Diuretics

in this presentation i have tried to briefly discuss about diuretics (water pills), their classification, mechanism of action, pharmacokinetics and pharmacodynamics of these drugs

1. Diuretics-Excretion of Water
and Electrolytes
By: Dr. Ankit Gaur
M.Sc, Pharm.D, RPh

2. Background
Primary effect of diuretics is to increase solute excretion,
mainly as NaCl
Causes increase in urine volume due to increased osmotic
pressure in lumen of renal tubule.
Causes concomitant decrease in extra-cellular volume (blood
volume)
Certain disease states may cause blood volume to increase
outside of narrowly defined limits
Hypertension
Congestive heart failure
Liver cirrhosis
Nephrotic syndrome
Renal failure
Dietary Na restriction often not enough to maintain ECF and
prevent edema  diuretics needed

3. Nephron sites of action of diuretics

6. Types of diuretics-Classification
1. Weak diuretics:
A. Carbonic anhydrase inhibitors (work in
proximal tubule): Acetazolamide
B. Potassium Sparing diuretics:
1. Aldosterone antagonist: Spironolactone
2. Inhibitors of Renal epithelial Na+ Channel:
Amiloride, Triamterene
C. Osmotic diuretics: (proximal tubule, loop of
Henle): Mannitol, Isosorbide, Glycerol

7. Types of diuretics-Classification
2. Medium Efficacy diuretics: Inhibitors of Na+cl-
symport
A. Benzothiadiazine Thaizides (work in proximal
tubule): Hydrochlorthiazide, Benzthiazide,
Hydroflumithiazide, Clopamide
B. Thiazide like: Chlorthalidone, Metolazone,
Xipamide, Indapamide
3. High efficacy Diuretics: Inhibitors of Na+-K+2
cl- cotransymport:
Sulfphamoyal derivatives: Furosemide, bumetamide,
torasemide

8. Salidiurecs (saluretics)
Thiazides
•Hydrochlorothiazide
•Cyclopenthiazide
Thiazide analogues
•Clopamide
•Chlorthalidone
Vasodilators with antihypertensive effect
•Indapamide (stimulates synthesis of renal PGs
with vasodilating action)

9. Types of diuretics and therapeutic uses
Carbonic anhydrase inhibitors (work in proximal
tubule)
Cystinuria (increase alkalinity of tubular urine)
Glaucoma (decrease occular pressure)
Acute mountain sickness
Metabolic alkalosis
Osmotic diuretics (proximal tubule, loop of Henle)
Acute or incipient renal failure
Reduce preoperative intraocular or intracranial pressure

10. Types of diuretics and therapeutic uses
Loop diuretics (ascending limb of loop)
Hypertension, in patients with impaired renal
function
Congestive heart failure (moderate to severe)
Acute pulmonary edema
Chronic or acute renal failure
Nephrotic syndrome
Hyperkalemia
Chemical intoxication (to increase urine flow)

11. Types of diuretics and therapeutic uses
Thiazide diuretics (distal convoluted tubule)
Hypertension
Congestive heart failure (mild)
Renal calculi
Nephrogenic diabetes insipidus
Chronic renal failure (as an adjunct to loop
diuretic)
Osteoporosis

12. Types of diuretics and
therapeutic uses
Potassium-sparing diuretics (collecting tubule)
Chronic liver failure
Congestive heart failure, when hypokalemia is a problem
Osmotic agents (proximal tubule, descending loop
of Henle, collecting duct)
Reduce pre-surgical or post-trauma intracranial pressure
Prompt removal of renal toxins
One of the few diuretics that do not remove large amounts
of Na
+
Can cause hypernatremia

13. Background to Mechanisms of Action of Diuretics
Previously told that reabsorption, secretion occurred along
renal tubule but not how this was accomplished
Movement from tubular fluid through renal epithelial cells and
into peritubular capillaries accomplished by three transport
mechanisms after cell interior is polarized by Na+/K+ pump
1.Channels
 formed by membrane proteins
 Allows only sodium to pass through
1.Cotransport
 Carrier mediated
 Simultaneously transports both Na+ and other solute (Cl-, glucose,
etc) from tubular lumen into renal epithelial cell
1.Countertransport
 Carrier mediated
 Transports Na in, another solute (H+) out of renal epithelial cell
Water moves transcellularly in permeable segments or via tight
junctions between renal epithelial cells

14. Electrolyte Transport Mechanisms
Channel
Cotransport
Countertransport
Na+/K+ pump
X = glucose, amino
acids, phosphate,
etc.

15. Mechanisms of Action:
Carbonic anydrase inhibitors
CAIs work on cotransport of Na
+
, HCO
3
-
and Cl
-
that is coupled to
H
+
countertransport
Acts to block carbonic anhydrase (CA),
1.CA converts HCO
3
-
+ H
+
to H
2
O + CO
2
in tubular lumen
2.CO
2
diffuses into cell (water follows Na
+
), CA converts CO
2
+ H
2
O
into HCO
3
-
+ H
+

3.H
+
now available again for countertransport with Na+, etc)
4.Na
+
and HCO
3
-
now transported into peritubular capillary
CA can catalyze reaction in either direction depending on
relative concentration of substrates

16. Site of Action of CAIs

17. 3. Carbonic anhydrase inhibitors
Acetazolamide inhibits carbonic
anhydrase (CA) manly in proximal tubules.
H
2
O + CO
2

CA
H
2
CO
3
H
2
CO
3
–
+ H
+

18. •Acetazolamide: has weak diuretic action.
•It significantly enhances urine K
+
excretion.
•The loss of HCO
3
–
anions decreases blood alkaline
reserve (for 48–72 h) and causes metabolic acidosis.
•In this state the drug becomes ineffective.
•Acetazolamide blocks not only renal CA, but also CA
in the ciliary body in the eye (reducing production of
eye liquid) and in the brain (facilitates GABA
synthesis).

19. Mechanisms of Action: Loop diuretics
No transport systems in descending loop of Henle
Ascending loop contains Na
+
- K
+
- 2Cl
-
cotransporter from lumen to ascending
limb cells
Loop diuretic blocks cotransporter  Na
+
, K
+
, and Cl
-
remain in lumen,
excreted along with water

21. Mechanisms of Action: Thiazide Diuretics
in the Distal Convoluted Tubule
Less reabsorption of water and electrolytes in the distal
convoluted tubule than proximal tubule or loop
A Na
+
- Cl
-
cotransporter there is blocked by thiazides

22. Mechanisms of Action: Collecting tubule
and potassium-sparing diuretics
Two cell types in collecting tubule
1.Principal cells – transport Na, K, water
2.Intercalated cells – secretion of H
+
and HCO
3
3.Blocking Na+ movement in also prevents K
+
movement out

23. 3%
Amiloride
Triamterene
Spironolactone
4. Potassium
sparing diuretics
They have weak
diuretic action
and save K
+
.
Often they are used
in combination with
diuretics, causing
hypokalemia.

24. Potassium sparing diuretics
Competitive
aldosterone
antagonists:
•Spironolactone
Blockers of the
amiloride-
sensitive
Na
+
channels:
•Amiloride
•Triamterene

25. Spironolactone is steroid compound,
which is competitive aldosterone antagonist.
It increases Na
+
excretion and decreases K
+

and urea excretion. Its diuretic action is
week and is achieved slowly.
Spironolactone is effective in oedemas,
caused by increased production of
aldosterone ascites in liver cirrhosis and
oedemas in congestive heart failure.

26. Spironolactone in low doses (25 mg/24 h)
potentiates the effect of ACE inhibitors. It
saves K
+
and Mg
2+
ions and has antiarrhyth-
mic effect. It also prevents development of
myocardial fibrosis, caused by aldosterone
and in this way contributes to enhancing
myocardial contractility.

27. Diuretidin
®

(triamterene/hydrochlorothiazide)
is indicated in oedemas cardiac, renal,
liver or other origin and for the
treatment of hypertension with
other antihypertensive drugs.
Moduretic
®
(amiloride/hydrochlorothiazide)
has the same indications too.

28. Mannitol
60–80%
5. Osmotic diuretics

29. After oral administration Mannitol is not
absorbed and has laxative effect. After i.v.
administration it is not metabolized, it
filtrates in the glomerulus and not reabsorbed
in renal tubules, causing increased osmotic
pressure and excretion of isoosmotic equivalent
of water. It increases blood flow in 30%.

30. Мannitol does not influence renin synthesis.

It does not cross tissue barriers (BBB too),
does not penetrate to the eye and brain and
in osmotic way reduces intraocular and intra-
cranial pressure.
It is included in the treatment of brain oedema,
initial stages of acute renal failure, chronic
renal failure, glaucoma, intoxications with
drugs, excreted in the urine.

31. 6. Phytodiuretics
Rhizoma Graminis
(Couch-grass)
Stipites Cerasorum
(Cherry)
Fructus Faseoli sine semine
(Haricot)
Fructus Petroselini
(Parsley)
Stigmata Maydis
(Maize, corn)

32. Levisticum
officinale KOCH
(cow-parsnip)

33. Equisetum arvense
(Common horsetail)
Contains
silicates with diuretic
and urolitholytic effects.

34. Rubia tinctorum L.
(madder)

35. Rubia tinctorum L. (madder). Radix Rubiae
contains 2–3% di- or trioxyanthraquinones
glycosides, flavonoids and other bioactive
substances with diuretic, urolitholytic and
spasmolytic effects.
Infusions (1:10) made from madder facilitate dilution
of calculi, containing calcium and magnesium sulfate
in the renal pelvis and bladder.
It is an important ingredient of many phytoproducts
(Cystenal
©
, Rowatinex
©
), indicated in urolithiasis.

36. Summary of sites of renal reabsorption of filtrate

37. Types and Names of Diuretics
Osmotic agentsMannitol
Proximal tubule
Descending loop
Collecting duct
Carbonic
anydrase inhib.
Acetazolamide
Proximal tubule
Thiazides Hydrochlorothiaz
ide
Distal convoluted
tubule
Loop diureticEthacrynic acid
Furosemide
Loop of Henle
Type Example Sites of Action
K
+
- sparing
Spironolactone
Amiloride
Collecting tubule

38. Structure of Classes of Diuretics

39. General Background of Diuretics
Pattern of excretion of electrolytes (how
much of which type) depends on class of
diuretic agent
Maximal response is limited by site of action
Effect of two or more diuretics from different
classes is additive or synergistic if there sites
or mechanisms of action are different

40. Osmotic diuretics
No interaction with transport systems
All activity depends on osmotic pressure
exerted in lumen
Blocks water reabsorption in proximal tubule,
descending loop, collecting duct
Results in large water loss, smaller
electrolyte loss  can result in hypernatremia

41. Carbonic anydrase inhibitors
Block carbonic-anhydrase catalyzation of
CO
2
/ carbonic acid/carbonate equilibrium
Useful for treating glaucoma and metabolic
alkalosis but can cause hyperchloremic
metabolic acidosis from HCO
3
-
depletion

42. Loop diuretics
Generally cause greater diuresis than
thiazides; used when they are insuffficient
Can enhance Ca
2+
and Mg
2+
excretion
Enter tubular lumen via proximal tubular
secretion (unusual secretion segment)
because body treats them as a toxic drug
Drugs that block this secretion (e.g.
probenecid) reduces efficacy

43. Thiazide diuretics
Developed to preferentially increase Cl
-

excretion over HCO
3
-
excretion (as from CAIs)
Magnitude of effect is lower because work on
distal convoluted tubule (only recieves 15%
of filtrate)
Cause decreased Ca excretion 
hypercalcemia  reduce osteoporosis

44. Comparison of loop and thiazide diuretics

45. Potassium-sparing diuretics
Have most downstream site of action
(collecting tubule)
Reduce K loss by inhibiting Na/K exchange
Not a strong diuretic because action is
furthest downstream
Often used in combination with thiazide
diuretics to restrict K loss