Toxicology Brief managing common poisonings in companion animals ❖ PEER-REVIEWED Breathe with ease when managing beta2 agonist inhaler toxicoses in dogs Donna Mensching, DVM, and Petra A.Volmer, MS, DVM, DABVT, DABT ombine more than 14.6 mil- beta2 agonists have minimal beta1 lion asthmatic people in the effects.6 Additionally, serum potas- C United States1 with more than sium concentrations may decrease 61.5 million playful pet dogs,2 and transiently as a result of intracellular it’s a sure bet that some curious translocation due to stimulation of Fidos will bite into their owners’ Na+,K+-ATPase.7 life-saving inhalers. Many metered dose inhalers con- TOXICOSIS tain selective beta2 agonist medica- tions that provide fast relief of bron- Toxic dose choconstriction in people. Examples Extrapolating from the nebulization 6 of beta2 agonists include albuterol dose in dogs, an appropriate dose of (also known as salbutamol), metapro- albuterol for a 60-lb (27.2-kg) dog is terenol, pirbuterol, isoetharine, terbu- 2.5 mg (equivalent to 91.9 µg/kg) taline, and bitolterol.3 Trade names in- four times a day. According to Glaxo- clude Ventolin HFA (albuterol sulfate SmithKline, a full Ventolin HFA 90-µg HFA inhalation aerosol—Glaxo- metered dose inhaler weighing 18 g SmithKline), Combivent (ipratropium contains 28.8 mg of albuterol sulfate.8 bromide and albuterol sulfate— Thus, a 60-lb dog that punctures a full Boehringer Ingelheim), and Alupent canister can be acutely exposed to (metaproterenol sulfate USP— cosis caused by these synthetic sym- about 10 times the therapeutic dose Boehringer Ingelheim).4 pathomimetic amines is rarely fatal through inhalation, ingestion, or a These relatively short-acting phar- in otherwise healthy dogs (ASPCA combination of these two routes. maceuticals are delivered by chloro- APCC Database: Unpublished data, fluorocarbon (CFC) or hydrofluo- November 2001–May 2007). Beta1, beta2, and roalkane (HFA) propellants,5 which catecholamine effects are critical to the intoxication of dogs MECHANISM OF ACTION The selective beta2 agonists lose their that bite into the pressurized canister. At therapeutic dosages, selective selectivity with overdosages, result- An accidental exposure delivers not beta2 agonists target beta2 receptors ing in undesirable beta1 (cardiac) ef- the indicated metered dose but po- on bronchial smooth muscle, result- fects in addition to excessive beta2 3 tentially the entire inhaler’s contents ing in bronchodilation via cyclic activity. Direct activation of beta1 re- instantaneously. If appropriate veteri- adenosine monophosphate pro- ceptors results in positive inotropic nary care is provided, the acute toxi- duced as a result of the activation of and chronotropic effects on the heart adenylate cyclase. A similar relax- (ASPCA APCC Database: Unpub- “Toxicology Brief” was contributed by Donna ation effect is seen with uterine, gas- lished data, November 2001–May Mensching, DVM, and Petra A.Volmer, MS, DVM, trointestinal, and vascular smooth 2007). A secondary catecholamine DABVT, DABT, Department of Veterinary muscle. Beta receptors are also surge also contributes to the devel- Biosciences, College of Veterinary Medicine, 2 University of Illinois, Urbana, IL 61802. Dr. present in skeletal muscle, the liver, opment of tachycardia and possible Volmer is the editor of “Toxicology Brief.” and the heart. At therapeutic doses, hypertension (ASPCA APCC Data- Photo ©iStockphoto.com/Ryan Tacay Photo ©iStockphoto.com/Ryan Veterinary Medicine June 2007 369 Toxicology Brief PEER-REVIEWED base: Unpublished data, November TABLE 1 2001–May 2007).9 Excessive periph- Clinical Findings in Dogs Accidentally Exposed eral vasodilation mediated by beta 2 to Inhalers Containing Beta Agonist Drugs* receptor activity typically predomi- 2 nates, however, resulting in a hypo- Percentage of tensive state, potentiating the tachy- Number Total Patients cardia via reflex mechanisms. Clinical Findings of Patients (total of 414) Premature ventricular contractions Cardiac Stimulation and other arrhythmias (intermittent Tachycardia 293 70.8 or sustained ventricular tachycardia, Premature ventricular 19 4.6 atrioventricular block, extreme sinus contractions tachycardia, R on T phenomenon) 312 75.4 may occur.5 The CFCs dichlorodiflu- Decreased Energy Level oromethane and trichloromonofluo- Lethargy 96 23.2 romethane can also contribute to car- Weakness 22 5.3 5 diotoxicity at high doses by Depression 9 2.2 9 sensitizing the myocardium. Addi- Listlessness 5 1.2 tional evidence of the potential dam- 132 31.9 age to the myocardium includes the Respiratory Stimulation development of cardiac fibrosis with Tachypnea 55 13.3 or without mineralization of papil- Panting 29 7 lary muscles in dogs experimentally Dyspnea 6 1.4 exposed to aerosolized albuterol Labored breathing 4 1 daily for two weeks (dose range 16 Shallow breathing 3 0.7 to 64 µg/L).10 Rarely, rupture of the 97 23.4 chordae tendineae and subsequent CNS Stimulation 9 pulmonary edema may be seen. Agitation 42 10.1 Tremors are caused by overstimu- Hyperactivity 25 6 lation of skeletal muscle beta2 recep- Restlessness 19 4.6 tors.9 Seizures are uncommon but Pacing 5 1.2 possible (ASPCA APCC Database: Un- Anxiety 5 1.2 published data, November 2001–May Aggression 3 0.7 2007). Behavioral changes such as Apprehension 2 0.5 anxiety, restlessness, and apprehen- Hiding 2 0.5 103 24.8 sion may occur in response to the acute sympathetic stimulation (ASPCA Other APCC Database: Unpublished data, Vomiting 79 19.1 November 2001–May 2007). In the ab- Trembling/tremors 54 13 sence of pulmonary edema, changes Hypokalemia 28 6.8 161 38.9 in respiratory rate and character are also likely a result of increased sym- *Reported to the ASPCA APCC November 2001 through May 2007. pathetic tone. Weakness and lethargy have been reported, particularly later public cases of dogs accidentally tients was reported to have died, in the course of the toxicosis when ini- exposed to beta2 agonist inhalers but death is possible, particularly if tial signs were untreated (ASPCA from November 2001 through May underlying cardiac disease is pres- APCC Database: Unpublished data, 2007 (Table 1) (ASPCA APCC Data- ent, veterinary attention is not November 2001–May 2007). base: Unpublished data, November sought, or the exposure is potenti- 2001–May 2007). These data repre- ated by the concurrent use of drugs CLINICAL FINDINGS sent accidental situations in which such as tricyclic antidepressants REPORTED TO THE the exposure was witnessed or evi- (e.g. clomipramine, imipramine, ASPCA APCC dence substantiated drug exposure amitriptyline), monoamine oxidase The ASPCA Animal Poison Control (a punctured canister). inhibitors (e.g. selegiline), or Center (APCC) has consulted on 414 Of the 414 cases, none of the pa- digoxin.6 Tricyclic antidepressants 370 June 2007 Veterinary Medicine Toxicology Brief PEER-REVIEWED can cause dysrhythmias even when ported potassium concentration was moved. In severe cases (serum phos- given therapeutically. Monoamine 1.76 mEq/L (reference range = 3.8 to phorus concentrations < 1 mg/dl; oxidases are responsible for cate- 5.1 mEq/L6) (ASPCA APCC Database: reference range = 2.5 to 6.2 mg/dl6), cholamine degradation; inhibiting Unpublished data, November intravenous supplementation with them allows for greater secondary 2001–May 2007). Because the total sodium or potassium phosphate catecholamine effects. body potassium is not depleted with may be necessary.11 The most common clinical find- this toxicosis, it is critical to monitor Hyperglycemia and hypomagne- ings seen with beta2 agonist inhaler serum potassium for a rebound hy- semia have also been associated with toxicoses can be grouped into gen- perkalemia as the effect of the beta2 beta2 agonist toxicosis but rarely eral categories: agonist wanes and the potassium re- need to be specifically addressed.9 TREATMENT Sinus tachycardia exceeding Because peak plasma concentrations are 180 to 200 beats/min, sustained achieved as quickly as five minutes after inhala- tion,6 decontamination by ventricular tachycardia, or severe inducing emesis or by ad- ministering activated hypokalemia requires treatment. charcoal or a sorbitol cathartic is not recom- • Cardiac stimulation (tachycardia, distributes to the blood. mended for patients exposed to premature ventricular contractions) Hypophosphatemia is a rare find- beta2 agonist inhalers. • Decreased energy level (lethargy, ing (ASPCA APCC Database: Unpub- weakness) lished data, November 2001–May Fluid therapy and monitoring • Respiratory stimulation (tachyp- 2007) that likely represents intracel- Many patients can be managed nea, panting) lular translocation. It may be due to with supportive care such as intra- • Behavioral changes associated with the beta2 agonist action itself or to venous fluids, but severe exposures central nervous system stimulation secondary responses including in- may require more aggressive ther- (aggression, agitation) creased catecholamine and insulin apy. Heart rate, rhythm, and blood • Vomiting and trembling or release or respiratory alkalosis.7,11 pressure need to be closely moni- tremors. Hypophosphatemia can potentiate tored. If catecholamine-induced hy- cardiac arrhythmias and predispose pertension predominates, cautious Hypokalemia was documented in the patient to hemolysis because of fluid administration is warranted. just 3% of cases. Twenty patients loss of red blood cell membrane in- Continuous electrocardiography is (3%) were reported to have no clini- tegrity.11