Page 281 - Feline Cardiology

288 Section G: Congestive Heart Failure

failure and acute anuric or oliguric renal failure are centration, indicating alternative mechanisms in addi-
uncommon, making the difference between classes of tion to generation of ATII for stimulation of aldosterone
ACE inhibitors clinically trivial. Chronic kidney disease, synthesis in the process of aldosterone escape (MacFadyen
with gradual loss of renal function, is much more et al. 1999). Similar to human medicine, persistent aldo-
common in cats, and drug dosage adjustments should sterone elevation has been found in 60% of Maine coon
be made periodically with all drugs based on timely cats receiving long-term treatment with ramipril and
assessment of renal function. 50% of dogs given long-term enalapril, despite low ACE
Pharmacokinetic and pharmacodynamic studies have activity, although ATII levels were not measured
been done with enalapril, benazepril, and ramipril in (MacDonald et al. 2006; Haggstrom et al. 1996). These
cats to define appropriate dose and dose intervals. The important findings suggest that patients may be receiv-
most important pharmacodynamic effect used to deter- ing inadequate neurohormonal blockade even though
mine appropriate dosing is the magnitude and duration they are given the medication as prescribed.
of ACE activity inhibition. Enalapril doses of 0.25 mg/kg, ACE activity ranges from low to high in humans with
0.5 mg/kg, and 1 mg/kg PO q 12 or 24 hr were evaluated, an elevated plasma ATII concentration while receiving
and there was equal ACE inhibition when a daily dose ACE inhibitors. In patients with high ACE activity, non-
of 0.5 mg/kg or 1 mg/kg were given (Uechi et al. 2002). compliance or inappropriate dose or dosing interval are
possible explanations. Because renin and angiotensin I
Therefore, an appropriate dose of enalapril is 0.5 mg/kg
Congestive Heart Failure used and is also acceptable. Benazepril causes acute and ACE activity can produce large variations in angiotensin
increase during ACEI therapy, even small differences in
PO q 24 hr. However, q 12 hr dosing is often clinically
II, making it imperative to have strict compliance with
sustained ACE inhibition of >90%, persisting over 24
the appropriate dose and dosing interval of the ACE
hours with doses of 0.25–1 mg/kg PO q 24 hr (King
inhibitor (Lee et al. 1999). Chronic ACE inhibitor
et al. 1999). Twenty-four hour trough ACE activity was
significantly less in cats treated with 0.5 or 1 mg/kg PO
would require higher doses of ACE inhibitors to ade-
q 24 hr than cats given 0.25 mg/kg PO q 24 hr (King
1999). Therefore, an appropriate dose of benazepril in therapy may up-regulate the production of ACE, which
quately suppress the activity over time. ACE polymor-
cats is 0.5 mg/kg PO q 24 hr. Ramipril is a long acting phisms are another important factor for the amount of
(terminal half-life >20 hr), lipophilic pro-drug that is ACE activity and ATII generation in people, and the ACE
converted to ramiprilat in the liver. Ramiprilat binds to DD genotype is associated with higher serum and tissue
circulating and tissue bound ACE, and inhibits its action ACE concentrations and activity and requires higher
(King et al. 2003). At a dose of 0.5 mg/kg PO q 24 hr, the ACEi doses for adequate inhibition (Cicoira et al. 2001).
maximal inhibition of plasma ACE activity was 100%, It is unknown whether cats or dogs have ACE polymor-
and 24 hours trough ACE inhibition was 81% in one phisms that could contribute to ACE and aldosterone
study (Desmoulins et al. 2008). Therefore, an appropri- escape. Therefore, there are multiple factors regarding
ate dose of ramipril in cats is 0.5 mg/kg PO q24 hr. the amount of ACE inhibitor needed for adequate sup-
pression of ACE activity and reduction in formation of
ACE and aldosterone escape angiotensin II.
Treatment with ACE inhibitors blocks conversion of Aside from ACE, there are alternate pathways that
angiotensin I to angiotensin II (and subsequently, pro- convert angiotensin I to angiotensin II, including
duction of aldosterone). Therefore, a properly treated chymase, serine proteases (cathepsin A, D, and G and
patient should theoretically have very low concentra- tonin), and ACE-2 (Wong et al. 2004). Ninety percent of
tions of these two hormones (ATII and aldosterone) in ventricular production of angiotensin II in humans,
circulation. However, a dilemma in ACE inhibitor dogs, and cats is due to ventricular α-chymase conver-
therapy involves the phenomenon of ACE and aldoste- sion of angiotensin I (Balcells et al. 1997; Aramaki et al.
rone escape, which may not be synonymous. There are 2003). Since renin and angiotensin I are elevated during
alternative mechanisms aside from ACE for conversion ACE inhibitor therapy, there is a greater substrate for
of angiotensin I to angiotensin II, most importantly bra- conversion to angiotensin II by alternative pathways.
dykinin (i.e., ACE escape). Likewise, aldosterone synthe- Extra-RAAS stimuli for aldosterone production include
sis may be increased by alternative mechanisms aside hyperkalemia or hyponatremia, which may be factors
from angiotensin II, including hyponatremia, hyperka- for persistent aldosterone elevation despite adequate
lemia, and adrenocorticotropic hormone (i.e., aldoste- ACE inhibition (Struthers 2004; Heintz et al. 1992).
rone escape) (Struthers 2004; Heintz et al. 1992). In Aldosterone receptor blockers and angiotensin II recep-
people treated with ACE inhibitors, 15% have an ele- tor blockers have been developed to circumvent the
vated plasma angiotensin II concentration compared to problem of ACE or aldosterone escape and may be used
40% who have an elevation in plasma aldosterone con- in patients with congestive heart failure who are already