Week 2: Diuretics

Question 1

What is the mechanism of carbonic anhydrase inhibitors? Name one commonly used.

Answer 1

-Acetazolamide (Diamox)
-MOA: Inhibit carbonic anhydrase in proximal tubule, which inhibits bicarbonate reabsorption from tubule, which decreases Na+ and H+ exchange
EFFECTS
-Natriuresis. Bicarbonaturia and metabolic acidosis
-hypokalemia
-limited natriuresis due to TGF and distal compensation. More Na delivered to macula tens a activates TGF and causes afferent arteriole vasoconstriction–>decrease GFR

Question 2

List names of loop diuretics. What is their MOA and effects?

Answer 2

-Furosemide (Lasix), Bumetanide (Bumex), torsemide, ethacrynic acid
-MOA: inhibits NKCC2
EFFECTs
-potent natriuresis b/c inhibits TGF due to inhibition of NKCC2 at macula densa
-hypokalemia
-metabolic alkalosis (increased Na delivery to CCD where reabsorbed in exchange for H+ secretion)
-increases Ca2+ and Mg2+ secretion
-impairment of urinary concentrating and diluting ability

Question 3

List thiazide diuretics. MOA? effects?

Answer 3

-hydrochlorothiazide (HCTZ), chlorothiazide, chlorthalidone, metolazone
-MOA: inhibits NCC in DCT
EFFECTS
-weak natriuresis b/c DCT only contributes to 5-10% of tubular Na reabsorption
-synergistic with loop diuretics
-hypokalemia
-metabolic alkalosis
-decreased Ca2+ excretion but increased Mg2+ excretion
-impairment of urinary diluting ability–>hyponatremia (b/c DCT reabsorbs NaCl but is impermeable to water)

Question 4

List the K+ sparing diuretics. MOA? Effects?

Answer 4

-Amiloride, triamterene, spironolactone, eplerenone
-Amiloride, Triamterene, TMP, pentamidine: block ENac
-Spironolactone, Eplerenone: block aldosterone receptor
EFFECTS
-weak natriuresis b/c works in CCD
-hyperkalemia, used in conduction with K wasting diuretics
-mild metabolic acidosis
-spironolactone/epleronone are only diuretics that enter the cell basolaterally and act intracellular. All others secreted into tubule lumen by organic anion or cation transport.

Question 5

Describe osmotic diuretics.

Answer 5

• Endogenous: glucose, urea
• exogenous: mannitol, urea
• MOA: shift water transport in direction of lumen (in PT), Na+ follows by solvent drag
• filtered but not reabsorbed
• Na+ reabsorption inhibited because of increased basolateral Na+ and solvent drag
• inhibit free water reabsorption–> hypernatremia

Question 6

Describe compensatory mechanisms to counteract loop diuresis.

Answer 6

• decreased ECF volume due to loop diuretics (and thiazides) cause activation of RAAS and SNS
• aldosterone increases Na reabsorption across distal tubule and collecting duct
• this increases Na reabsorption in PT via NHE. Increased Na+ reabsorption means increased H+ secretion. More H+ means more bicarbonate reabsorbed.
• can lead to metabolic alkalosis

Question 7

A patient with CHF has severe edema and is treated with loop diuretic and thiazide. He develops hyponatremia, hypokalemia, and metabolic alkalosis. What are mechanisms and what can be done?

Answer 7

Hyponatremia
-Impaired free water clearance plus water intake
-Decrease water intake
Hypokalemia
- Na delivery to CCD where reabsorbed in exchange for K secretion
-Add K-sparing diuretic
Metabolic alkalosis
-Na delivery to CCD where reabsorbed in exchange for H secretion
-Add carbonic anhydrase inhibitor