Diuretics

Question 1

Definitions

Answer 1

• Diuretics: causes increase in urine output
• Natriuretic: increases Na and water excretion
• Aquaretic: increases free water excretion
• Most diuretics are natriuretics

Question 2

Uses of diuretics

Answer 2

• Reduces ECFV (edematous states, HTN)

- Adjust ECF K, pH, or Ca

Question 3

Site of action of diuretics

Answer 3

• PT: osmotic diuretics, carbonic anhydrase inhibitors (CAIs)
• TAL: loop diuretics
• DT: thiazide diuretics
• CCD: K-sparing diuretics

Question 4

CAIs 1

Answer 4

• Work at the PT where HCO3 is reabsorbed
• Ex: acetazolamide
• If CA is blocked there is less CO2 being brought into the cell and thus less H+ formation
• As the H+ gradient is depleted there is reduced Na reabsorption thru NHE

Question 5

CAIs 2

Answer 5

• This causes natriuresis, but can also cause bicarbonaturia and metabolic acidosis
• Since there is more Na moved to the CCD there is increased K secretion and thus can lead to hypokalemia
• There is TGF and distal compensation which limits their effectiveness

Question 6

Similar side effects btwn CAIs, loop, and thiazide diuretics

Answer 6

• All of these inhibit Na reabsorption proximal to the CCD
• Increasing Na deliver to CCD increases K and H+ secretion by increasing Na reabsorption in the CCD (ENaC)
• Therefore its possible to see hypokalemia and metabolic alkalosis with these diuretics
• However its more common to see metabolic acidosis w/ CAIs

Question 7

TGF for CAIs

Answer 7

• Since there is more NaCl flowing to MD there will be TGF
• Vasoconstriction of the afferent arteriole will decrease GFR
• There is RAAS activation
• ATII will further constrict the efferent arteriole preferentially to maintain GFR but decrease RBF
• This limits the effectiveness of CAI diuresis

Question 8

Loop diuretics (furosemide) 1

Answer 8

• Inhibits NKCC in the TAL and MD
• This is also the region where Ca and Mg reabsorption occurs (based on activity of NKCC and ROMK in setting up electrical gradient)
• Thus inhibiting NKCC will decrease Ca and Mg reabsorption
• Inhibiting Na reabsorption here also increases reabsorption of Na in CCD thru ENaC, and can lead to metabolic alkalosis and hypokalemia
• There is no TGF response since the NKCC channels are blocked

Question 9

Loop diuretics (furosemide) 2

Answer 9

• There is impaired urinary diluting and concentrating ability since the TAL is responsible for the Na reabsorption that establishes the gradient allowing for adjusting how concentrated or dilute the urine is
• They are such a potent diuretic that there is a fall in ECFV and the body responds by activating RAAS and SNS to keep BP/GFR up and increase Na reabsorption in other parts of the nephron
• Na reabsorption mostly increased in PT, by activating NHE
• Leads to more bicarb reabsorption and furthers metabolic alkalosis

Question 10

Access routes to site of diuretic action

Answer 10

• Almost all diuretics must be secreted into the lumen to have an effect (90% not filtered)
• The exception is an osmotic agent (they are filtered straight into the lumen)
• All other diuretics use organic acid secretion to enter the lumen and have an effect (most PT)
• Spironolactone works from peritubular circulation

Question 11

Thiazide diuretics (hydrochlorothiazide) 1

Answer 11

• Work in the DT by blocking NCC (Na Cl cotransporter)
• The DT is a urine diluting site (Na permeable but H2O impermeable)
• B/c of this, reducing Na reabsorption here can cause a drop in serum [Na] (won’t happen in areas where H2O reabsorption occur concomitantly b/c as Na reabsorption falls so will H2O) and cause hyponatremia

Question 12

Thiazide diuretics (hydrochlorothiazide) 2

Answer 12

• These are weak diuretics but are synergistic w/ loop diuretics
• Can cause hypokalemia and metabolic acidosis (increased Na to CCD)
• There is decreased Ca excretion but increased Mg excretion
• Impairs diluting ability, but not concentrating ability (concentrating ability relies on TAL)

Question 13

K-sparing diuretics (amiloride)

Answer 13

• Inhibit ENaC activity in the CCD and thus reduce K and H+ secretion
• Spironolactone works by blocking the aldosterone receptor (not on ENaC directly- only ones that act intracellularly)
• Weak natriuresis, and can cause hyperkalemia and mild metabolic acidosis

Question 14

Osmotic diuretics

Answer 14

• Endogenous: urea, glucose
• Exogenous: mannitol, urea
• These agents are not reabsorbed but stay in the lumen and thus create an osmotic gradient that pulls water (and Na via drag) back into the lumen
• Primarily active in PT, since they inhibit free H2O reabsorption they can cause hypernatremia (lose more H2O than Na)
• This is impairing urinary concentrating ability (but not urinary diluting ability)