Class 4- LOOP DIURETICS High ceiling Diuretics Lec-4
Jan 18, 2016
Class 4- LOOP DIURETICSHigh ceiling Diuretics
Lec-4
• 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? )
ATP
Na
K
Na
Luminal membrane Basolateral membrane
Urine Blood
K
K
K
Na
Cl
Na
ClH
2Cl
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.
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High-ceiling or loop diuretics
Results from structure-activity relationship studies that led to the development of furosemide.
Loop Diuretics
active in “loop” of HenleFurosemide (prototype)BumetanideTorsemideEthacrynic acid
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Furosemide
Name:
5-(Aminosulfonyl)-4-chloro-2-[(2-furanylmethyl ) amino] benzoic acid
S
OO
H2N
Cl
O
OH
NH
O
Synthesis of FurosemideCl Cl
COOH
Cl Cl
COOHH2NO2S
1) ClSO3H
2) NH3
Cl NH
COOHH2NO2S
CH2O
Furfurylamine
, 130 C
H2NO2S
XHN
COOH
R
1
2
34
5
6 H2NO2S
X
COOH
N
R
5
4 3
2
1
6
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.
SAR of 5-Sulfamoyl-2- and -3-aminobenzoic acid derivatives
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.
Cl
OCl
C
CH2COOH
O
C
CH2
H3CH2C
Phenoxyacetic acids, Ethacrynic Acid, (Edecrin®).
Cl
OCl
C
CH2COOH
O
C
CH2
H3CH2C
Phenoxyacetic acids, Ethacrynic Acid, (Edecrin®).
SARs:
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 3-
position 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.
Cl
Cl
ONa
ClCH2COOH
Cl
Cl
O CH2COOH AlCl3
Cl
Cl O
H3CH2CH2COC
CH2COOH
HCHO
(CH3)2NH
Cl
OCl
C
CH2COOH
O
Cl
OCl
C
CH2COOH
O
C
CH2
H3CH2C
CH3CH2CH
H2C
NCH3H3C
2,3-dichloro sodium phenolate
+CH3CH2CH2COCL
Cl
OCl
C
CH2COOH
OH
CH3CH2C
CH2
NCH3H3C
heat
-NH-(CH3)2
Synthesis of Ethacrynic acid
Class 5:Potassium sparing diuretics
three groups1- steroid aldosterone antagonists
as spironolactone,
2- triamterene
3- Pyrazinoylguanidines
amiloride
Potassium-sparing diuretics
Competitivealdosteroneantagonists:•Spironolactone
Blockers of the amiloride-sensitiveNa+ channels:•Amiloride•Triamterene
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Spirolactones
Mechanism of Action
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
Keep K+
Aldosterone-stimulated sodium reabsorption in exchange for potassium and hydrogen ion, in the distal, collecting tubules and ducts
3%
AmilorideTriamterene
Spironolactone
5. Potassium- sparing diuretics
They have weakdiuretic actionand save K+.
Often they are usedin combination withdiuretics, causinghypokalemia.
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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.
Other potassium-sparing diuretics: triamterene and amiIoride:
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Interferes with cationic exchange by blocking
luminal Na+ channels in the late distal
convoluted tubule and collecting duct.
Triamterene & amiloride
amilorideTriamterene
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