Phenylpropanolamine toxicosis in dogs: 170 cases (2004–2009)

Katherine L. Peterson Pet Poison Helpline, a division of SafetyCall International, 3600 American Blvd W, Bloomington, MN 55431.
Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55455.

Search for other papers by Katherine L. Peterson in
Current site
Google Scholar
PubMed
Close
 DVM
,
Justine A. Lee Pet Poison Helpline, a division of SafetyCall International, 3600 American Blvd W, Bloomington, MN 55431.

Search for other papers by Justine A. Lee in
Current site
Google Scholar
PubMed
Close
 DVM, DACVECC
, and
Lynn R. Hovda Pet Poison Helpline, a division of SafetyCall International, 3600 American Blvd W, Bloomington, MN 55431.

Search for other papers by Lynn R. Hovda in
Current site
Google Scholar
PubMed
Close
 RPh, DVM, MS, DACVIM

Click on author name to view affiliation information

Abstract

Objective—To evaluate signalment, clinical signs, dose ingested, treatment requirements, duration of hospitalization, and outcome of dogs exposed to phenylpropanolamine.

Design—Retrospective case series.

Animals—170 dogs with potential PPA toxicosis evaluated between 2004 and 2009.

Procedures—Dogs with potential PPA toxicosis were identified by reviewing the electronic database of an animal poison control center.

Results—66 of the 170 (39%) dogs reportedly did not develop any clinical signs. Clinical signs reported in the remaining 104 (61%) dogs included agitation (n = 40), vomiting (27), mydriasis (19), lethargy (17), tremor or twitching (16), panting (15), bradycardia (13), tachycardia (12), hypertension (11), and erythema (8). Median dose ingested for all dogs was 29 mg/kg (13.2 mg/lb). Dogs developing clinical signs had a significantly higher median dose ingested (373 mg/kg [170 mg/lb]) than did dogs that did not develop clinical signs (18 mg/kg [8.2 mg/lb]). Likewise, median dose ingested for the 123 dogs treated as inpatients (36.9 mg/kg [16.8 mg/lb]) was significantly higher than the median dose for the 14 dogs treated as outpatients (20.5 mg/kg [9.3 mg/lb]). Median duration of hospitalization was 18 hours (range, 4 to 72 hours), and hospitalization time increased as the dose ingested increased. Survival rate was 99.4% (169/170); the dog that died had ingested a dose of 145 mg/kg (65.9 mg/lb).

Conclusions and Clinical Relevance—Results suggested that with supportive care, the prognosis for dogs that had ingested an overdose of phenylpropanolamine was excellent.

Abstract

Objective—To evaluate signalment, clinical signs, dose ingested, treatment requirements, duration of hospitalization, and outcome of dogs exposed to phenylpropanolamine.

Design—Retrospective case series.

Animals—170 dogs with potential PPA toxicosis evaluated between 2004 and 2009.

Procedures—Dogs with potential PPA toxicosis were identified by reviewing the electronic database of an animal poison control center.

Results—66 of the 170 (39%) dogs reportedly did not develop any clinical signs. Clinical signs reported in the remaining 104 (61%) dogs included agitation (n = 40), vomiting (27), mydriasis (19), lethargy (17), tremor or twitching (16), panting (15), bradycardia (13), tachycardia (12), hypertension (11), and erythema (8). Median dose ingested for all dogs was 29 mg/kg (13.2 mg/lb). Dogs developing clinical signs had a significantly higher median dose ingested (373 mg/kg [170 mg/lb]) than did dogs that did not develop clinical signs (18 mg/kg [8.2 mg/lb]). Likewise, median dose ingested for the 123 dogs treated as inpatients (36.9 mg/kg [16.8 mg/lb]) was significantly higher than the median dose for the 14 dogs treated as outpatients (20.5 mg/kg [9.3 mg/lb]). Median duration of hospitalization was 18 hours (range, 4 to 72 hours), and hospitalization time increased as the dose ingested increased. Survival rate was 99.4% (169/170); the dog that died had ingested a dose of 145 mg/kg (65.9 mg/lb).

Conclusions and Clinical Relevance—Results suggested that with supportive care, the prognosis for dogs that had ingested an overdose of phenylpropanolamine was excellent.

Phenylpropanolamine is a sympathomimetic amine, but its underlying mechanism of action is not completely understood. Given its clinical effects, PPA is believed to act directly as an α-adrenergic receptor agonist and indirectly through increased release of stored norepinephrine by α-adrenergic and β-adrenergic receptors.1–3 The drug was removed from the human market in 2003 because of FDA safety concerns, but remains a commonly prescribed medication in dogs. It is used in particular for treatment of urinary incontinence associated with primary urethral sphincter incompetence in spayed female dogs.1,4–8 Currently, PPA is available as regulara,b and extended-releasec formulations in chewable, capsule, and liquid forms; tablets and capsules containing 25, 50, or 75 mg of PPA and liquid preparations containing 25 or 50 mg of PPA/mL are sold. In dogs, few adverse events are reported at therapeutic dosages, which range from 1 to 1.5 mg/kg (0.5 to 0.68 mg/lb) or a total of 12.5 to 50 mg, PO, every 8 to 12 hours. Published adverse effects associated with PPA are due to its stimulant effects and include restlessness, behavioral changes, panting, and gastrointestinal abnormalities (anorexia, vomiting, and diarrhea).3,5–7 Anecdotally reported adverse events also include tachycardia, hypertension, and urine retention.3

Despite the extensive use of PPA in veterinary medicine, minimal information is available regarding the clinical signs, treatment, and overall outcome following an overdose. To the authors' knowledge, only a single case report2 exists describing PPA toxicosis in a dog that had received 48 mg of PPA/kg (21.8 mg/lb); this dog developed cardiac abnormalities and neurologic signs, but reportedly survived with treatment. The purpose of the study reported here was to retrospectively evaluate signalment, clinical signs, dose ingested, treatment requirements, duration of hospitalization, and outcome of a large group of dogs exposed to PPA. We hypothesized that dogs ingesting overdoses of PPA would develop clinical signs, even following ingestion of low doses, but that with decontamination and appropriate supportive care, the overall prognosis following PPA ingestion would be good.

Materials and Methods

Criteria for selection of cases—The electronic computer databased of Pet Poison Helpline,e an animal poison control center located in Bloomington, Minn, was searched to identify dogs exposed to PPA between November 2004 and July 2009. Inclusion criteria included witnessed or suspected (eg, missing medication in the house or evidence of a chewed medication container) exposure. Exclusion criteria included all incidences of exposure for which the medical record was incomplete and follow-up information was unavailable and all incidences of exposure for which dose could not be estimated or calculated. Cases involving multiple toxic agents were also excluded.

Procedures—Medical records were reviewed for signalment (including age, breed, sex, and body weight), clinical signs, dose ingested, time from exposure until the poison control center was contacted, veterinarian evaluation (characterized as inpatient or outpatient care), and, when applicable, duration of hospitalization. Data were recorded in a commercially available spreadsheet program.f If > 1 dog was exposed, potential ingested doses were calculated for each dog to determine maximum potential exposure. If there was a range in the dose that may have been ingested, the mean dose was used for calculations. When needed to complete the medical record, follow-up examination was obtained from the owner or hospital staff by means of telephone calls to obtain information on clinical signs, veterinary care requirements, and outcome.

Statistical analysis—The Kolmogorov-Smirnov test was used to determine whether continuous data were normally distributed. Parametric data were summarized as mean and SD; nonparametric data were summarized as median and range. A Wilcoxon-Mann-Whitney test was used to determine whether dose ingested was associated with the development of clinical signs (yes vs no), whether veterinary care was sought (yes vs no), and the type of veterinary evaluation performed (inpatient vs outpatient care). The Spearman correlation method was used to determine whether time from exposure until the poison control center was contacted was associated with duration of hospitalization. Simple linear regression analysis was used to determine whether dose ingested was associated with duration of hospitalization. All analyses were performed with a commercially available statistical software package.g Values of P < 0.05 were considered significant.

Results

During the study period, Pet Poison Helpline received 186 telephone calls regarding PPA ingestion involving 206 dogs. Thirty-six dogs were excluded because of incomplete medical records or the inability to estimate or calculate the dose ingested. The remaining 170 dogs were included in the study.

Of the 170 dogs included in the study, 72 (42%) were male and 91 (54%) were female (sex was not recorded for the remaining 7 [4%] dogs). Median age was 4 years (range, 3 months to 16 years); median body weight was 27.3 kg (60 lb; range, 1.3 to 68.2 kg [2.9 to 150 lb]). Forty-six (27%) dogs were of mixed breeding; the remainder represented 50 breeds, including Labrador Retriever (28 [16%]), Weimaraner (9 [5%]), German Shepherd Dog (5 [3%]), Dachshund (5 [3%]), Doberman Pinscher (5 [3%]), and Vizsla (4 [2%]). The remaining breeds were all represented by ≤ 3 dogs. Statistical analysis of whether sex, breed, or age was associated with outcome (survived vs did not survive) was not possible because only 1 dog did not survive.

Sixty-six of the 170 (39%) dogs reportedly did not develop any clinical signs. The remaining 104 (61%) dogs reportedly developed 1 or more clinical signs, including agitation (40/104 [38%]), vomiting (27/104 [26%]), mydriasis (19/104 [18%]), lethargy (17/104 [16%]), tremor or twitching (16/104 [15%]), panting (15/104 [14%]), bradycardia (13/104 [13%]), tachycardia (12/104 [12%]), hypertension (11/104 [11%]), erythema (8/104 [8%]), piloerection (5/104 [5%]), fever or hyperthermia (5/104 [5%]), ataxia (4/104 [4%]), anorexia (4/104 [4%]), salivation (4/104 [4%]), seizures (3/104 [3%]), high liver enzyme activities (2/104 [2%]), polydipsia (2/104 [2%]), vocalization (2/104 [2%]), arrhythmia (2/104 [2%]), hives (2/104 [2%]), hiding (1/104 [1%]), and death (1/104 [1%]).

Median ingested dose for all dogs was 29 mg/kg (13.2 mg/lb; range, 1.8 to 533 mg/kg [0.82 to 242.3 mg/lb]). Ingested dose was significantly (P < 0.001) higher for the 104 dogs that developed clinical signs (median, 37.3 mg/kg [17.0 mg/lb]; range, 1.9 to 450 mg/kg [0.86 to 204.5 mg/lb]) than for the 66 dogs that did not develop clinical signs (median, 18 mg/kg [8.2 mg/lb]; range, 1.8 to 533 mg/kg). Time from ingestion to development of clinical signs was recorded for 72 dogs and ranged from < 30 minutes (2/72 [3%]) to 24 hours (9/72 [13%]); most dogs (63/72 [88%]) developed clinical signs within 8 hours after PPA ingestion.

For 150 of the 170 (88%) dogs, the poison control center recommended that given the dose ingested or the presence of clinical signs, the owner seek veterinary care. Overall, 137 of the 170 (81%) dogs were brought to a veterinarian for evaluation, decontamination, and treatment as needed. Ingested dose was significantly (P < 0.001) higher for the 137 dogs evaluated by a veterinarian (35 mg/kg [15.9 mg/lb]; range, 1.9 to 533 mg/kg [0.86 to 242.3 mg/lb]) than for the 33 dogs monitored at home (10.2 mg/kg [4.6 mg/lb]; range, 1.8 to 97 mg/kg [0.82 to 44 mg/lb]). Of the 137 dogs evaluated by a veterinarian, 123 (90%) received inpatient treatment and 14 (10%) received outpatient treatment. Ingested dose was significantly (P < 0.006) higher for dogs that received inpatient treatment (36.9 mg/kg [16.8 mg/lb]; range, 4 to 533 mg/kg [1.8 to 242.3 mg/lb]) than for dogs that received outpatient treatment (20.5 mg/kg [9.3 mg/lb]; range, 1.9 to 44.4 mg/kg [0.86 to 20.2 mg/lb]). Information about treatments the dogs received while hospitalized was not readily available from the records and could not accurately be obtained from owners at the time of follow-up telephone calls. However, treatment generally included decontamination (eg, emesis and charcoal administration), IV fluid administration, and sedation. Information on duration of hospitalization was available for or estimated by the owners of 102 of the 123 dogs that were hospitalized and ranged from 4 to 72 hours (median, 18 hours). Duration of hospitalization increased significantly (P = 0.002) as ingested dose increased; however, examination of the linear regression plot suggested that this relationship was unlikely to be clinically important. For example, from the linear regression plot, anticipated duration of hospitalization for a dog that ingested 5 mg of PPA/kg (2.3 mg/lb) would be 15.9 hours, whereas duration for a dog that ingested 50 mg of PPA/kg (22.7 mg/lb) would be 18.9 hours.

Information on time from exposure until the poison control center was contacted was recorded for 129 of the 170 dogs, of which 103 received veterinary care (90 dogs that received inpatient care and 13 dogs that received outpatient care). This time did not differ significantly (P = 0.789) between dogs that received inpatient care (median, 120 minutes; range, 5 to 1,440 minutes) and dogs that received outpatient care (median, 210 minutes; range, 10 to 540 minutes). There was also no significant (P = 0.540) linear correlation between time from exposure until the poison control center was contacted and duration of hospitalization for those dogs that received inpatient care.

Survival rate was 99.4% (169/170). The 1 dog that died had been exposed to multiple medications, including PPA, in the garbage at a veterinary clinic. The exact dose of PPA ingested in this dog was unknown, but the total maximum dose ingested could have been as high as 145 mg/kg (65.9 mg/lb) if all of the PPA tablets in the garbage had been consumed. The time since ingestion was unknown, but the dog had reportedly ingested the tablets during clinic business hours (ie, between 8 am and 6 pm) that day. Limited information on history was available at the time of the initial call from the veterinary staff because of the urgency and critically ill nature of the dog; however, the information that was obtained suggested that the dog was having signs consistent with PPA toxicosis. Specific clinical signs and duration of clinical signs were not elaborated during the telephone consultation, which occurred at least 4 hours, but possibly up to 14 hours, after ingestion. Unfortunately, the dog developed grand mal seizures unresponsive to IV administration of diazepam and underwent cardiopulmonary arrest during the telephone call. The dog could not be resuscitated and died within 14 hours after presumed exposure, at approximately 10 pm. Because the dog died soon after the initiation of the telephone call, additional information regarding decontamination, treatments performed, and specific clinical signs was not obtained. Because the dog could have ingested other medications in addition to PPA, the cause of death could not be completely attributed to PPA ingestion. No confirmatory drug concentration testing or postmortem examination was performed on this dog.

Discussion

Results of the present study suggested that with appropriate care, the prognosis for dogs that had ingested an overdose of PPA was excellent. The high survival rate (169/170 [99.4%]) in the present study was likely due to owner compliance in seeking recommended veterinary care, the growing availability of animal-specific poison control help lines to assist with treatment recommendations for both pet owners and veterinary professionals, and the rapid decontamination and treatment of patients. Additionally, many dogs that did not develop clinical signs following PPA ingestion were hospitalized and received supportive care, which likely improved outcome.

Phenylpropanolamine, a synthetic catecholamine, has a structure and function similar to the structure and function of drugs such as amphetamine, ephedrine, methylphenidate,h and methamphetamine. Phenylpropanolamine was first synthesized in 1912 and was previously used in human over-the-counter weight-loss supplements and cold medications.1 Although the safety of this drug in people remains controversial,9 the use of PPA in human medicine was discontinued as of 2003 in the United States because of the narrow margin of safety and concerns about substantial morbidity and mortality rates associated with its use.1 Adverse effects were most typically seen with dietary weight-loss supplements or misuse of commercial products. A number of case reports and case reviews in human medicine describe hypertension,10–14 myocardial injury (including cardiac necrosis and arrhythmias),15–19 acute renal failure,20 intracranial hemorrhage and hemorrhagic stroke,21–24 psychotic episodes,25 and death26,27 after both therapeutic use of PPA and ingestion of overdoses of medications containing PPA. Despite this, PPA is still available and readily dispensed in veterinary medicine for the treatment of urinary incontinence. Canine exposures to potentially toxic doses of PPA typically occur with accidental ingestion of the pet's own medication or another pet's medication and may be attributed to the palatability of the chewable formulation of the medication that is available.

The exact mechanism of action of PPA in humans and dogs is incompletely understood, but the drug is hypothesized to function at similar adrenergic receptor locations in the 2 species. Phenylpropanolamine appears to exert its effects in the body directly via α-adrenergic receptor stimulation and indirectly by increasing norepinephrine release. However, drugs of the amine class, which include PPA, may have various effects on adrenergic receptors, making interpretation of studies across species challenging.1

The anticipated effect of PPA on adrenergic receptors is consistent with the clinical signs identified in the present study. α-Adrenergic receptors are found in the peripheral arteries and veins, coronary circulation, and myocardium. Stimulation of α1-adrenergic and α2-adrenergic receptors in the vasculature results in contraction of the arterial smooth muscle, causing vasoconstriction,28,29 whereas stimulation of α-adrenergic receptors in the myocardium may have a positive inotropic effect.29 Stimulation of α-adrenergic receptors can also result in mydriasis, contraction of the bladder sphincter, and contraction of the pilomotor muscles.28 β-Adrenergic receptors are found in the heart, vascular and visceral smooth muscle, and kidneys. Stimulation of β1-adrenergic receptors with norepinephrine will increase cardiac output through positive inotropic and chronotropic effects. These receptors have variable distribution and responsiveness throughout the body and mediate vasodilation in vital areas of the body (eg, the heart, brain, kidney, and skeletal muscle) to preserve blood flow during excessive sympathetic stimulation.29 The α-adrenergic and β-adrenergic receptor stimulation caused by PPA ingestion results in clinical signs such as tachycardia, hypertension, agitation, mydriasis, urine retention, piloerection, and muscle tremors.

Pharmacokinetic studies following oral administration of PPA to dogs have shown that the drug is well absorbed orally, with bioavailability of 98.2% in 1 study,30 but that individual variability exists.31 Bioavailability did not differ significantly between immediate-release (mean ± SD, 98.2 ± 6.9%) and controlled-release (93.7 ± 5.9%) formulations.30 With the immediate-release formulation, the peak plasma PPA concentration occurred 2 hours after administration and elimination half-life was approximately 4 hours. The controlled-release formulation had a similar peak plasma concentration at 2 hours, which is maintained for up to 16 hours, followed by a half-life similar to that for the immediate-release formulation.4,31 Phenylpropanolamine is well distributed throughout the body including the CNS, but it is unknown whether the drug crosses the placenta or enters the milk. A small amount of the drug is metabolized by the liver, with 80% to 90% of the unchanged drug excreted by the kidneys.3 Given the reported times to peak plasma PPA concentration, clinical signs would be expected to occur within 2 hours after ingestion for either the immediate-release or controlled-release formulation; however, as documented in the present study, some dogs may develop clinical signs as early as 30 minutes after ingestion, warranting immediate treatment when an overdose has been ingested. In the present study, 88% (63/72) of dogs had clinical signs within 8 hours after ingestion. On the basis of the pharmacokinetics of PPA and the results of the present study, we recommend that dogs exposed to toxic amounts of PPA be evaluated and monitored by a veterinarian for a minimum of 8 hours after ingestion. With the immediate-release PPA formulation, the elimination half-life is 4 hours; therefore, clinical signs may persist for at least 20 hours following ingestion of an overdose. In the present study, 44% (45/102) of dogs were hospitalized for at least 20 hours, emphasizing the potentially long duration of clinical signs with PPA toxicosis. We recommend that dogs be hospitalized and treated until clinical signs resolve.

Phenylpropanolamine can be detected in urine or blood by means of liquid and gas chromatography. Limited veterinary diagnostic laboratories, private laboratories, and human laboratories may still offer testing; however, this is not routinely performed in veterinary medicine. In this study, none of the dogs had serum or urine PPA concentrations measured.

The signalment of dogs in the present study appeared to reflect the population of dogs treated with PPA. Because spayed female dogs have primary urethral sphincter incompetence more commonly than do sexually intact female dogs and male dogs,32 it was not unexpected that more female than male dogs were included in the present study. In addition, women taking PPA products reportedly have more adverse effects than do men, which may reflect increased sensitivity to the drug, although this has not been confirmed.26 Although urethral sphincter incompetence is a less common condition in male dogs,33 there were a large number of male dogs in the study population. It was unknown whether these male dogs had urethral sphincter incompetence and ingested an overdose of their own medication or simply ingested an overdose of another dog's medication.

Age range of dogs in the present study coincided with the age range for dogs treated with PPA. In the present study, median age was 4 years, but ranged from 3 months to 16 years. Previous studies4–6,8 investigating primary urethral sphincter incompetence and PPA efficacy have reported similar median ages (3.7 to 5.6 years) and ranges (6 months to 13 years) for their study populations.

Median weight for dogs in the present study reflected weights previously reported for dogs with urinary incontinence. Scott et al7 reported that mean weight for dogs with primary urethral sphincter incompetence was 23.4 kg (51.5 lb), and a correlation between greater weight and higher incidence of urinary incontinence has been described.34 However, there was a wide weight range in the present study, and although larger dogs may have a tendency to ingest large numbers of tablets, smaller dogs may develop signs after ingesting fewer tablets.

Mixed-breed dogs were most common in the present study, followed by Labrador Retrievers. The high number of Labrador Retrievers may have been attributable to the popularity of this breed in the United States or the reported propensity of this breed for dietary indiscretion and toxic exposures.35 Although some of the breeds identified in the present study have been overrepresented in European studies of urethral incontinence,34,36 the large numbers of dogs of certain breeds may reflect regional breed prevalences and should not necessarily be interpreted to indicate that these breeds are more commonly exposed to PPA in the United States. Finally, because only 1 dog in the present study died, it was not possible to examine risk factors such as sex, age, weight, breed, or dose ingested for possible associations with outcome.

Clinical signs associated with PPA overdose in dogs have been reported to occur as early as 30 minutes after ingestion.37 In the present study, clinical signs were most commonly reported to occur within 2 to 8 hours after ingestion. This delay may have been due to several factors including variations in the true time for clinical signs to develop and inaccurate assessment by the owners. These findings may also have been related to the specific formulation ingested (eg, immediate-release vs controlled-release formulation), but the formulation ingested was inconsistently documented in the records.

In the present study, most dogs with clinical signs had neurologic, gastrointestinal, and cardiopulmonary signs. Although Crandell and Ware2 reported neurologic signs, which included ataxia, nystagmus, mydriasis, and hypermetria, in a dog with PPA toxicosis, the present study was the first, to our knowledge, to report seizures and muscle tremors following PPA ingestion. Although only 3 dogs in this study developed seizures, 2 were unresponsive to anticonvulsant treatment (IV administration of diazepam and propofol), making early identification and aggressive control with barbiturates important. Likewise, tremors should be controlled with sedation and muscle relaxants to prevent hyperthermia, disseminated intravascular coagulation (secondary to severe hyperthermia), and myoglobinuria (with secondary end organ damage). Other neurologic signs identified in the present study included behavioral changes (agitation, lethargy, vocalization, and hiding), mydriasis, muscle tremors or twitching, and ataxia. These neurologic signs were likely a result of CNS stimulation secondary to sympathetic stimulation; however, they may also have reflected other underlying effects, such as cardiovascular effects (tachycardia and hypertension), gastrointestinal signs (nausea and vomiting), and generalized anxiety or malaise. Although neurologic signs could have hypothetically represented a cerebral vascular problem such as a hemorrhagic stroke or intracranial hemorrhage, as reported in humans after PPA ingestion,21–24 we believe that cerebral vascular problems were an unlikely cause of the neurologic problems because of their rapid resolution. That said, none of the dogs in this study underwent advanced imaging (eg, magnetic resonance imaging or computed tomography), so the exact etiology of neurologic signs cannot be definitely determined. Finally, mydriasis, although not necessarily clinically important or life-threatening, may be an easily identifiable sign of toxicosis for owners to monitor at home after ingestion of PPA; if mydriasis is present, further veterinarian evaluation should be pursued.

Gastrointestinal signs, including vomiting, salivation, and anorexia, were the second most commonly documented abnormalities in the present study. Vomiting may have developed secondary to gastric distension associated with ingestion of a large number of tablets or foreign material if the plastic bottle itself was ingested. In addition, other effects may have resulted in vomiting, including tachyarrhythmia.38 Salivation may result from nausea but can also be attributed to sympathomimetic stimulation of β1-adrenergic receptors. Anorexia has been reported in dogs receiving therapeutic doses of PPA, but following ingestion of an overdose, anorexia is likely due to other effects of toxicosis (eg, nausea, tachycardia, and hypertension). These signs may not represent an immediate life-threatening problem, but if left untreated could contribute to patient morbidity and may require supportive care.

Cardiopulmonary signs identified in the present study included panting, bradycardia, tachycardia, and hypertension. Although PPA may result in bronchodilation as a result of β2-adrenergic receptor effects, the panting or tachypnea seen in this population of dogs was likely due to underlying factors such as agitation, arrhythmia, nausea, hyperthermia, or potentially acid-base imbalances. Bradycardia may develop secondary to hypertension, indicate myocardial damage, or reflect temperament variations among breeds. In the present study, 13 dogs were bradycardic and blood pressure was measured or recorded at the time of the telephone call in 8 of these 13 dogs. All 8 of these dogs had concurrent bradycardia and hypertension. This combination likely reflected reflex bradycardia in response to hypertension. Tachycardia and hypertension were likely due to α-adrenergic and β-adrenergic receptor stimulation, leading to increased heart rate and cardiac output as well as vasoconstriction, but may also have been due to breed and temperament variations. Although documented in human medicine16–18 and a previous case report2 involving a dog, myocardial injury and infarction were not identified in the present study. However, cardiac enzyme activities (including troponin activity) were not measured and echocardiography was not performed in any of these dogs. In addition, none of the dogs underwent necropsy to evaluate for the presence of cardiac damage. That said, the true incidence of arrhythmias, hypertension, and myocardial damage may have been underreported in the present study because of a lack of veterinary evaluation, client financial limitations, lack of appropriate testing equipment, and poor patient compliance with testing. The prevalence of cardiovascular signs in the present study supports the appropriate use of cardiac monitoring, including continuous ECG and blood pressure monitoring, and the potential need for advanced cardiac diagnostic testing, especially with ingestion of high doses and persistence of clinical signs. Unless adversely affecting perfusion, bradycardia should not be treated with anticholinergics because treatment of bradycardia may exacerbate hypertension. However, persistent, severe tachycardia (defined as a heart rate > 180 beats/min) and hypertension (defined as a systolic blood pressure > 180 to 200 mm Hg) should be treated with sedation, antiarrhythmics, or antihypertensives as needed to prevent secondary effects such as decreased cardiac output, hypoperfusion, secondary organ damage, and fatal arrhythmias.39

In the present study, clinicopathologic testing was not consistently performed and results were not consistently documented. Two dogs had high liver enzyme activities, which may have been a result of hypoperfusion. Typically, primary hepatic injury is not anticipated as a result of PPA metabolism, absorption, or toxicosis. In general, serum biochemical testing is recommended in dogs, particularly geriatric or pediatric dogs, with potential PPA toxicosis to evaluate for underlying metabolic conditions (eg, renal disease) that may affect drug excretion.

Although unlikely to be clinically important, cutaneous erythema and piloerection have not, to our knowledge, been previously reported following PPA ingestion. Cutaneous erythema may be due to hyperthermia or agitation, but was not a consistent finding in the present study. Agitation was noted in 4 of the 5 dogs with piloerection and can be attributed to α-adrenergic receptor stimulation and contraction of the pilomuscles. Hyperthermia was rarely reported in the present study, despite the prevalence of body tremors and erythema, but this may have reflected that body temperature was not recorded or may have been due to hypoperfusion of the rectum secondary to sympathomimetic stimulation or decreased cardiac output. Nevertheless, body temperature should be monitored closely in animals with tremors, seizures, and severe agitation; appropriate cooling measures should be instituted as needed.

In the present study, clinical signs were observed in dogs that had ingested as little as 1.9 mg of PPA/kg. In addition, although median ingested dose was 29 mg/kg, 39% (66/170) of the dogs reportedly did not develop any clinical signs. Reasons why this substantial percentage of dogs did not develop clinical signs likely were multifactorial. First, signs documented in the present study were often those described by the owner or identified at the time of initial examination, before a complete physical examination had been performed. Pet owners would not be able to assess their dogs for hypertension or tachyarrhythmias, resulting in underreporting of some clinical signs. Second, ingested doses often had to be estimated if owners were unable to recall the exact number of tablets they had, the bottle was destroyed or unreadable, or there were multiple dogs that may have had access to the drug. Early induction of emesis or spontaneous vomiting may have decreased the amount of PPA absorbed, thereby decreasing the incidence of clinical signs. Tachyphylaxis, which is a decreased response to PPA reported in humans with prolonged use,1 has not, to our knowledge, been reported in dogs that have received PPA for prolonged periods and was unlikely to have reduced the incidence of clinical signs in the present study.

For most toxic drugs, early decontamination will decrease drug absorption; however, because PPA is often obtained in chewable and liquid formulations, it may be difficult to assess whether induction of emesis has been successful in evacuating the drug from the stomach. In addition, because dogs do not completely evacuate their gastric contents with emesis (estimated percentage of gastric contents evacuated ranges from 17% to 62%),40 complete decontamination may not occur with emesis alone. Activated charcoal may be beneficial in decreasing the absorption of toxic drugs; however, it should not be used in dogs that have already developed clinical signs or that are at risk of aspiration.40 For dogs that have ingested an overdose of PPA but in which decontamination is not possible, whether because of a delay in veterinary evaluation, the presence of clinical signs, or an inability to protect the airway, hospitalization is necessary to evaluate the dogs and monitor for neurologic, cardiovascular, and gastrointestinal effects.

Because there is no antidote for PPA, treatment is supportive. In our experience, sedation with acepromazine or butorphanol can be successfully used to control agitation. In general, the use of benzodiazepines should be avoided because of the potential risk for idiosyncratic agitation.41 In dogs with seizures or tremors, the use of barbiturates and muscle relaxants (eg, methocarbamol) may be necessary. Antiemetics can be used but should be used cautiously in dogs that may have a gastric or intestinal foreign body as a result of ingestion of the medication package or bottle. In dogs with tachycardia or hypertension, the use of β-adrenoceptor blockers has been shown to be effective10; lidocaine can be used to treat ventricular tachycardia. Intravenous crystalloid fluid administration may be beneficial to maintain cardiac output and perfusion and may aid in drug excretion, but should be used judiciously in dogs with suspected or confirmed hypertension.

Overall, our results suggested that the prognosis for dogs ingesting PPA was excellent with appropriate decontamination and treatment. The present study represents the first reported case of death of a dog following PPA ingestion; however, PPA toxicosis cannot be confirmed as the cause of death because the dog may have been exposed to other medications.

Results of the present study highlight the need for pet owners to keep medications out of the reach of their pets. There are no human formulations of PPA currently available, and most dogs in the present study had ingested the chewable veterinary formulation of the drug. This formulation may be preferred by pet owners because of ease of dosing and palatability but may also contribute to ingestion of a large number of tablets by pets in the household. Veterinarians should warn clients about the potential for accidental ingestion and advise them to keep the medication in an inaccessible area and medicate dogs separately.

Limitations of the present study include those commonly encountered with any retrospective study. One important limitation was the inability to confirm the exact amount of PPA ingested because this information was often unavailable or because the amount ingested could not be quantified by the pet owner. Although an effort was made to exclude cases with exposure to multiple agents, this depended on the history provided by the pet owner or veterinarian. A limitation specific to the present study included the lack of confirmatory serum PPA concentrations, although PPA concentrations are rarely measured by veterinary diagnostic laboratories. The lack of necropsy results in the single dog that died hindered our ability to determine the cause of death and determine whether any myocardial injury had occurred. Also, although case management and medical treatments were recommended to the attending veterinarians during telephone consultations with the poison control center, the final decision as to which treatments were administered was determined by the pet owners and attending veterinarians.

ABBREVIATION

PPA

Phenylpropanolamine

a.

Proin, PRN Pharmacal, Pensacola, Fla.

b.

Propalin, Vetoquinol, USA Inc, Buena, NJ.

c.

Cystolamine, Veterinary Products Laboratories, Phoenix, Ariz.

d.

SafetyNotes, Minneapolis, Minn.

e.

Pet Poison Helpline, Minneapolis, Minn.

f.

Excel, Microsoft, Redmond, Wash.

g.

SAS, version 9.2 for Windows, SAS Institute Inc, Cary, NC.

h.

Ritalin, Novartis Pharmaceuticals Corp, East Hanover, NJ.

References

  • 1.

    Broadley KJ. The vascular effects of trace amines and amphetamines. Pharmacol Ther 2010; 125: 363375.

  • 2.

    Crandell JM, Ware WA. Cardiac toxicity from phenylpropanolamine overdose in a dog. J Am Anim Hosp Assoc 2005; 41: 413420.

  • 3.

    Plumb DC. Plumb's veterinary drug handbook. 6th ed. Ames, Iowa: Blackwell, 2008.

  • 4.

    Bacon NJ, Oni O, White RAS. Treatment of urethral sphincter mechanism incompetence in 11 bitches with a sustained-release formulation of phenylpropanolamine hydrochloride. Vet Rec 2002; 151: 373376.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Byron JK, March PA, Chew DJ, et al. Effect of phenylpropanolamine and pseudoephedrine on the urethral pressure profile and continence scores of incontinent female dogs. J Vet Intern Med 2007; 21: 4753.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Richter KP, Ling GV. Clinical response and urethral pressure profile changes after phenylpropanolamine in dogs with primary sphincter incompetence. J Am Vet Med Assoc 1985; 187: 605611.

    • Search Google Scholar
    • Export Citation
  • 7.

    Scott LS, Leddy M, Bernay F, et al. Evaluation of phenylpropanolamine in the treatment of urethral sphincter mechanism incompetence in the bitch. J Small Anim Pract 2002; 43: 493496.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    White RAS, Pomeroy CJ. Phenylpropanolamine: an α-adrenergic agent for the management of urinary incontinence in the bitch associated with urethral sphincter mechanism incompetence. Vet Rec 1989; 125: 478480.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Morgan JP, Funderburk R. Phenylpropanolamine and blood pressure: a review of prospective studies. Am J Clin Nutr 1992; 55:206S210S.

  • 10.

    Pentel PR, Asinger RW, Benowitz NL. Propranolol antagonism of phenylpropanolamine induced hypertension. Clin Pharmacol Ther 1985; 37: 488494.

  • 11.

    Salerno SM, Jackson JL, Berbano EP. The impact of oral phenylpropanolamine on blood pressure: a meta-analysis and review of the literature. J Hum Hypertens 2005; 19: 643652.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Blackburn GL, Morgan JP, Lavin, PT, et. al. Determinants of the pressor effect of phenylpropanolamine in healthy subjects. JAMA 1989; 261: 32673272.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Lake CR, Zaloga G, Bray J, et al. Transient hypertension after two phenylpropanolamine diet aids and the effects of caffeine: a placebo-controlled follow-up study. Am J Med 1989; 86: 427432.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Lake CR, Zaloga G, Clymer R, et al. A double dose of phenylpropanolamine causes transient hypertension. Am J Med 1988; 85: 339343.

  • 15.

    Leo PJ, Hollander JE, Shih RD, et al. Phenylpropanolamine and associated myocardial injury. Ann Emerg Med 1996; 28: 359362.

  • 16.

    Oosterbaan R, Burns MJ. Myocardial infarction associated with phenylpropanolamine. J Emerg Med 2000; 18: 5559.

  • 17.

    Conway EE, Walsh CA, Palomba AL. Supraventricular tachycardia following administration of phenylpropanolamine in an infant. Pediatr Emerg Care 1989; 5: 173174.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Pentel PR, Mikell FL, Zavoral JH. Myocardial injury after phenylpropanolamine ingestion. Br Heart J 1982; 47: 5154.

  • 19.

    Woo OF, Benowitz NL, Bialy FW, et al. Atrioventricular conduction block caused by phenylpropanolamine (lett). JAMA 1985; 253: 26462647.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Duffy WB, Senekjian HO, Knight TF, et al. Acute renal failure due to phenylpropanolamine. Southern Med J 1981; 74: 15481559.

  • 21.

    Mueller SM, Muller J, Asdell SM. Cerebral hemorrhage associated with phenylpropanolamine in combination with caffeine. Stroke 1984; 15: 119123.

  • 22.

    Kikta DG, Devereaux MW, Chandar K. Intracranial hemorrhages due to phenylpropanolamine. Stroke 1985; 16: 510512.

  • 23.

    Kernan WN, Viscou CM, Brass LM, et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med 2000; 343: 18261832.

  • 24.

    Cantu C, Arauz A, Murillo-Bonilla LM, et al. Stroke associated with sympathomimetics contained in over-the-counter cough and cold drugs. Stroke 2003; 34: 16671673.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Dietz AJ Jr. Amphetamine-like reactions to phenylpropanolamine. JAMA 1981; 245: 601602.

  • 26.

    Lake CR, Gallant S, Masson E, et al. Adverse drug effects attributed to phenylpropanolamine: a review of 142 case reports. Am J Med 1990; 89: 195208.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    Gunn VL, Taha SH, Liebelt EL, et al. Toxicity of over-the-counter cough and cold medications. Pediatrics 2001; 108: 15.

  • 28.

    Costanzo LS. Autonomic nervous system. In: Physiology. 2nd ed. Philadelphia: Saunders, 2002; 4056.

  • 29.

    Long KM, Kirby R. An update on cardiovascular adrenergic receptor physiology and potential pharmacological applications in veterinary critical care. J Vet Emerg Crit Care 2008; 18: 225.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Hussain MA, Aungst BJ, Lam G, et al. Phenylpropanolamine pharmacokinetics in dogs after intravenous, oral, and oral controlled-release doses. Biopharm Drug Dispos 1987; 5: 497505.

    • Search Google Scholar
    • Export Citation
  • 31.

    Noel S, Cambier C, Baert K, et al. Combined pharmacokinetics and urodynamic study of the effects of oral administration of phenylpropanolamine in female Beagle dogs. Vet J 2010; 184: 201207.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32.

    Root Kustritz MV, Olson PN. Early spay and neuter. In: Ettinger SJ, Feldman EC, eds. Textbook of veterinary internal medicine. 5th ed. Philadelphia: Saunders, 2000; 15391541.

    • Search Google Scholar
    • Export Citation
  • 33.

    Arnold S, Weber U. Urethral sphincter mechanism incompetence in male dogs. In: Bonagura JD, ed. Kirk's current veterinary therapy XIII small animal practice. Philadelphia: Saunders, 2000; 896899.

    • Search Google Scholar
    • Export Citation
  • 34.

    Arnold S. Relationship of urinary incontinence to neutering. In: Kirk RW, Bonagura, JD, eds. Kirk's current veterinary therapy XI small animal practice. Philadelphia: Saunders, 1992; 875877.

    • Search Google Scholar
    • Export Citation
  • 35.

    Hovda LR. Toxic exposure in small animals. In: Bonagura JD, ed. Kirk's current veterinary therapy XIV small animal practice. Philadelphia: Saunders, 2009; 9294.

    • Search Google Scholar
    • Export Citation
  • 36.

    Gregory SP. Developments in the understanding of the pathophysiology of urethral sphincter mechanism incompetence in the bitch. Br Vet J 1994; 150: 135150.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37.

    Vick J, Weiss L, Ellis S. Cardiovascular studies of phenylpropanolamine. Arch Int Pharmacodyn Ther 1994; 327: 1324.

  • 38.

    Pentel PR, Jentzen J, Siever J. Myocardial necrosis due to intraperitoneal administration of phenylpropanolamine in rats. Fundam Appl Toxicol 1987; 9: 167172.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39.

    Brown S. Hypertensive crisis. In: Silverstein DC, Hopper K, eds. Small animal critical care medicine. St Louis: Saunders, 2009; 176179.

    • Search Google Scholar
    • Export Citation
  • 40.

    Peterson ME. Toxological decontamination. In: Peterson ME, Talcott PA, eds. Small animal toxicology. Philadelphia: Elsevier, 2006; 127141.

    • Search Google Scholar
    • Export Citation
  • 41.

    Volmer PA. Recreational drugs. In: Peterson ME, Talcott PA, eds. Small animal toxicology. Philadelphia: Elsevier, 2006; 273311.

All Time Past Year Past 30 Days
Abstract Views 342 0 0
Full Text Views 1032 878 260
PDF Downloads 479 320 42
Advertisement