Diuretics, also called water pills, are medications designed to increase the amount of water and salt expelled from the body as urine. There are three types of prescription diuretics. They’re often prescribed to help treat high blood pressure, but they’re used for other conditions as well.

1. Site III Diuretics
Md. Saiful Islam
B.Pharm, M.Pharm (PCP)
North South University
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2.  Thiazide diuretics are called benzothiazine derivatives.
 Chemically they are 1,2,4-benzothiadiazine-7-
sulfonamide 1,1-dioxides or 3,4-dihydro-1,2,4-
benzothiadiazine-7-sulfonamide 1,1-dioxides. They are
synthesized from chloraminophenamide, which is
derived from the sulfanilamide.
 Sulfanilamide is an antibacterial drug but it was
found to have some diuretic activity.
Thiazide Diuretics

3. Indications
Thiazide diuretics is used in the treatment of
 Edema associated with mild to moderate congestive heart failure
 Liver cirrhosis
 Nephrotic syndrome
 Hypertension
 Diabetes insipidus
 Type -II renal tubular acidosis
 Hypercalciuoria

4. Pharmacokinetics of Thiazide Diuretics
 Thiazide drugs are administered orally because they are absorbed well except
chlorothiazide.
 Their action starts within 1 to 2 hours of administration & their peak diuretic
effect reaches within 8 to 48 hours.
 Thiazide drugs are bound to the plasma protein & are transported through out
the body & they are excreted by the kidney.
 Thiazide type of drugs undergoes little or no biotransformation in the body.

5. Chloraminophenamide
Hydrochlorothiazide Chlorothiazide
Acylating agentAldehydes or
ketons
Derivation of Thiazide like Diuretics

6. SAR of Thiazide Drugs
Prototype :
 An unsubstituted sulfamoyl moiety is needed for diuretic activity.
Presence of electron releasing groups like methyl or methoxy at C-6
reduces the diureticactivity.

7.  The presence of the activating group like Cl-, Br-, CF3 and NO2 in
position 6 is essential for diuretic activity. Substitution of CF3 group has
more lipid soluble and larger diuretic action than Chloro compound.
SAR of Thiazide Drugs
Hydroflumethiazide

8. SAR of Thiazide Drugs
 Position 2 must have small alkyl group like CH3, large alkyl will destroy
its activity.
2- methylchlorothiazide 2- butylchlorothaizide

9.  The substituent in position 3 will determine the potency and duration of action
of thiazide drugs. Lipophilic substituents such as aryalkyl, halo alkyl, thioether
will increase its activity. But lipophobic substituent will yield inhibitor of
thiazide drugs.
SAR of Thiazide Drugs
Methylclothiazide

10.  Saturation of carbon nitrogen double bond between 3 and 4 position
will increase its potency.
SAR of Thiazide Drugs
Chlorothiazide Hydrochlorothiazide

11.  Substitution of position 4, 5 or 8 with alkyl group will reduce
diuretic activity.
SAR of Thiazide Drugs
5- methylchlorothiazide

12. Drug Development
 Hydrochlorothiazide:
Hydrochlorothiazide has been derived from hydrothiazide.
Substitution at the 6 position of hydrothiazide by a chloride ion gives
hydrochlorothiazide which possesses more diuretic effect than hydrothiazide. The C-
N double bond between the 3 & 4 position of chlorothiazide is hydrogenated in
hydrochlorothiazide which increases its potency 3 to 10 times.
Chlorothiazide Hydrochlorothiazide

13.  Methyclothiazide:
Substitution at C3 position of hydrochlorothiazide by a lipophilic substituent &
at N2 position by an alkyl group increases its diuretic activity & duration of action, whereas
substitution by a lipophobic substituent at C3 position will create inhibitor of thiazide like
diuretics. Now if the substitution at position 3 is done by ethylchloride which is lipophilic in
nature, and at position N2 by a methyl group, then methyclothiazide is formed, which is more
potent than hydrochlorothiazide & gives prolonged duration of action.
Hydrochlorothiazide Methyclothiazide
Drug Development

14. Adverse Effects
 Thiazide diuretics contain sulfamoyl group, which cause
hypersensitivity reactions such as urticaria, drug fever, blood
dyscrasias & intestinal nephritis in some persons.
 Long term use of thiazide leads to hypokalemia.

15. Adverse Effects
 These diuretics produce a slight reduction in the cardiac output, plasma
volume and blood pressure. Long term use increases proximal tubular
reabsorption of water ,solutes, renin release, angiotensin II formation &
aldosterone secretion. Which creates further complication known as diuretic
braking phenomenon.
 A patient experience hypercalcemia or hyperuricemia after long term use of
a thiazide diuretic. This results in reduction of the plasma volume & increase
in the proximal tubule reabsorption of solute.