The document summarizes the physiology of diuretic action. It defines diuretics as substances that increase urine flow and water excretion. It describes the classes and sites of action of various diuretics including loop diuretics, thiazide diuretics, potassium-sparing diuretics, and aquaretics. It discusses factors that affect diuretic action such as the volume of extracellular fluid and delivery of diuretics to their site of action. It also covers the effects of diuretics on absorption of water, electrolytes, and other solutes as well as their clinical applications and side effects.

1. Physiology of Diuretic Action
Dr Saran A K
1
DEPARTMENT OF PHYSIOLOGY, GMCK

2.  Definition
 Class and Site of Action of Diuretics
 Factors Affecting Diuretic Action
 Diuretic Braking Effect
 Diuretics and their features
 Effect of Diuretics on the absorption of H2O and other solutes
 Applied Aspects
 Diuretic Resistance
 Diuretic Abuse
 Diuretics in Diagnosis
2

3. [ dahy-uh-ret- ik ] noun
origin : Greek
diu (through) uretic (urinate)
A diuretic is defined as any substance that increases urine flow
and thereby water excretion.
diuretic
3

4. • Most common action is by reducing sodium
chloride reabsorption at different sites of
nephron which leads to natriuresis.
• Drugs that block the action of arginine
vasopressin (AVP) on the distal tubule and
collecting duct are called aquaretics,
which cause a water diuresis.
• Results in alterations in the volume of
the ECF compartment - clinical uses for
diseases including hypertension.
Changes in the % of filtered substances along nephron
Fig 38-1 Ganong’s Review of Medical Physiology 26th Edition
4

5. Class of Diuretic Examples
Osmotic Diuretics Mannitol
Carbonic Anhydrase
Inhibitors
Acetozolamide
Loop Diuretics
Furosemide
Torasemide
Thiazide Diuretics
Chlorthalidone
Indapamide
K+ Sparing Diuretics
Amiloride
Triamterene
K+ Sparing Diuretics and
Aldosterone Antagonists
Spirinolactone
Eplerenone
Class and Site of Action of Various Diuretics
Site of Action of Diurectics along Nephron
Fig 10.2 MOSBY Renal Physiology 6th Edition
5

6. 1. Site of Action
• Diuretics acting on those sites of the nephron contributing more to Na
absorption produce more diuresis.
• Thick Ascending Limb > Distal Convoluted Tubule
2. Response of Other Nephron Segments
• The function of more distal segments and their ability or inability
to handle this increased load caused by a diuretic activity
upstream ultimately determine the overall effect of the diuretic on
urinary solute and water excretion
Factors determining overall effect of a diuretic
6

7. 3. Adequate Delivery of Diuretics to their
Site of Action
• With the exception of the some diuretics
which act intracellularly, diuretics act from
the lumen of the nephron.
• Diuretics gain access to the lumen by
glomerular filtration and through
secretion by the organic anion and
organic cation secretory systems
located in the proximal tubule
• Because some diuretics are bound to
plasma proteins (e.g., loop diuretics), their
secretion by the proximal tubule is the
primary mechanism for delivery of the
diuretic to its site of action in the lumen of
the nephron.
7
Action of K+ Sparing and Thiazide Diuretics
Diuretic Pharmacology TUSOM | Pharmwiki

8. 4. Volume of Extra Cellular Fluid
• When volume of ECF is decreased
• GFR is reduced, thereby reducing
amount of filtered Na+
• Na+ absorption by the nephron is
enhanced
• Thus the effect of a diuretic that acts
on the distal tube would be blunted
if administered in the setting of a
reduced ECF volume as a result of
the reduced delivery of Na to the
distal tubule.
8

9. Sodium excretion and extracellular fluid
volume during diuretic administration
Fig 10.2 MOSBY Renal Physiology 6th Edition
 Diuretic Braking Effect
• The immediate increase in sodium excretion
is accompanied by a decrease in
extracellular fluid volume.
• If sodium intake is held constant,
compensatory mechanisms will eventually
return sodium excretion to equal sodium
intake, thus re-establishing sodium balance.
• However this steady state occurs at a
reduced ECF volume.
9

10. A. Osmotic Diuretics / e.g. Mannitol
• They inhibit the reabsorption of solute and
water by altering osmotic driving forces
along the nephron
• They do not inhibit a specific membrane
transport protein.
• They affect fluid reabsorption in the
segments that have high permeability
to water (i.e., the proximal tubule and
portions of the thin descending limb of
Henle’s loop)
10
Action of Osmotic Diuretics
Diuretic Pharmacology TUSOM | Pharmwiki

11. • Normal Water Absorption in Proximal tubule
• Iso-osmotic process
• osmotic gradient of 3 to 5 mOsm/kg caused by Na+ reabsoprtion
• solvent drag drawing in more Na+.
• In presence of an Osmotic Diuretic
• an osmotic gradient develops opposite to the normal gradient
• both NaCl (solvent drag component) and water reabsorption are
reduced
• an increase in blood flow to the medulla of the kidney – dissipation of
medullary gradient – inhibits H20 reabsorption in tDL of LoH.
• Although Na+ excretion rates is as high as 60% , the usual natriuresis seen
is only about 10% of the filtered Na+ due to increased absorption of
sodium downstream. 11

12.  Indications for Use
• Increased intracranial or intraocular tension
• Head Injury
• Stroke
• Acute Congestive Glaucoma
• To maintain GFR and urine flow in impending
acute renal failure. E.g. cardiac surgery
• To counteract low osmolality of plasma due to
rapid hemodialysis or peritoneal dialysis.
• Never used for the treatment of chronic edema or as a
natriuretic
 Side Effects
• Water deficit
• Hypernatremia
12

13. B. Carbonic Anhydrase Inhibitors / e.g. Azetazolamide
• They reduce Na+ reabsorption by their effect on
carbonic anhydrase.
• Main site of action is the proximal tubule as
approximately one-third of proximal
tubule Na+ reabsorption occurs in exchange for H+
(through the Na+-H+ antiporter) and thus depends on
the activity of carbonic anhydrase.
• Typically administration of carbonic anhydrase
inhibitors results in Na+ excretion rates that are 5%
to 10% of the filtered Na+.
13
Action of CAI Diuretics
Diuretic Pharmacology TUSOM | Pharmwiki

14. • Does not result in a large natriuresis for several
reasons
• Na absorption still occurs in the
proximal tubule by other mechanisms.
• Increased absorption downstream
segments
• TGF activated by increased Na+ stimuli
to Macula Densa
14
The diuretic efficacy of carbonic anhydrase
inhibitors is relatively low, and it becomes further
diminished with over several days of treatment due
to the development of metabolic acidosis, with an
associated reduction in bicarbonate in the
glomerular filtrate.
Fig 1. Na Transport along Nephron
CJASN’s Renal Physiology for Clinician

15. • Indications
• Glaucoma
• Acute Mountain Sickness
• Metabolic Alkalosis
• Side Effects
• Hypokalemic metabolic acidosis
• The loss of base causes a metabolic
acidosis. The increased delivery of Na to
the collecting duct results in increased
exchange of Na for K, with resulting
hypokalemia.
15

16. C. Loop Diuretics / e.g. Furosemide
• They directly inhibit Na+ reabsorption by the
thick ascending limb of Henle’s loop by
blocking the Na+-K+-2Cl− symporter located
in the apical membrane of these cells.
• They also disrupt the ability of the kidneys
to dilute and concentrate the urine.
• NaCl reabsorption by the medullary portion of
the thick ascending limb also is critical for the
generation and maintenance of an elevated
medullary interstitial fluid osmolality.
• They are the most potent diuretics available,
increasing the excretion of Na+ to as
much as 25% of the amount filtered.
16

17. • Called as
• High ceiling diuretics because their
progressive increase in dose is accompanied
by an increasing diuresis.
• High efficiency diuretics because of
their ability to block the region of the nephron
with maximum capacity of sodium
reabsorption.
17
However, with long-term administration of
loop diuretics there is hypertrophy of cells in
the distal tubule, which is associated with
enhanced Na+ reabsorption. As a result, the
natriuresis associated with long-term loop
diuretic usage is blunted.
Fig 1. Na Transport along Nephron
CJASN’s Renal Physiology for Clinician

18. • Indications
• Edematous States (CHF, Pulmonary
Edema)
• Edema caused by heart failure: judicious use of loop
diuretics can mobilize interstitial edema without producing
a significant drop in plasma volume. However, excessive
use can reduce arterial blood pressure, resulting in
reduced perfusion of vital organs. Therefore the use of
diuretics requires careful monitoring
• Hypercalcemia
• Inhibition of this Na+K+Cl- cotransporter by loop diuretics
results in a reduction of the luminal voltage gradient,
resulting in reduced reabsorption of divalent cations that
occurs across a paracellular pathway
• Adverse Effects
• Hypokalemic Metabolic Alkalosis
• Ototoxicity
• Hyperurecemia 18

19. • Mutations in the gene for the Na+-K+-2Cl- co transporter called NKCC2
result in the classic form of a disorder called as the Bartter Syndrome.
• This causes the decrease in Na Cl reabsorption and K+ reabsorption by
the TAL
• which in turn causes hypokalemia (i.e., low plasma [K+]) and a decrease
in ECFV which activates RAAS mechansim.
• The clinical features are
• Hypokalemia
• Hypercalciuria
• Metabolic acidosis
• Hyperaldosteronism
19

20. D. Thiazide Diuretics / e.g. Hydrochlorothiazide
• They inhibit Na+ reabsorption in the early
portion of the distal tubule by blocking the
Na+-Cl− symporter in the apical
membrane of these cells
• As they are organic anions largely bound to plasma
proteins, they gain access to the tubular lumen
primarily by secretion in the proximal tubule .
• They affect the ability of the nephron to dilute the
urine but do not affect the concentration ability
significantly.
• Natriuresis with thiazide diuretics is 5% to 10% of
the filtered Na+.
20

21. 21
• The mutations in the Na+ Cl- symporter
lead to a form of inherited hypokalemic
alkalosis called as the Gittleman’s
syndrome.
• Indications
• Hypertension
• Heart Failure
• Kidney Stones (Calcium Subtype)
• Side Effects
• Hypokalemic Metabolic Acidosis
• Hyperuricemia
Fig 1. Na Transport along Nephron
CJASN’s Renal Physiology for Clinician

22. E. Potassium Sparing Diuretics
• K+-sparing diuretics act on the late portion of the distal
tubule and cortical collecting duct [ASDN].
• Small natriuresis 3% to 5% of the filtered Na+
• There are two classes of K+-sparing diuretics:
• One acts by antagonizing the
action of aldosterone on principal
cells (e.g., spironolactone and
eplerenone),
• Other inhibits the Na+-selective
channel ENaC in the apical
membrane of principal cells. (e.g.,
amiloride and triamterene)
22
Fig 1. Na Transport along Nephron
CJASN’s Renal Physiology for Clinician

23. • Spironolactone blocks both Na+ reabsorption
and K+ secretion by principal cells of the late
distal tubule and collecting duct.
• The ability of the Na+ channel blockers
amiloride and triamterene to inhibit Na+
reabsorption and K+ secretion is similar to that
of spironolactone, but the cellular mechanism
is different.
• Amiloride and triamterene block the entry of
Na+ into the principal cell by directly inhibiting
ENaC in the apical membrane.
• This effect in turn reduces cellular K+ uptake
and ultimately its secretion into the tubular
fluid.
• The membrane voltage effect also contributes
to the inhibition of K+ secretion.
23

24. • Indications
• Hyperaldosteronism
• Hypokalaemia
• Drug Resistant Hypertension
• Adverse Effects
• Gynaecomastia
24

25. Aquaretics / e.g., tolvaptan and lixivaptan
• antagonists of the AVP receptor (V2)
• act on the late portion of the distal tubule
and the collecting duct to block the action
of AVP.
• the urine cannot be concentrated and
dilute urine is excreted
• These drugs are particularly helpful in
cases of elevated AVP Syndrome of
inappropriate antidiuresis [SIAD]
25

26. Class of Diuretic Cause Effect
Osmotic Diuretics
Carbonic Anhydrase Inhibitors
• Increase in the delivery of NaCl and
water to Henle’s loop
• Load Dependent Sodium
reabsorpton
Increased Free Water Excretion
Increased Free Water Absorption
Loop Diuretics • Inhibition of thick ascending limb
Na+ reabsorption (major site)
Inhibition of both Solute Free Water
Excretion and Reabsorption
Thiazide Diuretics • Because the nephron sites of action
are located in the cortex
Impaired Free Water Excretion
No significant effect in Free Water
Reabsorption.
K Sparing Diuretics • Because Na transport is less and
the nephron sites of action are
located in the cortex
No change
Aquaretics • Act directly on the collecting duct,
including the medullary portion
increase solute-free water excretion
and impair solute-free water
reabsorption. 26
Effect of Diuretics on excretion of water and other solutes
1. Solute Free Water

27. 2. K+ Excretion
• Diuretics except K+ sparing ones lead to increased excretion of K+ causing
hypokalemia.
• Causes for increased excretion of K+
1. Inhibition of Na+ and water reabsorption in segments upstream tubular fluid flow
rate increases. The increased tubular fluid flow rate stimulates
K+ secretion at ASDN.
2. Diuretics decrease the ECF volume,
• leads to increased secretion of aldosterone which stimulate K+
secretion.
• AVP released also causes increased K+ excretion
• K+ sparing diuretics can be given in combination with other diuretics to
prevent hypokalemia 27

28. Class of Diuretic Cause Effect
Carbonic Anhydrase Inhibitors • Inhibit H+ secretion (proximal tubule) leads
to HCO3 − excretion
Metabolic Acidosis
Loop Diuretics
Thiazide Diuretics
With a decrease in the ECF volume
• Na+ is more reabsorbed in proximal tubule
results in enhanced H+ secretion through the
Na+-H+ antiporter. More HCO3 − is
reabsorbed.
• Stimulates aldosterone secretion which
stimulates H+ secretion by α-intercalated
cells of the distal tubule and collecting duct.
Metabolic Alkalosis
(secondary)
Potassium Sparing Diuretics • By inhibiting Na+ reabsorption in the late
portion of the ASDN, K+-sparing diuretics
secondarily inhibit H+ secretion by reducing
the negative luminal voltage.
Metabolic Acidosis
28
3. Bicarbonate Excretion

29. Class of Diuretic Cause Effect Others
Osmotic Diuretics
Carbonic Anhydrase
Inhibitors
• Reduction of solvent
drag
Reduced reabsorption of
Ca++
Excretion of Ca occurs in
an alkaline medium :
Renal stones
Loop Diuretics • Na-K-2Cl- block
abolishes lumen-
positive voltage Ca++
reabsorption through
paracellular pathway is
reduced
Increased Excretion of Ca
++
• LoH – 15% Ca++
reabsorption
• Used to treat
Hypercalcemia
Thiazide Diuretics • Hyperpolarization due
to blocking of Na-Cl
channel activates Ca
channels (TRPV5)
Reduces Excretion of Ca++
Potassium Sparing
Diuretic
No Effect
29
4. Calcium Excretion

30. Table 10.1 MOSBY Renal Physiology 6th Edition
30

31. Diuretic Resistance
• Diuretic resistance is defined as a failure to achieve the
therapeutically desired reduction in edema despite a full dose of
diuretic.
• The causes of diuretic resistance include
• poor adherence to drug therapy
• dietary sodium restriction
• pharmacokinetic issues
• compensatory increases in sodium reabsorption in nephron sites
that are not blocked by the diuretic.
31

32. Diuretic Abuse
• Diuretics are often abused by athletes to excrete water for rapid weight loss
and to mask the presence of other banned substances
• Diuretics have been included on The World Anti-Doping Agency's (WADA) list
of prohibited substances; the use of diuretics is banned both in competition
and out of competition and diuretics are routinely screened for by anti-doping
laboratories.
32

33. Diuretic Use in Diagnosis
• Furosemide Fludrocortisone Test
• Used to diagnose Distal Renal Tubular Acidosis (Type I RTA )
• Alternative to Ammonium Chloride Acidification Test
• The combination when given to a patient provides consistent stimuli to
elucidate an acidification defect in Type I RTA
33

34. 34

35. References
1. Ganong. Review of Medical Physiology 26th Edition McGraw Hill
2. Guyton & Hall. Textbook of Medical Physiology 11th Edition Saunders Elsevier
3. MOSBY Renal Physiology 6th Edition Elsevier
4. Ganong. Review of Medical Physiology 22nd Edition McGraw Hill
5. Wile D. Diuretics: a review. Annals of Clinical Biochemistry. 2012;49(5):419-431.
doi:10.1258/acb.2011.011281
35

36. THANK YOU !
36
saran.adhoc@gmail.com
DEPARTMENT OF PHYSIOLOGY, GMCK