Diuretics

1. DIURETICS
Nephron Physiology

8. Nephron sites of action of diuretics

10. CARBONIC HYDRASE INHIBITOR

11. Prototype: Acetazolamide
Developed from
sulfanilamide, after
it was noticed that
sulfanilamide
caused metabolic
acidosis and
alkaline urine.

12. Mechanism of action: Na+ bicarbonate diuresis
 Inhibit carbonic anhydrase in proximal tubule
 Blocks reabsorption of bicarbonate ion,
preventing Na/H exchange
 Pharmacological effect
 Sodium bicarbonate diuresis
 metabolic acidosis

14. Pharmacokinetics

15. Therapeutic Uses
 Urinary alkalinization
 Metabolic alkalosis
 Glaucoma: acetazolamide,
dorzalamide
 Acute mountain sickness

16. CA Inhibitor Toxicity
 Hyperchloremic metabolic
acidosis
 Nephrolithiasis: renal stones
 Potassium wasting

17. Osmotic Diuretics
 Mannitol (prototype)
 Urea
 Glycerin
 Isosorbide

18. Osmotic Diuretic Characteristics
 Freely filterable
 Little or no tubular reabsorption
 Inert or non-reactive
 Resistant to degradation by tubules

19. Mechanism of Action:
 Inhibition of Water Diffusion
 Free filtration in osmotically active concentration
 Osmotic pressure of non-reabsorbable solute
prevents water reabsorption and increase urine
volume
 Proximal tubule
 Thin Descending limb of the loop of Henle

20. Pharmacokinetics

21. Therapeutic Uses
Prophylaxis of renal failure
Mechanism:
 Drastic reductions in GFR cause dramatically
increased proximal tubular water reabsorption and a
large drop in urinary excretion
 Osmotic diuretics are still filtered under these
conditions and retain an equivalent amount of water,
maintaining urine flow

22. Therapeutic Uses (Cont.)
Reduction of CSF pressure and
volume
Reduction of intraocular pressure
Reduction of pressure in extravascular fluid
compartments

23. Toxicity of Osmotic Diuretics
 Increased extracellular fluid volume
 Hypersensitivity reactions
 Glycerin metabolism can lead to
hyperglycemia and glycosuria
 Headache, nausea and vomiting

24. Loop of Henle
 TDL permeable to water but not Na+
 TAL impermeable to water and transports Na+
 Differences in permeabilities creates the
countercurrent multiplier
 Countercurrent multiplier creates interstitial
osmolar gradient
 20% of filtered load of Na absorbed by the TAL

25. Loop Diuretics
 Furosemide
(prototype)
 Bumetanide
 Torsemide
 Ethacrynic acid

26. Molecular Mechanism of Action
 Enter proximal
tubule via organic
acid transporter
 Inhibition of the
apical Na-K-2Cl
cotransporter of
the TALH
 Competition with
Cl- ion for binding

27. Pharmacological Effects
 Loss of diluting ability: Increased Na, Cl and
K excretion
 Loss of concentrating ability:
 reduction in the medullary osmotic gradient
 Loss in ADH-directed water reabsorption in
collecting ducts
 Loss of TAL electrostatic driving force:
increased excretion of Ca2+, Mg2+ and NH4
+
 Increased electrostatic driving force in CCD:
increased K+ and H+ excretion

28. Pharmacokinetics
 Rapid oral absorption, bioavailability ranges
from 65-100%
 Rapid onset of action
 extensively bound to plasma proteins
 secreted by proximal tubule organic acid
transporters
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29. Pharmacokinetics

30. Therapeutic Uses
 Edema of cardiac, hepatic or renal origin
 Acute pulmonary edema – (parenteral route)
 Chronic renal failure or nephrosis
 Hypertension
 Symptomatic hypercalcemi

31. Loop Diuretic Toxicity
 Hypokalemia
 Magnesium depletion
 Chronic dilutional hyponatremia
 Metabolic alkalosis
 Hyperuricemia
 Ototoxicity

32. Drug Interactions
 Displacement of plasma protein binding of
clofibrate and warfarin
 Li+ clearance is decreased
 Loop diuretics increase renal toxicity of
cephalosporin antibiotics
 Additive toxicity w/ other ototoxic drugs
 Inhibitors of organic acid transport (probenecid,
NSAID's) shift the dose-response curve of loop
diuretics to the right

33. Distal Convoluted Tubule
 5% of filtered load of Na+ reabsorbed
 Segment mostly impermeable to water

34. Mechanis
m of
Action
 Thiazides freely filtered and secreted in proximal tubule
 Bind to the electroneutral NaCl cotransporter
 Thiazides impair Na+ and Cl- reabsorption in the early
distal tubule: “low ceiling”

35. Increased K+ Excretion Due To:
 Increased urine flow per se
 Increased Na+-K+ exchange
 Increased aldosterone release
Na+/K+ exchange
in the cortical
collecting duct

36. Whole Body Effects of Thiazides
 Increased urinary excretion of:
 Na+
 Cl-
 K+
 Water
 HCO3
- (dependent on structure)
 Reduced ECF volume (contraction)
 Reduce blood pressure (lower CO)
 Reduced GFR

37. Pharmacokinetics
 Oral administration - absorption poor
 Diuresis within one hour
 T1/2 for chlorothiazide is 1.5 hours,
chlorthalidone 44 hours

39. Therapeutic Uses
 Edema due to CHF (mild to moderate)
 Essential hypertension
 Diabetes insipidus
 Hypercalciuria

40. Diabetes Insipidus
 Thiazides: paradoxical reduction in urine
volume
 Mechanism: volume depletion causes
decreased GFR
 Treatment of Li+ toxicity:
 Thiazides useful
 Li+ reabsorption increased by thiazides. Reduce
Li dosage by 50%

41. Thiazide Use in Hypercalciuria -
Recurrent Ca2+ Calculi
 Thiazides promote
distal tubular Ca2+
reabsorption
 Prevent “excess”
excretion which could
form stones in the
ducts of the kidney
 50-100 mg HCT kept
most patients stone
free for three years of
follow-up in a recent
study

42. Thiazide Toxicity
 Hypokalemia due to:
 Increased availability of Na+ for exchange at
collecting duct
 Volume contraction induced aldosterone release
 Hyperuricemia
 Direct competition of thiazides for urate transport
 Enhanced proximal tubular reabsorption efficiency
 Hyperglycemia
 Diminished insulin secretion
 Related to the fall in serum K+
 Elevated plasma lipids

43. Cortical Collecting Duct
 Water permeability controlled by antidiuretic
hormone (ADH)
 Driving force for water reabsorption is
created by the countercurrent multiplier
 2-3% of filtered Na+ reabsorbed here via
Na+ channels that are regulated by
aldosterone
 Major site of K+ secretion

44. Spironolactone
 Mechanism of
action: aldosterone
antagonist
 Aldosterone receptor
function
 Spironolactone
prevents conversion
of the receptor to
active form, thereby
preventing the action
of aldosterone

45. Pharmacokinetics
 70% absorption in GI tract
 Extensive first pass effect in liver and
enterohepatic circulation
 Extensively bound to plasma proteins
 100% metabolites in urine
 Active metabolite: canrenone (active)
 Canrenoate (converted to canrenone)

47. Therapeutic Uses
 Prevent K loss caused by other
diuretics in:
 Hypertension
 Refractory edema
 Heart failure
 Primary aldosteronism

48. Administration
 Dose orally administered (100 mg/day)
 Spironolactone/thiazide prep (aldactazide,
25 or 50 mg of each drug in equal ratio)

49. Toxicity
 Hyperkalemia - avoid excessive K
supplementation when patient is on
spironolactone
 Androgen like effects due to it steroid structure
 Gynecomastia
 GI disturbances

50. Triamterene and Amiloride
 Non-steroid in
structure, not
aldosterone
antagonists

51. Mechanism of Action
 Blockade of apical Na+
channel in the principal
cells of the CCD
 Amiloride: blocks the Na/H
exchanger (higher
concentrations)
 Blockade of the
electrogenic entry of
sodium causes a drop in
apical membrane potential
(less negative), which is the
driving force for K+
secretion

52. Pharmacokinetics
 Triamterine
 50% absorption of oral dose
 60% bound to plasma proteins
 Extensive hepatic metabolism with active
metabolites
 Secreted by proximal tubule via organic cation
transporters
 Amiloride
 50% absorption of oral dose
 not bound to plasma proteins
 not metabolized, excreted in urine unchanged
 Secreted by proximal tubular cation transporters

54. Therapeutic uses
 Eliminate K wasting effects of other
diuretics in:
 Edema
 Hypertension

55. Toxicity
 Hyperkalemia. Avoid K+ supplementation
 Drug interaction - do not use in combination with
spironolactone since the potassium sparing
effect is greater than additive
 Caution with ACE inhibitors
 Reversible azotemia (triamterine)
 Triamterene nephrolithiasis. 1 in 1500 patients

56. Summary: Sites of Diuretic Action