Potassium-sparing diuretics Domina Petric, MD

Introduction Potassium-sparing diuretics prevent potassium secretion by antagonizing the effects of aldosterone in collecting tubules. Inhibition may occur by: direct pharmacologic antagonism of mineralocorticoid receptors (spironolactone, eplerenone) inhibition of sodium influx through ion channels in the luminal membrane (amiloride, triamterene)

Pharmacokinetics Spironolactone is a synthetic steroid that acts as competitive antagonist to aldosterone. Substantial inactivation of spironolactone occurs in the liver. It has slow onset of action, requiring several days before full therapeutic effect is achieved.

Pharmacokinetics Eplerenone is a spironolactone analog with much greater selectivity for the mineralocorticoid receptor. It is several hundredfold less active on androgen and progesterone receptors than spironolactone: fewer adverse effects.

Pharmacokinetics Amiloride and triamterene are direct inhibitors of sodium influx in the cortical collecting tubule (CCT). Triamterene is metabolized in the liver. Renal excretion is a major route of elimination for the active form of triamterene and the metabolites.

Pharmacokinetics Triamterene is extensively metabolized and it has shorter half-life. It must be given more frequently than amiloride, which is not metabolized.

Pharmacodynamics Potassium-sparing diuretics reduce sodium absorption in the collecting tubules and ducts. Potassium absorption and secretion at this site is regulated by aldosterone. Aldosterone antagonists interfere with this process.

Pharmacodynamics Spironolactone and eplerenone bind to mineralocorticoid receptors and blunt aldosterone activity. Amiloride and triamterene do not block aldosterone. They directly interfere with sodium entry through the epithelial Na+ channels (ENaC) in the apical membrane of the collecting tubule.

Pharmacodynamics Potassium secretion is coupled with sodium entry in the collecting tubule: potassium-sparing effect.

Pharmacodynamics The actions of the aldosterone antagonists depend on renal prostaglandin production. The actions of potassium-sparing diuretics can be inhibited by NSAIDs.

Dosage, combinations Trade Name Potassium-sparing agent Hydrochlorothiazide Aldactazide Spironolactone 25 mg 50 mg Aldactone Spironolactone 25, 50 or 100 mg Dyazide Triamterene 37,5 mg 25 mg Dyrenium Triamterene 50 or 100 mg Inspra Eplerenone 25, 50 or 100 mg Maxzide Triamterene 75 mg Maxzide-25 mg Midamor Amiloride 5 mg Moduretic

Clinical indications States of mineralocorticoid excess or hyperaldosteronism (aldosteronism): PRIMARY hypersecretion: Conn´s syndrome, ectopic adrenocorticotropic hormone production SECONDARY hyperaldosteronism: evoked by heart failure, hepatic cirrhosis, nephrotic syndrome

Clinical indications Thiazides and loop agents can cause or exacerbate volume contraction and may cause secondary hyperaldosteronism. These agents also cause potassium wasting. Potassium-sparing diuretics blunt the potassium secretory response.

Clinical indications Eplerenone 25-50 mg/day may interfere with some of the fibrotic and inflammatory effects of aldosterone. It can slow progression of albuminuria in diabetic patients. Eplerenone can reduce myocardial perfusion defects after myocardial infarction.

Clinical indications Eplerenone can also reduce mortality rates in patients with mild to moderate heart failure after myocardial infarction.

Toxicity Hyperkalemia Hyperchloremic metabolic acidosis Gynecomastia Acute renal failure Kidney stones

Hyperkalemia These agents reduce urinary excretion of potassium. They can cause mild, moderate or even life-threatening hyperkalemia.

Hyperkalemia The risk is increased by: renal disease use of other drugs that reduce or inhibit renine (β blockers, NSAIDs, aliskiren) use of drugs that reduce angiotensin II activity (ACE-inhibtors, angiotensin receptor inhibitors).

Hyperkalemia With fixed-dosage combinations of potassium-sparing and thiazide diuretics, the thiazide-induced hypokalemia and metabolic alkalosis are ameliorated. It is preferable to adjust the doses of the two drugs separately because thiazide-associated adverse effects predominate in fixed combinations.

Hyperchloremic metabolic acidosis Potassium sparing diuretics cause acidosis similar to acidosis in type IV renal tubular acidosis by inhibiting hydrogen ions secretion in parallel with potassium secretion.

Gynecomastia Spironolactone can cause gynecomastia, impotence and benign prostatic hyperplasia.

Acute renal failure Triamterene and indomethacin combination has been reported to cause acute renal failure.

Kindey stones Triamterene is only slightly soluble. It may precipitate in the urine, causing kidney stones formation.

Contraindications Potassium-sparing agents can cause severe, even fatal, hyperkalemia in susceptible patients. Patients with chronic renal insufficiency are especially vulnerable.

Contraindications Patients with liver disease may have impaired metabolism of triamterene and spironolactone. Strong CYP3A4 inhibitors can increase blood levels of eplerenone: erythromycin, fluconazole, diltiazem, grapefruit juice.

Loop agents and thiazides combinations

Loop agents and thiazides Some patients are refractory to the usual dose of loop diuretics or become refractory after an inital response. These agents have a short half-life (2-6 hours). Refractoriness may be due to an excessive interval between doses.

Loop agents and thiazides Renal sodium retention may be greatly increased during the time period when the drug is no longer active. After the dosing interval for loop agents is minimized or the dose is maximized, the use of two drugs acting at different nephron sites may exhibit synergy.

Loop agents and thiazides Salt reabsorption in either the thick ascending limb (TAL) or the distal convoluted tubule (DCT) can increase when the other segment is blocked. Inhibition of both can produce additive diuretic response.

Loop agents and thiazides Thiazide diuretics often produce a mild natriuresis in the proximal tubule that is usually masked by increased reabsorption in the TAL. The combination blocks sodium reabsorption from all three segments. Combination can mobilize large amounts of fluid.

Loop agents and thiazides Close hemodynamic monitoring of the patients on combination is necessary, as well as careful monitoring of fluid and electrolyte status, especially potassium.

Literature Katzung, Masters, Trevor. Basic and clinical pharmacology.