DIURETICS

Diuretics are
the hetero cyclic
chemical
therapeutic
agents which
promotes the
excretion of
sodium & water
by action on
the four major
anatomical
sites,results the
increases the
rate of urine
formation

.
 Diuretics are the hetero cyclic
chemical therapeutic agents which
promotes the excretion of sodium & water
by action on
the four major anatomical sites,results
the increases the rate of urine formation

.
 History of Diuretics
Greek word
flow of a drop.

Medicinal use starts from 400BC-metalic

mercury

1949-Sulfanilamide(diuretics & natriuretics)

1950s -the new hetero compounds

 Classification
SITE-1
Carbonic anhydrous inhibitors
SITE-2
Loop or high ceeling Diuretics
SITE-3
Thiazide or thiazide like diuretics
SITE-4
Potassium sparing diuretics
Xanthine diuretics
Osmotic diuretics
Miscellaneous
Site of Action of 6 group of Diuretics
 Renal Physiology & Pharmacology
Kidneys-the prim organ
for excretion & maintain
the homeostasis
Remove water, electrolytes,

products of metabolic waste

& other materials form blood
Possess endocrine functions,

i.e.-secrete erythropoietin
rennin & 1,2,5-hydroxy
cholecalciferol
Selective reabsorb water, The reddish brown organ weighed-300gms
Location-Either side of the vertebral column
electrolytes & needed Kidney embedded in perirenal fat &
nutrients from the urine. fibrous capsule
 Nephrons-the working unit of kidney

with each kidney

containing
1.2millon nephrons

Two types
Cortical nephrons-(80%-short)
Juxtamedullary nephrons-(long)
Glomerular filtration pressure-50mmof Hg
 intertitial nephritis
 About 650ml of
plasma flow through
the kidneys each minute
Approximately

125ml/min of which
are filter through the
glomerular capillaries
The remaining four-fifths(80%) of the renal plasma

flow is directed into the peritubular capillaries

Each minute

125mlof 1 ml of
glomerular filtrate urine
Fate of Luminal Fluid
 SITE-1:-The convoluted & straight portions of the
proximal tubules
The plasma in the peritubular
capillaries has a low
hydraulic pressure 7 a
higher oncotic pressure than
the luminal fiuid
The Na-K-ATPase,catalyzes
the counter transport of
intracellular Na interstitium
&K Proximal tubules
3Na interstitium
Proximal
tubule cells 2K+
A voltage oriented ve inside
proximal tubule cells
 The reabsorption of the Na takes place y 3 distinct process
The counter transport by the action of interacellular CA are exchanged by
the Na+-K+ ATPase in antiluminal membrane
Na+ H+
H+ + HCO3 H2CO3 CO2 + H2O

go to PT

Na moves out of the luminal fluid by the co-transport into proximal tubule
along with glucose, amino acid or phosphate-against concentration
gradient
Along with the Cl- ionsmove paracellularly
65-70% of Na,Cl,H2O,Ca:
80-90%of bicarbonates,phosphates
100% of glucose,amino acids & low Mr
proteins
 Carbonic Anhydrase Inhibitors
Carbonic anhydrase enzyme is a zinc containing enzyme
catalysing the reversible hydration of CO2 & the dehydration
of carbonic acid
CO2 + H2O H2CO3 H+ +HCO3-
Inhibits intracellular CA es in H+ ions to
be exchanged for luminal Na+.So Na+ is not reabsorbed
Inhibition of CA on the brush border membrane of proximal
tubule cells

es production of CO2 within the luminal fluid the

. . ..es proximal tubule reabsorbtion of CO2

 CLASSES
Simple heterocyclic sulphonamides
ACETAZOLAMIDE
METHAZOLAMIDE
BENZOLAMIDE
ETHOXAZOLAMIDE

Meta bisulfamoyl benzene derivative

DICHLORPHENAMIDE
CHLORAMINOPHENAMIDE
 Simple Heterocyclic sulphonamides
Sulfamoyl nitrogen atom-
CA inhibition for in vivo &
invitro activities
Methylation of N in the
thiadiazole ring-more active R''RN S
SO 2NH2
The moiety to which
sulfamoyl group is attached
must posses aromatic N N
character
Highest lipid/water partition
coefficient & lowest pKa
values have the greast
activity.
 S S
NH SO 2NH2
NH SO 2NH2
H3C
H3C
+
N N
O N N
O
H3C
Acetazolamide
Methazolamide- 5-acetylamino-1,3,4-thiadiazole-2-
5-acetylamino-3-methyl-1,3,4-thiadiazol-2- sulfonamide
sulfonamidemethylation of N high lipid/water partition
in the thiadiazole ring co-efficient &low pKa value

H5 C2O S
S H5 C6 NH SO 2NH2
SO 2NH2 S
+
O O N N
N
H3C

Ethoxazolamide Benzolamide

Sulfamoyl group is attached must posses aromatic character

 Meta- bisulfamayl Benzene Derivative
The parent 1,3-
disulfamoylbenzen lacked
the activity
R2-the substituted with R2 R1
Cl,Br,CF3 NO 2
increases(F,NH2,CH3
H2NO2S SO 2NH2
OCH3)
At position R1 substitution
with NH2 increase the
salurectic activity,but
decrease the CA inhibitory
activity
 Cl Dichlorphenamide-
4,5-dichloro 1-3-benzene
Cl disulfonamide
Substitution at R2 position produce
maximal activity
H2NO 2S SO 2NH2

Cl NH2

Chloraminophenamide
- H2NO 2S SO2NH2
 Pharmacokinetics
Absorbed well from the gastrointestinal tract

Distributed to the sites of major importance for

CA inhibition

Metabolism by undergoing biotransformation

Excreted through the kidney

Adverse effects
Inhibit the luminal fluid exchange

Hyperkalemia

Mild metabolic acidosis

Gynecomastia

Menstrual distribution

USE
Edema fluid in congestive heart failure & liver
cirrhosis
Combined with hydrochlorothiazides
 Therapeutical applications
Treatment of glaucoma- CA is a functionally important .
. enzyme in the
formation of aqueous
humor

Prophylactically used to counteract acute mountain

sickness

As an adjuvants for the treatment of epilepsy-

rise the amount of cabondioxide in brain & lowering the
pH sedation

SITE-2:-The thick ascending limb of Henles loop
The tubular cells are impermiable to water
& posses a capacious luminal membrane
bound transport system.
Major driving force-interacellur deficit of
Na-K ATPase
The electroneutral Na/K/Cl cotransport
system located on the membrane of thick
ascending limb transport Na along with K
&Cl from the luminal fluid-1:1:2
Reabsorbtion of Na to the thick ascending
limb by actively
Cl ions enters the interstitium through Cl
channel in the antilumenal membrane & by
co transport with K+ ions
The luminal K+ions that accopanies
Na&Cl into the thick ascending limb cells
recycles passively downhill back inti the
luminal fluid
3Na+ & 6 Cl- ions generates the
lumen-+ve transepithelial voltage
20-25% Na
20-30% Ca
 Inhibits the 1Na/1K/2Cl co-
transport system located in
luminal membrane
The carboxylate moieties of
furosemide & bumetamide are
compete with Cl for the Cl-
bindig site on the 1Na/1K/2Cl co-
transport system.
Destroy the hypertonicity of the
medullary interstitium.
inhibits the Na reabsorbtion
The diuretics increase the total
renal blood flow by enhancing thr
intra renal release of vasodilatory
prostaglandins.
Decrease the lumen-positive
transepithelial voltage which
interferes the Ca transport
 Classification
Organomercurials
5-sulfamoyl-2-aminobenzoic Acid
Furosemide
Azosemide
5-sulfamoyl-3-aminobenzoic Acid
Bumetanide
Piretanide
4-amino-3-pyridinesulfonylureas
Torsemide
Triflocin
Phenoxyacetic Acids
Ethacrynic Acid
Miscellaneous site 2 diuretics
Etozoline,MK-447,CRE 10904
 Substitusion at position 1 must
be acidic(carboxyl gps max
activity)
X NH
5 position always bear the R
sulfomyl gps
4 th position substitution H2NO2S COOH

with Cl /CF3
R-must be 5- Sulfamoyl-2-aminobenzoic Acid`
Furfuryl > benzyl > thienylmethyl
 X NH
R

H2NO2S COOH

Cl NH CH2 Cl NH CH2
O O

N
H2NO2S
H2NO2S COOH N
NH N
Furosemide Azosemide
 Substitusion at position
1 must be R

acidic(carboxyl gps . .
N
max activity)
X
5 position always bear
the sulfomyl gps
4 th position H2NO 2S
COOH

substitution with Cl
5- Sulfamoyl-2-aminobenzoic Acid`
/CF3
R-must be
a wide variety of alkyl
group
 R
. .
N
X

COOH
H2NO 2S

CH2-CH2-CH2-CH3
HN
N

O O

H2NO2S H2NO 2S COOH

COOH
Piretanide
Bumetanide
 Pharmacokinetics
Bumetanide is more potent than furosemide
Bumetanide produces equieffective diuresis in about 1/4 th dose
Bioavailability of furosemide 60-69%
Bioavailability of bumetanide 80-90%
Both having rapid onset of action( 3-5 min) after parentral adm
Duration of action(parentral adm) furosemide -2hrs
bumetanide -3.5-4hrs
Oral adm :-30-60min furosemide -6-8hrs
bumetanide -4-6hrs
Extensive plasma protein binding for both
Furosemide 88% excreted by kidney
smal % by glucuronide conjugation
Bumetanide undergo extensive biotransformation -- 81% in urine
45% as unchanged drug
 4-AMINO-3-PYRIDINE SULFONYL UREAS

CH3
Torsemide:-
1-isopropyl-3-(4-(3-methyl phenyl amino)
NH
pyridine)-3 sulfonyl)urea
N C CH3
SO 2 NH NH HC

O CH3

CH3

NH
Triflocin
N
COOH
 PHARMACOKINETICS
TORSEMIDE-quick absorption & 80% bioavailability after
oral adm
98-99%plasma protein binding
t1/2 =3-4hrs
Peak serum conc. Attained with in 1hrs
Metabolism by hepatic Cy P450 system by oxidation of
aromatic methyl group to hydroxy & carboxyl derivative &
para hydroxylation of methyl phenyl amino moiety
ADR
Fatigue , dizziness ,muscles cramps
Nausea , orthostatic hypotension
Ototoxicity
USE
Mild & moderate hypertension
 Cl
Cl
Ethacrynic acid
O 2,3-dichloro-4-(2-
methylene-
C OCH2COOH1-oxobutyl)phenoxy
H5C 2
Acetic acid
SAR

H 2C

Oxyacetic acid gp on the 1st positionof the benzene

A sulfhydryl reactive acryloyl moeity is located para to the
oxyacetic acid gp
Activating (gp:Cl/CH3) occupy either the 3 position or 2 or 3
position
Alkyl substituents of 2-4 C atoms in length occupy the position
to the carbonyl on the acryloyl moeity
H atom occupy the terminal position of the C=C of the
acryloyl moeity
 PHARMACOKINETICS OF ETHACRYNIC ACID
Excellent oral absorption
Rapid onset of action for both oral( 2-3hrs) & I V(3-5hrs)
>95% of plasma protein binding
Metabolism to its cysteine adduct after oral administration has
much greater activity than parent compound.
Ethacrynic acid alkylated the thio gp of glutathione & the
resulting conjugate is converted to the ethacrynic acid-cysteine
&ethacrynic acid-N-acetyl cysteine conjugates
Excreated by kidney in the form of cysteine adduct, small
amount through bile.
ADR-Ototoxicity, GI haemorrhage.
 Indacrinon O
e
Cl

HOOC O

Is a derivative of ethacrynic acid

Both enantiomers have uricosuric activity
(-) enantiomer is more potent diuretic
 CH2 CH2 O F
CH2 CH2 O F

OH CRE10904 O
SO3-

These compounds undergo bioconversion to a sulphated active

metabolite
Secreted by OATS in proximal tubular & hence attains high
levels in luminal fluid
Highly vely charged sulfate moiety binds to Cl- binding site on
luminal membrane- bound 1Na/K/Cl co transport system of thick
ascending limb & macula densa
H3C MK- H3C
447
H3C C CH2 NH2 H3C C CH2 NH2

H3C H3C
OH O SO 3-
I
I
 Etozoline Ozolinone

N
H N
O H
O
S
N S
N
H3C C
H3C C
C O CH2CH3
C O-
H
H
O
O

Etozoline undergo hydrolyzed to ozolinone, which acts the

transport process in the cells of the thick ascending limb, of
Henles loop. Ozolinone secreted actively into proximal
tubule luminal fluid by the OATS
The high conc. Of ozolinone delivered to thick ascending limb
& inhibit the luminal membrane-bound1Na/1K/2Cl- co
transport system
Adverse effects
Hypokalemic alkalosis

Short term- tubuloglomerular feedback mechanism

long term-reduce the plasma volume

Gout- bcoz diuretic induce plasma volume reduction

leads to increased reabsorbtion of solutes by proximal

tubule( uric acid)
Hypersensitivity reaction urticaria , drug fever ,

intertitial nephritis
USE
Pulmonary edema associated with heart failure

Edema by cirrhosis of liver , nephrotic syndromes

 SITE-3:-The distal convoluted tubule
5-8%of Na
Water impermiable
MAJOR DRIVING FORCE
The luminal membrane
bound Na/Cl- co transport
Na down hills
Cl up hills
Reaction completed when
the anti luminal membrane-
bound Na+,K+ATPase
actively pumps into the
interstitium
 THIAZIDE DIURETICS
CLASSES
1. Thaiazides/Benzothiadiazines
2. Hydrothiazides
3. Thiazide like diuretics
1. Substituted m-disulfamoyl benzene
2. Salicylanilide
3. Benzhydrazides
4. Tetrahydroquinazolinones
5. 1-oxoisoindolines
6. Phthalimidines
 THIAZIDE DIURETICS
Weakly acidic
2nd position small alkyl gps (CH3),es
polarity
3rd position-determine the potency & R1 N R2
duration of action
(lipophilic gps -es diuretic ) eg:- NH
haloalkyl,arylalkyl or thioether gps H2NO2S S
benzothiazide.>>chlorthiazide
O O
Saturation of C=N b/w 3&4 es the
potency 3-10 times
Substitution at 4,5,8 with alkyl es Benzothiadiazine-1,
6th position with activating gp es 1-dioxide nucleus
7th position with sulfamoyl-diuretic
 Cl N
Chlorthiazide
NH
H2NO 2S S

O O

Benzthiazide
Cl N CH2SCH2

NH
H2NO2S S

O O
 HYDROTHIAZIDES
Saturation of C=N-es the

potency
H H
6th position with Cl, Br or R1 N
R2
CF3-es with H or NH2
N
,weakly active H2NO 2S S R3
3rd position with alkyl,
O O
cycloalkyl, haloalkyl -- es
action (hydrophobic)

7th position with sulfamoyl

gives diuretic action
 H Cyclopenthiazide
Cl N
CH2 C5H9

N
H2NO 2S S R3

O O

CH3
H
Cl N
CH2 HC

N CH3
Buthiazide H2NO 2S S R3

O O
 THIAZIDE LIKE DIURETICS
Cl Mefruside-substitution
m- disulfamoyl benzene
NH
O
H2NO 2S S CH3

O O

Cl OH
CH3

NH
Xipamide -salicylanilide H2NO2S C

O
H3C
 Cl
CH3

NH Clopamide-Benhydrazides
H2NO 2S C N

O
H3C

Cl

H3C

NH
Indapamide H2NO2S C N

O
 SITE-4:-The connecting tubule 2-3%Na,H+
The nephron in the connecting tubules composed of 2
distinct cell type
Principal cells Na reabsorption & K+ secreation

Intercalate cells H +generation & secreation

CA catalyses the
formation of
carbonic acid
The carbonic acid ionizes to H+ & bicarbonate
The H+ ions can be pumped actively into the luminal
fluid by the luminal membrane bound H+ -ATPase`
 The driving force
PC the deficit of
intracellular Na+ created by
the Na+-K+ATPase

3Na PC IN

2K+ IN PC
Creates lumen negative
transepithelial voltage
Cl moves paracellularly
K+-potassium channels

H+ -H+ATPase
 Mineralocorticoids Na reabsorbed
K+ & H+ excreated

Luminal fluid flow rate & % of the filtered load of Na present

to the exchange site the greater the flow rate & the load of Na
the greater the amount of exchange

Acid Base states of the indivitual

acidosis favours exchange of Na & H ion
alkalosis favours exchange of Na & K ion
 O

Spironolacton -Aldosterone antagonist O

Steroidal group
H3C
7-acetylothio-17 hydroxy-3-
H3C
oxopregn-
4-ene-21-carboxilyic acid--lactones H
H

Pharmacokinetics O
S C CH3
Well oral absorption- bioavailability >90%
O
Biotransformation by liver ~80% -Canrenone

Site of action
Inhibition of aldosterone

Action is slow-12-72hrs(last for 2 or 3 days)

 FATE OF SPIRONOLACTONE

O
O

O
H3C

H3C metabolit H3C

e H3C
H H

H H
O
S C CH3
O
O Canrenone
Spironolacton
e
 Triamterene 2,4,7-Triamino-6-arylpteridines

2,4,7-TRIAMINO-6-PHENYLPTERIDINE H 2N

SAR N
N

Pteridine analogues
N N
H N 2 NH2
Structural similarities to

folic acid & dihydrofolate reductase

 A-gastrointestinal tract
D-bound to plasma protein

M-under biotransformation in liver

E- biliary route & renal route

Site of action
Plugs the Na+ channels in luminal membrane

of principal cells
Adverse effects
Hyperkalemia

Kidney stone.
Amiloride. HCl Pyrazinoylguanidines

3,5-diamino-N-
+
(aminoiminomethyl)- O -ClH 2N
6-chloropyrazinecarboxamide Cl NH
N C C NH2
monohydrochloride dehydrate

H2N N NH2

SAR
6 position-with Cl optimal activity
Amino gps in 3 &5 are unsubstituted
The guanidino nitrogen are not multiply substituted
with alkyl gps
 Pharmacokinetics
Absorbed incompletely & erracticaly
Passive diffusion of uncharged drugs
Contains the stronger basic guanidine moiety,pKa

value-8.7
Bound with the plasma proteins no biotransformation

Action with in 2hrs,last for 24hrs

SITE OF ACTION
Inhibits the electrogenic entry of filtered load of Na

into the principal cells of CT & Cortical collecting

tubule by plugging the Na channel in the luminal
membrane
USE
Mild edema associated with congestive heart

failure, cirrhosis of the liver

Combination with other diuretics
New drug
O

A specific aldrosterone antagonist O

CH3

H3C O

O
C O CH3

Eplerenone
 XANTHINE DIURETICS
Theophylline is a weak diuresis
by stimulation of cardiac function O
& by direct action on the nephron H3C
N
N
Adenosine receptor
antagonism( adenosin produces O +
N N
antidiuretics & antinatriuretic H
respons ) H3C

Renal action of adenosine is due

to the stimulation of adenosine
A1 receptor
A1 receptor antagonists 8-(dicyclopropyl
methyl)
O
-1,3-dipropylxanthine
H3C H
N
N

N
N
O

H3CH 2CH2C

H3CH2CH2C H
N
N

N
N
O
8-Cyclopentyl-
1-3-dipropyl xanthine H3CH2CH2C
 Osmotic Diuretics
Undergo passive filtration at glomerulus

Undergo limited reabsorbtion in the renal

tubules

Metabolically & pharmacologically inert

This agents hinders salt & water reabsorbtion

from the proximal tubules
 Mannitol
Non electrolyte of low molecular weight CH2OH

Rise osmolarity of plasma & HO .

tubular fluid
HO .
Freely filtered through the
. OH
glomerulus & undergo limited reabsorbtion
. OH
Expands extracellular fluid

volumeincrease g.f.r & inhibits renin release CH2OH

Increases renal blood flow, specially to the medulla

medullary hypertonicity is reducedcorticomedullary osmotic

gradient is dissipatedpassive salt reabsorption is reduced
Retains water isoosmotically in PTdilutes luminal fluid

which opposes NaCl reabsorption

Inhibits transport prosses in the thick AscLH by an unknown

mechanism
 USE
In prophylaxis of acute renal failure---500-1000ml
To low intraocular pressure in ophthalmologic procedures
(increase intra cranial or intraocular tensionacute congestive
glaucoma ,head injury , stroke etc.)---1-1.5g/kg
To counteract low osmolarity of plasma/e.c.f due to rapid
haemodialysis or peritoneal dialysis
Eg:- isosorbide}
glycerol} 1.5g/kg as oral solution
 Adverse Side Effects and Contraindications
Class Adverse Side Drug Interactions
Effects
Thiazide hypokalemia
metabolic alkalosis
hypokalemia potentiates
digitalis toxicity
dehydration (hypovolemia), non-steroidal anti-
leading to hypotension inflammatory drugs:
hyponatremia
reduced diuretic efficacy
hyperglycemia in diabetics
beta-blockers: potentiate
hypercholesterolemia;
hyperglycemia,
hypertriglyceridemia hyperlipidemias
increased low-density
corticosteroids: enhance
lipoproteins
hyperuricemia (at low doses) hypokalemia
azotemia (in renal disease

patients)
Loop hypokalemia
metabolic alkalosis
hypokalemia potentiates
digitalis toxicity
hypomagnesemia non-steroidal anti-

hyperuricemia
inflammatory drugs:
reduced diuretic efficacy
dehydration
corticosteroids: enhance
(hypovolemia), leading to
hypotension hypokalemia
aminoglycosides: enhance
dose-related hearing loss

(ototoxicity) ototoxicity, nephrotoxicity

K+-sparing hyperkalemia
metabolic acidosis
ACE inhibitors: potentiate

hyperkalemia
gynecomastia (aldosterone non-steroidal anti-

antagonists) inflammatory drugs:

reduced diuretic efficacy
gastric problems including

peptic ulcer

Carbonic Hypokalemia
metabolic acidosis
anhydrase
inhibitors
 ANP Clearance Receptor Blocker & Neutral
Endopeptidase Inhibitors
ANP
Atrial Natriuretic Peptides is a 28-amino acid peptides that
released into circulation from the heart aterial distensions

ANP exerts natriuretic , diuretic , vasorelaxant & suppresses

renin & aldosterone levels

ANP increases the GFR significantly by vasodialation of

afferent arterioles & vasoconstriction of efferent vessels

ANP also inhibits Na reabsorption in collecting tubules

ANP is eliminated from circulation by enzymatic degradation
 NEPNeutral Endo Peptidase
NEP is a zinc-metallopeptidase that
cleaves -amino bond of
hydrophobic amino acidsis a
major degradative enzyme
ANP Clearance Receptor Blockers

SC46542is a biologically inactive
analogue of ANP that has similar
affinity for c-receptor as ANP, thus HS NH COOH
prolong the t1/2 of the ANP.
Both R & S enantiomers of O
thiorphan have same enzyme Thiorphan
inhibitory potency
 Why thiazide diuretics are used for diabetes
insipidus?
They reduce urine volume
Thiazide diuretics alone or -blockers impair glucose
metabolisms in hypertensive patients with abdominal
obesity.
The metabolic analogue of thiazide act on the
pituitaryADH releases--anti diuretic effect
Increase the cell permiability of the collecting duct
& reabsorbtion of water
A synthetic analogue-(immuno cyto chemical
charaterization) 1-3-mercaptopropionic acid)-8-D-
arginin vasopressin monoacetate trihydrate acts the
pituitary gland--ADH
DIURETIC SITE OF ACTION
 CONCLUSION
In medicine, diuretics are used to treat heart failure, liver cirrhosis,
hypertension and certain kidney diseases. Some diuretics, such as
acetazolamide, help to make the urine more alkaline and are helpful
in increasing excretion of substances such as aspirin in cases of
overdose or poisoning. Diuretics are often abused by sufferers of
eating disorders, especially bulimics, in attempts at weight loss.
The antihypertensive actions of some diuretics (thiazides and loop
diuretics in particular) are independent of their diuretic effect. That
is, the reduction in blood pressure is not due to decreased blood
volume resulting from increased urine production, but occurs
through other mechanisms and at lower doses than that required to
produce diuresis. Indapamide was specifically designed with this in
mind, and has a larger therapeutic window for hypertension
(without pronounced diuresis) than most other diuretics.
 References
Burgers Medicinal chemistry-6th edition volume-3 pg
no:55-142
Text Book of Organic Medicinal & Pharmaceutical
Chemistry(Wilson & Gisvolds)-10th edition pg
no:553-579
Foyes principles of medicinal chemistry pg no:
Essentials of medical pharmacology5th
edition-KD Tripathi pg no:525-542
Sites:-Medicap,wikepedia,Science direct.com