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1
Q

What is diuretics?

What is natriuresis?

A

Increase urine volume by inhibiting reabsorption of salt and water
Principal therapeutic uses- treatment of edema (management of heart failure, peripheral edema, cerebral edema), treatment of mild essential hypertension
Getting rid of water = diuresis

Natriuresis- getting rid of plasma sodium

2
Q

What are the 6 diuretics?

A
  1. Carbonic anhydrase inhibitors (CAI)- acetazolamide
  2. Osmotic diuretics- mannitol
  3. Loop diuretics- furosemide
  4. Thiazide diuretics- blocks hydrochlorothiazide
  5. Aldosterone antagonist- spironolactone
  6. V2 selective antagonist- blocks ADH action (tolvaptan)

Slide 5-6 diuretics

3
Q

Where is each of the 6 diuretics sites of action?

A
  1. Carbonic anhydrase inhibitors (CAI)- proximal tubule (65% NaCl is reabsorbed here)
  2. Osmotic diuretics- proximal tubule (thin descending limb)
  3. Loop diuretics- thick ascending limb (25% NaCl is reabsorbed here)
  4. Thiazide diuretics- distal convoluted tubule (7% NaCl is reabsorbed here)
  5. Aldosterone antagonist- cortical collecting ducts (3% NaCl is reabsorbed here)
  6. V2 selective antagonist- medullary collecting ducts

Slide 5-8 diuretics

4
Q

What is each of the 6 diuretics functions at their sites of action?

A
  1. Carbonic anhydrase inhibitors (CAI)- 65% filtrate reabsorbed, 40% Na+ reabsorbed (Major bicarbonate NaHCO3)
  2. Osmotic diuretics- passive reabsorption of H2O
  3. Loop diuretics- 15% filtrate reabsorbed, 35% Na+ reabsorbed
  4. Thiazide diuretics- 10% filtrate reabsorbed, 10% Na+ reabsorbed
  5. Aldosterone antagonist- 2-5% Na+ reabsorption, K+ and H+ secretion
  6. V2 selective antagonist- H2O reabsorption under ADH control

Slide 7 diuretics

5
Q

What are the primary drug targets of the 6 diuretics?

Channels

A
  1. Carbonic anhydrase inhibitors (CAI)- carbonic anhydrase
  2. Osmotic diuretics- none
  3. Loop diuretics- Na/K/2Cl cotransporter
  4. Thiazide diuretics- Na/Cl cotransporter
  5. Aldosterone antagonist- Na channels
  6. V2 selective antagonist- aquaporins

Slide 7 diuretics

6
Q

What is the proximal convoluted tubule (PCT)?

A

PCT is major site of reabsorption of glucose, amino acids, bicarbonate, sodium chloride, and water

Bicarbonate is mainly absorbed as CO2 through action fo carbonic anhydrase (CA)
When CA is inhibited, increase excretion if HCO3 as NaHCO3

Carbonic anhydrase inhibitors work on proximal convoluted tubule

Slide 9 diuretics

7
Q

What are carbonic anhydrase inhibitors (CAI)?

Actions, adverse effects, etc

A

Acetazolamide

Actions- excretion of alkaline urine, increased excretion if NaHCO3 & K+, retention fo hydrogen ion
Used for- glaucoma, petitmal seizures, edema with several metabolic alkalosis, acute high altitude mountain sickness (CAI promotes respiration)

Adverse effects- metabolic acidosis, hypokalemia, hypersensitivity reactions

8
Q

What is the thin descending loop of henle?

A

Water reabsorption into hypertonic medulla through osmotic forces
Osmolarity increases along the descending portion of the loop

End result- tubular fluid is high with 3x Na+ than that left the PCT

Osmotic diuretics work on thin descending loop of Henle

9
Q

What are osmotic diuretics?

Actions, adverse effects, etc

A

Mannitol

Actions- potent diuretic causing minimal loss of electrolytes (little natriuresis)
Used for- cerebral edema, acute renal failure (maintains high urine flow)

Adverse effect- dehydration (followed by increased water intake so ineffective in long run)

10
Q

What is the thick ascending loop of henle?

A

Impermeable to H2O
Na/K/2Cl Co-transport

35% of NaCl returns to the interstitial fluid (major site of salt reabsorption)
Diluting segment of the nephron (dilates tubular fluid)

Loop diuretics work on thick ascending loop of
Henle

Slide 13 diuretics

11
Q

What are loop diuretics?

Actions, adverse effects, etc

A
Sulphonamide derivatives (furosemide)
Phenoxyacetic acid derivative (ethacrynic acid)

Actions- blocks Na/K/2Cl transport, potent diuretics, increased excretion if Na, K, H, Ca and Mg
Used for- edema due to CHF, hepatic or renal diseases, hypercalcemia

Adverse effects- hypokalemia, hyponatremia, hypocalcemia, hypovolemia, alkalosis, ototoxicity, hypotension, hyperuricemia

12
Q

What is the distal convoluted tubule (DCT)?

A

Na/Cl cotransporter
Ca2+ reabsorption- Ca actively reabsorbed by the cell via Ca channel
Na/Ca exchanger moves Ca into the interstitial fluid
Regulated by PTH

Thiazide diuretics work on DCT

Slide 15 diuretics

13
Q

What are thiazide diuretics?

Actions, adverse effects, etc

A

Hydrochlorothiazide (HCTZ)

Actions- inhibit Na/Cl co transport
Increased excretion if Na, Cl, K and H
Enhances Ca reabsorption
Used for- essential hypertension (mild), hypocalcemia

Adverse effects- hypokalemia, alkalosis, hyperuricemia, hypercalcemia, impaired glucose tolerance- could worsen DM

Slide 16 diuretics

14
Q

What is the cortical collecting tubule?

Regulated by?

A

Final site of NaCl reabsorption (2-5%)- responsible for final Na concentration in urine
ENaC is epithelial Na channel

Most important site of K excretion by the kidney
Principal cells- Na, K, H2O transport
Intercalated cells- H+ secretion

Regulated by aldosterone

Aldosterone antagonists act on cortical collecting tubule

Slide 17 diuretics

15
Q

What is K+ sparing diuretics (aldosterone antagonists)?

Actions, adverse effects, etc

A

Spironolactone
Inhibit ENaC as well (triamterene)

Action- spironolactone are comp. ALDO antagonists
Used for- Rx of hypertension and CHF to lower hypokalemia in patients taking loop or thiazide diuretics

Adverse effects- hyperkalemia, acidosis, spironolactone (can cause gynecomastia)

Slide 18 diuretics

16
Q

What is the medullary collecting tubule?

A

Site of final urine concentration- responsible for tight regulation of body fluid volume

Anti-diuretic hormone (ADH) facilitates water movement by insertion of preformed H2O channels into the membrane (aquaporins)

V2 selective antagonists work on medullary collecting tubule

17
Q

What are antidiuretic hormone antagonist X diuretics (V2 selective antagonists)?

(Actions, adverse effects, etc)

A

Tolvaptan
Selective blockade of renal V2-R leads to increased water excretion

Uses- SIADH (syndrome of inappropriate antidiuretic hormone secretion, high blood volume, low plasma Na+), heart failure with low plasma Na+ (hyponatremia)

Adverse effect- hypernatremia (osmotic demyelination occurs if hyponatremia is corrected too quick)

18
Q

What is the order of diuretic potency of the diuretic drugs?

A
Loop diuretics- most potent
Osmotic diuretics
Thiazides
CAI
K+ sparing (aldosterone)
ADH antagonist (V2 selective)- least 

Slide 21 diuretics

19
Q

Study the summary of plasma electrolyte levels and diuretics on slide 22 diuretics

A

Ok

20
Q

How does tolerance develop to diuretics?

A

First dose- negative sodium balance produced (blood volume reduced and edema appears)
After a few days- sodium balance is restored (blood volume increases and edema MAY return)

Segments of nephron that aren’t affected by drug begin to adjust and increase reabsorption of Na
Macula densa cells sense reduction in Na and stimulate renin release with increases Ang II (aldosterone action)
Baroreceptors sense reduction in blood and stimulate sympathetic nervous system to act on β1 receptors to increase renin release (increase sodium reabsorption)

Slide 23 diuretics

21
Q

How do you overcome tolerance to diuretics?

A

Increase dose of diuretic
Reducing the intake of sodium and water
Adding second or third diuretic which acts by diff mechanism
Use furosemide and if tolerance develops, increase the dose of furosemide and consider combining it with K+ sparing diuretic to overcome hypokalemia

22
Q

What’s the rationale in combining a K+ sparing diuretic with a thiazide or loop diuretic?

A

To reduce hypokalemia and the alkalosis caused by thiazide or loop diuretic, add a K+ sparing diuretic as second agent to maintain diuretic potency as well as overcome the adverse effect of hypokalemia