Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 17 DRUGS USED IN THE MANAGEMENT OF HEART DISEASE AND CARDIAC ARRHYTHMIAS
Once the dog is stable, reassess the need for an ACE
inhibitor. If the ACE inhibitor was being administered
because of its potential (rather than actual) benefits and
the patient does not require its administration it is
advised not to attempt to readminister the ACE
inhibitor.
If the patient is refractory to furosemide administration
there are several options
● Initiate pimobendan if the patient is not already
receiving it.
● Readminister the ACE inhibitor but at a lower
dose and then try to gradually titrate the dose into
the therapeutic range.
● Use a short-acting ACE inhibitor, such as captopril,
if a longer-acting agent, such as enalapril,
lisinopril, or benazepril, was administered
initially.
● Add a thiazide diuretic.
● Add hydralazine or amlodipine.
One study of human patients with heart failure has
documented that captopril acutely decreases the natriuretic
and diuretic effects of furosemide. In this study,
furosemide increased sodium excretion 623% above
baseline while captopril plus furosemide only increased
it 242% above baseline. Urine volume increased 225%
above baseline with furosemide but only 128% above
baseline in patients receiving both furosemide and captopril.
This was an acute study. The chronic effects of
administering captopril to patients stabilized on furosemide
are unknown. This finding suggests that an ACE
inhibitor should not be administered to a patient with
severe, acute heart failure that needs the diuretic effect
of furosemide to maintain life.
Known drug interactions
The arteriolar dilating effect of enalapril, and probably
other ACE inhibitors, is attenuated by the concomitant
administration of aspirin in humans. ACE inhibitors
also decrease the breakdown of bradykinin, which stimulates
prostaglandin synthesis. The predominant effect
of prostaglandins in the systemic circulation is vasodilation.
In one study in humans, the normal decrease in
systemic vascular resistance induced by an ACE inhibitor
was blocked by the concomitant administration of
aspirin. However, a study has been performed in experimental
dogs with heart failure in which low-dose aspirin
produced no decrease in hemodynamic response to
enalaprilat. In addition, the potential renal adverse
effects associated with ACE inhibition may be potentiated
by concurrent use of any NSAID particularly in
dogs with heart failure receiving furosemide.
The combination of an ACE inhibitor and spironolactone
has the potential to cause clinically significant
hyperkalemia. There is only one retrospective report of
the relative safety of this combination in dogs with heart
failure who are also receiving concurrent furosemide.
However, the author (Gordon) has observed clinically
significant hyperkalemia when an ACE inhibitor and
spironolactone were administered to a dog not receiving
concurrent furosemide.
Enalapril
Enalapril is structurally and pharmacologically similar
to captopril but contains a disubstituted nitrogen rather
than the sulfhydryl group. The lack of the sulfhydryl
group may result in decreased risk of certain side effects
in humans, such as taste disturbances and proteinuria.
These adverse effects have not been documented in dogs
or cats administered ACE inhibitors.
Formulations and dose rates
The veterinary formulation of enalapril maleate is supplied as
tablets. The human formulation is also supplied as tablets. There is
also a formulation of enalapril maleate and hydrochlorothiazide that
contains 10 mg enalapril maleate and 25 mg hydrochlorothiazide in
one tablet. Enalaprilat is available for intravenous injection as enalaprilat
in 0.9% alcohol at a concentration of 1.25 mg/mL of anhydrous
enalaprilat.
DOGS
• Dose range studies have been performed with enalapril in dogs
with surgically induced mitral regurgitation and heart failure. In
these dogs, a dose of 0.5 mg/kg enalapril PO produced a
greater decrease in pulmonary capillary pressure than a dose of
0.25 mg/kg. A dose of 0.75 mg/kg produced no better
response. After 21 days of administration, the 0.5 mg/kg q.24 h
dose produced a signifi cant decrease in heart rate while the
0.25 mg q.24 h dose did not. Consequently, the enalapril dose
is 0.5 mg/kg
• Whether this dose should be administered q.12 h or q.24 h is
debatable. The package insert recommends starting with dosing
q.24 h, increasing to q.12 h if the clinical response is
inadequate
• Based on the pharmacodynamics presented below, we
generally start the drug by administering it twice a day to dogs
in heart failure, at approximately 12 h intervals
CATS
• PO: 1–2.5 mg/cat q.12–24 h
• PO: 0.2–0.7 mg/kg q.12–24 h
Pharmacokinetics
Enalapril is the ethyl ester of enalaprilat. It has little
pharmacological activity until it is hydrolyzed in the
liver to enalaprilat. Enalapril is available commercially
as the maleate salt. Enalapril maleate is absorbed better
from the gastrointestinal tract in dogs than enalaprilat.
The affinity for enalaprilat for the angiotensin I binding
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