Moustafa K.Soltan
Diuretic
is substance that increases the urine excretion by kidney so decrease body fluids
mainly the extracellular fluids.
*the functional unit in the kidney is the nephron and each kidney has about one
million nephron.
*To increase water excretion, a diuretic has to increase Na+ secretion from blood
to nephron lumen, Or decrease Na+ reabsorption from lumen to blood.
*Natriuretic is substance increase Na+ excretion,
Saliuretic is substance increase Na+ and Cl- excretion,
Kaliuretic is substance increase K+ excretion.
General used of diuretics:
1)treatment of all types of edema associated with congestive heart failure, liver
dysfunction or cirrhosis,
Renal failure and during pregnancy.
2)used in treatment of hypertension either alone if hypertension is mild or in
combination with antihypertensive drug if severe hypertension.
,-unsaturated ketones
HOOC
Cl Ethacrynic acid
3 Cl
CH2
CH3 HOOC
2,3-dichloro-4-(2-methylene
butanoyl)phenoxyacetic acid
synthesis
Cl
Cl
O
Mannich RXN
HCHO / (CH3)2NH
HOOC
Cl
AlCl3
(CH2)2CH3
O
F.C.acylation
-HCl
ClCl
(CH2)2CH3
O
Butanoyl Cl-
MOA:
it inhibit Na+ reabsorption in ascending loop of Henle, and in distal tubule and
commonly called
( Loop diuretic ), thus increase also Cl- excretion so cause systemic alkalosis.
Uses:
used in refractory edema.
NH 3
N
N
N
CH 3
Aminophylline
NH 3
***Assay: 1) for ethylene diamine: dissolve in water and then titrate with
standard acid and methyl orange indicator.
2) for theophylline: to the above neutral solution add Kn xss of
AgNO3, which pricipitate theophylline as insoluble silver salt
liberate equivalent amount of HNO3 titrated with st base,
indicator , or determine residual AgNO3 by st SCN-, ferric alum
Sulphonamides.
1-Carbonic anhydrase inhibitors
General mechanism of action: they act mainly in proximal tubules.
they have SONH2 group which is structurally similar to carbonic acid so inhibit
carbonic anhydrase enzyme which catalyze the following process:
H2O + CO2
carbonic anhydrase
H2CO3
O
H3 C
S
HN
N
NH2
O S O
NH 2
O
Acetazolamide
Cl
Cl O
O
S
NH2
Dichlorophenamide
H
N
O
SO2NH2
-H2O
Cl 6 5
H2NO2S
1 NH 2
7
8
S
O O
MOA:
Inhibit Na+ reabsorption in proximal tubule and ascending loop of Henle what
cause diuresis.
They have SO2NH2 so has certain degree of carbonic anhydrase inhibition
SAR: 1) Cl, F, CF3 in the position 6 activates the nucleus.
2) substitution on the position 5 or 8 reduces the activity.
3) free sulfamoyl group is essential for activity, removal or replacement of
one of the two hydrogens of sulfamoyl group by methyl group abolishes activity
4) free sulfamoyl group in position 7 is equal in activity to that in position
5, if in position 6 it will reduce the activity
H 2NO2S
Cl
O O
S
NH
N
Chlorothiazide
H2 NO 2S
Cl
O O
S
NH
N
H
Hydrochlorothiazide
H 2NO2 S
F3 C
O
NH
N
H
Bendrof luazide
Uses: 1) oedema associated with heart failure and hepatic or renal disorders.
2) hypertension alone or with other antihypertensives.
Phthalimidine derivatives
O
1 2
NH
3
OH
NH4OH
SOCl2
Cl
Cl
Cl
heat
Cl
OH
Chlorothalidone SO2NH2
chlorophthalide SO2Cl
SO2Cl
*3-hydroxy-3-(3--sulfamoyl-4--chlorophenyl) phthalimidine
**1-oxo-3-(3--sulphamoyl-4--chlorophenyl)-3-hydroxy-2,3-dihydro-1H-isoindole
***Assay: as in hydrochlorothiazide
**** potent, long acting, orally effective diuretic and antihypertensive.
O
OH
O
Cl
SO2Cl
benzophenone2-carboxylic
acid derivative
H2NO2S
Cl
N
H
H2N
COOH
O
H2NO2S
Cl
Cl
COOH
COOH
ClO2S
NH4OH
Cl
ClSO3H
Cl
Cl
Cl
NaHCO3
Frusemide
*4-chloro-N-furfuryl-5-sulfamoylanthranilic acid
**Assay: non aqueous titration as weak acid.
***MOA: highly effective saliuretic agent that has rapid diuresis in short duration of action (6-8) hours,
it acts as loop diuretic, inhibit Na+ reabsorption in loop of Henle, it promotes K+ excretion also, so it is
used with potassium supplements or pot. sparing diuretics to avoid hypokalemia.
MOA:
aldosterone stimulate Na+ reabsorption and K+ excretion so cause hypokalemia
and decrease diuresis,
Spironolactone antagonize the effects of aldosterone in the collecting duct so as
to decrease Na+ rabsorption and also decrease K+ excretion so called potassium
sparing diuretic and it has steroidal structure.
** spironolactone is metabolized to an active metabolite which is canrenone.
Amiloride O
Triamterene
8
H2N 7 N
6
N
5
N1
NH2
2
4 N3
NH2
2,4,7-triamino-6phenylpteridine
Cl
H2N
N
H
NH2
NH
NH2
3,5-diamino-N(aminoiminomethyl)-6chloropyrazine-2-carboxamide
MOA:1) act in the late distal convoluted tubule and in the early collecting duct.
2)It exerts the same action of spironolactone but without any relation to the
aldosterone.
3) it is really mild natriuretic, saliuretic and antikaliuretic.
Uses: 1) mild edema associated with congestive heart failure or liver cirrhosis.
2)not enough alone in treatment of hypertension.
3) mainly used with hydrochlorothiazide to prevent associated hypokalemia of
the latter.