What drug for what disease (Proceedings)

Case 1: Drake, a 9 y MN Doberman Pinscher, presenting for dyspnea

     • CV examination: HR 180, irregularly irregular rhythm, II/VI left apical holosystolic murmur, RR 60, adventitious lung sounds with moderate effort, coughing, weak pulses with deficits. Hydrated, quiet and alert.

     • Diagnostic tests: blood work unremarkable. Oxygen saturation 92%. Doppler blood pressure 85-90 mmHg

     • Thoracic radiographs: moderate perihilar to caudodorsal interstitial infiltrates consistent with moderate pulmonary edema, moderate cardiomegaly and left atrial dilation, pulmonary venous distension.

     • Electrocardiogram: atrial fibrillation, HR 200

     • Echocardiogram: severe dilated cardiomyopathy with a fractional shortening of 7%, severe left atrial dilation (LA:Ao 2.7), severe left ventricular eccentric (compensatory) hypertrophy, moderate mitral regurgitation (functional, centrally arising)

What Drug(s) are critical for this dog?

Problem 1: Moderate pulmonary edema and hypoxemia

Drug of choice

     • Furosemide, intravenous

Dose

     • initial doses 4-6 mg/kg IV q 1-4 hrs until RR decreases ~30%, then decrease to 3-4 mg/kg IV q 4-6 hrs, until RR < 50, then rapidly taper to lower dose (~2 mg/kg) q 8-12 hrs.

Mechanism of action

     • As a loop diuretic, it inhibits the Na+/K+/2Cl- cotransporter in the thick ascending loop of henle, leading to urinary loss of water, sodium, chloride, potassium, calcium, and magnesium

Drug properties

     • Furosemide is highly protein bound (86-91%), which traps the diuretic in the vascular space to deliver it to the proximal renal tubule, where 55% is excreted in the urine, and 45% is eliminated by the liver.(1) A small amount (<15%) is conjugated with glucuronic acid (not by the liver) and excreted. Therefore, there must be adequate blood flow to deliver the furosemide to the kidney (a problem with low output heart failure), and adequate renal function to excrete the drug. Renal insufficiency prolongs the plasma half life of furosemide since the excretion is slower. Non-steroidal anti-inflammatory drugs also reduce the diuretic response to furosemide by increasing the solute reabsorption at the thick ascending LOH.

Bioavailability

     • ~50% oral bioavailability, marked individual variability, ranging from 10-100%

Pharmacodynamic effects

     • IV: diuretic effect seen 5 minutes post-IV injection, peak diuretic effect 30 minutes post IV injection, duration of diuresis 2- 3 hrs. Venodilation seen 5-15 minutes after IV injection.

     • PO: diuretic effect seen by 1 hr, peak effect at 1-2 hrs, duration of diuresis 6 hrs

     • Additional physiologic effects of furosemide: bronchodilation (horses, people, unknown in cats and dogs), increases renal blood flow by reducing renal vascular resistance (possibly mediated by prostaglandins), increases thoracic duct lymph flow following very high IV doses (8-10 mg/kg)

Adverse effects

     • Hypovolemia, dehydration, electrolyte losses (hyponatremia, hypochloridemia, hypokalemia) which are more profound with aggressive IV diuresis than chronic oral treatment

     • Tricks to handle the adverse effects: never with- hold water, always have water available or there will be much more significant dehydration and azotemia. Do not start an ACE inhibitor during the aggressive acute diuresis stage, as it will exacerbate azotemia. Wait a few days until the animal is home, eating and drinking until the ACE inhibitor is started. Know what the renal function is before the animal is given furosemide by obtaining urine specific gravity and renal values, which may identify patients that are at higher risk of significant azotemia during diuretic therapy. Monitor renal values ~q12 hrs during the acute diuresis stage, but don't panic with mild to moderate azotemia. When to be concerned? If the animal is vomiting, not drinking, not eating, and creatinine has increased to 3 if baseline was normal. Often BUN increases to a much greater extent than the creatinine, but there would be concern if it increased from normal to ~60. If there is marked dehydration and azotemia, judicious low rate (1/2 maintenance IV fluids) may be cautiously given, consider 0.45% saline and the diuretic dose should be significantly reduced.

What drug is NOT for this disease?

     • Mannitol, an osmotic diuretic, is contraindicated for treatment of heart failure, as it will hasten pulmonary edema formation by increasing the intravascular blood volume.

     • In the acute setting, spironolactone and ACE inhibitors are not useful, since their effects are mild and exert a more chronic subtle benefit, but may be added later during chronic treatment.

Transitioning from acute to chronic treatment of congestive heart failure

Oral furosemide

Dose

     • 1-4 mg/kg PO q24 hr to TID; note: ~40-50% bioavailability, so the PO dose does not translate to the IV dose given acutely

     • In this case above, he was started on 2 mg/kg PO TID for several days, then decreased to 2 mg/kg PO BID, and a recheck planned for 1 week after discharge. The lowest effective chronic dose should be found, this is based on clinical response (owners should chart daily the respiratory rate and effort, cough) and follow-up radiographic assessment of whether pulmonary edema or pulmonary vascular distension is present.

Adjunctive therapy

     • ACE inhibitor, pimobendan, +/- spironolactone

Mechanisms of loss of diuretic potency

     • Acute "braking" effect after the first injection: decreased intravascular blood volume and activation of the RAAS system cause rebound sodium reabsorption

     • Chronic diuretic resistance: There is RAAS activation with heart failure and also with use of furosemide, which increases plasma aldosterone. Aldosterone causes hypertrophy of the cells of the distal tubule and collecting duct, which increase reabsorption of sodium through the Na+/K+/ H+ counter transporter.

Problem #2: Atrial fibrillation with a rapid ventricular response rate

     • Drug of choice: diltiazem

Dose

     • PO: 0.5- 1.5 mg/kg PO TID for atrial fibrillation, starting at low end and up-titrating. Note: dose for SVT is often much higher (1-4 mg/kg)

     • There are several sustained release formulations including Dilacor, which has several 60 mg tablets within a larger capsule. Studies are lacking regarding the pharmacokinetics of sustained release diltiazem in dogs. Anecdotal doses are 2-4 mg/kg PO BID.

     • IV: 0.125 mg/kg – 0.25 mg/kg over 2 minutes, repeat if needed in 15 minutes, CRI 2-6 mcg/kg/min, often used for severe sustained supraventricular tachycardia, or if the atrial fibrillation rate is >220 bpm incessantly

Treatment goal

     • Slow the ventricular response rate to 140 bpm or less. Tachycardia increases myocardial oxygen consumption, increases diastolic filling pressure, and exacerbates the severe myocardial failure and heart failure present in this dog with DCM.

Mechanism of action

     • Cardiac selective L-type calcium channel antagonist (non-dihydropyridine)

Drug Properties

     • Highly protein bound (70%), peak blood concentration 30 minutes after oral dose, elimination half- life 2-4 hours (2)

Bioavailability

     • Low (25%) in dogs

Pharmacodynamic effects

     • Negative chronotrope affecting the SA and AV nodes, with minimal to very mild vasodilator effects on the arteriolar smooth muscle, mild negative inotropic effects likely dose dependent. Potent coronary artery vasodilator.

Electrophysiologic effects

     • Sslows the AV nodal depolarization and prolongs the AV nodal refractory period, which reduces the number of atrial fibrillation wavelets that reach the ventricle, thereby slowing the ventricular response rate.

     • Slows the sinus nodal depolarization rate

Adverse effects

     • Bradycardia, AV block (first or second degree)

     • Decreased contractility and cardiac output, especially in dogs with severe myocardial failure and heart failure, usually at higher doses or IV administration

     • Hypotension: Decreased contractility and mild systemic arteriolar vasodilation may lead to hypotension.

What drug is NOT for this disease?

     • Beta blockers will reduce the ventricular rate of atrial fibrillation, but also exert powerful negative inotropic effects, which could be fatal in this patient with severe DCM, hypotension, and moderate heart failure. Beta blockers should not be given in animals with uncontrolled heart failure and significant myocardial failure. They can be slowly up-titrated over several weeks in dogs with DCM for other additional possible beneficial effects, but this patient requires more significant negative chronotropic therapy now. Combination of beta blockers and calcium channel blockers can be very dangerous and can lead to potentiation of negative inotropic and chronotropic effects.

     • Sotalol is a Class III potassium channel blocker, and also a beta blocker, so I would avoid it in this dog with severe DCM and heart failure, given the possibility of worsening the myocardial failure.

What drugs may be helpful in addition to diltiazem for rate control of atrial fibrillation?

     • Digoxin is a mild negative chronotrope (by increasing vagal tone) and weak positive inotrope that may help slow the ventricular rate of atrial fibrillation, and could be added. It is not likely to have enough rate lowering effects on its own to dramatically reduce the rate enough in this patient.

Problem #3: Severe Myocardial Failure

Drug of choice

     • pimobendan. Note: dobutamine is an additional choice for this hospitalized patient with DCM and heart failure

Dose

     • 0.25- 0.3 mg/kg PO BID

Mechanism of action

     • phosphodiesterase III inhibitor and calcium sensitizer

Drug Properties

     • highly protein bound, rapidly absorbed with peak plasma levels 0.5-1 hr following oral administration. It is metabolized by the liver (oxidatively demethylated) to more potent metabolite, and is excreted (95%) in the feces, 5% renal excretion. The elimination half-life is 0.5 hr for the parent drug and 2 hrs for the active metabolite. Duration of effect is > 8 hr.

Bioavailability

     • 60% without food. Chronic dosing may be done with food, but initial doses may be best on an empty stomach.

Pharmacodynamic effects

     • Cardiovascular effects are prolonged > 8 hr after oral administration despite short elimination half life. Acute hemodynamic effects have been measured after 30 minutes of oral administration.

     • Myocardial effects: Pimobendan is a potent positive inotrope by sensitizing myofilaments and cardiac proteins (including troponin C) to calcium. Phosphodiesterase inhibition reduces degradation of cAMP, an important second messenger involved in contraction and relaxation. Pimobendan increases contractility comparable to dobutamine, but without increasing myocardial oxygen consumption.(3) Pimobendan improves diastolic function, and reduces diastolic filling pressure.

     • Vasodilation: Pimobendan moderately reduces systemic vascular resistance (via PDE III inhibition), reduces pulmonary vascular resistance (~30%), and causes coronary artery vasodilation.(4) Renal blood flow is also increased in dogs given pimobendan.(4;5)

     • Improved myocardial energetics and efficiency: by reducing afterload, improving contractility and increasing coronary artery blood flow, pimobendan increases cardiac output without the expense of increased myocardial oxygen consumption, providing a more favorable energetic profile for a failing heart.

     • Pimobendan reduces regurgitant fraction in dogs with mitral regurgitation, likely as a result of afterload reduction.

     • Pimobendan also reduces several inflammatory cytokines including tumor necrosis factor- α, interleukin-1, and inducible nitric oxide synthase, which exert negative inotropic effects.

Adverse effects

     • Side effects are uncommon, and include diarrhea, anorexia, or vomiting. Pro-arrhythmic effects such as potentiating ventricular arrhythmias have not been demonstrated in several clinical canine studies. Pimobendan should not be given in asymptomatic dogs, as a small case series reported worsened myxomatous valve degeneration and regurgitation in asymptomatic dogs given pimobendan.(6)

What drug is NOT for this disease

     • General anesthesia is contraindicated in this patient with severe DCM and heart failure. Opioids and other sedatives may worsen myocardial failure and depress respiratory function. Acepromazine should be avoided since he already has hypotension.

What drugs may be added in addition to pimobendan for treatment of severe myocardial failure?

     • Digoxin may be added as a weak positive inotrope (unmeasurable on echocardiogram). In the acute intensive care setting, a dobutamine CRI could be started to help stabilize this dog.

CASE #2

Fred, a 10 yr MN Bassett hound, presenting complaint: dyspnea, cough

Past history

     • Six months ago, Fred was diagnosed with severe mitral regurgitation due to myxomatous valve degeneration and mild congestive heart failure. Heart failure has progressed over the past few months, and required increasing furosemide dose to 4 mg/kg PO TID. Other medications include: pimobendan and enalapril.

CV examination

     • HR 150 bpm, VI/VI left apical pansystolic murmur with S3 gallop, RR 60 with adventitious lung sounds, SPO2 92%

     • Doppler systolic blood pressure 140 mmHg

     • Chemistry: BUN 40, creatinine 2, K 3.8.

     • Thoracic radiographs: severe cardiomegaly, severe left atrial dilation, progressive and moderate perihilar to caudodorsal pulmonary interstitial infiltrates and pulmonary edema, pulmonary venous distension.

Assessment

     • Refractory congestive heart failure

Drug of choice

     • Parenteral furosemide + afterload reducer (amlodipine)

Dose

     • Amlodipine 0.2-0.6 mg/kg PO q24 hr – BID; target is to reduce BP by 10-15 mmHg, and systolic BP should be <140 mmHg in dogs with severe mitral regurgitation and heart failure.

Mechanism of action

     • Dihydropyridine, vascular selective calcium channel blocker

Drug properties

     • Highly protein bound (93%), peak plasma concentrations 6-9 hours post oral administration. Amlodipine is extensively metabolized by the liver to inactive metabolites. Elimination half-life 30 hours in dogs.(7)

Bioavailability

     • 88% in dogs

Pharmacodynamic effects

     • Potent systemic arteriolar vasodilation with slow onset and prolonged duration of effect. There are minimal effects on the calcium channels of the heart at the level of the myocardium and the nodal excitatory tissue.

     • As an afterload reducer, it reduces systemic vascular resistance, which promotes forward flow and reduces mitral regurgitant fraction in dogs with mitral regurgitation. When mitral regurgitation is decreased, the left ventricular diastolic pressure, left atrial pressure, and pulmonary capillary wedge pressure also decrease, which lessens pulmonary edema formation. This is especially useful in dogs with refractory heart failure. Amlodipine also activates the RAAS system which increases plasma aldosterone concentration and may contribute to furosemide resistance, so it should be given in combination with enalapril in dogs with heart failure.(8)

Adverse effects

     • Hypotension is unusual in animals placed on amlodipine. A rare idiosyncratic side effect in people and dogs is gingival hyperplasia, which occurs in 8.5% of dogs on chronic (>6 months) amlodipine therapy.(9) The gingival hyperplasia resolves within a few weeks of discontinuing the treatment. Patients can be placed on hydralazine as an arteriolar vasodilator instead of amlodipine.

What drug is NOT for this disease?

     • Osmotic diuretics (mannitol) are contraindicated for heart failure. Phenylpropanolamine is a sympathomimetic amine used for treatment of urethral sphincter hypotonus and resulting incontinence, and has both alpha and mild beta adrenergic agonist effects. Diuretics often unmask urinary incontinence. Rather than chancing possible deleterious effects of PPA in heart failure patients, diethylstilbesterol may be a better choice in these patients.

What other drugs could be used in addition to amlodipine in this patient?

     • Hydrochlorothiazide is a second diuretic that may aid in reduction in pulmonary edema in patients already maximized on furosemide. In addition, spironolactone may be added in patients with refractory heart failure, but has negligible diuretic effects and effects are related to neurohormonal antagonism. If this patient had fulminant heart failure, a more rapid acting arteriolar vasodilator would be needed, such as nitroprusside, to rapidly reduce blood pressure to 95-100 mmHg. Amlodipine can be started, and nitroprusside weaned off once the vasodilatory effects of amlodipine are seen.

     • Combination therapy of amlodipine with L-type calcium channel blockers, ACE inhibitor, pimobendan, or beta blockers is safe, but care must be taken to monitor for hypotension.

CASE # 3:

6 yr MN Boxer, presenting complaint: syncopal episodes

CV examination

     • HR 220 bpm, I/VI left basilar holosystolic murmur, weak pulses, pale MM

     • ECG ventricular tachycardia

     • Echocardiogram: unremarkable

     • Bloodwork: unremarkable

     • Thoracic radiographs: unremarkable

     • Blood pressure: 80 mmHg systolic

Assessment

     • Sustained ventricular tachycardia, hypotension secondary to severe tachyarrhythmia.

Drug of choice

     • Lidocaine

Dose

     • 1-2 mg/kg IV over 1-2 minutes, repeated to total dose of 6 mg/kg IV, followed by CRI of 30-90 mcg/kg/min

Mechanism of action

     • Class Ib antiarrhythmic, fast sodium channel blocker

Drug Properties

     • Large first pass effect eliminates possibility of oral administration. It is extensively metabolized by the liver to active metabolites, with an elimination half-life 60-90 min. There is prolonged half-life in states with poor hepatic perfusion, such as with heart failure. Hypokalemia decreases sodium channel blocking effect of lidocaine, so should be corrected.

Bioavailability

     • Significant first pass effect and toxic metabolites limit use to IV use

Pharmacodynamic effects

     • Here is a rapid onset of action of 2 minutes and duration of action of 10-20 minutes, usually necessitating use of CRI after IV bolus.

     • Electrophysiologic effects

     • Lidocaine preferentially depresses abnormal automaticity of diseased ventricular myocytes, as well as prolongs conduction time and refractory time of diseased ventricular myocardium to interrupt reentrant ventricular arrhythmias.

Adverse effects

     • Hypotension and negative inotropic effects can occur if given rapid high dose boluses or high CRI dose, especially in animals with myocardial failure. CNS side effects are most common, including sedation, nausea, vomiting, nystagmus, muscle twitching, or seizures.

What drug is not for this disease?

     • Diltiazem, an L-type calcium channel blocker (Class IV antiarrhythmic) would have no effect on ventricular arrhythmias.

What other drugs can be used in addition to lidocaine in this dog?

     • If the ventricular arrhythmia is refractory to up to 6 mg/kg IV of lidocaine, procainamide IV bolus can be given, knowing that there is likelihood of hypotension when combining both medications. Esmolol may be used if procainamide fails, as long as the myocardial function is not poor. The last resort is intravenous amiodarone, which is not readily available in most veterinary clinics in an injectable form. Rapid acting injectable drugs are recommended in this case of life threatening ventricular tachycardia, and oral medications may be helpful long-term.

Transition to chronic oral therapy

Drug of choice

     • Sotalol

Dose

     • 1-3 mg/kg PO BID, initial dose may be 1- 1.5 mg/kg PO TID for 1-2 days during initial treatment, and lidocaine can be weaned off after 1- 2 days of starting sotalol.

Mechanism of action

     • Potassium channel blocker (Class III antiarrhythmic), non-selective beta blocker

Drug Properties

     • Sotalol is not metabolized and is eliminated via renal clearance, with an elimination half-life of 5 hours. Steady state is usually reached in 2-3 days. It is not protein bound in the plasma.

Bioavailability

     • 90%(10;11)

Pharmacodynamic effects

     • Electrophysiologic effects: As a potassium channel blocker, sotalol increases the refractory period and action potential duration of atrial and ventricular myocardium as well as the AV node. It increases the fibrillatory threshold of myocardial cells and may break up reentrant circuits within the myocardial cells. It decreases the slope of phase 4 pacemaker depolarizing potential, which slows the sinus nodal depolarization. Sotalol is especially effective in Boxer dogs with arrhythmogenic right ventricular cardiomyopathy. It is useful in treatment of both supraventricular and ventricular tachyarrhythmias. It has approximately 30% of the beta blocking potency of propranolol, so has less potential for negative inotropic effects than Class II beta blockers.

Adverse effects

     • Sotalol can decrease myocardial function since it has non-selective beta blocking effects, so should be used very cautiously in dogs with decreased myocardial function, and avoided if there is severe decompensated DCM. Low doses that are up-titrated may be needed to avoid low output heart failure in dogs with significant myocardial failure. Sinus bradycardia and first degree AV block often develop, and sometimes second degree AV block can occur. It is unusual but possible for any antiarrhythmic drug including sotalol to exert pro-arrhythmic effects, so careful assessment of post-treatment ECG and ideally a holter monitor is needed.

What drug is NOT for this disease?

     • Diltiazem, see above comments. Digoxin has no ventricular antiarrhythmic properties, and in toxic doses can cause serious ventricular arrhythmias. Use of amiodarone or beta blockers concurrently with sotalol should be avoided. Diltiazem may exacerbate negative inotropic and chronotropic effects of sotalol, and should be avoided if possible.

What other drugs may be added to sotalol in this case?

     • In animals with refractory ventricular arrhythmias receiving high doses of sotalol, addition of mexilitene, a class Ib antiarrhythmic, can have synergistic effects in suppressing ventricular arrhythmias.

Case 4: 10 yr MN terrier- mix presenting for seizure- like episodes

     • This patients was initially referred to the neurology service for evaluation of episodes of collapse and loss of consciousness. Neurologic examination was unremarkable. Several year history of moderate mitral valve degeneration.

     • Cardiovascular examination: V/VI left and right apical pansystolic murmurs, regular rhythm, HR 150 bpm.

     • Doppler BP 140 mmHg. ECG was unremarkable

     • Thoracic radiographs revealed severe cardiomegaly, severe left atrial dilation, and mild pulmonary edema with pulmonary venous congestion consistent with mild left sided congestive heart failure

     • Echocardiogram showed severe mitral regurgitation, moderate tricuspid regurgitation, and severe pulmonary hypertension.

Problem 1

Syncopal episodes and concurrent severe pulmonary hypertension

Drug of choice

     • sildenafil

Dose

     • 1-2 mg/kg PO TID

Mechanism of action

     • Selective phosphodiesterase 5 inhibitor, which decreases degradation of cyclic GMP in the pulmonary vasculature. Cyclic GMP causes pulmonary arteriolar vasodilation and inhibits smooth muscle proliferation through increases in protein kinases.

Drug Properties

     • Highly protein bound (86% in the dog), lipophilic. Metabolism of sildenafil occurs primarily by hepatic cytochrome P450 enzymes yielding one active metabolite with a potency of approximately 50% of the parent drug. Relatively long half life of 6.1 hr in the dog. Maximal absorption occurs in less than 1 hour after dosing.

Bioavailability

     • High; 54%

Pharmacodynamic effects

     • Mild to moderate pulmonary arteriolar vasodilation occurs, which decreases pulmonary vascular resistance and pulmonary artery pressure. It can reverse pathologic pulmonary arteriolar remodeling and smooth muscle hypertrophy through nitric oxide and cyclic GMP modulation of smooth muscle cell hypertrophy, which is also beneficial for patients with pulmonary hypertension. In dogs, sildenafil may also reduce systemic vascular resistance, although there are contradictory results in several experimental studies. Sildenafil has been shown to reduce the severity of pulmonary hypertension in people as well as dog, and improve QOL, reduce syncopal episodes, reduce dyspnea, and increase exercise capacity.(12;13)

Adverse effects

     • Sildenafil is safe to use in combination with other cardiac drugs such as pimobendan, furosemide, and ACE inhibitors. It could contribute to systemic vasodilation when given in combination with other vasodilators, so monitoring of blood pressure and starting at the low end of the dose is recommended.

     • What other drugs are for this disease? This dog has severe mitral regurgitation causing mild left heart failure. Triple therapy with furosemide, an ACE inhibitor, and pimobendan are indicated for the severe left heart disease. Pimobendan may also reduce the severity of the pulmonary hypertension by cyclic AMP induced pulmonary arteriolar vasodilation.

References

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Piepho, R. W., Bloedow, D. C., Lacz, J. P., Runser, D. J., Dimmit, D. C., and Browne, R. K. Pharmacokinetics of Diltiazem in Selected Animal Species and Human Beings. Am.J.Cardiol. 1982;49:525-8.

Fitton, A. and Brogden, R. N. Pimobendan. A Review of Its Pharmacology and Therapeutic Potential in Congestive Heart Failure. Drugs Aging. 1994;4:417-41.

van Meel, J. C. and Diederen, W. Hemodynamic Profile of the Cardiotonic Agent Pimobendan. J Cardiovasc.Pharmacol. 1989;14 Suppl 2:S1-S6.

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Chetboul, V., Lefebvre, H. P., Sampedrano, C. C., Gouni, V., Saponaro, V., Serres, F., Concordet, D., Nicolle, A. P., and Pouchelon, J. L. Comparative Adverse Cardiac Effects of Pimobendan and Benazepril Monotherapy in Dogs With Mild Degenerative Mitral Valve Disease: a Prospective, Controlled, Blinded, and Randomized Study. J Vet Intern Med.2007.Jul.-Aug.;21(4):742.-53. 2007;21:742-53.

Stopher, D. A., Beresford, A. P., Macrae, P. V., and Humphrey, M. J. The Metabolism and Pharmacokinetics of Amlodipine in Humans and Animals. J Cardiovasc.Pharmacol. 1988;12 Suppl 7:S55-S59.

Atkins, C. E., Rausch, W. P., Gardner, S. Y., DeFrancesco, T. C., Keene, B. W., and Levine, J. F. The Effect of Amlodipine and the Combination of Amlodipine and Enalapril on the Renin-Angiotensin-Aldosterone System in the Dog. J Vet Pharmacol.Ther.2007.Oct.;30.(5):394.-400. 2007;30:394-400.

Thomason, J. D., Fallaw, T. L., Carmichael, K. P., Radlinsky, M. A., and Calvert, C. A. Gingival Hyperplasia Associated With the Administration of Amlodipine to Dogs With Degenerative Valvular Disease (2004-2008). J Vet Intern Med.2009.Jan.-Feb.;23(1):39.-42. 2009;23:39-42.

Schnelle, K. and Garrett, E. R. Pharmacokinetics of the -Adrenergic Blocker Sotalol in Dogs. J.Pharm.Sci. 1973;62:362-75.

Gomoll, A. W., Lekich, R. F., Bartek, M. J., Comereski, C. R., and Antonaccio, M. J. Comparability of the Electrophysiologic Responses and Plasma and Myocardial Tissue Concentrations of Sotalol and Its d Stereoisomer in the Dog. J.Cardiovasc.Pharmacol. 1990;16:204-11.

Barnett, C. F. and Machado, R. F. Sildenafil in the Treatment of Pulmonary Hypertension. Vasc.Health Risk Manag.2006.;2(4):411.-22. 2006;2:411-22.

Bach, J. F., Rozanski, E. A., MacGregor, J., Betkowski, J. M., and Rush, J. E. Retrospective Evaluation of Sildenafil Citrate As a Therapy for Pulmonary Hypertension in Dogs. J Vet Intern Med.2006.Sep.-Oct.;20.(5):1132.-5. 2006;20:1132-5.