Phenylpropanolamine for Urinary Incontinence

Urethral sphincter mechanism incompetence (USMI) is the most common cause of urinary incontinence in spayed female dogs.¹ Studies have estimated the prevalence of USMI in dogs to be between 5.1% and 20%, with large-breed dogs being predisposed.^1-3 While the pathophysiology of USMI is multifactorial, medical management is often directed at increasing urethral tone with drugs such as α-adrenergic agents or estrogen derivatives. 

Proin (PRN Pharmacal, prnpharmacal.com) is the only veterinary Food and Drug Administration (FDA)-approved phenylpropanolamine hydrochloride medication marketed in the United States to treat urinary incontinence due to hypotonicity of the urethral sphincter. Proin chewable tablets were first approved by the FDA in 2011, and an extended-release formulation, Proin ER, was approved in 2019.^4-6 In Europe and Canada a liquid formulation of phenylpropanolamine, Propalin (Vetoquinol, vetoquinol.ca), is available. Formulations that are no longer commercially available include Uriflex-PT, Uricon, Cystolamine, and Proin Drops.

Mechanism of Action

Phenylpropanolamine is a sympathomimetic amine that indirectly stimulates the α₁– adrenergic receptors (and, to a lesser extent, β-receptors) by causing release of norepinephrine, leading to constriction of the smooth muscle internal urethral sphincter.^7,8 It is also thought to prolong its effect by inhibiting norepinephrine reuptake at the synaptic junction.⁷ Phenylpropanolamine may have decreased efficacy in patients on long-term therapy owing to either depletion of norepinephrine stores or desensitization of the α-adrenergic receptors.^7-9 

Dosing

The recommended labeled dose for Proin is 2 mg/kg PO q12h, to be dosed to the nearest half-tablet.⁶ Proin is commercially available in 25-, 50-, and 75-mg tablets. The recommended dose of Proin ER is 2 to 4 mg/kg PO q24h (to be given with food).¹⁰ Proin ER is available in 18-, 38-, 74-, and 145-mg tablets. It is not labeled for use in dogs weighing less than 10 pounds.¹⁰ Owing to a lack of safety and efficacy studies, using Proin ER tablets and Proin chewable tablets interchangeably is not recommended, nor is the use of Proin in pregnant or lactating animals.¹⁰ 

Efficacy

Phenylpropanolamine has been found to be efficacious at controlling incontinence secondary to USMI in several studies. In one study, phenylpropanolamine was found to be effective at controlling unconscious urination in 85.7% of dogs treated with 1 mg/kg PO q8h.¹¹ Studies funded by a manufacturer (Pegasus Laboratories Inc.) showed a significant reduction in urinary incontinence at 2 mg/kg PO q12h compared with placebo, with 91.3% of owners reporting satisfactory urinary continence by day 30 and 98.1% at day 180. However, during short-term efficacy studies, no significant improvement was noted in incontinent male dogs when accounting for a sex effect.⁴ In a manufacturer-funded study with 107 dogs, there was no significant difference in efficacy between standard-release Proin tablets and Proin ER. 

Analysis of urethral pressure profiles has shown that phenylpropanolamine causes a significant increase in urethral resistance compared with controls.⁸ Similarly, a study measuring urethral pressure profiles and continence scores of incontinent dogs with USMI showed that phenylpropanolamine was significantly more effective than its analog, pseudoephedrine, at increasing maximum urethral closure pressure and functional area as well as continence score.¹ 

Pharmacokinetics

Phenylpropanolamine has an excellent bioavailability for both controlled-release and immediate-release formulations (93.7% and 98%, respectively) in dogs.¹² Maximal concentrations (C_max) are reached 2 hours after administration, with a half-life of 3 to 4 hours for the immediate-release formulation.^8,12 Phenylpropanolamine absorption in the controlled-release formulation is biphasic, with a rapid initial absorption phase followed by a second slower absorption phase that continues for up to 16 hours.¹² Pharmacokinetic studies of Proin ER showed a slightly higher C_max than Proin; however, overall drug exposure (area under the curve) was less.⁵ Phenylpropanolamine is primarily excreted unchanged by the kidneys.¹²

Safety and Adverse Effects

Manufacturer-reported side effects include weight loss of >5%, vomiting, hypertension, anorexia, proteinuria, and anxiety/behavior change, including aggression.⁴ In the authors’ experience, therapy with estrogen-based products, such as estriol (Incurin; Merck Animal Health, merck-animal-health-usa.com), is preferable for patients with known behavioral concerns. 

Safety studies performed by the manufacturer showed that dosing at up to 5 times the recommended dose for 6 months resulted in hypertension; however, the mean arterial pressure was not significantly different than that in the ideal dosing group and no evidence of target organ damage was noted at necropsy.⁴ Despite this, the heart rates of dogs in the 3× and 5× dosing groups were found to be significantly lower than control.⁴ Independently conducted studies showed a similar increase in hypertension with a compensatory decrease in heart rate.⁸ One case report has also associated the long-term use of phenylpropanolamine with the development of ventricular hypertrophy.¹³ Pets on phenylpropanolamine therapy should have their blood pressure closely monitored. If significant hypertension is noted, therapy with an alternative agent should be considered.

In addition to hypertension, dogs in the 3× and 5× manufacturer safety dosing groups were found to have significant elevations in platelet counts, alanine aminotransferase (ALT), and lactate dehydrogenase.⁴ Similarly, short-term dosing of phenylpropanolamine at 10× the recommended dose for 21 days resulted in hypertension, bradycardia, vomiting, leukocytosis, thrombocytosis, and elevations in ALT. 

While not reported in companion animal species, the use of sympathomimetic drugs, including phenylpropanolamine, has been associated with birth defects in people, rabbits, and chickens.^14,15 Safety studies in this population of companion animals are lacking; therefore, therapy with phenylpropanolamine should be avoided in pregnant or lactating bitches. 

Several drug interactions are possible. An increased risk of hypertension has been documented in patients receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs), reserpine, or tricyclic antidepressants.⁷ Phenylpropanolamine should not be given within 2 weeks of a patient receiving a monoamine oxidase inhibitor such as amitraz.⁷ Finally, anesthesia with halothane is associated with an increased risk of arrhythmias and should be avoided.⁷

Phenylpropanolamine Versus Estrogen

In addition to phenylpropanolamine, estrogen or estrogen derivatives such as estriol and diethylstilbestrol (DES) are commonly used for dogs with USMI. One study showed that sympathomimetic drugs (pseudoephedrine) were more effective at controlling urinary incontinence than DES (82.4% versus 64.5%).¹⁶ However, more recent studies of estriol have shown reported efficacies between 83% and 89.8%, similar to that of phenylpropanolamine.^17,18 

Prior to its discontinuation in humans, combined therapy with phenylpropanolamine and estrogen derivatives was found to be synergistic, with increases in maximum urethral closure and reductions in leakage episodes.^19-21 One recent study in healthy beagles without USMI showed no improvement in maximum urethral pressure or closure pressure when phenylpropanolamine was added to estriol.²² However, as there are likely differences in the functional urodynamics of unaffected animals and dogs with USMI, additional studies are warranted. In the authors’ experience, dogs affected with USMI that do not respond to phenylpropanolamine may respond to estriol or vice versa, and in some cases combination therapy is warranted.

Conclusion

Phenylpropanolamine is effective at improving continence in dogs with USMI. Generally, therapy with phenylpropanolamine is safe; however, routine blood pressure monitoring should be performed to screen for hypertension, and special consideration should be taken before prescribing phenylpropanolamine to animals with behavioral concerns. Therapy with concurrent NSAIDs, reserpine, or tricyclic antidepressants may increase the risk of hypertension. If unacceptable hypertension is observed, therapy with an alternative agent should be considered.