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 maceuticals are delivered by chloro- APCC Database: Unpublished data,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 Most cases of hypophos- recommended.12 Sinus tachycardia cal signs at the time of consultation phatemia spontaneously resolve exceeding 180 to 200 beats/min, with the ASPCA APCC. This lack of once the underlying cause is re- other life-threatening arrhythmias clinical signs could be attributable to a low level of drug present in the TABLE 2 canister or a lack of follow-up as a result of successfully managing sub- Dosage Guidelines for Pharmaceuticals sequent clinical signs. Useful in Beta2 Agonist Intoxicated Dogs*

CLINICAL PATHOLOGY Pharmaceutical Dosage Hypokalemia as a result of an intra- Propranolol 0.02 mg/kg IV slowly (maximum of 1 mg/kg) cellular shift can be severe in an acute toxicosis with albuterol and re- Metoprolol 0.2–0.4 mg/kg b.i.d. orally lated drugs. Life-threatening ar- Diazepam 0.2–0.6 mg/kg IV (to effect) rhythmias and profound muscle Lidocaine 2–4 mg/kg slow IV bolus to effect weakness are possible sequelae of se- vere hypokalemia.6 Among the 414 *Source: Plumb DC. Veterinary drug handbook. 5th ed. Stockholm, Wis: PharmaVet Inc, 2005;238,461,522,637. inhaler toxicosis cases, the lowest re-

372 June 2007 Veterinary Medicine such as sustained ventricular tachy- TABLE 3 cardia, or severe hypokalemia re- Guidelines for Intravenous Potassium Supplementation 5 quires treatment. Based on Serum Potassium Concentrations* Meticulous monitoring of serum potassium throughout the toxicosis Potassium Chloride Maximum Rate period is warranted; check it every Serum Potassium (mEq/L) to Add to (ml/lb/hr) (maximum two hours unless there is a clinical (mEq/L) 1 L of Fluids of 0.5 mEq/kg/hr) indication to check it sooner (e.g. 3.6–5 20 12 change in heart rate or rhythm indi- 3.1–3.5 30 8 cating potassium aberrations, brady- cardia due to hyperkalemia). 2.6–3 40 5.5 2.1–2.5 60 4 Beta antagonists, < 2 80 3 diazepam, and lidocaine A nonselective beta antagonist such *Source: Macintire DK. Metabolic derangements in critical patients, in Proceedings. Am Coll Vet Intern Med, 2003. as propranolol can be given to re- verse both beta1 and beta2 effects. Be- can estimate the duration of signs to mitigate the adverse effects, toxi- cause the norepinephrine release as- based on exposure evidence and me- coses due to albuterol and other sociated with beta agonists is tabolism and excretion data extrapo- beta2 agonists can be managed suc- primarily mediated by beta2 activ- lated from human exposure. The cessfully. However, when existing ity,13 propranolol is a good choice to plasma half-life in people for inhaled cardiac disease is present or the toxi- minimize secondary catecholamine albuterol is about 3.8 hours (1.7- to cosis is compounded by the concur- effects such as behavioral aberra- 7.1-hour range in a separate study).14 rent use of tricyclic antidepressants, tions. Diazepam may also be used to Albuterol is metabolized in the liver monoamine oxidase inhibitors, or alleviate anxiety, hyperactivity, mus- to the relatively inactive albuterol 4’- digoxin, complications such as car- cle tremors, and rare seizures. Meto- O-sulfate. Excretion of the parent diac decompensation or sudden ❖ prolol, a selective beta1 antagonist, is drug and metabolites occurs rapidly, death may occur. an alternative to propranolol to nor- predominantly through the kid- malize the heart rate.5 Ventricular neys,14 but about 10% is excreted in REFERENCES 9 1. Castro HJ, Malka-Rais J, Bellanti, JA. Current epidemiology tachycardia may be treated with ei- the feces. Most dogs with mild signs of asthma: emerging patterns of asthma. Allergy Asthma Proc ther propranolol or lidocaine.6 Table 2 recover within 12 hours of exposure 2005;26:79-82. 2. American Veterinary Medical Association. Veterinary market provides dosage guidelines for with appropriate supportive care, statistics: U.S. pet ownership & demographics sourcebook;80. drugs useful in beta2 agonist intoxi- but signs can persist for 24 to 48 3. Landsberg L,Young JB. Pharmacology of the sympathoad- renal system. In: Braunwald MD, ed. Harrison’s principles of inter- cated patients. hours with large overdoses. nal medicine. 15th ed. New York, NY: McGraw Hill, 2001;443-448. 4. Physicians’ Desk Reference. 56th ed. Montvale, NJ: Medical UMMARY Economics Company, 2002;308,309,318,1029,1041,1679. Potassium S 5. Stiles J, Plumb D.Toxicity associated with beta-agonist aerosol Monitor the serum potassium con- The immediate delivery of massive exposure in three dogs. J Am Anim Hosp Assoc 1993;29:235-238. 6. Plumb DC. Veterinary drug handbook. 5th ed. Stockholm, Wis: centration closely, and provide sup- amounts of beta2 agonists from in- PharmaVet Inc, 2005;15-16,36,188,410,697,877. plemental potassium according to halers punctured by dogs warrants 7.Vite CH, Gfeller RW. Suspected albuterol intoxication in a dog. J Vet Emerg Crit Care 1994;4:7-12. the severity of hypokalemia (Table prompt veterinary attention. Clinical 8. GlaxoSmithKline, Customer Service, 1-888-825-5249, per- 3).12 Keep in mind, however, that a signs reported in such exposures are sonal communication, June 13, 2005. 9. Rosendale M. Bronchodilators. In: Plumlee KH, ed. Clini- rebound hyperkalemia can ensue fairly predictable; lethargy, tachyp- cal veterinary toxicology. Philadelphia, Pa: Mosby Inc, after aggressive potassium supple- nea, agitation, and trembling are 2004;305-307. 10. Petruska JM, Beattie JG, Stuart BO, et al. Cardiovascular ef- mentation because of extracellular among the most common. Tachycar- fects after inhalation of large doses of albuterol dry powder in translocation of potassium as the dia is the most consistent clinical rats, monkeys, and dogs: a species comparison. Fundam Appl Toxicol 1997;40:52-62. toxicosis abates. Patients treated finding. Be aware of the potential for 11. Hardy RM, Adams LG. Hypophosphatemia. In: Kirk RW, ed. with propranolol may also have an this type of toxicosis and recognize Current veterinary therapy X small animal practice. Philadelphia, Pa: WB Saunders Co, 1989;43-47. increase in serum potassium because it as a possible cause when signs 12. Macintire DK. Metabolic derangements in critical patients, in 6 of propranolol’s direct effects. consistent with beta2 agonist over- Proceedings. Am Coll Vet Intern Med, 2003. 13. Murugaiah KD, O’Donnell JM. Facilitation of norepinephrine dose are encountered. With appro- release from cerebral cortex is mediated by beta 2-adrenergic re- Duration of signs priate monitoring of vital signs and ceptors. Life Sci 1995;57:PL327-PL332. 14. McEvoy GK. Sympathomimetic (adrenergic) agents. The endpoint of therapy is resolution electrolytes, supportive care, and Bethesda, Md: American Hospital Formulary Service, American of the abnormal clinical findings. We administration of pharmaceuticals Society of Health-System Pharmacists, Inc., 2003;1228.

Veterinary Medicine June 2007 373