Arrhythmias

Cynthia A. Sanoski

Andrew M. Peterson

Cardiac arrhythmias are abnormal cardiac rhythms, including tachyarrhythmias (an increase in heart rate) and bradyarrhythmias (a decrease in heart rate). Arrhythmias may be asymptomatic or symptomatic, causing palpitations, weakness, loss of consciousness, heart failure (HF), and sudden death. Searching for a reversible cause of the arrhythmia is the first step in patient care. However, in many cases, antiarrhythmic drugs (AADs) are necessary to permit stabilization until the underlying condition is normalized. Many patients require chronic drug therapy for an arrhythmia due to an underlying disease condition that makes them chronically susceptible to cardiac arrhythmias that are associated with high morbidity and mortality rates.

CAUSES

Arrhythmias may result from structural or electrical/conduction system changes in the heart that may compromise cardiac function and cardiac output. Conditions that give rise to arrhythmias include myocardial ischemia, chronic HF, hypertension, valvular heart disease, hypoxemia, thyroid abnormalities, electrolyte disturbances, drug toxicity, excessive caffeine or ethanol ingestion, anxiety, and exercise. Some of these conditions are reversible, and some cause structural changes that are not reversible.

PATHOPHYSIOLOGY

Basic Electrophysiology

Electrically active myocardial cells (non-pacemaker-type cells) at rest maintain a potential difference between their intracellular fluid and the extracellular fluid. When excited, these cells manifest a characteristic sequence of transmembrane potential changes called the action potential. The resting membrane potential is -90 mV with respect to the extracellular fluid. The activity of the sodium-potassium pump and the permeability of the membrane to sodium, potassium, and calcium ions determine the membrane potential of a cardiac cell at any given time. Permeability is defined by the diffusion of ions across the membrane through various ion-selective channels. The phases of the action potential correspond to the excitation state of a myocardial cell (Box 23.1).

Arrhythmias can result from disorders of impulse formation and/or impulse conduction. Several factors are believed to be involved in precipitating arrhythmias. There may be a defect in the normal mechanism of spontaneous phase 4 depolarization or an increased automaticity of pacemaker cells. In addition, ectopic pacemakers in normally quiescent tissue are responsible for arrhythmias originating from disorders of impulse formation. Impulse conduction defects occur when the impulse is slowed or blocked because of functional unidirectional block, a change in conduction velocity, or a change in the refractory period. Furthermore, simultaneous abnormalities of impulse formation and conduction may occur.

AADs are used to treat abnormal electrical activity of the heart. The drugs outlined in this chapter are used to treat, suppress, or prevent two major mechanisms of arrhythmias—an abnormality in impulse formation (i.e., increased automaticity) or an abnormality in impulse conduction (i.e., reentry).

Automaticity

Automaticity refers to the ability of the cardiac cells to depolarize spontaneously. Three factors determine automaticity: maximum diastolic depolarization, the rate of depolarization,
and the level of the threshold potential. Arrhythmias resulting from abnormal automaticity include sinus tachycardia and junctional tachycardia. The sinoatrial (SA) node has the most rapid rate of depolarization during diastole and reaches threshold first. Cells of the atrioventricular (AV) node and His-Purkinje system have automaticity but a slower rate of phase 4 depolarization. The primary role of the SA node is as the pacemaker of the heart. The SA node is sensitive to alterations in autonomic nervous system output and in its biochemical surroundings. Catecholamine stimulation leads to a shorter action potential duration and increases the spontaneous rate of depolarization. Vagal stimulus and endogenous purines such as adenosine increase outward potassium currents, thus inhibiting depolarization. Increased adrenergic innervation produces major changes in ionic current activity in the SA node.

BOX 23.1
Phases of the Action Potential

Phase 0 is when rapid depolarization occurs due to the rapid influx of Na⁺.
Phase 1 is a brief initial repolarization period. Inactivation of the inward Na⁺ current and activation of the outward K⁺ current cause this brief but rapid phase of repolarization.
Phase 2 is a plateau period during which there is little change in membrane potential. The outward K⁺ current and the influx of Ca²⁺ through calcium channels typify the plateau period. The offsetting effect of these currents creates only a small net change in potential, thus creating a plateau.
Phase 3 is a period of repolarization that is characterized primarily by K⁺ efflux.
Phase 4 is a gradual depolarization of the cell, with Na⁺ gradually leaking into the intracellular space, balanced by decreasing efflux of K⁺. As the cell is slowly depolarized during this phase, an increase in Na⁺ permeability occurs, which again leads to phase 0.

Another mechanism for arrhythmias due to abnormal impulse formation is intracellular calcium overload, called after-depolarization. If after-depolarizations reach threshold, a new action potential is generated and propagated in adjacent cells. After-depolarizations may occur in response to hypothermia, electrolyte imbalance, catecholamine excess, or stretch. Late after-depolarizations may also be of particular importance in some of the arrhythmias caused by digoxin toxicity.

Reentry

Reentry involves indefinite propagation of the impulse and continued activation of previously refractory tissue. Reentrant foci occur if there are two pathways for impulse conduction, an area of unidirectional block (prolonged refractoriness) in one of these pathways, and slow conduction in the other pathway. A refractory period occurs when the cell cannot be activated after having already fired. Excitability determines the strength of a stimulus required to initiate a new action potential at any given point during the action potential cycle.

Types of Arrhythmias

Arrhythmias evolve either above or below the ventricles and can be regular or irregular. Supraventricular arrhythmias evolve above the ventricles in the atria, SA node, or AV node. These arrhythmias may present with either tachycardia or bradycardia or with regularity or irregularity. AV nodal arrhythmias originate at or within the AV node and are caused by delayed or absent SA node conduction to the AV node. Supraventricular and AV nodal arrhythmias are not usually life threatening; however, they may become troublesome and lead to reduced cardiac output related to decreased ventricular filling.

Ventricular arrhythmias originate in the ventricles or the bundle of His. These types of arrhythmias are usually symptomatic and may cause loss of consciousness or death. Therefore, arrhythmias in this category require immediate intervention. Underlying clinical conditions that usually give rise to these arrhythmias are myocardial ischemia/infarction, dilated and hypertrophic cardiomyopathies, electrolyte disorders, hypoxia, hyperthyroidism, valvular diseases, and drug toxicity. Box 23.2 lists arrhythmias by category.

DIAGNOSTIC CRITERIA

The practitioner must first assess the patient via a thorough and sometimes urgent history and physical examination. There may be no symptoms, or the patient may present with symptoms such as chest pain, shortness of breath, decreased level of consciousness, syncope, confusion, diaphoresis, weakness, and palpitations. The practitioner should ask when the symptoms started, how long they have lasted, their frequency, and how the patient tolerated the symptoms.

It also is important to assess the patient’s risk factors for development of arrhythmias, such as previous coronary artery disease (CAD), myocardial infarction (MI), dilated or hypertrophic cardiomyopathy, hypertension, valvular heart disease, alcohol or drug abuse, or prescription drug use (e.g., digoxin, AADs). The practitioner should focus the physical examination on heart rate and blood pressure; presence of extra, irregular, or skipped beats; rate, rhythm, amplitude, and symmetry of peripheral pulses; and response to exercise.

Laboratory and diagnostic studies also are vital in diagnosing arrhythmias. The practitioner should examine the 12-lead electrocardiogram (ECG) for evidence of myocardial ischemia; calculation of the PR interval, QRS interval, and QT interval; presence of premature atrial or ventricular contractions;
characteristics of Wolff-Parkinson-White (WPW) syndrome; presence or absence of P waves; and relationship between P waves and QRS complexes. Continuous cardiac monitoring is needed for patients who have episodes of life-threatening arrhythmias so that electrical cardioversion and/or AADs can be administered as immediate interventions.

BOX 23.2
Categories of Supraventricular, Junctional, and Ventricular Arrhythmias

SUPRAVENTRICULAR ARRHYTHMIAS

Sinus tachycardia

PSVT (originates above or within the AV node and conducts to the His-Purkinje system) (e.g., AV nodal reentrant tachycardia, AV reentrant tachycardia)

Sinus bradycardia

AFl

Atrial tachycardia

Premature atrial contractions

WPW syndrome

JUNCTIONAL ARRHYTHMIAS

Nonparoxysmal AV junctional tachycardia (heart rate > 60 beats/min)

Junctional escape rhythm (heart rate 40-60 beats/min)

Premature AV junctional complexes

AV dissociation

First-degree heart block

Second-degree heart block (Mobitz type I [Wenckebach], Mobitz type II)

Third-degree (complete) heart block

VENTRICULAR ARRHYTHMIAS

Premature ventricular contractions

TdP (a rapid form of polymorphic VT associated with a long QT interval)

A complete blood count, basic metabolic profile (to assess electrolyte concentrations), thyroid function tests, and a digoxin level should be performed as necessary to determine any underlying causes of the arrhythmia. In addition, an echocardiogram should be performed to assess left ventricular (LV) function. If myocardial ischemia is suspected as a cause of the arrhythmia, the patient should undergo further evaluation with measurement of cardiac enzymes, performance of cardiac stress testing, and, possibly, cardiac catheterization.

INITIATING DRUG THERAPY

During the past several decades, the treatment approach for both atrial and ventricular arrhythmias has been gradually shifting away from the use of AADs toward the use of various nonpharmacological therapies. Several factors have likely contributed to the decline in AAD use over the years. The negative results of the Cardiac Arrhythmia Suppression Trial (CAST) likely had a significant influence on the downward prescribing patterns of class I AADs. In addition, increasing clinical evidence to support the use of nonpharmacological strategies for the treatment of both supraventricular and ventricular arrhythmias has likely contributed to the decline in the use of AADs as a whole. Numerous studies establishing that a rhythm-control regimen does not confer any benefit over a rate-control regimen in patients with persistent atrial fibrillation (AF) may have also contributed to this decline in AAD use.

Treatable conditions may cause the arrhythmia. Identification of treatable causes before administering an AAD is a priority. Conditions that may cause arrhythmias are electrolyte imbalances (e.g., hypokalemia, hypomagnesemia), drug overdose, drug interactions with other medications or herbal supplements, renal failure, thyroid disorders, metabolic acidosis, hypovolemia, MI, pulmonary embolism, cardiac tamponade, tension pneumothorax, dissecting aortic aneurysm, hypoxemia, and valvular or congenital defects in the heart.

Nonpharmacological therapies, such as radiofrequency catheter ablation and implantable cardioverter-defibrillators (ICDs), are also available to treat various arrhythmias. ICDs are used in the management of ventricular arrhythmias, and their benefits have been demonstrated in several clinical trials (Antiarrhythmics Versus Implantable Defibrillators [AVID] Investigators, 1997; Bardy et al., 2005; Buxton et al., 1999; Connolly et al., 2000; Kuck et al., 2000; Moss et al., 1996, 2002). Radiofrequency catheter ablation permanently terminates the arrhythmia by ablating the focal area where the arrhythmia occurs. This procedure can be used for AF, atrial flutter (AFl), and symptomatic drug-refractory ventricular tachycardia (VT).

Goals of AAD Therapy

The overall goals of AAD therapy are to relieve the acute episode of irregular rhythm, establish sinus rhythm (SR), and prevent further episodes of the arrhythmia. Typical agents used to treat arrhythmias include AADs (classes I through IV), digoxin, adenosine, and atropine (Table 23.1).

Drug Classification

AADs are organized into four classes, I (Ia, Ib, Ic), II, III, and IV (Vaughan Williams, 1984). Although the Vaughan Williams classification system is the most widely used method for grouping AADs based on their electrophysiologic actions, using this classification system requires some points of exception to be made. This system is somewhat incomplete, and it excludes certain drugs including digoxin, adenosine, and

atropine. In addition, the classification is not pure, and there is some overlapping of drugs into more than one category. For instance, amiodarone and dronedarone have electrophysiologic properties of all four Vaughan Williams classes. Furthermore, this system does not take into account that the active metabolites of AADs may have different electrophysiologic effects than their parent drugs. For example, N-acetyl procainamide (NAPA), the major active metabolite of procainamide, blocks outward potassium channels and therefore can be considered a class III AAD. Although procainamide blocks outward potassium channels, it also primarily blocks inward sodium currents, thereby making it a class Ia AAD. Therefore, the overall electrophysiologic effect produced by procainamide depends upon the relative concentrations of procainamide and NAPA that are present in the body, which can vary based on several clinical factors. The Vaughan Williams classification scheme (Box 23.3) identifies drugs that block sodium channels (class Ia, Ib, and Ic), those that are β-blockers (class II), those that block potassium channels (class III), and those that are nondihydropyridine calcium channel blockers (CCBs) (class IV).

TABLE 23.1 Overview of Selected Antiarrhythmic Agents

Generic (Trade) Name and Dosage		Selected Adverse Effects	Contraindications	Special Considerations
adenosine (Adenocard)		Headache, chest pain, lightheadedness, dizziness, nausea, flushing, dyspnea, blurred vision	2nd-/3rd-degree heart block or sick sinus syndrome in the absence of a pacemaker	Monitor ECG during administration. Use cautiously in patients with asthma (bronchoconstriction may occur). Each dose should be immediately followed with a 10-mL saline flush.
	Adult: 6 mg IV push over 1-2 s; repeat with 12 mg IV push if sinus rhythm not obtained within 1-2 min after first dose; may repeat 12-mg dose a second time if no response in 1-2 min
amiodarone (Cordarone, Nexterone, Pacerone) AF		IV: hypotension, bradycardia, heart block, phlebitis	2nd-/3rd-degree heart block or sick sinus syndrome in the absence of a pacemaker	Advise patient to apply sunscreen and to minimize areas of exposure to sun.
	Adult IV: 5 mg/kg over 30 min, then continuous infusion of 1 mg/min for 6 h, then 0.5 mg/min; convert to PO when hemodynamically stable and able to take PO medications Adult PO: 400 mg bid-tid for 1 wk, until patient receives ˜10 g total, then 200 mg PO daily	PO: corneal microdeposits, optic neuritis, nausea, vomiting, anorexia, pulmonary fibrosis, bradycardia, tremor, ataxia, paresthesias, insomnia, constipation, abnormal liver function tests, hypothyroidism, hyperthyroidism, blue-gray discoloration of skin, photosensitivity		Patients should have chest x-ray performed annually. Liver function and thyroid function tests should be performed every 6 mo. Pulmonary function tests and ophthalmologic exam should be performed if patient becomes symptomatic. A chest x-ray, pulmonary function tests, liver function tests, and thyroid function tests should also be performed at baseline. An ophthalmologic exam should be performed at baseline if the patient has significant visual abnormalities. Monitor for drug interactions (CYP3A4 substrate; CYP3A4, 2C9, 2D6, and P-gp inhibitor).
Pulseless VT/VF
	Adult IV: 300 mg IV push/IO; can give additional 150 mg IV push/IO if persistent VT/VF; if stable rhythm achieved, initiate continuous infusion at 1 mg/min for 6 h, then 0.5 mg/min; convert to PO when hemodynamically stable and able to take PO medications (see PO dose under stable VT)
Stable VT (with a pulse)
	Adult IV: 150 mg (diluted in 100 mL of D5W or saline) over 10 min; may repeat dose every 10 min, if necessary for breakthrough VT; if stable rhythm achieved, initiate continuous infusion at 1 mg/min for 6 h, then 0.5 mg/min; convert to PO when hemodynamically stable and able to take PO medications Adult PO: 1,200-1,600 mg/d in 2 or 3 divided doses for 1 wk, until patient receives ˜15 g total, then 300-400 mg PO daily
atropine		Palpitations, tachycardia, dry mouth, dizziness	Acute angle-closure glaucoma, obstructive uropathy, tachycardia, obstructive disease of GI tract	Administer IV over 1 min. Monitor ECG during administration.
	Adult: 0.5 mg IV every 3-5 min; not to exceed 3 mg total dose
digoxin (Lanoxin)		Anorexia, nausea, vomiting, diarrhea, headache, dizziness, vertigo, visual disturbances (yellow-green halos), confusion, hallucinations, arrhythmias, AV conduction disturbances (heart block, AV junctional rhythm, bradycardia)	2nd-/3rd-degree heart block or sick sinus syndrome in the absence of a pacemaker	Teach patient how to take pulse. Dose adjustment required in renal impairment. Monitor for drug interactions (P-gp substrate).
	Adult LD (IV or PO): 0.25-0.5 mg over 2 min; may give 0.125-0.25 mg q6h for 2 more doses for a total dose of 1 mg or 10-15 mcg/kg Adult MD: 0.125-0.25 mg IV or PO daily in normal renal function
diltiazem (Cardizem)		Dizziness, headache, edema, heart block, bradycardia, HF exacerbation, hypotension	2nd-/3rd-degree heart block or sick sinus syndrome in the absence of a pacemaker, LVSD	Teach patient how to take pulse and blood pressure. Monitor for drug interactions (CYP3A4 substrate and inhibitor).
	Adult IV: 0.25 mg/kg over 2 min; if ventricular rate remains uncontrolled after 15 min, can repeat with 0.35 mg/kg over 2 min; then initiate continuous infusion of 5-15 mg/h Adult PO: Start with 30 mg four times daily and ↑ to 180-480 mg/d in divided doses (SR can be given once daily)
disopyramide (Norpace)		Hypotension, HF exacerbation, nausea, anorexia, dry mouth, urinary retention, blurred vision, constipation, TdP	2nd-/3rd-degree heart block or sick sinus syndrome in the absence of a pacemaker, LVSD	Dose adjustment required in renal impairment (CrCl ≤ 40 mL/min; SR form not recommended when CrCl ≤40 mL/min). Monitor for drug interactions (CYP3A4 substrate).
	Adult (<50 kg): IR: 100 mg PO q6h; SR: 200 mg PO q12h Adult (>50 kg): IR: 150 mg PO q6h; SR: 300 mg PO q12h; may ↑ up to 800 mg/d
dofetilide (Tikosyn)		Chest pain, headache, dizziness, insomnia, nausea, diarrhea, dyspnea, TdP	CrCl < 20 mL/min, QT interval >440 msec, concomitant use of cimetidine, dolute-gravir, hydrochlorothiazide, ketoconazole, megestrol, prochlorperazine, QTc-prolonging drugs, trimethoprim/sulfamethoxazole, or verapamil	Patients must be hospitalized for ≥3 days for therapy initiation. Dose adjustment required in renal impairment (CrCl ≤60 mL/min). Dose must also be adjusted based on QT interval. Monitor for drug interactions.
	Adult: 125-500 mcg PO bid
dronedarone (Multaq)		Nausea, vomiting, diarrhea, HF exacerbation, hepatic impairment, pulmonary toxicity, renal impairment/failure	Permanent AF, NYHA class IV HF, NYHA class II-III HF with recent hospitalization for decompensated HF, 2nd-/3rd-degree heart block or sick sinus syndrome in the absence of a pacemaker, heart rate <50 beats/min, concurrent use of potent CYP3A4 inhibitors or QTc-prolonging drugs, QT interval ≥500 msec, PR interval >280 msec, severe hepatic impairment, history of amiodarone-induced hepatic or pulmonary toxicity	Instruct patient to report adverse reactions or any signs/symptoms of HF immediately. Monitor for drug interactions (CYP3A4 substrate; CYP2D6, CYP3A4, and P-gp inhibitor).
	Adult: 400 mg PO bid (with meals)
esmolol (Brevibloc)		Hypotension, wheezing, bronchospasm, heart block, bradycardia, HF exacerbation	2nd-/3rd-degree heart block in the absence of a pacemaker, decompensated HF, sinus bradycardia	Use with caution in patients with LVSD.
	Adult: 500 mcg/kg/min IV for 1 min, then maintenance infusion of 50 mcg/kg/min; if inadequate response, rebolus with 500 mcg/kg/min for 1 min and ↑ infusion rate by 50 mcg/kg/min; repeat this process until desired response achieved or maximum infusion rate of 300 mcg/kg/min is reached
flecainide		Dizziness, headache, lightheadedness, syncope, blurred vision or other visual disturbances, dyspnea, HF exacerbation, arrhythmias	2nd-/3rd-degree heart block in the absence of a pacemaker, recent MI, ischemic heart disease, cardiogenic shock, HF	Dose adjustment required in renal impairment (CrCl ≤ 50 mL/min). Monitor for drug interactions (CYP2D6 substrate).
	Adult: 50 mg PO q12h up to a maximum of 300 mg/d
ibutilide (Corvert)		TdP, hypotension, heart block, headache, nausea	Preexisting hypokalemia or hypomagnesemia, QT interval >440 msec	Monitor ECG during administration. Stop infusion if QT interval prolongation or ventricular arrhythmias occur. Correct electrolyte abnormalities before administering.
	Adult (<60 kg): 0.01 mg/kg IV over 10 min; can repeat with another dose if AF/AFl does not terminate within 10 min after end of initial dose Adult (≥60 kg): 1 mg IV over 10 min; can repeat with another dose if AF/AFl does not terminate within 10 min after end of initial dose
lidocaine (Xylocaine) Pulseless VT/VF		Seizures, confusion, stupor, dizziness, bradycardia, respiratory depression, slurred speech, blurred vision, muscle twitching, tinnitus	Hypersensitivity to amide local anesthetics, 2nd-/3rd-degree heart block in the absence of a pacemaker	A lower infusion rate (1-2 mg/min) should be used in older adults or patients with HF or hepatic disease. Monitor for drug interactions (CYP1A2 and CYP3A4 substrate)
	Adult: 1-1.5 mg/kg IV push/IO; may give additional 0.5-0.75 mg/kg IV push/IO every 5-10 min, if persistent VT/VF (maximum cumulative dose = 3 mg/kg); if stable rhythm achieved, initiate continuous infusion of 1-4 mg/min
Stable VT (with a pulse)
	Adult: 1-1.5 mg/kg IV push; may give additional 0.5-0.75 mg/kg IV push every 5-10 min, if persistent VT (maximum cumulative dose = 3 mg/kg); if stable rhythm achieved, initiate continuous infusion of 1-4 mg/min
metoprolol (Lopressor)		Bradycardia, HF exacerbation, heart block, bronchospasm, fatigue, ↓ exercise tolerance, dizziness, hypotension	2nd-/3rd-degree heart block in the absence of a pacemaker, decompensated HF, heart rate <45 beats/min	Use IV with caution in patients with LVSD. Teach patient how to take pulse and blood pressure. Instruct patient to not discontinue drug abruptly (may lead to hypertensive crises, angina, or MI). Use metoprolol succinate (SR) when initiating PO therapy in patients with LVSD.
	Adult IV: 2.5-5 mg over 2 min; can repeat every 5 min (maximum cumulative dose = 15 mg over 10- to 15-min period) Adult PO: IR: 25 mg bid; SR: 50 mg daily; may ↑ up to 400 mg/d
mexiletine		Dizziness, drowsiness, paresthesias, blurred vision, tremor, seizures, confusion, arrhythmias, nausea, vomiting	2nd-/3rd-degree heart block in the absence of a pacemaker, cardiogenic shock	Monitor for drug interactions (CYP1A2 and CYP2D6 substrate).
	Adult: 200 mg PO q8h; may ↑ up to 400 mg PO q8h
procainamide		Bradycardia, heart block, hypotension, HF exacerbation, TdP	Hypersensitivity to procaine, 2nd-/3rd-degree heart block in the absence of a pacemaker	Monitor ECG during administration. Stop infusion if QT interval prolongation or ventricular arrhythmias occur. Use with caution, if at all, in renal impairment.
	Adult: 15-18 mg/kg IV over 60 min, then continuous infusion of 1-4 mg/min
propafenone (Rythmol)		Dizziness, drowsiness, HF exacerbation, blurred vision, arrhythmias, heart block, bradycardia, taste disturbances, bronchospasm	2nd-/3rd-degree heart block in the absence of a pacemaker, bradycardia, cardiogenic shock, HF, bronchospastic disorders	Teach patient how to take pulse and blood pressure. Instruct patient to not discontinue drug abruptly (may lead to hypertensive crises, angina, or MI).
	Adult: IR: 150 mg PO q8h (up to a maximum of 300 mg PO q8h); SR: 225 mg PO q12h (up to a maximum of 425 mg PO q12h)
propranolol		Bradycardia, HF exacerbation, heart block, bronchospasm, fatigue, ↓ exercise tolerance, dizziness, hypotension	2nd-/3rd-degree heart block or sick sinus syndrome in the absence of a pacemaker, LVSD Relatively contraindicated in asthma	Teach patient how to take pulse and blood pressure. Instruct patient to not discontinue drug abruptly (may lead to hypertensive crises, angina, or MI).
	Adult IV: 1 mg over 1 min; may repeat every 5 min up to a total dose of 5 mg Adult PO: 10-20 mg q6-8h; can ↑ to 80-240 mg/d in 2-4 divided doses
quinidine		TdP, heart block, hypotension, tinnitus, diarrhea, nausea, vomiting, fever, HF exacerbation, thrombocytopenia	Allergy or sensitivity to quinidine or cinchona derivatives, long QT syndrome (may predispose to TdP)	Instruct patient to take drug with food if GI distress occurs. Monitor for drug interactions (CYP3A4 substrate; CYP2D6 inhibitor).
	Adult: Sulfate: 200-400 mg PO q6h, up to a maximum of 600 mg PO q6h Gluconate: 324 mg PO q8-12h, up to a maximum of 972 mg PO q8-12h
sotalol (Betapace, Betapace AF) AF (Betapace AF)		Bradycardia, heart block, HF exacerbation, TdP, bronchospasm	2nd-/3rd-degree heart block in the absence of a pacemaker, bradycardia, HF, asthma, long QT syndrome (may predispose to TdP)	Patients must be hospitalized for ≥3 days for therapy initiation. Teach patient how to take pulse and blood pressure. Dose adjustment required in renal impairment (CrCl ≤ 60 mL/min) Instruct patient to not discontinue drug abruptly (may lead to hypertensive crises, angina, or MI).
	Adult: 80 mg PO bid, up to a maximum of 160 mg PO bid
Ventricular Arrhythmias (Betapace)
	Adult: 80 mg PO bid, up to a maximum of 320 mg PO bid
verapamil (Calan)		Constipation, bradycardia, heart block, HF exacerbation, hypotension, dizziness, peripheral edema	2nd-/3rd-degree heart block or sick sinus syndrome in the absence of a pacemaker, LVSD	Encourage patient to ↑ fluid and fiber intake to combat constipation. Teach patient how to take pulse and blood pressure. Monitor for drug interactions (CYP3A4 substrate and inhibitor).
	Adult IV: 2.5-5 mg over 2 min; if ventricular rate remains uncontrolled after 15-30 min, can double initial dose and administer over 2 min; then initiate continuous infusion of 5-10 mg/h Adult PO: 240-360 mg/d in 3 divided doses (SR can be given once daily)
AF, atrial fibrillation; AFl, atrial flutter; AV, atrioventricular; bid, twice daily; CrCl; creatinine clearance; CYP, cytochrome P-450, D5W, 5% dextrose in water; ECG, electrocardiogram; GI, gastrointestinal; HF, heart failure; IO, intraosseous; IR, immediate-release; IV, intravenous; LD, loading dose; LVSD, left ventricular systolic dysfunction; MD, maintenance dose; MI, myocardial infarction; NYHA, New York Heart Association; P-gp, P-glycoprotein; PO, oral; SR, sustained release; TdP, torsades de pointes; tid, 3 times daily; VF, ventricular fibrillation; VT, ventricular tachycardia.

Class I AADs

This class of drugs, known as the sodium channel blockers, may be subdivided into classes Ia, Ib, and Ic according to the rate of sodium channel dissociation. These agents vary in the rate at which they bind and then dissociate from the sodium channel receptor. Class Ib AADs bind to and dissociate from the sodium channel receptor quickly (“fast on-off”), while class Ic AADs slowly bind to and dissociate from this receptor (“slow on-off”). The binding kinetics of the class Ia AADs are intermediate between those of the class Ib and Ic agents. In addition, class I AADs possess rate dependence, whereby sodium channel blockade is greatest at fast heart rates (i.e., tachycardia) and least during slower heart rates (i.e., bradycardia) (see Table 23.1).

Class Ia Drugs

Quinidine

Quinidine is a broad-spectrum AAD that may be used to treat supraventricular and ventricular arrhythmias. This drug slows conduction velocity (phase 0), prolongs refractoriness (phase 3), and decreases automaticity (phase 4). Quinidine widens the QRS complex, prolongs the QT interval, and slightly prolongs the PR interval on the ECG. Quinidine has been used in the management of AF, AFl, AV nodal reentrant tachycardia, and VT.

Quinidine has potent anticholinergic properties that affect the SA and AV nodes. Therefore, quinidine can increase the SA nodal discharge rate and AV nodal conduction. Consequently, in patients with AF or AFl, these anticholinergic effects may lead to a more rapid ventricular rate. Therefore, the AV node should be adequately inhibited with the use of an AV nodal blocking drug, such as a β-blocker, nondihydropyridine CCB (e.g., diltiazem or verapamil), or digoxin prior to administering quinidine in these patients. Quinidine also blocks α₁-receptors, which can lead to vasodilation and subsequent dose-related hypotension, especially when administered intravenously.

The most common adverse effects associated with quinidine are gastrointestinal (GI) (nausea, vomiting, and diarrhea). As with other class Ia drugs, quinidine can cause
proarrhythmia, specifically torsades de pointes (TdP). Other adverse effects associated with quinidine include thrombocytopenia, hepatitis, cinchonism (tinnitus, blurred vision, headache), worsening of underlying HF, and hemolytic anemia.

Quinidine is a substrate of the cytochrome P-450 (CYP) 3A4 isoenzyme and an inhibitor of the CYP2D6 isoenzyme. Therefore, quinidine can interact with any drug that inhibits or induces CYP3A4 (e.g., inhibitors: ketoconazole, erythromycin, amiodarone, verapamil, diltiazem; inducers: rifampin, phenobarbital, phenytoin) or is a substrate of CYP2D6 (e.g., β-blockers). Quinidine can also significantly increase serum digoxin concentrations.

Procainamide

Procainamide has basically the same electrophysiologic effects as those of quinidine, except that procainamide does not have the anticholinergic activity of quinidine. Procainamide slows conduction velocity (phase 0), prolongs refractoriness (phase 3), and decreases automaticity (phase 4). Procainamide widens the QRS complex, prolongs the QT interval, and slightly prolongs the PR interval on the ECG. NAPA, the major metabolite of procainamide, blocks outward potassium currents and thereby has class III electrophysiologic properties. NAPA prolongs the QT interval. Procainamide is a broad-spectrum AAD and has been used to treat supraventricular and ventricular arrhythmias.

Procainamide is only available in the intravenous (IV) formulation; all of its oral formulations have been discontinued. Therefore, adverse effects that would most likely occur with chronic therapy (e.g., systemic lupus erythematosus, agranulocytosis) should no longer be a concern. Most of the adverse effects associated with IV administration of procainamide include bradycardia, AV block, hypotension, worsening of underlying HF, and TdP.

Procainamide and NAPA can accumulate in patients with renal impairment. Therefore, serum concentrations must be monitored regularly to assess for efficacy and toxicity. The therapeutic ranges of procainamide and NAPA are 4 to 10 mcg/mL and 15 to 25 mcg/mL, respectively.

Disopyramide

Disopyramide slows conduction velocity (phase 0), prolongs refractoriness (phase 3), and decreases automaticity (phase 4). These effects are manifested as a prolonged QT interval and a slightly prolonged QRS complex on the ECG. Disopyramide has direct and indirect effects on the heart rate similar to those of quinidine. Disopyramide is a broad-spectrum AAD and has been used to treat supraventricular and ventricular arrhythmias. However, the clinical use of this agent is limited because of its potent anticholinergic and negative inotropic effects. If disopyramide is used to treat AF or AFl, the practitioner should give an AV nodal blocking agent (e.g., β-blocker, diltiazem, verapamil, or digoxin) to minimize its vagolytic effect.

The primary adverse effects associated with disopyramide are precipitation of HF and anticholinergic effects (e.g., dry mouth, urinary retention, constipation, blurred vision). Disopyramide is contraindicated in patients with HF with reduced ejection fraction (HFrEF) (left ventricular ejection fraction [LVEF] of 40% or less) because it can cause significant depression of myocardial contractility. Disopyramide can also cause TdP.

Class Ib Drugs

The class Ib AADs include lidocaine and mexiletine. These agents decrease automaticity and conduction velocity and shorten refractoriness. These AADs primarily exert their electrophysiologic effects on the ventricular myocardium since they have little or no effect on atrial tissue.

Lidocaine

Lidocaine is categorized as a class Ib AAD; however, its electrophysiologic effects are different in that it is selective to ischemic tissue, and especially to active fast sodium channels in the bundle of His, Purkinje fibers, and ventricular myocardium. Thus, lidocaine has little effect on conduction in nonischemic tissue and the atrial myocardium. Lidocaine also has very little effect on the automaticity of the SA node. However, lidocaine does suppress the automaticity of ectopic ventricular pacemakers and Purkinje fibers. In normal tissues, the action potential duration is shortened and conduction velocity shows little change with lidocaine. However, in depolarized fibers or in fibers damaged by ischemia, lidocaine prolongs the action potential and slows conduction.

Lidocaine is primarily effective in treating ventricular arrhythmias, especially those associated with acute MI. Prophylactic administration in patients with acute MI demonstrated a decreased incidence of ventricular fibrillation (VF) but no difference in prehospital treatment outcomes of acute MI and no improvement or even higher mortality rates in hospitalized patients. Selective administration of lidocaine to patients with VF associated with MI or cardiac arrest also demonstrated no improvement in survival rates (Wyse et al., 1988). The use of lidocaine as prophylaxis against VT or VF in patients with MI is not warranted. Its use should be reserved for the treatment of ventricular arrhythmias.

Lidocaine is not effective in the treatment of supraventricular arrhythmias such as AF or AFl. However, lidocaine can be used for the treatment of digoxin-induced arrhythmias (atrial and ventricular) because of its selectivity for depolarized myocardium.

Lidocaine is eliminated primarily by hepatic metabolism, with the metabolic rate being proportional to hepatic blood flow. In patients with HFrEF, the volume of distribution in the central compartment is decreased and hepatic blood flow may be reduced if cardiac output is depressed. Hepatic impairment slows lidocaine’s clearance rate but does not affect its volume of distribution.

The principal adverse effects associated with lidocaine are central nervous system (CNS) effects (i.e., dizziness, paresthesia, disorientation, tremor, agitation). At higher concentrations, seizures and respiratory arrest may occur with the use of lidocaine. Lidocaine’s adverse effects are more frequent in the elderly, in patients with HFrEF or hepatic disease, and during prolonged administration (more than 24 hours). Therefore, these patients should be closely monitored for signs and symptoms of lidocaine toxicity. Lidocaine concentrations should also be closely monitored in these patients. The therapeutic range of lidocaine is 1.5 to 6 mg/L. Lidocaine toxicity is most commonly observed at concentrations greater than 5 mg/L.

Mexiletine

Mexiletine is a structurally related oral analog of and has similar electrophysiologic effects, antiarrhythmic effects, and adverse events to lidocaine. Mexiletine decreases conduction velocity (phase 0) preferentially in ischemic tissue.

Mexiletine is effective in the treatment of VT. Combining mexiletine with a second AAD (class IA or III) is more effective than mexiletine monotherapy for the treatment of refractory VT. However, its clinical use is limited by a high incidence of GI reactions such as nausea and vomiting. CNS adverse effects such as dizziness, confusion, ataxia, and speech disturbances may lead the practitioner to discontinue treatment with this drug. Mexiletine can also cause proarrhythmia, although the incidence is lower when compared to other AADs.

Class Ic Drugs

Flecainide

Flecainide is a potent blocker of sodium channels during phase 0 of the action potential, thereby slowing conduction velocity in the Purkinje fibers and AV node and diminishing automaticity in the Purkinje fibers. Because of the slowed cardiac conduction, increases in the PR interval and QRS duration may be seen on the ECG.

Flecainide is most commonly used in clinical practice for the treatment of supraventricular arrhythmias, such as AF and AFl. Flecainide has very good efficacy in terms of restoring and maintaining SR in patients with AF (Camm et al., 2012; Slavik et al., 2001). Flecainide has been shown to restore SR in 75% to 90% of patients with AF at 8 hours (with single, oral loading doses of 300 mg) as well as maintain SR in up to 77% of patients at 1 year. Although flecainide is approved by the U.S. Food and Drug Administration (FDA) for the treatment of life-threatening sustained VT, it is rarely, if ever, used for this indication, primarily due to its suboptimal efficacy and the potential for proarrhythmic events (Anderson et al., 1983). There may be a resurgence in the use of flecainide for the use of ventricular arrhythmias, as this AAD has been more recently shown to be effective in suppressing exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic VT that is refractory to β-blocker therapy (Van der Werf et al., 2011).

The CAST was conducted to determine if suppression of asymptomatic or mildly symptomatic premature ventricular contractions (PVCs) with the class Ic AADs, flecainide, encainide, or moricizine would reduce the incidence of death from arrhythmia in post-MI patients (CAST Investigators, 1989). Despite adequate suppression of ventricular arrhythmias, flecainide significantly increased mortality from arrhythmia or cardiac arrest (presumably due to proarrhythmia) and significantly increased total mortality. Overall, the results of this trial demonstrated that the use of AADs to suppress asymptomatic PVCs in post-MI patients does not improve survival and is most likely detrimental. The use of flecainide should be avoided in patients with any form of structural heart disease (SHD), which includes CAD, HF, or LV hypertrophy.

Adverse effects associated with flecainide include blurred vision, dizziness, headache, tremor, nausea, vomiting, conduction disturbances, and ventricular arrhythmias (sustained VT) that can be quite resistant to cardioversion. Flecainide also has potent negative inotropic effects that may lead to worsening HF.

Propafenone

Propafenone has the same ability to block sodium channels, slow conduction velocity, and diminish automaticity in the AV node and Purkinje fibers as flecainide. However, propafenone also has a mild, nonselective β-blocking effect. Although propafenone is FDA approved for the treatment of life-threatening ventricular arrhythmias, its use in clinical practice has been limited to the management of supraventricular arrhythmias such as AF. Propafenone has been shown to be effective for restoring and maintaining SR in patients with AF (Miller et al., 2000; Roy et al., 2000). The use of single, oral loading doses of propafenone (450 to 600 mg) in patients with recent-onset AF has been associated with conversion rates of 72% to 76% at 8 hours (Slavik et al., 2001). Although propafenone was not evaluated in the CAST and has not been associated with increased mortality in other trials, there still tends to be an overall negative perception of this drug’s safety in patients with SHD. Until the safety of propafenone can be demonstrated conclusively in a large, randomized, prospective trial in patients with SHD, its use should be avoided in this population.

Adverse effects associated with propafenone include blurred vision, dizziness, headache, nausea, vomiting, fatigue, bronchospasm, taste disturbances (metallic taste), conduction disturbances (bradycardia, heart block, QRS prolongation), and ventricular arrhythmias (sustained VT) that can be quite resistant to cardioversion. Propafenone also has potent negative inotropic effects that may lead to worsening HF.

Class II AADs

β-Blockers are useful in suppressing ventricular arrhythmias. They also are used for treating many supraventricular arrhythmias because of their ability to block receptor sites in the conduction system and subsequently slow AV nodal conduction and the SA nodal rate, which in turn slows the ventricular rate. Furthermore, β-blockers are helpful when used in combination with other AADs or in treating the underlying cause of some arrhythmias (ischemia, catecholamine excess) (see Table 23.1).

β-Blockers decrease automaticity (decrease the slope of phase 4 depolarization in the sinus node and in the Purkinje fibers) and conduction velocity (phase 0) and prolong refractoriness (phase 3). Changes in the ECG caused by β-blockers are a sinus bradycardia, consisting of a normal or slightly prolonged PR interval and occasional shortening of the QT interval. In addition to being negative chronotropic drugs (decrease AV nodal conduction), β-blockers are also negative inotropic agents (decrease cardiac contractility). Both of these properties enable β-blockers to decrease myocardial oxygen consumption, which is useful especially in patients with underlying CAD. Patients with sinus node dysfunction or AV conduction system defects may have significant sinus bradycardia when a β-blocker is initiated.

In general, β-blockers lower the heart rate and blood pressure, decrease myocardial contractility, decrease oxygen consumption in the myocardium, and lower cardiac output. β-Blockers have a diverse range of uses, including paroxysmal supraventricular tachycardia (PSVT), AF, AFl, and arrhythmias caused by catecholamine excess, ischemia, mitral valve prolapse, hypertrophic cardiomyopathy, and MI. β-Blockers also reduce complex ventricular arrhythmias, including VT. The VF threshold is increased with the use of β-blockers in animal models, and β-blockers have been found to decrease VF in patients with acute MI. β-Blockers reduce myocardial ischemia, which may reduce the likelihood of VF. All β-blockers (without intrinsic sympathomimetic activity) are relatively similar in efficacy for the treatment of supraventricular and ventricular arrhythmias. Selection of a particular β-blocker is usually based on the safety profile of the individual agent.

The adverse effects associated with β-blockers depend on their selectivity for β₁ or β₂ receptors. Bronchospasm may be seen in patients with asthma and chronic obstructive pulmonary disease; this adverse effect is not eliminated by the use of selective β₁-blockers since these agents gradually become nonselective as the dose is increased. HF, hypotension, bradycardia, and depression also are common adverse effects of β-blockers. In addition, patients receiving β-blockers often report fatigue and impotence.

Class III AADs

Class III AADs include amiodarone, dofetilide, dronedarone, ibutilide, and sotalol. Ibutilide and dofetilide are used to treat AF and AFl. Amiodarone and sotalol can be used to treat both supraventricular and ventricular arrhythmias. Dronedarone is FDA approved to reduce the risk of hospitalization from cardiovascular (CV) causes in patients in SR with a history of paroxysmal or persistent AF.

Patients receiving class III AADs should be monitored closely for ECG changes such as increased ventricular ectopy and changes in PR interval, QRS duration, and QT interval. Practitioners should avoid using class III AADs concomitantly with other drugs that can prolong the QT interval to minimize the risk of TdP (see Table 23.1).

Amiodarone

Amiodarone is a unique drug in that it possesses electrophysiologic characteristics of all four Vaughan Williams classes of AADs. While amiodarone is primarily a potassium channel blocker (blocks the rapid and slow components of the delayed rectifier potassium current), it also blocks sodium channels, has nonselective β-blocking activity, and has weak calcium channel blocking properties. As a result, amiodarone reduces automaticity (phase 4) and conduction velocity (phase 0) and prolongs refractoriness (phase 3). When administered intravenously, amiodarone’s β-blocking and calcium channel blocking activities are more predominant. Amiodarone has minimal to no negative inotropic effects, which makes it one of the few AADs that can be safely used in patients with HFrEF.

Amiodarone is approved by the FDA for the management of life-threatening recurrent ventricular arrhythmias. However, its off-label use for AF has increased over the past decade not only because of its increased efficacy in maintaining
SR as compared to other AADs but also because of it is one of the few AADs proven to be safe in patients with concomitant SHD. Amiodarone is often given IV for the acute treatment of life-threatening ventricular arrhythmias, such as VT or VF. IV amiodarone can also be used to terminate AF acutely. Even though ICDs now play a primary role in the chronic management of ventricular arrhythmias, amiodarone is still used in patients who refuse or are not candidates for these devices. Also, amiodarone (with a β-blocker) can also be used as adjunctive therapy in these patients if frequent ICD discharges occur (Connolly et al., 2006).

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Tags: Pharmacotherapeutics for Advanced Practice: A Practical Approach

Nov 11, 2018 | Posted by drzezo in PHARMACY | Comments Off

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