INTRODUCTION
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.
| Action | Class | Example Medications |
|---|---|---|
| Sodium channel blockers | Class Ia | Disopyramide, quinidine, procainamide |
| Class Ib | Lidocaine, mexiletine, phenytoin, | |
| Class Ic | Flecainide, propafenone | |
| β-Blockers | Class II | Esmolol, labetalol, metoprolol, propranolol |
| Potassium channel blockers | Class III | Amiodarone, dronedarone, dofetilide*, ibutilide, sotalol†, vernakalant‡ |
| Calcium channel blockers | Class IV | Diltiazem, verapamil |
| Unclassified agents# | Adenosine, atropine, digoxin, isoproterenol, magnesium |
CLASS I ANTIARRHYTHMICS: FAST SODIUM CHANNEL BLOCKERS
Class I agents block fast sodium channels (INa) 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 (IK) and exhibit antimuscarinic effects.
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 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.
See Table 19-2.6
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
See Table 19-3.6
| Advanced Cardiac Life Support (ACLS)–Ventricular Arrhythmia |
|---|
Initial: 20–50* milligrams/min IV until the arrhythmia is suppressed, hypotension ensues, or the QRS complex is prolonged by 50% from its original duration (maximum dose: 17 milligrams/kg) Maintenance infusion rate: 1–4 milligrams/min OR 100 milligrams IV every 5 min until the arrhythmia is controlled or one of the above conditions is met |
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 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 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.
See Table 19-4.6
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
See Table 19-5.6
| Ventricular Arrhythmia | Ventricular Fibrillation |
|---|---|
Loading dose: 50–100 milligrams (0.7–1.4 milligrams/kg) IV over 2–3 min. May repeat in 5 min (up to 300 milligrams in any 1-h period) Maintenance: 1–4 milligrams/min IV (0.014–0.057 milligrams/kg/min) | Initial dose: 1–1.5 milligrams/kg IV If VF/pulseless VT persists, additional doses of 0.5–0.75 milligrams/kg IV every 5–10 min (maximum total dose: 3 milligrams/kg) |
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 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 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 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.
CLASS II ANTIARRHYTHMICS: β-BLOCKERS
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.
| Generic Name | Onset of Action | Duration of Action | Metabolism | Half-Life | IV Dose (Adult) | Indications |
|---|---|---|---|---|---|---|
| Noncardioselective | ||||||
| Propranolol | Oral: 1–2 h IV: ≤1 min | Oral: IR: 6–12 h ER: 24–27 h IV: 4–6 h | Hepatic, extensive first-pass elimination | 3–6 h ER formulations: 8–10 h | Tachyarrhythmias: 1–3 milligrams/dose slow IVP; may repeat every 2–5 min up to a total of 5 milligrams OR 0.5–1 milligrams over 1 min; may repeat, if necessary, up to a total maximum dose of 0.1 milligram/kg | HTN, SVT arrhythmias, VT |
| Cardioselective | ||||||
| Esmolol | IV: 2–10 min | IV: 10–30 min | In blood by RBC esterases | 9 min | See text | HTN, SVT arrhythmias, AFib/AFlut (rate control) |
| Metoprolol | Oral: 1–2 h IV: 20 min | Oral: IR: variable ER: 24 h IV: 5–8 h | Hepatic, extensive first-pass elimination | 3–4 h | Initial: 1.25–5 milligrams IV every 5 min up to 15 milligrams initial dose (titrate to response) | HTN, acute MI (oral), angina, rate control in AFib/AFlut |
| Vasodilatory, Nonselective | ||||||
| Labetalol | Oral: 20 min–2 h IV: 2–5 min | Oral: 8–12 h IV: 2–18 h | Hepatic, extensive first-pass elimination | Oral: 6–8 h IV: 5.5 h | IV bolus (initial): 20 milligrams IVP over 2 min; may administer 40–80 milligrams at 10-min intervals (up to 300 milligrams total cumulative dose) IV infusion (acute loading): Initial: 2 milligrams/min, titrate to response (up to 300 milligrams total cumulative dose) | HTN |
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 is a nonselective antagonist of β1– and β2-receptors.
See Table 19-6.
See Table 19-6.
See Table 19-6.
Serious adverse effects associated with IV propranolol administration include bradycardia, heart block, hypotension, worsening heart failure, and bronchospasm.
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.
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.
See Table 19-6.4
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).
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 is a selective antagonist of β1-receptors and exerts its antihypertensive effects by decreasing cardiac output, reducing sympathetic outflow, and suppressing renin activity.
See Table 19-6.
See Table 19-6.
See Table 19-6 and Table 19-7.
Significant adverse effects associated with metoprolol include bradycardia, heart block, hypotension, and bronchospasm.
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.
See Table 19-6.
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”).
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
| Medication | IV to PO Conversion |
|---|---|
| Labetalol | Upon discontinuation of IV infusion, initiate 200 milligrams orally, followed in 6–12 h with an additional dose of 200–400 milligrams. Thereafter, dose patients with 400–2400 milligrams/d in divided doses depending on blood pressure response. |
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.
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