 Hypokalemia from diuretics may exacerbate arrhythmias seen in chronic digoxin poisoning or other antiarrhythmics (see Chapter 193, “Digitalis Glycosides”). SYMPATHOLYTIC AGENTS Catecholamines produced by the sympathetic nervous system play a key role in maintaining blood pressure. Drugs with action at α-adrenergic receptors are used to diminish peripheral sympathetic tone in order to decrease blood pressure. There are two subtypes of α-adrenergic recep tors. Stimulation of the α 1-adrenergic receptors causes vasoconstriction of arterioles and veins, increasing peripheral vascular resistance and elevating blood pressure.

renergic receptors are used to diminish peripheral sympathetic tone in order to decrease blood pressure. There are two subtypes of α-adrenergic recep tors. Stimulation of the α 1-adrenergic receptors causes vasoconstriction of arterioles and veins, increasing peripheral vascular resistance and elevating blood pressure. Stimulation of the α 2-adrenergic receptors produces different effects in the peripheral and central nervous systems. In the peripheral nervous system, stimulation of the α 2-receptors produces vasoconstriction and increases blood pressure. In the CNS, stimulation of the α 2-receptors at presynaptic sympathetic terminals inhibits the release of catecholamines, thereby decreasing sympathetic tone, promoting peripheral vasodilation, and decreasing blood pressure.  DOXAZOSIN, PRAZOSIN, AND TERAZOSIN Doxazosin, prazosin, and terazosin antagonize α 1-adrenergic receptors, reducing peripheral vascular resistance. Although the aforemen tioned drugs are used for the treatment of hypertension, other members of this class, such as tamsulosin, are used exclusively for management of benign prostatic hyperplasia and as an adjunct in nephrolithiasis management. Because an increase in peripheral vascular resistance is required to maintain blood pressure when changing from a supine to an upright position, it is not surprising that the most typical adverse effect observed with α 1-adrenergic antagonists is orthostatic hypotension, particularly within 30 to 90 minutes after ingestion, and is most prominent after taking the first dose. Although orthostatic hypotensive episodes may be associated with lightheadedness and adverse events such as falls resulting in hip fracture, patients rarely come to the ED with prolonged hemodynamic instability. Patients who do present with hypotension associated with α 1-adrenergic antagonist use should be placed supine and receive a crystalloid bolus. Based on the mechanism of action of these drugs, α 1-adrenergic agonists should be used if blood pressure does not improve with IV fluids. 7  CLONIDINE Clonidine is the most commonly used α 2-adrenergic agonist. Clonidine is available in an oral formulation and as a transdermal patch. This class of drugs, which also includes guanabenz and guanfacine, stimulates α 2adrenergic receptors in the CNS, inhibiting release of catecholamines in the periphery, which results in decreased heart rate, contractility, and peripheral vascular resistance. Clonidine shares the imidazoline func tional group with the nasal spray decongestant oxymetazoline and topical eye vasoconstrictor medication tetrahydrozoline. Inappropriately ingesting oxymetazoline or tetrahydrozoline can result in toxicity similar to clonidine poisoning. 8,9 In addition to hemodynamic effects, clonidine also possesses opioid agonist properties at the µ receptor. 10 For this reason, clonidine is used in some opioid-dependent patients to ameliorate symptoms of withdrawal. Clonidine poisoning typically results from either intentional overdose or exploratory pediatric poisoning. 11,12 Even a single tablet may cause significant symptoms in a child. 13,14 Toxicity can develop from ingesting clonidine patches.15,16 Compounded ointments used for chronic pain may contain clonidine; application of these patches to small children (or to adults in excessive quantity) may produce toxicity. 17-19 Shortly after an ingested overdose of clonidine, the peripheral α 2adrenergic stimulation may cause hypertension.12,20 By the time of pre sentation, however, the clinical manifestations of central α 2-adrenergic stimulation and imidazoline toxicity are present with bradycardia, CNS depression, and hypotension.

y. 17-19 Shortly after an ingested overdose of clonidine, the peripheral α 2adrenergic stimulation may cause hypertension.12,20 By the time of pre sentation, however, the clinical manifestations of central α 2-adrenergic stimulation and imidazoline toxicity are present with bradycardia, CNS depression, and hypotension. 11,21 Clonidine may produce miotic pupils in a manner similar to opioids.22 Hypothermia may occur as a result of opioid or adrenergically mediated pathways. Somnolence is typical and may progress to apnea in severe cases. 8,11,23 Although clonidine is intended to be dosed twice daily, symptoms may last days with an overdose. Focus on ventilatory and hemodynamic support in clonidine toxicity.21,24 Clonidine-induced respiratory and neurologic depression has variable response to naloxone, and its use is unlikely to be helpful in adults 21,25-29; however, it is considered to be more effective in children. 28 Bradycardia may be treated with atropine. When encountered, hypertension should be treated only if it is severe and prolonged, because hypertension may unpredictably give way to hypotension. If it is necessary to treat clonidine-associated hypertension, use a short-acting drug that can be quickly discontinued (e.g., nitroprusside). Hypotension associated with clonidine typically responds well to crystalloid fluid resuscitation.  METHYLDOPA Methyldopa is also a centrally acting antihypertensive, although it has a unique mechanism. Methyldopa is a dopamine analog that, in the CNS, is converted in two steps to α-methylnorepinephrine, which in turn substitutes for norepinephrine in adrenergic neuron secretory vesicles. In the CNS, α-methylnorepinephrine stimulates presynaptic α 2-adrenergic receptors, reducing peripheral sympathetic tone. In therapeutic dosing, the peak effect of methyldopa is delayed for 6 to 8 hours, because time is required for methyldopa to pass into the brain and be converted to its active form. Methyldopa use is also associated with an autoimmune hemolytic anemia, which can occur during long-term therapeutic use. 30,31 If symptomatic hypotension is encountered in association with methyldopa, IV crystalloid solution should be administered. In cases Tintinalli_Sec15_p1187-1332.indd 1281 8/2/19 8:40 PM

ive form. Methyldopa use is also associated with an autoimmune hemolytic anemia, which can occur during long-term therapeutic use. 30,31 If symptomatic hypotension is encountered in association with methyldopa, IV crystalloid solution should be administered. In cases Tintinalli_Sec15_p1187-1332.indd 1281 8/2/19 8:40 PM 1282 SECTION 15: Toxicology of refractory, severe hypotension, a direct-acting vasopressor such as norepinephrine should be administered.32  GUANADREL AND RESERPINE Guanadrel and reserpine are antihypertensives that interfere with the release of catecholamines from synaptic terminals. Guanadrel, which has no intrinsic sympathetic activity, substitutes for norepinephrine in presynaptic storage vesicles. Reserpine inhibits formation of biogenic amine storage vesicles in central and peripheral neurons. In each case, there is a decreased capacity to release catecholamines in response to a sympathetic stimulus. Sympathetic tone is diminished, and peripheral vascular resistance decreases. There is little experience with these drugs in overdose. However, because the common mechanism of both drugs is a decrease in circulating catecholamines, it would seem reasonable to administer boluses of crystalloid as first-line therapy and to use a directacting vasopressor, such as norepinephrine or phenylephrine, to treat refractory hypotension. ANGIOTENSIN-CONVERTING ENZYME INHIBITORS AND ANGIOTENSIN RECEPTOR BLOCKERS Angiotensin II raises blood pressure by several mechanisms, including triggering aldosterone release, increasing response to catecholamines, and acting as a direct vasoconstrictor. Angiotensin II is created in a two-step process. In the first step, renin, released by the kidneys, cleaves angiotensinogen, forming angiotensin I. The second step uses angiotensin-converting enzyme, which separates the carboxy terminus off angiotensin I, forming angiotensin II. Inhibition of this conversion at either step results in decreased blood pressure. ACEIs are thought to slow the progression of diabetic glomerulopathy and have been shown to improve mortality and left ventricular function when administered after myocardial infarction. Members of this large class of drugs can be identified by their shared “-pril” suffix: benazepril, captopril, enalapril, fosinopril, moexipril, perindopril, quinapril, and trandolapril. Inhibition of angiotensin-converting enzyme results in decreased production of angiotensin II, which causes vasodilation. Despite their widespread use, these medications have not been associ ated with significant morbidity in overdose. ACEIs can cause hyperkalemia in therapeutic dosing. If hypotension is encountered, initial therapy focuses on basic management, including administration of boluses of crystalloid and vasopressors for refractory cases. Captopril, and possibly other ACEIs, are thought to inhibit the metabolism of the enkephalins, a group of endogenous opioids. Naloxone, a µ-opioid antagonist, may reverse captopril-associated hypotension 33 but is not universally effective.34 ARBs produce vasodilatation and increase renal salt elimination. Members of this class end with the suffix “-artan” and include losartan, candesartan, irbesartan, valsartan, telmisartan, and eprosartan . When they are taken therapeutically, the peak antihypotensive effect of agents in this class is not observed for 4 weeks. Typically, these drugs are not associated with significant morbidity in overdose. There are no reported cases of isolated ARBs overdose causing life-threatening hypotension. Like ACEIs, ARBs can cause hyperkalemia, which results from decreased aldosterone production. This effect is typically seen in patients with renal insufficiency.

e drugs are not associated with significant morbidity in overdose. There are no reported cases of isolated ARBs overdose causing life-threatening hypotension. Like ACEIs, ARBs can cause hyperkalemia, which results from decreased aldosterone production. This effect is typically seen in patients with renal insufficiency. Persistent dry cough occurs in 5% to 20% of patients treated with ACEIs.35 Cough typically develops within a few weeks after ACEI ther apy is started and is more common in women, and the rate of occurrence or severity does not correlate with dose. Cough will usually resolve in 1 to 4 weeks after the drug is stopped, although resolution may take up to 3 months for some patients. The only effective treatment is discontinu ing the ACEI, substituting a different antihypertensive. ARBs are not associated with an increased incidence of chronic cough and may be used in patients with ACEI-induced cough. Angioedema is the most consequential adverse effect associated with ACEIs and ARBs (see Chapter 14, “ Allergy and Anaphylaxis”).37-39 Angioedema is an idiopathic reaction that occurs in 0.1% to 0.7% of patients prescribed these drugs. 38,40 Because these agents are widely used, this small percentage represents a large number of events. Patients present with swelling of the lips, larynx, pharynx, tongue, or vocal cords, which can range in severity from mild to airway compromise. Symptoms develop over several hours and may not resolve for 24 hours or longer. The absence of urticaria, abdominal swelling, and genitourinary swelling differentiates ACEI-induced angioedema from histaminemediated causes. 41 The mechanism is thought to be related to inhibition of ACE-mediated degradation of bradykinin, a peptide associated with vasodilatation and tissue edema, and accumulation of substance P and other prostaglandins. 39,41 ARBs do not inhibit bradykinin, so the exact pathophysiology of angioedema associated with drugs from this class is not clear. The mean time from first use to development of angio edema has been reported as about 2 years, 42 but angioedema can occur at any time during therapy, with 12% of patients developing this reaction in the first week of ACEI use. Management of ACEI-induced angioedema begins with evaluation of the airway. If the patient has difficulty breathing, stridor, or lingual or oropharyngeal edema, secure the airway, usually by intubation. Fiberoptic-guided laryngoscopy is recommended because it requires minimal sedation and provides direct visualization in an edematous airway. Regardless of the method employed, a skilled operator should secure the airway early because angioedema can progress rapidly and anatomic landmarks may become obscured. Allergic-reaction drugs, such as epinephrine, antihistamines, and corticosteroids, are often given but not likely beneficial because ACEIinduced angioedema is not mediated by histamines or immunoglobulins. 38 Agents reported beneficial in ACEI-induced angioedema include icatibant, a bradykinin-2 antagonist, at a dose of 30 milligrams SC44; C1 esterase inhibitor (human) 1000 units IV 45; and fresh frozen plasma 2 units,46,47 but the overall quality of evidence is mixed.48,49 Patients with milder symptoms should be observed and managed medically. There is no consensus regarding the disposition of patients with ACEI-associated angioedema who do not require ED airway intervention. Patients with milder swelling only around the lips or face should be observed for 6 to 12 hours and considered for discharge when swelling begins to regress. 41 Patients should be instructed that angio edema can recur if they continue to take the same agent or switch to another agent of the same class.

ay intervention. Patients with milder swelling only around the lips or face should be observed for 6 to 12 hours and considered for discharge when swelling begins to regress. 41 Patients should be instructed that angio edema can recur if they continue to take the same agent or switch to another agent of the same class. 50,51 After an episode of angioedema, the safest and recommended course of action is to discontinue all ACEIs and ARBs. VASODILATORS  HYDRALAZINE AND MINOXIDIL Hydralazine is an antihypertensive agent most commonly used during pregnancy. Hydralazine relaxes arteriolar smooth muscle but does not affect venous smooth muscle or epicardial coronary arteries. Hydrala zine is metabolized to an inactive compound by hepatic acetylation. Roughly half of Americans are fast acetylators and therefore require a higher dose to achieve a given clinical effect. The peak effect of the drug is seen 30 to 120 minutes after ingestion, although effects may last as long as 12 hours. The most common adverse effects of hydralazine overdose result from vasodilatation, but serious events are rare. Patients with hydralazine overdose with mild hypotension may develop ST-segment depression on ECG. 52 This myocardial ischemia is thought to result from a steal syndrome in which peripheral vasodilatation is accompanied by reflex tachycardia without an increase in epicardial blood flow, so that myocardial demand increases while coronary perfusion does not. Because of this reflex tachycardia, hydralazine should not be used for treatment of acute coronary syndrome or cocaine-associated chest pain. Patients on continuous treatment with hydralazine are at risk for development of a lupus-like syndrome. The mechanism is thought to be formation of autoantibodies, but it is not known how hydralazine con tributes to this process. Risk factors include high dose, female gender, slow-acetylator phenotype, and white ethnic background. Symptoms of this syndrome include arthralgia, arthritis, fever, and pericardial Tintinalli_Sec15_p1187-1332.indd 1282 8/2/19 8:40 PM