This document discusses diuretics, including their classification, mechanisms of action, uses, adverse effects, and drug interactions. It covers loop diuretics like furosemide that work by inhibiting sodium-potassium-chloride transport in the thick ascending limb of the loop of Henle, and thiazide diuretics that inhibit sodium-chloride transport in the distal convoluted tubule. Loop diuretics have more side effects like hypokalemia and ototoxicity compared to thiazides. Both classes are commonly used to treat hypertension and edema due to their ability to increase sodium and water excretion. Their effects need to be monitored due to drug interactions that can enhance toxicity.

1. Diuretics
Dr. Pravin Prasad
M.B.B.S., MD Clinical Pharmacology
Assistant Professor, Maharajgunj Medical Campus
19 November 2021 (3 Mangsir 2078), Friday

2. By the end of this class, BDS 2nd Year
students will be able to:
Classify diuretics
Explain the mechanism of action of loop diuretics and thiazide
diuretics
Compare the adverse effects of loop diuretics and thiazide
diuretics
List their uses
Identify their common drug interactions

3. Preliminaries

4. Relevant Physiology
Functional Unit of Kidney
Nephron
Parts of nephron:
Glomerulus
Proximal Tubule
Loop of Henle
Distal Tubule
Collecting Duct

5. Relevant Physiology
Process of urine formation
Ultrafiltration
Tubular reabsorption
Tubular secretion

6. Relevant Physiology
Pharmacologically, nephron is divided
into:
Site I: Proximal Convoluted Tubule
Site II: Thick Ascending Limb of
Loop of Henle
Site III: Cortical Diluting segment of
Loop of Henle
Site IV: Distal Convoluted Tubule
and Collecting Duct

7. Urinary constituent movements: Site I
Sodium Potassium Water
Reabsorbed Reabsorbed
Along the osmotic
gradient
Processes:
• Direct entry
• Coupled to absorption of
anions
• Exchanged with H+
• Passive diffusion
Process:
• Paracellular
pathways
Process:
• Transcellular
aquaporin-1
channels
• Paracellular
pathways

8. Urinary constituent movements: Site II
Movement of only salts occur
Impermeable to water
Luminal fluid
Cuboidal
cells of TAL
(medullary
portion)
Na+-K+-2Cl-
K+ Cl-
K+
Na+
Na+
Ca2+, Mg2+
Extracellular fluid

9. Urinary constituent movements: Site III
Movement of only salts occur
Impermeable to water
Luminal fluid
Extracellular fluid
Cl-
Na+
Na+-Cl- symporter No reabsorption or secretion of K+

10. Urinary constituent movements: Site IV
Comprises of
Distal tubule
Collecting duct
Two types of cells
Principal cells
Intercalated cells

11. Urinary constituent movements: Site IV
Principal cells
Intercalated
cells
Luminal fluid
Extracellular fluid
K+
Na+
Na+
Na+
Amiloride sensitive renal epithelial Na+
channels
• Sodium channel
• Present in renal epithelial cells
• Sensitive to amiloride
Modulated by aldosterone
H+

12. Diuretics
Causes net loss of Na+ and water in urine
Natriuretics
Reabsorption of Na+
PT: 65-70%
TAL: 20-25%
DT: 8-9%
CD: 2-3%

13. Diuretics: Classification
High ceiling
Medium efficacy
Weak / adjunctive
• Furosemide
• Bumetanide
• Ethacrynic acid

14. Diuretics: Classification
High ceiling
Medium efficacy
Weak / adjunctive
Benzothiadiazines
• Hydrochlorothiazide
• Polythiazide
• Bendroflumazide
Thiazide like
• Chlorthalidone
• Metolazone
• Xipamide
• Indapamide
• Clopamide

15. Diuretics: Classification
High ceiling
Medium efficacy
Weak / adjunctive
Carbonic Anhydrase
Inhibitors
• Acetazolamide
Osmotic Diuretics
• Mannitol
• Isosorbide, Glycerol
Potassium sparing
diuretics
• Spironolactone,
Eplerenone
• Amiloride,

16. High ceiling diuretics
Furosemide, Bumetanide, Torasemide; Ethacrynic acid
Dose dependent diuresis occurs
Up to 10L/d of urine can be produced
Quick onset of action
Intravenous: 2-5 mins, Oral 20-40 mins
Short duration of action
4-6 hours

17. Furosemide: Mechanism of Action
Secreted by Organic anion transporter (OATP) present in PT
cells
Reaches Thick Ascending Limb of LoH
Inhibits Na+-K+-2Cl- cotransporter
• Decreased absorption of Na+
• High amount of Na+ and water excreted in urine

18. Furosemide: Mechanism of Action
Luminal fluid
Cuboidal
cells of TAL
(medullary
portion)
Na+-K+-2Cl-
K+ Cl-
K+
Na+
Na+
Ca2+, Mg2+
Extracellular fluid

19. Furosemide: Mechanism of Action
Minor actions:
Inhibits Carbonic anhydrase enzyme in PT
• Increase HCO3
- excretion
• Mild alkalosis in high dose (due to loss of Cl-)
Increased local PG synthesis
• Altered intrarenal haemodynamic
• Decreased PT reabsorption

20. Furosemide: Other Actions
Prompt increase in systemic venous capacitance
PG mediated
Decreases left ventricular filling pressure
Affords quick relief in Left ventricular failure and Pulmonary
oedema

21. Furosemide: Pharmacokinetics
Absorption after oral administration takes 2-3 hours
Bioavailability 60%
Reduced in severe congestive heart failure
Plasma t1/2 1-2 hour
Single oral dose acts for 4-6 hrs
Prolonged in pulmonary oedema, renal and hepatic
insufficiency

22. Loop diuretics: Uses
Oedema
Acute pulmonary oedema
Hypertension
Co-existing renal insufficiency, CHF, resistant cases,
hypertensive emergencies
Along with Blood Transfusion
Hypercalcemia of malignancy
Cerebral oedema

23. Medium efficacy diuretics
Thiazide and thiazide like drugs
Have flat dose-response curves
Acts in cortical diluting segment of LoH or early DT
Acts by inhibiting Na+-Cl- symporter
Additional carbonic anhydrase inhibitor action
Alkaline urine rich in Cl- produced

24. Thiazide: Mechanism of action
Secreted by OATP in PT
Reaches cortical diluting segment or early DT along luminal
fluid
Inhibits Na+-Cl- symporter
Decreased Na+ and Cl- absorption
Increased urine passed

25. Thiazide: Mechanism of action
Luminal fluid
Extracellular fluid
Cl-
Na+
Na+-Cl- symporter No reabsorption or secretion of K+

26. Thiazides: Other actions
Additional carbonic anhydrase inhibitory action
Increase HCO3
- and PO4
3- excretion
Reduces GFR
By reducing blood volume and by inducing intrarenal
haemodynamic changes
• Not effective in patients with low GFR
Extrarenal actions
Slow developing fall in BP
Elevation of blood sugar

27. Thiazides: Pharmacokinetics
Well absorbed orally
Action starts within 1 hour, duration 6-48 hrs
Hydrochlorothiazide: 6hrs
Chlorthalidone: 48 hrs
Variable distribution (depends on lipid solubility)
Eliminated mainly unchanged in urine
Elimination t1/2: 3-4 hrs

28. Thiazides: Uses
Hypertension
One of the First line drugs (Chlorthalidone)
Oedema
Diabetes Insipidus (DI)
Nephrogenic DI
Hypercalciuria with recurrent calcium stones in the kidney

29. ADRs: Loop Diuretics vs Thiazides
Loop Diuretics Thiazide
Hypokalaemia Less common More common
Acute Saline Depletion Seen Not So Common
Dilutional Hyponatremia
After vigorous use of
Loop diuretics in
CHF
Rare

30. ADRs: Loop Diuretics vs Thiazides
Loop Diuretics Thiazide
GIT and CNS
Disturbances
Nausea/Vomiting, diarrhoea, headache,
giddiness, weakness, paraesthesia,
impotence
Allergic
manifestation
• Rashes, photosensitivity
• Rarely blood dyscrasias
• Sulphonamide hypersensitivity
Hearing Loss Only with Loop diuretics

31. ADRs: Loop Diuretics vs Thiazides
Loop Diuretics Thiazide
Mental Confusion
and hepatic coma
Due to brisk diuresis
in cirrhotic patients
Magnesium
depletion
Seen after prolonged use
Renal insufficiency
Can be used in renal
insufficiency
Aggravated due to
decreased GFR

32. ADRs: Loop Diuretics vs Thiazides
Loop Diuretics Thiazide
Hyperuricemia Less common
High dose thiazides
Hyperglycaemia,
hyperlipidaemia
Hypocalcaemia
Seen on chronic
administration
Not seen
Hypercalcaemia Seen

33. Drug Interactions: Loop diuretics and
Thiazides
Potentiates all other antihypertensives
As it induces Hypokalaemia:
Enhances digitalis toxicity
Increased risk of Cardiac arrhythmia
Reduces sulfonylurea action (oral hypoglycaemics)

34. Drug Interactions: Loop diuretics and
Thiazides
Additive ototoxicity and nephrotoxicity of aminoglycosides
Actions reduced when used with indomethacin and other
NSAIDs
Probenecid and diuretics reduces each other’s actions
Serum Lithium level rises

35. Post Test
All of the following are the adverse effects of thiazide diuretics
EXCEPT:
?Hypomagnesemia
?Hypovolaemia
?Hypocalcaemia
?Hypokalaemia

36. Conclusion
Diuretics can be broadly grouped into three categories
Loop diuretics acts by inhibiting Na+-K+-2Cl- cotransporter,
Thiazides act by inhibiting Na+-Cl- symporter
Loop diuretics and thiazides share some side effects and have
some specific side effects
Are commonly employed in HTN, oedema
Drug interactions of loop diuretics can enhance therapeutic
effect as well as aggravate adverse effects

37. Any queries?
Next class:
Friday
Continue Diuretics
Revise the topics from BOOK
Thank you.