1. Clinical Use of Diuretics

2. Review of Anatomy and Physiology
Glomerulus
-forms ultrafiltrate of plasma

3. Review of Anatomy and Physiology
Proximal Tubule
-reabsorbs isosmotically 65-70% of
-reclaims all the glucose, amino acids, and bicarbonate
Secretes protein bound drugs

4. Review of Anatomy and Physiology
Loop
-reabsorbs 15-25% of filtered NaCl
-Creates the gradient for the countercurrent multiplier

5. Review of Anatomy and Physiology
Distal Tubule
-reabsorbs few percent
-fine tunes- volume, osmolarity (ADH), K (aldosterone), acid-base

6. Location of Diuretic Activity
Distal Tubule
“High-ceiling diuretics”- HCTZ, Zaroxlyn (metolazone)
K-sparing diuretics-amiloride, spironolactone, triamterene
Proximal Tubule
Acetazolamide
Loop
Loop diuretics- Lasix, Bumex, Ethacrynic Acid, Torsemide

7. Loop diuretics
4 loops- furosemide, bumetanide, ethacrynic acid, torsemide
Can block a maximum of 20-25% of filtered Na+
Increases the excretion of Ca+
Use therapeutically in cases of hypercalcemia
Loop
-reabsorbs 15-25% of filtered NaCl
-Creates the gradient for the countercurrent multiplier

8. Distal Tubule
Thiazide-type– HCTZ, Chlorthalidone, Zaroxlyn (metolazone), IV form
Mild diuretics- even if maximally block– excretion only increased 3-5%
Therefore poor choice for edematous states, but excellent for hypertension (where large volume loss isn’t required)
Blocks calcium excretion
Useful for stone patients
Distal Tubule
-reabsorbs 3-5% percent
-fine tunes the ultimate urine composition- k, acid-base, volume, Calcium

9. Distal Tubule
K-sparing diuretics- amiloride, spironolactone, and triamterene
Because 98% of sodium already absorbed, maximal increased excretion of only 1-2%
Peri-capillary space (blood)
Tubular lumen (urinary space)
Na+
Distal Tubule
-reabsorbs 3-5% percent
-fine tunes the ultimate urine composition- k, acid-base, volume, Calcium K+
Aldosterone sensitive channel =

10. Distal Tubule Mechanism of Action
Spironolactone competitively inhibits aldosterone
Distal Tubule Mechanism of Action
K-sparing diuretics- amiloride, spironolactone, and triamterene
Aldosterone
Tubular lumen (urinary space)
Peri-capillary space (blood)
Na+ K+
Aldosterone sensitive channel --- in the presence of aldosterone the channel is open =
Amiloride and triamterene directly block the channel can use to minimize lithium toxicity

11. Distal Tubule Diuretics
Amiloride
Once a day
Best tolerated– only mild hyperkalemia
Can be used to minimize lithium toxicity- by directly blocking the Na-channel used by lithium to enter the cell and cause DI
Picture of periodic table- explain why na and li use the same channel
Tubular lumen (urinary space)
Peri-capillary space (blood)
Na+ K+
Aldosterone sensitive channel --- in the presence of aldosterone the channel is open =
Li+

12. Distal Tubule Diuretics
Triamterene
Found in Maxzide
Direct nephrotoxin- causes crystalluria and cast formation in up to 50% of patients
Known cause of interstitial nephritis
Approximately 1 case/year at NNMC
Tubular lumen (urinary space)
Peri-capillary space (blood)
Na+ K+
Aldosterone sensitive channel --- in the presence of aldosterone the channel is open =

13. Distal Tubule Diuretics
Aldosterone
Spironolactone
Long-half life– slow onset and resolution
Frequent side effects
Gynecomastia (10% ) Ax
Tubular lumen (urinary space)
Peri-capillary space (blood)
Na+ K+
Aldosterone sensitive channel --- in the presence of aldosterone the channel is open =

14. Other diuretics Mannitol
Only diuretic which causes water loss in excess of Na
Means only diuretic which causes a dilute urine (specific gravity of <1.010)
Therefore significant risk for hypernatremia 2nd to losses of free water
?use to therapeutic advantage in hyponatremia?
Theoretical risk with CRI– mannitol is retained causing hyperosmolarity

15. Time course of diuresis
Patient Fallacies
“Lasix makes me pee all day”- Wrong, lasix causes increased urine output for approximately 6 hours ( LASt sIX), then urine output actually DECREASES for the remainder of the day.

16. Time course of diuresis
Patient Fallacies
“Lasix causes me to make extra urine”- Wrong, after the first three days of diuresis patients are in steady-state. What they drink = what they urinate. Intuititively makes sense. If patients made extra urine everyday, eventually they would have no fluid left in their bodies, turn into dust, and blow away.

17. Time course of diuresis
Why does this occur?
Negative feedback loop automatically dampens the diuresis as it progresses. Given a stable dose of lasix, the counter-regulatory hormones eventually balance the lasix and NO FURTHER DIURESIS OCCURS FOR A GIVEN DOSE- input=output
Decreased volume, blood pressure, GFR, hormonal activation
- increased norepi, renin, angiotensin, aldosterone
Lasix - +
Diuresis

18. Time course of diuresis Steady-state implications
Assuming stable lasix dose and sodium intake,
Weight stable after 72hours (urine output = po intake)
Electrolyte abnormalities (if they are going to occur) will occur
-this is why you don’t need to check lytes every visit
Decreased volume, blood pressure, GFR, hormonal activation
- increased norepi, renin, angiotensin, aldosterone
Lasix - +
Diuresis

19. Time course of diuresis
Patient fallacy #3
Lasix qd can be used as an anti-htn agent
Can result in a net increase in volume (especially in the face of high sodium intake)
After lasix wears off, kidney then holds on to Na for the next 18 hours
Dinner 100meq Na intake
LASIX
Lunch 100meq Na intake
Breakfast 100meq

20. Time course of diuresis
For anti-htn- give BID to TID
Prevents the post-lasix sodium retention which would otherwise occur with lunch and dinner
Net effect is increased diuresis with improved bp control
Dinner 100meq Na intake
LASIX
LASIX
LASIX
Lunch 100meq Na intake
Breakfast 100meq

21. Time course of diuresis
Why not just increase the am dose?
1. Dose response curve flattens, such that larger doses with minimal increased benefit. But toxicity increases with increasing dose

22. Time course of diuresis
Why not just increase the am dose?
2. Even if higher dose effective, patient unlikely to tolerate such a rapid diuresis
Less hypotension risk urinating 200cc/hr x 10hrs vs. 2000cc/hr x 1hr

23. Diuretic Complications
Volume depletion
Azotemia
Hypokalemia
Metabolic Alkalosis
Hyponatremia
Hyperuricemia
Hypomagnesemia

24. Diuretic Complications
Volume depletion
Azotemia
Hypokalemia
Metabolic Alkalosis
Hyponatremia
Hyperuricemia
Hypomagnesemia

25. Diuretic Complications
Volume depletion
Azotemia
Hypokalemia
50mg HCTZ decreases K an average of meq/l
Metabolic Alkalosis
Hyponatremia
Hyperuricemia
Hypomagnesemia

26. Diuretic Complications
Volume depletion
Azotemia
Hypokalemia
Metabolic Alkalosis
Hyponatremia
Hyperuricemia
Hypomagnesemia

27. Diuretic Complications
Volume depletion
Azotemia
Hypokalemia
Metabolic Alkalosis
Hyponatremia
Common in CHF/Cirrhosis
Almost all cases 2nd to thiazide diuretic
Loops don’t cause because they block the concentration gradient. No gradient, no impairment in free H20 excretion
Hyperuricemia
Hypomagnesemia

28. Diuretic Complications
Volume depletion
Azotemia
Hypokalemia
Metabolic Alkalosis
Hyponatremia
Hyperuricemia
Due to increased proximal urate absorption associated with hypovolemia
Dose related- see graph
Hypomagnesemia

29. Diuretic Complications
Volume depletion
Azotemia
Hypokalemia
Metabolic Alkalosis
Hyponatremia
Hyperuricemia
Hypomagnesemia
Primarily handled in loop of Henle– therefore loops are etio
Thiazides also cause via a 2nd hyperaldosterone state

30. Diuretic resistance Two important determinants Other determinants
Site of action of the diuretic
Presence of counterbalancing antinaturic forces (angiotension, aldosterone), a fall in bp
Other determinants
Rate of drug excretion
All loops are highly protein bound
Not well filtered. Enter the urine via the proximal tubule secretory pump
Higher doses cause higher (initial) levels of sodium excretion

31. Diuretic resistance Dose response
Must reach a threshold amount before any naturesis
Once threshold reached, naturesis increased with increasing doses
Plateau is reached after which increased doses have no effect
Makes sense- once receptor is completely blocked, extra lasix will have no impact
Normal subject- max effect is seen with 40 lasix or 1 bumex

32. Diuretic resistance Dose response
Initial aim is to find the effective single dose (on the steep part of the curve)
Double the dose until response seen (or a max of of oral lasix)
Increasing a sub-opt dose to bid will have no effect
Higher doses required in:
CHF- 2nd to counter-regulatory hormones and decreased absorption
Renal failure- 2nd to competition for tubular secretion from retained cations

33. Diuretic resistance Dose response
Initial aim is to find the effective single dose (on the steep part of the curve)
Double the dose until response seen (or a max of of oral lasix)
Increasing a sub-opt dose to bid will have no effect
Higher doses required in:
CHF- 2nd to counter-regulatory hormones and decreased absorption
Renal failure- 2nd to competition for tubular secretion from retained cations

34. Diuretic resistance Mechanisms of resistance
Excess sodium intake
Possible to eat more sodium than lasix makes the patients lose
Check a 24hr urine sodium level to confirm. Anything over 100meq/day is excessive
Decreased or delayed intestinal drug absorption
Decreased drug entry into the tubular lumen
Increased distal absorption
Decreased loop sodium delivery due to low GFR

35. Diuretic resistance Mechanisms of resistance
Excess sodium intake
Decreased or delayed intestinal drug absorption
Common in CHF/Cirrhosis/Nephrosis
Delay in intestinal absorption 2nd to decreased intestinal perfusion, reduced motility, and mucosal edema
Explains the preferential response to Bumex or IV lasix
Decreased drug entry into the tubular lumen
Increased distal absorption
Decreased loop sodium delivery due to low GFR

36. Diuretic resistance Mechanisms of resistance
Excess sodium intake
Decreased or delayed intestinal drug absorption
Decreased drug entry into the tubular lumen
Occurs for the same reasons as above
Increased distal absorption
Decreased loop sodium delivery due to low GFR

37. Diuretic resistance Mechanisms of resistance
Excess sodium intake
Decreased or delayed intestinal drug absorption
Decreased drug entry into the tubular lumen
Increased distal absorption
Effect of diuretic is blunted by “downstream” compensation
Proximal Diuretic (Acetazolamide)- theoretically should block 60-75%. But actually a poor diuretic 2nd downstream compensation

38. Diuretic resistance Mechanisms of resistance
Excess sodium intake
Decreased or delayed intestinal drug absorption
Decreased drug entry into the tubular lumen
Increased distal absorption
Effect of diuretic is blunted by “downstream” compensation
Compensation can occur in distal tubule limiting loop effectiveness
Loop Diuretic- only blocks 15-20% of sodium reabsorption, but because less downstream tubule to compensate, an effective diuretic

39. Diuretic resistance Mechanisms of resistance
Excess sodium intake
Decreased or delayed intestinal drug absorption
Decreased drug entry into the tubular lumen
Increased distal absorption
Effect of diuretic is blunted by “downstream” compensation
Distal compensation is overcome by SEQUENTIAL BLOCKING
-this is the rational for giving a loop + a thiazide
-seen in the usual combination of lasix and Zaroxlyn

40. Diuretic resistance Mechanisms of resistance
HCTZ vs. Zaroxlyn
Similar mechanism of action. Zaroxlyn is simply more powerful mg for mg
5mg of Zaroxlyn = mg HCTZ (approx)
Zaroxlyn has a much longer duration of action
Allows for biw dosing

41. Diuretic resistance Nuances of use
HCTZ and CRF– still works
Ethacrynic acid
Torsemide use
Bumex nitch– shorter half life
Zaroxlyn use
Practical points of acetazolamide use