Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

NEUROENDOCRINE MODULATION
and the owner can afford the treatment. However,
dietary change (reduction in phosphate) carries significantly
greater potential benefits in slowing the progression
of renal failure and ACE inhibitor therapy should
not be regarded as a substitute for it. Treating cats and
dogs that are severely azotemic or that have prerenal
azotemia with ACE inhibitors may actually speed their
demise.
Mechanism of action
The RAAS plays an important role in regulating cardiovascular
homeostasis in normal individuals and patients
with heart failure. Renin is released from the juxtaglomerular
apparatus in response to sympathetic stimulation
and to decreased sodium flux by the macula densa.
In the plasma, renin is a protease that acts on the glycoprotein
angiotensinogen to form the polypeptide
angiotensin I. Angiotensin converting enzyme (ACE)
cleaves two amino acids from the decapeptide angiotensin
I to form the octapeptide angiotensin II. This conversion
primarily occurs in the vascular endothelium of the
lung although other vascular beds are involved.
ACE inhibitors bind to the same site on ACE as
angiotensin I, effectively arresting its action. This site
contains a zinc ion and ACE inhibitors contain a sulfhydryl,
carboxyl or phosphoryl group that interacts
with this site. The relative potency of these compounds
depends on the affinity of the compound for the active
site. ACE inhibitors that are more tightly bound to the
active site tend to be more potent. They also tend to
have a longer duration of effect.
The effects of ACE inhibitors occur as a result of the
decreased concentration of circulating angiotensin II.
Angiotensin II has several important effects in patients
with heart failure.
● It is a potent vasopressor.
● It stimulates the release of aldosterone from the
adrenal gland.
● It stimulates vasopressin (ADH) release from the
posterior pituitary gland.
● It facilitates the central and peripheral effects of the
sympathetic nervous system.
● It preserves glomerular filtration when renal blood
flow is decreased via glomerular efferent arteriolar
constriction.
● It stimulates hypertrophy and thus contributes to
maladaptive remodeling in heart failure.
ACE inhibitors have several effects in patients with
heart failure. Balanced vasodilation (arteriolar and
venodilation) occur as a direct result of the decreased
concentration of angiotensin II. Consequently, ACE
inhibitors are generally classified as vasodilators. ACE
inhibitors also decrease activation of the RAAS and this
is their most important role.
The effects of ACE inhibitors become evident at different
times following the onset of administration. Arteriolar
dilation is observed after the first dose is
administered, while the lessening of sodium and water
retention takes days to become clinically significant.
Since most dogs presenting for severe heart failure are
dying from pulmonary edema, the ACE inhibitors are
poor emergency heart failure drugs and their potential
to cause adverse renal effects is enhanced when aggressive
parenteral furosemide is used. Thus this author
does not initiate or continue ACE inhibitor therapy
when intravenous furosemide is being used.
The ability of ACE inhibitors to decrease plasma
aldosterone secretion may become attenuated or lost
with time. In one study of cavalier King Charles spaniels
with severe mitral regurgitation, enalapril significantly
decreased plasma aldosterone concentration after 3
weeks of administration. However, 6 months later the
plasma aldosterone concentration had increased to an
even higher level than at baseline. These dogs were also
on furosemide at 6 months, which may have contributed
to the increase. However, it is known that other
enzymes, such as chymase, are capable of converting
angiotensin I to angiotensin II and so may contribute to
the lack of prolonged effect.
In most canine patients the arteriolar dilating effect
of ACE inhibitors is relatively mild when compared to
the more potent arteriolar dilators like amlodipine and
hydralazine. In general, ACE inhibitors can decrease
systemic vascular resistance by 25–30% while hydralazine
can decrease it by 50%.
Benefits
Clinical cardiovascular disease
The clinical benefits of ACE inhibitors in heart failure
are well documented in human and canine studies and
are considered a class effect. Thus if enalpril has been
shown to be beneficial one could use benazepril and
expect the same effect. In human medicine there are
currently head to head ACE inhibitor trials under way
that may address potential differences in efficacy between
ACE inhibitors. In general, ACE inhibitors improve
clinical signs and improve quality of life in dogs and
cats with heart failure due to diverse causes. The
improvement in clinical signs is primarily due to reduction
in capillary pressures and edema formation and to
increased perfusion of vascular beds. ACE inhibitors are
one of the few drug types used to treat heart failure that
have been proved to both improve symptoms and
prolong life in humans and to prolong the time until
treatment failure in dogs.
A number of studies have evaluated enalapril’s efficacy
in dogs with dilated cardiomyopathy and with
primary mitral regurgitation and heart failure. In the
first study (IMPROVE: invasive multicenter prospective
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