Salty Mineral Food Court Potassium Sparing Diuretics

2.4 – “Salty Mineral Food Court”: Potassium Spari Sparing ng Diuret Diuretics ics (am (amiloride, iloride, triamterene, ep eplerenone, lerenone, spironolactone) Collecting duct ((CD) CD) phys physiology iology • The CD is the final resorptive location of the kidneys (collecting duct gutter for lumen; park map; right side of sketch). It’s responsible for 2-5% of sodium resorption by the kidney. As the final site of resorption, is important for tight regulation of body water & sodium levels, as well as final osmolality of the urine. Most important site of potassium excretion by the kidney. • Principal cells are the major site of Na, K, & water transport (Principal Court signs indicating empty intracellular space). Transporters include: o Na-K-ATPase on basolateral membrane (banana vending machine). o ENaCs (epithelial Na channels) resorb Na across luminal membrane of the collecting duct (Salt-E sNAC carts along the edge of the luminal gutter). o K channels allow excretion of K into the tubular lumen of the collecting duct to maintain electric neutrality (banana man getting hit by Salt-E snack cart). o ENaC only draws Na, leaving a negative potential in the lumen → K+ excretion in order to maintain neutrality. This differs from elsewhere in the kidney, where NaCl transport is electrically neutral. • Alpha intercalated cells: excrete H+ into the lumen via H-ATPase pump on the apical membrane (Inter-continental food truck powered by 3Ⓟ batteries spewing acid into the gutter). Are involved in acid-base homeostasis. • Aldosterone’s main site of action is the CD; it is key to maintaining homeostasis (mineral court service man, holding intracellular mineral crystal [i.e. aldosterone] key). Promotes CD sodium resorption & volume retention. o Is a steroid hormone produced in adrenal cortex as the final product of RAAS. Receptor is intracellular and functions as a transcription factor to upregulate certain genes, including ▪ K+ channels on the apical membrane of the principal cells →↑K+ excretion (key on banana stand) ▪ ENaCs on the apical membrane of the principal cells →↑Na+ resorption (key in Salt-E snack cart) ▪ Na-K-ATPase on the basolateral membrane of the principal cells (key in banana vending machine) ▪ H-ATPase on apical membrane intercalated cells, increasing H+ secretion (key on food truck) o Results in ↑transepithelial electrical potential & dramatic rise in both sodium resorption & K secretion. • Note that loop & thiazide diuretics indirectly facilitate these same mechanisms by a few mechanisms o block sodium resorption → ↑CD Na concentration. This prompts ↑CD K+ secretion, causing hypokalemia. o Sodium resorption in the CD causes a negative luminal potential, favoring H+ secretion. Increase Na+ resorption can result in a metabolic alkalosis o all drop volume → upregulation of the RAAS. The end result is mineralocorticoid mediated increase in potassium loss & proton secretion PotassiumPotassium-sparing sparing diuret diuretics ics • Potassium sparing diuretics work directly on the CD (left side of sketch). Enhance activity of mineralocorticoid aldosterone. • Amiloride (almond box) o Inhibits sodium influx through ENaCs, thereby reducing Na resorption, promoting natriuresis (angry moms bumping Salt-E Snack cart into the lumen) o Useful in treatment of Liddle’s syndrome which results in overactivation of ENaCs. By blocking, can correct HTN & ↓K associated with the disorder (mom blocking little gnome) o Useful in treatment of Lithium-induced nephrogenic DI (peeing cherub statue). Blocks lithium entry into CD cells →↑lithium excretion. • Triamterene (tangerines) o Inhibits sodium influx through ENaCs, thereby reducing Na resorption, promoting natriuresis (angry moms bumping Salt-E Snack cart into the lumen) o Useful in treatment of Liddle’s syndrome which results in overactivation of ENaCs. By blocking, can correct HTN & ↓K associated with the disorder (mom blocking little gnome) • Eplerenone (woman with apple) & Spironolactone (health inspector with spiral notebook) o Directly antagonize mineralocorticoid receptors (antagonizing miner food court service employee so he cannot use crystal key) o Disrupted gene transcription means ↓activation of sodium & potassium currents at apical membrane → less sodium retention & less K wasting. o Recommended in some cases of severe HFrEF d/t blockage of aldosterone effects on the heart, with morbidity & mortality benefits (kid in angel outfit with deflated heart balloon). Produces regression in fibrosis; inhibition of remodeling, especially post-MI (remodeling rock behind kid); and improvement in ventricular ejection. Can be used in conjunction with loop diuretics to blunt K+ wasting. o most useful in states of mineralocorticoid excess, i.e. primary or secondary hyperaldosteronism (primary: Conn’s syndrome, ectopic ACTH; secondary: HF, hepatic cirrhosis, nephrotic syndrome, ↓intravascular volume) (Nephron Fun Zone Mineral Mountain, with abundant salty minerals) ▪ Clinical tip: HTN + ↓K levels suggest hyperaldosteronism! May also see metabolic acidosis, depressed plasma renin activity, or adrenal mass on CT o Treat symptoms of androgen excess in PCOS (e.g. hirsutism), as well as insulin resistance. Possible d/t lack of specificity for renal aldosterone receptors. • Side effects/toxicities o Hyperkalemia; may be mild or life-threatening (lady with raised bananas). ▪ Increased risk in kidney disease or concomitant use of drugs that inhibit renin or angiotensin-II activity (e.g. β blockers, ACE-inhibitors). o Normal anion gap metabolic acidosis (↓aldosterone → ↓function of H-ATPase) (Intercontinental food truck driving away, trailing acid) ▪ Similar to a type-4 renal-tubular acidosis, the only RTA with associated hyperkalemia (4 test tubes held in K-shape) o Spironolactone is not very specific to renal aldosterone Rs. Can have effects on other mineralocorticoid receptors & processing enzymes. Directly antagonizes androgen receptors. ▪ Block testosterone synthesis by blocking 17 α-hydroxylase → ↑cholesterol (17-α FRY-droxylase food cart) ▪ Treats symptoms of androgen excess in PCOS & the insulin resistance that often accompanies it; treats hirsutism in this case. ▪ Gynecomastia (dude holding plates to chest) ▪ Impotence & ↓libido (floppy churro)