Diuretics

A summarized and complete description on diuretics.

1. DIURETICS
BY
ROHIT AGRAWAL
B.PHARMACY

2. •Diuretics are the drugs or agents which promotes
diuresis i.e. increased urine production and
increased rate of urine flow
•The site of action is kidney, specifically different
parts of a nephron
•Diuretic action is achieved by increasing excretion
of Na
+
ions (natriuretic) which increases excretion
of water
•However some diuretics (osmotic diuretics) have
no natriuretic but only aquaretic action
•Na
+
ions are excreted accompanied with other
ions, particularly Cl
-
ions, also Ca
++
, Mg
++
, K
+
etc.

3. THERAPEUTIC USES
•As antihypertensive agent (decreases blood
volume)
•In treatment of edema (by mobilizing
extracellular fluids as NaCl is the major
determinant of extracellular volume)
•To maintain urine volume

4. Structure of nephron

6. PHYSIOLOGY OF URINE FORMATION

7. CLASSIFICATION OF DIURETICS
Type Example Site of action Mechanism of action
Carbonic anhydrase
inhibitors
Acetazolamide
Methazolamide
Proximal convoluted
tubule
Inhibition of carbonic
anhydrase enzyme
Loop diuretics Furosemide
Torasemide
Loop of Henle Blocks Na
+
/K
+
/Cl
-
symporter
Thiazide and thiazide
like diuretics
Hydrochlorthiazide
Metolazone
Distal convoluted
tubule
Blocks Na
+
/Cl
-

symporter
Osmotic diuretics Mannitol
Isosorbide
Proximal convoluted
tubule;
Loop of Henle

Potassium sparring
diuretics



Collecting tubule
Blocks renal
epithelial Na
+

channel
Na+ channel blockers

Triamterene

Blocks the action of
aldosterone Aldosterone
antagonist
Spironolactone

9. SITE OF ACTION OF VARIOUS DIURETICS

10. SITE OF ACTION OF VARIOUS DIURETICS

11. CARBONIC ANHYDRASE INHIBITORS
•Weak type of diuretics
•Act by inhibiting carbonic anhydrase enzyme
•Examples: Acetazolamide, Methazolamide,
Dorzolamide

12. ACTION OF CARBONIC ANHYDRASE
•Catalyzes the following reaction
•Located in proximal convoluted tubule; both
in the cytoplasm of tubular cells and on
luminal membrane
•Plays a key role in NaHCO
3 reabsorption

13. Fig. Action of Carbonic Anhydrase Enzyme

14. •Basolateral Na
+
pump maintain a lesser
concentration of Na
+
inside the tubular cells
which activated Na
+
/H
+
exchanger present on
luminal membrane
•H
+
, transported into lumen in exchange of Na
+
,
bind with HCO
3
-
to form H
2CO
3 which in presence
of luminal CA breaks down into H
2O and CO
2
•CO
2 diffuses into tubular cells where it binds with
H
2O and then breaks into HCO
3
-
via cytoplasmic
CA enzyme
•This creates electrochemical gradient of HCO
3
-

across basolateral membrane which is used by
Na
+
/HCO
3
-
symporter present on basolateral
membrane resulting in reabsorption of NaHCO
3
followed by water reabsorption isotonically

15. MOA OF CARBONIC ANHYDRASE
INHIBITORS (ACETAZOLAMIDE)
•Inhibition of both luminal and cytoplasmic
carbonic anhydrase enzyme results in
blockage of NaHCO
3 reabsorption in PCT
•And thereby increase excretion of water
•Besides Na
+
and HCO
3
-
, CA inhibitors also
increase excretion of Cl
-
and K
+
; but have no
effect on Ca
++
and Mg
++
reabsorption
•It shows self limiting diuretic action

16. EXTRARENAL ACTIONS OF CA
INHIBITORS
•Ciliary processes of eye:
–CA mediates formation of HCO
3
-
in aqueous
humor
–CA inhibitors decrease rate of formation of
aqueous humor and decrease IOP
•CNS
–Lowering of pH resulting in sedation and elevation
of seizure threshold

17. THERAPEUTIC USES
•Because of self limiting action, production of
acidosis and hypokalemia, it is not used as
diuretic
•Edema (in combination with other distal
diuretics)
•Used in glaucoma
•To alkalinize urine (during UTI and to promote
excretion of acidic drugs)
•Altitude sickness (for symptomatic relief as well
as prophylaxis; due to reduced CSF formation as
well lowering of brain and CSF pH)
•Epilepsy
•To treat metabolic alkalosis

18. ADRs
•Metabolic acidosis
•Hypokalemia
•Drowsiness
•Tinnitus
•Parasthesias
•Abdominal discomfort
•Bone marrow depression
•Renal lesions, allergic reactions
•Renal stones

19. Contraindications
•Liver cirrhosis
–May precipitate hepatic coma by interfering with
urinary elimination of NH3 due to alkaline urine
•COPD
–Increased risk of acidosis

20. DOSE
•Adult dose for Glaucoma
–Open angle glaucoma: tab or inj. 250 mg 1 to 4
times a day
–Closed angle glaucoma: 250 to 500 mg PO/IV
followed by 125-250 mg PO q 4 hrs
•For altitude sickness: 125 to 250 mg orally q
6-12 hrs
•For seizure prophylaxis: 8 to 30 mg/Kg/day in
1 to 4 divided doses

21. Drug – Drug Interactions
•Acetazolamide + Aspirin
–Inhibit each others renal tubular secretion resulting
increased plasma levels; also CAIs displace salicylates
from plasma to CNS resulting to neurotoxicity
•Acetazolamide + Carbamazepine
–Increased levels of carbamazepine, due to inhibition
of CYP3A4 by acetazolamide
•Acetazolamide + ephedrine
–Increase tubular reabsorption of ephedrine

22. LOOP DIURETICS
•Also called high ceiling diuretics
•High efficacy diuretics
•Site of action is thick ascending limb of loop of
Henle, specifically Na
+
/K
+
/2Cl
-
symporter
•Ex: Furosemide, Torasemide, Bumetanide

23. MOA OF FUROSEMIDE
(LOOP DIURETICS)

24. MOA OF FUROSEMIDE
(LOOP DIURETICS)

25. •Na
+
/K
+
/2Cl
-
symporter present on luminal
membrane of TAL is responsible for
reabsorption of NaCl and KCl
•By inhibiting this symporter, furosemide
inhibits the reabsorption of Na
+
, K
+
and Cl
-

thereby resulting in diuretic action
•TAL is responsible for reabsorption of 35% of
Na
+
; hence inhibition at this site helps in
achieving highly efficacious diuretic action
•Besides, it also inhibits reabsorption of Ca
++

and Mg
++

26. THERAPEUTIC USES
•Edema (Drug of choice for edema in nephrotic
syndrome)
•Acute pulmonary edema
•Cerebral edema
•Hypertension
•Hypercalcaemia

27. ADR
•Hypokalemia
•Hyperuricaemia
•Hypomagnesaemia, hypocalcemia
•Hypotension
•Nausea, vomiting, diarrhoea
•Ototoxicity
•Hypersensitivity reactions
•Alkalosis

28. CONTRA INDICATIONS
•Severe hyponatremia
•Severe dehydration
•Anuria
•Hypersensitivity to sulfonamides

29. DOSE
•For edema
–20 to 80 mg PO OD
•For hypertension
–20-80 mg PO q 12hr
•Acute pulmonary edema
–0.5-1 mg/Kg IV over 1-2 minutes

30. DRUG-DRUG INTERACTION
•Furosemide + Aminoglycoside antibiotics
(amikacin, gentamycin, streptomycin)
–Synergistic pharmacological effects results in
ototoxicity and nephrotoxicity
•Furosemide + NSAIDS
–Diminished action of furosemide
•Furosemide + Probenecid
–Inhibit tubular secretion of furosemide decreasing
their action
–Diminish uricosuric action of probenecid

31. •Furosemide + Lithium
–Increased plasma levels of Lithium due to
enhanced reabsorption
•Furosemide + cardiac glycosides
–Enhances digitalis toxicity

32. THIAZIDE AND THIAZIDE LIKE
DIURETICS
•These are diuretics of medium efficacy
•Site of action is distal convoluted tubule;
specifically Na
+
/Cl
-
symporter
•E.g.: Hydrochlorthiazide, Benzthiazide,
Metalozone, etc.

33. MOA OF HYDROCHLORTHIAZIDE

34. •Na
+
/Cl
-
symporter, present on luminal
membrane of DCT, is responsible for Na
+

reabsorption at this site (about 5%)
•Thiazides compete for Cl
-
binding site of this
symporter and by blocking this, it inhibits Na
+

reabsorption
•Simultaneously, it also inhibit reabsorption of
Cl
-
, K
+
and Mg
++
•It increases the reabsorption of Ca
++

35. THERAPEUTIC USES
•To treat edema associated with heart
(congestive heart failure), liver (cirrhosis), and
renal (nephrotic syndrome, chronic renal
failure, and acute glomerulonephritis) disease
•As antihypertensive agents (mainly used
diuretics)
•Osteoporosis

36. ADR
•Hypotension
•Hypokalemia
•Metabolic alkalosis
•Hypernatremia
•Hypochloremia
•Hypomagnesaemia
•Hypercalcemia
•Hyperuricaemia

37. CONTRA INDICATIONS
•Sulfonamides hypersensitivity

38. DOSE
•For hypertension
–12.5-50 mg PO OD
•For edema
–25-100 mg PO OD or BD
•For osteoporosis
–25 mg PO OD

39. DRUG-DRUG INTERACTION
•Thiazides + NSAIDS/Bile acid sequestrants
–Reduced activity of thiazides due to reduced
absorption
•Thiazides + antiarrythmic drugs (Quinidine)
–Increased risk of polymorphic ventricular tachycardia
due to hypokalaemia induced by thiazides
•Thiazides + Probenecid
–Inhibit tubular secretion of furosemide decreasing
their action
–Diminish uricosuric action of probenecid

40. POTASSIUM SPARRING DIURETICS
•These are the diuretics that have are able to
conserve K
+
while inducing mild natriuresis
•Includes:
1.Aldosterone antagonists
–E.g.: Spironolactone, Eplerenone
2.Renal epithelial Na+ channel inhibitors
–E.g.: Triamterene, Amiloride

41. SPIRONOLACTONE
•Steroid, chemically related to
mineralocorticoid aldosterone
•Acts as antagonist of aldosterone

42. ACTION OF ALDOSTERONE

43. ACTION OF SPIRONOLACTONE

44. MOA OF SPIRONOLACTONE
•Aldosterone penetrates the late DT and CD
cells
•Bind to intracellular mineralocorticoid
receptor (MR)
•Induces formation of aldosterone induced
proteins (AIP)
•AIPS promote Na
+
reabsorption by a number
of mechanism and K
+
secretion

45. •Spironolactone binds to MR and inhibits
formation of AIPs
•As a result it increases Na
+
and decreases K
+

excretion

46. THERAPEUTIC USES
•In combination with other diuretics to
counteract K
+
loss
•Edema
•Hypertension
•Congestive heart failure
•Primary Hyperaldosteronism

47. ADR
•Hyperkalemia
•Metabolic acidosis in cirrhotic patients
•Diarrhoea, gastritis
•Gynaecomastia
•Erectile dysfunction
•Menstrual irregularities
•Drowsiness, mental confusion

48. CONTRA INDICATIONS
•In case of severe hyperkalemia
•Peptic ulcer (may aggravate)

49. DOSE
•For edema
–25-200 mg/day orally
•Hypertension
–50-100 mg/day orally
•Congestive heart failure
–25 mg orally OD
•Primary Hyperaldosteronism
–400 mg/day orally

50. DRUG-DRUG INTERACTION
•Spironolactone + Salicylates
–Inhibit tubular secretion of spironolactone thus
reducing its action
•Spironolactone + Cardiac glycosides
–Increase plasma levels of cardiac glycosides by
altering its elimination

51. MANNITOL
•It is a osmotic diuretic
•Its major site of action is loop of henle
•Chemically it is sugar alcohol
•It is a nonelectrolyte of low molecular weight
•Pharmacologically inert

52. MOA OF MANNITOL
•Mannitol is freely filtered at glomerulus, undergo
limited reabsorption
•Being a hypertonic solute, it increase intraluminal
osmotic pressure
•This OP extract from the tubular cells and also
prevents water reabsorption
•Thereby increasing the urine volume
•Though primary action is to increase urinary
volume, mannitol also results in enhanced
excretion of all ions

53. THERAPEUTIC USES
•To treat increased intracranial or intraocular
pressure
•Drug of choice for cerebral edema
•In acute renal failure

54. ADR
•Pulmonary edema
•Headache
•Nausea
•Vomiting
•Dehydration

55. CONTRA INDICATIONS
•Active intracranial bleeding
•Pulmonary edema
•CHF
•Anuria

56. DOSE
•For Cerebral edema
–1.5-2 g/kg IV infused over 30-60 minutes
•For increased IOP
–1.5-2 g/kg IV infused over 30-60 minutes

57. DRUG-DRUG INTERACTION
•Mannitol + aminoglycosides
–Increased risk of nephrotoxicity

58. REFERENCES
•TRIPATHI, K.D., (2014). Essentials of Medical
Pharmacology. 7
th
Edition. New Delhi, India:
Jaypee Brothers Medical Publishers Pvt. Ltd.
•BRUNTON, L.L., PARKER, K.L., BLUMENTHAL,
D.K., BUXTON, I.L.O, (2006). Goodman and
Gilman’s Manual of Pharmacology and
Therapeutics. 11
th
Edition. USA: The McGraw-
Hill Companies, Inc.

59. THANK YOU