Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

NEUROENDOCRINE MODULATION
sites on ACE is approximately 200,000 times that of
ACE.
In dogs, enalapril maleate achieves peak concentration
within 2 h of administration. Bioavailability is
approximately 60%. Enalapril is metabolized to enalaprilat.
Peak serum concentration of this active form
occurs 3–4 h after an oral dose. The half-life of accumulation
is approximately 11 h and duration of effect
is 12–14 h. Steady-state serum concentration is achieved
by the fourth day of administration. Excretion of enalapril
and enalaprilat is primarily renal (40%) although
36% is excreted in the feces. Approximately 85% of an
oral dose is excreted as enalaprilat.
The pharmacodynamics of enalapril have been examined
in experimental dogs. A dose of 0.3 mg/kg administered
per os results in approximately 75% inhibition
of the pressor response to angiotensin I. This effect lasts
for at least 6 h and is completely dissipated by 24 h after
administration. A dose of 1.0 mg/kg produces only
slightly better inhibition (approximately 80%) for at
least 7 h. About 15% inhibition is still present 24 h after
oral administration.
Adverse effects
The adverse effects of enalapril are the same as for
all ACE inhibitors, as outlined above. Chronic highdose
enalapril toxicity appears to be confined to the
kidneys. In healthy dogs administered doses up to
15 mg/kg/d over 1 year, drug-induced renal lesions are
not seen. High-dose (30–60 mg/kg/d) enalapril administration
to dogs results in dose-related renal toxicity. At
30 mg/kg/d, increasing degrees of renal damage are
observed that are shown to be a direct nephrotoxic
response of enalapril itself on proximal tubular epithelium.
This damage is permanent only when potentiated
by marked hypotension. The damage is confined to the
proximal tubules, primarily to the juxtamedullary
regions of the cortex where necrosis of the tubular cells,
but not the basement membrane, is present. Dogs that
survive the initial insult to the proximal tubules undergo
regeneration. A dose of 90–200 mg/kg/d is rapidly lethal
through renal failure. The renal toxicity appears to be
due to a direct nephrotoxic effect of the drug and to an
exaggerated decrease in systemic blood pressure. Saline
administration ameliorates the toxicity.
Benazepril
Benazepril can be used in dogs or cats with heart failure
as any other ACE inhibitor. Benazeprilat has been
studied in dogs with experimentally induced acute left
heart failure. Benazeprilat decreased left ventricular
end-diastolic pressure by approximately 15%, peripheral
resistance by approximately 30% and aortic pressure
by 30%. Cardiac output did not increase in these
anesthetized dogs.
Formulations and dose rates
Benazepril
Benazepril is supplied as tablets and can be made into suspension by
a formulation pharmacy.
DOGS
• PO: 0.3 mg/kg and 0.5 mg/kg q.24 h (some clinicians use it
in advanced heart failure)
CATS
• PO: 1–2.5 mg/cat q.12–24 h
• PO: 0.2-0.7 mg/kg q.12–24 h
Benazeprilat
• Dog: 30 µg/kg IV
Pharmacokinetics
Benazepril is a nonsulfhydryl ACE inhibitor. Like enalapril,
it is a prodrug that is converted to benazeprilat by
esterases, mainly in the liver. Benazeprilat is approximately
200 times more potent as an ACE inhibitor than
is benazepril. The conversion of benazepril to benazeprilat
is incomplete and other metabolites are formed
in the dog.
Benazeprilat is poorly absorbed from the gastrointestinal
tract whereas benazepril hydrochloride is well
absorbed in the dog. Bioavailability increases by about
35% with repeated dosing. Following the administration
of oral benazepril, plasma benazeprilat concentration
reaches peak concentration in plasma within 1–3 h.
Benazeprilat is rapidly distributed to all organs except
the brain and placenta. Benazeprilat is excreted approximately
equally in the bile and the urine in dogs. The
terminal half-life is approximately 3.5 h. There may be
an additional slow terminal elimination phase in dogs
that may have a half-life between 55 and 60 h. This
combined excretion may allow better dosing control in
patients with pre-existing renal insufficiency however
benazepril is no more renal protective than any other
ACE inhibitors at equipotent doses.
The pharmacodynamics of benazepril have been
studied in dogs by measuring plasma ACE activity before
and after various doses of the drug. A dose of 0.125 mg/kg
benazepril q.24 h appears to be too low. It only inhibits
plasma ACE activity to approximately 80% of baseline.
A dose of 0.25 mg/kg decreases plasma ACE activity
to less than 10% of baseline within 3 h of administration.
This effect lasts for at least 12 h. By 16 h plasma
ACE activity is back to 20% of baseline and by 24 h
it is approximately 30% of baseline. Doses of 0.5 and
1.0 mg/kg cause the >90% suppression to last at least
16 h. When benazepril is administered chronically, doses
from 0.25 mg/kg to 1.0 mg/kg produce indistinguishable
effects at the time of peak effect (2 h after oral administration)
and at trough effect (24 h after oral administration).
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