Angiotensin-Converting Enzyme Inhibitors in Veterinary Medicine

Abstract

Angiotensin-converting enzyme (ACE) inhibitors represent one of the most commonly used categories of drugs in canine and feline medicine. ACE inhibitors currently approved for use in veterinary medicine are benazepril, enalapril, imidapril and ramipril. They are all pro-drugs administered by oral route. A physiologically based model taking into account the saturable binding to ACE has been developed for pharmacokinetic analysis. The bioavailability of the active compounds from their respective pro-drug is low. The active metabolites are eliminated by renal, hepatorenal or biliary excretion, according to the drug. The elimination half-life of the free fraction of the active compounds is very short (ranging from approximately 10 min to 2 h). ACE inhibitors are generally well tolerated. Benazepril, enalapril, imidapril and ramipril are approved for dogs with chronic heart failure (CHF). The efficacy of ACE inhibitors has been convincingly demonstrated in dogs with CHF, especially in those with chronic valvular disease. In such clinical settings, ACE inhibitors improve hemodynamics and clinical signs, and increase survival time. In cats with cardiovascular disease, little information is available except for reports of some benefit in cats with hypertrophic cardiomyopathy in two non-controlled investigations. ACE inhibitors have also a mild to moderate hypotensive effect. There is also evidence to recommend ACE inhibitors in dogs and cats with chronic renal failure (CRF). They decrease the glomerular capillary pressure, have antiproteinuric effects, tend to delay the progression of CRF and to limit the extent of renal lesions.

Chronobiology and Pharmacologic Modulation of the Renin–Angiotensin–Aldosterone System in Dogs: What Have We Learned?

“…The pro-inflammatory and pro-fibrotic effects of the RAAS are also mediated by ALD, which further promotes insulin resistance and vascular remodeling (Martinez 2010;Cascella et al 2010). While the relation of systemic hypertension (HT) to the development of CKD has not been extensively documented in small animals, there is reasonable evidence to justify extrapolation of these considerations from human to dog patients (Lefebvre et al 2007). Elevations of AII and ALD systemic levels have been associated with poorer prognosis and increased mortality in human patients with CHF.…”

“…Inhibition of the RAAS, as part of a global therapeutic scheme to decrease AII and ALD exposure, and lower BP for preventing or delaying end-organ damage has proven to be effective in human and canine CHF (Chobanian et al 2003;Lefebvre et al 2007). Among RAAS inhibitors, two classes of drug directly target AII through complementary mode of actions: (i) ACE inhibitors prevent the formation of AII and the degradation of bradykinin, which increases the stimulation of nitric oxide and has positive effects on endothelial function, while (ii) angiotensin receptor blockers (ARBs) selectively antagonize AII at AT 1 receptors.…”

“…By decreasing systemic vascular resistance, ACE inhibitors are known to improve cardiac hemodynamics and exercise capacity in human and dog patients (Levine et al 1984;Uretsky et al 1988;Lefebvre et al 2007). Benazepril, enalapril, imidapril, and ramipril are currently approved for use in dogs with CHF.…”

“…Benazepril, enalapril, imidapril, and ramipril are currently approved for use in dogs with CHF. Benazepril hydrochloride (Fortekor ® ; Novartis Animal Health, Basel, Switzerland) is a nonsulfhydryl prodrug which is converted in vivo by esterases into its active metabolite, benazeprilat, a highly potent and selective inhibitor of ACE (Webb 1990) with well-documented effectiveness in symptomatic canine CHF (King et al 1995;Lefebvre et al 2007). In the BENCH (BENazepril in Canine Heart Disease) Study Group (1999), the mean survival time of benazepril-treated dogs with mild to moderate CHF was improved by a factor of 2.7, as compared with the placebo group (428 vs. 158 days, p < 0.05).…”

The Protein Metabolism in Small Animals With Chronic Renal Failure and Its Correction

“…Enapril as other angiotensin-converting enzyme inhibitors decreases the glomerular capillary pressure, has antiproteinuric effect, tends to delay the progression of CRF and to limit the extent of renal lesions [15].…”