Vasodilator drugs can be categorized as afterload reducers or preload reducers. Afterload is reduced by dilation of arterioles (ie, resistance vessels), whereas preload is reduced by dilation of veins (ie, capacitance vessels). Arterial dilators are administered in treatment of systemic hypertension in dogs and cats and as adjunctive treatment for congestive heart failure (CHF) in dogs, particularly when CHF is secondary to degenerative mitral valve disease.
Arterial Dilators
Hydralazine is an arteriolar vasodilator, the mechanism of action of which is not clearly elucidated. It directly relaxes the vascular smooth muscle in systemic arterioles by inhibiting calcium fluxes into the cell or by increasing local prostacyclin concentrations. Hydralazine has no effect on systemic venous tone. It is bound to smooth muscle, which results in a biological half-life longer than plasma half-life. Hydralazine is well absorbed after administration PO but (in humans) is subject to first-pass metabolism.
Toxic effects of hydralazine may be notable and related to its potency as an arterial dilator leading to hypotension. Its potency results in good to profound improvement in most animals in which it is indicated, but it can also result in systemic hypotension.
The effective dosage range in dogs is 0.5–3 mg/kg, PO, every 12 hours. This dose must be titrated, starting with a low dose and titrating up to an effective clinical endpoint while monitoring for hypotension. Doses may need to be even lower when hydralazine is combined with other drugs that have arterial dilatory effects.
Calcium channel blockers as a class are considered vasodilators; however, individual agents have different relative potencies and additional effects. Calcium channel blockers are also class IV antiarrhythmics, negative inotropes (an adverse property), and positive lusitropes (drugs that improve relaxation of cardiomyocytes).
Amlodipine primarily affects the calcium channels in the small arterioles, leading to arterial dilation. Amlodipine is the only calcium channel blocker administered in veterinary medicine that has potent arterial dilatory effects with negligible effects on inotropy and conduction. The effects of amlodipine are similar to those of hydralazine, and it is administered for similar indications in dogs and cats. Amlodipine appears to be better tolerated by the GI tract.
The effective dosage range in dogs is 0.1–0.2 mg/kg, PO, every 12 hours, or 0.2–0.4 mg/kg, PO, every 24 hours. The effective dosage range in cats is 0.625–1.25 mg/cat, PO, every 12–24 hours. This dose must be titrated, starting with a low dose and titrating up to an effective clinical endpoint while monitoring for hypotension. Doses may need to be even lower when amlodipine is combined with other drugs that have arterial dilatory effects. In resistant systemic hypertension, doses at the higher end of the range are needed. In CHF in dogs, initial dosages should be at the lower end of the range and titrated to effect with appropriate monitoring.
Gingival hyperplasia has been reported as an adverse effect of amlodipine in both dogs and cats.
Arterial and Venous Dilators
Organic nitrates and nitrites relax both arterial and venous vascular smooth muscle via a complex series of events. At low concentrations, which are generally administered clinically, venous dilation predominates, and net systemic vascular resistance is usually not affected. Pharmacological effects occur rapidly. First-pass metabolism limits the use of these drugs to IV, sublingual, and topical (ointment) administration. Tolerance is a problem with sustained administration.
Nitroglycerin, an organic nitrate, relaxes vascular smooth muscle. However, the dosage of nitroglycerin administered clinically results in predominantly venous dilation and preload reduction. Nitroglycerin is indicated for acute (emergency) adjunctive treatment of CHF in dogs and cats; however, efficacy for this indication in these species is anecdotal. It is available for IV and sublingual use and as an ointment. The 2% ointment preparation is the most commonly administered; it is applied to the hairless portion of the animal's skin (abdomen or ear).
The dosage of nitroglycerin in dogs is 4–12 mg, topically, every 12 hours (maximum of 15 mg/dog per dose) for 1–2 days, and in cats, 2–4 mg/cat, topically, every 6–8 hours for 1–2 days.
The most prevalent adverse effect involves accidental exposure of veterinary personnel, which can be avoided by careful application and labeling of application sites.
Nitroprusside is one of the most potent vasodilators available. It is an organic nitrate and reduces preload (venous dilation) and afterload (arterial dilation) in a dose-dependent manner. Advantages of nitroprusside include potency, rapid onset of action, and short half-life. The main disadvantage is that it must be administered by IV constant-rate infusion (1–10 mcg/kg/min), with appropriate, typically invasive, blood pressure monitoring.
Nitroprusside is indicated in dogs for emergency reduction of blood pressure in a hypertensive crisis and for immediate afterload reduction (severe, life-threatening CHF). Nitroprusside should only be administered for 48–72 hours because of buildup of its toxic metabolite, cyanide.
Prazosin is an alpha1-adrenergic receptor antagonist and thus considered to be a mixed vasodilator. It is effective when administered PO, but tolerance develops rapidly. It also undergoes pronounced first-pass metabolism. Prazosin is rarely administered clinically in small animals to treat primary cardiac disease.
The dosage in dogs and cats is 0.5–2 mg/animal, PO, every 8–12 hours, or 0.07 mg/kg, PO, every 8–12 hours.
Phosphodiesterase 5 Inhibitor
Sildenafil is an orally active phosphodiesterase 5 inhibitor. Phosphodiesterase 5 (PDE5) is found in a relatively high concentration in the lungs and the corpus cavernosum of the penis.
In dogs, pulmonary hypertension is a clinically important disease with high morbidity and mortality rates. It is typically a sequela of another disease process and thus requires a balanced therapeutic approach that targets the underlying etiology as well as palliation of clinical signs. An important goal of treatment is to decrease pulmonary artery resistance.
Conventional systemic arteriolar dilators have no preferential effect on pulmonary vasculature and thus have no benefit and may worsen clinical signs attributable to pulmonary hypertension. Inhibition of PDE5 in the small arterioles of the lung leads to dilation that is greater than dilation of the systemic arterioles. With pulmonary hypertension in humans, PDE5 inhibitors improve both exercise tolerance and quality of life.
Sildenafil has been administered to dogs for adjunctive treatment of clinical signs related to pulmonary hypertension secondary to a variety of etiologies. Proof of efficacy remains predominantly anecdotal, although it does appear to be safe and well tolerated for this indication.
The typical starting dosage in dogs is 1 mg/kg, PO, every 8 hours, or 1–2 mg/kg, PO, every 12 hours. The reported dosage range is 1–3 mg/kg, PO, every 8–12 hours. Efficacy may be potentiated with coadministration of L-arginine at 250–500 mg/dog, PO, every 12 hours.
Adverse effects of sildenafil appear to be rare in dogs, but anecdotally, systemic hypotension is possible. There are no reported drug interactions, and published reports have documented use of sildenafil in dogs in combination with many other medications, including conventional heart failure medications (eg, diuretics, ACE inhibitors, pimobendan), with no recognized adverse effects.
