A practical guide to antiproteinuric drugs in dogs - Veterinary Medicine
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A practical guide to antiproteinuric drugs in dogs
Appropriately treating a dog with glomerular disease prolongs the dog's survival; however, knowing what drug at what dosage is appropriate isn't as clear. Fortunately, this internist lays out the case for administering ACE inhibitors and angiotensin II-receptor blockers—and offers a suggested treatment protocol.


VETERINARY MEDICINE


ACE INHIBITORS

Inhibition of ACE activity decreases serum concentrations of angiotensin II and aldosterone, thereby reducing both intraglomerular hydrostatic pressure and systemic blood pressure.11,12 ACE inhibition in people with chronic proteinuric nephropathies slows the decline in glomerular filtration rate, delays progression to end-stage renal disease, and prolongs overall survival time, independent of the severity of initial proteinuria.6-8 Administering enalapril or benazepril to dogs with naturally occurring idiopathic glomerular disease9 or azotemic chronic kidney disease of undetermined etiology13 reduces the UPC ratio and stabilizes or improves renal disease, respectively, as compared with dogs receiving placebos.

Enalapril

Enalapril is the ACE inhibitor most commonly prescribed to dogs in the United States. Maximal reduction in proteinuria is desirable, so I recommend initial administration of the maximum recommended dosage (0.5 mg/kg orally b.i.d.) in nonazotemic dogs with serum creatinine concentrations < 3 or 4 mg/dl. However, because ACE inhibitors reduce the glomerular filtration rate, when treating dogs with serum creatinine concentrations between 3 and 5 mg/dl, it is prudent to initiate therapy at a lower dosage (0.25 mg/kg orally b.i.d.) and recheck serum creatinine concentrations within four to seven days. If the azotemia has not worsened, increase the enalapril dosage to the maximum recommended dose (0.5 mg/kg orally b.i.d.) and recheck serum creatinine concentrations again in four to seven days.

Adverse effects of enalapril—and ACE inhibitors, in general—in people include hyperkalemia and gastrointestinal disturbances.14,15 Although these have not been reported in published studies in dogs, I have occasionally noted both of these adverse events in dogs with glomerular disease that have been administered standard dosages of enalapril. Temporarily discontinuing drug administration in dogs with enalapril-associated anorexia and then administering a lower dosage after the appetite returns is usually successful. The dosage can be increased back to the desired total daily dose after two to four weeks.

Alternative ACE inhibitors

Alternative ACE inhibitors that can be considered include benazepril, lisinopril, captopril, ramipril, and quinapril, although there are no studies directly comparing the efficacy of these drugs with enalapril in dogs with naturally occurring disease. All ACE inhibitors except captopril reach therapeutic serum concentrations with half-lives that permit once- or twice-a-day dosing in healthy dogs.16-19 In people, however, tissue-specific differences in lipophilicity and variable-binding affinity to the various ACE inhibitor pro-forms suggests that substituting one ACE inhibitor for another may require validation of each drug.20

Variable effectiveness and recommendation

Indirect evidence as to the variability of the effectiveness of the various ACE inhibitors includes greater reduction in the severity of echocardiographic variables in Cavalier King Charles spaniels with asymptomatic mitral regurgitation treated with quinapril vs. enalapril,21 renal excretion of serum enalaprilat (the active metabolite of enalapril) and possible accumulation in dogs with subnormal glomerular filtration rate vs. hepatic metabolism of benazeprilat,18 and failure of captopril to reduce serum ACE activity in healthy dogs as well as other ACE inhibitors.16 The significance of these differences in dogs with naturally occurring kidney diseases and renal impairment is unknown; however, they imply that substitution of one ACE inhibitor for another may not be without consequences.

Thus, I recommend enalapril as my ACE inhibitor of choice in dogs with glomerulopathies, as it was the drug evaluated in the previously mentioned study reporting effects in animals with naturally occurring glomerular disease.9 Anecdotal reports suggest that alternative ACE inhibitors are also effective, but I reserve them for administration to dogs that develop refractory enalapril-associated side effects.

Dosage

Published dosages of ACE inhibitors are based on the pharmacodynamic endpoint of plasma ACE activity reduction in healthy dogs to 25% of baseline.16 Although this dosage is appropriate for initial dosage establishment, prospective clinical trials in people now suggest that higher ACE inhibitor dosages that aim to maximally reduce the UPC ratio or plasma angiotensin II concentration may further improve patient survival times.

In people with diabetic nephropathy, doubling their lisinopril dosage further decreases the UPC ratio from 66% to 72% below baseline values. Likewise, patients with nondiabetic glomerular disease receiving standard vs. up-titrated dosage of benazepril to minimize proteinuria had a 37.5% vs. 52.5% decrease in UPC ratio below baseline22,23; blood pressure and rate of glomerular filtration rate decline were both reduced with higher drug dosages.

Dogs administered > 0.5 mg/kg twice a day enalapril or > 0.5 mg/kg daily benazepril anecdotally may have reductions in UPC ratio beyond that achieved with standard dosages; however, no controlled studies have evaluated whether this decrease in UPC ratio is associated with delay in onset of azotemia or increased survival. Additionally, ACE inhibitors may induce or exacerbate azotemia in both people and dogs24-27; whether higher drug dosages increase the risk of this uncommon adverse effect is unknown.

Nonresponders and aldosterone escape

Up to 50% of people with proteinuric nephropathies fail to respond appropriately to initial ACE inhibitor therapy, defined as a reduction in the UPC ratio of ≥ 50%.28-30 Additionally, proteinuria will increase to pretreatment concentrations within 1.5 to three years in 50% of the one-half of all patients initially classified as ACE inhibitor responders.28-30 These nonresponders have increases in serum angiotensin II and aldosterone concentrations that parallel their increase in UPC ratio and, thus, are assumed to have lost most renoprotective benefits of ACE inhibitor therapy. This phenomenon of aldosterone escape presumptively occurs secondary to up-regulated ACE or other kinase cleavage of angiotensin I to angiotensin II or increased metabolism of excretion of ACE inhibitor.


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Source: VETERINARY MEDICINE,
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