Transcript Thiazide and Thiazide

Lec-3
Class 3:Thiazide and Thiazide-like
diuretics
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.
Class 3: Thiazide and Thiazide-like diuretics
O
O
O
O
H2NS
SNH2
Cl
NH2
Chloraminophenamide
Aldehydes
(or Ketones)
Acylating Agents
O
O
O
H2NS
O
O
O
H2NS
S
O
O
S
NH
NH
Cl
N
Thiazides
R
Cl
N
H
R
Hydrothiazides
(Hydrochlorothiazide)
 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.
4
Mechanism of Action
inhibit Na+ and Cl- transporter in distal convoluted
tubules
increased Na+ and Cl- excretion
increased K+/Mg2+ excretion
decrease Ca2+ excretion
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
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.
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.
Cl
class 3 Diuretics;
Thiazide and Thiazide-like Diuretics
 Chlorothiazide

N
NH
H2NO2S
S
6-Chloro-2H-1, 2,4-benzothiadiazine-7-sulfonamide
1,1-dioxide.
Chlorothiazide
H
N
Cl

Hydrochlorothiazide, (Esidrix)

6-Chloro-3, 4-dihydro-2H-1, 2,4-benzothiadiazine-7-
NH
H2NO2S
sulfonamide 1,1 -dioxide
O
O
S
O
Hydrochlorothiazide
Cl
N
CH2SCH2
F3C
H
N
H2NO2S
S
CH2
NH
H2NO2S
S
O
NH
O
Benzthiazides
O
O
Bendroflumethiazide
O
Structure-Activity Relationships:
4
5
Cl
N
6
7
H2NO2S
3
2
S
8
O
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.
1
NH
O
R
Synthesis:
Cl
NH2
Cl
NH2
ClSO2OH
+
ClO2S
SO2Cl
NH3
Cl
H
N
Cl
NH2
HCHO
NH
H2NO2S
Hydrochlorothiazide O
H2NO2S
S
O
HCOCl
H2
SO2NH2
HCOOH
Cl
N
NH
Chlorothiazide H2NO2S
S
O
O
OH2
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
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
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.
X
H2NO2S
R'
SO2NH2
X
R'
H2NO2S
R
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.
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.