In the pathogenesis of CHF, the proteolytic enzyme renin is released by the kidneys and acts on angiotensinogen, which is produced by the liver and distributed in the blood, to produce angiotensin I. The formation of angiotensin II from angiotensin I occurs via the action of ACE. Angiotensin II causes retention of Na+ and water, in part via stimulation of the synthesis and release of aldosterone by the adrenal cortex. Angiotensin II also causes vasoconstriction, thus increasing systemic vascular resistance. ACE also results in degradation of bradykinin and, thus, ACE inhibitors lead to increased concentrations of bradykinin that contribute to their vasodilatory effects.
By inhibiting the formation of angiotensin II, ACE inhibitors prevent vasoconstriction and decrease retention of Na+ and water in animals with CHF. Angiotensin-converting enzyme inhibitors are balanced vasodilators, reducing both preload and afterload. The effects during CHF include decreased vascular resistance and cardiac filling pressures as well as increased cardiac output and exercise tolerance. However, ACE inhibitors have only a mild effect on afterload reduction and should not be administered as monotherapy in animals with severe systemic hypertension (> 160 mm Hg).
Preparations and Disposition of Angiotensin-converting Enzyme Inhibitors in Animals
Enalapril and benazepril are widely administered ACE inhibitors and are available in a variety of tablet sizes for oral administration. Compared with enalapril and benazepril, captopril has a greater propensity for GI adverse effects and a shorter half-life in dogs, necessitating more frequent dosing; thus, its use has fallen out of favor. A wide variety of other ACE inhibitors (eg, lisinopril, ramipril) are sometimes administered in veterinary medicine. Choice in part is often related to drug availability, cost, and access to canine and feline pharmacokinetic and pharmacodynamic data.
After absorption from the GI tract, enalapril is converted in the liver to the active metabolite enalaprilat. Oral bioavailability is ~60%. Serum concentration of enalaprilat peaks in 3–4 hours. The half-life is ~11 hours, and effects last 12–14 hours, indicating the need for dosing intervals of every 12 hours if 24-hour suppression of angiotensin-converting enzyme is desired. Excretion of enalapril and enalaprilat is primarily renal; therefore, the half-life of enalapril (and enalaprilat) is increased in animals with severe CHF (decreased renal perfusion) or renal failure, and dose reduction may be warranted.
Like enalapril, benazepril is a prodrug converted to its main active metabolite, benazeprilat, in the liver. Benazepril is well absorbed in dogs, and oral bioavailability increases by ~35% with repeated dosing. After administration of oral benazepril, benazeprilat concentration peaks in plasma within 1–3 hours and is rapidly distributed.
Benazeprilat is excreted approximately equally in the bile and urine in dogs. The terminal half-life is ~3.5 hours. This combined excretion may allow better dosing control in animals with preexisting renal insufficiency; however, benazepril is no more renal protective than any other ACE inhibitor at equipotent doses.
When benazepril is administered longterm, doses from 0.25–1 mg/kg produce indistinguishable effects at the time of peak effect (2 hours after PO administration) and at trough effect (24 hours after PO administration). Thus, dosing intervals may be as long as 24 hours, but benazepril is often dosed every 12 hours to ensure continuous ACE inhibitor activity throughout the day.
Drug Interactions and Toxicity of Angiotensin-converting Enzyme Inhibitors in Animals
Hypotension may develop with concurrent use of ACE inhibitors and other vasodilators (eg, amlodipine) or diuretics. Concurrent use of potassium-sparing diuretics (eg, spironolactone) may cause hyperkalemia. Enalapril and benazepril appear safe when administered concomitantly with furosemide, pimobendan, digoxin, antiarrhythmics Antiarrhythmics for Use in Animals Antiarrhythmics are typically classified according to their predominant electrophysiologic effect on myocardial cells. However, the electrophysiologic effects of some agents span more than one... read more , beta-adrenergic receptor antagonists, bronchodilators, and cough suppressants.
ACE inhibitors have a good safety profile and have been administered safely in combination with other cardiovascular drugs (including diuretics and pimobendan). However, azotemia may develop, and monitoring of BUN and creatinine (with possible dosage adjustments) is warranted. This possible complication is the result of the partial loss of renal autoregulation of blood flow mediated by angiotensin II.
Concurrent use of ACE inhibitors and NSAIDs has the potential to induce acute kidney injury (AKI), and diligent monitoring is necessary. Additionally, ACE inhibitors are less effective at reducing systemic blood pressure when combined with NSAIDs.
Other possible, albeit rare, adverse effects include GI disturbances (anorexia, vomiting, diarrhea); syncope due to hypotension; weakness; and ataxia. Preexisting renal disease and dehydration increase the risk of adverse effects; thus, animals with these predisposing conditions should be monitored closely. Cough is a common adverse effect of this class of drugs in humans but is not a recognized problem in dogs or cats.
Clinical Use of Angiotensin-converting Enzyme Inhibitors in Animals
ACE inhibitors are indicated in treatment of dogs and cats for CHF stemming from a wide variety of diseases. However, there is no proof that ACE inhibitors delay the onset of CHF in animals with subclinical cardiac disease.
ACE inhibitors are also frequently administered (typically in combination with other arterial dilators) to manage systemic hypertension in dogs and cats. Somewhat paradoxically, ACE inhibitors such as benazepril have been shown to be beneficial in treatment of certain forms of renal disease.
Enalapril is approved in the US to treat CHF secondary to dilated cardiomyopathy (DCM) and myxomatous mitral valve degeneration (MMVD) in dogs. Benazepril is approved in several countries besides the US to treat CHF in dogs.
The recommended dosage of enalapril and benazepril for treatment of CHF in dogs is 0.25–0.5 mg/kg, PO, every 12–24 hours. However, based on the half-life, if continuous ACE inhibition is desired and well tolerated, then a 12-hour dosing interval is recommended. The recommended dosage for adjunctive treatment of CHF in cats is 0.25–0.5 mg/kg, PO, every 12 hours, or 0.5 mg/kg, PO, every 24 hours. Similar doses are administered when enalapril or benazepril is used to treat systemic hypertension. However, enalapril and benazepril have only modest arterial vasodilatory effects and should not be administered as monotherapy in animals with severe systemic hypertension (systolic blood pressure > 160–180 mm Hg).
In general, regardless of clinical indication, starting at the lower dose range and increasing to maximal dose with monitoring of renal function, serum potassium, and systemic blood pressure is recommended. Higher doses of benazepril, if tolerated, may be indicated to treat some forms of renal disease (eg, protein-losing glomerulopathy).
ACE inhibitors are administered in horses with severe valvular disease Valvular Disease The following mechanisms can result in abnormalities of the cardiovascular system: the cardiac valves fail to close or open properly (valvular disease) the heart muscle pumps inefficiently or... read more . Benazepril in horses is the most effective drug for inhibition of serum angiotensin-converting enzyme activity. Research suggests that oral enalapril is likely poorly absorbed in horses and furthermore should not be used. Quinapril is an additional ACE inhibitor, which has been demonstrated to change stroke volume and cardiac output in horses.