Adverse effects

By reducing concentrations of angiotensin II, angiotensin-converting enzyme inhibitors decrease the kidney’s ability to autoregulate glomerular filtration fraction. In patients being treated with renin–angiotensin antagonists with marginal cardiac output, low blood pressure or concomitant use of Na⁺K⁺2Cl symport inhibitors, the glomerular filtration fraction may decline and an increase in serum creatinine concentrations may ensue.⁷ A significant decline in blood pressure may occur after an initial dose of angiotensin-converting enzyme inhibitors necessitating initiation of the drug with a low dose. Cough may develop weeks to months after initiation of therapy.¹ Angioedema is a rare side effect in human patients.

Drug interactions

There is no interaction with digoxin. Angiotensin-converting enzyme inhibitors are eliminated by the kidney and caution should be taken in patients with decreased renal function. They are contraindicated in pregnancy due to malformation of the fetal kidneys.

Mechanism of action

Categories of diuretics are based on their molecular pharmacology. The most commonly used diuretic in the horse is frusemide, a Na⁺K⁺2Cl symport inhibitor, previously referred to as a loop diuretic. Potassium sparing diuretics, which may decrease the risk of digoxin toxicity, fall into two categories, epithelial sodium channel inhibitors (amiloride) and type I mineralocorticoid/glucocorticoid receptor antagonists (spironolactone). Osmotic diuretics, such as mannitol, increase extracellular fluid volume and are contraindicated in decompensated heart failure. Carbonic anhydrase inhibitors (acetazolamide) may induce a metabolic acidosis that may be beneficial in patients with hypochloraemic metabolic alkalosis secondary to prolonged use of a Na⁺K⁺2Cl symport inhibitor.

Inhibitors of the Na⁺K⁺2Cl symport

Inhibitors of an ion transport protein, the Na⁺K⁺2Cl symport, in the thick ascending limb of the loop of Henle were previously known as loop diuretics. They are the only diuretics that are effective alone in moderate to advanced heart failure. The other diuretics act more distally and are less effective because of the enhanced water and solute resorption in proximal nephron segments in heart failure. The Na⁺K⁺2Cl symport inhibitors may need to be combined with other diuretics in advanced stages of heart failure.³ Evidence suggests the Na⁺K⁺2Cl symport inhibitors bind to the chloride binding site but the exact mechanism is unknown.⁹ Inhibition of the symporter prevents the renal epithelial cell from absorbing sodium and chloride. Lack of ions in the medullary interstitium reduces its tonicity and decreases the driving force for water resorption in the collecting duct. Excessive sodium and fluid in the distal nephron enhances the secretion of potassium and hydrogen ions. Loop diuretics also inhibit absorption of calcium and magnesium because they are linked to sodium and chloride transport. Frusemide is the most widely used diuretic in this category. Effects of frusemide on the cardiovascular system have been well documented in the normal horse. Decrease in plasma volume, right atrial pressure, stroke volume and cardiac output and an increase in systemic vascular resistance occur acutely following administration. These rapid haemodynamic actions of loop diuretics are attenuated in studied human patients with chronic congestive heart failure.³ Chronic use of frusemide may induce hypokalaemia, hypochloraemic alkalosis, hyponatraemia and hypomagnesaemia. These electrolyte disturbances increase the risk for development of digoxin toxicity in patients treated with both drugs. Frusemide should be used intermittently to control the symptoms of heart failure. Horses treated with long-term digoxin and frusemide should have serum electrolyte concentrations monitored routinely. Supplementation with the appropriate electrolyte or change of diuretic is warranted if electrolyte disturbances are detected. The dosage of frusemide in the horse is 1 mg/kg IV, IM as needed, usually twice daily.¹⁰ Continuous rate infusions have been evaluated in the horse and cause more profound diuresis in the first 8 hours of treatment using a loading dose of 0.12 mg/kg followed by an infusion of 0.12 mg/kg/hour.¹¹ This may be useful for initial stabilization of horses presenting with acute congestive heart failure, although there is no improvement in diuresis after the first 8 hours of treatment over conventional intravenous medication every 8 hours.¹¹ The oral bioavailability of frusemide is poor and highly variable¹² and therefore intramuscular administration is recommended for ongoing therapy. ( PH, VMD)

Potassium-sparing diuretics

Potassium-sparing diuretics are divided into two categories based on their molecular pharmacology. Diuretics, such as amiloride, inhibit sodium selective channels in the late distal convoluted tubule and the cortical collecting duct. The other category of potassium sparing diuretics are inhibitors of type I mineralocorticoid/glucocorticoid receptors and act as an aldosterone antagonist, such as spironolactone. Neither of these diuretics is sufficient alone in advanced heart failure although they may affect cardiac remodelling as discussed in Chapter 2. Care should be taken when using these diuretics with ACE inhibitors or in patients with reduced renal function, which may increase the serum potassium concentration. Potassium-sparing diuretics also cause less magnesium wasting than the Na⁺K⁺2Cl symport inhibitors. Pharmacokinetics and dosage for the potassium-sparing diuretics have not been established in the horse.

Inhibitors of the Na⁺ Cl⁻ symporter

Thiazide diuretics inhibit the sodium/chloride symporter in the renal epithelial cell in the distal convoluted tubule increasing loss of sodium, chloride and water into the urine. Excessive sodium and fluid in the distal nephron enhances the secretion of potassium and hydrogen ions. Alone, these diuretics are only useful in mild heart failure. However, when combined with loop diuretics, they exhibit synergism which may be useful in patients resistant to loop diuretics. Pharmacokinetics and dosage for the thiazide diuretics have not been established in the horse.

Mechanism of action

Pharmacokinetics

Digoxin is available as oral tablets, elixir and intravenous formulations. Because there is considerable variability in the systemic availability of oral formulations of digoxin on the market, the same product should be used consistently during maintenance therapy.³ Digoxin should not be given intramuscularly as it causes local irritation and is absorbed erratically.³ Pharmacokinetic studies of digoxin have been performed in the normal horse and in horses in congestive heart failure.^15–20 Digoxin is eliminated by glomerular filtration and tubular secretion.³ In patients with decreased kidney function or those on diuretics or sympathomimetic agents with increased renal clearance, the dosage of the drug should be adjusted. Because of its large volume of distribution, digoxin cannot be removed by peritoneal dialysis.³ Digoxin is stored in the skeletal muscle, not fat, so dosage should be calculated on lean body mass. Digoxin has been shown to cross the placenta in humans.³ In the horse, 20–40% of digoxin in the plasma is protein bound.¹⁵

Bioavailability of oral digoxin is approximately 20%.^17,19,20 Time to peak serum concentration is 1–2 hours after oral administration.^16,19,20 A second rise in serum concentration occurs 4–8 hours later most likely due to enterohepatic recycling of the drug, slowed absorption or delayed availability of partially dissolved tablets.^17,20 There is considerable variation in the serum concentration of digoxin following oral administration in individual animals.^17,19 The reported range for the biological half-life of digoxin in the horse is 17–23 hours.^15,17,19 Without loading doses, the serum concentration of digoxin reaches a steady state in the horse within 3.5 days for 12 hour dosing interval.¹⁹ The dosage for intravenous maintenance is 2.2 µg/kg every 12 hours and for oral maintenance is 11 µg/kg every 12 hours.²⁰ An initial maintenance dose (2.2 µg/kg IV) given intravenously will result in achievement of therapeutic concentration more rapidly than oral administration for a portion of the dosing interval. Larger loading doses will increase the chance of toxicity.²⁰ The therapeutic plasma concentration of digoxin is between 0.5 and 2.0 ng/mL.¹⁷

Therapeutic drug monitoring and adverse effects( VT)

Because there is a narrow safety margin between the therapeutic and toxic levels of digoxin and because digoxin interacts with many commonly used medications, digitalis toxicity may occur during treatment. The initial signs of digoxin toxicity are anorexia, colic and diarrhoea due to alterations in sympathetic tone. Cardiac dysrhythmias are a common and potentially life-threatening result of digitalis intoxication. Close monitoring of the clinical response and plasma digoxin concentration must be performed in treated horses to avoid toxicity. The level at which clinical symptoms of toxicity show a rapid increase in prevalence is above 2.0 ng/mL. Some patients may show signs of toxicity within the “therapeutic” range. Serum levels should be taken 3.5 days after initiation of therapy since individual animals vary in their response.^19,20 Serum samples should be taken at the time of peak and trough concentrations, 2 and 12 hours, respectively, after the last dose is administered.²⁰

There are many drugs that may potentially interact with digoxin; H₂ blockers, bran and albuterol may decrease the blood concentration of digoxin¹ while propafenone, quinidine, verapamil, erythromycin, omeprazole, phenylbutazone and tetracycline may increase serum concentrations of digoxin.^1,10 Hypoproteinaemia may decrease protein binding thereby increasing the unbound, metabolically active, concentration of the drug. Hypokalaemia, hypomagnesaemia and hypocalcaemia make the patient more sensitive to the toxic effects of digoxin. Hyperkalaemia decreases the binding affinity for digoxin and decreases the sensitivity to toxic effects, although it may exacerbate digoxin-induced conduction disorders and result in high-grade atrioventricular nodal block.³

Digoxin toxicity produces an increase in sympathetic tone and progressive inhibition of the Na⁺K⁺ATPase. The inhibition of Na⁺K⁺ATPase leads to a loss of cardiac cellular potential and excessive accumulation of intracellular calcium that alters cardiac conduction.¹⁰ Ectopic beats of atrioventricular junctional or ventricular origin, first-degree atrioventricular block and an excessively slow ventricular response to atrial fibrillation are the most common dysrhythmias in humans.¹

In the case of digoxin toxicity, digoxin therapy should be immediately discontinued. Serum electrolyte and digoxin concentrations and acid-base status should be determined. Treatment for fluid, electrolyte and acid-base disturbances should be instituted. Even if the serum concentration of potassium is in the normal range, potassium can be administered to animals with life-threatening dysrhythmias, unless high-degree atrioventricular block is present. Hypomagnesaemia, hypokalaemia and hypocalcaemia make the patient more susceptible to toxic effects and should be corrected. Lignocaine or phenytoin may be used for worsening ventricular dysrhythmias that cause the patient to be haemodynamically unstable.²¹ Care should be taken with quinidine administration as it will increase unbound digoxin levels. If symptomatic, sinus bradycardia, sinoatrial arrest and 3rd degree atrioventricular block usually respond to the administration of atropine.¹ Antidigoxin immunotherapy is available for humans, but is prohibitively expensive for equine patients.