Diuretics

Name the specific part of the nephron described by the following..

(1) area which creats hypertonic medullary fluid that is the driving force for later water reabsorption = THICK ASC LOOP OF HENLE

(2) principal site of salt & water reabsorption = PROXIMAL TUBULE

(3) site of aldosterone action = COLLECTING TUBULE

(4) 10% of filtered Na reabsorbed here; very low permeability = DISTAL CONVULTED TUBULE

(5) site of bicarb reabsorption = PROXIMAL TUBULE

(6) site of K and H secretion = COLLECTING TUBULE

(7) site of organic acid & base secretory systems = PROXIMAL TUBULE

(1) 2-5% = COLLECTING TUBULE

(2) 4-8% = DCT

(3) 25% = ASC LOOP OF HENLE

(4) 65% = PROX TUBULE

(1) variable permeability = COLLECTING TUBULE

(2) very low permeability = ASC LOOP OF HENLE & DCT

(3) very high permeability = PROX TUBULE

The low water permeability of the cells that comprise the ascending loop of Henle leads to HYPERTONIC medullary fluid and DECREASED tubular fluid tonicity.

(1) Proximal tubule = Na, Cl, bicarb & water are reabsorbed; H+ ions are secreted

(2) Asc loop of Henle = Na, K, Cl ions are reabsorbed; there is no water reabsorption

(3) DCT = NaCl reabsorption; no water reabsorption

(4) Collecting tubule = Na reabsorption; K & H secretion; water reabsorption depending on ADH

Bicarb reabsorption in the proximal tubule is dependent on
(1) the activity of carbonic anhydrase enzyme and
(2) the secretion of H.

Mannitol is an osmotic diuretic.

Two possible mechanisms
(1) increase osmolality of tubular fluid & decrease water (and Na) reabsorption

(2) cause movement of water out of cells, thus increasing renal blood flow, which decreases medullary hypertonicity & fluid reabsorption

Carbonic anhydrase inhibitors prevent breakdown of carbonic acid, which leads to a decrease in bicarb reabsorption. The Na-H antiporter is also involved in NaCl reabsorption, so acetazolamide also inhibits NaCl reabsorption...This decreases the osmotic gradient for water reabsorption which leads to increased delivery of bicarb, NaCl and water to the rest of the nephron.

Example: acetazolamide

(1) osmotic diuretics
(2) loop diuretics
(3) thiazides
(4) K-sparing diuretics
(5) carbonic anhydrase inhibitors

(1) furosemide
(2) bumetanide
(3) ethacrynic acid
(4) torsemide

Mechanism: block salt reabsorption in thick asc loop of Henle by inhibiting Na-K-2Cl symporter

osmotic diuretics (mannitol)

carbonic anhydrase inhibitors (acetazolamide)

Hazards of hypokalemia:
--cardiac arrhythmias
--increased risk of digitalis cardiac toxicity

These diuretics can produce hypokalemia:
--loop diuretics
--thiazides

Loop diuretics decrease left ventricular filling pressure and improve pulmonary congestion.

Loop: increase urinary calcium excretion by decreasing Ca reabsorption in asc loop of Henle

Thiazide: decrease urinary calcium excretion by increasing Ca reabsorption in proximal tubule and DCT

(1) hydrochlorothiazide
(2) chlorthalidone
(3) metolazone
(4) chlorothiazide (IV preparation)

They act on the DCT and inhibit the luminal NaCl symporter, thus, blocking salt reabsorption.

Thiazide diuretics

Common to loop & thiazide diuretics:
--hypokalemia
--hyponatremia
--metabolic alkalosis
--hyperuricemia
--hyperglycemia
--lipid alteration
--volume depletion

Loop diuretics -- namely ethacrynic acid -- may cause ototoxicity.

K-sparing diuretics include..

(1) sodium channel blockers (triamterene, amiloride)

(2) mineralocorticoid receptor antagonists (spironolactone, eplerenone)

Triamterene & amiloride act on the late distal tubule and the collecting duct to inhbiit Na channels. This causes decreased Na reabsorption and decreased K & H excretion.

Na-channel blockers.

Na-channel blockers reduce the amount of Na getting into the cells from the nephron lumen. This reduces Na reabsorption and K secretion, leading to higer levels of K in the blood.

Hyperkalemia

(1) K supplements
(2) ACE inhibitor
(3) angiotensin II blocker
(4) beta blocker
(5) NSAIDs

Spironolactone is a mineralocorticoid receptor antagonist and has an intracellular site of action.

It is a competitive antagonist of aldosterone and binds to the cytoplasmic receptor, preventing the binding of aldosterone. This leads to a decreased Na reabsorption and decreased excretion of H & K in the late distal tubule & collecting duct.

Spironolactone can cause gynecomastia in males.

Eplerenone is more selective than spironolactone and is less likely to cause gynecomastia.

(1) hypertension
(2) heart failure
(3) liver failure w/ ascites
(4) hypercalcemia
(5) kidney stones due to idiopathic hypercalcemia
(6) nephrogenic diabetes insipidus

(1) hydrochlorothiazide : inhibit NaCl symporter in DCT

(2) spironolactone : competively binds cytoplasmic aldosterone receptor, causing decreased Na reabsorption in late distal & collecting duct

(3) amiloride : inhibit Na channels in late distal tubule & collecting duct

(4) mannitol : inc osmolality of tubular fluid causing dec water reabsorption & increases renal blood flow leading to dec medullary hypertonicity & fluid reabsorption

(5) acetazolamide : inhibit carbonic anhydrase & dec bicarb reabsorption

(6) furosemide : inhibits Na-K-2Cl symporter in thick asc loop of Henle

(1) hydrochlorothiazide : distal tubule

(2) spironolactone : late distal tubule & collecting duct

(3) amiloride : late distal tubule & collecting duct

(4) mannitol : everywhere; mannitol is filtered into the nephron leading to increased osmolality of tubular fluid

(5) acetazolamide : proximal tubule

(6) furosemide : asc loop of Henle

(1) glaucoma : acetazolamide (carbonic anhydrase inhibitor)

(2) hypercalcemia : furosemide, buemtanide (loop)

(3) increased intracranial pressure : mannitol (osmotic diuretic)

(4) hypertension : hydrochlorothiazide, chlorthalidone (thiazides)

(5) kidney stones due to idiopathic hypercalciuria : hydrocholorothiazide, metolazone (thiazides)

(6) SIADH in hospitalized pt : conivaptan (ADH antag)

(7) high left ventricular filling pressure : furosemide, bumetamide, torsemide (loop)

(8) central diabetes insipidus : desmopressin, vasopressin

(9) 2ndary hyperaldosteronism : spironolactone (K-sparing)

(1) hypokalemia can be caused by... loop diuretics & thiazide diuretics

(2) hyperkalemia can be caused by... K-sparing diuretics

(3) metabolic alkalosis can be caused by... loop & thiazide diuretics

(4) metabolic acidosis can be caused by...acetazolamide, K-sparing diuretics

(5) hyperuricemia can be caused by... loop & thiazide diuretics

(6) hyponatremia can be caused by... loop & thiazide diuretics

Desmopressin has an increased anti-diuretic-to-pressor activity compared to vasopressin.

Desmopressin is more selective for V2 receptors vs. V1 receptors.

Desmopressin is less likely to cause vascular & GI effects due to its decreased pressor action.

Conivaptan is not approved for the treatment of heart failure.

(1) block Na transport

(2) interfere with water reabsorption