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
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 NaHCO3 reabsorption
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 HCO3
- to form H2CO3 which in presence
of luminal CA breaks down into H2O and CO2
• CO2 diffuses into tubular cells where it binds with
H2O and then breaks into HCO3
- via cytoplasmic
CA enzyme
• This creates electrochemical gradient of HCO3
-
across basolateral membrane which is used by
Na+/HCO3
- symporter present on basolateral
membrane resulting in reabsorption of NaHCO3
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 NaHCO3 reabsorption in PCT
• And thereby increase excretion of water
• Besides Na+ and HCO3
-, 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 HCO3
- 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
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
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
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.
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
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
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
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
58. REFERENCES
• TRIPATHI, K.D., (2014). Essentials of Medical
Pharmacology. 7th 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. 11th Edition. USA: The McGraw-
Hill Companies, Inc.
