Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

PURE VASODILATORS
Formulations and dose rates
Amlodipine is supplied as tablets containing the besylate salt of amlodipine
(2.5, 5 and 10 mg tablets). To treat refractory pulmonary
edema secondary to severe mitral regurgitation, the dose needs to be
titrated. The starting dose can be as low as 0.1 mg/kg q.24 h and can
peak as high as 0.5 mg/kg q.12 h. The same protocol can be used to
treat systemic hypertension in dogs but the peak dose may be as high
as 3 mg/kg q.12 h.
Pharmacokinetics
The pharmacokinetics of amlodipine have been studied
in dogs. Bioavailability is about 90%, compared to bioavailability
in humans of about 65%. Time to peak
plasma concentration is 6 h in dogs and 8 h in humans.
Following intravenous or oral administration, about
45% of the drug is excreted in the feces and 45% in the
urine as metabolites. Only 2% of the drug is excreted
unchanged. Initial metabolism involves oxidation of the
dihydropyridine ring to the pyridine analog. Further
metabolism involves side-chain oxidation and hydrolysis
of one or both side-chain ester groups. Plasma halflife
is similar to that in humans at about 30 h following
intravenous administration. Volume of distribution is
also similar to that in humans at 25 L/kg. Approximately
95% of amlodipine is protein bound in all species
studied.
Adverse effects
Theoretically, amlodipine overdose can cause clinically
significant systemic hypotension. In practice, this
appears to be very uncommon. However, further experience
with the drug is required before any definitive
statements can be made. Amlodipine produces no electrocardiographic
effects in humans administered the
drug. Amlodipine and a β-blocker can be administered
together. The drug has been too expensive to use in
large dogs. However, a generic formulation has recently
become available.
Hydralazine
Clinical applications
The primary indication for hydralazine administration
in veterinary medicine is severe mitral regurgitation that
is refractory to conventional therapy. Hydralazine is
also very effective for treating canine and feline patients
with severe aortic regurgitation and patients with a
large ventricular septal defect. Hydralazine can also
be used to decrease systemic blood pressure in dogs
with systemic hypertension. Administration of an α-
adrenergic blocking drug is frequently required when
the drug is used to treat systemic hypertension to block
the reflex increase in cardiac output brought about by
the sympathetically mediated increase in contractility
and heart rate.
Mechanism of action
Hydralazine directly relaxes the smooth muscle in systemic
arterioles, probably by increasing the prostacyclin
concentration in systemic arterioles. It also increases
aortic compliance. Hydralazine has no effect on systemic
venous tone. It decreases vascular resistance in
renal, coronary, cerebral and mesenteric vascular beds
more than in skeletal muscle beds. Hydralazine also
reflexly increases myocardial contractility. This is most
probably secondary to hydralazine-induced histamine
release resulting in noradrenaline (norepinephrine)
release.
Hydralazine is a very potent arteriolar dilator. In dogs
it is able to decrease systemic vascular resistance to less
than 50% of baseline in comparison to captopril, which
can only decrease systemic vascular resistance by about
25%. Hydralazine’s potency can be both beneficial
and detrimental to its use. Its potency is of benefit
because it results in good to profound improvement
in the majority of patients in which it is indicated. Its
potency can be detrimental if it results in systemic
hypotension.
In small dogs with severe mitral regurgitation refractory
to the administration of furosemide, regurgitant
flow may constitute 75–85% of cardiac output. Left
ventricular contractile function is usually normal or
only mildly depressed. Consequently, the major hemodynamic
abnormalities are caused by marked regurgitant
flow through an incompetent mitral valve. The
ideal treatment would be mitral valve repair but currently
this is not technically feasible. Consequently, the
theoretical treatment of choice is arteriolar dilator
administration.
ACE inhibitors are usually the first choice for achieving
mild arteriolar dilation. Hydralazine is more potent
and is reserved for patients that are refractory to ACE
inhibitors. Hydralazine decreases regurgitant flow,
increases forward aortic flow and venous oxygen tension
and decreases radiographic evidence of pulmonary
edema. A therapeutic dosage decreases mean arterial
blood pressure from 100–110 mmHg to 60–80 mmHg.
These effects improve the quality of life and appear to
prolong survival time.
In dogs with dilated cardiomyopathy, hydralazine
also improves cardiac output but does not usually
appreciably reduce edema formation. Consequently, the
drug does not seem to improve the quality of life for the
patient nor does it usually result in appreciable prolongation
of life.
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