Vasoactive Drugs

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 biologic half-life longer than plasma half-life. Hydralazine is well absorbed after administration PO but (in people) is subject to first-pass metabolism. The incidence of toxicity caused by hydralazine may be significant and related to its potency as an arterial dilator leading to hypotension. The potency of hydralazine can be both beneficial and detrimental: it 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, bid. 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, but 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 used 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 used 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, bid, or 0.2–0.4 mg/kg/day, PO. The effective dosage range in cats is 0.625–1.25 mg/cat, PO, once to twice daily. 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 dogs and cats.

Organic nitrates and nitrites relax both arterial and venous vascular smooth muscle through a complex series of events. At low concentrations, which are generally used clinically, venous dilation predominates, and net systemic vascular resistance is usually not affected. Pharmacologic 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 used 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 (1 in. = 15 mg) is the most commonly used; it is applied to the hairless portion of the animal's skin (abdomen or ear). The dosage in dogs is 4–12 mg, topically, bid (maximum of 15 mg/dog per dose) for 1–2 days, and in cats, 2–4 mg/cat, topically, every 6–8 hr 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 CRI (1–10 mcg/kg/min, IV), 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 used for 48–72 hr because of buildup of its toxic metabolite, cyanide.

Prazosin is an α₁-adrenergic receptor blocker and thus considered to be a mixed vasodilator. It is effective when given PO, but tolerance develops rapidly. It also undergoes significant first-pass metabolism. Prazosin is rarely used clinically in small animals to treat primary cardiac disease. The dosage in dogs and cats is 0.5–2 mg per animal, PO, bid-tid, or 0.07 mg/kg, PO, bid-tid.

Sildenafil is an orally active phosphodiesterase 5 inhibitor. Phosphodiesterase 5 (PDE 5) 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 therapy is to reduce 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 PDE 5 in the small arterioles of the lung leads to dilation that is more significant than dilation of the systemic arterioles. In people with pulmonary hypertension, PDE 5 inhibitors improve both exercise tolerance and quality of life. Sildenafil has been used in 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, tid, or 1–2 mg/kg, PO, bid. The reported dosage range is 1–3 mg/kg, PO, bid-tid. Efficacy may be potentiated with coadministration of L-arginine at 250–500 mg/dog, PO, bid. 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.