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Kidney Lect 10

Pharmacology of Diuretics

QuestionAnswer
Furosemide Loop Diuretic (aka high ceiling diuretic); Na-K-2Cl symport inibitor
Bumetanide Loop Diuretic (aka high ceiling diuretic); Na-K-2Cl symport inibitor
Ethacrynic acid Loop Diuretic (aka high ceiling diuretic); Na-K-2Cl symport inibitor
Torsemide Loop Diuretic (aka high ceiling diuretic); Na-K-2Cl symport inibitor
Loop Diuretic (aka high ceiling diuretic) inhibit the activity of the absorptive Na+-K+-2Cl- symporter (also called ENCC2, NKCC2 or BSC1) in the luminal membrane of the TAL in Henle’s Loop;
Even though the PT normally reabsorbs 65% of filtered Na+, diuretics acting exclusively in the PT have low efficacy because... the TAL has a large reabsorptive capacity and reabsorbs most of the rejectate from the PT. Also, diuretics acting at sites past the TAL have low efficacy because only a small percentage of the filtered Na+ reaches these distal sites.
The efficacy of inhibitors of Na+-K+- 2Cl- symport is due to two factors: (1) 25% of the filtered Na+ normally is reabsorbed by the TAL, and (2) nephron segments distal to the TAL do not possess the reabsorptive capacity to rescue the flood of rejectate from the TAL.
Movement of Na+, K+, and Cl- from the lumen into TAL epithelial cells is mediated by the absorptive ____ Na+-K+-2Cl- symporter
This symporter uses the energy of the Na+ electrochemical gradient for “uphill” transport of K+ and Cl- into the cell Na+-K+-2Cl- symporter
provide a conductive pathway for the apical recycling of K+ K+ channels in the luminal membrane (referred to as ROMK)
provide a mechanism for basolateral exit of Cl- basolateral Cl- channels (called CLC-Kb)
Luminal membranes of TAL epithelial cells are hyperpolarized because they have many channels for ___; consequently, the transmembrane potential for these apical membranes is strongly dependent on the equilibrium potential for __ K+; K+
conductance for ___ depolarizes the basolateral membrane Cl-
How does Na+, Ca++, and Mg++ flow into the interstitial space? The lumen-positive potential provides an important driving force for the paracellular flux of Na+, Ca2+, and Mg2+ into the interstitial space.
How do Na+K+2Cl- symport inhibitors affect Ca++ and Mg++ transport? Inhibitors of Na+-K+-2Cl- symport also attenuate Ca2+ and Mg2+ reabsorption in the TAL by abolishing the transepithelial potential difference
Bartter’s Syndrome inherited hypokalemic alkalosis with salt wasting and hypotension casued by Mutations in genes coding for the Na+-K+-2Cl- symporter, the apical K+ channel, the basolateral Cl- channel, or the chloride channel subunit Barttin
Thiazide diuretics inhibit the ___. Na+/Cl- symporter
Mutations in the Na + -Cl - symporter cause a form of inherited ____ called _____. hypokalemic alkalosis; Gitelman’s Syndrome.
What are the only two drugs used clinically as diuretics that block the Na+ Channel? Triamterene and amiloride
How do K-sparin diuretics work? They block Na+ channels in the principal cells in the late distal tubule; cause small increases in NaCl excretion and usually are used because they are K+ sparing
Triamterene Na+ Channel inhibitor; K-sparing
Amiloride Na+ Channel (ENaC) inhibitor; K-sparing
In the distal tubule, how does the cell morphology create a more negative lumen-negative transepithelial PD? Luminal membrane is more Na+ permeable than the basolateral membrane, which drives secretion of K+ into lumen via ROMK.
Why do loop and thiazide diuretics increase Na+ delivery to the late distal tubule and CD? What effect do they have on K+ and H+? They prevent Na+ reabsorption in the earlier parts of the Loop of Henle-->more Na+ in lumen makes its way to the distal end-->drives up Na+ movement across principal cell-->more K+ and H+ lost
How would increased Na+ concentration in the lumen of the distal tubule lead to greater K+ wasting? It is likely that the elevation in luminal Na + concentration in the distal nephron induced by such diuretics augments depolarization of the luminal membrane and thereby enhances the lumen-negative PD which facilitates K + excretion via ROMK
How would increased [Na+] in the lumen lead to H+ loss in the urine? CD also contains Type A intercalated cells that mediate H + secretion into the tubular lumen. Tubular acidification is driven by a luminal H + -ATPase (proton pump), and this pump is aided by partial depolarization of the luminal membrane.
Activation of the ___ by diuretics also contributes to diuretic induced K + and H + excretion, as discussed in the section on mineralocorticoid antagonists. renin- angiotensin-aldosterone axis
Liddle’s Syndrome An autosomal dominant form of low-renin, volume expanded hypertension that is due to mutations in the β or γ subunits, leading to increased basal ENaC activity.
Mineralcorticoid receptor antagonists: general mode of action Work on distal tubule and CD with cytosolic MR that have high aldosterone affinity; prevent the activation of aldosterone-inducing proteins (AIPs)
What are the effects of AIPs by which AIPs increase Na+ conductance in the apical membrane and basolateral Na+ pumping? activate 'silent' Na+ pumps and channels already in membrane; increase Na+ channel+pump concentration; increased expression of Na+ channel/pumps; tight junction permeability change; increased mitochondrial ATP
What is the net effect of AIPs NET EFFECT: increase Na+ conductance in luminal membrane and sodium pump activity of the basolateral membrane
How do the effects of AIPs on Na+ handling affect NaCl transport? NaCl transport enhanced and lumen negative transepithelial voltage increased-->increased driving force for secretion of K+ and H+ ions into the tubular lumen
How does aldosterone alter the removal of ENaC? A downstream effect is to upregulate SGK1 (serum and glucocorticoid stimulated kinase) which phosphorylates (and deactivates) Nedd4-2 (ubiquitin ligase that ubiquitinates ENaC)
type II 11-β hydroxysteroid dehydrogenase (11-β-HSD) found in mineralocorticoid target tissues, it converts cortisol to the inactive cortisone-->allows mineralocorticoids to bind to receptor (as opposed to glucocorticoids, which are in > concentrations and have same binding affinity for MR)
Syndrome of Apparent mineralcorticoid excess inherited disorder where type II 11-β-HSD is issing-->glucocorticoid>mineracorticoid binding to MR in distal tubule-->hypertension
What effect could excessive natural licorice ingestion lead to? Syndrome of Apparent Mineralocorticoid Excess. Excessive natural licorice ingestion can cause hypertension because a chemical in natural licorice inhibits type II 11-β-HSD.
How do Na+K+2Cl- inhibitors affect: Na, Cl, Mg, Ca, K, uric acid, medullary interstitium Increased Na+ and Cl- urinary loss (direct); Ca++ and Mg++ loss (due to loss of potential difference across membrane); chronic use-->uric acid excretion (due to volume depletion); dilute hypertonic medullary interstitium-->can't concentrate urine as well
How does furosemide help patients with pulmonary edema? Loop diuretics have direct vascular effects: acutely increase venous capacitance-->decrease LVFP
What important side effect (!) should be kept in mind about loop diuretics (f Na + – K + –2Cl – symport blockers)? can inhibit electrolyte transport in many tissues. Only in the inner ear, where alterations in the electrolyte composition of endolymph may contribute to drug-induced ototoxicity, is this effect important clinically.
What is the major use of loop diuretics? Acute pulmonary edema (due to increase in venous capacitance + brisk natriuresis reducing left ventricular filling presures)
___ diuretics often are the only drugs capable of reducing the massive edema associated with this renal disease loop
What diuretic could be used to treat hypercalcemia? Loop diuretics in combination with isotonic saline to prevent volume depletion
What are the therapeutic effects of loop diuretics? Increase Na+ exretion to 25% of filtered load; increased urine volume; increased Ca++ excretion; impair free water reabsorption; increased venous capacitnace
What can loop diuretics be used to treat? PULMONARY EDEMA; severe edema, oliguric ARF, hypercalcemia, and hyponatremia
Why should loop diuretics be avoided in postmenapausal women? Recent evidence suggests that loop diuretics should be avoided in postmenopausal osteopenic women, in whom increased Ca 2+ excretion may have deleterious effects on bone metabolism.
Ethacrynic acid loop diuretic; most ototoxic-->avoid unless patient cannot tolerate other loop diuretics
What are the adverse effects of loop diuretics? profound ECFV depletion; hypokalemia; metabolic acidosis; hypomagnesia; hyperglycemia; hyperuriceemia; ototoxicity; hypocalcemia
Nonsteroidal anti-inflammatory drugs (NSAIDs) ___ the diuretic response to loop diuretics in part by ____. attenuate; preventing prostaglandin-mediated increases in RBF
How do loop diuretics affect GFR and TGF? Loop diuretics block TGF by inhibiting salt transport into the macula densa so that the macula densa no longer can detect NaCl concentrations in the tubular fluid. Therefore, loop diuretics do not decrease GFR by activating TGF.
Why do loop diuretics stimulate renin release? interference with NaCl transport by the macula densa and, if volume depletion occurs, to reflex activation of the SNS and stimulation of the intrarenal baroreceptor mechanism; Prostaglandins may play an important role
What are the other physiological effects of loop diuretics (not adverse effects necessarily)? Release PGs; block TGF; increase renin release; increase & redistribute RBF
What do Na+,Cl- symport inhibitors do? As name implies, they increase Na+ and Cl- excretion; they also increase K+ and titrable acid excretion in the same way as loop diuretics
What limits the efficacy of thiazides? 90% of filtered Na+ load is reabsorbed before reaching the DCT
When administered chronically, thiazide diuretics ___ Ca 2+ excretion. Why? decrease; due to increased proximal reabsorption due to volume depleteion and direct effects of thiazides
What deficiency is common in patients chronically using thiazide diuretics? Who's at greatest risk? magnesium; elderly
Will thiazide diuretics affect the body's ability to concentrate urine? How? Attenuate ability to excrete a dilute urine during water diuresis; However, since the DCT is not involved in the mechanism that generates a hypertonic medullary interstitium,no alteration of the kidney’s ability to concentrate urine during hydropenia.
What are the uses of thiazides? used to treat edema in CHF, LV, renal disease; calcium nephrolithiasis and osteoporosis (by increasing Ca++ resorption); nephrogenic diabetes insipidus (reduce urine volume--counterintuitive!),
Thiazide diuretics decrease blood pressure in hypertensive patients by ____ the slope of the renal pressure–natriuresis relationship increasing
The ALLHAT study showed that in uncomplicated hypertension, the best treatment was... thiazide diuretics
Most thiazide diuretics innefective when GFR... < 30 to 40 ml/min
Why are thiazides useful in treating nephrogenic diabetes insipidus? reduce kidney’s ability to excrete free water by increasing proximal tubular water reabsorption (secondary to volume contraction) and by blocking the ability of the distal convoluted tubule to form dilute urine-->increase in urine osmolality
Thiazide diuretics increase Na+ secretion up to ___% of the filtered load. 5
What are the adverse effects of being on thiazide diuretics? ECFV depletion, electrolyte imbalances (- K, Na, Mg; + Ca), metabolic alkalosis, impotence, increased LDL, hyperglycemia, hyperuricemia
What is the mechanism by which Thiazide diuretics can induce hyponatremia? decreased ECFV-->increased Thirst and ADH secretion-->increased H2O intake and retention-->initiation of hyponatremia. Also block transport in diluting segment in DCT-->loss of ability to excrete diluted urine-->sustained hyponatremia
How do loop diuretics alter H2O excretion? How would you tell the difference between a person on thiaizide diuretics from someone on loop diuretics? They do not since they destroy medullary hypertonicity; they also do not block DCT diluting segments; loop diuretics would NOT result in decreased H2O secretion
What is the effect of Na+ channel inhibitors? (that is, how much do they affect Na+ excretion?) In late distal tubule and CD (limited capacity to reabsorb solutes), Na+ channel blockade in this part of the nephron only mildly increases Na + and Cl – excretion rates (approximately 2% of filtered load)->hyperpolarize membrane
By hyperpolarizing the membrane, what effect do Na+ channel inhibitors have on other ions? Since the lumen-negative potential difference normally opposes cation reabsorption and facilitates cation secretion, attenuation of the lumen-negative voltage decreases K + , H + , Ca 2+ , and Mg 2+ excretion rates
Chronic administration of amiloride and triamterene may decrease ___ excretion due to... uric acid; volume contraction --> increase reabsorption of uric acid in the PT
Why are Na+ channel inhibitors seldom used by themselves to treat edema or hypertension? Due to mild natriuresis; much more effective with other diuretics
How can you offset the antikaliuretic effects of thiazide and loop diuretics? administer Na+ Channel inhibitors (which reduce K+ excretion)
Liddle's syndrome can be effectively treated with ___. Na+ Channel inhibitors
___ also is useful for lithium-induced nephrogenic diabetes insipidus because it blocks Li + transport into collecting tubule cells. amiloride
What is the most dangerous side effect of Na+ Channel inhibitors? Hyperkalemia (due to decreased K+ excretion); contraindicated in patients with or at risk for hyperkalemia
What are risk factors for developing hyperkalemia? older age, high dose therapy, renal impariment, hypoaldosteronism, and treatment with other drugs that impair renal K excretion (NSAIDs and ACE inhibitors)
Why should you avoid treating patients with cirrhosis with triamferene? Could develop megaloblastosis because of folic acid deficiency (triamterene is a weak folic acid antagonist)
What are the risk factors of amiloride? Hyperkalemia
What are the risk factors of triamterene? hyperkalemia, renal stones, interstital nephritis, megaloblastosis
The effects of ____ on urinary excretion are very similar to those induced by renal epithelial Na + -channel inhibitors MR antagonists
Unlike Na + -channel inhibitors, the clinical efficacy of MR antagonists is a function of ... endogenous aldosterone levels. The higher the endogenous aldosterone level, the greater the effects of MR antagonists on urinary excretion.
____ is considered the diuretic of choice in patients with hepatic cirrhosis Spironolactone
As with other K + -sparing diuretics, spironolactone often is co-administered with ___ in the treatment of edema and hypertension. thiazide or loop diuretics; Such combinations result in increased mobilization of edema fluid while causing lesser perturbations of K + homeostasis.
Treatment of primary hyperaldosteronism (adrenal adenomas or bilateral adrenal hyperplasia) spironolactone (mineralocorticoid receptor antagonist)
What therapy should you consider in refractory edema associated with secondary aldosteronism (cardiac failure, hepatic cirrhosis, nephrotic syndrome, and severe ascites)? spironolactone
What is the major risk of using MR antagonists? hyperkalemia (since it is a K+ sparing diuretic)
What are the adverse effects of MR antagonists? Hyperkalemia, metabolic acidoses (in cirrhotic patients), impotence, CNS side effects, gynecomastia, gastritis, peptic ulcers, deepening of voice, hirstuism, menstrual irregulation
anasarca severe edema
edema accumulation of abnormal amounts of fuid in the extravascular, extracellular compartment; forms whenever sterling imbalance favoring movement into the Extracellular space overwhelms the lympathic system
Can diuretics be used to treat local edema? No, only more generalized edema
What etiologies can cause localized edema? inflammation, lymphatic obstruction, venous obstruction, thrombophlebitis
What renal etiologies (general) can lead to generalized edema? nephrotic syndrome, acute gn, crf
What type of heart failure typically leads to pulmonary edema? left ventricular dysfunction; HOWEVER, it can lead to generalized edema since hypotension-->renal sodium retention
Right ventricular dysfunction typically leads to... hypotension-->salt retention-->systemic edema
Cardiac edema diagnosis history of heart disease, evidence of pulmonary edema, orthopnea, SOB, exertional dyspnea, evidence of volume expansion, hepatic congestion, hepatojugular reflux, ventricular gallop rhythm
Hepatic edema diagnosis history of liver disease, diminished CrCL (normal serum Cr), evidence of chronic liver disease (spider angiomata, palmar erythema, jaundice, hypoalbuminemia), evidence of portal hypertension (venous pattern on abdominal wall, exophageal varices, ascites)
What is the pathophysiology of hepatic edema? liver disease-->cirrhosis-->increased pressure in hepatic sinusoids-->exudation of fluid into peritoneal cavity-->ascites + neurohormonal activation-->hepatorenal syndrome-->renal Na+ retention-->systemic edema
What is the major use of diuretics? The treatment of edema due to kidney disease
Renal edema diagnosis: findings + imaging evidence of albumin loss, narrow, pale transverse bands in nail beds, proteinuria (3+ to 4+), hypoalbuminemia; renal imaging shows either enlarged kidneys (nephtoric syndrome or AGN) or shrunken kidneys (CRF)
nepthrotic syndrome: urinalysis hyaline casts, oval fat bodies, lipid droplets/casts
Acute glomerulonephritis: urinalysis hematuria, erythrocyte casts, leukocyte casts, pyuria
chronic renal failure: urinalysis broad wavy casts
renal edema: nephrotic pathway pathophysiology renal disease-->urinary loss of albumin-->hypoalbuminemia-->altered starling forcess-->systemic edema
renal edema: nephritic pathway pathophysiology renal disase-->reduced GFR-->renal retention-->systemic edema
Cardiac edema: dependent edema, facial edema, ascites, hypoalbuminemia, proteinuria sever, absent, absent/mild, absent, absent/trace
Hepatic edema: dependent edema, facial edema, ascites, hypoalbuminemia, proteinuria moderate, absent, severe, moderate/mild, absent/trace
Renal edema: dependent edema, facial edema, ascites, hypoalbuminemia, proteinuria mild, severe/moderate, absent/mild/severe, severe
Idiopathic edema: diagnosis women of childbearing age, associated with eating disorders, dependent edema, facial edema, abdominal bloating
Ceiling dose diuretic dose which provides concentrations of diuretic in the tubular lumen that yield the near maximal / ceiling effect; exceeding ceiling dose does NOT increase effect and may result in adverse events
What factors determine the ceiling dose of a given diuretic? potency of the drug for its molecular target, renal diseases that interfere with the transport of diuretic to its site of action in the tubules and urinary proteins that bind the diuretic
diuretic resistance Often times the response to a diuretic is inadequate to provide the desired level of therapeutic response (edema resolution).
what are the most common mechanisms for diuretic resistance? Noncompliance, NSAIDs, decreased tubular transport, decreased RBF, changes in volume hormones, compensation by distal nephron, diminished nephron response
postdiuresis sodium retention limits diuretic efficacy; after dose of diuretic but during time that transport is sub-maximally inhibited-->loss of Na-->Na+ retention mechanisms turn on; solution: limit Na+ intake!
Diuretic drug interactions: with NSAIDs, salt, decongestant, probenecid diminished diuretic response
Diuretic drug interactions: ACE inhibitors, beta blockers, K-supplements, K-sparing diuretics, heparin Hyperkalemia induced by K-sparing diuretics
Diuretic drug interactions: ototoxic drugs enhanced ototoxicity of loop diuretic
How does Na+ excretion rate vary with mean arterial blood volume? MORE excretion of Na+ with higher MABP
Massive pulmonary edema in patients with acute left-sided heart failure is a medical emergency ... requiring rapid, aggressive therapy including intravenous administration of a loop diuretic. In this setting, use of oral diuretics or diuretics with lesser efficacy is inappropriate.
Created by: karkis77