Angiotensin-converting Enzyme Inhibitors
Angiotensin-converting enzyme (ACE) inhibitors are widely used to treat chronic CHF in dogs and cats. 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 through the action of ACE. Angiotensin II causes retention of Na+ and water, in part through 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 levels of bradykinin that contribute to their vasodilatory effects. By inhibiting the formation of angiotensin II, ACE inhibitors prevent vasoconstriction and reduce retention of Na+ and water in animals with CHF. ACE inhibitors are balanced vasodilators, reducing both preload and afterload. The effects during CHF include decreased vascular resistance and cardiac filling pressures and increased cardiac output and exercise tolerance. However, ACE inhibitors have only a mild effect on afterload reduction and should not be used as monotherapy in animals with severe systemic hypertension (>160 mmHg).
Enalapril and benazepril are widely used 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, lisonopril, ramipril) are sometimes used in veterinary medicine. Choice in part is often related to drug availability, cost, and availability of 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 hr. The half-life is ~11 hr, and effects last 12–14 hr, indicating the need for dosing intervals of every 12 hr if 24-hr suppression of ACE is desired. Excretion of enalapril and enalaprilat is primarily renal; therefore, the half-life of enalapril/enalaprilat is increased in animals with severe CHF (reduced 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 hr and is rapidly distributed. Benazeprilat is excreted approximately equally in the bile and urine in dogs. The terminal half-life is ~3.5 hr. 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, dosages from 0.25–1 mg/kg produce indistinguishable effects at the time of peak effect (2 hr after PO administration) and at trough effect (24 hr after PO administration); thus, dosing intervals may be as long as 24 hr, but benazepril is often dosed every 12 hr to ensure continuous ACE throughout the day.
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 used concomitantly with furosemide, pimobendan, digoxin, antiarrhythmics, β-blockers, bronchodilators, and cough suppressants. However, it has been suggested that concurrent use of NSAIDs may increase risk of adverse effects.
ACE inhibitors have a good safety profile and have been used 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. 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 people but is not a recognized problem in dogs or cats.
ACE inhibitors are indicated in treatment of CHF in dogs and cats stemming from a wide variety of diseases. However, there is no proof that ACE inhibitors may delay the onset of CHF in asymptomatic animals with cardiac disease. ACE inhibitors are also frequently used (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 some forms of renal disease. Enalapril is approved in the USA to treat CHF secondary to DCM and MMVD in dogs. Benazepril is approved in several countries other than the USA 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, once to twice daily. However, based on the half-life, if continuous ACE inhibition is desired and well tolerated, then a 12-hr dosing interval is recommended. The recommended dosage for adjunctive treatment of CHF in cats is 0.25–0.5 mg/kg, PO, bid, or 0.5 mg/kg/day, PO. Similar doses are used when enalapril or benazepril is used to treat systemic hypertension. However, enalapril and benazepril have only modest arterial vasodilatory effects and should not be used as monotherapy in animals with severe systemic hypertension (systolic blood pressure >160–180 mmHg). 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).