1. Class 3:Thiazide and Thiazide-like diuretics
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Class 3:Thiazide and Thiazide-like diuretics

2. Thiazides and Thiazide-like diuretics
They were synthesized accidentally in an attempt to create more potent carbonic anhydrase inhibitors.
They act by inhibiting sodium reabsorption at the cortex level specifically at just distal to the loop of Henle.
They exert their effect from the luminal side of the nephron membrane thus, must be filtered to reach the site of action.

3. Class 3: Thiazide and Thiazide-like diuretics

4. Chloraminophenamide became a key intermediate in the development of diuretics that lack the undesirable properties of the CA inhibitors (???).
When Chloraminophenamide was treated with acylating agents, cyclization resulted in the formation of Thiazides. The use of aldehydes or ketones in place of the acylating reagents yielded the corresponding dihydro derivatives. The products of these reactions became known as thiazides and hydrothiazides, respectively.
The thiazides were the first orally effective saluretic agents diuretic activity was not influenced by the patient’s acid-base status.

6. Mechanism of Action
inhibit Na+ and Cl- transporter in distal convoluted tubules
increased Na+ and Cl- excretion
increased K+/Mg2+ excretion
decrease Ca2+ excretion

7. Diuretics Thiazide and Thiazide-like Diuretics Mechanism of Action
Actions:
Acts in the distal convoluted tubule
Inhibit tubular resorption of sodium, chloride, and potassium ions
Result: water, sodium, and chloride are excreted
Potassium is also excreted to a lesser extent
Dilate the arterioles by direct relaxation
Results:
Lowered peripheral vascular resistance
Sodium, water, chloride and potassium are excreted

8. Overview of the group They are generally medium potency diretics.
The first thiazide in the market is chlorthiazide suffered poor GI absorption and low bioavailability.
Hydrochlorthiazide is the second member introduced to the market with higher bioavailability.
The main side effects are the possibility of inducing slight hyperglycemia and hyperlipidemia.

9. Overview of the group continued
Thiazide like drugs don’t have true thiazide ring but share the same mechanism of action and chemically related.
All members are available in oral forms except chlorthiazide ( oral and parentral): no clinical significance for their parentral forms.

10. Thiazide and Thiazide-like Diuretics
class 3 Diuretics;
Thiazide and Thiazide-like Diuretics
Chlorothiazide
6-Chloro-2H-1, 2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide.
Hydrochlorothiazide, (Esidrix)
6-Chloro-3, 4-dihydro-2H-1, 2,4-benzothiadiazine-7-sulfonamide 1,1 -dioxide

11. Structure-Activity Relationships:
1) The 2-position can tolerate small alkyl groups as CH3.
2) Substitutents in the 3-position determine
the potency and duration of action of the thiazides.
3) Saturation of C-N bond between the 3 and 4 positions of the
benzothiadiazine-1,1-dioxide nucleus increases the potency
of this class of diuretics approximately 3-10 fold.
4) Direct substitution of the 4-, 5-, or 8-position with an alkyl group
usually results in diminished diuretic activity,
5) Substitution of the 6-position with an activating group is essential
for diuretic activity. The best substituent include Cl-, Br-, CF3-, and
NO2- groups.
6) The sulfamoyl group in the 7-position is essential for diuretic
activity.

12. Synthesis:

13. Diuretics Thiazide and Thiazide-like Diuretics Indications
Hypertension – first line drug for HTN
Edematous states
Idiopathic hypercalciuria (condition characterized by recurrent stone formation in the kidneys due to excess calcium excretion) because thiazide diuretics used to prevent calcium loss and protect the kidneys
Diabetes insipidus
Heart failure due to diastolic dysfunction

14. Diuretics Thiazide and Thiazide-like Diuretics Adverse Effects
Body System Adverse Effects
CNS Dizziness, headache, blurred vision, paresthesias, decreased libido
GI Anorexia, nausea, vomiting, diarrhea
Integumentary Urticaria, photosensitivity
Metabolic Hypokalemia, glycosuria, hyperglycemia,
hyperuricemia

15. Thiazide-like diuretics
The sulfamoyl group para to the activating group of thiazides could be replaced by several other electronegative groups (X-) with retention of diuretic activity (as R = amide, carbonyl, carboxyl groups, etc) in the meta-disulfamoylbenzene,
These diuretics known as thiazide-like diuretics.
Their site of action, efficacy, electrolyte excretion pattern, and adverse effects resemble the thiazides.

16. Quinazoline derivatives 1- Metolazone
is a thiazide like drug
It is primarily used to treat congestive hear failure and HTN
Metolazone indirectly decreases the amount of water reabsorbed into the bloodstream by the kidney, so that blood volume decreases and urine volume increases. This lowers blood pressure and prevents excess fluid accumulation in heart failure.
Metolazone is sometimes used together with loop diuretics such as furosemide, but these highly effective combinations can lead to dehydration and electrolyte abnormalities.

17. Quinazoline derivatives 2-Chlorthalidone
A diuretic with actions and uses similar to those of the thiazide diuretics even though it does not contain a thiazide ring system
A benzenesulfonamide-phthalimidine that tautomerizes to a BENZOPHENONES form. It is considered a thiazide-like diuretic.