Diuretics

Question 1

What is the glomerular filtration rate?

Answer 1

amount of plasma (in ml/min) that is filtered by the kidneys normally 125 ml/min or 180L/day

Question 2

How much filtered plasma is eliminated as urine?

Answer 2

1-2 mil/min or 1.5 - 2.0 L/day

Question 3

What happens in the glomerulus?

Answer 3

H2O and solutes are freely filtered

Question 4

What happens at the proximal convoluted tubule?

Answer 4

Majority of electrolytes get reabsorbed: 60-65% Na+ Cl H2O HCO3- glucose

Question 5

What happens in the descending limb of Henle?

Answer 5

Only H2O is reabsorbed

Question 6

What happens in the ascending limb of Henle?

Answer 6

Reabsorb: 20-25% Na+ K+ Cl- Mg2+ Ca2+

Question 7

What happens in the distal convoluted tube?

Answer 7

Reabsorb: 4-8% Na+ K+ Cl-

Question 8

What happens in the cortical collecting duct?

Answer 8

Secrete K+ and H+ Reabsorb Na+ (2-5%) and Cl-

Question 9

What happens in the medullary collecting duct?

Answer 9

only reabsorb H2O (depending on whether or not ADH is present - antidiuretic hormone)

Question 10

How much sodium is excreted in the urine?

Answer 10

1-2% of Na+ that initially is filtered

Question 11

What are the types of transport mechanisms across renal epithelial cell membranes?

Answer 11

Passive transport: 1. convective solute flow (solvent drag). solutes are being dragged along in the direction of water 2. simple diffusion 3. channel-mediated diffusion 4. carrier-mediated (facilitated) diffusion (uniport) Active Transport: 5. ATP-mediated transport (opposite direction of concentration gradient) 6. symport (co-transport) - same direction 7. antiport (countertransport) - opposite direction

Question 12

What are the modes of transport in the proximal tubule?

Answer 12

On interstitium/blood side: ATP- mediated transport: Na+ out of tubule, K+ into cell (60-65% Na is reabsorbed here) highly water permeable (water gets reabsorbed from the lumen into the cell) 100% of filtered glucose and amino acids reabsorbed here glucose via the SGL2 (sodium-glucose transporter-2) site of action for carbonic anhydrase (CA) inhibitors

Question 13

What do carbonic anhydrase inhibitors do?

Answer 13

In the proximal convoluted tubule, Block carbonic anhydrase (CA) in the tubule lumen, which inhibits the Na+/H+ exchange (on the lumen side) and Na+ reabsorption

Question 14

What are the carbonic anhydrase inhibitors?

Answer 14

Acetazolamide PO (diamox) Dorzolamide (Trusopt 2% soln) brinzolamide (Azopt 1% susp) Clinical uses: reduce aqueous humor production in glaucoma decrease CSF (cerebral spinal fluid) formation & pH –> increased ventilation and improvement in symptoms of acute mountain sickness SEs/precautions: don’t use in patients with sulfonamide allergy can cause metabolic acidosis hypokalemia kidney stones parethesias worsening of hepatic encephalopathy

Question 15

What is the basic transport in the thick ascending limb of Henle?

Answer 15

Na+, K+, 2Cl- move from lumen to cell via symporter Na+ moves from cell to interstitium/blood and K+ moves from interstitium/blood to inside of cell via primary active transport. Mg2+ and Ca2+ move from urine to interstitial/blood via paracellular pathway reabsorb 20-25% of filtered Na impermeable to water plays an important role in the hypertonic medullary interstitium –> the concentration of urine by collecting duct (countercurrent multiplier)

Question 16

How do loop diuretics work?

Answer 16

• actively secreted by organic acid transporters in proximal tubular cells - exert effect on lumen (urine) side
• Inhibit the Na/K/2Cl symporter in the ALH (ascending limb of henle), so incrase Na+, Cl-, K+, Mg2+, Ca2+ excretion in the urine
• block kidney’s ability to concentrate the urine during hydropenia and dilute the urine during water diuresis
• can’t make interstitium as salty when ascending limb of henle is blocked, so you can’t concentrate the urine as much - you are going to have MORE urine.

Question 17

What is important about the thick ascending loop of henle?

Answer 17

it is important for creating concentrated urine.

you get rid of more free water with a loop diuretic than you do with other diuretics by blocking NaCl reabsorption at the ALH, you are increasing free water excretion in the medullary collecting duct

Question 18

What are the loop diuretics and their pharmacokinetics?

Answer 18

Furosemide (Lasix)

Bumetanide (Bumex)

Torsemide (Demedex)

• Furosemide: sulfonamide, ~50% bioavailability, 1.5-2 hr 1/2 life, >80% renal elimination
• Bumetanide: sulfonamide, ~ 80-100% bioavailability, ~1 hr half life, 62% renal & 38% liver elimination
• Torsemide: sulfonylurea, ~80-100% bioavailability, ~3.5 hr half life, 20% renal & 80% liver elimination
• all are highly protein bound (>90%), so alterations in protein binding can affect the delivery of diuretics to the kidney: someone with low blood protein could impair ability to get to site of action

Question 19

What are the main clinical uses for loop diuretics and adverse effects?

Answer 19

• Clinical uses:
  
  • management of edema & edematous conditions (e.g. heart failure)
  • ascities - in combination with spironolactone
  • HTN in patients with chronic kidney disease
  • acute hypercalcemia (blocks section of tubule that absorbs excess calcium, helps excrete more calcium)
• Adverse effects: hypokalmeia, hypomagnesemia, hyponatremia (low sodium), hypotension, dehydration (lower ECFV [extracellular fluid volume]), metabolic alkalosis. Other: ototoxicity, hyperuricemia, hyppocalcemia

Question 20

what is the basic transport in the distal convoluted tubule?

Answer 20

• reabsorbs 4-8% of filtered Na
• relatively impermeable to water
• site of action for thiazide diuretics

Question 21

What are the thiazide diuretics?

Answer 21

• Chlorothiazide (Diuril) (only one that is IV)
• Hydrochlorothiazide (Hydrodiuril)
• Chlorthalidone (Hygroton)
• Indapamide (lozol)
• Metolazone (Zaroxylyn)
• actively secreted into the urine by the organic acid transporters in the proximal tubular cells - exert effect on lumen side (like loop diuretics)
• inhibits the Na/Cl symporter, so increases Na+, Cl-, K+ and Mg2+ excretion in the urine
• blocks the kidney’s ability to dilute the urine during water diuresis
• volume of urine that you produce with thiazide diuretics is smaller than with loop diuretics

Question 22

What are the pharmacokinetics of thiazide diuretics?

Answer 22

• Chlorothiazide
  
  • bioavailability 30-50%
  • 1/2 life 1.5 hrs
  • renal elimination
  • relative potency 0.1
• Hydrochlorothiazide
  
  • bioavailability 70%
  • 1/2 life 12 hrs
  • renal elimination
  • relative potency 1
• chlorthalidone
  
  • bioavailability 65%
  • 1/2 life 40-60 hrs
  • 65% renal, 10% bile, 25% unknown elimination
  • relative potency 1
• indapamide
  
  • bioavailability 93%
  • 1/2 life 5-26 hrs
  • liver elimination
  • relative potency 20
• metolazone
  
  • bioavailability 40-65%
  • 1/2 life 8-14 hrs
  • 80% renal, 10% bile, 10% liver elimination
  • relative potency 10
• all are sulfonamides
• all are highly protein bound (>90%)

Question 23

What are the clinical uses and adverse effects of thiazide diuretics?

Answer 23

Clinical uses:

• HTN
• Management of mild edema or in combination with a loop diuretic for moderate to severe edema
• other: nephrolithiasis, nephrogenic diabetes insipidus

decreased efficacy at a GFR < 30 ml/min

Adverse effects:

• hypokalemia, hypomagnesemia, hyponatremia (more than loop diuretics), hypochloremia, hypotension, dehydration (decreased ECFV), metabolic alkalosis
• Other: hyperuricemia, hyperglycemia, increased cholesterol

Question 24

What is the basic transport in the collecting system?

Answer 24

• only 2-5% of Na reabsorption
• most important site for K+ secretion
• site of action for K+ sparing diuretics

Question 25

What are the potassium-sparing diuretics?

Answer 25

* actively secreted into the urine by organic BASE transporters in the proximal tubular cells - exert effect on lumen side * amiloride and triamterene work by inhibiting Na influx through ion channels in the luminal membrane of the collecting tubules ENaC = epithelial Na Channel

Question 26

What are the pharmacokinetics of potassium-sparing diuretics?

Answer 26

Amiloride (dyrenium) * 30-90% bioavailability * 6-9 hr half life * 50% renal, 40-50% bile elimination * relative potency 1 Triamterene (midamor) * 30-70% bioavailability * 4 hr half life * 80% liver elimination- active metabolite is excreted renally * relative potency 0.1 neither are sulfonamides

Question 27

What are the clinical uses and adverse effects of potassium-sparing diuretics?

Answer 27

Clinical uses: * HTN (in combination with a thiazide to minimize K+ loss) Adverse effects: * **_Hyperkalemia_** * amiloride (better tolerated) - n/v/d, headache * triamterene - hyperglycemia, photosensitization, interstitial nephritis, nephrolithiasis * other - metabolic acidosis, hyperuricemia

Question 28

How does a mineralocorticoid receptor (aldosterone) antagonist work?

Answer 28

* competitively inhibits the binding of aldosterone to the mineralocorticoid receptors preventing the transcription and translation of aldosterone-induced proteins * ONLY diuretic that works on the blood side

Question 29

What are the aldosterone antagonists & their pharmacokinetics?

Answer 29

Spironolactone (Aldactone) * 70% bioavailability * 1.6 hr half life (half life of active metabolite - 15 hours) * 50% renal 40% feces elimination Epleronone (Inspra) * 70% bioavailability * 5 hr half life * extensive liver elimination

Question 30

What are the clinical uses and adverse effects of aldosterone antagonists?

Answer 30

Clinical uses: * HTN (in combination with other agents for resistant hypertension) * alone for mild ascites or in combination with furosemide for moderate to severe ascites * heart failure Adverse effects: * **_Hyperkalemia_**, hyperchloremic metabolic acidosis * Other - gynecomastia, impotence

Question 31

What is the basic transport in the collecting system?

Answer 31

* final urine concentration is determined * ADH regulates the insertion of preformed water channels (aquaporin-2 = AQP2) into apical lumen - creates a door for water to get out * no ADH present = impermeable to water --\> dilute urine * + ADH present = increased water permeability --\> concentrated urine * movement of water out of the tubule is driven by the hypertonic medullary interstitium

Question 32

What are the diuretic sites of action?

Answer 32

Proximal Convoluted tubule * carbonic anhydrase inhibitor: Acetazolamide * inhibits reabsorption of HCO3- * weak diuretic properties Ascending Loop of Henle * Loop diuretics: bumetanide, furosemide, torsemide, ethacrynic acid * inhibit Na+/K+/2Cl- cotransport, resulting in retention of Na+, Cl- and water in the tubule * most efficacious diuretics distal convoluted tubule * Thiazides * inhibit reabsorption of Na+ and Cl-, resulting in retention of water in the tubule * most commonly used diuretics collecting tubule and duct * aldosterone antagonists: spironolactone, * Potassium-sparing diuretics: amiloride, triamterene * inhibit aldosterone-mediated reabsorption of Na+ and secretion of K+ * amiloride & triamterene block Na+ channels * can prevent loss of K+ that occurs with thiazide or loop diuretics

Question 33

Proximal Convoluted tubule: functions, primary transporter, diuretic

Answer 33

_Functions_: reabsorption of 60-65% of filtered Na+/K+/Ca2+, Mg2+, 85% of NaHCO3 and almost 100% glucose/amino acids _primary transporter_: Na+/H+ (NHE3), carbonic anhydrase, Na/glucose cotransporter 2 (SGLT2) _Diuretic_: carbonic anhydrase inhibitors

Question 34

Proximal Tubule functions, primary transporter, diuretic

Answer 34

Functions: secretion of most diuretics Primary transporter: acid and base transporter diuretic: none

Question 35

Thin descending limb of henle functions, primary transporter, diuretic

Answer 35

Functions: passive reabsorption of water Primary transporter: aquaporins Diuretic: none

Question 36

thick ascending limb of henle functions, primary transporter, diuretic

Answer 36

_Functions_: active reabsorption of 25% of filtered Na+/K+/Cl-, secondary reabsorption of Ca2+ and Mg2+, impermeable to water _primary transporter_: Na/K/2Cl co-transporter or symporter (NKCC2) _diuretic_: loop diuretics

Question 37

distal convoluted tubule functions, primary transporter, diuretic

Answer 37

_Functions_: active reabsorption of 4-8% of filtered Na+ and Cl-, Ca2+ reabsorption under PTH control _Primary Transporter_: Na/Cl co-transporter or symporter (NCC) _diuretics_: thiazides

Question 38

cortical collecting tubule functions, primary transporter, diuretic

Answer 38

_functions_: Na+ reabsorption (2-5%) coupled to K+ and H+ secretion _primary transporter_: Na channels (ENaC), K channels, aquaporins _diuretics_: K+ sparing diuretics, mineralcorticoid receptor

Question 39

medullary collecting duct functions, primary transporter, diuretic

Answer 39

_functions_: water reabsorption under the control of antidiuretic hormone (ADH) _primary transporter_: aquaporins _diuretic_: vasopressin antagonists

Question 40

What are clinical uses of diuretics?

Answer 40

* hypertension * edema/edematous conditions (e.g. heart failiure, CKD, nephrotic syndrome) * ascites due to liver cirrhosis * other conditions (e.g. hypercalemia)

Question 41

What is edema?

Answer 41

clinically detectable increase in interstitial volume due to cardiac, renal or vascular disease states that reduce blood flow to kidney edema formation occurs when there is a * decrease in effective arterial blood volume --\> hypoperfusion of kidneys --\> stimulation of renal Na+ and H2O retention (causes kidney to sense drop in circulation, makes kidney release aldosterone to make you hold onto sodium to hold onto water) * altered capillary hemodynamics

Question 42

What are the types of edema?

Answer 42

Peripheral edema * gravity dependent sites * evaluated as 1+ to 4+ pitting (4+ is the most severe) * typically 10% or 10 lb. weight gain before clinically evident anasarca (severe): total body edema pulmonary edema (severe): only form of edema that is dangerous/life-threatening

Question 43

What are the principles of edema management?

Answer 43

* treat underlying cause * dietary sodium restriction (1-2 g/day) * loop diuretic: drug of choice, effective at ClCr \< 30 ml/min (moderate-severe CKD) - allows most volume of urine to be excreted * thiazide diuretics: mild edema or adjunctive therapy. Not effective alone at ClCr \< 30 ml/min

Question 44

How is peripheral edema managed?

Answer 44

* usually outpatient * optimize therapies for underlying disease state * institute dietary sodium restriction * check for hidden sources of sodium * check for medications which can cause edema (NSAIDs, dihydropyridine calcium channel blockers, thiazolidinediones (TZDs), estrogens * implement non-pharm measure (raising legs) * start with low dose oral loop (e.g. furosemide 20-40 mg orally once daily to twice daily - may need higher starting dose if HF, nephrotic syndrome, or CKD) * goal: slowly reduce edema * titrate dose & interval based on response * if patient does not respond as expected, check compliance & look for mechanisms of resistance & treat accordingly

Question 45

How is acute severe edema managed?

Answer 45

* usually managed in the hospital * optimize therapies for underlying disease state * check for hidden sources of sodium * check for medications which can cause edema * if patient is already on diuretic therapy: assess adherence with medication & sodium restriction * use IV bolus dosing initially * dose of loop diuretic will depend on previous dosing history & underlying disease state * double the initial dose until adequate response (1 ml/kg/hr urine output - depending on kidney function) * once you find the most effective dose (or maximal dose is reached), give it as often as needed (typically bid to tid) * if loop alone is inadequate, use combo of loop + thiazide (or K+ sparing diuretic if normal renal function or low K+). If loop is IV, administer oral thiazide 0.5 to 1 hr before loop * once adequate diuresis has occurred & patient is stable, switch from IV to equivalent oral regimen.

Question 46

How is ascites managed?

Answer 46

* spironolactone diuretic of choice due to hyperaldosteronism * use alone only if mild ascites * dosing = 50-100 mg once daily with food (starting), up to 400 mg po daily (max dose) * titrate dose no faster than every 3-5 days * if moderate to severe ascites or patient has peripheral edema, use combination therapy with a loop diuretic * ideal ratio: 100 mg/day po spironolactone to 40 mg/day po furosemide * usual starting dose of oral furosemide is 40 mg dailiy. Maximal oral effective dose = 80 mg * can administer loop diuretic more often to improve response * goal fluid loss (ascites w/out edema = 500 ml/day (0.5 kg/day) * goal fluid loss (ascites w/edema) = 1000 ml/day (1.0 kg/day)

Question 47

How is efficacy and safety of diuretics monitored?

Answer 47

* daily weight * inputs (oral and IV) & outputs (urine) * electrolytes (K+, Na+, Cl-, CO2, Mg2+ * vital signs (blood pressure, HR) * kidney function (BUN Scr)