Drugs for Treatment of Heart Failure in Dogs

Chapter 175


Drugs for Treatment of Heart Failure in Dogs




Therapy for canine heart failure (HF) requires careful orchestration of a multiple-drug treatment regimen. Cardiovascular drugs are potent in their relief of clinical signs and can be life prolonging, but these compounds also can injure the patient. In this chapter we consider the general classification, mechanism of action, indications, uses, and adverse effects of drugs used for treatment of canine HF. The coordinated use of these drugs and some of the clinical trial data indicating their benefit are discussed next in Chapter 176. The reader also is directed to the Appendix for a listing of alternative dosages. The dosages summarized in Table 175-1 focus exclusively on dogs; dosages for cats can be found in Chapters 173 and 180. One of the authors (BK) also has developed an on-line dosage calculator that veterinarians and veterinary technicians may find useful (see www.cardiologycarenetwork.com/network/dosage_calc.php).



The number of drugs capable of affecting heart and vascular functions is considerable (Box 175-1), and the pharmacologic effects of drugs used in treatment of HF can become confusing. Some treatments for congestive heart failure (CHF) affect ventricular pumping (inotropes), whereas others reduce venous pressures and ventricular preload (diuretics and venodilators), improving or preventing signs of congestion. Drugs with arterial vasodilator effects decrease blood pressure (BP), ventricular afterload, and mitral regurgitant volume, with the consequence of increasing forward stroke volume leaving the ventricle. Some agents demonstrate very rapid hemodynamic effects (e.g., intravenously administered diuretics, nitrovasodilators, and catecholamines). Others confer benefits by modulating the chronically activated neurohormonal, inflammatory, and profibrotic mediators of CHF (these include the “cardioprotective” drugs such as the angiotensin-converting enzyme [ACE] inhibitors, β-adrenergic blockers, and aldosterone receptor blockers).



Box 175-1   General Classes of Cardiovascular Drugs Used in the Treatment of Canine Heart Failure








The clinician should be mindful of the clinical pharmacology of these compounds (Brunton et al, 2010; Gordon and Kittleson, 2008; Opie and Gersh, 2013) and also appreciate that many drugs we use in veterinary practice are prescribed in an extralabel manner. For example, most of the vasodilator drugs and all of the antiarrhythmic drugs mentioned in this chapter are approved for human use and administered off label to dogs based on current standards of care. Although this chapter offers an overview of the important drugs used to manage HF in dogs, the reader is directed to comprehensive textbooks in the reference list for a fuller recounting. The ABCD stages of HF are described fully in the next chapter, but for reference, stage C represents CHF that is manageable with standard four-drug therapy and dosages and stage D represents refractory CHF that requires additional therapies and higher dosages of the standard-treatment drugs. In this context, standard therapy for CHF in the dog is furosemide, an ACE inhibitor, pimobendan, and spironolactone.


Many HF drugs are available in generic formulations, which can help to control the cost of multiple-medication regimens such as the one just mentioned. However, proprietary formulations must be used in some countries based on applicable laws: this can create problems for some clients faced with high drug costs in the absence of any insurance reimbursement. Therefore the cost of drugs should be discussed with owners before prescribing and adjustments made as practical.



Diuretics


Diuretics are administered to cardiac patients in acute situations for mobilization of edema and in chronic HF to prevent ongoing sodium and water retention. Low dosages also may be useful (when combined with an ACE inhibitor) in the control of cough related to left bronchial compression when it occurs before the onset of overt CHF. When diuretics are prescribed for long-term use, dietary sodium intake should be restricted (see Chapter 168) and an ACE inhibitor and aldosterone receptor blocker (spironolactone) coadministered.



Furosemide and Torsemide


Furosemide and torsemide are potent diuretics that block the 2-chloride symporter in the thick loop of Henle and increase urinary losses of chloride, sodium, potassium, hydrogen ions, and water. Furosemide (also known as frusemide) is the most commonly used diuretic for management of CHF in dogs. Loop diuretics also block free-water clearance and increase the loss of magnesium ions. These agents are “high ceiling,” demonstrating high potency in preventing renal sodium reabsorption with a strong dose-response relationship. There is far less experience with torsemide in veterinary medicine, but this drug is thought to have better oral bioavailability and a longer duration of action than furosemide. It is used increasingly in advanced CHF when furosemide seems to become less effective. Furosemide is effective when administered by intravenous, intramuscular, subcutaneous, and oral routes, and the relative onset of diuresis also follows this order from fastest to slowest. When used in dogs, torsemide is administered by mouth.


Furosemide is carried by renal blood flow to the proximal nephron and actively secreted into the plasma filtrate where it is carried to the loop of Henle. If renal blood flow is impaired because of severe CHF, plasma volume contraction, or the administration of a nonsteroidal antiinflammatory drug, the delivery of drug to the proximal nephron may be inadequate. Because of this possibility, a relatively high initial furosemide dose (such as 2 to 4 mg/kg IV) usually is administered to patients with severe CHF. When relative diuretic resistance is evident, a constant-rate IV infusion of furosemide can be initiated after the initial bolus. For a continuous IV infusion, 0.5 to 1 mg/kg/hr is administered using an accurate syringe pump for 3 to 12 hours. The patient is monitored closely for evidence of effective diuresis (by counting the respiratory rate, assessing respiratory effort, and checking for urination every 15 to 30 minutes; the bladder also can be palpated or imaged by ultrasonography if there is a question about urine formation). Once diuresis begins and the respiratory rate falls (to <40 to 45 breaths/min) the furosemide dosage is reduced to 2 mg/kg q6-12h IV, IM, or SC.


Oral maintenance dosages of furosemide can be initiated once the dog is in clinically stable condition and ready to be released from the hospital. The usual oral dosage is 2 to 4 mg/kg two times daily. The frequency can be increased to three times daily and the dosage up-titrated to as high as 12 mg/kg daily in refractory cases of CHF provided renal function and electrolyte status are monitored. When fluid retention becomes unresponsive to standard dosages of furosemide (stage D CHF), other diuretic options should be considered, including flexible subcutaneous dosing of furosemide or the addition of another diuretic such as torsemide or hydrochlorothiazide (see Chapter 176 for details). Torsemide ostensibly is more potent than furosemide in this setting and may be considered at approximately image of the furosemide milligram dosage. It can be substituted for one or more daily doses of furosemide.


Adverse effects of loop diuretics include polydipsia, polyuria, reduction in BP, plasma volume depletion, (prerenal) azotemia, and depletion of electrolytes, especially chloride, potassium, and magnesium. Monotherapy with a loop diuretic activates the renin-angiotensin-aldosterone system; accordingly, long-term diuretic therapy should incorporate an ACE inhibitor (and optimally spironolactone) as part of the treatment plan. Clients should be instructed not to administer the drug at bedtime to avoid urinary accidents, and they should never restrict water (except in rare circumstances of profound hyponatremia). Mild azotemia is not a reason to discontinue diuretic therapy, but moderate to severe azotemia should prompt dosage reductions (see Chapter 176 for a detailed discussion of this issue). Potassium supplements are needed infrequently in dogs receiving combined therapy with furosemide, spironolactone, and enalapril because the latter two drugs “spare” potassium by reducing urinary losses. Ototoxicity and renal failure are potential adverse effects, especially when aminoglycosides are coadministered.



Spironolactone


Spironolactone is a synthetic, antiandrogenic, steroidal compound that blocks aldosterone receptors in the kidney, heart, and in other tissues (eplerenone is a related drug not sufficiently studied in veterinary medicine). Despite its classification as a diuretic, the urine-enhancing effects of spironolactone are weak to nonexistent in the dog, likely related to the locus of its antimineralocorticoid activity in the most distal segments of the renal tubule. The major reasons for prescribing spironolactone in heart disease relate to its potassium-sparing action and the potential for antifibrotic effects in the heart, kidneys, and other tissues. Drugs of this class (including eplerenone) also may normalize baroreceptor function, which has been shown to be depressed in canine CHF. There is some evidence—although it is not definitive—for a survival benefit in canine HF when spironolactone is dosed at approximately 2 mg/kg daily PO. Based on the available tablet sizes, the daily dose can be administered in a single pill or divided into two daily doses. Some cardiologists also use this drug empirically for cardioprotection in cases of preclinical dilated cardiomyopathy (DCM) based on evidence from experimental models of myocardial disease.


When compared with humans, dogs appear to have minimal adverse effects from spironolactone. Breeders should be advised of potential effects on reproduction. Elevated serum potassium levels may be observed with spironolactone, especially in the setting of ACE inhibitor cotherapy, but this typically is mild and is ignored. Potassium supplements should not be given routinely to dogs receiving spironolactone unless hypokalemia is documented.



Hydrochlorothiazide


Hydrochlorothiazide (HCT) occasionally is used in combination with furosemide for the management of refractory stage D CHF, especially in dogs with intractable edema or effusions. This drug blocks the sodium-chloride symporter that is insensitive to loop diuretics, inhibiting sodium, chloride, and water reabsorption in the distal tubule and the connecting segment. Additionally, potassium and magnesium are lost in the urine. When used in combination with furosemide, HCT prevents some of the distal sodium reabsorption that escapes the effects of the loop diuretics (as part of a sequential nephron blockade). The usual dosage is 1 to 2 mg/kg once or twice daily PO, provided the drug is tolerated. To prevent rapid volume depletion and electrolyte disturbances, when HCT is added to furosemide, the authors recommend administering the drug once a day or every other day for the first week, starting at the lower end of the dosage range. Laboratory values should be checked within 7 days, or immediately if the dog becomes depressed or ill. If renal function and electrolyte levels remain stable, the frequency of dosing can be increased.


Adverse effects are similar to those described earlier for furosemide. When combination diuretic therapy is administered, profound azotemia, hypokalemia, hypochloremia, and hyponatremia can develop within a matter of days, regardless of cotreatment with spironolactone or an ACE inhibitor.



Angiotensin-Converting Enzyme Inhibitors and Other Vasodilators


Vasoconstriction is a feature of HF and is mediated by the interaction of calcium with myosin light-chain kinase within the smooth muscle cell. Calcium enters the cell by crossing L-type channels to release intracellular stores of calcium. Opening of the calcium channel is modulated by a number of receptors on the vascular smooth muscle, including the α-adrenergic receptor, the angiotensin II receptor, the endothelin receptor, and the vasopressin receptor, among others. Conversely, the generation of cyclic nucleotides by stimulation of vascular β2-receptors, natriuretic peptide receptors, or muscarinic receptors leads to vasodilation by interfering with intracellular calcium dynamics.


The chronic activation of vasoconstricting systems observed in CHF is considered maladaptive, and ACE inhibitors are mainstays of CHF therapy. Additionally other vasodilator drugs may be useful in specific situations. For example, phosphodiesterase inhibitors such as pimobendan and sildenafil prevent the breakdown of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), respectively, thereby potentiating the physiological vasodilator effect.


Drugs that induce venodilation can cause pooling of blood in systemic veins and reduce venous pressures and pulmonary congestion, while drugs that cause systemic arteriolar dilation lower arterial BP and potentially ventricular afterload. Mitral regurgitant volume usually is reduced by the lowering of diastolic BP; this is another potential benefit of ACE inhibitors and arterial vasodilators like sodium nitroprusside, amlodipine, pimobendan, and hydralazine.



Angiotensin-Converting Enzyme Inhibitors


The renin-angiotensin-aldosterone system (RAAS) is activated by the sympathetic nervous system, reduced renal perfusion, and impaired sodium delivery to the juxtaglomerular apparatus of the kidneys. The results of RAAS activation are direct vasoconstriction and augmented release of norepinephrine and vasopressin via central pathways; aldosterone release with resultant sodium and water retention; and activation of growth-promoting systems in tissues. The ACE inhibitors, including benazepril, enalapril, imidapril, lisinopril, ramipril, and quinapril, inhibit the RAAS by blocking the kininase (converting enzyme) that converts angiotensin I to the active peptide hormone angiotensin II. This leads to decreased plasma angiotensin II and as well as delayed degradation of vasodilating kinins, which have effects on both arteries and veins. The RAAS also can be blocked earlier in the pathway with renin inhibitors (e.g., aliskiren) or at the level of the angiotensin II receptor (e.g., losartan or valsartan); however, drugs in these classes have not been studied sufficiently in the treatment of canine CHF. Angiotensin II receptor blockers are currently under clinical investigation.


ACE inhibitors reduce serum aldosterone concentration and limit sodium retention and potassium loss in the urine. Additionally, ACE inhibitors protect cardiac muscle, renal tissues, and blood vessels from RAAS-induced injury while down-regulating the sympathetic nervous system. Vasodilation associated with ACE inhibition is not as dramatic as that observed with calcium channel blockers or intravenous nitrates so the overall effect on arterial BP is modest, especially in the treatment of dogs with systemic hypertension. The published dosage ranges for enalapril and benazepril vary considerably from as low as 0.25 mg/kg once or twice daily to as high as 0.5 mg/kg twice daily. The authors generally start with enalapril at approximately 0.25 mg/kg q12h PO and double the dosage to approximately 0.5 mg/kg q12h PO at the time of first reevaluation as long as arterial BP and renal function are acceptable (see Chapter 176).


The use of ACE inhibitors is considered a standard of care for management of established CHF in dogs caused by chronic valvular disease or DCM. They also are used more controversially for treatment of advanced, preclinical mitral valve disease and with greater acceptance for treatment of preclinical (occult) DCM. ACE inhibitors are appropriate treatments for dogs with systemic hypertension associated with chronic kidney disease, but as stated earlier, are less potent than amlodipine or the α-adrenergic blocker prazosin for control of moderate to severe hypertension.


The main adverse effects of ACE inhibitors and other vasodilator drugs are systemic hypotension (causing weakness or lethargy) and impairment of renal function. Glomerular filtration is augmented by angiotensin II constriction of the efferent arteriole of the glomerulus. Therefore the sudden blocking of the RAAS can induce acute renal failure by suddenly lowering pressure in the glomerular tuft, especially in dogs that have been volume depleted with furosemide. In most cases, this adverse effect is responsive to withdrawal of the ACE inhibitor, reduction of the diuretic dose, and judicious volume replacement with 0.45% saline with potassium chloride supplementation. Most of these dogs eventually can tolerate an ACE inhibitor, but slow up-titration of the dose is necessary once a stable diuretic dosage that controls CHF has been established. Hyperkalemia is a risk with all ACE inhibitors, especially when they are combined with spironolactone (but mild hyperkalemia is acceptable).

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Drugs for Treatment of Heart Failure in Dogs
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