This presentation was used for theory class of MBBS Sem III

1. Diuretics-II
Dr. Pravin Prasad
M.B.B.S., MD Clinical Pharmacology
Lecturer, Lumbini Medical College & TH
10 April 2019 (27 Chaitra 2075), Wednesday

2. Answer the following…
Classify diuretics
Why loop diuretics are also known as high ceiling
diuretics?
Mechanism of action of thiazide diuretics?
Which class diuretic is preferred in essential
hypertension?
Any two important drug interaction of diuretics.

3. By the end of this class, MBBS
Sem III students will be able to:
Explain the mechanism of action of weak diuretics
Discuss the salient pharmacological aspects of
weak diuretics
Differentiate between the two types of potassium
sparing diuretics

4. Diuretics: Classification
High ceiling
Medium efficacy
Weak / adjunctive

5. Weak/ Adjunctive Diuretics:
Classification
Carbonic Anhydrase
Inhibitors
• Acetazolamide
Osmotic Diuretics
• Mannitol
• Isosorbide, Glycerol
Potassium sparing diuretics
Renal epithelial Na+
channel blockers
• Amiloride,
Triamterene
Aldosterone antagonists
• Spironolactone,
Eplerenone

6. Carbonic Anhydrase Inhibitors
Acetazolamide, Methazolamide, Dorzolamide
Reversible, non-competitive inhibitor of carbonic
anhydrase
Action limited by the availability of HCO3
- in
luminal fluid
Self limited diuretic action
Na+ absorption in distal segment occurs in
exchange with K+
Marked kaliuresis

7. CAse Inhibitors: Mechanism of
Action
PT cells
Luminal fluid
H+
Extracellular fluid
NaHCO3
Na+
HCO3
-
H2CO3
H2O +
CO2CAse IV
CAse II
H2CO3
HCO3
-
CAse Inhibitors

8. CAse inhibitors: Mechanism of
Action
Inhibits Carbonic anhydrase enzyme at multiple sites
Type II in cells of PT
• Less H+ available for exchange with Na+
Type IV on the membrane of PT cells
• Less CO2 available for diffusion into cells
Inhibition of Na+ and HCO3
- reabsorption in PT
Na+ gets absorbed in exchange with K+ in DT, CD
HCO3
- lost in excess in urine

9. CAse inhibitors: Mechanism of
Action
Inhibits Carbonic anhydrase enzyme at multiple
sites
Present in intercalated cells of DT and CD
• Less H+ available for secretion by H+-ATPase
Principal cells
Intercalated
cells
Luminal fluid
Extracellular
H+
Na+ Na+
Na+ Na+
Na+
Na+

10. Acetazolamide: Uses
Glaucoma
Decrease formation of aqueous humour
Mountain sickness
Alters CO2 transport in lungs, tissues and brain
Decreases CSF formation, lowers pH
To alkalinise urine
Periodic paralysis
Epilepsy

11. Acetazolamide: Adverse effects
Acidosis, hypokalaemia
To be cautiously used in COPD patients
Drowsiness
Paraesthesia, fatigue, abdominal discomfort
Hypersensitivity reaction
Bone marrow depression
Interferes with elimination of NH3 in urine
CONTRAINDICATED in liver disease

12. Aldosterone antagonists
Spironolactone, Eplerenone
Conserve K+ indirectly, produces mild natriuresis
Potassium sparing diuretics
No effect in the absence of aldosterone
Useful in states related to high aldosterone
activity
Spironolactone has hormonal side effects
Eplerenone is safer in this regard

13. ECF
Luminal
Fluid
Spironolactone: Mechanism of
Action
Aldosterone
Mineralocorticoi
d receptor
Nucleus
AIP
ATP
Na+
K+
K+
Spironolactone

14. Spironolactone: Mechanism of
Action
Binds to Mineralocorticoid receptors
Blocks aldosterone activity
• Competitive antagonist
Aldosterone Induced Protein / Na+ channels not
expressed
Decreased absorption of Na+ and water and
secretion of K+
• K+ loss in urine is decreased

15. Spironolactone: Uses
Hypertension
Adjuvant to thiazide, loop diuretics
• Counteracts K+ loss
• Attenuates hypertensive nephropathy
Oedema
Cirrhotic/ nephrotic patients
Refractory
Congestive Heart Failure
Primary hyperaldosteronism

16. Spironolactone: Adverse effects
Drowsiness, mental confusion, ataxia, epigastric
discomfort, loose motions
Interacts with progestin and androgen receptors:
Gynaecomastia, erectile dysfunction, loss of
libido
Breast tenderness, menstrual irregularities
Hyperkalaemia in renal impaired patients
Acidosis in cirrhotics
Peptic ulcer: CONTRAINDICATION

17. Eplerenone
Lower affinity for androgen and progestin receptors
Inactivated by CYP3A4 enzyme
Indications:
Moderate to severe CHF
Post infarct left ventricular dysfunction
Hypertension

18. Renal epithelial Na+ Channel
inhibitors
Triamterene, Amiloride
Decreases K+ excretion, accompanied with small
increase in Na+ loss
Potassium sparing diuretics
Alkaline urine produced
Cl-, HCO3
-
Reduces Ca2+ and Mg2+ excretion

19. Amiloride: Mechanism of Action
ECF
Luminal
Fluid
Principal cells of late DT and CD
• Rich in K+, Low Na+
• Activity of Na+-K+ ATPase at
basolateral membrane
Na+
K+
K+
Amiloride
Na+ Na+
K+
K+K+
K+
K+
K+
Na+
Na+

20. Amiloride: Mechanism of Action
Blocks luminal amiloride sensitive renal epithelial
Na+ channels
Decrease reabsorption of Na+ in DT and CD
Luminal negative charge not developed
Less secretion of K+ from principal cells
Less secretion of H+ from intercalated cells

21. Amiloride: Uses
Hypertension
As adjuvant
• Prevents hypokalaemia
• Increase natriuretic response
More likely to develop hyperkalaemia if given
along with ACEI/ARBs, NSAIDs, β blockers
Cystic fibrosis

22. Adverse effects
Amiloride:
Nausea, diarrhoea, headache
Decreases entry of lithium in CD cells
• Lithium induced diabetes insipidus
Triamterene:
Impaired glucose tolerance, photosensitivity
Rise in blood urea

23. Osmotic diuretics
Mannitol, glycerol, isosorbide
Non-electrolyte, low molecular weight
Pharmacologically inert
Acts by:
• Raising osmolarity of plasma and tubular fluid
• Gets freely filtered at glomerulus
• Limits tubular water and electrolyte
reabsorption (cations as well as anions)

24. Mannitol
Tubular water and electrolyte reabsorption action of
mannitol mediated by:
Retaining water isosmotically in PT and
Descending limb of LoH
Inhibit transport process in TAL
Expands extracellular fluid volume
Increases renal blood flow
• Corticomedullary osmotic gradient lost

25. Mannitol
Given intravenously
Uses:
Increased intracranial pressure
Increased intraocular pressure
Counteract low osmolarity of plasma and ECF
due to rapid haemodialysis or peritoneal dialysis
(dialysis disequilibrium)

26. Mannitol
CONTRAINDICATIONS:
Renal insufficiency
Acute tubular necrosis
Anuria
Pulmonary oedema
Acute left ventricular failure
CHF
Cerebral haemorrhage
• Side Effects
• Headache
• Nausea/
vomiting
• Hypersensitiv
e reactions

27. Post Test
Inhibition of CAse by Acetazolamide is:
? Competitive and reversible
? Non-competitive and reversible
? Competitive and irreversible
? Non-competitive and irreversible

28. Post Test
All of the following are a potassium sparing
diuretics EXCEPT:
? Acetazolamide
? Triamterene
? Eplerenone
? Spironolactone

29. Post Test
All of the following are indications of
acetazolamide EXCEPT:
? Epilepsy
? Angle closure glaucoma
? High altitude pulmonary oedema
? As diuretic

30. Conclusion
Weak diuretics either act early in PT or in late DT and
CD
Acetazolamide has its self limiting action, produces
acidosis and marked kaliuresis
Not used as diuretics
Spironolactone has activity on progestin and androgen
receptors
Eplerenone safer in this regard
Potassium sparing diuretics acts either by antagonising
the activity of aldosterone or by directly inhibiting
action of epithelial Na+ channels

31. Any queries?
Next class:
Today afternoon
Practical class
Revise the topics from
BOOK
Thank you.