Renal Medications

Question 1

ACEi MOA and possible causes of individual variation in response

Answer 1

Most ACEi are administered as pro-drugs, requiring esterification in the liver become active.
Drugs in this class inhibit ACE and not only decreased formation of AngII, but also decrease the degradation of the vasodilatory compound bradykinin

Variabile efficacy may occur due to differences in ACE protein conformation from genetic variation
Further study is necessary to determine whether differences in RAAS phenotypes impact the response to RAAS suppressive treatment

Another theory is tissue chymase which has a greater catalytic efficiency than ACE and is thought to serve as the primary generator of AngII in the tissues, and likely contributes to apparent inefficacy of ACEI in humans

Aldosterone breakthrough may also explain lack of efficacy

Question 2

Theoretical benefit of ARB over ACEi

Answer 2

blockade of the actions of AngII at the AT1R,regardless of the pathway of its formation (via ACE or non-ACE path-ways, such as chymase).

Increased circulating AngII, resulting from AT1 R blockade, might stimulate the AT2 R, thought to be counterregulatory to the maladaptive actions mediated by the AT1 R

Whether ARBs are superior to ACEI in dogs and cats with either cardiovascular or renal disease is not known, though the early experience with telmisartan in cats with hypertension, chronic kidney disease (CKD), and proteinuria suggests that this may be the case

Question 3

Spironolactone MOA

Answer 3

Mineralocorticoid receptor antagonism in the distal renal tubule cells causes an increase in urinary Na+ excretion and a decrease in K+ excretion
(minimal effect on Na excretion in healthy dogs)

In dogs with chronic heart failure and chronic aldosterone excess, however, spironolactone likely increases urinary sodium excretion and urine volume