Phosphodiesterase 5 inhibitors
There are several phosphodiesterase 5 (PDE5) inhibitors, including sildenafil (Viagra—Pfizer), tadalafil (Cialis, Adcirca—Eli
Lilly), and vardenafil (Levitra, Staxyn—GlaxoSmithKline). These drugs all specifically inhibit PDE5, which is highly concentrated
in pulmonary vessels. As discussed in the Part 1 of this article series, PDE5 normally breaks down cyclic guanosine monophosphate
(cGMP). When PDE5 is inhibited, cGMP concentrations increase and vasodilation is promoted. In people, PDE5 inhibitors all
cause pulmonary arterial vasodilation, but there are subtle differences between the three substances in regard to onset and
duration of action, degree of decreased pulmonary vascular resistance, and ability to reverse cardiac hypertrophy.8,27
Sildenafil is a short-acting PDE5 inhibitor. It has been evaluated for treating canine pulmonary hypertension in the clinical
setting and has been shown to decrease pulmonary arterial pressure, improve quality of life, and improve survival time.28,29 Sildenafil has rare gastrointestinal side effects and, while relatively expensive, may be affordable for many clients. It
is considered the drug of choice for treating pulmonary hypertension in dogs. The recommended sildenafil dose is 1 to 3 mg/kg
by mouth every eight to 12 hours.
Tadalafil is a long-acting PDE5 inhibitor. There is a single published case study evaluating a dog treated with tadalafil.
The patient was diagnosed with idiopathic pulmonary hypertension and was treated with tadalafil (1 mg/kg orally every 48 hours)
in addition to other medications.30 The patient demonstrated decreased pulmonary arterial pressure and improved clinical signs with tadalafil treatment but
was euthanized 10 days later because of signs of weakness, tremor, and decreased appetite.30 Ultimately, the clinicians felt the patient suffered systemic hypotension secondary to tadalafil use, but that was not confirmed.
While there is some evidence that tadalafil can improve echocardiographic signs and clinical signs in dogs with pulmonary
hypertension, this medication should be used cautiously.
Vardenafil is another long-acting PDE5 inhibitor. To date, vardenafil has not been studied either experimentally or in the
clinical setting for its effectiveness in treating canine pulmonary hypertension and should not be considered if other options
Other phosphodiesterase inhibitors
Theophylline is a weak, nonselective PDE inhibitor and affects PDE3, PDE4, and PDE5. This medication is used commonly for
its ability to relax smooth muscle in patients with bronchial disease. In human medicine, it has been shown to improve pulmonary
hypertension secondary to chronic obstructive pulmonary disease and may be useful in dogs with clinical class III pulmonary
hypertension. In general, theophylline is not considered an effective single agent for treating pulmonary hypertension.2
Pimobendan (Vetmedin—Boehringer Ingelheim Vetmedica) and levosimendan are dual mechanism drugs. They exert positive inotropic
effects associated with calcium sensitization as well as vasodilatory effects mediated by PDE3 inhibition. Clinically, pimobendan
has been shown to improve pulmonary hypertension secondary to degenerative mitral valve disease (clinical class II).31 Pimobendan has not been well-studied as a single agent therapy in dogs with other clinical classes of pulmonary hypertension
and is not considered an effective therapy for those dogs with pulmonary hypertension for any clinical class other than II.2