This presentation was used for lecture class of MBBS Sem III of LMCTH

1. Diuretics
Dr. Pravin Prasad
M.B.B.S., MD Clinical Pharmacology
Lecturer, Lumbini Medical College & TH
8 April 2019 (25 Chaitra 2075), Monday

2. By the end of this class, MBBS
Sem III 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

7. Urinary constituent
movements: Site I
Sodium Potassium Water
Reabsorbed Reabsorbed
Along the
osmotic gradient
4 Processes:
• Direct entry
• Coupled to
absorption of
anions
• Exchanged with H+
• Passive diffusion
Utilizes:
• Paracellula
r pathways
Utilizes:
• 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
• Torasemide

14. Diuretics: Classification
High ceiling
Medium efficacy
Weak / adjunctive
Benzothiadiazines
• Hydrochlorothiazide
• Hydroflumethiazine
• Benzthiazide
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
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

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

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
Hyperglycaemi
a,
hyperlipidaemi
a
Hypocalcaemia
Seen on
chronic Not 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

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