Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 17 DRUGS USED IN THE MANAGEMENT OF HEART DISEASE AND CARDIAC ARRHYTHMIAS
Formulations and dose rates—cont’d
administered 5–10 min after the second dose. This dosage schedule
is effective at terminating supraventricular tachycardia in approximately
85% of dogs. The effect following termination of administration
is short-lived, often lasting less than 30 min. For longer control, the
initial bolus injections can be followed by a constant infusion of
verapamil at 2–10 µg/kg/min.
Pharmacokinetics
In dogs, verapamil is absorbed well (more than 90%)
but undergoes extensive first-pass hepatic metabolism
so that bioavailability is only 10–23%. Verapamil is
metabolized to several active and inactive metabolites.
Most of the metabolites are excreted in bile. The halflife
of verapamil is 1.8–3.8 h in anesthetized experimental
dogs and the volume of distribution 2.6 ± 1.0 L/kg.
The effective plasma concentration is probably in the
range 50–200 ng/mL. A plasma concentration of
approximately 100 ng/mL increases the P-R interval in
normal dogs and a plasma concentration of approximately
200 ng/mL will produce second-degree AV
block. Myocardial concentration of the drug is linearly
related to plasma concentration and is approximately
nine times the plasma concentration. Left ventricular
and AV nodal region concentrations are greater than
the atrial concentration.
Adverse effects
● Verapamil can depress cardiac contractility and
cause peripheral vasodilation. It should not be used
in patients with severe myocardial failure or patients
in heart failure unless hemodynamic monitoring can
be done and calcium or catecholamines can be
administered immediately.
● In mild to moderate myocardial failure patients,
verapamil may increase cardiac output by dilating
arterioles.
● Occasionally, severe hypotension and cardiovascular
collapse can be induced in dogs with normal cardiac
function, especially if the drug is administered too
quickly.
● Verapamil should not be used in patients with sick
sinus syndrome or AV block because of its ability to
depress automaticity in these diseased tissues.
● Adverse effects can be reversed by calcium or catecholamine
administration. Catecholamine administration
is more effective than calcium for treating
calcium channel blocker-induced AV blocks in
experimental conscious dogs.
Known drug interactions
● Verapamil and β-blockers should not be used together
for several reasons.
– Coadministration of verapamil and β-blockers
results in additive negative inotropic, chronotropic
and dromotropic (conduction properties)
effects on the heart. This produces profound myocardial
depression, prolonged AV nodal conduction
and depressed heart rate, resulting in severe
cardiovascular depression.
– Verapamil can increase the bioavailability of
some β-blockers by decreasing first-pass hepatic
metabolism.
– Addition of β-blocker administration to dogs
with a stable plasma concentration of verapamil
results in an increase in the plasma verapamil
concentration.
● Coadministration of verapamil and lidocaine to isoflurane-anesthetized
experimental dogs produces
profound cardiovascular depression and severe systemic
hypotension.
● Cimetidine decreases total body clearance of verapamil.
This increases the plasma concentration of
intravenously and orally administered verapamil.
This effect probably occurs because of cimetidine’s
ability to inhibit hepatic microsomal enzymes.
● Verapamil increases the serum digoxin concentration
in humans and probably does the same in dogs. The
increase is thought to be due to reduced renal and
extrarenal clearances of digoxin.
Diltiazem
Clinical applications
The clinical pharmacology of diltiazem when used to
treat heart failure in cats is described earlier in the
chapter (p. 422).
Diltiazem is also popular for decreasing ventricular
rate in dogs with atrial fibrillation. In most canine
patients, digoxin is administered first and the heart-rate
response determined once a therapeutic serum concentration
is achieved. If an adequate response is not
achieved, diltiazem can be added to treatment protocol.
Diltiazem can also be used in dogs to treat supraventricular
tachycardia.
Mechanism of action
Diltiazem slows AV conduction and prolongs the AV
refractory period to a similar degree to verapamil. It has
minimal effects on myocardial contractility at clinically
relevant plasma concentrations in normal dogs. Diltiazem’s
effects on peripheral vascular smooth muscle are
mild, although it is a potent coronary vasodilator.
In normal experimental dogs, one study found that
diltiazem (0.8 mg/kg IV) did not alter left ventricular
myocardial contractility but did decrease peripheral vascular
resistance and increased the heart rate in response
to a reflex increase in plasma catecholamine concentra-
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