Page 97 - Small Animal Internal Medicine, 6th Edition

CHAPTER 3 Management of Heart Failure 69

POSITIVE INOTROPIC AGENTS positive inotropic effect and a narrow therapeutic window,
Pimobendan so it must be dosed and monitored carefully. Digoxin is used
VetBooks.ir Pimobendan (Vetmedin) is called an inodilator because it most often for heart rate control in dogs with AF; it is mod-
erately effective for slowing AV conduction. Digoxin also can
increases contractility while also causing systemic and pul-
monary vasodilation (see Table 3.3). Pimobendan has a
Chapter 4). Digoxin generally is contraindicated when sinus
calcium-sensitizing effect on the contractile proteins by suppress some other supraventricular arrhythmias (see
increasing the affinity of the regulatory protein troponin C or AV node disease is present. Other potential contraindica-
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for Ca . This promotes increased contractility without an tions include azotemia, ventricular tachyarrhythmias
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increase in free cellular Ca and therefore myocardial O 2 (because it can exacerbate such arrhythmias), and concur-
requirement. As a benzimidazole-derivative phosphodies- rent use of a drug that can potentiate digoxin’s effects.
terase III inhibitor, pimobendan also slows cAMP break- Digoxin usually is contraindicated in patients with HCM,
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down and enhances adrenergic effects on Ca fluxes and especially those with ventricular outflow obstruction. It is
myocardial contractility. The drug potentially has other ben- almost never used in cats now. Digoxin is not helpful in
eficial effects by modulating NH and proinflammatory cyto- patients with pericardial disease. Because of its potential tox-
kine activation. It also has some antithrombotic properties icity, low doses are used and serum concentrations should
but only at high doses. Peak plasma concentrations occur be monitored. Serum concentrations in the low to mid thera-
within an hour of oral dosing. Bioavailability is about 60% peutic range are desired (see p. 70).
in dogs, but this decreases in the presence of food, so admin- Digoxin increases contractility by competitively binding
+
+
istration at least an hour before feeding sometimes is recom- and inhibiting the Na , K -ATPase pump at the myocar-
+
mended. Pimobendan is highly proteinbound. Elimination dial cell membrane. Intracellular Na accumulation then
++
is mainly via hepatic metabolism and biliary excretion. There promotes Ca entry via the sodium-calcium exchange.
is an active metabolite with phosphodiesterase III inhibitory However, digoxin’s inotropic effect may be minimal in dis-
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effect that contributes to the drug’s systemic and pulmonary eased myocardial cells in which systolic Ca release and dia-
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vasodilatory effects. Concurrent Ca or β-blocker therapy stolic reuptake are impaired, and it can predispose to cellular
++
may diminish the drug’s positive inotropic effect. Adverse Ca overload, delayed afterdepolarizations, and electrical
effects are uncommon but can include anorexia, vomiting, instability.
or diarrhea. The antiarrhythmic effects of digoxin are mediated pri-
Pimobendan has been shown to improve clinical status marily by increased parasympathetic tone to the sinus and
and survival in dogs with CHF from DCM or chronic MR AV nodes and atria. Some direct effects further prolong con-
when added to standard therapy. Pimobendan is associated duction time and refractory period of the AV node. Sinus
with longer survival times when compared with ACEI in rate slowing, reduced ventricular response rate to AF and
dogs with CHF, although the combination of pimobendan atrial flutter, and suppression of atrial premature depolariza-
with an ACEI usually is employed clinically. Pimobendan tions are resulting effects. Although some ventricular
does not appear to increase the frequency of ventricular arrhythmias might be suppressed (probably via enhanced
arrhythmias and sudden death in dogs with CHF. Pimoben- vagal tone), digoxin has potential arrhythmogenic effects,
dan also is now recommended therapy for dogs with especially in patients with heart failure.
advanced preclinical chronic mitral valve disease (stage B2) Oral maintenance doses are used to initiate digoxin
because it can delay the onset of CHF, as shown in a large therapy. When a more rapid increase in serum concentration
prospective multinational study (Epic trial). Likewise, pimo- is important, the drug can be given at twice the oral main-
bendan was shown to delay CHF onset and improve survival tenance dose for 1 to 2 doses. However, loading doses can
in Doberman Pinschers and Irish Wolfhounds with occult result in toxic concentrations. IV digoxin loading is not rec-
DCM. It presumably benefits other animals with progressive ommended. Alternate IV drug therapy for supraventricular
myocardial function deterioration as well. There is disagree- tachycardia usually is more effective (see Chapter 4), and
ment regarding pimobendan’s use in cats with first-onset other positive inotropic drugs (see p. 63 and Box 3.1) are
CHF caused by HCM, and it may be contraindicated for safer and more effective than digoxin for immediate support
HOCM, as previously noted (p. 65). However, pimobendan of myocardial contractility.
is a recommended component of CHF therapy for cats with Digoxin is well absorbed orally and undergoes minimal
dilated, restrictive, and other end-stage cardiomyopathies. hepatic metabolism; absorption is approximately 60% for the
tablet form and 75% for the elixir. Kaolin-pectin compounds,
Digoxin antacids, the presence of food, and malabsorption syndromes
As an oral positive inotropic drug, digoxin has been eclipsed decrease bioavailability. About 27% of the drug in serum is
by pimobendan. However, digoxin still is used in some cases proteinbound. The serum half-life in dogs ranges from less
of advanced DCM and end-stage MR as an adjunct to, and than 23 to more than 39 hours; therapeutic serum concentra-
combined with, pimobendan to support myocardial func- tions are achieved within 2 to 4.5 days with every 12-hour
tion. Digoxin’s ability to sensitize baroreceptors and thereby dosing. In cats, the reported serum half-life ranges widely
modulate NH activation probably is its most important attri- from about 25 to more than 78 hours; chronic oral admin-
bute in patients with heart failure. Digoxin has only a modest istration increases the drug’s half-life. The alcohol-based