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CHAPTER 19:  Pharmacology of An tiarrhythmics and An tihypertensives      123 tachycardia or ventricular fibrillation, and/or sudden cardiac death), family history (close relative with sudden cardiac death, diagnosed syn drome, or sudden infant death syndrome), and identified mutations in one of eight known genes. 98,114,115  TREATMENT Asymptomatic, incidental discovery should result in cardiology refer ral. Symptomatic presentation with concerning findings should include cardiology evaluation and/or admission. Current recommendations are that an implanted defibrillator be placed in patients who have had episodes of ventricular tachycardia or fibrillation and be considered in those with a strong family history of sudden cardiac death. 115 Pharmacologic therapy with quinidine is recommended in symptomatic individuals and in asymptomatic patients with a strong family history of sudden cardiac death. 114,115 ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY  DESCRIPTION Arrhythmogenic right ventricular cardiomyopathy, also known as arrhythmogenic right ventricular dysplasia, is an inherited myocardial disease associated with sudden cardiac death. 116-118 The pathogenesis includes a fibrofatty replacement of right ventricular myocardium. The prevalence of arrhythmogenic right ventricular cardiomyopathy is 1 in 5000 to 10,000 persons; it is more common in men (3:1 male:female ratio) and those with a Mediterranean heritage. As with the other inherited arrhythmogenic disorders, a family history of unexplained (or explained) sudden cardiac death is present. Patients may also develop subacute to acute right ventricular heart failure, eventually progressing to biventricular failure.  CLINICAL FEATURES Patients typically present with palpitations and syncope due to ventric ular tachycardia, which may be transient or sustained. Other manifestations include circulatory shock, cardiac arrest, and right ventricular failure. ECG features suggestive of arrhythmogenic right ventricular cardiomyopathy include the following: epsilon wave (seen in 30% of patients); T-wave inversions in leads V 1 to V 3 (85% of patients); a prolonged S-wave upstroke (55 milliseconds) in leads V 1 to V 3 (95% of patients); QRS complex widening (110 milliseconds) seen in leads 1 to V 3; and in patients with ventricular dysrhythmia, paroxysmal episodes of ventricular tachycardia with left bundle branch block morphology. 116,117 The epsilon wave—a terminal irregularity of the QRS complex occur ring at the J point—is the most specific finding of arrhythmogenic right ventricular cardiomyopathy yet is seen in only 30% of afflicted patients. A prolonged upstroke of the S wave of 55 milliseconds in the anterior leads is also suggestive of arrhythmogenic right ventricular cardiomyopathy. The diagnosis of arrhythmogenic right ventricular cardiomyopathy is complex and based on a combination of clinical, ECG, biopsy, and echocardiographic features, with little application in the ED. 116,117 For the emergency provider, when the ECG demonstrates the combination of an epsilon wave and anterior ECG lead findings (deep S-wave upstroke and T-wave inversion), the diagnosis can be considered, particularly in a patient with palpitations, syncope, family history of sudden death, and/ or resuscitation from cardiac arrest.  TREATMENT Asymptomatic discovery of an epsilon wave should prompt a referral to a cardiologist.

G lead findings (deep S-wave upstroke and T-wave inversion), the diagnosis can be considered, particularly in a patient with palpitations, syncope, family history of sudden death, and/ or resuscitation from cardiac arrest.  TREATMENT Asymptomatic discovery of an epsilon wave should prompt a referral to a cardiologist. Symptomatic patients with suggestive clinical features should be admitted for cardiology evaluation. Active dysrhythmias, most often a malignant ventricular dysrhythmia, are managed in standard manner. Patients with high-risk features (e.g., prior history of cardiac arrest, ventricular tachydysrhythmias, or strong family history of sudden car diac death) likely require insertion of an implantable cardiac defibrilla tor. Patients lacking high-risk features can be managed with β-blockers (e.g., sotalol) or amiodarone, as prescribed by a cardiologist. Persistent malignant dysrhythmias can be managed with ablation. Heart failure, whether right or biventricular, is managed in standard fashion. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Pharmacology of Antiarrhythmics and Antihypertensives Sara Haney Shields Rachel M. Holland Benjamin Small This chapter reviews common antiarrhythmic and antihypertensive medications administered in the ED. Acute medical conditions presenting with systemic hypertension and the specific recommended antihy pertensive agents are presented in Chapter 57, “Systemic Hypertension. ” Antiarrhythmic medications treat cardiac rhythm abnormalities by modifying autonomic function or myocardial ion channels, leading to changes in conduction velocity or duration of the effective refractory period. 1 Long-term use of these agents to prevent arrhythmias has not been proven to reduce mortality 2-5; however, this chapter focuses on medications used for acute pharmacologic conversion or rate control of common arrhythmias. In general, electrical cardioversion is prefer able to pharmacologic conversion in patients who are hemodynamically unstable. The majority of antiarrhythmics are organized based on the Vaughan-Williams classification system (classes I to IV) ( Table 19-1). This chapter also discusses the emergency applications of atropine, adenosine, magnesium, and isoproterenol. CLASS I ANTIARRHYTHMICS: FAST SODIUM CHANNEL BLOCKERS Class I agents block fast sodium channels and are further categorized based on their degree of blockade into classes Ia (moderate blockade), Ib (weak blockade), and Ic (strong blockade). They increase the excitability threshold, requiring more sodium channels to open in order to over come the potassium current and generate an action potential. This effect CHAPTER TABLE 19-1 Vaughan-Williams Classification of Antiarrhythmic Medications Action Class Selected Example Medications Sodium channel blockers Class Ia Procainamide Class Ib Lidocaine Class Ic Flecainide, propafenone β-Blockers Class II Esmolol, labetalol, metoprolol, propranolol Potassium channel blockers Class III Amiodarone, dronedarone, dofetilide, ibutilide, sotalol*, vernakalant† Calcium channel blockers Class IV Diltiazem, verapamil, nicardipine *Also a β-blocker. †Not available in the United States; available in Canada and Europe. Tintinalli_Sec03_p0053-0142.indd 123 8/2/19 2:57 PM

olol Potassium channel blockers Class III Amiodarone, dronedarone, dofetilide, ibutilide, sotalol*, vernakalant† Calcium channel blockers Class IV Diltiazem, verapamil, nicardipine *Also a β-blocker. †Not available in the United States; available in Canada and Europe. Tintinalli_Sec03_p0053-0142.indd 123 8/2/19 2:57 PM 124 SECTION 3: Resuscitation TABLE 19-2 Procainamide Pharmacokinetics (Adults) Distribution Metabolism Excretion Half-Life Onset/ Duration of Action 2 L/kg Hepatic and renal Active metabolite: NAPA (renal elimination) Urine, feces Procainamide: 2.5–4.7 h NAPA: 6–8 h (prolonged with renal impairment) Onset (IV): immediate Duration: 3–6 h Abbreviation: NAPA = N-acetylprocainamide. TABLE 19-3 Procainamide IV Dosing and Administration (Adults) for Regular Wide-Complex Tachycardia* •   Initial: 20–50† milligrams/min OR 100 milligrams every 5 min until arrhythmia is suppressed, hypotension occurs, or the QRS complex is prolonged by 50% from its original duration (maximum dose: 17 milligrams/kg) •   Maintenance infusion rate: 1–4 milligrams/min *Not recommended in patients with pulseless ventricular arrhythmias due to prolonged administration rate and unclear efficacy. †Slower administration preferred if patient is stable. TABLE 19-4 Lidocaine Pharmacokinetics (Adults) Distribution Metabolism Excretion Half-Life Onset/ Duration of Action 0.9–2.1 L/kg Hepatic Active metabolites Urine Initial: 7–30 min Terminal: 1.5–2 h (prolonged in congestive heart failure, liver disease, and severe renal impairment) Onset: 45–90 s Duration: 10–20 min TABLE 19-5 Lidocaine IV Dosing and Administration (Adults) Ventricular Arrhythmia Ventricular Fibrillation Loading dose: 50–100 milligrams over 2–3 min. May repeat in 5 min (up to 300 milligrams in any 1-h period) Maintenance: 1–4 milligrams/min (start low in patients with liver dysfunction or CHF) Initial dose: 1–1.5 milligrams/kg If refractory VF/pulseless VT, repeat 0.5–0.75 milligram/kg every 5–10 min (maximum total dose: 3 milligrams/kg) Abbreviations: CHF = congestive heart failure; VF = ventricular fibrillation; VT = ventricular tachycardia. increases the refractory period and can be useful in terminating reentry currents. In addition, some class I agents block potassium channels and exhibit antimuscarinic effects.  PROCAINAMIDE Actions Procainamide increases the refractory period, decreases automaticity and conduction, and prolongs cardiac action potentials through intermediate blockade of open sodium and potassium chan nels. N-Acetylprocainamide, the active metabolite of procainamide, lacks sodium channel effects but does block potassium channels, which can lead to QT prolongation. Pharmacokinetics See Table 19-2.6 Indications Procainamide is indicated for life-threatening ventricu lar arrhythmias and supraventricular arrhythmias. Although it can be used to treat supraventricular tachycardia, the proarrhythmic nature of this agent (including torsades de pointes) and the risk of toxicity make procainamide less desirable for this indication. For hemodynamically stable ventricular tachycardias, procainamide, at a dose of 10 milli grams/kg, was shown in the PROCAMIO trial to be more effective than amiodarone, 5 milligrams/kg, for conversion to sinus rhythm (68% vs. 48%) with fewer adverse events (24% vs. 48%). 7 Procainamide should be avoided in patients with prolonged QT intervals or symptomatic congestive heart failure (CHF). 8,9 Procainamide is reported as an effec tive agent for rhythm control in atrial fibrillation of onset <48 hours. 10 The dose is not standardized, but one method is administering 1 gram of procainamide in 250 mL of 5% dextrose in water over 60 to 120 minutes with continuous cardiac and blood pressure monitoring.

(CHF). 8,9 Procainamide is reported as an effec tive agent for rhythm control in atrial fibrillation of onset <48 hours. 10 The dose is not standardized, but one method is administering 1 gram of procainamide in 250 mL of 5% dextrose in water over 60 to 120 minutes with continuous cardiac and blood pressure monitoring. Stop the infusion for blood pressure <100 mm Hg or heart rate <60 beats/min or rate conversion. Dosing and Administration See Table 19-3.6 Adverse Effects The most common adverse effects associated with procainamide are hypotension, cardiac conduction abnormalities, and rash. Serious adverse effects include prolonged QT interval, torsades de pointes, ventricular fibrillation, paradoxical increase in ventricular rate in atrial fibrillation/flutter, hepatotoxicity, and CHF .  LIDOCAINE Actions Lidocaine is a class Ib agent with weak sodium channel– blocker properties that preferentially acts on ischemic myocardial tissue to decrease conduction; in addition, it has local anesthetic properties. Effects exerted on the cardiac action potential are negligible, with very minimal decrease to no effect on the QT interval and the refractory period. Pharmacokinetics See Table 19-4.6 Indications Lidocaine is indicated in the acute management of ven tricular arrhythmias. Consider lidocaine for patients with pulseless ventricular tachycardia or ventricular fibrillation as an alternative agent to amiodarone in patients unresponsive to CPR, defibrillation, and vasopressors. Also, consider lidocaine maintenance in the event of return of spontaneous circulation after lidocaine is used in the treatment of pulseless ventricular tachycardia/ventricular fibrillation. Dosing and Administration See Table 19-5.6 Adverse Effects Adverse effects of lidocaine are typically dose dependent or due to rapid bolus infusion rates. Lower infusion rates reduce adverse hemodynamic effects. Patients should be monitored for CNS effects, including numbness, speech impairment, somnolence, dizziness, and seizures.  PROPAFENONE AND FLECAINIDE Class Ic agents, propafenone and flecainide, evoke strong blockade of fast sodium channels. They are most commonly used for supraven tricular tachycardia because they slow conduction and frequently restore sinus rhythm. Propafenone has additional β-adrenergic–blocking properties; therefore, it can cause bradycardia and bronchospasm. It is more selective for cells with high rates of conduction. Flecainide reduces excitability primarily in the His-Purkinje system and ventricular myo cardium. Both agents are indicated for the conversion of recent-onset atrial fibrillation (<7 days) to sinus rhythm. 11 They also carry indications for paroxysmal supraventricular ventricular tachycardia and ventricular tachycardia but are rarely used for these indications in the ED. Propafenone is given as a one-time oral dose of 450 milligrams (weight <70 kg) or 600 milligrams (weight ≥70 kg). Adverse effects include hypotension, bradycardia, bronchospasm, atrial flutter, and ventricular arrhythmias. Propafenone should be avoided in patients with CHF , coronary artery disease, structural heart disease, bronchospasm, or hepatic dysfunction. Flecainide is given as a one-time oral dose of 200 milligrams (weight <70 kg) or 300 milligrams (weight ≥70 kg). Adverse effects are similar to propafenone with the exception of bradycardia and bronchospasm. Flecainide should be avoided in patients with hypokalemia, atrioven tricular block, coronary artery disease, significant structural heart dis ease, or CHF . Long-term use of these agents for arrhythmia prevention Tintinalli_Sec03_p0053-0142.indd 124 8/2/19 2:57 PM

one with the exception of bradycardia and bronchospasm. Flecainide should be avoided in patients with hypokalemia, atrioven tricular block, coronary artery disease, significant structural heart dis ease, or CHF . Long-term use of these agents for arrhythmia prevention Tintinalli_Sec03_p0053-0142.indd 124 8/2/19 2:57 PM CHAPTER 19:  Pharmacology of An tiarrhythmics and An tihypertensives      125 TABLE 19-6 Class II Antiarrhythmics: β-Blockers (Selected) Generic Name Onset of Action Duration of Action Metabolism Half-Life Indications Adverse Effects Noncardioselective Propranolol Oral: 1–2 h IV: ≤1 min Oral: IR: 6–12 h ER: 24–27 h IV: 4–6 h Hepatic, extensive first-pass elimination IR: 3–6 h ER: 8–10 h HTN, supraventricular arrhythmias, ventricular tachycardias Bradycardia, heart block, hypotension, worsening heart failure, bronchospasm Propranolol dose Tachyarrhythmias: 1–3 milligrams/dose slow IVP; may repeat every 2–5 min up to a total of 5 milligrams OR 0.5–1 milligram IV over 1 min; may repeat, if necessary, up to a total maximum dose of 0.1 milligram/kg OR 1 milligram IV over 1 min; may be repeated every 2 min up to 3 doses for rate control in patients with AFib Oral: 10–30 milligrams every 6–8 h for tachyarrhythmias Cardioselective Esmolol IV: 2–10 min IV: 10–30 min In blood by RBC esterases 9 min HTN, SVT, AFib/AFL (rate control) Hypotension, bradycardia, heart block, injection site reaction, nausea, bronchospasm, pulmonary edema; abrupt discontinuation may cause rebound HTN or angina Esmolol dose 500 micrograms/kg bolus (optional) over 1 min followed by an infusion starting at 50 micrograms/kg/min titrated to therapeutic effect in 50 micrograms/kg/min increments every 4 min to a maximum of 200 micrograms/kg/min. To achieve more rapid response, two additional 500 micrograms/kg bolus doses may be given prior to increasing the infusion rate to 100 micrograms/kg/min (after second bolus) and 150 micrograms/kg/min (after third bolus), as required. After 4 min at the rate of 150 micrograms/kg/min, the infusion rate may be increased to a maximum rate of 200 micrograms/kg/min (without an additional bolus dose).

may be given prior to increasing the infusion rate to 100 micrograms/kg/min (after second bolus) and 150 micrograms/kg/min (after third bolus), as required. After 4 min at the rate of 150 micrograms/kg/min, the infusion rate may be increased to a maximum rate of 200 micrograms/kg/min (without an additional bolus dose). Metoprolol Oral (IR): ≤1 h IV: 20 min Oral: IR: variable ER: ~24 h IV: 5–8 h Hepatic, extensive first-pass elimination 3–4 h HTN, acute MI, angina Bradycardia, heart block, hypotension, bronchospasm Metoprolol dose AFib/AFL (rate control): 2.5–5 milligrams IV every 2–5 min (maximum total dose: 15 milligrams IV over 10–15 min) SVT: 2.5–5 milligrams IV bolus over 2 min; may repeat within a 10-min period, up to 3 doses HTN: 1.25–5 milligrams IV every 6–12 h; titrate to response Oral: start 50 milligrams immediate release twice daily; maximum 200 milligrams twice daily Vasodilatory, Noncardioselective Labetalol Oral: 20 min–2 h IV: ≤5 min Oral: 8–12 h* IV: 16–18 h* Hepatic, extensive first-pass elimination Oral: 6–8 h IV: ~5.5 h HTN Orthostatic hypotension, heart failure, hyperkalemia, hepatotoxicity, bronchospasm, nausea, dizziness, fatigue Labetalol dose Initial: 10–20 milligrams IVP over 2 min; may administer additional injections using double the dose (maximum: 80 milligrams/dose) at 10-min intervals until target SBP is reached (up to 300 milligrams total cumulative dose) Continuous infusion: Initial: 0.5–2 milligrams/min; titrate to response (range: 2–10 milligrams/min) Oral: start 100 milligrams twice daily, maximum 400 milligrams twice daily Carvedilol 30–60 min IR 14–20 h Hepatic IR 7–10 h HTN Hypotension, bradycardia, syncope, dizziness, hyperglycemia, weight gain Carvedilol dose 6.25 milligrams orally twice daily, reduce dose if heart rate drops to <55 beats/min; if tolerated, may double dose in 2 wk as needed Abbreviations: AFib = atrial fibrillation; AFL = atrial flutter; ER = extended release; HTN = hypertension; IR = immediate release; IVP = IV push; MI = myocardial infarction; RBC = red blood cell; SBP = systolic blood pressure; SVT = supraventricular tachycardia. *Dose dependent. in patients with cardiovascular disease, particularly after myocardial infarction, is associated with increased mortality.3,12 CLASS II ANTIARRHYTHMICS: β -BLOCKERS β-Blockers have various indications, including hypertension, supra ventricular ventricular tachycardia and ventricular arrhythmias, rate control in recurrent atrial fibrillation, and symptom control in thyro toxicosis. Although these medications share the principal characteristic of blocking catecholamine effects on β-receptors, individual agents dif fer with respect to their cardioselectivity, α-adrenergic–blocking activity, intrinsic sympathomimetic activity, membrane-stabilizing effect, and pharmacokinetic properties ( Table 19-6). β-Receptors are divided into two subtypes. β 1-Receptors are found in heart muscle, and β 2-receptors are found in bronchial and vascular smooth muscle. Nonselective β-blockers target all β-receptors, thereby affecting heart rate, conduc tion, and contractility, as well as smooth muscle contraction, thus increasing the risk of bronchospasm. In contrast, cardioselective agents have relative selectivity for β 1-receptors and decrease heart rate and blood pressure. These agents may be a better option for patients with a history of asthma, chronic obstructive pulmonary disease, or insulindependent diabetes because they are less likely to act on β 2-receptors. Because cardioselectivity is dose dependent, it decreases or is lost at higher doses. This is variable between agents, and the dose at which this occurs has not been clearly established. With the exception of sotalol (discussed below), all listed β-blockers are indicated for the treatment of hypertension.

2-receptors. Because cardioselectivity is dose dependent, it decreases or is lost at higher doses. This is variable between agents, and the dose at which this occurs has not been clearly established. With the exception of sotalol (discussed below), all listed β-blockers are indicated for the treatment of hypertension. These agents are also used for ventricular rate control in atrial fibrillation because they slow atrioventricular nodal conduction by decreasing sympathetic tone.  PROPRANOLOL Actions Propranolol, a nonselective β-blocking agent, decreases heart rate, myocardial contractility, blood pressure, and myocardial oxygen demand. Tintinalli_Sec03_p0053-0142.indd 125 8/2/19 2:57 PM

in atrial fibrillation because they slow atrioventricular nodal conduction by decreasing sympathetic tone.  PROPRANOLOL Actions Propranolol, a nonselective β-blocking agent, decreases heart rate, myocardial contractility, blood pressure, and myocardial oxygen demand. Tintinalli_Sec03_p0053-0142.indd 125 8/2/19 2:57 PM 126 SECTION 3: Resuscitation For pharmacokinetics, indications, dosing and administration, and adverse effects, see Table 19-6.6  ESMOLOL Actions Esmolol is a short-acting, selective β 1-antagonist that exhibits negative inotropic and chronotropic effects. By blocking β 1-receptors, esmolol prevents excessive adrenergic stimulation of the myocardium, thus causing an increase in sinus cycle length, prolongation of sinoatrial nodal recovery time, and a decrease in conduction through the atrio ventricular node. For pharmacokinetics, indications, dosing, administration, and adverse effects, see Table 19-6.  METOPROLOL Actions Metoprolol is a selective antagonist of β 1-receptors and exerts its antihypertensive effects by decreasing cardiac output, reducing sympathetic outflow, and suppressing renin activity. For pharmacokinetics, indications, and adverse effects, see Table 19-6. For dosing and administration, see Table 19-6 and Table 19-7.  LABETALOL Actions Labetalol is a combined selective α1-blocking and nonselective β-blocking agent with direct vasodilatory action. The β-blocking effects of labetalol are greater than the α 1-blocking effects, with ratios of 3:1 in the oral and 7:1 in the parenteral formulation. Labetalol is useful as an antihypertensive agent because it decreases heart rate, contractility, cardiac output, and total peripheral vascular resistance. For pharmacokinetics, see Table 19-6. Indications Labetalol is used primarily for its antihypertensive effects. It is used in patients with acute hypertensive emergencies where rapid blood pressure reduction is indicated (see Chapter 57, “Systemic Hypertension”) and is considered safe for use in the treatment of hypertension in pregnancy (see Chapter 99, “Comorbid Disorders in Pregnancy, ” and Chapter 100, “Maternal Emergencies After 20 Weeks of Pregnancy and in the Peripartum Period”). Dosing and Administration See Table 19-6 and Table 19-8. Once control of blood pressure has been established with IV labetalol, patients may transition to PO labetalol (Table 19-8). Adverse Effects See Table 19-6.  CARVEDILOL Actions Carvedilol is a nonselective β-blocker and α-adrenergic blocker. Carvedilol reduces cardiac output, reduces exercise-induced TABLE 19-7 IV to Oral Conversion of Metoprolol Medication IV to Oral Conversion Metoprolol 5 milligrams IV = 12.5 milligrams oral TABLE 19-8 IV to Oral Conversion of Labetalol Medication IV to Oral Conversion Labetalol Upon discontinuation of IV infusion, initiate 200 milligrams orally, followed in 6–12 h with an additional dose of 200–400 milligrams. Thereafter, dose patients with 400–2400 milligrams/d in divided doses depending on blood pressure response TABLE 19-9 Pharmacology of Class III Antiarrhythmic Agents Ion Channels and Receptors Antagonized K+ Channels Na+ Channels Ca2+ Channels β-Adrenergic α-Adrenergic Amiodarone + + + + + Dronedarone + + + + + Sotalol +     + Dofetilide + Ibutilide +* Activates a slow inward Na+ current Vernakalant +† +† *Lesser effect. †Ultrarapid and acetylcholine K+ currents. tachycardia, reduces reflex orthostatic tachycardia, and prompts vasodilation and decreased peripheral vascular resistance, thereby reducing blood pressure. For patients with CHF , carvedilol lowers heart rate, increases stroke volume index, and decreases right atrial pressure. Indications Carvedilol is indicated for hypertension.

reduces reflex orthostatic tachycardia, and prompts vasodilation and decreased peripheral vascular resistance, thereby reducing blood pressure. For patients with CHF , carvedilol lowers heart rate, increases stroke volume index, and decreases right atrial pressure. Indications Carvedilol is indicated for hypertension. Carvedilol is recommended for patients with compensated heart failure with reduced ejection fraction as an alternative or in addition to an angiotensinconverting enzyme inhibitor or an angiotensin receptor blocker, which are considered first line. For pharmacokinetics, dosing and administration, and adverse effects, see Table 19-6.6 CLASS III ANTIARRHYTHMICS: INHIBIT POTASSIUM CURRENTS Class III antiarrhythmic medications inhibit inward potassium currents (Table 19-9), 6 leading to a significantly longer refractory period. Myocardial tissue in a refractory state is resistant to reentrant conduction circuits that may produce arrhythmia. These agents prolong the QT interval, which is associated with significant risk for torsades de pointes. Clinical indications for class III antiarrhythmics are contrasted in Table 19-10.  AMIODARONE Amiodarone is a “broad-spectrum” antiarrhythmic indicated in the acute management and chronic suppression of supraventricular ven tricular tachycardia and ventricular arrhythmias. Potential benefits of amiodarone must be weighed against an array of potentially serious adverse effects, and clinical use is further complicated by distinctive pharmacokinetics and significant drug interactions. Actions Amiodarone possesses properties of all four classes of antiar rhythmics (Table 19-11).6,14 Pharmacokinetics See Table 19-12.6 Amiodarone is highly lipophilic and extensively distributed to bodily tissues.15 Although IV amiodarone produces a rapid antiarrhythmic effect, it quickly redistributes from the serum into tissue, causing a precipitous drop in serum concentration. Therefore, large oral or IV loading doses, generally given over a week or more, are needed to fill this large tissue reservoir and achieve sustained serum concentrations. As tissue stores become saturated after long-term oral therapy, terminal-phase elimination dominates and is characterized by a long half-life and duration of action. Indications See Table 19-13.8,11,17-19 Tintinalli_Sec03_p0053-0142.indd 126 8/2/19 2:57 PM

ge tissue reservoir and achieve sustained serum concentrations. As tissue stores become saturated after long-term oral therapy, terminal-phase elimination dominates and is characterized by a long half-life and duration of action. Indications See Table 19-13.8,11,17-19 Tintinalli_Sec03_p0053-0142.indd 126 8/2/19 2:57 PM CHAPTER 19:  Pharmacology of An tiarrhythmics and An tihypertensives      127 TABLE 19-11 Electrophysiologic and Electrocardiographic Effects of Amiodarone Ion Channels and Receptors Effects on Cardiac Electrophysiology Effects on the ECG Blocks inactivated Na+ channels Noncompetitive blockade of α- and β-adrenergic receptors Blocks inward K+ channel rectifier Blocks myocardial Ca+ channels Prolongs the refractory period Decreases sinoatrial node function Slows atrioventricular node conduction Modifies automaticity of Purkinje fibers Decreases heart rate and may cause sinus bradycardia Prolongs: PR interval QRS interval* QT interval* *More common with chronic oral administration than with acute IV use. TABLE 19-10 Class III Antiarrhythmic Indications

trial node function Slows atrioventricular node conduction Modifies automaticity of Purkinje fibers Decreases heart rate and may cause sinus bradycardia Prolongs: PR interval QRS interval* QT interval* *More common with chronic oral administration than with acute IV use. TABLE 19-10 Class III Antiarrhythmic Indications Clinical Indications Supraventricular Arrhythmias Ventricular Arrhythmias Amiodarone Acute rate control or cardioversion and maintenance of sinus rhythm* Acute management of life-threatening arrhythmias; chronic suppression Dronedarone AFib (history of paroxysmal or persistent, but currently in sinus rhythm) to reduce risk of hospitalization Sotalol AFib or AFL Monomorphic VT† Dofetilide AFib or AFL; conversion to and maintenance of sinus rhythm Ibutilide Acute cardioversion of AFib or AFL No Vernakalant Acute cardioversion of AFib‡ No Abbreviations: AFib = atrial fibrillation; AFL = atrial flutter; VT = ventricular tachycardia. *Off-label. †Off-label in United States, but guideline recommended with IV formulation if available. ‡Approved in Europe but not available in United States. TABLE 19-12 Amiodarone Pharmacokinetics Absorption Distribution Metabolism Excretion Half-Life Onset/Peak/Duration of Action Oral BA: 35%–65% Slow and variable GI absorption Oral: Vd: 66 L/kg (range: 18–148 L/kg) Plasma protein binding: >96% Hepatic via CYP450 3A4 and 2C8 Active metabolite Feces; urine (<1% as unchanged drug) IV single dose: 9–36 d Oral chronic therapy: 40–55 d Onset Oral: 2 d–3 wk IV: initial effects rapid Peak 1 wk–5 mo Duration (variable) 2 wk to several mo Abbreviations: BA = bioavailability; Vd = volume of distribution. Dosing and Administration See Table 19-14. 6 IV amiodarone is associated with bradycardia, hypotension, and phlebitis. Hypotension may be dose and infusion rate dependent; therefore, infusion rates should not exceed 30 milligrams/min, and total daily doses should not exceed 2.2 grams. Preparations of IV amiodarone should be mixed in 5% dextrose in water, as amiodarone has precipitated in compatibility studies with normal saline. 20 Dose adjustments are not required for renal insufficiency but should be considered for severe hepatic dysfunction. Adverse Effects See Table 19-15. 6,21 Long-term amiodarone has many common, serious, and potentially fatal adverse effects that limit TABLE 19-13 Acute Intravenous Amiodarone Clinical Indications Indications Comments Atrial fibrillation Ventricular rate control Consider the potential risks of cardioversion (thromboembolic complications)* Consider when other measures are ineffective or contraindicated† Considered a first-line option in patients with HF† Avoid IV amiodarone in patients with WPW syndrome who have preexcited atrial fibrillation as it is potentially harmful and can accelerate the ventricular rate† Atrial fibrillation Pharmacologic Cardioversion Not first line; considered a reasonable option for pharmacologic cardioversion† Acceptable option in patients with structural heart disease† Slow onset; average time to cardioversion is 24 h Monomorphic, sustained A first-line agent for hemodynamically stable VT* Polymorphic, not associated with long QT interval If not associated with long QT interval (i.e., TdP)* Polymorphic VT with normal QT interval may be associated with myocardial ischemia, and amiodarone may be effective in arrhythmia suppression* Pulseless VT or VF Antiarrhythmic of choice in ACLS algorithm* Abbreviations: ACLS = advanced cardiovascular life support; HF = heart failure; TdP = torsades de pointes; VF = ventricular fibrillation; VT = ventricular tachycardia; WPW = Wolff-Parkinson-White syndrome. *2015 ACLS guideline recommendation.

a suppression* Pulseless VT or VF Antiarrhythmic of choice in ACLS algorithm* Abbreviations: ACLS = advanced cardiovascular life support; HF = heart failure; TdP = torsades de pointes; VF = ventricular fibrillation; VT = ventricular tachycardia; WPW = Wolff-Parkinson-White syndrome. *2015 ACLS guideline recommendation. †2014 American College of Cardiology Foundation/American Heart Association/Heart Rhythm Society atrial fibrillation management guideline recommendation. TABLE 19-14 Amiodarone IV Dosing and Administration by Indication Indications Dosing and Administration Cardiac Arrest (refractory to defibrillation) Pulseless ventricular tachycardia Ventricular fibrillation 300 milligrams rapid bolus (may give undiluted) May give a single repeat 150 milligrams bolus if needed Ventricular tachycardia with pulses Stable monomorphic Polymorphic with normal QT interval 150 milligrams in 100 mL of D5W over 10 min, followed by infusion at 1 milligram/ min for 6 h, then 0.5 milligram/min for the next 18 h If breakthrough arrhythmia occurs, may give repeat 150-milligram boluses over 10 min Maximum total daily dose is 2.2 grams Atrial fibrillation/atrial flutter Conversion to sinus rhythm To control rapid ventricular rate due to accessory pathway conduction in preexcited atrial arrhythmias Abbreviation: D5W = dextrose 5% in water. Tintinalli_Sec03_p0053-0142.indd 127 8/2/19 2:57 PM

ram boluses over 10 min Maximum total daily dose is 2.2 grams Atrial fibrillation/atrial flutter Conversion to sinus rhythm To control rapid ventricular rate due to accessory pathway conduction in preexcited atrial arrhythmias Abbreviation: D5W = dextrose 5% in water. Tintinalli_Sec03_p0053-0142.indd 127 8/2/19 2:57 PM 128 SECTION 3: Resuscitation TABLE 19-15 Amiodarone Adverse Effects* Cardiovascular Sinus bradycardia (5% with oral) Ventricular arrhythmias Torsades de pointes (<1%) Increased risk with: Concomitant QTc-prolonging agent Hypokalemia, hypomagnesemia Female gender Thrombophlebitis (consider in-line IV filter if given via peripheral IV) Atrioventricular nodal block Hypotension (16% with IV); may be related to infusion rate or the IV solution emulsifier polysorbate 80 CNS Paresthesias and peripheral neuropathy Dizziness GI Nausea/vomiting, anorexia, constipation (10%–33% with oral) Usually responds to a dose reduction or divided doses Hepatic Increased liver enzymes (15%–50%) Hepatic injury is typically mild and reversible, but liver failure and death have been reported Monitor baseline LFTs and every 6 mo thereafter Pulmonary Pulmonary toxicity (2%–7%, as high as 17%) May be most serious adverse effect other than cardiac. Often reversible, but fatalities have been reported after only 8–14 d of treatment Various manifestations Pulmonary fibrosis, eosinophilia, interstitial pneumonia, allergic alveolitis Monitor baseline PFTs and chest radiograph; repeat chest radiograph annually Thyroid Hypothyroidism, more common (4%–22% in some studies) Hyperthyroidism (3%–10%) Hyperthyroidism may diminish antiarrhythmic effect Monitor thyroid function at baseline and every 3–6 mo thereafter Pregnancy Contraindicated in pregnancy Abbreviations: LFTs = liver function tests; PFTs = pulmonary function tests. *Incomplete listing: excludes nonacute/non–life-threatening dermatologic, ocular, and other effects. TABLE 19-16 Dronedarone Pharmacokinetics Absorption Distribution Metabolism Excretion Half-Life Bioavailability Fasting: 4% High-fat meal: 15% Vd: ~1400 L Plasma protein binding: >98% Hepatic via CYP450 3A4 Active metabolite Primarily as metabolites Feces: 84% Urine: ~6% 13–19 h Abbreviation: Vd = volume of distribution. TABLE 19-17 Contraindications and Significant Adverse Effects of Dronedarone Contraindications Patients with NYHA class IV HF or NYHA class II–III HF with recent decompensation requiring referral to a specialized HF clinic Permanent AFib (in patients in whom sinus rhythm will not or cannot be restored) Severe hepatic impairment or previous liver or lung toxicity with amiodarone Bradycardia <50 beats/min, QTc ≥500 ms or PR interval >280 ms, second-degree or third-degree AV block or sick sinus syndrome (except when used with a pacemaker) Drug–drug interactions with strong CYP450 inhibitors and QTc-prolonging medications Pregnancy Significant adverse effects Cardiovascular New-onset or worsening HF; QTc prolongation Hepatic Severe liver injury, including acute liver failure Renal Upon initiation, serum creatinine may increase ~0.1 milligram/dL Respiratory Interstitial lung disease; pulmonary fibrosis and pneumonitis Abbreviations: AFib = atrial fibrillation; AV = atrioventricular; HF = heart failure; ms = milliseconds; NYHA = New York Heart Association. widespread clinical use and require regular monitoring of liver, pulmo nary, thyroid, and ocular function. Although amiodarone prolongs the QT interval, it has a relatively low incidence of torsades de pointes even in patients with structural heart disease. Amiodarone is responsible for many clinically significant drug interactions. As a strong inhibitor of hepatic enzymes, amiodarone can increase serum concentrations of many other medications.

rolongs the QT interval, it has a relatively low incidence of torsades de pointes even in patients with structural heart disease. Amiodarone is responsible for many clinically significant drug interactions. As a strong inhibitor of hepatic enzymes, amiodarone can increase serum concentrations of many other medications. Amiodarone may also augment the effects of medications that concomitantly prolong the QT c interval or cause bradycardia. Specific dose reductions are rec ommended for colchicine, digoxin, warfarin, procainamide, quinidine, simvastatin, and lovastatin when used concomitantly with amiodarone. Given the extremely long half-life of amiodarone, drug interactions may persist for months after discontinuation of therapy.  DRONEDARONE Actions Dronedarone is a noniodinated, less lipophilic derivative of amiodarone, designed to have fewer adverse effects. It is categorized as a class III antiarrhythmic, but has all four antiarrhythmic class effects and also blocks α-adrenergic receptors. Electrophysiologic action is primar ily mediated through class III antiarrhythmic effects by prolonging the refractory period. Pharmacokinetics See Table 19-16. Indications Dronedarone is indicated to reduce the risk of hospitalization for atrial fibrillation in patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation. Dosing and Administration The dose of dronedarone is 400 milligrams orally twice daily, and it should be administered with food to increase bioavailability. Coadministration with grapefruit or grapefruit juice is contraindicated, as this may increase serum concentrations. Contraindications and Adverse Effects See Table 19-17. Compared to amiodarone, dronedarone has lower rates of pulmonary toxicity and has not demonstrated adverse effects on thyroid function. Two clinical trials with dronedarone were prematurely discontinued due to significantly higher rates of serious adverse events in the dronedarone treatment groups, prompting black box warnings that dronedarone is contraindicated in severe or decompensated heart failure and in patients with permanent atrial fibrillation. 5,23 It is also contraindicated in pregnancy. ECGs should be monitored every 3 months while on dronedarone. If the patient is found to be in atrial fibrillation, he or she should be cardioverted (if clinically indicated) or dronedarone should be discontinued. Liver function should also be monitored periodically, especially during the first 6 months of therapy.  SOTALOL Actions Sotalol is a noncardioselective β-blocker that exhibits electro physiologic characteristics of class III antiarrhythmics, thus prolonging repolarization and refractoriness without affecting conduction. Pharmacokinetics The onset of action of sotalol is 1 to 2 hours for the oral formulation and 5 to 10 minutes after IV administration. The Tintinalli_Sec03_p0053-0142.indd 128 8/2/19 2:57 PM

ogic characteristics of class III antiarrhythmics, thus prolonging repolarization and refractoriness without affecting conduction. Pharmacokinetics The onset of action of sotalol is 1 to 2 hours for the oral formulation and 5 to 10 minutes after IV administration. The Tintinalli_Sec03_p0053-0142.indd 128 8/2/19 2:57 PM CHAPTER 19:  Pharmacology of An tiarrhythmics and An tihypertensives      129 elimination half-life is 12 hours and increases with renal dysfunction. Sotalol is eliminated unchanged in the urine. Indications Sotalol is an effective agent for the suppression of lifethreatening ventricular arrhythmias refractory to other antiarrhythmic drugs. It can suppress supraventricular ventricular tachycardia and atrial fibrillation, but is not indicated for cardioversion of atrial fibrillation. Dosing and Administration The recommended dose of IV sotalol for hemodynamically stable monomorphic ventricular tachycardia is 1.5 milligrams/kg infused over 5 minutes. The usual oral starting dose is 80 milligrams twice daily, titrated to a typical maintenance dose of 160 to 320 milligrams per day. Patients with renal insufficiency (creatinine clearance of 40 to 60 mL/min) require a dose frequency reduction of 50%, and sotalol should not be used (except in special cases) if cre atinine clearance is <40 mL/min. During initiation of sotalol therapy, pretreatment QT c should be <450 milliseconds, QT c intervals should be monitored after each dosage administration, and therapy should be discontinued or the dosage reduced if QT c measures ≥500 milliseconds. Hypokalemia and hypomagnesemia should be corrected prior to initiation to minimize the risk of torsades de pointes. Adverse Effects The most common adverse effects of sotalol are bra dycardia and hypotension. Sotalol does possess a significant proarrhythmic effect with a 4.3% rate of new or worsened ventricular arrhythmias and a 2.4% rate of torsades de pointes.  DOFETILIDE Actions and Indications Dofetilide is a pure class III antiarrhythmic and is indicated for the conversion to, and maintenance of, normal sinus rhythm in patients with atrial fibrillation or atrial flutter. Because dofetilide has a significant proarrhythmic effect, it is reserved for patients in whom atrial fibrillation or atrial flutter is highly symptomatic and alternative safer agents are contraindicated or otherwise not desired. 11 Hospitalization is required for 3 days upon initiation of therapy to allow for monitoring of QT c interval, continuous ECG, and creatinine clearance. The U.S. Food and Drug Administration announced the elimination of the Risk Evaluation and Mitigation Strategy for dofetilide (Tikosyn®) on March 9, 2016. Adverse Effects Serious adverse effects of dofetilide are ventricular tachycardia and QTc interval prolongation, which can result in torsades de pointes. Drug Interactions Dofetilide therapy is contraindicated with concomitant verapamil , hydrochlorothiazide, cimetidine, ketocon azole, trimethoprim, prochlorperazine, megestrol, and dolutegravir because these medications may cause an increase in dofetilide plasma concentration.  IBUTILIDE Actions and Pharmacokinetics Ibutilide prolongs the refractory period in atrial and ventricular cardiac tissues. This action is caused by activation of a slow inward sodium current. Blockade of the delayed rectifier potassium current, which slows repolarization, may also contribute to its clinical effects. The onset of action of ibutilide is ≤90 minutes after starting the infusion. Ibutilide is metabolized in the liver, is excreted in the urine and feces, and has a half-life of approximately 6 hours after IV administration.

tifier potassium current, which slows repolarization, may also contribute to its clinical effects. The onset of action of ibutilide is ≤90 minutes after starting the infusion. Ibutilide is metabolized in the liver, is excreted in the urine and feces, and has a half-life of approximately 6 hours after IV administration. Indications, Dosing and Administration, and Adverse Effects Ibutilide is indicated for the rapid conversion of recent-onset atrial fibril lation or atrial flutter to sinus rhythm. 11 If effective, cardioversion is expected to occur within 1 hour of administration. Ibutilide is also rec ommended to restore sinus rhythm or slow ventricular rate for patients with preexcited atrial fibrillation and rapid ventricular rate who are not hemodynamically compromised. 11 For patients with atrial fibril lation and an accessory pathway, ibutilide is considered a reasonable option for pharmacologic cardioversion. 19 A 2018 ED trial reported a 50.5% conversion rate for atrial fibrillation and a 75% conversion rate for atrial flutter. 26 The loading dose is 1 milligram IV (weight ≥60 kg) or 0.01 milligram/kg IV (weight <60 kg) over 10 minutes and may be repeated once every 10 minutes after completion of the first dose. ECG monitoring is continued for at least 4 hours or until the QT c interval returns to baseline. Cardiovascular adverse effects of ibutilide include hypotension, hypertension, bradycardia, sinus arrest, syncope, QT interval prolongation, CHF , and torsades de pointes. Hypokalemia and hypomagnesemia should be corrected prior to initiation to minimize the risk of torsades de pointes.  VERNAKALANT Vernakalant is a class III antiarrhythmic that inhibits sodium and potassium currents. The atria are more susceptible to vernakalant-induced refractory period prolongation. Vernakalant is not U.S. Food and Drug Administration approved for use in the United States due to concerns over safety. 27 In Europe and Canada, vernakalant is indicated for rapid conversion of recent-onset atrial fibrillation in adults at a dose of 3 milligrams/kg over 3 minutes. 28 Compared to other agents, vernaka lant has the shortest median time to conversion (8 to 11 minutes). 29 CLASS IV ANTIARRHYTHMICS: CALCIUM CHANNEL BLOCKERS Calcium channel blockers inhibit L-type calcium channels, resulting in slowing of atrioventricular nodal conduction and an increase in the refractory period of nodal tissue. In the myocardium, calcium channels primarily affect the action potential plateau and modulate the strength of muscle contraction. Calcium channel blockers are divided into two categories, dihydropyridine and nondihydropyridine. Nondihydro pyridine calcium channel blockers have greater cardioselectivity and are generally used for paroxysmal supraventricular tachycardias and rate control in atrial fibrillation, whereas dihydropyridine calcium channel blockers are more selective for the vasculature at therapeutic doses and are used to treat hypertension.  DILTIAZEM/VERAPAMIL Actions Diltiazem and verapamil are nondihydropyridine calcium channel blockers that slow atrioventricular nodal conduction, increase the atrioventricular node’s refractory period, decrease automaticity, and prolong the PR interval. Verapamil is more potent than diltiazem, resulting in greater atrioventricular nodal depression. Pharmacokinetics See Table 19-18. Immediate-release oral diltiazem has a relatively rapid onset of action; therefore, transitioning from an IV infusion to an oral preparation can be accomplished with relative ease. In addition, IV diltiazem has a short duration of action, necessitating either a continuous infusion or repeat bolus doses.

ee Table 19-18. Immediate-release oral diltiazem has a relatively rapid onset of action; therefore, transitioning from an IV infusion to an oral preparation can be accomplished with relative ease. In addition, IV diltiazem has a short duration of action, necessitating either a continuous infusion or repeat bolus doses. Indications Diltiazem and verapamil are indicated for paroxysmal supraventricular ventricular tachycardia as well as for rate control in atrial fibrillation 11; however, verapamil is used more commonly to abort supraventricular ventricular tachycardia with a conversion rate to sinus rhythm similar to adenosine (90%), 30 whereas diltiazem is used more commonly to control rapid ventricular rate in atrial fibrillation. 11 Both agents are contraindicated for wide-complex tachyarrhythmias, which may be a result of Wolff-Parkinson-White syndrome due to the high risk of life-threatening ventricular arrhythmia when given to these patients. Other contraindications include sick sinus syndrome, second- or thirddegree AV block, severe hypotension, cardiogenic shock, administration concomitantly or within a few hours of IV β-blockers, and ventricular tachycardia. Diltiazem Dosing and Administration When initiating diltiazem, an IV bolus of 0.25 milligram/kg over 2 minutes is administered, and a continuous infusion is started at 5 to 10 milligrams/h (if bolus is effec tive). A repeat bolus of 0.35 milligram/kg over 2 minutes may be given if there is inadequate response to initial bolus. The continuous infusion may be increased in increments of 5 milligrams/h until rate control is achieved to a maximum rate of 15 milligrams/h. Once rate control is achieved, patients may be transitioned to oral diltiazem (Table 19-19). Immediate-release formulations should be used when initially start ing a patient on oral diltiazem. Once stable on immediate-release Tintinalli_Sec03_p0053-0142.indd 129 8/2/19 2:57 PM

eved to a maximum rate of 15 milligrams/h. Once rate control is achieved, patients may be transitioned to oral diltiazem (Table 19-19). Immediate-release formulations should be used when initially start ing a patient on oral diltiazem. Once stable on immediate-release Tintinalli_Sec03_p0053-0142.indd 129 8/2/19 2:57 PM 130 SECTION 3: Resuscitation TABLE 19-18 Diltiazem and Verapamil Pharmacokinetics Absorption Distribution Metabolism Excretion Half-Life Onset/Peak/Duration of Action Diltiazem IR: ~98% ER capsule: ~93% to >95% Oral BA: ~40% (undergoes extensive first-pass metabolism) Vd: 3–13 L/kg Plasma protein binding: 70%–80% Hepatic via CYP450 and conjugation Active metabolites Urine (2%–4% as unchanged drug); feces IR: 3–4.5 h ER tablet: 6–9 h ER capsule: 4–9.5 h IV bolus: ~3.4 h Continuous infusion: 4–5 h Onset IV: 3 min Oral, IR: 30–60 min Peak Oral, IR: 2–4 h Oral, ER tablet: 11–18 h Oral, ER capsule: 10–14 h Duration IV bolus: 1–3 h Continuous infusion (after discontinuation): 0.5–10 h Verapamil Oral: >90% Oral BA: 20%–35% (undergoes extensive first-pass metabolism) Vd: 3.89 L/kg Plasma protein binding: ~90% Hepatic via CYP450 Active metabolites Urine (~70% as metabolites, 3%–4% as unchanged drug); feces (≥16%) Injection (terminal): 2–5 h Oral, IR: 2.8–7.4 h (single dose); 4.5–12 h (multiple doses) Oral, ER: ~12 h Onset/peak IV: 3–5 min Oral, IR: 1–2 h Duration IV: 0.5–6 h Oral, IR: 6–8 h Abbreviations: BA = bioavailability; ER = extended release; IR = immediate release; Vd = volume of distribution. TABLE 19-19 Conversion From IV to Oral Diltiazem Medication IV to Oral Conversion Diltiazem After continuous infusion at typical rate of 5–15 milligrams/h has heart rate controlled, may convert to oral. Oral dose (milligrams daily) is approximately equal to [rate (milligrams/h) × 3 + 3] × 10. Discontinue infusion 2–3 h after oral dose is given. Diltiazem Infusion Rate Equivalent Oral Dose (Immediate Release) 3 milligrams/h 120 milligrams daily 5 milligrams/h 180 milligrams daily 7 milligrams/h 240 milligrams daily 11 milligrams/h 360 milligrams daily diltiazem, patients can be transitioned to an extended-release formula tion by giving an equivalent daily dose. Verapamil Dosing and Administration For acute treatment of supraventricular ventricular tachycardia and atrial fibrillation (rate control), administer 5 to 10 milligrams (0.075 to 0.15 milligram/kg) IV over 2 minutes. If no response, a second dose of 10 milligrams (0.15 milligram/kg) may be given 15 to 30 minutes after the initial dose. If the patient responds to the initial or repeat bolus dose, a con tinuous infusion may be initiated. Adverse Effects Diltiazem is generally well tolerated by patients and has a favorable safety profile when compared to other antiarrhythmic agents. Adverse effects associated with diltiazem and verapamil administration are bradyarrhythmia, asystole, fatigue, headache, hypotension, atrioventricular block, peripheral edema, syncope, and dizziness.  NICARDIPINE Actions Nicardipine is a dihydropyridine calcium channel blocker that causes relaxation of smooth muscle, thereby lowering blood pressure. It has no antiarrhythmic properties and little to no effect on the myocar dium at therapeutic doses. Pharmacokinetics See Table 19-20.6 Indications Nicardipine is primarily used for the treatment of hyper tension and is contraindicated in patients with aortic stenosis. It is especially useful in patients with acute neurologic emergencies where progressive rapid blood pressure reduction over 15 to 30 minutes is indicated. Dosing and Administration Nicardipine is administered as an IV infusion with an initial rate of 5 milligrams/h.

is contraindicated in patients with aortic stenosis. It is especially useful in patients with acute neurologic emergencies where progressive rapid blood pressure reduction over 15 to 30 minutes is indicated. Dosing and Administration Nicardipine is administered as an IV infusion with an initial rate of 5 milligrams/h. The infusion may be titrated in increments of 2.5 milligrams/h every 5 to 15 minutes based on blood pressure response, with a maximum infusion rate of 15 milligrams/h. Adverse Effect Profile Nicardipine is generally well tolerated by patients. Common side effects include hypotension/orthostatic hypotension, edema, flushing, tachycardia, palpitations, and nausea.  CLEVIDIPINE Actions Clevidipine is a fourth-generation dihydropyridine calcium channel blocker with potent vasodilating activity that reduces blood pressure by decreasing systemic vascular resistance. Pharmacokinetics The onset of action after initiating a clevidipine infusion is 2 to 4 minutes, and the duration of action is 5 to 15 minutes. Clevidipine undergoes rapid metabolism via hydrolysis by esterases in the blood and has a half-life of 1 minute. Clevidipine is delivered in a lipid emulsion. Indications Clevidipine is indicated for the management of acute hypertension when oral therapy is not deemed desirable. It has been studied in the ED and found to be safe and effective in reducing blood pressure in the treatment of various hypertensive emergencies, stroke, heart failure, and aortic dissection (adjunct to esmolol). Dosing and Administration Clevidipine should be initiated as an IV infusion, starting at 1 to 2 milligrams/h; the dose may be doubled at 2-minute intervals. The usual dose is 4 to 6 milligrams/h, with a maxi mum infusion rate of 21 milligrams/h. When the treatment goal is near, slow the rate of rise in stepped increases in therapy to stabilize blood pressure and avoid unwanted hypotension. Adverse Effects Adverse effects of clevidipine include atrial fibrillation, nausea, vomiting, hypotension, and elevation in serum creatinine. Tintinalli_Sec03_p0053-0142.indd 130 8/2/19 2:57 PM

oal is near, slow the rate of rise in stepped increases in therapy to stabilize blood pressure and avoid unwanted hypotension. Adverse Effects Adverse effects of clevidipine include atrial fibrillation, nausea, vomiting, hypotension, and elevation in serum creatinine. Tintinalli_Sec03_p0053-0142.indd 130 8/2/19 2:57 PM CHAPTER 19:  Pharmacology of An tiarrhythmics and An tihypertensives      131 TABLE 19-20 Nicardipine Pharmacokinetics (IV) Distribution Metabolism Excretion Half-Life Onset/Peak/Duration of Action Vd: 8.3 L/kg Plasma protein binding: >95% Hepatic via CYP450 3A4, 2C8, 2D6; extensive first-pass effect (saturable) Urine (49% as metabolites, <1% as unchanged drug); feces (43%) Follows dose-dependent (nonlinear) pharmacokinetics; half-life dependent on serum concentrations After IV infusion, serum concentrations decrease tri-exponentially α half-life: 3 min β half-life: 45 min Terminal half-life: 14 h (seen only after long-term infusions) Continuous infusion Onset: within minutes Peak: 50% of maximum effect seen by 45 min Duration: upon discontinuation, 50% decrease in effect seen in ~30 min with gradual discontinuing antihypertensive effects for ~50 h Abbreviation: Vd = volume of distribution. TABLE 19-21 Atropine Drug Information Onset of Action Metabolism Half-Life IV Dose (Adult) Indications IM: ≤15–30 min IV: immediate Hepatic Adults: 2.1–3.9 h 0.5 milligram every 3–5 min (maximum total dose: 3 milligrams or 0.04 milligram/kg) Symptomatic sinus bradycardia TABLE 19-22 Adenosine Pharmacokinetics Metabolism Half-Life Onset/Duration of Action Systemic Active metabolites <10 s Onset: rapid Duration: very brief OTHER ANTIARRHYTHMIC MEDICATIONS  ATROPINE Actions Atropine blocks the effects of acetylcholine at parasympathetic sites in smooth muscle thus increasing cardiac output.6 Pharmacokinetics See Table 19-21. Indications Atropine is considered first-line therapy for the treat ment of symptomatic bradycardia. Atropine is no longer recommended for the treatment of asystole or pulseless electrical activity. 8 Atropine may precipitate or worsen myocardial ischemia in patients with coro nary artery disease, acute coronary syndrome, CHF , tachycardia, and hypertension. Dosing and Administration See Table 19-21.6,8 IV doses <0.5 mil ligram and slow injection have been associated with paradoxical bradycardia. Adverse Effects The most common adverse effects of atropine include tachyarrhythmia, constipation, xerostomia, blurred vision, and photophobia.  ADENOSINE Actions Adenosine, an endogenous nucleoside, slows conduction time through the atrioventricular node, interrupts reentry pathways through the atrioventricular node, and restores normal sinus rhythm for patients in supraventricular tachycardia. Pharmacokinetics See Table 19-22.6 Indications Adenosine is used for the treatment of paroxysmal supraventricular ventricular tachycardia with or without reentry pathways, after failure of vagal maneuvers. It is ineffective for conversion of atrial fibrillation, atrial flutter, or ventricular tachycardia. 6,30 Dosing and Administration See Table 19-23.6 Adverse Effects Common adverse effects include chest discomfort/ pressure, headache, flushing, and nausea and are usually temporary due to the short half-life of the drug. Bronchospasm and atrial fibrillation can also occur, but the incidence is rare. Severe adverse effects, including cardiac conduction abnormalities and hypotension, are more common with continuous infusion adenosine used in stress testing.  MAGNESIUM SULFATE Actions, Indications, and Dosing and Administration The antiarrhythmic activity of IV magnesium sulfate is mediated by inhibiting calcium currents that cause pathologic early afterdepolarizations and thereby cardiac dyssynchrony.

more common with continuous infusion adenosine used in stress testing.  MAGNESIUM SULFATE Actions, Indications, and Dosing and Administration The antiarrhythmic activity of IV magnesium sulfate is mediated by inhibiting calcium currents that cause pathologic early afterdepolarizations and thereby cardiac dyssynchrony. Magnesium slows sinoatrial node activity, prolongs myocardial conduction time, stabilizes excitable membranes, and is a cofactor in ion movement. 31 IV magnesium sulfate has a rapid onset of action and is indicated in the treatment of torsades de pointes, polymorphic ventricular tachycardia associated with a prolonged QT interval, and cardiac arrest when ventricular fibrillation/pulseless ven tricular tachycardia is associated with torsades de pointes. In patients with a pulse, 1 to 2 grams IV are diluted in normal saline or 5% dextrose in water and administered as a rapid bolus. Rapid IV administration is associated with vasodilation, flushing, and hypotension.  ISOPROTERENOL Actions, Pharmacokinetics, and Indications Isoproterenol exerts antiarrhythmic effects by stimulating β 1- and β 2-receptors. The β 1receptor interaction results in increased chronotropic and inotropic activities in the myocardium and vasodilation by β 2-receptor–mediated relaxation of smooth muscle. IV isoproterenol has an immediate onset of action, a half-life of 2.5 to 5 minutes, and a duration of 10 to 15 minutes. It is indicated for refractory bradyarrhythmias, atrioventricular nodal block, and refractory torsades de pointes; however, it is rarely used in the ED. Isoproterenol is contraindicated in patients with angina, preexisting ventricular arrhythmias, tachyarrhythmias, or digoxin toxicity. Dosing and Administration A continuous IV infusion should be initiated at 2 micrograms/min and titrated every 5 to 10 minutes based on patient response (usual range, 2 to 10 micrograms/min). Adverse Effects Serious adverse effects of isoproterenol include hypotension, premature ventricular contractions, tachyarrhythmia, ventricular arrhythmia, dyspnea, and pulmonary edema.  DIGOXIN Actions Digoxin, a cardiac glycoside, has positive inotropic, negative chronotropic, and negative dromotropic effects on the myocardium due to inhibition of the sodium-potassium ATPase. It also causes direct suppression of the atrioventricular node, leading to an increased refractory period and decreased conduction velocity. Pharmacokinetics See Table 19-24.6 Many disease states such as CHF , hypokalemia, renal failure, and thyroid disease can have a substantial Tintinalli_Sec03_p0053-0142.indd 131 8/2/19 2:57 PM

es direct suppression of the atrioventricular node, leading to an increased refractory period and decreased conduction velocity. Pharmacokinetics See Table 19-24.6 Many disease states such as CHF , hypokalemia, renal failure, and thyroid disease can have a substantial Tintinalli_Sec03_p0053-0142.indd 131 8/2/19 2:57 PM 132 SECTION 3: Resuscitation TABLE 19-23 Adenosine Dosing and Administration Indication Dosing and Administration Paroxysmal supraventricular tachycardia Initial dose: 6 milligrams IV If ineffective after 1–2 min, may give second dose of 12 milligrams IV May repeat 12 milligrams IV if needed Note. Rapid IV push over 1–2 seconds via peripheral line. Flush line after each dose with 20 mL of normal saline. Patients usually experience transient asystole (<5 seconds). Initial dose should be reduced to 3 milligrams in heart transplant patients, in patients taking dipyridamole or carbamazepine, and when administered via central line. Patients taking caffeine or theophylline may require larger doses. TABLE 19-24 Digoxin Pharmacokinetics Distribution Metabolism Excretion Half-Life Onset/Peak/Duration of Action Normal renal function: 6–7 L/kg Plasma protein binding: ~25% GI tract Hepatic Active metabolites Urine (50%–70% as unchanged drug) Age, renal, and cardiac function dependent Parent drug: 38 h Metabolites: digoxigenin (4 h); monodigitoxoside (3–12 h) Onset Oral: 1–2 h IV: 5–60 min Peak Oral: 2–8 h IV: 1–6 h Duration: 3–4 d effect on the pharmacokinetics of digoxin. It has a narrow therapeutic index (therapeutic range, 0.5 to 2 nanograms/mL), and toxicity can develop at levels >2 nanograms/mL. In addition, digoxin has numerous drug interactions that can be clinically significant. Indications Digoxin is indicated for rate control in atrial fibrillation (not first line)11 and for symptom reduction in CHF unrelieved by diuretics and angiotensin-converting enzyme inhibitors. Although digoxin is only contraindicated in patients with ventricular arrhythmias, its use should be avoided in patients with Wolff-Parkinson-White syndrome (increased risk of ventricular fibrillation), acute myocardial infarction, untreated beriberi heart disease, electrolyte imbalances, sinus node dis ease, atrioventricular block, and renal impairment. Studies on mortality associated with long-term digoxin use report conflicting results. 32-36 Dosing and Administration There are several dosing strategies for digoxin initiation. For atrial fibrillation (rate control) in adults, current guidelines recommend 0.25 milligram IV with repeat dosing to a maximum of 1.5 milligrams over 24 hours, followed by an oral maintenance regimen (0.125 to 0.25 milligram once daily). 6,11 Dose adjustments are often necessary based on age, comorbidities, concomitant medications, and renal dysfunction. Digoxin levels should be monitored for safety and efficacy. Adverse Effects Adverse effects of digoxin are generally GI, including nausea, vomiting, and diarrhea. Other rarer adverse effects may include gynecomastia, skin rash, eosinophilia, and thrombocytopenia. Digoxin can also cause cardiac arrhythmias, such as sinus bradycardia, atrioventricular or sinoatrial nodal block, and ventricular arrhythmias. Symptoms of digoxin toxicity include mental status changes, visual disturbances, delirium, hyperkalemia, and seizures. Many types of arrhythmias can occur as a result of digoxin toxicity, and clinicians must be able to recognize the signs and symptoms associated with toxicity and treat accordingly. SELECTED ANTIHYPERTENSIVE MEDICATIONS See earlier sections for discussion of β-blockers, nicardipine, and clevi dipine. Eleven of the most commonly prescribed oral antihypertensive agents are listed in Table 19-25.

inicians must be able to recognize the signs and symptoms associated with toxicity and treat accordingly. SELECTED ANTIHYPERTENSIVE MEDICATIONS See earlier sections for discussion of β-blockers, nicardipine, and clevi dipine. Eleven of the most commonly prescribed oral antihypertensive agents are listed in Table 19-25. Actions of Selected Antihypertensive Classes Lisinopril, captopril, and benazepril are angiotensin-converting enzyme inhibitors, which act by preventing the conversion of angiotensin I to angiotensin II (a potent vasoconstrictor), ultimately reducing aldosterone secretion and blood pressure. 6 Valsartan and losartan are angiotensin receptor blockers , which reduce blood pressure by blocking the vasoconstrictor effects and aldosterone-secreting stimulus of angiotensin II. 6 Amlodipine and nifedipine are dihydropyridine calcium channel blockers , which lower blood pressure by relaxing vascular smooth muscle to produce arterial vasodilation and decreased systemic vascular resistance. 6 Amlodipine and nifedipine have very few chronotropic effects. Chlorthalidone, a thiazide-related diuretic , inhibits sodium and chloride reabsorp tion in the cortical-diluting segment of the ascending loop of Henle; hydrochlorothiazide, a thiazide diuretic, inhibits sodium reabsorption in the distal tubules, causing increased excretion of sodium and water as well as potassium and hydrogen ions. 6 Clonidine stimulates α 2adrenoceptors in the brainstem, decreasing sympathetic outflow and thereby reducing peripheral resistance, heart rate, and blood pressure. Hydralazine is a smooth muscle relaxant that decreases tone in arterial walls, yielding vasodilation and a decrease in peripheral vascular resistance. Indications Medications from the antihypertensive classes of diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor block ers, and calcium channel blockers are considered preferred initial drugs for the initiation of antihypertensive therapy (Table 19-25), with a few important exceptions. 37 For patients with chronic kidney disease being started on an angiotensin-converting enzyme inhibitor or an angioten sin receptor blocker, there is a risk of hyperkalemia. Also, with these two drug classes, there is a risk of acute kidney injury in the setting of severe bilateral renal artery stenosis, a condition that affects up to 1.4% of the hypertensive population. 38 Nifedipine and labetalol (discussed earlier) are preferred agents in hypertensive women who are pregnant or planning to become pregnant. 37 Calcium channel blockers should be avoided in patients with a history of heart failure with reduced ejection fraction; the initial antihypertensive drug for these patients should be an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. 13 Of the diuretics, chlorthalidone is the preferred agent because of its long duration of action (40 hours) and trial-proven reduction of cardiovascular disease. 37 Thiazide diuretics should be avoided in patients with a history of gout. Clonidine and hydralazine are frequently used in cases of hypertensive urgency (see Chapter 57, “Systemic Hypertension”). Hydralazine is not recommended as an initial drug for hypertension. 37 Hydralazine is not recommended for hypertensive emergencies,6 except when associated with pregnancy 39 (see Chapter 100, “Maternal Emergencies After 20 Weeks of Pregnancy and in the Peripartum Period”). With abrupt discontinuation, clonidine is associ ated with rebound hypertension. Most patients taking medication to control their hypertension will require at least two medications.

cept when associated with pregnancy 39 (see Chapter 100, “Maternal Emergencies After 20 Weeks of Pregnancy and in the Peripartum Period”). With abrupt discontinuation, clonidine is associ ated with rebound hypertension. Most patients taking medication to control their hypertension will require at least two medications. While the dose of one medicine may be increased to its maximum recommended daily dose (Table 19-25), 6,37 when lower doses do not sufficiently reduce blood pressure, two drugs of the same class should not be used simultaneously. Also, an angio tensin receptor blocker should not be combined with an angiotensinconverting enzyme inhibitor. The most commonly prescribed two-drug antihypertensive combinations are a diuretic added to an angiotensinconverting enzyme inhibitor or an angiotensin receptor blocker. See Table 19-25 for dosing information and adverse effects. Tintinalli_Sec03_p0053-0142.indd 132 8/2/19 2:57 PM