DIURETICS, PHARMACOLOGY, STRUCTURE ACTIVITY RELATIONSHIP, PHARMACOKINETICS, METABOLISM, MECHANISM OF ACTION

1. Souvik Mukherjee
B.Pharm, M.Pharm(Natural Product Chemistry), JRF(Chemistry)
Center for Natural Product Studies
Central University of Bilaspur
Diuretics

2. Diuretics
 substances that help the body to get rid of Na and H2O
or
Chemicals that increase the volume of the urine excreted by the kidney
through increase the rate of urine formation, without affecting reabsorption
of- i) Protein
ii)Vitamin
iii) Glucose
iv)Amino acid
 Reduce the extracellular fluid volume by promoting the excretion of Na+
or Cl- or HCO3- ions which constitute the main electrolytes of the
extracellular fluid.

3. Need of diuretics
 Increasing urine flow rate leads
i. Increase excretion of electrolytes
ii. Water from the body
 Diuretics are used
i. In the treatment of CHF (Congestive Heart Failure)
ii. In the treatment of Nephrotic syndrome
iii. In the treatment of Chronic liver disease
iv. Adjunct therapy in hypercalcemia, Dibetes insipidus, Acute mountain sickness
v. Management of Hypertension
Diuretics decrease blood pressure, because a decrease in plasma volume = decrease in blood pressure

4. Primary target organ for diuretics: kidney
Functions of Kidney

5. Nephron: structural & functional unit of kidney

6. Ions reabsorption in nephron & major classes of diuretics
Golden rule of Kidney: water tends
to follow Na

8. Diuretics Drug History
 One of the earliest substance known to induce diuresis is water, an inhibitor of ADH release
 Calomel (mercurous chloride) was used as early as the 16th century as a diuretic, but poor absorption from GIT and
toxicity, it was replaced by the Chlormerodrin
 Now, variety of drugs are being discovered and modified accordingly as to emulsifying the effect

9. •Acting at proximal convoluted tubules (PCT)
1. Osmotic diuretics: These drugs are : mannitol, urea, glycerin & isosorbide
2. Carbonic anhydrase inhibitors: These drugs are: Acetazolamide, methazolamide
•Acting at loop of Henle
1. Loop diuretics: Furosemide, torsemide, Ethacrynic acid
•Acting at distal convoluted tubule (DCT)
1. Thiazides diuretics: Chlorothiazide, chlorothalidone, Hydrochlorothiazide
• Acting at collecting duct system
1. K- sparing diuretics
Classification:
(According to site of action and mechanism of action)

10. 1. Osmotic Diuretics

11. Osmotic diuretics
 helps to prevent reabsorption of H2O & Na in body.
form a hypertonic solution and cause water to pass
from the body into the tubules, producing a diuretic
effect.
 increase amount of blood flowing into kidney
 All activity depends on osmotic pressure exerted in
lumen
 Blocks water reabsorption in PCT, DCT & collecting
duct
 prevent the urine to get concentrated
 used during heart- problems
 Results in large water loss, smaller electrolyte loss
Mechanism of action
 osmotic diuretics are not reabsorbed
 increases osmotic pressure specifically in PCT and
loop of Henle
 prevents passive reabsorption of H2O
 osmotic force solute in lumen > osmotic force of
reabsorbed Na+
 increase H2O and Na+ excretion

12. Mechanism of action

14. Absorption & elimination
Absorption
Mannitol and urea are given orally
Glycerine & isosorbide administered orally
Elimination
They have short duration of activity and so, metabolize quickly

15. Therapeutic uses
 most efficient is- Mannitol
drug of choice: non-toxic, freely filtered, non-
reabsorbable and non-metabolized
 administered prophylatically for acute renal failure
 Urea, glycerol and isosorbide are less efficient
 can penetrate cell membranes
 increase unine volume
 decrease intracranial or intraocular pressure.
Side effects
 increased extracellular fluid volume
 cardiac failure
 pulmonary edema
 hypernatremia
 hyperkalemia secondary to diabetes or impaired renal
function
 headache, nausea, vomiting

16. 2. Loop diuretics

17. Diuretics Acting on the Thick Ascending Loop of Henle: (loop diuretics) High ceiling
(most efficacious)
► e.g. Furosemide (LasixR), Torsemide, Bumetanide (BumexR), Ethacrynic acid.
► Phrmacodynamics:
1) Mechanism of Action : Simply inhibit the coupled Na/K/2Cl cotransporter in the loop of Henle. Also, they have potent
pulmonary vasodilating effects (via prostaglandins).
2) They eliminate more water than Na.
3) They induce the synthesis of prostaglandins in kidney and NSAIDs interfere with this action.
They are the best diuretics for 2 reasons:
1- they act on thick ascending limb which has large capacity of reabsorption.
2- action of these drugs is not limited by acidosis

18. Mechanism of Action

19. Drugs of loop diureticsHigh ceiling diuretics
1. 2-Aminobenzoic acid
derivatives.
(Furosemide and azosemide )
2. Phenoxyacetic acid derivatives
(ethacrynic acid).

20. 5-Sulfamoyl-2-aminobenzoic Acids
Site and mechanism of action:
• They inhibit co-transport system located on the thick ascending limb of Henle’s loop (1Na+, 1K+, 2 Cl-). They cause
hypokalemia.
• The net result is increased excretion of Na+, K+, Cl - .

21. SAR
1. Position-1 must be acidic (optimal activity with COOH).
2. SO2NH2 group at position 5 is prerequisite for activity, must be free.
3. Activating group at position 4- as Cl or CF3.

22. Ethacrynic acid (α,β-unsaturated ketones of phenoxyacetic acid)
They are capable of covalent bonding to the –SH group in the ATPase enzyme involved in the solute re-absorption.
SAR of ethacrynic acid revealed that:
1. The α,β-unsaturated ketone system is essential for activity.
2. The removal of one of the chlorine atoms reduces the activity.
3. The total removal of both halogens abolishes the activity.

23. Loop
diuretics
Furosemide:
Taken orally or i.v
If taken orally only 50 % is
absorbed
Torsemide:
Taken orally.
Better absorption
Fast onset of action
↑t1/2
Bumetanide (Bumex®)
Taken orally
40 times potent than
furosemide.
Fast onset
Short duration of action
Absorption

24. Therapeutic Uses
a) Edema (in heart failure, liver cirrhosis, nephrotic syndrome)
b) Acute renal failure
c) Hyperkalemia
d) Hypercalcemia
Side effects:.
• Ototoxicity;
• Hypokalemic metabolic alkalosis;
• hypocalcemia and hypomagnesemia;
• hypochloremia;
• Hypovolemia;
• hyperuricemia (the drugs are secreted in PCT so they compete with uric acid’s secretion)
• hypersensitivity reactions(contain sulfur)

25. 3. Thiazide Diuretics

26. Thiazide diuretics
 Inhibit re-absorption of Na+ and consequently Cl- in the DCT by inhibition of Na+/ Cl- co transport system present in
the luminal membrane (saluretic).
 They lead to loss of 5-8% of the load of sodium.

27. Mechanism of Action
 inhibit Na+ and Cl- transporter in distal convoluted tubules
 increased Na+ and Cl- excretion
 weak inhibitors of carbonic anhydrase, increased HCO3- excretion
 increased K+/Mg2+ excretion
 decrease Ca2+ excretion

28. Mode of action of Thiazide and Thiazide-like diuretics

29. SAR of thiazide diuretics
1. The sulfamoyl group in the 7-position is essential for diuretic activity.
2. Substitution of the 6-position with an activating group (Electronegative) is essential
for diuretic activity. The best substituent include Cl-, Br-, CF3- and NO2- groups.
3. N.B. NH at 2-position is acidic can form water soluble sod. Salt and can be used for IV administration (in drugs with free
NH at 2-position.

30. 4. The 2-position can tolerate relatively small alkyl group as -CH3
5. Substitution at 3-position affect potency and duration of action, when H is
replaced by CH2Cl gives activity up to 24h. While –CH2- S-CH2-CF3 increase up to 48h.
6. Loss of the C-C double bond between the 3- and 4- positions increases the potency 3-10
times.

31. 7. Direct substitution of the 4-, 5- or 8-position with an alkyl group usually results in diminished diuretic
activity.

32. Chlorothiazide (Diuril)
6-Chloro-2H-1, 2,4-benzothiadazine-7-sulfonamide 1,1-dioxide.
The duration of action from 6 -12 hours
Hydrochlorothiazide (Esidrix)
The duration of action up to 18 hours
Polythiazide (Renses)
The duration of action from 24 -48 hours Cl
Thiazide diuretic drugs

33. Thiazide-like diuretics
Substitution of the SO2 at position-1 in thiazide diuretics with another
electronegative group as well as the opening of bicyclic hetero-system in
benzthiadiazines not affect the diuretic activity.
This group of diuretics known as thiazide-like diuretics. Why?
Their site of action and efficacy and side effects are similar to thiazide diuretics.
e.g. Mefruside (Baycaron)

34. Pharmacokinetics
 orally administered
 poor absorption
 onset of action in ~ 1 hour
 wide range of T 1/2 amongst different thiazides, longer then loop diuretics
 free drug enters tubules by filtration and by organic acid secretion

35. 4. K- Sparing Diuretics

36. 4. Potassium Sparing Diuretics
1. Blockade of Na+ uptake at the luminal
membrane and blocks excretion of
K+(triamterene, amiloride)
2. Inhibition of Na+ and H2O reabsorption
by: Competitive inhibition of aldosterone
(spironolactone)
 Potassium sparing diuretics act mainly in the late DCT and the early collecting tubule.
 They mainly inhibit re-absorption of 2-3% of Na+, and in turn, the driving force for K+ secretion is reduced or
diminished

37. Mechanism of Action
K+ sparing diuretics function in CCD
decrease Na+ transport in collecting tubule
Spironolactone
competitive antagonist for mineralocorticoid receptor
prevents aldosterone stimulated increases in Na+ transporter expression
Triamterene/Amiloride
organic bases
secreted into lumen by proximal tubule cells
inhibit apical Na+ channel

38. Triamterene (2,4,7-Triamino-6-phenyl pteridine)
Amiloride HCl (Midamor)
Amiloride
Most serious side effect is hyperkalemia.
K+ level should regularly be shacked.

39. Spironolactone (AldactoneR)
► Synthetic steroid acts as a competitive antagonist of aldosterone with a slow onset of action.
► Mechanism of action: Aldosterone cause ↑K and H+ secretion and ↑Na reabsorption

40. 2,4,7-TRIAMINO-6-ARYLPTERIDINES
Triamterene
SARs:
1. Para-substitution of phenyl ring with (-OH group) increase activity
2. The phenyl group can be replaced by small heterocyclic rings
3. The amino groups must be un-substituted.
4. It has a structural similarity to folic acid and certain dihydrofolate reductase inhibitors, but it has
little, if any, of their activities.
N
NN
N
H2N NH2
NH2
1
2
3
4
5
6
7
8

41. Pharmacokinetics
Spironolactone
 orally administered
 aldactazide: spironolactone/thiazide combo
Amiloride
 oral administration, 50% effective
 not metabolized
 not bound to plasma proteins
Triamterine
 oral administration, 50% effective
 60% bound to plasma proteins
 Liver metabolism, active metabolites

42. Therapeutic Uses
 primary hyperaldosteronism (adrenal adenoma,
bilateral adrenal hyperplasia)
 congestive heart failure
 cirrhosis
 nephrotic syndrome
 in conjunction with K+ wasting diuretics
Side effects
 hyperkalemia: monitor plasma [K+]
 spironolactone: gynecomastia
 triamterene: megaloblastic anemia in cirrhosis
patients
 amiloride: increase in blood urea nitrogen,
glucose intolerance in diabetes mellitus

43. 5. Carbonic Anhydrase Inhibitors (CA inhibitors).

44.  limited uses as diuretics in PCT
e.g. Acetazolamide
 prototype carbonic anhydrase inhibitor
 developed from sulfanilamide (caused metabolic acidosis and alkaline urine)
They inhibit the enzyme carbonic anhydrase which is found in the proximal convoluted tubule. They suppress the activity of
carbonic anhydrase.
Carbonic anhydrase is an enzyme that catalyzes the rapid interconversion of carbon dioxide and water to bicarbonate
and protons (or vice versa) i.e. the hydration of CO2 and its conversion to H2CO3
The net result of CA inhibition is increased excretion of Na+, K+, HCO3 -.

45. Mechanism of Action
 inhibits carbonic anhydrase in PCT
 carbonic anhydrase catalyzes formation of HCO3- and H+ from H2O and CO2
 inhibition of carbonic anhydrase decreases [H+] in tubule lumen
less H+ for for Na+/H+ exchange
increased lumen Na+, increased H2O retention

46. SULFANILAMIDE
 After its introduction for the treatment of bacterial infections , it was observed to
produce a mild diuresis.
 It was shown that it induced this effect through inhibition of renal Carbonic
Anhydrase .
- but weakly , severe side effect.
To improve the CA inhibitory property of sulfanilamide many sulfamoyl - containing compounds ( - SO2NH2 ) were
synthesized and screened for their diuretic activity and their ability to inhibit CA.
 Two groups of CA inhibitors emerged:
1-Simple heterocyclic sulfonamides.
2- Metadisulfamoylbenzene derivatives.

47. 1. HETEROCYCLIC SULFONAMIDES
N
S
N
NHH2NO2S C
O
CH3
N
S
N
NHH2NO2S
CH3
C
O
CH3
Acetazolamide
( Diamox )
Methazolamide
(Neptazane)
H2NO2S
NH2
Sulfanilamide

48. STRUCTURE- ACTIVITY RELATIONSHIPS
-The prototype is Acetazolamide .
N
S
N
NHH2NO2S C
O
CH3
The sulfamoyl group
is essential for the
production of diuresis
The sulfamoyl nitrogen atom
must remain unsubstituted to
retain the activity .
The derivatives with
the highest lipid / water
partition coefficient
and lowest pKa have
the greatest CA
inhibitory and diuretic
activity.

49. 49
Methazolamide
NN
S
N
O
CH3
S
H2N
OO
CH3
N-(3-Methyl-5-sulfamoyl-1,3,4-thiadiazol-2(3H)-ylidene)-acetamide
Methazolamide is more potent CA inhibitor than acetozolamide (the prototype), but is rarely used as
diuretic. It is used in treatment of glaucoma, because it displays improved penetration into the eye.

50. 2. Metadisulfamoylbenzene derivatives: SAR
Maximal diuretic activity is observed
When this position is substituted with:
Cl , Br , CF3 or NO2
SO2NH2 An unsubstituted sulfamoyl is
of paramount importance
SO2NH2 The sulfamoyl moiety can be
replaced with a similarly electrophilic
Group ( carbonyl , carbamoyl ) that may increase diuretic
potency While decreasing CA inhibitory activity
Substitution with an amino group
increases saluretic , but decrease CA
inhibitory activity
Cl
SO2NH2
Cl
H2NO2S
SO2NH2
Cl
H2NO2S
NH2
Dichlorphenamide
( Daranide )
Chloraminophenamide

51. Therapeutic Uses
 used to treat chronic open-angle glaucoma
 aqueous humor has high [HCO3-]
 acute mountain sickness
 prevention and treatment
 metabolic alkalosis
 sometimes epilepsy
 mostly used in combination with other diuretics in
resistant patients
Side effects
• rapid tolerance
• increased HCO3- excretion causes metabolic acidosis
• drowsiness
• fatigue
• CNS depression
• paresthesia (pins and needles under skin)
• nephrolithiasis (renal stones)
• K+ wasting

52. Summary: sites of action & MoA
Class Site of action MoA
Osmotics Proximal tubule Osmotic effect ↓se Na+ & H2O reabsorption
Loop of henle ↑se medullary blood flow to ↓se hypertonicity and reduce the
Na+ & H2O reabsorption
Collecting tubule Na+ & H2O reabsorption ↓se because of ↓se in medullary
hypertonicity and elevated urinary flow rate
Carbonic
anhydrase
inhibitors
Proximal convoluted tubule Inhibit the renal carbonic anhydrase ↓se the sodium
bicarbonate reabsorption
Thiazides &
likes
Cortical portion of the thick
ascending limb of loop of Henle and
distal tubule
Inhibition of Na+/Cl- symporter
Loop or high –
ceiling
Thick ascending limb of the loop of
the Henle
Inhibition of Na+/K+/2Cl- transport system
Potassium-
sparing
Distal tubule and collecting duct Inhibition of sodium and water reabsorption by inhibiting
aldosterone