Angiotensin-Converting Enzyme Inhibitors

By | 2011-12-12

ACE Inhibitors

Despite their symptomatic benefits, diuretics should not be used as monotherapy in the management of congestive heart failure because they further activate the renin-angiotensin system. Drugs designed to inhibit angiotensin-converting enzyme block the formation of AT II, promote an increase in the circulating levels of bradykinin, and may temporarily reduce circulating aldosterone levels. Although angiotensin-converting enzyme inhibitors are frequendy categorized as balanced vasodilators, it appears likely that their beneficial effect on mortality is not mediated purely by hemodynamic alterations. They are relatively weak vasodilators compared with direct-acting arterial vasodilators such as hydralazine, and their ability to promote diuresis is much overshadowed by the less expensive loop diuretics. Rather, it is believed that angiotensin-converting enzyme inhibitors reduce mortality through their ability to blunt the detrimental consequences associated with long-standing activation of the RAS. Their early success has helped spearhead the current pharmacologic trend toward neurohormonal antagonism.

Activation of the neurohormonal cascade often begins with detection of arterial underfilling by mechanoreceptors in the carotid sinus and kidney. Regardless of whether this relative “hypotension” occurs secondary to low-output heart failure, severe mitral insufficiency, or profound hypovolemia, the common end-point is activation of the sympathetic nervous system and RAS. Additional activators of the renin-angiotensin-aldosterone system are reduced sodium delivery to the macula densa and sympathetic stimulation. Release of the protease renin from the juxtaglomerular apparatus promotes conversion of angiotensinogen to angiotensin I. Angiotensin-converting enzyme cleaves the C-terminal dipeptide from angiotensin I, thereby forming the octapeptide angiotensin II. In addition to being a potent vasoconstrictor, AT II has several other properties: (1) it is a primary secretagogue for aldosterone; (2) it potentiates presynaptic norepinephrine release; (3) it stimulates the release of antidiuretic hormone (vasopressin); (4) it promotes renal tubular sodium resorption; and (5) it has been linked to cardiomyocyte necrosis, apoptosis, and progression of ventricular fibrosis. Angiotensin-converting enzyme is also capable of cleaving the C-terminal dipeptide from bradykinin, therefore it appears to be a regulator of vasoconstrictive/ sodium retentive and vasodilative/natriuretic mechanisms. Although tissue angiotensin-converting enzyme and additional enzymatic pathways (e.g., chymase, cathepsin G, tonin, and tissue plasminogen activator) capable of producing AT II have been identified, their significance is unknown at this time.

ACE-inhibiting compounds are numerous and vary in their chemical structure, potency, bioavailability, and route of elimination. Most angiotensin-converting enzyme inhibitors, excluding captopril and lisinopril, are administered in the form of prodrugs that require conversion to their active form by hepatic metabolism. Enalapril requires conversion to enalaprilat, and benazepril is metabolized to benazeprilat. Although claims have been made that some formulations produce more profound angiotensin-converting enzyme inhibition, prolonged periods of efficacy, or superior tissue angiotensin-converting enzyme inhibition, the importance of these characteristics is unclear in naturally occurring heart failure.

The degree of angiotensin-converting enzyme inhibition and the duration of action of several agents, including benazepril, captopril, enalapril, lisinopril, and ramipril, have been evaluated in normal dogs. Hamlin and Nakayama documented that benazepril, enalapril, lisinopril, and ramipril were able to achieve similar degrees of angiotensin-converting enzyme inhibition after drug administration (about 75% inhibition at 1.5 hours and about 50% inhibition through 12 hours). Enalapril, lisinopril, and ramipril continued to display significant activity (about 25% inhibition) beyond 24 hours. These researchers also found that captopril was unable to reduce angiotensin-converting enzyme activity substantially, compared with control, beyond the 1 -5-hour sample. Whether captopril’s inability to suppress angiotensin-converting enzyme activity was a consequence of sample handling or merely an inability to suppress circulating versus tissue angiotensin-converting enzyme is uncertain. Evaluations of enalapril and benazepril in normal cats have identified maxima] angiotensin-converting enzyme inhibition of 48% and 98%, respectively, after single-dose administration. Benazepril was reported to show greater than 90% angiotensin-converting enzyme inhibition beyond 24 hours.

Excretion of the angiotensin-converting enzyme inhibitors is primarily via the kidneys, although benazepril appears to undergo significant biliary excretion in companion animals (about 50% in dogs and about 85% in cats). When angiotensin-converting enzyme inhibitors have been prescribed for patients with mild renal insufficiency, the recommendation historically has been to reduce both the dosage and frequency interval by approximately 50%. Administration of enalapril to dogs with experimental mild renal insufficiency is associated with a significant increase in the area under the curve (AUC) for the active metabolite enalaprilat. After benazepril was administered to the same dogs, no significant increase was seen in the AUC for benazeprilat. Whether concurrent cardiac disease, with its relatively depressed cardiac output, would be associated with impaired benazeprilat excretion is unclear. Current trends using “standard” doses of enalapril to treat glomerulonephritis and renal insufficiency are difficult to extrapolate to patients with heart failure and renal insufficiency because of their limited ability to increase cardiac output in the face of a reduced rate of glomerular filtration. In summary, the merits and limitations of the different formulations are unknown, and only the angiotensin-converting enzyme inhibitor enalapril has been specifically approved in the United States for the treatment of heart failure in dogs. The hypothesized improved safety of using benazepril rather than enalapril in patients with renal insufficiency has not been clinically evaluated in companion animals with cardiac disease.

Enalapril Enalapril is one of the few drugs that has been closely evaluated in dogs with naturally occurring congestive heart failure. The first reported placebo-controlled studies in dogs were short-term investigations, the Invasive Multicenter Prospective Veterinary Evaluation of Enalapril study (IMPROVE; 21 days) and the Cooperative Veterinary Enalapril study (COVE; 28 days), both published in 1995. These studies enrolled dogs with mitral valve insufficiency or dilated cardiomyopathy (DCM) to evaluate the hemodynamic (IMPROVE) and clinical (COVE) benefits of enalapril. The drug decreased pulmonary capillary wedge pressures in dogs with dilated cardiomyopathy and improved the heart failure class, pulmonary edema scores, and overall evaluation for both groups of dogs with heart failure. The benefits of these short-term studies were more pronounced for dogs with dilated cardiomyopathy than for those with mitral valve insufficiency. The COVE investigators found that twice daily oral administration of enalapril (0.5 mg/kg) appeared to promote more significant improvements than once daily therapy. The LIVE study group followed a subpopulation of dogs from the two short-term studies to evaluate the long-term effects of enalapril administration. These researchers found that dogs treated with enalapril were able to continue the study for longer than those receiving placebo (157.5 versus 77 days, P = 0.006). In contrast to the results of the short-term studies, the beneficial effect was more prominent in dogs with mitral valve insufficiency (P = 0.041) than in those with dilated cardiomyopathy (P = 0.06). An additional study supporting the benefits of angiotensin-converting enzyme inhibitor administration to dogs with heart failure found that enalapril significandy increased the exercise tolerance of dogs with experimentally created mitral insufficiency.

Despite these symptomatic benefits, the hope that early institution of angiotensin-converting enzyme inhibition will delay the onset of heart failure may go unfulfilled. To date, enalapril has been unable to delay the onset of heart failure in asymptomatic cases of mitral insufficiency. Whether angiotensin-converting enzyme inhibitors can reduce mortality in dogs or cats with heart failure has yet to be determined; even so, preliminary evidence reported in 2003 looks supportive, although not conclusive, for cats with diastolic dysfunction.

Benazepril Similar to enalapril, benazepril is a prodrug that must undergo hepatic metabolism to produce the active compound, benazeprilat. Oral administration of benazepril has produced variable and conflicting degrees of angiotensin-converting enzyme inhibition. An initial study reported that peak plasma benazeprilat concentrations were achieved 2 hours after oral administration. The percentage of angiotensin-converting enzyme inhibition after a single dose of 0.5 mg/kg of benazepril administered to normal dogs was 99.7% after 2 hours, 95.2% after 12 hours, and 87.3% after 24 hours. Similar results were found for the same intervals at doses of 0.25 mg/kg (97.8%, 89.2%, and 75.7%) and 1 mg/kg (99.1%, 94.0%, and 83.1%). Maximal angiotensin-converting enzyme inhibition after 15 doses was attained in dogs receiving 0.25 mg/kg of benazepril once daily (96.9% at 2 hours, 92.5% at 12 hours, and 83.6% at 24 hours). A second study, which also evaluated a single dose of 0.5 mg/kg of benazepril in normal dogs, showed angiotensin-converting enzyme inhibition of 81% at 1.5 hours, 37% at 12 hours, and 10.3% at 24 hours. Prolonged administration of benazepril was not evaluated. A final study, in which 0.5 mg/kg of benazepril was administered orally once daily to dogs with mitral insufficiency, showed angiotensin-converting enzyme inhibition to be 33.3% at 1 week, 28% at 2 weeks, and 42.7% at 4 weeks.

Based on these conflicting results, the current dosing recommendations are broad (0.25 to 0.5 mg/kg given orally once or twice daily). Whether benazepril is clinically more effective or safer than enalapril for dogs and cats with congestive heart failure remains unclear.

Adverse effects The mechanism by which angiotensin-converting enzyme inhibitors exert their beneficial properties (e.g., inhibition of angiotensin II production) also lends to the potential for adverse consequences. Although infrequendy encountered, complications may include systemic hypotension, azotemia, and hyperkalemia.

ACE inhibitors reduce systemic vascular resistance by decreasing circulating levels of angiotensin II and increasing circulating levels of bradykinin. In patients with severe heart failure in which an increase in cardiac output is unable to sustain systemic blood pressure, symptomatic hypotension may develop. Although this complication is infrequent, its likelihood increases with concomitant overzealous use of diuretics. Unfortunately, the clinical signs associated with severe low-output heart failure and systemic hypotension are very similar (e.g., weakness, exercise intolerance, and possibly stupor), a fact that lends emphasis to an important point: if a patient appears refractory to medical management, the blood pressure should be evaluated before more aggressive measures to combat heart failure are instituted.

A second adverse effect attributed to angiotensin-converting enzyme inhibitors’ unique ability to decrease angiotensin II production is a reduction in the glomerular filtration rate (GFR) and the development of azotemia. The glomerular filtration rate is determined by the glomerular capillary pressure (GCP). Based on the knowledge that pressure is equal to the product of flow and resistance (P = Q x R), it can be ascertained that the glomerular filtration rate ultimately is determined by renal plasma flow and the degree of efferent arteriolar vasoconstric-tion. In cases of heart failure in which renal plasma flow is diminished, the glomerular filtration rate is supported by the ability of ATII to constrict the efferent renal arte-riole. angiotensin-converting enzyme inhibitors’ ability to depress production of AT II promotes efferent renal arteriolar vasodilatation and hence a reduction in the GFR. The failing heart cannot further increase cardiac output, and an acute bout of azotemia may subsequendy develop. A recent study evaluating early institution of enalapril therapy in dogs with compensated mitral valve insufficiency found that dogs allocated to an angiotensin-converting enzyme inhibitor were not at a more significant risk of developing azotemia compared with dogs receiving placebo. In the authors’ experience, mild increases in blood urea nitrogen (BUN) and creatinine occur frequendy after institution of therapy with an angiotensin-converting enzyme inhibitor and furosemide. However, the development of severe azotemia, necessitating discontinuation of the angiotensin-converting enzyme inhibitor or a reduction in its dosage, occurs infrequently. This complication seems to occur most often in patients with severe heart failure that require aggressive diuretic administration to control congestive signs. Prior to institution of enalapril therapy, the authors evaluate the baseline biochemical parameters and perform a second measurement of the BUN, creatinine, and electrolytes 5 to 7 days after the start of treatment. If patients become anorectic or develop gastrointestinal signs during this time, we instruct the owners to discontinue all drugs and immediately present the animal for veterinary attention.

Hyperkalemia may be encountered during therapy with angiotensin-converting enzyme inhibitors as the result of a reduction in the glomerular filtration rate and a decline in circulating aldosterone levels. In the absence of aldosterone, sodium loss is favored and potassium levels rise. This complication appears to occur infrequently, presumably because most of the potent diuretics have potassium-wasting properties and tend to prevent the development of hyperkalemia. The authors have rarely encountered an increase in potassium that necessitated a dosage reduction for or discontinuation of an angiotensin-converting enzyme inhibitor. There is concern that the addition of spironolactone may potentiate hyperkalemia, therefore periodic electrolyte monitoring is prudent in patients receiving an angiotensin-converting enzyme inhibitor and a potassium-sparing diuretic.

Drug interactions Because aspirin inhibits cyclooxygenase and decreases prostaglandin formation, some have questioned whether administration of aspirin may negate some of the beneficial vasodilative properties exerted by angiotensin-converting enzyme inhibitors. An additional concern is that aspirin’s ability to reduce renal prostaglandin formation may worsen the angiotensin-converting enzyme inhibitor-induced reduction in the GFR. A recent retrospective analysis of six long-term, randomized trials of angiotensin-converting enzyme inhibitors found that aspirin did not significantly alter the beneficial effects of angiotensin-converting enzyme inhibitors in CHE Whether other commonly prescribed, non-steroidal anti-inflammatory agents blunt the potentially beneficial vasodilative properties of angiotensin-converting enzyme inhibitors is uncertain.