Chapter 19: Pharmacology of Antiarrhythmics and Antihypertensives

This chapter reviews the pharmacology of selected antiarrhythmics and antihypertensives (β-blockers and calcium channel blockers) used in the ED. Discussion of additional antihypertensives can be found 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 Failure to reduce mortality has been a criticism of many agents in this class of drugs.^2,3,4,5 In general, electrical cardioversion is preferable 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). Other medications used to treat arrhythmias include digoxin, atropine, adenosine, magnesium, and isoproterenol.

Class I agents block fast sodium channels (I_Na) and are further subcategorized based on their degree of blockade into Classes Ia (moderate blockade), Ib (weak blockage), and Ic (strong blockade). Sodium channel blockers increase the excitability threshold, requiring more sodium channels to open in order to overcome the potassium current and generate an action potential. This effect increases refractoriness and can be useful in terminating reentry currents. In addition, some Class I agents block potassium channels (I_K) and exhibit antimuscarinic effects.

CLASS Ia AGENTS

Class Ia antiarrhythmics block open sodium channels and have a slow dissociation from their target, causing an increase in the refractory period. The use of these agents is limited by their side effect profile and proarrhythmic nature. Quinidine and disopyramide are Class Ia agents but are not discussed here because they are infrequently used in the ED. Quinidine can cause torsades de pointes. Disopyramide is used orally in patients with hypertrophic cardiomyopathy due to its negative inotropic properties; however, its association with heart failure and hypotension and its anticholinergic effects, including urinary retention, limit its use.

PROCAINAMIDE

Actions

Procainamide is a Class Ia agent that increases the refractory period, decreases automaticity and conduction, and prolongs cardiac action potentials through intermediate blockade of open sodium and potassium channels. NAPA, 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 ventricular 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 can be considered as a therapeutic option; however it should be avoided in patients with prolonged QT intervals or congestive heart failure.⁷

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 congestive heart failure.

CLASS Ib AGENTS

Class Ib agents have weak sodium channel–blocking properties and a high affinity for both open and inactive sodium channels with very rapid dissociation. The cumulative effects of these agents result in decreased automaticity due to an increase in the threshold for excitability. Because of their quick dissociation, these drugs are less effective on myocardial tissues with rapid conduction, such as atrial tissue.

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 ventricular arrhythmias. Per advanced cardiac life support guidelines, lidocaine is considered a second-line therapy, if amiodarone is unavailable, in patients with ventricular fibrillation or pulseless ventricular tachycardia due to the failure of clinical studies to show improved rates of return of spontaneous circulation when compared to amiodarone.⁵

Dosing and Administration

See Table 19-5.⁶

Adverse Effects

Adverse effects of lidocaine are typically dose dependent, with few hemodynamic effects at lower infusion rates. Patients should be monitored for CNS effects, including numbness, speech impairment, somnolence, dizziness, and seizures.

CLASS Ic AGENTS

Class Ic agents are most commonly used for the treatment of supraventricular tachycardia. They have the highest degree of fast sodium channel blockade, resulting in marked prolongation of the QRS interval without QT prolongation. These agents act only on open sodium channels and demonstrate slow dissociation from their targets, leading to increased refractoriness and decreased conduction. They have a high proarrhythmic potential that can be amplified in cases of diseased myocardial tissue, increased sympathetic tone, and higher heart rates. Large clinical studies have associated several Class Ic agents with increased mortality when used in patients with cardiovascular disease or after myocardial infarction.^8,9

PROPAFENONE

Propafenone is a Class Ic agent with additional β-adrenergic–blocking properties; therefore, it can cause bradycardia and bronchospasm. It is more selective for cells with high rates of conduction. Propafenone is indicated for the conversion of recent-onset atrial fibrillation (<7 days) to sinus rhythm.¹⁰ Under continuous cardiac monitoring, the patient can be given 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 with 1:1 atrioventricular conduction, and ventricular proarrhythmia. This drug should be avoided in patients with coronary artery disease or significant structural heart disease, and should be given with caution to patients with asthma, hepatic dysfunction, or congestive heart failure. Although propafenone carries an indication for paroxysmal supraventricular tachycardia and ventricular tachycardia, it is rarely used for these indications in the ED.

FLECAINIDE

Flecainide is a Class 1c agent that reduces excitability, primarily in the His-Purkinje system and ventricular myocardium. Flecainide is indicated for the conversion of recent-onset atrial fibrillation (<7 days) to sinus rhythm.¹⁰ Under continuous cardiac monitoring, the patient can be given a one-time oral dose of 200 milligrams (weight <70 kg) or 300 milligrams (weight ≥70 kg). Adverse effects include hypotension, atrial flutter with 1:1 atrioventricular conduction, and ventricular pro-arrhythmia. This drug should be avoided in patients with coronary artery disease, significant structural heart disease, congestive heart failure, or hypokalemia. Although flecainide carries an indication for paroxysmal supraventricular tachycardia and ventricular tachycardia, it is rarely used for these indications in the ED.

β-Blockers are used for the treatment of various indications including hypertension, supraventricular tachycardia and ventricular arrhythmias, recurrent atrial fibrillation (rate control), and thyrotoxicosis (symptom control). Although these medications share the principal characteristic of blocking catecholamine effects on β-receptors, individual agents differ 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. β₁-Receptors are found in heart muscle, and β₂-receptors are found in bronchial and vascular smooth muscle. Nonselective β-blocking medications target all β-receptors, thereby affecting heart rate, conduction, and contractility, as well as smooth muscle contraction, thus increasing the risk of bronchospasm. In contrast, cardioselective agents have relative selectivity for β₁-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 insulin-dependent diabetes because they are less likely to act on β₂-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, all listed β-blockers are indicated for the treatment of hypertension. These agents are also used for ventricular rate control in atrial fibrillation as they slow atrioventricular nodal conduction by decreasing sympathetic tone.

PROPRANOLOL

Actions

Propranolol is a nonselective antagonist of β₁- and β₂-receptors.

Pharmacokinetics

See Table 19-6.

Indications

See Table 19-6.

Dosing and Administration

See Table 19-6.

Adverse Effects

Serious adverse effects associated with IV propranolol administration include bradycardia, heart block, hypotension, worsening heart failure, and bronchospasm.

ESMOLOL

Actions

Esmolol is a short-acting, selective β₁-antagonist that exhibits negative inotropic and chronotropic effects. By blocking β₁-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 atrioventricular node.

Pharmacokinetics

See Table 19-6.⁶ Esmolol is available as a parenteral formulation only and has a rapid onset of action and short duration of action, with complete reversal of medication effects seen within 10 to 30 minutes after discontinuation.

Indications

See Table 19-6.⁴

Dosing and Administration

All listed doses are in micrograms. For the treatment of supraventricular tachycardia, the dose of esmolol is a 500 microgram/kg bolus (optional) over 1 minute, followed by an infusion starting at 50 micrograms/kg/min titrated to therapeutic effect in 50 microgram/kg/min increments every 4 minutes. To achieve a more rapid response, two additional 500 microgram/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 minutes 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).

Adverse Effects

Cardiovascular adverse effects of esmolol include hypotension (most common), bradycardia, and heart block. Abrupt discontinuation may cause rebound hypertension or angina. Other adverse effects may include injection site reaction, nausea, bronchospasm, and pulmonary edema.

METOPROLOL

Actions

Metoprolol is a selective antagonist of β₁-receptors and exerts its antihypertensive effects by decreasing cardiac output, reducing sympathetic outflow, and suppressing renin activity.

Pharmacokinetics

See Table 19-6.

Indications

See Table 19-6.

Dosing and Administration

See Table 19-6 and Table 19-7.

Adverse Effects

Significant adverse effects associated with metoprolol include bradycardia, heart block, hypotension, and bronchospasm.

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 α₁-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 resistance.

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 chapters 99, "Comorbid Disorders in Pregnancy" and 100, "Maternal Emergencies after 20 Weeks of Pregnancy and in the Postpartum Period").

Dosing and Administration

See Table 19-6 and Table 19-8. Labetalol can be administered IV by multiple boluses or as a continuous infusion. Once control of blood pressure has been established, patients may transition to oral labetalol (Table 19-8).⁶

Adverse Effects

The most common adverse effect of labetalol is orthostatic hypotension, which occurs primarily with IV administration. Other common adverse effects include nausea, dizziness, and fatigue. Serious adverse effects include heart failure, hyperkalemia, hepatotoxicity, and bronchospasm.

Class III antiarrhythmic medications inhibit inward potassium currents (Table 19-9),⁶ which leads 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 highly effective "broad-spectrum" antiarrhythmic indicated in the acute management and chronic suppression of supraventricular 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 antiarrhythmics (Table 19-11).^6,11

Pharmacokinetics

The pharmacokinetics of amiodarone are listed in Table 19-12.⁶ Amiodarone is highly lipophilic and extensively distributed to bodily tissues.¹² Although IV amiodarone produces a rapid antiarrhythmic effect, it quickly redistributes from the serum into tissue, causing a precipitous drop in serum concentration.¹³ 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 (≤55 days) and duration of action (≤50 days). Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion.

Indications

Specific indications for amiodarone are listed in Table 19-13.^{7,10,14,15,16}

Dosing and Administration

Amiodarone dosing is detailed in Table 19-14.⁶ Intravenous 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.¹⁷ Dose adjustments are not required for renal insufficiency but should be considered for severe hepatic dysfunction.

Adverse Effects

Adverse effects of amiodarone are listed in Table 19-15.^6,18 Long-term amiodarone has many common, serious, and potentially fatal adverse effects that limit widespread clinical use and require regular monitoring of liver, pulmonary, thyroid, and ocular function. As a result, patients should be regularly monitored for these toxicities. 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 liver enzymes, amiodarone increases 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 required for digoxin, warfarin, procainamide, quinidine, simvastatin, and lovastatin when used concomitantly with amiodarone. Given amiodarone's extremely long half-life, drug interactions may persist for months after discontinuation of therapy.

DRONEDARONE

Actions

Dronedarone is a noniodinated, less lipophilic derivative of amiodarone, designed to have a more favorable adverse effect profile than its predecessor. Dronedarone is categorized as a Class III antiarrhythmic but has all four antiarrhythmic class effects and blocks α-adrenergic receptors. Electrophysiologic action is primarily mediated through Class III antiarrhythmic effects by prolonging the refractory period.⁶

Pharmacokinetics

Pharmacokinetics of dronedarone are listed in Table 19-16. Dronedarone is ≤94% absorbed, but significant first-pass metabolism decreases the overall bioavailability to ≤15%. With sustained oral dosing, the half-life increases to 27 to 32 hours, and steady-state concentrations are achieved in 4 to 8 days. Dronedarone displays nonlinear kinetics, so doubling a dose may increase plasma concentrations by 2.5- to 3-fold.

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. It is less efficacious than amiodarone for maintenance of sinus rhythm.

Dosing and Administration

The dose of dronedarone is 400 milligrams orally twice daily and should be given with the morning and evening meal to increase bioavailability. Coadministration with grapefruit or grapefruit juice is contraindicated, as this may increase serum concentrations.

Adverse Effects

Contraindications and significant adverse effects of dronedarone are highlighted in 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.^5,19 ECGs should be monitored at least 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 unique, noncardioselective β-blocker that exhibits electrophysiologic 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 hours after IV administration, with a duration of action of 8 to 16 hours after one dose. The elimination half-life is 12 hours and increases with renal dysfunction. No metabolites are formed, and the drug is primarily eliminated unchanged in the urine.

Indications

Sotalol is an effective agent for the suppression of life-threatening ventricular arrhythmias refractory to other antiarrhythmic drugs. It can suppress supraventricular tachycardia and atrial fibrillation but is not indicated for cardioversion of atrial fibrillation.¹⁰

Dosing and Administration

The usual starting dose is 80 milligrams PO twice daily (which can be titrated), and the usual maintenance dose is 160 to 320 milligrams/d; the dose should be reduced by 50% or more in patients with renal insufficiency (creatinine clearance <60 mL/min), and sotalol should not be used (except in special cases) if creatinine clearance is <40 mL/min. IV sotalol is indicated in the current advanced cardiac life support guidelines for hemodynamically stable monomorphic ventricular tachycardia at 1.5 milligrams/kg infused over 5 min. Monitoring of cardiac and renal function is recommended when sotalol is started. During initiation of sotalol therapy (pretreatment QT_c should be <450 milliseconds), QT_c intervals are measured 2 to 4 hours after each oral dose or at the end of an infusion, and therapy is discontinued if QT_c measures ≥500 milliseconds.

Adverse Effects

The most common adverse effects of sotalol are bradycardia 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.²⁰

DOFETILIDE

Actions/Indications/Dosing

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 flutter. Because dofetilide has a significant proarrhythmic effect, it is reserved for patients in whom atrial fibrillation or flutter is highly symptomatic. Dofetilide prescribing is restricted to physicians who have received specific education on dosing and administration and, therefore, is not covered here in detail.²¹

Adverse Effects

Serious adverse effects of dofetilide are ventricular tachycardia and QT_c interval prolongation, which can result in torsades de pointes. The risk of developing torsades de pointes is associated with higher dofetilide doses, initiation of therapy, and electrolyte abnormalities.

IBUTILIDE

Actions/Pharmacokinetics

Ibutilide prolongs the refractory period in atrial and ventricular cardiac tissues. This action is caused by activation of a slow inward sodium current, as opposed to inhibition of outward potassium currents. 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 2 to 12 hours after IV administration.

Indications/Dosing and Administration/Adverse Effects

Ibutilide is indicated for the rapid conversion of recent-onset atrial fibrillation or flutter (greater efficacy) to sinus rhythm.¹⁰ If effective, cardioversion is expected to occur within 1 hour of administration. For patients with atrial fibrillation and an accessory pathway, ibutilide is considered a reasonable option for pharmacologic cardioversion.¹⁶ Serum magnesium and potassium levels should be evaluated and resuscitation equipment made available before ibutilide administration. 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. Electrocardiographic monitoring is continued for at least 4 hours or until the QT_c interval returns to baseline (longer if arrhythmias are observed). Cardiovascular adverse effects of ibutilide include hypotension, hypertension, bradycardia, sinus arrest, syncope, QT_c interval prolongation, congestive heart failure, and 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. In Europe, vernakalant is indicated for rapid conversion of recent-onset atrial fibrillation in adults.²²

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. Nondihydropyridine calcium channel blockers have greater cardioselectivity and are generally used for paroxysmal supraventricular tachycardia and rate control in atrial fibrillation, whereas dihydropyridine calcium channel blockers are more selective for the vasculature 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; therefore, verapamil is used more frequently to abort supraventricular tachycardia than diltiazem.

Pharmacokinetics

See Table 19-18. Oral diltiazem has a relatively rapid onset of action (15 to 60 minutes); therefore, transitioning from an IV infusion to an oral preparation can be accomplished with relative ease. In addition, diltiazem has a short duration of action (1 to 3 hours), necessitating either a continuous infusion or repeat oral doses. Compared to diltiazem, verapamil has a longer half-life and duration of action. Verapamil also has active metabolites that can accumulate if renal or hepatic disease is present.

Indications

Diltiazem and verapamil are indicated for paroxysmal supraventricular tachycardia as well as for rate control in atrial fibrillation¹⁰; however, verapamil is used more commonly to abort supraventricular tachycardia with a conversion rate to sinus similar to adenosine (90%),²³ whereas diltiazem is used more commonly to control rapid ventricular rate in atrial fibrillation.¹⁰ 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 third-degree atrioventricular 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 given, and a continuous infusion is started at 5 to 10 milligrams/h (if bolus is effective). 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 5 milligram/h increments 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 converting the patient to oral diltiazem. Once stable on immediate-release diltiazem, patients can be transitioned to an extended-release formulation by giving an equivalent daily dose.

Verapamil Dosing and Administration

For treatment of supraventricular tachycardia, give 2.5 to 5 milligrams IV over 2 minutes. A second dose of 5 to 10 milligrams (~0.15 milligram/kg) may be given 15 to 30 minutes after the initial dose if the patient does not respond to the initial dose and can tolerate a second dose (maximum total dose: 20 to 30 milligrams).⁶

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 antagonist that causes relaxation of smooth muscle, thereby lowering blood pressure. It has no antiarrhythmic properties and little to no effect on the myocardium.

Pharmacokinetics

See Table 19-20.

Indications

Nicardipine is primarily used for the treatment of hypertension 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. The infusion may be titrated in 2.5 milligram/h increments 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 associated with nicardipine administration include hypotension/orthostatic hypotension, edema, flushing, tachycardia, palpitations, and nausea.

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.

Pharmacokinetics

See Table 19-21.⁶ Many disease states such as congestive heart failure, hypokalemia, renal failure, and thyroid disease can have a substantial 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 greater than 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)¹⁰ and for symptom reduction in congestive heart failure 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 (potential for ventricular fibrillation), acute myocardial infarction, beri-beri heart disease, electrolyte imbalances, sinus node disease, atrioventricular block, and renal impairment. Studies on the mortality associated with digoxin use report conflicting results.^{24,25,26,27,28}

Dosing and Administration

There are many dosing strategies for digoxin initiation. For atrial fibrillation, current guidelines recommend 0.25 milligram IV every 2 hours up to 1.5 milligrams total. Repeat dosing is necessary when loading digoxin due to the prolonged distribution phase. Maintenance dosing is 0.125 to 0.375 milligram daily. 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. Other more rare 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, and seizures. Many types of arrhythmias can occur as a result of digoxin toxicity, and the clinician must be able to recognize the signs and symptoms associated with toxicity and treat accordingly.

ATROPINE

Actions

Atropine blocks the effects of acetylcholine at parasympathetic sites in smooth muscle thus increasing cardiac output.⁶

Pharmacokinetics

See Table 19-22.

Indications

Atropine is considered first-line therapy for the treatment of symptomatic bradycardia. Based on the current advanced cardiac life support treatment guidelines, it is no longer recommended for the treatment of asystole or pulseless electrical activity.⁷ Atropine should be used with caution in patients with coronary heart disease, acute myocardial ischemia, congestive heart failure, tachycardia, and hypertension.⁶

Dosing and Administration

See Table 19-22.^6,7 Doses <0.5 milligram 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 is an endogenous nucleoside that exerts multiple effects mediated by binding adenosine receptors and inhibiting adenylate cyclase, resulting in the decreased flow of calcium ions in the atrioventricular node. It also decreases sinoatrial nodal depolarization by activation of acetylcholine-sensitive potassium currents. These effects result in hyperpolarization and automaticity in cardiac nodal tissue. Adenosine is a first-line agent used in the treatment of narrow-complex supraventricular tachycardia in patients who have failed vagal maneuvers, and it may also be used in the setting of stable monomorphic, wide-complex tachycardias as a diagnostic tool.

Pharmacokinetics

See Table 19-23.

Indications

Adenosine is used for the treatment of supraventricular tachycardia with or without reentry pathways, after failure of vagal maneuvers. It is ineffective for the treatment of atrial fibrillation and flutter and ventricular tachycardias.

Dosing and Administration

See Table 19-24.⁶

Adverse Effects

The most common adverse effects associated with adenosine administration include transient asystole (treatment goal), chest discomfort/pressure, headache, flushing, and nausea. The adverse effects 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/Dosing and Administration

Intravenous magnesium sulfate exerts antiarrhythmic effects in the treatment of torsades de pointes. Its antiarrhythmic activity is mediated by inhibiting calcium currents that cause pathologic early after-depolarizations and thereby cardiac dyssynchrony. Magnesium slows sinoatrial node activity, prolongs myocardial conduction time, stabilizes excitable membranes, and is a cofactor in ion movement.²⁹ 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 ventricular tachycardia is associated with torsades de pointes. In patients with a pulse, 1 to 2 grams IV is diluted in normal saline or 5% dextrose in water and administered as a rapid bolus. Rapid IV administration of magnesium sulfate is associated with vasodilation, flushing, and hypotension.

ISOPROTERENOL

Actions/Pharmacokinetics/Indications

Isoproterenol exerts antiarrhythmic effects by stimulating β₁- and β₂-receptors. The β₁-receptor interaction results in increased chronotropic and inotropic activities in the myocardium and vasodilation by β₂-receptor–mediated relaxation of smooth muscle. 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. Isoproterenol is contraindicated in patients with angina, preexisting ventricular arrhythmias, tachyarrhythmias, or digoxin toxicity.

Dosing and Administration

Isoproterenol should be initiated at 2 micrograms/min (maximum rate, 10 micrograms/min) and titrated every 5 to 10 minutes based on patient response.

Adverse Effect Profile

Serious adverse effects of isoproterenol include hypotension, premature ventricular beats, tachyarrhythmia, ventricular arrhythmia, dyspnea, and pulmonary edema.