Continuing Education:  Cardiac Drugs – Lecture III
Antiarrhythmic Agents
Larry Birnbaum, PhD, FASEP, EPC
Associate Professor
Department of Exercise Physiology
The College of St. Scholastica
Duluth, MN  55811

Drugs used to treat arrhythmias include sodium channel blockers, beta-blockers, calcium channel blockers, and others that have different mechanisms of action [1].  Antiarrhythmic medicines can be classified into four categories [2]:

1.  Class I antiarrhythmics are sodium-channel blockers.

2.  Class II antiarrhythmics are beta-blockers.

3.  Class III antiarrhythmics are potassium-channel blockers and prolong the action potential.  Amiodarone and sotalol are examples of class III medicines.

4.  Class IV antiarrhythmics are calcium-channel blockers.

As the name implies, sodium channel blockers block sodium channels and are subclassified as I-A, I-B, and I-C, based on how strongly they reduce the rate of membrane depolarization (A – moderate, B – weak, C – strong).  Class I-A drugs also block potassium channels, alpha adrenergic receptors, and muscarinic receptors.  Muscarinic receptors are those membrane-bound acetylcholine receptors that are more sensitive to muscarine than to nicotine.  Those for which the contrary is true are known as nicotinic acetylcholine receptors.

Sodium channel blockers decrease ectopic impulse formation in the atria and ventricles.  Thus, they decrease HR, conduction, contractility and dilate the vascular bed.  As such, they are used to treat atrial or ventricular arrhythmias such as premature atrial contractions (PACs), atrial fibrillation and flutter, AV nodal reentrant arrhythmias, ventricular tachycardia (VT), ventricular fibrillation (VF), and premature ventricular contractions (PVCs). 

Non-therapeutic effects of sodium channel blockers include hypotension and a reflex increase in HR due to peripheral vasodilation (due to blocking of alpha-adrenergic receptors).  Decreased vagal tone is due to an antimuscarinic action (works against the direct effect on the SA and AV nodes).  Most sodium channel blockers can aggravate AV nodal conduction defects.  Toxicities may include hypersensitivity reactions and cinchonism, a syndrome characterized by nausea, vomiting, diarrhea, tinnitus, headache, auditory and visual disturbances and vertigo.  Because procainamide can cause or aggravate lupus erythematosus and can adversely affect the CNS (giddiness, psychosis, depression, hallucinations), it’s use is discouraged.  Disopyramide may produce general anti-cholinergic effects (dry mouth, blurred vision, urinary retention, constipation) and lidocaine may produce CNS effects such as drowsiness, disorientation, slurred speech, respiratory depression, tinnitus, muscle twitching, psychosis, seizures.  Since lidocaine is only available for I.V. administration, it usually is only used for acute care. 

Clinicians should be alert to potential drug interactions.  For example, quinidine and procainamide produce an increase in digoxin levels that can give rise to digitalis toxicity.  Concurrent use of tocainide or mexiletine with lidocaine can cause CNS toxicity, including seizures.

Examples of Class I-A sodium channel blockers are quinidine (Quinidex), procainamide (Pronestyl), disopyramide (Norpace).  Class I-B drugs include lidocaine (Xylocaine), tocainide (Tonocard), mexiletine (Mexitil).  Encainide (Enkaid) and flecainide (Tambocor) are class I-C sodium channel blockers.

Calcium channel blockers and beta-blockers are also used to treat arrhythmias.  These drugs were discussed in lecture II (October issue).  Sotalol (Betapace) is a special type of beta-blocker that prevents irregular heart rhythms in addition to slowing the HR and lowering the blood pressure.  It blocks beta-adrenergic receptors and potassium channels (in cardiac muscle), which is the underlying mechanism for its negative inotropic and chronotropic effects.  It is used to treat atrial fibrillation, atrial flutter, and ventricular tachycardias.  It is similar to other beta-blockers with respect to adverse effects, contraindications, and drug interactions.

Miscellaneous drugs used to treat arrhythmias include amiodarone (Cordarone), adenosine (Adenocard), and digoxin (Lanoxin).  Amiodarone is rather unique in that it blocks sodium channels, potassium channels, calcium channels (weakly), and noncompetitively blocks alpha- and beta-adrenergic receptors.  These mechanisms of action produce a prolonged action potential and refractory period, which decreases the HR.  Side effects and toxicities of amiodarone are severe and common (more than 75% of patients) and increase after a year of treatment; some toxicities result in death.  Adverse effects include the following:

1.  Pulmonary toxicity and fibrosis - can be life threatening.

2.  Liver disease - can be irreversible or persist for months after treatment has stopped.

3.  CNS symptoms - ataxia, dizziness, depression, nightmares, hallucinations.

4.  Hypothyroidism or hyperthyroidism.

5.  Cutaneous photosensitivity and blue-grey discoloration of skin.

6.  Peripheral neuropathy.

7.  Increased serum levels of LDL-cholesterol.

  8.  Increased serum concentrations of many drugs.

Amiodarone is used to treat life-threatening ventricular arrhythmias, but because toxicities are common, severe and irreversible, amiodarone is considered to be the drug of last choice, after other drugs have been shown to be ineffective.  It also has an unusually long half-life (25-110 days), exacerbating problems of toxicity.

Adenosine increases potassium conductance and inhibits cAMP-activated calcium channels, which results in decreased AV nodal conduction and increased AV nodal refractory period.  Adverse effects include flushing, shortness of breath/burning sensation in lungs, brief high-grade AV block, transient atrial fibrillation, headache, GI upset, hypotension, and paresthesia (tingling sensation).  Since adenosine is only available as an IV solution, and because of its short half life (a matter of seconds) it is only used for acute therapy in the treatment of supraventricular tachycardias.  Because of its short half life, and low toxicity, many doctors chose it over verapamil for acute therapy.

Digoxin is a cardiac glycoside extracted from the foxglove plant, digitalis lanata.  It binds to the Na⁺/K⁺ ATPase pump in the membranes of heart cells (myocytes).  This causes an increase in the level of sodium ions in the myocytes, which then leads to a rise in the level of calcium ions.  The proposed mechanism is that inhibition of the Na⁺/K⁺ pump leads to increased Na⁺ levels, which in turn slows down the extrusion of Ca⁺⁺ via the Na⁺/Ca⁺⁺ exchange pump [3].  Increased amounts of Ca⁺⁺ are then stored in the sarcoplasmic reticulum and released by each action potential, which may be responsible for the inotropic effect (increased contractility).  Digoxin also increases vagal activity via its central action on the CNS, thus decreasing the conduction of electrical impulses through the AV node.  Atrial fibrillation, atrial flutter, and congestive heart failure (CHF) may be treated with digoxin. 

Digoxin has a narrow therapeutic index.  Adverse effects are rare when plasma digoxin concentration is <0.8 μg/L and more common in patients with low potassium levels (hypokalemia), since digoxin normally competes with K⁺ ions for the same binding site on the Na⁺/K⁺ ATPase pump.  Common adverse effects include loss of appetite, nausea, vomiting, diarrhea, blurred vision, visual disturbances (yellow-green halos), confusion, drowsiness, dizziness, nightmares, agitation, and/or depression.  Increased intracellular Ca⁺⁺ may causebigeminy, eventually ventricular tachycardia or fibrillation.  Digoxin may produce ST depression or T wave inversion, which do not indicate toxicity.  However, prolongation of the PR interval may be a sign of digoxin toxicity.  Digoxin should be stopped 10-14 days prior to an exercise test to avoid confounding the interpretation.  Digoxin has potentially dangerous interactions with verapamil, amiodarone, and erythromycin.

 References

1.  http://heartdisease.about.com/cs/cardiacdrugs/index.htm

2.  http://medlineplus.gov

3.  http://www.rxlist.com/cgi/generic/dig_cp.htm