What drug for what disease (Proceedings)

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What drug for what disease (Proceedings)

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Aug 01, 2011

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.