diuretics

Question 1

What does ADH require in order to mediate its MOA?

Answer 1

1. functinal tubular system
2. medullary concentration gradient of sodium + urea
3. functional ADH receptors

Question 2

Why do serum diuretic concentrations remain low in face of proteinuria and nephrotic syndrome?

Answer 2

• decreased tubular secretion
• partial neutralizing of diuretic by binding to urinary proteins

Question 3

Name 6 classes of diuretics and where they exert their effect, and their global effect on:
* water
* electrolytes
* minerals (Ca, Ph, Mg)
* acid-base balance

Answer 3

1. osmotic diuretics: mannitol –> filtered at the level of glomerulum - all segments (mostly LOH)
2. carboanhydrase inhibitors –> PCT + late DCT
3. loop diuretics: thick ascending LOH
4. thiazide diuretics: early DCT
5. distal diuretics: late DCT + collecting durct
6. aldosterone antagonists: late DCT + collecting duct

Question 4

How does mannitol work?

Answer 4

= osmotically active, nonreabsorbed sugar alcohol

–> causes hyperomolality in IV space –> redistribution of water from IC to IV –> freely filtered at the glomerulum + not reabsorbed –> osmotic diuresis + increased tubular flow –> reduced reabsorption of urea –> increased urinary clearance + decreased serum concentration –> intensified fluid diuresis

Question 5

What are proposed benefits of mannitol?

Answer 5

• prostaglandin-induced renal vasodilation
• positive rheological effect: reduced tendency of RBCs to aggergate
• decreased renal vascular congestion
• decreased hypoxic cellular damage
• protection of mitochondrial function
• decreased oxidative damage
• renoprotection when given before toxic insult

BUT: no data to support a clinical benefit in established renal failure
CAVE: oliguric patients –> VO, hyperosmolality, renal damage

Question 6

What is the adverse effect of high doses of mannitol?

Answer 6

• renal vasoconstriction
• tubular vacuolization

Question 7

How do carbonic anhydrase inhibitors work? What is their main clinical application?

Answer 7

Reduction in type II (cytoplasmic) + type IV (membrane) CAs in PCT –> decreased reabsorption of Na+ and HCO3- –> metabolic acidosis + natriuresis

This effect is limited due to:
* decreased filtration of HCO3-
* incrased Na+ reeabsorption in distal nephron segement
* decreased responsiveness of the PCT to CA inhibition

main indication: glaucoma –> inhibits ocular CA
Other CAs: brain (CSF production), RBC CA (decreased CO2 transport)

Question 8

How do loop diuretics work?

Answer 8

Na+/K+/2Cl- cotransporter inhibition in thick ascending loop of Henle at the Cl- site –>

• inhibition of tubuloglomerular feedback (due to increased Cl+- delivery to macula densa)
• natriuresis
• diuresis
• dissipation of medullary osmotic gradient
• increased Kaliuresis due to increased Na+ delivery to distsal nephron segments (Na+/K+ exchanger)

Question 9

What are 3 proposed renoprotective effects of furosemide?

Answer 9

• decreased energy expenditure due to blockage of Na/K/2Cl- cotransporter
• decreased renal vascular resistance
• improved renal perfusion

Question 10

What causes loop diuretic resistance?

Answer 10

• compensatory increase in distal sodium reabsorption
• intermittent re-bound Na+ retention with loss of efficacy due to short half-life of furosemide (1-1.5hr)

Question 11

What is the half-life of furosemide and torasemide?

Answer 11

furosemide: 1-1.5hr
torasemide: 8hr

Question 12

With what has furosemide been combined recently to reated refractory CHF?

Answer 12

hypertonic saline:

• better maintainance or restoration of diuresis
• causes less neuro-humoral activation
• preserves renal function

Question 13

How do thiazide diuretics work? What are 2 indications to use these drugs appart from diuresis?

Answer 13

= inhibition of natriuresis via Na/Cl- cotransported in apical membrane of early DCT

indication:
* DI –> causes mild hypovolemia + subsequent increased Na+ reabsorption in PCT
* calciuresis to prevent calcium-containing urolith formation

Question 14

How do aldosterone antagonists work? What other beneficial effect do they have?

Answer 14

= competitive bind aldosterone receptors on the late DCT and CD –>

• natriuresis
• diuresis
• calciuresis
• increasd K+ reabsorption

Ohter effect: positive effect on cardiac remodeling + reduction of cardiac fibrosis

Question 15

What are other potassium sparing diuretics, apart from spironolactone?

Answer 15

Amiloride + triamterene –> inhibit electrogenic sodium reabsorption in late DCT + VD –> suppress driving force for K+ secretion

Question 16

What are aquaretics?

Answer 16

also called “vaptans”: conivaptan, tolvaptan, mozavaptan

–> inhibit V2 receptor on CD cells –> inhibition of Aquaporin-2 insertion in luminal membrane –> inhibition of ADH induced water reaborption

Indication: hypervolemic hyponatremic states (e.g. CHF, liver disease) or normovolemic hyponatremia (e.g. SIADH)

Question 17

Name 14 indication for diuretic use and the goal of diuretic use.

Answer 17

1. Oligoanuria –> restore diuresis, increase kaliuresis, decrease tubular obstruction
2. uremic crisis –> decrease BUN
3. nephrotic syndrome –> decreased interstitial fluid volume
4. urinary diseases –> increase urine flow
5. CHF –> reduced preload + ECV + PE + pleural effusion
6. Hypertension –> reduce preload + IV volume
7. liver failure –> reduce interestitial fluid volume
8. hypercalcemia –> calciuresis
9. hyperkalemia –> kaliuresis
10. iatrogenic fluid overload –> decrease total body water
11. IHT –> decreased intracellular fluid volume
12. glaucoma –> decrease intraocular pressure
13. DI –> decrease polyuria
14. chemothreapy with cyclophosphamide –> decrease risk of sterile hemorrhagic cystitis