Diuretics

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Hydrochlorothiazide; HCTZ (HydroDIURIL, Microzide)

thiazide; 1hr onset; 8-12hr halflife

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Chlorthalidone (hygroton, hylidone)

thiazide

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Indapamide (lozol)

thiazide-like diuretic; 1-2hr onset; 18-36hr halflife

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Furosemide (lasix)

loop diuretic; 1hr onset; 6hr half-life

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Bumetanide (bumex)

loop diuretic; 0.5-1hr onset; 4-6hr half-life

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Torsemide (demadex)

loop diuretic

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Ethacrynic acid (edecrin)

loop diuretic

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Amiloride (midamor)

potassium-sparing diuretic

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Triamterene (dyrenium)

potassium-sparing diuretic

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Spironolactone (aldactone)

K-sparing diuretic/aldosterone receptor blocker; 1-2 day onset; 2-3d halflife; acts at collecting duct (inhibits Na/H2O reabs); directly prop to [aldosterone serum]; hyperaldosteronism adenoma, CHF, liver cirrhosis, nephrotic syndrome, HTN, hypokalemia

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Acetazolamide (diamox)

carbonic anhydrase inhibitor; 1hr onset; 5hr half-life; inhibit membrane CA and interior of lumen cell to dec Na and HCO3 reabsorption by 80%; minor effect in descending loop and collecting ducts

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Dorzolamide (trusopt)

carbonic anhydrase inhibitor; inhibit membrane CA and interior of lumen cell to dec Na and HCO3 reabsorption by 80%; minor effect in descending loop and collecting ducts

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Mannitol (osmitrol)

osmotic diuretics; IV (poor oral absorption); not metabolized & freely filtered by glomerulus w/o absorption or secretion; *inc osmotic pressure w/in tubule and ECF*

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Amiloride + HCTZ (moduretic)

combo therapy; 2hr onset; 24hr half-life

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Triamtrene + HCTZ (maxzide, dyazide)

combo therapy

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Spironolactone + HCTZ (aldactazide)

combo therapy

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Diuretics defined

inc water and solute excretion

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Natriuresis defined

increased excretion of Na in urine

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Diuresis defined

increased urine outflow

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Osmosis

net diffusion of water across selectively permeable membrane from region of high water conc. to region of lower water concen

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Reabsorption of Na and Water

Proximal tubue (65% and 65%); Descending loop (15% water); Ascending loop (25% Na), Distal collecting duct (10% and 20%)

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Proximal Tubule

highly permeable to H2O, Na reabsorption to interstitial fluid creates [ ] diff that results in osmosis of water in same direction in a 1:1 ratio; reabsorbes 65% of filtered Na, K, and H2O

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Proximal Tubule: Early

Na is countertransported via Na-H exchange which is linked to HCO3 reabsorption

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Proximal Tubule: Middle and Late

Na is reabsorbed w/Cl

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Descending Limb

freely permeable to H2O; impermeable to Na and K

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Ascending Limb

"diluting segment" - dec lumen osmolarity; impermeable to H2O; Na-K-2Cl cotransporter (25% filtered Na, 20% filtered K, NaCl reabsorbed w/o H2O); **good site for drug target**

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Distal Tubule: Early

"cortical diluteing segment" - dec lumen osmolarity; reabsorbs 10% of filtered Na; impermeable to H2O, Na-Cl cotransporter, NaCl reabsorbed w/o H2O

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Late Distal Tubule and Collecting Duct: Principal Cells

aldosterone increases reabsorption of Na and secretion of K; Antidiuretic hormone (ADH, AVP, vasopressin) increases reabsorption of H2O

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Late Distal Tubule and Collecting Duct: Intercalated Cells

Aldosterone increases secretion of H by H-ATPase pump

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Osmotic Diuretics: Proximal Tubule

limit osmosis of H2O from lumen to interstitial space

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Osmotic Diuretics: Descending Loop

Cannot reabsorb increased load of H2O and Na

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Osmotic Diuretics: Ascending Loop

Increased load of H2O and Na reduces efficiency of Na-K-2Cl cotransporter

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Osmotic Diuretics: Distal Tubule and Collecting Ducts

cannot reabsorb increased load of H2O and Na

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Collecting Tubule

reabsorbs 2-5% of filtered Na; final site of NaCl reabsorption; determines final urine [Na]; regulated blood vol;

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Collecting Tubule: Principal Cells - Distinct Na and K Channels

Na reabsorption > K reabsorption; Lumen negative potential (+75 to +60mV) inc K secretion; Inc Na delivery to collecting tubule inc K secretion into lumen

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General characteristics of diuretics

inhibit absorption of Na & H2O; ptn-bound, not freely filtered at glomerulus, secreted into prox tubule & subject to compet inhib; Dec ECF vol (d/t Na & H2O excretion; limited d/t breaking phenomena: Na/H2O reaborption inc in segments not inhibited

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Relative Naturetic Potency of Various Diuretics

Loop (20-25%) > Osmotic (>10%); > Thiazide (5%) > K+ Sparing (1-3%) > Carbonic Anhydrase Inhibitor (1-3%)

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Mechanism of Action for Osmotic Diuretics - Descending Limb

proximal tubule is secondary site; Rx reduces Na and H2O reabsorption; inc osmotic pressure w/in lumen opposes H2O reabsorption, continued Na reabsorption dec [Na] in lumen causing backflux of interstitial Na into lumen

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Osmotic Diuretics: MOA - Expanded ECF

decreases renin release (less vasoconstriction), inc renal blood flow, inc NaCL reabsorption from medulla; hypotonic medulla = less reabsorption of H2O from descending limb; Result: dilute NaCL entering ascending limb

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Summary of Osmotic Diuretics: Ascending limb, distal tubule and collecting duct

Ascending limb (reduced NaCl reabsorption d/t dilute filtrate); Distal Tubule + Collecting Duct (cannot reabsorb inc Na and H2O load)

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Osmotic Diuretics: Indications

Dec intraocular pressure prior to ocular surgery; Reduce cerebral edema (used to extract H2O d/t inc osmotic pressure of plasma); Maintain renal blood flow during surgery

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Osmotic Diuretics: Adverse Drug Reactions

ECF expansion: worsening CHF and pulm edema; reversible acute renal dysfxn; N &V, headache, dehydration

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Carbonic Anhydrase Inhibitors: metabolic effects and indications

Urinary alkalization (enhance excretion of weak acids which are ionized in alk pH (aspirin, uric acid); Open angle glaucoma (dec aq humor synth 50% ); Acute mountain sickness (dec synth of CSF, pulm/cerebral edema); Use as diuretic for metabolic acidosis

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Thiazides: MOA - Proximal Tubule

2* site; binds to Cl site of NaCl; dec Na reabsorption; inc flow of Na & H2O to ascending limb; diuresis limited b/c most Na is absorbed prior to DCT

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Thiazides: MOA - Early Distal Tubule

1* site; inc flow of Na & H2O to downstream segments of distal tubule; Na reabsorption is 10%

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Thiazide Indications: Hypertension

80% efficacy, dec BP; more effective than loops; acutely dec plasma vol, chronically dec periph vasc resistance; 1st therapy w/ClCr >30%; enhances efficacy of other antihypertensives!

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Thiazide Indications: Mild and Severe CHF

Mild: infreq monotherapy (effective if ClCr >50%); Severe: combo therapy (CHF dec renal blood flow & allows more time for Na reabsorption in prox tubule; minimal efficacy for action in distal tubule)

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Thiazide Indications: Acute renal failure

management of hypervolemia w/NaCL and H2O restriction

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Thiazide Indications: Hyperkalemia w/normal renal function

may be used w/loop diuretics

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Thiazide Indications: Other

Edema

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Thiazides: Metabolic Effects - Hyperuricemia

compets w/uric acid for secretion from blood into tubules; increases serum uric acid and can cause gouty arthritis

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Thiazides: Metabolic Effects - Hypokalemia

onset w/in hrs of first dose; lowest pt ~1mo; it takes several wks to restore normal serum K after stopping drug

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Thiazides: Hypokalemia normal mechanism

late distal + collecting ducts: basolat lumen membrane (Na-K-ATPase establishes Na/K gradient); Lumen Surface Membrane (Na diffuses thru Na channels to cell interior; relative neg charge of lumen inc K diffusion into lumen)

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Thiazides: Metabolic Effects - Hyponatremia

reduced blood flow vol increases secretion of ADH; increases absorption of H2O dilutes plasma Na

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Thiazides: Adverse Drug Reactions

Impaired CHO tolerance (impairs insulin release, dec tissue utilization of glucose); Impotence; Hyponatremia; Hemolytic anemia; Thrombocytopenia

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Loop Diuretics: Ascending loop

1* site; Inhibits Na-K-2Cl cotransporter; inc delivery of Na and Cl to distal tubule; distal tubule & collecting ducts do not reabsorb extra Na and Cl

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Loop Diuretics: Descending Loop

2* site; inhibits Na reabsorption into interstitial fluid surrounding loop of henle; reduces osmolarlity of interstitial fluid; there is less reabsorption or H2O from descending loop

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Loop Diuretics: Proximal Tubule

3* site; weak inhibition of carbonic anhydrase

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Loop Diuretics: "Ceiling effect" - Indications

dose above which additional effect is not likely; edema, HTN (pts w/impaired renal fxn); CHF; Pts w/renal dysfxn

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Loop Diuretics: Adverse Drug Reactions

hyponatremia, hypokalemia, metabolic acidosis, ototoxicity (reverses if drug is stopped); severe dehydration; hypomagnesemia

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Potassium Sparing Diuretics: MOA

Distal tubule + Collecting Duct; blocks Na channels in lumen membrane; dec development of relative negative charge at lumen membrane (less diffusion of K into lumen); limited diuretic effect

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Potassium Sparing Diuretics: Indications - HTN or CHF

adjunct with HCTZ (minor enhanced anti-HTN or diuretic effect in combo);

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Potassium Sparing Diuretics: Indications - Hypokalemia

only when persistent hypokalemia is documented (titrate dose and monitor serum electrolytes)

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Potassium Sparing Diuretics: Indications - HTN or Edema

for pts who develop hypokalemia on HCTZ or pts who cannot risk hypokalemia (Hx of cardiac arrhythmias or concomitant digitalis glycosides); enhances effect of antihypertensives

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Potassium Sparing Diuretics: Adverse Drug Reactions

Hyperkalemia, dec glucose tolerance, photosensitivity, N&V, headache

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Potassium Sparing Diuretics: WARNING

Hyperkalemia (>5.5mEq/L); Amiloride (10% occurance; risk d/t renal impairment, DM, & elderly); Amiloride + HCTZ (risk drops to 1-2%)

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Potassium Sparing Diuretics: Contraindications

Potassium supplements; Other K+ sparing drugs (angiotensin-converting enzyme ACE-inhibitors)

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Potassium Sparing Diuretics: Spironolactone - Adverse Drug Reactions, Warnings, Contraindications

reversible gynecomastia; similar to other K sparing diuretics

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Combo Diuretic Therapy

loop resistance; NSAIDs block prostaglandin-ind release of renal blood flow; chronic renal failure (dec RBF dec diuretic delivery to kidney; inc organic acids compete w/diuretics for secretion into prox tubule); Inc lumen Na d/t block reab by DCT

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Combined Rx: Loop + Thiazide Diuretic

may result in large diuresis (requires close hemodynamic monitoring); K loss may be significant (monitor); few pts are refractory at start; 2 drugs acting at diff sites may be synergistic

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Created by: bscaryp