Sympathomimetic Agents

Phenylpropanolamine (PPA) is an indirect α-agonist amine producing a contraction of the bladder neck and proximal urethra by acting on the α-adrenergic receptors. PPA is very effective in the treatment of USMI, resulting in continence in 75% to 90% of the patients. PPA traditionally has been administered two or three times daily. However, recurrence of incontinence can be observed after prolonged administration. Urodynamic studies in beagle dogs have shown lack of modification of urethral resistance after 1 week of three-times-daily administrations of PPA, whereas significant increase in urethral resistance was observed clearly after 1 week of once-daily administration. In the author’s experience, the administration of a single daily dose of PPA (1.5 mg/kg) in dogs affected with USMI can achieve long-term continence in 90% of cases (Claeys et al, 2011). This administration regimen obviously is more convenient and less expensive for owners. Adverse effects of PPA include hypertension, restlessness, anxiety, and tachycardia. Therefore PPA should be administered cautiously to dogs with concurrent cardiovascular diseases or hypertension.

Ephedrine is a mixed-action sympathomimetic drug whose efficacy is slightly less predictable than that of PPA, with a complete response to treatment observed in about 75% of treated bitches. Adverse effects are those of sympathomimetic drugs. Experimental studies have shown that both PPA and ephedrine improved urethral function; however, bladder storage function also was improved after administration of ephedrine (Noël et al, 2012). This latter effect can be explained by stimulation of the β₃-adrenoreceptors present in the bladder dome. Therefore ephedrine potentially could be a useful drug in the treatment of refractory urinary incontinence with concurrent bladder dysfunction, but this hypothesis still needs to be confirmed in clinical cases.

Treatment with either ephedrine or PPA should be initiated at the recommended starting dosage, and then the dosage should be decreased progressively once the incontinence is controlled.

Pseudoephedrine is a stereoisomer of ephedrine that was shown to produce a lower increase in urethral resistance, a lower continence score, and more adverse effects in bitches with USMI compared with PPA (Byron et al, 2007). Pseudoephedrine generally is not recommended for the management of urinary incontinence.

Estrogenic Compounds

High-affinity estradiol receptors are located at the level of the proximal urethra, and estrogens are known to increase the number and the responsiveness of α-adrenergic receptors to sympathetic stimulation. Additional potential effects of estrogenic compounds include improvement of urethral vascularization, stimulation of collagen synthesis, and cellular proliferation leading to an increase in urethral wall thickness. Long-acting synthetic estrogen preparations are associated with bone marrow depletion and should no longer be used. Estriol is a short-acting natural estrogen compound with few adverse effects. It recently has received U.S. Food and Drug Administration approval for use in veterinary medicine. Long-term administration is associated in rare cases with adverse effects such as pyometra or bone marrow suppression. Minor associated adverse effects include swelling of the vulva, attraction to males, and metrorrhagia. Success rate is lower with estrogen administration than with administration of sympathomimetic compounds, and complete continence is achieved in 65% of treated bitches (Mandigers and Nell, 2001). Estrogen administration can be chosen when the use of sympathomimetic agents is contraindicated, such as in dogs with concurrent cardiovascular disease or hypertension. Estrogen use is contraindicated in immature bitches with congenital USMI because of adverse effects associated with the negative feedback on the hypophysis. Estrogen administration also should be avoided in intact bitches and in male dogs.

Although the combination of estrogens and sympathomimetic agents has been advocated in cases of refractory incontinence to achieve a theoretical synergetic effect, the superiority of this combination still remains to be documented. Indeed, experimental urodynamic studies have failed to demonstrate a superior effect of this combination on urethral function compared with the effect of either estrogens or α-agonists alone (Hamaide et al, 2006). However, the combination still may be useful in individual dogs. If the drugs are used in combination, the dosage of each drug is identical to that used when the drug is given alone, and dosages of both medications also can be tapered over time.