Page 96 - Small Animal Internal Medicine, 6th Edition

68 PART I Cardiovascular System Disorders

hyperkalemia (especially when used with a potassium- tolerated. It may also slow renal function deterioration in
sparing diuretic or potassium supplement). Angiotensin cats with kidney disease.
VetBooks.ir II is important in mediating renal efferent arteriolar con- Other Angiotensin-Converting
striction, which maintains glomerular filtration when renal
Enzyme Inhibitors
blood flow decreases. As long as cardiac output and renal
perfusion improve with therapy, renal function is usually Other ACEIs used in animals with heart failure have included
maintained. Poor glomerular filtration is more likely to ramipril, imidapril, lisinopril, and captopril. Ramipril is
result with overdiuresis, excess vasodilation, or severe rapidly absorbed and converted to ramiprilat, although bio-
myocardial dysfunction. Measurement of serum creatinine availability is fairly low (similar to benazepril). Ramipril pro-
and electrolytes is recommended within 1 week of initiat- duces good ACE inhibition within 1-2 hours; with high
ing therapy and periodically thereafter. Azotemia is first affinity for ACE, its ACEI effect can last ~24 hours despite
addressed by decreasing the diuretic dosage. If necessary, rapid clearance of free ramiprilat. Ramipril’s pharmacoki-
the ACEI dosage is decreased or discontinued. Hypotension netic properties are not significantly altered by moderate
can usually be avoided by starting with low initial doses. renal dysfunction. Imidapril also is comparable to enalapril
Other adverse effects reported in people include rash, pru- and benazepril in efficacy. It appears to have a longer half-
ritus, impairment of taste, proteinuria, cough, and neutro- life, about 18-20 hours, in dogs. Elimination of both ramipril
penia. The mechanism of ACEI-induced cough in people and imidapril is about 40% through the kidney and 60% by
is unclear but may involve inhibition of endogenous bra- the liver. Captopril, the first ACEI used clinically, contains a
dykinin degradation or may be associated with increased sulfhydryl group, in contrast to enalapril and others.
NO generation. NO has an inflammatory effect on bronchial Although disulfide metabolites can act as free radical scav-
epithelial cells. engers, the clinical significance of this for animals in heart
failure is unclear. Captopril is rarely used as it requires more
Enalapril frequent dosing. Hemodynamic effects peak in 1 to 2 hours
Enalapril is about 20% to 40% bioavailable; administration after oral administration and last less than 4 hours in dogs.
with food does not reduce its bioavailability. It is hydrolyzed Captopril is excreted in the urine. Lisinopril is a lysine analog
in the liver to enalaprilat, its most active form. Peak ACE- of enalaprilat with direct ACE-inhibiting effects. Its bioavail-
inhibiting activity occurs within 4 to 6 hours in dogs. Dura- ability is between 25% and 50%, and absorption is not
tion of action is 12 to 14 hours, and effects are minimal by affected by feeding. The time to peak effect is 6 to 8 hours.
24 hours at the recommended once-daily dose. Enalapril The duration of ACE inhibition appears long, but more spe-
often is given once daily initially but usually is increased to cific information in animals is lacking. Once-daily adminis-
every 12 hours in dogs being treated for CHF. In cats, tration has been tried with apparent effectiveness.
maximal activity occurs within 2 to 4 hours after an oral dose
of either 0.25 or 0.5 mg/kg; some ACE inhibition (50% of Angiotensin Receptor Blockers
control) persists for 2 to 3 days. Enalapril and its active The angiotensin receptor blockers (ARBs) are drugs that
metabolite are excreted in the urine. Renal failure and severe directly block type I angiotensin II receptors rather than
CHF prolong its half-life, so reduced doses or use of benaz- reduce the production of angiotensin II. The ARB agents
epril instead are recommended in such patients. Severe liver sometimes are called “sartans” (valsartan, losartan, telmisar-
dysfunction will interfere with the conversion of the prodrug tan, etc.). In experimental models of myocardial ischemia
to the active enalaprilat. Injectable enalaprilat is also avail- and heart failure, ARB treatment has reduced ventricular
able, but sparse veterinary data exist on its use; this form is remodeling, fibrosis, and dysfunction, as does ACEI. Some
not well absorbed orally. experimental evidence suggests the combination of an ARB
with an ACEI might reduce ventricular remodeling to a
Benazepril greater degree than with either agent alone. However, their
Benazepril is metabolized to its active form, benazeprilat. combined use is not advocated in people with heart failure.
Only about 40% is absorbed when administered orally, but Clinical experience with ARB use in dogs and cats with CHF
feeding does not affect absorption. After oral administration, is slim, although some studies are underway. Whether, or in
peak ACE inhibition occurs within 2 hours in dogs and cats; what situations, an ARB instead of an ACEI (or possibly both
its effect can last more than 24 hours. In cats doses of 0.25 together) would be most effective in the setting of CHF in
to 0.5 mg/kg result in 100% inhibition of ACE, which is dogs and cats is not clear.
maintained at greater than 90% for 24 hours and tapers off A new combination drug for heart failure in people
to about 80% by 36 hours. Benazepril has an initial half-life (Entresto, Novartis) incorporates the ARB valsartan with
of 2.4 hours and terminal half-life of about 29 hours in cats. sacubitril, an inhibitor of neprilysin (the enzyme that
Repeated doses produce moderate increases in drug plasma degrades natriuretic peptides). In people with CHF and
concentration. Benazepril is a preferred ACEI for animals reduced myocardial contractility, this combination drug has
with renal disease. This drug is eliminated equally in urine reduced mortality and hospitalization, compared with enala-
and bile in dogs. In cats about 85% of the drug is excreted pril. Clinical experience with this agent in dogs (and cats)
in the feces and only 15% in urine. The drug is generally well with CHF is limited so far.