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Treatment of Arrhythmias
Pharmacologic therapy for clinical arrhythmias
Antiarrhythmic Agents
Adenosine
Adenosine is an intravenous (IV) purinergic blocker that inhibits sinus node and atrioventricular (AV) node automaticity and conduction, similar to high parasympathetic activity. Adenosine binds to the adenosine A1 receptor and activates a potassium current in the atrium (I KAdo ) with clinical transient effects of sinus node slowing, AV node block, and atrial refractory period shortening.
Indications
Termination of AV node– and sinus node–dependent tachycardias, such as AV node reentry tachycardia (AVNRT), reentrant tachycardias using an accessory pathway and the AV node, and sinus node reentrant tachycardia. Adenosine may also terminate some atrial tachycardias (ATs) and idiopathic ventricular tachycardias (VTs), particularly those that originate from the right ventricular outflow tract.
Dosage
Because adenosine has a very short half-life of about 10 seconds, it should be given as a rapid 6-mg IV bolus followed by a bolus of saline. If needed, a 12- to 18-mg IV bolus can be given 1 to 2 minutes later, followed by another 12- to 18-mg IV bolus 1 to 2 minutes after the second dose. Each IV dose should be followed with a rapid saline flush (20 cc).
Contraindications
Avoid in drug-induced tachycardias, wide QRS tachycardias of unknown origin, heart transplant patients (it may cause prolonged asystole), patients taking dipyridamole (it may cause prolonged asystole), and in those in whom severe bronchospasm can be produced. It will be ineffective if the patient is taking theophylline and will be less effective if the patient has just consumed large amounts of caffeine-containing substances.
Comments
Does not terminate AV node–independent tachycardias such as atrial fibrillation (AF), atrial flutter (AFL), and multifocal AT, although the AV block produced can allow the atrial rhythm to be more easily diagnosed. Transient side effects include flushing, chest pain, dyspnea, bronchospasm, brief asystole, bradycardia, and premature ventricular contractions (PVCs). Patients should be forewarned that such marked discomfort may occur, but reassured that the sensation should pass after a few seconds. Transient sinus bradycardia (SB) and PVCs are common after conversion to sinus rhythm. Large doses can initiate AF. If used to diagnose the presence of AFL, the hypotension resulting from the drug can (rarely) facilitate AV conduction and produce 1:1 AV conduction.
Amiodarone
Amiodarone is a class I, II, III, and IV antiarrhythmic drug with a large volume of distribution, a long loading phase, and a long half-life. As a β-adrenergic blocker, it is noncompetitive.
Indications
Amiodarone is a complex drug with many potential arrhythmia indications. It is currently the most used antiarrhythmic drug despite the fact that it has only one U.S. Food and Drug Administration (FDA)-approved indication, which is for potentially life-threatening ventricular arrhythmias. It is the most versatile antiarrhythmic drug and can be used for virtually all ATs and VTs. Although it may be FDA approved specifically for potentially life-threatening VTs, amiodarone has not been shown to reduce the risk of death or sudden cardiac death in patients with cardiovascular disease or arrhythmias, although in patients with out-of-hospital cardiac arrest due to refractory VT/ventricular fibrillation (VF), IV amiodarone has been shown to improve survival to hospital admission. Nevertheless, the drug is excellent in reducing episodes of AF and VT. It is important to recognize that IV amiodarone has different electrophysiological effects from oral amiodarone. IV amiodarone loading does not provide the same electrophysiological benefit as oral drug therapy, and for reasons that are not entirely clear, it takes some time for IV amiodarone to be effective even if drug levels are high. IV amiodarone has a greater effect on blocking conduction through the AV node and has less effect on refractoriness. IV amiodarone can cause vasodilation and reflex sympathetic effects. The indications for IV amiodarone include cardiac arrest caused by VF or pulseless VT, VT that is hemodynamically better tolerated and has a monomorphic or polymorphic morphology with normal QT interval (and is not torsades de pointes ventricular tachycardia [TdP VT]), nonsustained VTs that are symptomatic, VTs that cause implantable cardioverter defibrillator (ICD) shocks, and atrial arrhythmias, including AT, AF, and AFL. It is useful for prevention of atrial arrhythmias after sinus rhythm has been restored and for prophylaxis of AF after open heart surgery.
Dosage
Intravenous Use
In the setting of a cardiac arrest, the initial IV bolus is 300 mg. Repeat 150- to 300-mg bolus doses can be given as needed up to a total maximum dose of 2.1 g in 24 hours. If there is restoration of sinus rhythm, large doses of IV amiodarone can cause hypotension and bradycardia.
For recurrent or refractory VF or VT, hemodynamically unstable VT, or stable wide QRS complex tachycardia of unknown origin, begin with IV infusion of 150 mg over no less than10 minutes, followed by an infusion of 1 mg/minute for 6 hours, then a maintenance infusion of 0.5 mg/minute for 18 hours or until the switch to oral amiodarone is made. Additional bolus infusions of 150 mg over no less than 10 minutes can be administered for breakthrough arrhythmias.
For patients with acute-onset AF, such as in the postoperative setting, and for patients who cannot take oral drugs, IV amiodarone may be a quick way to load patients and to help control the ventricular response rate. The half-life of amiodarone given intravenously is less than it is after the patient is fully loaded and is 24 to 48 hours.
For treatment of AFL and AF, IV amiodarone can be used to rapidly obtain clinically effective levels of the drug and to help control the ventricular rate, if not restore the rhythm to normal, but it is important to recognize that IV amiodarone levels do not necessarily provide the same electrophysiological effects as does long-term use of the drug. IV amiodarone slows AV conduction, thus reducing the ventricular rate in AFL and AF. IV amiodarone is used in the setting of perioperative AFL and AF and in conditions in which paroxysmal arrhythmias have rapid rates that are hemodynamically decompensating, such as in hypertrophic cardiomyopathy.
The drug may also help block conduction through accessory pathways and the AV node. IV dosing is much the same as it is for VT, but the speed at which the infusion is given can often be reduced because the rhythm disturbance is usually better tolerated than VTs. As such, there is less risk of hypotension.
Oral Use
Oral dosing for recurrent VF or hemodynamically unstable VT and for prevention of ICD shocks: Loading dose of 800 to 1600 mg per day for 5 to 7 days (occasionally longer) until the arrhythmia is controlled or significant side effects occur. These large doses are preferably initiated in the hospital. The dose should then be reduced to 400 to 800 mg/day for 1 month, followed by the usual maintenance dose of 200 to 400 mg/day. Maintenance doses should be administered once daily (or in divided doses with meals for total daily doses that can be as low as 100 mg/day). Use lowest clinically effective doses because plasma levels do not reflect tissue levels and are therefore not useful. The half-life of oral amiodarone is approximately 40 to 45 days.
Typical oral dosing can be initiated in the hospital at up to 1200 mg/day for 3 to 5 days, with a decrease to 800 mg/day for 1 week, then 600 mg/day for 1 week, then 400 mg/day for several weeks, and finally 100 to 200 mg/day. Alternatively, the drug can be started more slowly in the outpatient setting at 600 or 400 mg/day for 3 to 4 weeks. Amiodarone is unlikely to convert AFL and AF to sinus rhythm acutely and should not be used for this purpose.
Contraindications
Severe sinus node dysfunction causing marked SB, second-degree or third-degree AV block (AVB), and symptomatic bradyarrhythmias, unless rate support is provided by a pacemaker. Although the drug is best avoided in patients with interstitial lung disease, it can be used with caution in patients with chronic obstructive pulmonary disease (COPD). Although the incidence of proarrhythmia is low using amiodarone alone, caution should be used if given with other drugs that prolong the QT interval. Avoid this in patients with hepatic dysfunction. Amiodarone is absolutely contraindicated in pregnant women because of neonatal hypothyroidism, prematurity, bradycardia, and congenital abnormalities. Statin dosing may need to be reduced.
Comments
The most common serious side effects of IV amiodarone include hypotension, bradycardia, AV block, TdP VT (< 2%), interstitial pulmonary fibrosis, an acute respiratory distress syndrome (ARDS)-like condition if used acutely (2%), and liver toxicity. Thyroid dysfunction and central nervous system (CNS) side effects are not rare.
Side effects of oral amiodarone include hypothyroidism, hyperthyroidism, photosensitivity, blue discoloration of the skin, corneal deposits that can cause halos around lights, liver function abnormalities, nausea, tremor, neuropathy, or difficulty with gait due to neurotoxicity, pulmonary fibrosis, and bradycardia. Although the QT interval can lengthen significantly with oral amiodarone, TdP VT is rare. Optic neuritis has been rarely reported.
When given for high-risk ventricular arrhythmias or poorly controlled atrial arrhythmias, therapy should be initiated in the hospital after withdrawal of other antiarrhythmic drugs. Liver, lung (chest x-ray at minimum and pulmonary function tests with diffusing capacity of the lung for carbon monoxide [DLCO] in selected patients), and thyroid function should be evaluated at baseline and periodically thereafter. Plasma concentrations (normal, 1 to 2.5 mcg/mL) may be helpful in evaluating nonresponsiveness or unexpected severe toxicity but do not reflect tissue levels of the drug. Patients should be monitored closely after dose adjustments because of the drug’s long half-life. Amiodarone can increase serum levels of digoxin, quinidine, procainamide flecainide, cyclosporine, and warfarin (prothrombin times must be followed closely, and dosage of warfarin may need to be reduced). Because of increased risk of rhabdomyolysis, concomitant doses of simvastatin greater than 20 mg should be avoided. Phenytoin and cholestyramine can reduce amiodarone levels. Amiodarone generally does not increase myocardial stimulation threshold in patients with pacemakers but will elevate the defibrillation threshold in patients with ICDs. It may also slow VT below the programmed detection interval in patients with ICDs.
Atropine
Atropine is an IV antimuscarinic drug.
Indications and Dosage
Ventricular asystole, pulseless electrical activity, bradycardia associated with hypotension: 1-mg IV push (may repeat).
Symptomatic SB or intranodal (Mobitz type I) AV block; nausea and vomiting caused by morphine: 0.5 to 1.0 mg. This may be repeated up to a total dose of 3 mg. Tracheal dose/route: 1 to 2.5 mg in 10 to 25 cc normal saline.
Contraindications
Use with caution in acute coronary syndromes (increased heart rate can provoke myocardial ischemia, acute myocardial infarction [MI], and rarely VT or VF). Avoid in patients with cardiac denervation (e.g., transplant patients) and those taking dipyridamole. This can have antimuscarinic effects, including urinary retention in patients with prostate disease. Use caution if there is glaucoma. This can cause constipation and blurred vision.
Comments
Atropine can worsen infranodal (Mobitz type II) second-degree AVB, due to an increase in sinus rate and enhanced AV nodal conduction, resulting in the atrial impulses encountering refractoriness in the His-fascicular system.
β-Adrenergic Blockers
This class of drugs (class II antiarrhythmics) blocks the β-sympathetic nervous system at the receptor level.
Arrhythmic Indications
β-adrenergic blockers may be used acutely for patients with AFL and AF with a rapid ventricular response rate, although adequate rate control in flutter is not likely to be achieved. β-adrenergic blockers can be used chronically for rate control in AFL and AF and to prevent some recurrences of AF. β-adrenergic blockers can also be used for prevention of catecholamine-related VTs. β-adrenergic blockers reduce the risk of total mortality and sudden cardiac death in patients with underlying coronary artery disease (CAD), especially after MI. β-adrenergic blockers also reduce the risk of death in patients with cardiomyopathy and congestive heart failure (CHF) due to systolic left ventricular dysfunction.
β-adrenergic blockers may also help to prevent recurrences of ATs and other supraventricular tachycardias (SVTs) after conversion to sinus rhythm, although it is uncertain if β-adrenergic blockade alone actually helps to achieve the conversion to sinus rhythm. IV β-adrenergic blockade may also be used for VT and VF storm and for prevention of recurrent catecholaminergic-dependent VT.
The types of β-adrenergic blockers that are useful in treating arrhythmias include metoprolol, esmolol (acutely), carvedilol, and acebutolol. Metoprolol is longer acting than esmolol (half-life of approximately 9 minutes) but is more cardioselective. Propranolol and long-acting propranolol are useful because they cross the blood-brain barrier; they may have greater effects in neurocardiogenic syncope, although β-adrenergic blockade does not appear to be very effective to treat this disorder. Propranolol is no more effective than any other β-adrenergic blocker for any antiarrhythmic effects. Atenolol is relatively short acting. It is best to use one or two β-adrenergic blockers and become familiar with them. Nadolol has been used particularly for long QT syndrome and some arrhythmias. It has a longer half-life and is a nonselective β blocker. Acebutolol and pindolol have some sympathomimetic effects. Acebutolol appears to be well tolerated in young individuals with palpitations and SVTs.
Acute Use
Indications and Dose
Start oral therapy unless there is a compelling reason to give IV (e.g., ventricular arrhythmias or significant hypertension). Metoprolol: Begin with 12.5 or 25 mg by mouth (PO) every 12 hours × 1, 50 mg every 12 hours × 2, then 100 mg PO every 12 hours, as tolerated. If IV metoprolol is indicated, 2.5 to 5 mg over 1 to 2 minutes, repeated every 5 minutes to a total dose of 15 mg before transitioning to oral therapy. Initial doses can be reduced to 1 to 2 mg if a conservative regimen is desired.
Esmolol may be preferred because of its brief half-life: 0.1 mg/kg per minute (IV) infusion, titrated in increments of 0.05 mg/kg per minute every 5 to 15 minutes (as tolerated by blood pressure [BP]) until the desired therapeutic response is achieved, limiting symptoms develop, or a dose of 0.25 mg/kg per minute is reached. For more rapid onset of action, a loading dose of 0.5 mg/kg can be given IV over 2 to 5 minutes followed by the usual maintenance dose.
For patients with left ventricular ejection fraction (LVEF) less than or equal to 0.40 post-MI, carvedilol (starting dose 3.125 to 6.25 mg twice per day [BID], titrated over 4 to 6 weeks to 25 mg BID as tolerated) is reasonable. For hospitalized patients unable to tolerate β-adrenergic blockers, attempts to reinitiate therapy after 1 to 2 weeks of clinical stability are recommended.
Atenolol is not particularly good for treating arrhythmias because the half-life is relatively short. The dose starts at 25 mg twice a day and goes up to 100 mg twice a day. For atenolol to be used for arrhythmias, it should be given BID.
Contraindications (Relative)
Systolic BP less than 90 mm Hg; sinus rate less than 50 bpm; initiation during severe, decompensated heart failure (although patients already receiving these drugs may be continued on them); PR interval greater than 0.24 seconds, or higher degrees of AV block or sinus node dysfunction unless rate support is provided by a permanent pacemaker; history of clinically important bronchospasm. Concurrent use with verapamil or diltiazem can result in severe hypotension, heart failure, or cardiac arrest.
Comments
Monitor heart rate, BP, echocardiogram (ECG); evaluate lungs for rales and wheezing. For mild wheezing or COPD, consider using low doses of a β 1 -selective drug (e.g., metoprolol). Patients with a contraindication to β-adrenergic blockers in the first 24 hours should be reevaluated for candidacy later in the hospital course.
Chronic Use
Indications
Long-term treatment of SVT, AFL, and AF to control the ventricular response rate, VTs to prevent recurrence, and premature ventricular beats if highly symptomatic; inappropriate sinus tachycardia and palpitations if treatment is deemed necessary. It is for any catecholamine-dependent arrhythmia.
Dose
Metoprolol 50 to 200 mg PO every 12 hours. Acebutolol 200 to 800 mg/day. Carvedilol 3.125 to 25 mg BID. Atenolol 50 to 200 mg PO every 12 hours. Propranolol short-acting 40 to 80 mg four times a day or its long-acting equivalent. Nadolol 10 to 80 mg daily (preferable β-blocker for LQTS), although higher doses to 240 to 320 mg have been used for angina or hypertension. Atenolol is generally not recommended for treatment of arrhythmias, but does have cardioselectivity. Atenolol is contraindicated in the pregnant patient. There has been no evidence of risk in humans using acebutolol and pindolol in pregnancy; the chance of fetal harm is felt to be remote with these agents. The use of other β-adrenergic blockers in pregnancy is likely safe, although risk to the fetus cannot be ruled out.
Calcium Antagonists
This class of drugs (class IV antiarrhythmics) can suppress triggered activity, slow or block AV nodal conduction, and slow sinus rates. These include diltiazem and verapamil.
Indications
Calcium antagonists are used to treat ventricular ectopy and to control rate during SVTs such as AFL, AF, and reentrant SVT (especially those that use the AV node as part of the circuit). Calcium antagonists should not be used with AF that is associated with ventricular preexcitation because AV nodal blockade can facilitate AV conduction over the accessory pathway. IV verapamil is often used in patients with AV node reentry and orthodromic AV reciprocating tachycardias if the arrhythmia recurs after adenosine or if the tachycardia is adenosine unresponsive. IV diltiazem can also be used to control the ventricular rate in AFL and AF.
Dose
Verapamil 120 to 480 mg/day PO in single or divided doses, depending on the preparation. Diltiazem: Initial IV bolus of 0.25 mg/kg (approximately 20 mg) over 2 minutes. If response is inadequate, a second bolus of 0.35 mg/kg (approximately 25 mg) can be given 15 minutes later. For continued reduction of ventricular rate (up to 24 hours), an IV infusion of 5 to 15 mg/hour can be started immediately after the bolus and titrated to heart rate. Infusion rates of more than 15 mg/hour are not recommended. IV verapamil: Initial IV bolus of 2.5 to 5.0 mg over 1 to 2 minutes (3 minutes in older patients). The peak effect should be seen in 3 to 5 minutes. If required, a second 5- to 10-mg bolus can be given 15 to 30 minutes later; alternatively, 5-mg IV boluses can be given every 15 minutes to a cumulative dose of 30 mg.
To terminate paroxysmal SVT in patients with adequate BP and preserve left ventricle (LV) function in lieu of adenosine or if adenosine terminates SVT only temporarily: Diltiazem or verapamil IV can be given in doses as described previously.
Contraindications
Diltiazem and verapamil should be used with extreme caution, if at all, with IV β-adrenergic blockers or in patients with heart failure, significant LV dysfunction, or sick sinus syndrome or greater than first-degree AVB without a functioning pacemaker. Neither drug should be used IV to slow the ventricular response to AF or AFL in Wolff-Parkinson-White (WPW) syndrome, due to an increased risk of one-to-one conduction and subsequent VF, or to treat VT (increased risk of fatal hypotension).
Comment
The risk to the fetus from the use of most calcium channel blocking drugs has not been excluded.
Digoxin
Digoxin enhances vagal activation of the heart to specifically slow AV nodal conduction and to have a mild effect on the sinus node function.
Indications
The main use for digoxin is to control the ventricular response rate to AF. It can also be effective in prevention of AV node–dependent SVTs. Furthermore, it can help to control the ventricular response rate to ATs and AFL.
Dosing
Digoxin is available intravenously and orally. Potassium levels should be in the therapeutic range when using digoxin. The loading dose is 1 mg over 24 hours in divided doses. It is not clear that patients need to be loaded unless they have an uncontrolled ventricular response rate to AF. The maintenance dose is usually between 0.125 and 0.25 mg. In patients with renal insufficiency and in older patients, smaller doses are recommended. For patients with renal failure, the dose may have to be much smaller and given only several times a week. Propafenone, verapamil, and amiodarone will increase digoxin levels. The Digitalis Investigation Group (DIG) trial showed that serum levels less than 0.9 ng/mL were associated with lower mortality than higher levels, and so dosing should aim at such lower levels.
Comments
Used separately, in younger active individuals, digoxin is not particularly effective in controlling the ventricular response rate to AF because it is not a direct-acting AV node-blocking drug, but acts through vagal mechanisms. Its main use is in older patients and in the pediatric age range where it can have a more potent effect. The risk is that the toxic-to-therapeutic ratio is higher than for many modern drugs. Alternatively, it has important synergistic effects with β-adrenergic blockers and calcium channel antagonists. The combination of β-adrenergic blockers and digoxin can be very effective in controlling the ventricular response rate to AF. Digoxin toxicity is often associated with evidence of high-grade AV block in the presence of triggered arrhythmias such as AT (classically with 2:1 AV conduction ratio) or frequent ventricular ectopy. It can cause VT or VF at high levels. Adverse noncardiac effects include anorexia, nausea, vomiting, and change in color perception. Treatment of digoxin toxicity or refractory proarrhythmia may include use of antidigoxin Fab antibody fragments.
Disopyramide
Disopyramide is a class IA antiarrhythmic drug that is similar to procainamide and quinidine but with greater negative inotropic and more anticholinergic effects. It should be used in individuals who are not at risk for urinary retention and should not be used in older men with known prostatic hypertrophy or patients with glaucoma.
Indications
This drug may be useful in vagally mediated AF. The main use now for disopyramide is AF with or without preexcitation. When used in patients with AF, it should be used with AV nodal blocking drugs, because it is vagolytic and can increase conduction through the AV node. Some early data suggested that it is valuable for neurocardiogenic syncope, but it now appears to be of little use. Disopyramide has been used for its negative inotropic effect in patients with hypertrophic obstructive cardiomyopathy and in neurocardiogenic syncope (with little firm evidence as to effectiveness).
Dosing
The dose is 400 to 600 mg in divided doses. With controlled-release disopyramide formulation, the dose can be given twice daily. Otherwise, it should be given three to four times daily.
Comments
Disopyramide is rarely used due to its adverse effects, including TdP VT (perhaps less likely than quinidine or procainamide), negative inotropic effect, which can trigger CHF, and anticholinergic effects. It is a third-line antiarrhythmic drug but may be useful for vagally mediated AF.
Dofetilide
Dofetilide is a pure class III antiarrhythmic (I Kr blocker).
Indications
It is used to treat persistent AF. It is also effective for AFL. In some instances, dofetilide will terminate persistent AF and AFL, and in other cases, it will prevent its recurrence. As with amiodarone, dofetilide is useful regardless of ventricular function and does not appear to increase the risk of death when ventricular function is poor or when there has been a recent MI. The drug is perhaps less used because of the complexity of its initiation, which requires hospitalization and a physician who is approved for its use. However, despite the 3-day observation period required to initiate the drug in the hospital, it is one of the most effective antiarrhythmic drugs for AF.
Dose
Initiate the dose in the hospital in a monitored setting (125 to 500 mcg twice daily). The higher dose is for patients with normal renal function. The initial dose must be adjusted in patients with calculated creatinine clearance (CrCl) of less than 60 mL/minute (250 mcg twice daily if CrCl is 40 to 60 mL/minute or 125 mcg twice daily if CrCl is 20 to 40 mL/minute). Electrocardiographic monitoring must be performed for a minimum of 3 days in the hospital. ECGs must be obtained 2 to 3 hours after giving each of the first five doses of the drug. If the QTc increases more than 15% of baseline or if the QTc is more than 500 ms (550 ms in patients with abnormal ventricular conduction), the dose should be reduced. The patient must be compliant with taking the medications, because missing one or two doses means starting the dosing process over again. Medication must be given by an individual considered qualified to use the drug. The QTc interval should not exceed 500 ms.
Contraindications
Patients with a long QT interval (QTc > 440 ms, or if intraventricular conduction abnormality, > 500 ms), severe renal dysfunction (CrCl < 20 mL/minute).
Comments
Dofetilide should not be used with verapamil, cimetidine, trimethoprim, and ketoconazole, because these can cause significant increases in dofetilide concentration. Other known renal cation transport system inhibitors, such as prochlorperazine and megestrol, should also not be used with dofetilide. Hydrochlorothiazide has also been shown to increase dofetilide concentrations and should not be used concurrently. Dofetilide is generally well tolerated. It has no negative inotropic effects. It does not facilitate conduction through the AV node. It must be given with adequate maintenance of potassium levels. Adherence to the hospital initiation guidelines appears to reduce the risk of TdP VT.
Dronedarone
Dronedarone is an oral antiarrhythmic drug with an uncertain mechanism of action. It has a formula similar to amiodarone except without the iodine. It appears to be less toxic than amiodarone but it is also less effective as an antiarrhythmic drug.
Dronedarone was given a class I indication to maintain sinus rhythm and to decrease cardiovascular events in patients with paroxysmal AF or after conversion of persistent atrial ablation and to control the ventricular response during AF. It was also given a class III indication; that is, there is no benefit to those patients with NYHA FC IV CHF or those patients who have had recent decompensated heart failure and for those with permanent AF, due to higher mortality with dronedarone observed in these groups in clinical trials.
Indications
For long-term use, to reduce the risk of hospitalization in patients with AFL or AF and cardiovascular risk factors (age > 70 years, hypertension, diabetes, prior stroke, left atrial diameter > 50 mm, or LVEF < 40%), who are in sinus rhythm or who will be cardioverted. The drug may not only reduce the incidence of AF but also slow the ventricular response rate.
Dose
Dosage of 400 mg BID with morning and evening meals. Dronedarone should be discontinued if the QTc interval increases to 500 ms or more.
Contraindications
Dronedarone is contraindicated in patients with New York Heart Association (NYHA) FC IV heart failure or NYHA FC II-III heart failure with recent decompensation requiring hospitalization or referral to a specialized heart failure clinic. Dronedarone is also contraindicated in second-degree or third-degree AVB or sick sinus syndrome unless rate support is provided by a pacemaker, bradycardia less than 50 bpm, QTc greater than or equal to 500 ms, and severe hepatic dysfunction.
Comments
The drug can increase serum creatinine by about 0.1 mg/dL due to an inhibition of the tubular secretion of creatinine, but with no effect on the glomerular filtration rate; it is thus not nephrotoxic and the effect on serum creatinine is reversible after drug discontinuation. The drug can be initiated in the outpatient setting. The risk of TdP VT is low. It does not have pulmonary toxicity. The most common adverse reactions (≥ 2%) are diarrhea, nausea, abdominal pain, vomiting, and asthenia. Dronedarone may increase mortality in patients with acute CHF and LVEF of less than 35%. It should not be administered together with strong cytochrome P450 3A (CYP3A) inhibitors (e.g., ketoconazole), grapefruit juice, or other QT-prolonging drugs or herbals. Simvastatin exposure is increased by dronedarone, and adjustment of statin dose may be necessary. Discontinuation or halving of the dose of digoxin should be considered and concomitant β-adrenergic blockers and calcium channel blockers used with ECG verification of tolerability. Normal potassium and magnesium levels should be maintained. Rare, but potentially severe, liver injury has been reported. Monitoring of liver enzymes would be prudent, especially during the first 6 months of therapy. If heart failure develops or worsens, suspension or discontinuation of dronedarone should be considered. Higher mortality was reported in one study of patients with severe heart failure requiring recent hospitalization or referral to a specialized heart failure clinic for worsening symptoms. Dronedarone is a teratogen and is contraindicated in pregnancy or nursing mothers. Women of childbearing potential should use appropriate contraception.
Droxidopa
Droxidopa, l -threo-dihydroxyphenylserine, is a norepinephrine precursor, that has been recently approved in the United States as an “orphan” drug for treatment of symptoms in patients who have neurogenic orthostatic hypotension; that is, symptomatic orthostatic hypotension as a result of a neurologic deficiency as can occur in multiple-system atrophy, Parkinson disease, and pure autonomic failure. It has been used in dopamine β-hydroxylase deficiency and nondiabetic autonomic neuropathy. It can treat dizziness, lightheadedness, syncope, and falls related to changes in BP.
Indications
Droxidopa is indicated for neurogenic orthostatic hypotension. Although potentially an off-label use, some have considered using this drug in patients (younger individuals as well) with postural orthostatic tachycardia syndrome and those with a transient orthostatic drop in BP not associated with extreme elevation in heart rate but also not due to an explainable cause.
Dose
The initial recommended dose is 100 mg PO TID with titration in increments of 100 mg TID every 24 to 48 hours, not to exceed 600 mg TID based on symptoms.
Comments
Droxidopa has been used and approved for short-term use. There have been some long-term follow-up data but because it is not completely certain that the long-term efficacy is as good as the short-term efficacy, patients should be watched carefully for recurrence of symptoms. Droxidopa may cause hypertension and may exacerbate supine hypertension in patients who have severe orthostatic hypotension but have baseline supine hypertension. Droxidopa has not been tested rigorously in patients with underlying ischemic heart disease or structural heart disease with regard to safety. The drug is not been tested in patients with diabetes. For patients who have supine hypertension but have severe orthostatic hypotension, there are no specific drugs that have been used to treat both the hypertension in the supine position in combination with droxidopa, but if an antihypertensive medication is required, an angiotensin-converting enzyme inhibitor may be the best drug to consider.
Epinephrine
Epinephrine is a catecholamine that activates α- and β-receptors.
Indications
Asystole; pulseless electrical activity; VF or pulseless VT resistant to electrical defibrillation; severe hypotension; anaphylactic shock; symptomatic bradycardia after atropine.
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