Diuretics of biochemistry

2. Introduction
• Diuretic: substance that promotes the
excretion of urine
• Natriuretic: substance that promotes
the renal excretion of sodium
• But natriuretic drugs increase water
excretion also
• So, any substance which increases
sodium & water excretion  Diuretic

3. • Appr. 120 ml of ultrafiltrate is formed each
minute, yet only 1 ml/min of urine is
produced
• Greater than 99% of the glomerular
ultrafiltrate is reabsorbed
• Appr. 65% of filtered solutes are
reabsorbed in the proximal tubule
• The descending thin limb is highly permeable
to water, yet its permeability to NaCl and urea
is low

4. • The ascending thin limb (ATL) is permeable to
NaCl and urea but impermeable to water
• The thick ascending limb actively reabsorbs
NaCl but is impermeable to water and urea
• Approximately 25% of filtered solutes are
reabsorbed in the loop of Henle, mostly in the
thick ascending limb, which has a large
reabsorptive capacity

5. • The hypertonicity of the medullary
interstitium plays a vital role to concentrate
urine and is therefore a key adaptation
necessary for living in a terrestrial
environment
• In the presence of ADH, the collecting duct
system is permeable to water
• Final adjustments in electrolyte composition
are made, by the adrenal steroid, aldosterone
in the collecting duct system

6. Classification
HIGH
EFFICACY
MEDIUM
EFFICACY
LOW
EFFICACY

7. High Efficacy / Ceiling Diuretics
(Inhibitors of Na+-K+-2Cl- Symport)

8. Medium Efficacy Diuretics
(Inhibitors of Na+-Cl- Symport)
1. Thiazides
(Benzothiadiazines)
• Chlorothiazide,
Hydrochlorothiazide,
Benzthiazide,
Hydroflumethiazide,
Clopamide
2. Thiazide Like
Diuretics
• Chlorthalidone,
Metolazone,
Xipamide,
Indapamide

9. Low Efficacy Diuretics
1. Carbonic Anhydrase Inhibitor Acetazolamide
2. Potassium Sparing Diuretics:
a. Aldosterone Antagonist  Spironolactone
b. Inhibitors of Renal Epithelial Sodium
Channel  Triamterene, Amiloride
3. Osmotic Diuretics  Mannitol, Isosorbide,
Glycerol
4. Miscellaneous  Sodium, Potassium &
Ammonium salts, Xanthine
derivatives (Theophylline), etc.

10. Site of Action of Diuretics

11. Na+-K+-2Cl- SYMPORT INHIBITORS
Also Called:
•Loop Diuretics
•High Ceiling Diuretics
Ethacrynic
Acid
Torsemide
Bumetanide
Furosemide

12. Loop Diuretics: Mechanism

13. • Kidney:
– Site of Action  Ascending Thick Limb
of Loop of Henle
– Abolishes cortico-medullary osmotic
gradient  ↓ free water reabsorption
– ↑↑ Na, K & Cl excretion
– More Na reaches CD  exchanged for K
 ↑↑↑ K excretion
– But, hypokalemia is less than that with
thiazides
Loop Diuretics: Actions

14. – Weak carbonic anhydrase inhibitor  ↑ HCO3
-
– No distortion of acid base balance
– Transient ↑ RBF  redistribution of blood
from outer to mid-cortical zone  ↓ PT
reabsorption
– Due to ↑ local PG synthesis
– ↑↑ Ca & Mg excretion
– Hyperuricemia, hyperglycemia; less than
thiazides
Loop Diuretics: Actions

15. • Other Actions:
– ↑↑ Systemic vascular capacitance 
↓ left ventricular filling pressure
– Action may be mediated by PG
Loop Diuretics: Actions

16. • Rapid oral absorption
• Extensive plasma protein binding
• Secreted in the proximal tubule by organic
anion transporter
• Drugs that block this secretion (e.g.
probenecid) reduces efficacy
• Furosemide  metabolized in kidney;
bumetanide & torsemide  in liver
• Short half life
• “Post diuretic Na retention”
Loop Diuretics: Pharmacokinetics

17. 1. Edema:
– Cardiac / hepatic / renal origin
– For rapid mobilization of edema fluid
– DOC in nephrotic failure & resistant
edema
2. Acute LVF/ pulmonary edema:
– i.v. furosemide
3. Cerebral edema:
– Second choice to osmotic diuretics
Loop Diuretics: Uses

18. 4. Forced Diuresis:
– In case of poisoning
– Second choice to osmotic diuretics
5. Hypertension:
– Associated with CHF
– In presence of renal insufficiency
– Emergency
6. Along with blood transfusion
7. Hypercalcemia & renal Ca stones
Loop Diuretics: Uses

19. THERAPEUTIC EFFECTS
Increase Na Excretion
Treatment of
Oliguric ARF
Increase Ca
Excretion
Treatment of
Hypercalcemia
Impair Free Water
Reabsorption
Treatment for
Hyponatremia
Increase Venous
Capacitance
Treatment of
Pulmonary
Edema
Increase Urine Volume
Treatment of
Severe Edema

20. ADVERSE EFFECTS
Hypomagnesemia
Metabolic
Alkalosis
Hypokalemia
Profound ECFV
Depletion
Hyperglycemia
Hyperuricemia
Ototoxicity
Hypocalcemia

21.  Clofibrate, warfarin  Displacement from
plasma protein binding  toxicity
 Li+  clearance decreased
 Cephalosporins, aminoglycosides renal
toxicity ↑↑
 Other ototoxic drugs  additive toxicity
 Probenecid  Inhibit organic acid
transporter  decrease potency
Loop Diuretics: Drug Interactions

22.  NSAIDs  inhibit PG synthesis  reduce
diuretic & antihypertensive efficacy
 Hypokalemia  ↑↑ digitalis, quinidine
toxicity, potentiate NM blockers & reduces
sulfonylurea action
 Synergistic with all anti-hypertensives
Loop Diuretics: Drug Interactions

23. Na-Cl SYMPORT INHIBITORS
Includes:
•Thiazide Diuretics
•Thiazide-Like Diuretics
Chlorthalidone
Metolazone
Chlorothiazide
Hydrochlorothiazide

24. Comparison of Loop & Thiazide
Diuretics

25. Thiazide Diuretics: Mechanism

26. Thiazide Diuretics: Actions
• Kidney:
– ↑ Na & Cl excretion
– ↑ Na delivery to CD exchanged with
K  ↑↑↑ K excretion
– Weak carbonic anhydrase inhibitors 
↑ HCO3
- excretion
– Hyperuricemia
– ↓ Ca excretion, ↑ Mg excretion
– Reduce GFR

27. Thiazide Diuretics: Actions
• Other Actions:
– Slow & sustained fall in BP  due to
persistent Na deficit in vascular
smooth muscle cells
– Decreased insulin release 
hyperglycemia

28. Thiazide Diuretics: Pharmacokinetics
• Route  oral
• Secreted into PT by Organic anion
transporter  can be blocked by probenecid
• Diuretic action starts within 1 hr
• Duration  more than loop diuretics
• Metolazone  effective in severe renal
failure
• Indapamide  ↓ diuretic action, ↑
antihypertensive action

29. Thiazide Diuretics: Uses
1. Edema:
– Mild to moderate cases, better for
maintenance therapy
– Best in cardiac edema
– Ineffective in presence of renal failure
2. Hypertension:
– First line drug
– Potentiates other antihypertensives

30. Thiazide Diuretics: Actions
3. Hypercalciuria, Ca nephrolithiasis,
osteoporosis
4. Management of Br intoxication
5. Nephrogenic Diabetes Insipidus:
– Paradoxical reduction in urine volume
– Volume depletion  decreased GFR

31. THERAPEUTIC EFFECTS
Increase Na Excretion
Treatment of
Hypertension
Decrease Ca
Excretion
Treatment of
Calcium
Nephrolithiasis
Treatment of
Mild Edema

32. ADVERSE EFFECTS
Hypomagnesemia
Metabolic
Alkalosis
Hypokalemia
Hypovolemia
Hyperglycemia
Hyperuricemia
Hyponatremia
Hypercalcemia
Hyperlipidemia

33. Thiazide Diuretics: Drug
Interactions
 Li+  clearance decreased
 Probenecid  Inhibit organic acid
transporter  decrease potency
 NSAIDs  inhibit PG synthesis  reduce
diuretic & antihypertensive efficacy
 Hypokalemia  ↑↑ digitalis, quinidine
toxicity, potentiate NM blockers & reduces
sulfonylurea action
 Synergistic with all anti-hypertensives

34. K Sparing Diuretics
Include:
•Na channel Inhibitors
•Aldosterone antagonist

35. Na CHANNEL INHIBITORS
Also Called:
•K-Sparing Diuretics
Amiloride
Triamterene

36. Na Channel Inhibitors: Mechanism

37. • Mild diuretic effect
• ↓ K, H, Ca & Mg excretion
• ↓ Uric acid excretion
Na Channel Inhibitors: Action

38. 1. In combination with other diuretics
– To prevent hypokalemia
– Increase diuretic & anti-hypertensive
efficacy
2. Cystic fibrosis  amiloride aerosol
3. Lithium induced nephrogenic DI 
amiloride
Na Channel Inhibitors: Uses

39. THERAPEUTIC EFFECTS
Enhance Natriuresis
Caused by Other
Diuretics
Block Na
Channels
Prevent Hypokalemia
Used in
Combination with
Loop &
Thiazide Diuretics
Treatment of
Lithium-Induced
Diabetes Insipidus

40. • Hyperkalemia
• Triamterene  nausea, dizziness,
muscle cramps, impaired glucose
tolerance, photosensitivity
• Amiloride  nausea, diarrhoea,
headache
Na Channel Inhibitors: Adverse Effects

41. MINERALOCORTICOID RECEPTOR
ANTAGONISTS
Also Called:
•K-Sparing Diuretics
•Aldosterone Antagonists
Spironolactone Eplerenone

42. Spironolactone: Mechanism

43. • Converted to active metabolite 
canrenone
• Mild increase in Na excretion
• Decreases K excretion
• K retaining action develops over 3-4
days
• Increases Ca excretion  direct
action on renal tubules
Spironolactone: Actions

44. 1. Edema:
– Cirrhotic & nephrotic edema
– Re-establishes response to thiazides
 refractory edema
2. Counteract K loss due to thiazide &
loop diuretics
Spironolactone: Uses

45. 3. Hypertension:
– In combination with thiazides
4. CHF:
– Along with other drugs in moderate to
severe CHF
– Prevents aldosterone induced cardiac
remodeling
Spironolactone: Uses

46. THERAPEUTIC EFFECTS
Enhances Natriuresis
Caused by Other Diuretics
Blocks Aldosterone
Treatment of
Primary Hyper-
aldosteronism
Prevents Hypokalemia
Used in
Combination
with Loop &
Thiazide
Diuretics
Treatment of
Hypertension
Treatment of
Heart Failure

47. ADVERSE EFFECTS
Impotence
Gynecomastia
Metabolic
Acidosis
Hyperkalemia
Hirsutism
CNS Side
Effects
Peptic Ulcer
Gastritis
Menstrual
Irregularities
Deepening of
Voice

48.  Along with K supplements  hyperkalemia
 Aspirin  blocks spironolactone action by
inhibiting tubular secretion of canrenone
 Increases plasma digoxin levels
 Blocks Na & water retention by
carbenoxolone sodium; but its therapeutic
effect is also lost
Spironolactone: Drug Interactions

49. Carbonic Anhydrase Inhibitor
Acetazolamide
Developed from sulfanilamide,
after it was noticed that
sulfanilamide caused metabolic
acidosis and alkaline urine.

50. Acetazolamide: Mechanism
• Inhibit carbonic anhydrase in proximal
tubule
• Blocks reabsorption of bicarbonate ion,
preventing Na/H exchange

51. Acetazolamide: Mechanism

52. • Kidney:
– ↑ HCO3
- & Na excretion
– Only mild ↑ Na excretion; as most of
the Na is reabsorbed by loop of Henle
– ↑ Na delivery to CD  exchanged with
K  ↑↑ K excretion
– ↑ Urinary pH (~ 8)
– Depletion of body HCO3
-  acidosis 
less HCO3
- is filtered at glomerulus 
self limiting action
Acetazolamide: Actions

53. • Extra-renal Actions:
– ↓ Formation of aqueous humor  ↓ Intra-
ocular tension
– ↑ Brain CO2 levels, ↓ pH  produces
sedation & raises seizure threshold
– Alteration of CO2 transport in lungs &
tissues
– ↓ Gastric HCl & pancreatic HCO3
-
secretion  at very high doses
Acetazolamide: Actions

54. 1. Glaucoma:
– Management of severe glaucoma
– Topical CA inhibitors also available 
dorzolamide, brinzolamide
2. Urinary Alkalinization:
– To increase excretion of uric acid &
other weak acids
3. Metabolic Alkalosis:
– Due to excessive use of diuretics in
patients with CHF
Acetazolamide: Uses

55. 4. Acute Mountain Sickness:
– ↓ CSF formation & ↓ pH of CSF
– Symptomatic relief
5. Other Uses:
– Adjuvant in treatment of epilepsy
– Hypokalemic periodic paralysis
– Hyperphosphatemia  to ↑ urinary
phosphate excretion
Acetazolamide: Uses

56. Acetazolamide: Adverse Effects
Acidosis Hypokalemia
Hypersensitivity
Parasthesias,
fatigue
Abdominal
discomfort
Bone Marrow
Depression
Ppt hepatic coma
in liver disease

57. Osmotic Diuretics
Mannitol Glycerol
Isosorbide

58.  Freely filterable
 Little or no tubular reabsorption
 Pharmacologically inert
 Resistant to metabolism
Osmotic Diuretics: Characteristics

59. • Extracts water from intracellular compartments
 ↑ECF volume ↓renin release ↑RBF  ↑GFR
• ↑ Renal medullary blood flow  removal of NaCl
& urea from renal medulla  washout of
medullary osmotic gradient  ↓salt reabsorption
• Retains water in PT by osmotic action  dilutes
luminal fluid  ↓ Na reabsorption
• Inhibits transport processes in the thick
ascending limb of loop of Henle
Mannitol: Mechanism

60. • ↑ Urinary excretion of all
electrolytes  Na, K, Ca, Mg,
Cl, HCO3
-, PO4
3-
• ↑ RBF, ↑ GFR
Mannitol: Actions

61. • Administered i.v. as a 10 – 20%
solution
Mannitol: Administration

62. 1. To reduce intracranial or
intraocular tension:
– In acute congestive glaucoma, head
injury, stroke, etc
– Before & after ocular / brain surgery
– Movement of water out of CSF &
aqueous humor by osmotic action
Mannitol: Uses

63. 2. Impending Acute Renal Failure:
– In shock, severe trauma, C-V surgery
– To maintain GFR
– C/I if acute renal failure has already set in
3. Forced diuresis:
– In case of poisoning
4. To counteract low osmolality of
plasma/ECF due to rapid hemodialysis or
peritoneal dialysis
Mannitol: Uses

64. Mannitol: Adverse Effects
Headache Nausea &
Vomiting
Hypersensitivity

65. • Acute tubular necrosis
• Anuria
• Pulmonary edema
• Acute left ventricular failure
• CHF
• Cerebral hemorrhage
Mannitol: Contraindications