Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

NEUROENDOCRINE MODULATION
of humans taking ACE inhibitors. The incidence of
clinically significant hypotension in dogs appears to be
much less, probably because dogs do not walk
upright.
The second risk is seen in patients that are very dependent
on angiotensin II to maintain GFR. Glomerular
efferent arteriolar constriction maintains normal GFR
in mild to moderately severe heart failure when renal
blood flow is reduced. The primary stimulus for this
vasoconstriction is increased plasma angiotensin II concentration,
which is elaborated in response to the
decrease in renal blood flow. Glomerular capillary pressure
provides the force for filtration and glomerular
capillary pressure is determined by renal plasma flow
and efferent arteriolar resistance.
When renal plasma flow is low (as in heart failure)
and potentiated by concurrent diuretic use, angiotensin
II causes efferent arterioles to constrict, bringing glomerular
capillary pressure back to normal. GFR is then
preserved despite the decrease in renal blood flow and
normal serum urea and creatinine concentrations are
maintained. The filtration fraction (ratio of GFR to
renal plasma flow) is increased. When an ACE inhibitor
is administered, efferent arteriolar dilation must occur.
In some patients this dilation appears to be excessive,
resulting in a moderate to marked reduction in GFR and
subsequent azotemia.
Those human patients that are at greatest risk for
developing azotemia include patients with high plasma
renin activity, low renal perfusion pressure, hyponatremia
and excessive volume depletion. When angiotensin
II concentration is decreased in at-risk patients, GFR
becomes decreased and azotemia results. The azotemia
is generally mild but occasionally can be severe in both
human and canine patients.
Functional azotemia can occur secondary to the
administration of any ACE inhibitor. The longer-acting
agents (e.g. enalapril) may more frequently produce azotemia
in human patients than the shorter-acting agents
(e.g. captopril). However, in one study in rats, captopril
produced a marked reduction in GFR while perindopril
did not. Treatment consists of reducing the diuretic dose
or stopping the administration of the ACE inhibitor.
Although this functional azotemia may develop with
greater frequency in at-risk patients, it should be stressed
that azotemia sometimes develops in a canine patient
that appears to have no risk factors other than heart
failure.
Decreased GFR and an increase in serum urea and
creatinine concentration are seen in 35% of human
patients receiving ACE inhibitors. In most cases the
increase in urea is mild and requires no intervention. In
dogs, the incidence of clinically significant azotemia
(plasma urea >35 mmol/L) is low. However, it occurs
frequently enough that any veterinarian using these
drugs should be aware of the potential occurrence of
azotemia. Mild to moderate increases in plasma urea
concentration (between 12 and 21 mmol/L) also occur
at a low rate. In these patients, urea concentrations may
increase without a concomitant increase in serum creatinine,
or the increase in creatinine may be milder. As
long as these patients continue to eat and act normally,
these changes can generally be ignored.
Recommended guidelines for ACE inhibitor therapy
with regards to azotemia based on human studies
include the following.
● Identify high-risk patients (patients with moderate
to severe dehydration, hyponatremia) before
therapy.
● Ensure that the patient is not clinically dehydrated
and ensure adequate oral fluid intake throughout
therapy.
● Evaluate renal function at least once within 1 week
after commencing therapy.
● Decrease the dose of furosemide if moderate azotemia
develops or discontinue the ACE inhibitor if the
azotemia is severe or if a reduction in furosemide
dose does not improve renal function.
● Do not initiate or continue ACE inhibitor therapy
when parenteral furosemide is required for severe or
decompensated heart failure.
● Be cautious when combining an ACE inhibitor with
agents that have potential renal toxicity or drugs that
have the potential to also reduce GFR in susceptible
patients such as all NSAIDs (see Chapter 13 for
mechanism).
The prescribing information for one ACE inhibitor
states that if azotemia develops the dose of diuretic
should be reduced and if azotemia persists the dose
should be reduced further or discontinued. This implies
that diuretic administration should be discontinued
permanently. Recommendations to permanently
discontinue furosemide therapy in a patient with a clear
history of moderate to severe heart failure are not
tenable. In human medicine, the recommendation is to
discontinue diuretic therapy for 24–48 h if needed, not
permanently.
It is important to warn owners of the clinical signs of
severe azotemia (usually anorexia and other gastrointestinal
signs) and to measure serum creatinine and/or urea
concentrations within the first week of ACE inhibitor
therapy.
If a patient develops severe azotemia, it is usually wise
to discontinue ACE inhibitor therapy and ensure that
the patient is not significantly dehydrated.
If dehydration is moderate to severe, it is advisable to
reduce the furosemide dose or discontinue its administration
for 1–2 days and administer intravenous fluids
cautiously.
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