Download Class 4- LOOP DIURETICS High ceiling or Site 2 Diuretics

Lec-4
Class 4- LOOP DIURETICS
High ceiling Diuretics
• The diuretics that belong to this class are of extremely
diverse chemical structure, such as:
• The organomercurial diuretics,
• The 5-Sulfamoyl-2- and -3-aminobenzoic acid
derivatives. Examples, furosemide and bumetanide
• Phenoxyacetic acid derivatives as ethacrynic acid
Loop diuretics
• Act by inhibition of Na+, K+, and Cl- reabsorption from
the ascending limb of the loop of Henle in the renal
tubule.
• They also tend to reduce renal Ca+ reabsorption, thus
they are used in treatment of hypercalcemia.
• High efficiency diuretics.
• High ceiling diuretics.( what is mean? )
Mechanism of Action:
They inhibit the 1Na+/1K+/2Cl- cotransport system located on the
luminal membrane of cells of the thick ascending limb of Henle’s
loop
Adverse Effects:
1. Hypokalemic alkalosis.
2. Fluid and electrolyte losses
3. Reduction in plasma volume
may result from long-term use
of these diuretics.
4.Hypersensitivity reactions such
as urticaria,
fever, and
interstitial nephritis.
Luminal membrane
Basolateral membrane
Na
Na
ATP
2Cl
K
K
Na
K
H
K
Cl
Cl
Na
Urine
Blood
High-ceiling or loop diuretics
Results from structure-activity relationship studies that
6
led to the development of furosemide.
Loop Diuretics
active in “loop” of Henle
Furosemide (prototype)
Bumetanide
Torsemide
Ethacrynic acid
Furosemide
O O
H2N
O
S
Cl
OH
O
N
H
 Name:
5-(Aminosulfonyl)-4-chloro-2-[(2-furanylmethyl）
amino] benzoic acid
8
Synthesis of Furosemide
Cl
Cl
Cl
Cl
1) ClSO3H
COOH
2) NH3
H2NO2S
COOH
Furfurylamine
, 130 C
Cl
NH
CH2
O
H2NO2S
COOH
SAR of 5-Sulfamoyl-2- and -3-aminobenzoic acid derivatives
H
N
3
X
4
R
R
2
1
6
COOH
3
4
X
5
H2NO2S
N
2
1
5
H2NO2S
6
COOH
1) The substituent at the 1-position must be acidic, The carboxyl
group provides optimal diuretic activity, but other groups, as
tetrazole, may have respectable diuretic activity.
2) A sulfamoyl group in the 5-position is essential for optimal
high-ceiling diuretic activity.
3) The activating group (x-) in the 4-position can be Cl- or CF3-,
a phenoxy-, alkoxy-, anilino-, benzyl-, or benzoyl- group.
4) Substitutents that can be tolerated on the 2-amino group
series: only furfuryl-, > benzyl-, > thienylmethyl.
5) Substituent, on the 3-amino group series: can very widely
without affecting optimal diuretic activity.
Phenoxyacetic acids,
Ethacrynic Acid, (Edecrin®).
Cl
Cl
O
CH2COOH
CH2
C
H3CH2C
C
O
2,3-Dichloro-4-(2-methylene-1-oxobutyl) phenoxyacetic acid
Uses:
Ethacrynic acid is prescribed for individual who has a known
hypersensitivity to Sulfamoyl containing drugs.
Phenoxyacetic acids,
Cl
Cl
Ethacrynic Acid, (Edecrin®).
O
CH2COOH
CH2
C
SARs:
H3CH2C
C
O
Optimal diuretic activity is achieved when:
1. An oxyacetic acid moiety is placed in the 1-position on
the benzene ring,
2. A sulfhydryl-reactive acryloyl moiety is located para to
the oxyacetic acid group,
3. Activating groups (Cl- or CH3-) occupy either the 3position or the 2- and 3-positions.
4. Alkyl substituent of two- to four-carbon atoms in length
occupy the position α to the carbonyl on the acryloyl
moiety.
Synthesis of Ethacrynic acid
Cl
Cl
Cl
Cl
ONa
Cl
O
+ ClCH2COOH
Cl
AlCl3
CH3CH2CH2COCL
O
CH2COOH
CH2COOH
H3CH2CH2COC
2,3-dichloro sodium phenolate
HCHO
(CH3)2NH
Cl
Cl
Cl
O
CH2COOH
Cl
OH
O
C
CH3CH2C
CH3CH2CH
CH2
N
H3C
CH3
H2C
heat
-NH-(CH3)2
N
H3C
Cl
Cl
CH2
C
H3CH2C
C
O
O
C
CH2COOH
CH3
O
CH2COOH
Class 5:Potassium sparing diuretics
three groups
1- steroid aldosterone antagonists
as spironolactone,
2- triamterene
3- Pyrazinoylguanidines
amiloride
Potassium-sparing diuretics
Competitive
aldosterone
antagonists:
Blockers of the
amiloride-sensitive
Na+ channels:
•Spironolactone
•Amiloride
•Triamterene
Spirolactones
18
Mechanism of Action
Keep K+
Aldosterone-stimulated sodium reabsorption in
exchange for potassium and hydrogen ion, in the distal,
collecting tubules and ducts
K+ sparing diuretics function in CCD decrease Na+
transport in collecting tubule
all previous-discussed diuretics is that they increase
the renal excretion rate of K+ and thus can induce
hypokalemia
5. Potassiumsparing diuretics
Amiloride
Triamterene
Spironolactone
3%
They have weak
diuretic action
and save K+.
Often they are used
in combination with
diuretics, causing
hypokalemia.
Other potassium-sparing diuretics:
triamterene and amiIoride:
Mechanism and site of action:
• Triamterene and amiloride (organic bases) inhibit
sodium transport in nephron segments beyond the
distal convoluted tubule.
• They do not interact with aldosterone receptors.
21
Triamterene & amiloride
Interferes with cationic exchange by blocking
luminal Na+ channels in the late distal
convoluted tubule and collecting duct.
Triamterene
amiloride
22
Activity
• Brain Storming