The main site of diuretic action is well established for the different groups of diuretics: carbonic anhydrase inhibitors act on the proximal tubulus, loop diuretics on the diluting segment, thiazides on the cortical diluting segment/distal tubulus, and potassium-sparing agents on distal tubulus/collecting ducts.

1. Md. Saiful Islam
B.Pharm, M.Pharm (PCP)
North South University
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2. The Site IV Diuretics
•Thediureticsacting atsite IVarealso called potassium-sparing diuretics.
•TheSite IVdiureticsare classified into the following groups:
i)Spirolactones- E.g.. Spironolactone. Drugs in this group are
aldosterone antagonists.
ii)2,4,7-Triamino-6-arylpteridines- E.g. Triamterene
iii)Pyrazinoylguanides- E.g. Amiloride

3. i) Spironolactone:

4. Spironolactone
This became the socalled prototype for this classof diuretics.

5. Structure-Activity Relationship (SAR)
Evolution of spironolactone:
One of the first compounds of significance
androsten-17-alpha-yl)-propanoicacid lactone.
3-(3-oxo-17beta-hydroxy-4-androsten-17-alpha-yl)-propanoic acid lactone
was 3-(3-oxo-17beta-hydroxy-4-

6. •Attemptswere made to increase potency . Thecompound had poor
bioavailability, this wasovercome by several modifications.
1. Presenceof double bond at C1-C2
2. Presenceof double bond at C6-C7(canrenone)
3. Presenceof double bond at C1-C2 and C6-C7 simultaneously
4. substitution at C1 with thioacetyl group
5. Substitution of thioacetyl moiety at C7 of the steroid nucleus
Modification of by Substitution of thioacetyl moiety at C7 of the steroid
nucleuswas the most widelyaccepted.

7. Structureactivity-relationships of spironolactoneareas follows:
•If the spirolactonering at C17 Position were to occur in the opposite configuration
(i.e. adiastereoisomer) then the subsequent compound becomes inactive.
•If the thioacetyl moiety in the C7 position essential should have α-configuration.
Inversion of this to β-configuration causes a reduction of both oral and paraentral
activity by 90%.

8. •Aγ-lactam at C-17 rather than the conventional lactone ring (i.e. acyclicamid
ratherthat a cyclicester) reducesaldosteroneantagonist activity.
compound containing lactam

9. •Manyanaloguesof spironolactonecontaining extra functional groups
wereexamined. These include:
- Introduction of methyl groupat 2,4,6,7 and 16 position
- Hydroxyl or ketone groupat the 11 position
- Fluorineat the 9 position
Thesesubstituents have no inf luenceon improvementof compound
profile.

10. •Bysaponfication of the lactone ring awide rangeof open lactone potassium salt
derivatives wereobtained.
Potassium mexrenoate Potassium canrenoate

11. •Spironolactone has binding affinities for both progesteroneand androgen
receptors. This is reduced by:
1. Formation of cyclopropanering across the C15 and
C16. e.g. Mespirenone
Mespirenone
2. Oxygenation of the steroid nucleus byepoxide
formation, resulted in 9,ll-α-epoxy steroids
Eeplerenone

12. Triamterene

13. StructureActivity Relationship of Triamterene:
1. Replacementof anyoneof the primaryamino groups by loweralkylamino
groupsresulted in compounds that have similardiuretic activity to triamterene.
2. Mostsubstitution on the phenyl group renders the compound inactive, only a
few substitutions can be made.
3. Decreasing the basestrength of the pteridine nucleusalways lead to decrease in
activity.
4. The phenyl group is not essential foractivity but hasgreat importance in terms
of the degreeof binding and give an optimum orientation of moleculeat the
receptorsite.

14. Amiloride
It belongs to the group
Pyrazinoylguanidines.

15. SAR
 If chlorine is substituted at C-6 then optimal
diuretic activity is observed.

16. In C-3 and C-5 position the amino
group must be unsubstituted.
SAR

17. The guanidino nitrogens cannot be substituted
with alkyl groups in order to retain diuretic
activity.
SAR

18. Indicationof Site IV Diuretics:
•Mineral corticoid excess/ hyperaldosteronism
•Removal of edema fluid in patients with congestive heart failure, liver cirrhosis, the
nephroticsyndrome
•Antihypertensive drug- it is used with site 2 and 3 diuretics to prevent urinary loss
of K+
Toxicityof Site IV Diuretics:
•Hyperkalemia
•MetabolicAcidosis
•Gynecomastiaand impotence
•Acuterenal failure
•Kidney stones