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Oral Antiarrhythmic Therapy

By Rebecca L. Malakoff, DVM, DACVIM (Cardiology)
angell.org/cardiology
617-541-5038

 

When your patient’s heart beats too fast or irregularly, it’s enough to make a veterinarian’s heart speed in response. My hope is that this review of the most commonly used oral antiarrhythmic medications in veterinary medicine will help to reduce the heart rate of patient and doctor alike. Below you will find a quick reference of the actions, side-effects, and considerations for selection of the four drugs you are most likely to prescribe or encounter. (Dosages for the medications can be found in Plumb’s Veterinary Drugs).

Quick Review of Antiarrhythmic Classifications

You may not have spent much time thinking about the Vaughan-Williams classification scheme for antiarrhythmic drugs since veterinary school, but it can be useful for a reminder of both the intended effects and side-effects of various medications. For example, any drug with beta-blocking or calcium channel blocking action will be both negatively chronotropic (lowering the heart rate) but also negatively inotropic (reducing contractility). The scheme divides antiarrhythmic drugs into classes according to the ion channels they block:

  • Class I: Sodium channel blockers (e.g. Lidocaine, procainamide, mexiletine)
  • Class II: Beta blockers (e.g. Atenolol, metroprolol)
  • Class III: Potassium channel blockers (sotalol and amiodarone both have class III activity in addition to other channel blockade(s), making them mixed agents)
  • Class IV: Calcium channel blockers (e.g. Diltiazem, verapamil)

Atenolol

In addition to being used for heart rate reduction in cases of outflow tract obstructions (e.g. hypertrophic obstructive cardiomyopathy, pulmonic or aortic stenosis), atenolol is a commonly used medication either alone or in combination with other drugs to treat supraventricular or ventricular arrhythmias. Although it is not particularly efficacious as a solo drug for ventricular tachycardia in dogs, it can be more useful in treating ventricular premature complexes or tachycardia in cats. Atenolol is a beta-blocker (class II agent), and one that is relatively specific for the beta 1 receptors (found in the heart muscle). However, it does have some beta 2 activity (affecting bronchial and smooth muscle), and as such caution should be taken when using the drug in poorly controlled asthmatic patients due to potential bronchoconstriction. It could mask physiologic response to hypoglycemia, so caution in poorly controlled diabetics is also warranted. Because atenolol will also have negative inotropic effects, caution should be used with reduced systolic function, and it is best to avoid starting the drug during active congestive heart failure.1

Atenolol Highlights

  • Inexpensive
  • Does not work well alone for ventricular tachycardia in dogs (but may in cats)
  • Caution with systolic dysfunction, CHF, AV block
  • Caution in poorly controlled asthmatics, diabetics
  • Reduce dose with severe renal dysfunction
  • Avoid stopping suddenly after chronic use

Atenolol has the advantage of being inexpensive, and generally well-tolerated. Due to renal metabolism, doses should be adjusted when significantly reduced renal function is present. Avoid stopping the drug suddenly or missing doses with chronic use. Since the number of beta receptors increases with long term administration, stopping suddenly could lead to hyperreaction to physiologic adrenergic stimulation.

Sotalol

Sotalol is one of the most commonly used oral antiarrhythmic agents for ventricular tachycardia, for good reason. Sotalol has the benefits of being relatively inexpensive, fast-acting, tends to be well tolerated, and only requires twice daily administration. A mixed agent, with both beta-blocking (class II) and potassium channel blocking (class III) properties, sotalol tends to have more potent effect against ventricular arrhythmias than a solo beta-blocker such as atenolol in dogs.2 What many veterinarians may not realize, is that sotalol can also be effective in treating supraventricular tachycardia.

Sotalol Highlights

  • Inexpensive
  • Twice daily dosing
  • Well tolerated
  • Quick onset of action
  • Caution with systolic dysfunction, congestive heart failure, AV block

Due to negative inotropic effects, caution must be taken when the patient has concurrent congestive heart failure, especially with reduced systolic function such as with dilated cardiomyopathy. As sotalol is a nonselective beta blocker (albeit a relatively weak one; most of its pharmacologic actions are related to its class III potassium channel blockade), it may also cause bronchoconstriction and should be used with caution in patients with lower airway disease. Elimination of sotalol is almost entirely via the kidney, and dosage intervals may need to be extended in patients with renal dysfunction. Sotalol has a quick onset of action, reaching peak plasma levels 2-4 hours after dose administration, providing enhanced usefulness in the ER setting.3

Mexiletine

Mexiletine is a class I agent (sodium channel blocker) with similar properties to lidocaine. Mexiletine is most commonly used along with a beta-blocker such as atenolol or sotalol which further enhances arrhythmic suppression through cooperative drug action.4 When used as a solo agent, higher doses are often required which increases risk of adverse effects. Mexiletine does have disadvantages compared to sotalol monotherapy, including increased cost, and typically three times daily dosing (some patients may respond adequately to twice daily dosing when given with sotalol5). Given routine availability in only three different doses of capsules (150 mg, 200 mg, 250 mg), mexiletine can be challenging to dose, especially in smaller patients. Mexiletine does have the advantage of not possessing negative inotropic actions, making it a safer choice in patients with significant systolic dysfunction (even if it requires concurrent beta-blocker use, it may allow reduced doses of those agents to be used).

Mexiletine Highlights

  • More effective with concurrent atenolol or sotalol
  • Typically requires TID dosing
  • No negative inotropic effects
  • Higher risk of side-effects (GI upset, CNS signs)
  • Caution in dogs with MDR1 gene mutation

Mexiletine has higher potential to cause adverse side-effects compared to sotalol, most commonly GI upset (reduced appetite, vomiting and/or diarrhea). Giving the drug with food reduces this risk. Potential CNS effects (trembling, unsteadiness, dizziness, depression) in people taking the drug have been reported. Similar signs have been seen in dogs, with a subset of patients exhibiting mildly dull or disoriented behavior. In my experience, this reaction does not appear to be dose-dependent, and does resolve if the drug is stopped.

Due to liver metabolism, the half-life of mexiletine may be significantly increased in patients with moderate to severe hepatic disease. It is recommended to test dogs of breeds susceptible to the MDR1 gene mutation prior to using the drug, as those homozygous for the MDR1 gene defect may be susceptible to mexiletine toxicity.6

Diltiazem

Calcium channel blockers are very useful agents for treatment of supraventricular arrhythmias such as atrial fibrillation or atrial tachycardia, and diltiazem is the most commonly used oral calcium channel blocker in veterinary medicine. Studies have shown it is most effective for heart rate control with atrial fibrillation when used in conjunction with digoxin,7 but it may be adequately effective on its own. It is important to be aware that oral diltiazem comes in numerous human dosage forms, including standard release tablets (e.g. Cardizem®) and various sustained-release products (e.g. Dilacor XR®, Cardizem CD® & LA®). Standard release forms are typically used three times daily for arrhythmia control in dogs, whereas the sustained release products are typically used twice daily (although there is limited pharmacokinetic data for use of the sustained release products in veterinary patients). The most critical thing to note is that the recommended or utilized mg/kg dose for the two forms are not equivalent (sustained release products are typically used at a higher dose BID), and they are not simply interchangeable.

Diltiazem Highlights

  • omes in standard (TID) and sustained release (BID) forms- dosing is not equivalent
  • GI side effects common in cats
  • Some negative inotropic effects
  • Better heart rate reduction in atrial fibrillation when used in conjunction with digoxin

Standard forms of diltiazem are relatively inexpensive, whereas the sustained release forms can be more costly. Both forms have been associated with decreased appetite and weight loss, especially in cats. Diltiazem possesses negative inotropic properties, and so caution must be used with systolic dysfunction and ideally the drug would not be started during active congestive heart failure. It also should not be started with severe hypotension, sick sinus syndrome, or significant AV block. Caution is warranted with use in geriatric patients, or those with serious hepatic or renal impairment.8

 

References

  1. Reviewed and updated by Scansen, Brian A and Eischstadt Forsythe, Lauren. Plumb’s Veterinary Drugs. Online version (last update August 2017).
  2. Comparison of the effects of four antiarrhythmic treatments for familial ventricular arrhythmias in Boxers. Meurs, Kathyrn M et al. JAVMA. Volume 221, No.4, 522-527.
  3. Reviewed and updated by Eichstadt Forsythe, Lauren and Barletta, Michele. Plumb’s Veterinary Drugs. Online version (last update August 2017).
  4. Combined mexiletine and propranolol treatment of refractory ventricular tachycardia. Leahey Edward B. Br Med J. Volume 281 (6236), 357-358.
  5. Mexiletine serum levels with twice-daily dosing in combination with sotalol in healthy dogs. Scollan, Katherine. Proceedings: 23rd ECVIM-CA Congress 2013.
  6. Reviewed and updated by Eichstadt Forsythe, L. Plumb’s Veterinary Drugs. Online version (last update August 2017).
  7. Combination therapy with digoxin and diltiazem controls ventricular rate in chronic atrial fibrillation in dogs better than digoxin or diltiazem monotherapy: a randomized crossover study in 18 dogs. Gelzer, Anna et al. JVIM. Volume 23, 499-508.
  8. Reviewed and updated by Barletta, Michele and Eichstadt Forsythe, Lauren. Plumb’s Veterinary Drugs. Online version (last update July 2017).
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