Diuretics for Pharm. D 3 year Medicinal Chemistry

1. Diuretics
Dr. Rakam Gopi Krishna,
Associate Professor,
M. Pharm. Ph.D.,
Pharmaceutical Chemistry,
Marri Laxman Reddy Institute of Pharmacy,
Hyderabad.

2. Diuretics
 A diuretic is defined as a chemical that increases the rate of urine
formation.
 The primary action of most of the diuretics is the direct inhibition of
sodium reabsorption at one or more anatomical sites of nephron.
 Main organ involved in diuresis is kidney.
 A diuretic usually possess some combination of Natriuretic,
Chloruretic, Saluretic, Kaliuretic, Bicarbonaturetic, and Calciuretic
properties depending on increase in the renal excretion of Sodium,
Chlorine, Sodium chloride, Potassium, Bicarbonate Or Calcium
respectively.

3. Diuretics
• Diuretics are drugs that increase secretion of
excess water and salt that accumulates in tissues
and urine.
• An excess quantity of intercellular fluid is formed
in the organism as a result of an inability of the
kidneys to release sodium ions fast enough to
ensure that a sufficient quantity of water is
excreted along with them

4. Diuretics
• The primary therapeutic use of diuretics is to
reduce the overall swelling, correct specific ion
imbalance, lower blood pressure, lower the rate of
intraocular fluid formation and to lower pressure
on pulmonary vessels.

5. Diuretics
• Diuretics are widely used in medicine for very
diverse pathologies, primarily for relieving
Edema, treating Hypertension, Cardiac
Insufficiency, Hypercalcinuria, Glaucoma, and a
few forms of Epilepsy, Liver Cirrhosis, and
Nephrosis.

6. Anatomy and Physiology of
Nephron
 The functional unit of kidney is Nephron with its
accompanying glomerulus.
There are approximately one million nephrons in
each kidney.

7.  Nephron consists of Bowman’s capsule, Proximal convoluted tubule,
Descending loop of Henle, loop of Henle, Ascending loop of Henle,
Distal convoluted tubule and a Collecting duct.

8. Sites of Nephron
• There are four major sites along the nephron
which involve in active absorption of sodium
which include
 Site 1: The convoluted and straight part of
proximal tubule
 Site 2: the thick ascending limb of Henle loop
 Site 3: Distal convoluted tubule and
 Site 4: The collecting tubule.

10. Classification of Diuretics
 The agents which involve in the inhibition of sodium
reabsorption are classified on the basis of the site of action into.
 Site 1 Diuretics: Carbonic
anhydrase inhibitors.
 Site 2 Diuretics: High-
Ceiling or Loop diuretics.
 Site 3 Diuretics: Thiazide
and Thiazide like diuretics.
 Site 4 Diuretics: Potassium-
Sparing diuretics and
 Miscellaneous diuretics.

11. Site 1 Diuretics: Carbonic anhydrase inhibitors
 These diuretics had evolved from sulfanilamide and sulfonamide
antibiotics. After the administration of sulfanilamide for bacterial infection
mild diuresis was observed, this was characterized by the presence of
urinary sodium and a substantial amount of bicarbonate. It was
subsequently shown that it induces this effect through inhibition of renal
carbonic anhydrase. But the effect was minimum and by structural
modification of sulfanilamide effective drugs were prepared.

12. Carbonic anhydrase inhibitors
• Carbonic anhydrase is an enzyme found in various
segments of the nephron especially in the cells of
the proximal convoluted tubule (PCT).
• Carbonic anhydrase functions to catalyze the
reversible reaction involved the formation of
carbonic acid (H2CO3) from water and
carbondioxide.

13. • This carbonic acid dissociates to form H+
and HCO3
- ions.
• Carbonic anhydrase inhibitors inhibit this
reaction leading to urinary excretion of
Na+, K+ and HCO3- ions .

14. Carbonic anhydrase inhibitors

15. Synthesis of Acetazolamide
Acetazolamide is synthesized by the reaction of
ammonium thiocyanate and hydrazine, forming
hydrazino-N,N-bis-(thiourea) which cycles into
thiazole (9.7.2) upon reaction with phosgene.
Acylation of thiazole with acetic anhydride gives 2-
acetylamino-5-mercapto-1,3,4-thiadiazol (9.7.3).

16. Synthesis of Acetazolamide
• The obtained product is chlorinated to give 2-
acetylamino-5-mercapto-1,3,4-thiadiazol-5-
sulfonylchloride (9.7.4), which is transformed into
acetazolamide upon reaction with ammonia

17. Synthesis of Acetazolamide
Ammonium
thiocyanate
Hydrazine
1,2-bis (thiocarbamoyl) hydrazine
Thiazole
Acetylation
2-acetylamino-5-mercapto
-1,3,4-thiadiazol
Acetazolamide
2-acetylamino-5-mercapto-1,3,4-
thiadiazol-5-sulfonylchloride

18. SAR of carbonic anhydrase inhibitors
• After several efforts, two groups of carbonic
anhydrase inhibitors were synthesized.
• They are heterocyclic sulphonamides and
derivatives of m-disulphamoyl benzene.
• Both these group of compounds retain the
essential sulphamoyl (-SO2NH2) group.

19. SAR
• So the general SAR of carbonic anhydrase
inhibitors would be studied under two
headings.

20. Structural Activity Relationship (SAR)
 As these compounds are evolved from Sulfanilamide the basic
structure to be considered is sulfanilamide.
 Maximum diuretic activity is observed when 3rd position is
substituted with –Cl, -Br, -CF3 or –NO2.
 An unsubstituted sulfamoyl group at 4th position is a must for
diuretic activity.
 Substitution at 1st position with –NH2 group increases saluretic
(sodium chloride excretion) activity, but decreases carbonic
anhydrase inhibitory activity.
 Sulfamoyl group at 6th position increases activity and if it is
replaced with other electrophilic groups like carboxyl or carbamoyl
may increase diuretic potency while decreasing carbonic
anhydrase inhibitory activity.

21. For Heterocylic agents
 Sulfamoyl group at 2nd position
is essential for diuretic activity.
 Substitution with methyl group at 4th position yielded
methazolamide which exhibits appreciable carbonic
anhydrase inhibitory activity, but is not superior to
the prototype drug.
 An acetamino group at 5th position is must for
diuretic activity.

22. SAR
• Diuretic potency and carbonic
anhydrase inhibitory activity is entirely
due to the sulphamoyl group present at
C-5.

23. Mechanism of Action
 These agents inhibit Carbonic anhydrase which is
essential for the production of H+.
When there are no H+ the exchange of H+ with
sodium is prevented which leads to diuresis.
Sulphamoyl (-SO2NH2) group is entirely responsible
for their inhibitory effect on carbonic anhydrase
enzyme.

24. USES
 Used in the treatment of glaucoma,
motion sickness, as adjuvant for
treatment of epilepsy, and to create
alkaline urine to dissolve certain poorly
water soluble endogenous weak acids
like uric acid.

25. Adverse Effects
Carbonic anhydrase inhibitors are associated with
 Development of metabolic acidosis due to renal loss of
bicarbonate.
 Hypokalemia due to renal loss of potassium.
 Typical sulfonamide associated hypersensitivity reactions like
urticaria, fever, and intestinal nephritis.
 Symptoms associated with liver cirrhosis and hepatic
encephalopathy are seen.
 Drowsiness, fatigue, anorexia, gastrointestinal disturbances
and renal caliculi.

26. Site 2 Diuretics: High-Ceiling or Loop Diuretics
 Those agents which prevent the reabsorption of sodium on thick
ascending loop of Henle’s are considered as loop diuretics.
 Previously organomercurials were used and because of several serious
limitations like poor oral absorption, time lag in onset of action after
parentral administration and nephro and cardio toxicities, these were
replaced by other agents like 1. Amino benzoic acid derivatives
(Bumetanide, Furosemide), 2. Phenoxy acetic acid derivative (Ethacrynic
acid), and 3. Pyridine sulfonyl ureas (Torsemide, Triflocin).
1. Aminobenzoic acid derivatives:

27. High-ceiling diuretics
• Loop diuretics are the most potent and
efficacious diuretics.
• They are also termed as high-ceiling diuretics as
they exhibit a steep dose response curve.
• In normal doses loop diuretics are capable of
inducing upto 20-30% of Natriuresis and on
increasing the dose upto 30-40% natriuresis can
be achieved.

28. high-ceiling diuretics
Such an excretion is not exhibited by any other
diuretics like thiazides(only 10-12% natriuresis)
or K+ sparing diuretics (5-6% natriuresis).
The site of action for loop diuretics is the thick
ascending limb of loop of Henle.

29. Furosemide
• Furosemide: Furosemide, 4-chloro-N-furfuryl-5-
sulfamoylanthranylic acid.
• Synonyms of this drug are Lasix, Lazizix, Franil,
Urosemide,

30. Synthesis of Furosemide
• It is synthesized in a relatively simple manner
from 2,4-dichlorobenzoic acid, which is
converted into 3-aminosulfonyl-4,6-
dichlorobenzoic acid (21.4.10) during
subsequent reaction with Chlorosulfonic Acid
and Ammonia.
• Reacting this with furfurylamine gives
Furosemide.

31. Synthesis of Furosemide
2,4-dichlorobenzoic acid
3-aminosulfonyl-4,6-
dichlorobenzoic acid
Chlorosulfonic
Acid
furfurylamine
Furosemide

32. SAR of High-ceiling diuretics
• The loop or high ceiling diuretics are divided
into two classes based on their structure.
• The first class of drugs are derivatives of 5-
sulfamoyl-2-aminobenzoicacid
(Eg:- Furosemide, Azosemide).
• The second class comprises of 5-sulfamoyl-3-
aminobenzoic acid derivatives. (Eg:-
Bumetanide, Piretanide).

33. SAR of High-ceiling diuretics

34. Structural Activity Relationship
 –COOH group is essential at position 1 for diuretic activity.
 –SO2NH2 group at position 5 is also essential for diuretic activity
 Compounds with halogen group or benzoyl group at 4th position
shown maximum activity.
 Amino group may be at 3rd or 2nd position and the substituent on
amino group may be Furfuroyl or n-butyl for maximum activity.

35. SAR
Compounds with halogen group or benzoyl
group at 4th position shown maximum
activity.
The heterocyclic aromatic moieties are
better substituents than halogen and
substituted halogen derivative at 4th position.

36. Mechanism of Action
 All the loop diuretics prevent the
reabsorption of sodium in exchange of H+ or
K+ and also inhibit the Na+/K+/ Cl−
cotransport system located in the luminal
membrane of cells in the thick ascending
limb of Henle’s loop.

37. Uses
• In a number of cases, furosemide has proven
more effective than other diuretics.
• Besides a diuretic effect, it also dilates
peripheral vessels.
• It is frequently used in combination with other
antihypertensive drugs

38.  Used in the treatment of Oedema,
Symptomatic hypercalcemia and
hypertension.

39. Adverse Effects
 Hypokalemic alkalosis, Electrolyte losses,
Hyperuricemia, Utricaria, Drug fever, Blood
dyscrasias and intestina nephritis are the
common side effects associated with
aminobenzoic acid compounds of loop
diuretics.

40. Thiazide Diuretics
• Thiazide Diuretics are a group of moderately efficacious
diuretics which has vast clinical applications.
• Most of the diuretics of the thiazide class are structurally
related to antibacterial drugs of the sulfonamide class;
however, these compounds exhibit no antibacterial activity.
• Drugs of this group are derivatives of benzothiadiazine, and
as a rule they are substituted at C7 of the benzyl ring by a
sulfonamide group and a chlorine atom, or by another
electron-accepting group (trifluoromethyl) at C6.

41. Thiazide Diuretics
• All the thiazide diuretics are inhibitors of
Na+-Cl- symporter
• The major site of action being the early
segment of the Distal convoluted tubule
(DCT).
• Their secondary site of action is thought to
be Proximal convoluted tubule (PCT).

42. • The Na-K-Cl cotransporter (NKCC) is a
protein that aids in the active transport of
sodium, potassium, and chloride into and
out of cells.

43. Thiazide Diuretics
• The Na+-Cl- symporter is associated with the
reabsorption of both Na+ and Cl- ions.
• Thiazide diuretics inhibit this symporter resulting
in urinary excretion of both Na+ ions and water.

44. Site 3 Diuretics: Thiazide and Thiazide like Diuretics
 The thiazides were the first orally effective saluretic agents and their
activity was not influenced by the acid-base status of the individual.
Examples: Thiazide Diuretics includes Chlorthiazide and Benzthiazide
Hydrothiazides includes Hydrochlorthiazide,
Hydroflumethiazide’ Trichlormethiazide
Thiazide Diuretics
-H2C-S-H2C
Name of the Compound R R1
Chlorthiazide -Cl -H
Benzthiazide -Cl

45. Structures

46. Hydrochlorothiazide
• Hydrochlorothiazide is one of the most widely
used drugs of this series, and it is used for the
same indications, as is Chlorothiazide.
• Hydrochlorothiazide causes less inhibition of
Carbonic anhydrase, but causes 5–10 times more
diuresis of sodium ions than chlorothiazide using
the same dose.

47. Synonyms
• Synonyms of this drug are Chlorozide,
Diaqua, Esidrix, Hydrodiuril, Hydrozide,
Hypothiazide, Novohydrazide, Urozide, and
others.

48. Synthesis of Hydrochlorthiazide
• Hydrochlorothiazide: 1,1-dioxide 6-chloro-3,4-
dihydro-2H-1,2,4-benzothiadiazin-7-sulfonamide is
synthesized by cyclization of 4,6-sulfonamido-3-
chloroaniline (21.3.2) using paraformaldehyde,
during which simultaneous reduction of the double
bond occurs at position C3–C4.

49. Synthesis of Hydrochlorthiazide
Hydrochlorthiazide
4,6-sulfonamido-3-chloroaniline
Paraformaldehyde
1,1-dioxide 6-chloro-3,4-dihydro-
2H-1,2,4-benzothiadiazin-7-
sulfonamide

50. Structural Activity Relationship
 Smaller alkyl group like methyl group present on position 2 increases the
activity.
 Substitution on the 3rd position plays an important role in determining the
potency and duration of action of thiazide diuretics.
 Loss of double bond between 3rd and 4th position as in the case of
hydrothiazide increases diuretic activity.
 Substitution on 4th, 5th and 8th position decreases activity.
 Substitution at the 6th position with activating groups like –Cl, -Br, -CF3,
and –NO2 groups increases activity.
 A sulfamoyl group at 7th position is must for diuretic activity.

51. Name of the Compound R R1 R2
Hydrochlorthiazide -Cl -H -H
Hydroflumethiazide -CF3 -H -H
Trichlormethiazide -Cl -CHCl2 -H

52. Mechanism of action
The exact mechanism of action is not known;
 The effector regions of thiazide diuretics are the
distal nephron tubules.
 Drugs of this group inhibit reabsorption of
Sodium, Chloride, Magnesium, and Calcium ions
and cause increased excretion from the organism
along with an osmotically equivalent amount of
water.

53. Mechanism of action
These agents block the reabsorption of sodium in
the distal convoluted tubule by inhibiting the
luminal bound Na+/Cl- co-transport system, there
by eliminates sodium in the form of sodium
chloride.

54. Uses
 These are used in the treatment of edema associated with mild or
moderate congestive heart failure, cirrhosis of liver, or nephrotic syndrome.
They are also used in the treatment of hypertension, diabetes insipidus,
type II renal tubular acidosis and hypercalciuria.

55. Uses
• Thiazides are also effective in acidosis or
alkalosis, inhibiting carbonic anhydrase in vitro,
and lowering arterial pressure in hypertensive
patients.

56. Adverse Effects
These agents are associated with
hypersensitivity reactions such as utricaria,
drug fever, blood dyscrasias and intestinal
nephritis.
They may also cause Hypokalemia,
Hypotension and occasional Hypocalcemia.

57. Blood dyscrasias
• The pathologic conditions or disorders such
as leukemia or hemophilia in which the
constituents of the blood are abnormal or
are present in abnormal quantity.
• blood dyscrasias a pathologic condition of
the blood, usually referring to a disorder of
the cellular elements of the blood.

58. Urticaria
• commonly referred to as hives, is a kind of
skin rash notable for pale red, raised, itchy
bumps.
• Hives may cause a burning or stinging
sensation. They are frequently caused by
allergic reactions

59. Interstitial nephritis
• Interstitial nephritis is a kidney disorder in
which the spaces between the kidney
tubules become swollen (inflamed).

60. Site 4 Diuretics: Potassium-
Sparing Diuretics
• These agents increase sodium and chlorine
excretion with out increasing the rate of
potassium excretion.
• As these agents do not affect the rate of
excretion of potassium these are called
Potassium Sparing Diuretics Or Antikaliuretic
Agents. These agents act on the connecting
and collecting tubule of nephron.

61. Examples: Aldosterone antagonist – Spironolactone, Arylpteridines –
Triamterene and Pyrazinoylguanidine – Amiloride.
Structural Activity Relationship
 For spironolactone –SCOCH3 at 6th position is essential for diuretic activity.
 For triamterene an unsubstituted 2,4,7-triamine is essential for diuretic
activity.
 For amiloride an –Cl at 6th position and unsubstituted –NH2 groups at 3rd and
5th position is must for increased activity.

62. Mechanism of Action
Aldosterone increases the sodium reabsorption
into the luminal fluid.
 Spironolactone inhibits the actions of
aldosterone and prevents the sodium
reabsorption.

63. MOA
Triamterene and Amiloride does not requires
the presence of aldosterone to produce
diuresis.
They decrease the Na+-K+ ATPase activity
and prevent the loss of K+ in exchange of
sodium.

64. Uses
All these agents are used to remove the edema
fluid in individuals with congestive heart failure,
heart failure, cirrhosis, nephritic syndrome and
with hypertension.
However, its primary use is to be given in
combination with other diuretics to prevent
potassium loss.

65. Adverse Effects
 The major adverse effects of spironolactone include
hyperkalemia and mild metabolic acidosis. In addition,
spironolactone may produce gynecomastia in men and
breast tenderness and menstrual disturbances in
women.
 Triamterene produces hyperkalemia, nausea,
vomiting, leg cramps and dizziness.
 Amiloride is associated with hyperkalemia, nausea,
vomiting, diarrhea and headache.

66. Miscellaneous Diuretics
 These agents act by different ways. Examples include Mannitol and
Theophylline.
N
N
N
H
N
O
O
H3C
CH3
Theophylline
 The osmotic effect induced by the mannitol prevents the reabsorption
of water along with sodium and theophylline promotes weak diuresis by
stimulation of cardiac function and by a direct action on nephron.