Toxicology Brief: Breathe with ease when managing beta-2 agonist inhaler toxicoses in dogs

Toxicology Brief: Breathe with ease when managing beta-2 agonist inhaler toxicoses in dogs


Combine more than 14.6 million asthmatic people in the United States1 with more than 61.5 million playful pet dogs,2 and it's a sure bet that some curious Fidos will bite into their owners' life-saving inhalers.

Many metered dose inhalers contain selective beta2 agonist medications that provide fast relief of bronchoconstriction in people. Examples of beta2 agonists include albuterol (also known as salbutamol), metaproterenol, pirbuterol, isoetharine, terbutaline, and bitolterol.3 Trade names include Ventolin HFA (albuterol sulfate HFA inhalation aerosol—GlaxoSmithKline), Combivent (ipratropium bromide and albuterol sulfate—Boehringer Ingelheim), and Alupent (metaproterenol sulfate USP—Boehringer Ingelheim).4

These relatively short-acting pharmaceuticals are delivered by chlorofluorocarbon (CFC) or hydrofluoroalkane (HFA) propellants,5 which are critical to the intoxication of dogs that bite into the pressurized canister. An accidental exposure delivers not the indicated metered dose but potentially the entire inhaler's contents instantaneously. If appropriate veterinary care is provided, the acute toxicosis caused by these synthetic sympathomimetic amines is rarely fatal in otherwise healthy dogs (ASPCA APCC Database: Unpublished data, November 2001–May 2007).

MECHANISM OF ACTION

At therapeutic dosages, selective beta2 agonists target beta2 receptors on bronchial smooth muscle, resulting in bronchodilation via cyclic adenosine monophosphate produced as a result of the activation of adenylate cyclase. A similar relaxation effect is seen with uterine, gastrointestinal, and vascular smooth muscle. Beta2 receptors are also present in skeletal muscle, the liver, and the heart. At therapeutic doses, beta2 agonists have minimal beta1 effects.6 Additionally, serum potassium concentrations may decrease transiently as a result of intracellular translocation due to stimulation of Na+ ,K+ -ATPase.7

TOXICOSIS

Toxic dose

Extrapolating from the nebulization dose in dogs,6 an appropriate dose of albuterol for a 60-lb (27.2-kg) dog is 2.5 mg (equivalent to 91.9 μg/kg) four times a day. According to GlaxoSmithKline, a full Ventolin HFA 90-μg metered dose inhaler weighing 18 g contains 28.8 mg of albuterol sulfate.8 Thus, a 60-lb dog that punctures a full canister can be acutely exposed to about 10 times the therapeutic dose through inhalation, ingestion, or a combination of these two routes.

Beta1, beta2, and catecholamine effects

The selective beta2 agonists lose their selectivity with overdosages, resulting in undesirable beta1 (cardiac) effects in addition to excessive beta2 activity.3 Direct activation of beta1 receptors results in positive inotropic and chronotropic effects on the heart (ASPCA APCC Database: Unpublished data, November 2001–May 2007). A secondary catecholamine surge also contributes to the development of tachycardia and possible hypertension (ASPCA APCC Database: Unpublished data, November 2001–May 2007).9 Excessive peripheral vasodilation mediated by beta2 receptor activity typically predominates, however, resulting in a hypotensive state, potentiating the tachycardia via reflex mechanisms. Premature ventricular contractions and other arrhythmias (intermittent or sustained ventricular tachycardia, atrioventricular block, extreme sinus tachycardia, R on T phenomenon) may occur.5 The CFCs dichlorodifluoromethane and trichloromonofluoromethane can also contribute to cardiotoxicity at high doses5 by sensitizing the myocardium.9 Additional evidence of the potential damage to the myocardium includes the development of cardiac fibrosis with or without mineralization of papillary muscles in dogs experimentally exposed to aerosolized albuterol daily for two weeks (dose range 16 to 64 μg/L).10 Rarely, rupture of the chordae tendineae and subsequent pulmonary edema may be seen.9