Diuretics

DIURETICSDIURETICS

Diuretics are Diuretics are the hetero the hetero cyclic cyclic

chemical chemical therapeutic therapeutic agents which agents which promotes the promotes the excretion of excretion of sodium sodium & & water by water by action on action on

the four the four major major anatomical anatomical sites,results sites,results the increases the increases the rate of the rate of urine urine formation formation

. .

Diuretics are the hetero cyclic Diuretics are the hetero cyclic chemical therapeutic agents which chemical therapeutic agents which

promotes the excretion of sodium promotes the excretion of sodium & water & water by action on by action on

the four major anatomical sites,results the four major anatomical sites,results the increases the rate of urine formation the increases the rate of urine formation

. .

History of DiureticsHistory of Diuretics Greek wordGreek word

““flow of a drop…….”flow of a drop…….”

Medicinal use starts from 400BC-metalic Medicinal use starts from 400BC-metalic mercurymercury

1949-Sulfanilamide(diuretics 1949-Sulfanilamide(diuretics & natriuretics)& natriuretics)

1950s -the new hetero compounds1950s -the new hetero compounds

ClassificationClassification SITE-1SITE-1 Carbonic anhydrous inhibitorsCarbonic anhydrous inhibitors SITE-2SITE-2 Loop or high ceeling DiureticsLoop or high ceeling Diuretics SITE-3SITE-3 Thiazide or thiazide like diureticsThiazide or thiazide like diuretics SITE-4SITE-4 Potassium sparing diureticsPotassium sparing diuretics Xanthine diureticsXanthine diuretics Osmotic diureticsOsmotic diuretics MiscellaneousMiscellaneous

Site of Action of 6 group of DiureticsSite of Action of 6 group of Diuretics

Renal Physiology Renal Physiology & Pharmacology& Pharmacology Kidneys-the prim organKidneys-the prim organ for excretion for excretion & maintain & maintain the homeostasisthe homeostasis Remove water, electrolytes,Remove water, electrolytes, products of metabolic waste products of metabolic waste & other materials form blood& other materials form blood Possess endocrine functions,Possess endocrine functions, i.e.-secrete erythropoietin i.e.-secrete erythropoietin rennin & 1,2,5-hydroxy rennin & 1,2,5-hydroxy cholecalciferolcholecalciferol Selective reabsorb water,Selective reabsorb water,electrolytes & needed electrolytes & needed nutrients from the urine.nutrients from the urine.

The reddish brown organ weighed-300gmsLocation-Either side of the vertebral column

Kidney embedded in perirenal fat & fibrous capsule

Nephrons-Nephrons-the working unit of kidneythe working unit of kidney

with each kidney with each kidney

containingcontaining

1.2millon nephrons1.2millon nephrons

Two typesTwo types

Cortical nephrons-(80%-short)Cortical nephrons-(80%-short)

Juxtamedullary nephrons-(long)Juxtamedullary nephrons-(long) Glomerular filtration pressure-50mmof HgGlomerular filtration pressure-50mmof Hg

intertitial nephritis intertitial nephritis

About About 650ml650ml of of

plasma flow through plasma flow through

the kidneys each minutethe kidneys each minute ApproximatelyApproximately

125ml/min125ml/min of which of which

are filter through the are filter through the

glomerular capillaries glomerular capillaries The remaining four-fifths(80%) of the renal plasma The remaining four-fifths(80%) of the renal plasma

flow is directed into the peritubular capillariesflow is directed into the peritubular capillaries Each minuteEach minute

125ml125mlof of 1 ml1 ml of of

glomerular filtrate urineglomerular filtrate urine

Fate of Luminal FluidFate 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 processThe reabsorption of the Na takes place y 3 distinct process The counter transport by the action of interacellular CA are exchanged by The counter transport by the action of interacellular CA are exchanged by

the Na+-K+ ATPase in antiluminal membranethe Na+-K+ ATPase in antiluminal membrane Na+ H+ Na+ H+ H+ + HCO3 H+ + HCO3 → → H2CO3 CO2 + H2OH2CO3 CO2 + H2O

go to PTgo to PT

Na moves out of the luminal fluid by the co-transport into proximal tubule Na moves out of the luminal fluid by the co-transport into proximal tubule along with glucose, amino acid or phosphate-against concentration along with glucose, amino acid or phosphate-against concentration gradientgradient

Along with the Cl- ions—move paracellularly Along with the Cl- ions—move paracellularly 65-70% of Na,Cl,H2O,Ca:80-90%of bicarbonates,phosphates100% of glucose,amino acids & low Mr proteins

Carbonic Anhydrase InhibitorsCarbonic Anhydrase Inhibitors Carbonic anhydrase enzyme is a zinc containing enzyme Carbonic anhydrase enzyme is a zinc containing enzyme

catalysing the reversible hydration of COcatalysing the reversible hydration of CO2 & the dehydration & the dehydration

of carbonic acidof carbonic acid COCO2 + H + H2O HO H2CO3 HCO3 H+ +HCO+HCO3

-

Inhibits intracellular CA Inhibits intracellular CA eses in H in H+ ions to ions to be exchanged for luminal Nabe exchanged for luminal Na+.So Na.So Na+ is not reabsorbed is not reabsorbed

Inhibition of CA on the brush border membrane of proximal Inhibition of CA on the brush border membrane of proximal tubule cells tubule cells

es production of CO production of CO2 within the luminal fluid the within the luminal fluid the

. . . . ..es proximal tubule reabsorbtion of CO proximal tubule reabsorbtion of CO2

CLASSESCLASSES

Simple heterocyclic sulphonamidesSimple heterocyclic sulphonamides ACETAZOLAMIDEACETAZOLAMIDE

METHAZOLAMIDEMETHAZOLAMIDE

BENZOLAMIDEBENZOLAMIDE

ETHOXAZOLAMIDEETHOXAZOLAMIDE

Meta bisulfamoyl benzene derivative DICHLORPHENAMIDE

CHLORAMINOPHENAMIDE

Simple Heterocyclic sulphonamidesSimple Heterocyclic sulphonamides

Sulfamoyl nitrogen atom-Sulfamoyl nitrogen atom-CA inhibition for in vivo & CA inhibition for in vivo & invitro activitiesinvitro activities

Methylation of N in the Methylation of N in the thiadiazole ring-more activethiadiazole ring-more active

The moiety to which The moiety to which sulfamoyl group is attached sulfamoyl group is attached must posses aromatic must posses aromatic charactercharacter

Highest lipid/water partition Highest lipid/water partition coefficient & lowest pKa coefficient & lowest pKa values have the greast values have the greast activity.activity.

S

NN

SO2NH2R''RN

S

NN

SO2NH2NH

O

CH3

S

NN+

SO2NH2NH

O

CH3

CH3

S

NN+

SO2NH2NH

S

O

H5C6

CH3

O

S

N

SO2NH2

H5C2O

Acetazolamide –5-acetylamino-1,3,4-thiadiazole-2-

sulfonamidehigh lipid/water partition

co-efficient &low pKa value

BenzolamideEthoxazolamide

Methazolamide-5-acetylamino-3-methyl-1,3,4-thiadiazol-2-

sulfonamidemethylation of N in the thiadiazole ring

Sulfamoyl group is attached must posses aromatic character

Meta- bisulfamayl Benzene DerivativeMeta- bisulfamayl Benzene Derivative The parent 1,3-The parent 1,3-

disulfamoylbenzen lacked disulfamoylbenzen lacked the activitythe activity

RR2-the substituted with -the substituted with

Cl,Br,CFCl,Br,CF3 NONO 2

increases(F,NHincreases(F,NH22,CH3 3

OCH3)) At position R1 substitution At position R1 substitution

with NH2 increase the with NH2 increase the salurectic activity,but salurectic activity,but decrease the CA inhibitory decrease the CA inhibitory activityactivity

R1R2

H2NO2S SO2NH2

NH2Cl

H2NO2S SO2NH2

Cl

H2NO2S SO2NH2

Cl

Chloraminophenamide-

Dichlorphenamide-4,5-dichloro 1-3-benzene disulfonamideSubstitution at R2 position produce maximal activity

PharmacokineticsPharmacokinetics AAbsorbed well from the gastrointestinal tractbsorbed well from the gastrointestinal tract

DDistributed to the sites of major importance for istributed to the sites of major importance for

CA inhibitionCA inhibition

MMetabolism by undergoing biotransformationetabolism by undergoing biotransformation

EExcretedxcreted through the kidney through the kidney

Adverse effectsAdverse effects Inhibit the luminal fluid exchangeInhibit the luminal fluid exchange HyperkalemiaHyperkalemia Mild metabolic acidosisMild metabolic acidosis GynecomastiaGynecomastia Menstrual distributionMenstrual distributionUSEUSE Edema fluid in congestive heart failure & liver Edema fluid in congestive heart failure & liver

cirrhosiscirrhosis Combined with hydrochlorothiazidesCombined with hydrochlorothiazides

Therapeutical applicationsTherapeutical applications Treatment of glaucoma-Treatment of glaucoma- CA is a functionally important . CA is a functionally important .

. enzyme in the . enzyme in the formation of … aqueous formation of … aqueous humor humor

Prophylactically used to counteract acute mountain Prophylactically used to counteract acute mountain sicknesssickness

As an adjuvants for the treatment of epilepsyAs an adjuvants for the treatment of epilepsy--

rise the amount of cabondioxide in brain & lowering the rise the amount of cabondioxide in brain & lowering the pH sedationpH sedation

SITE-2:-The thick ascending limb of Henle’s loop The tubular cells are impermiable to water The tubular cells are impermiable to water

& posses a capacious luminal membrane & posses a capacious luminal membrane bound transport system.bound transport system.

Major driving force-interacellur deficit of Major driving force-interacellur deficit of Na-K ATPaseNa-K ATPase

The electroneutral Na/K/Cl cotransport The electroneutral Na/K/Cl cotransport system located on the membrane of thick system located on the membrane of thick ascending limb transport Na along with K ascending limb transport Na along with K &Cl from the luminal fluid-1:1:2&Cl from the luminal fluid-1:1:2

Reabsorbtion of Na to the thick ascending Reabsorbtion of Na to the thick ascending limb by activelylimb by actively

Cl ions enters the interstitium through Cl Cl ions enters the interstitium through Cl channel in the antilumenal membrane & channel in the antilumenal membrane & by co transport with K+ ions by co transport with K+ ions

The luminal K+ions that accopanies The luminal K+ions that accopanies Na&Cl into the thick ascending limb cells Na&Cl into the thick ascending limb cells recycles passively downhill back inti the recycles passively downhill back inti the luminal fluidluminal fluid

3Na+ & 6 Cl- ions generates the 3Na+ & 6 Cl- ions generates the lumen-+ve transepithelial voltagelumen-+ve transepithelial voltage

20-25% Na20-25% Na 20-30% Ca 20-30% Ca

Inhibits the 1Na/1K/2Cl co-Inhibits the 1Na/1K/2Cl co-transport system located in transport system located in luminal membraneluminal membrane

The carboxylate moieties of The carboxylate moieties of furosemide & bumetamide are furosemide & bumetamide are compete with Cl for the Cl- compete with Cl for the Cl- bindig site on the 1Na/1K/2Cl co-bindig site on the 1Na/1K/2Cl co-transport system.transport system.

Destroy the hypertonicity of the Destroy the hypertonicity of the medullary interstitium.medullary interstitium.

inhibits the Na reabsorbtioninhibits the Na reabsorbtion The diuretics increase the total The diuretics increase the total

renal blood flow by enhancing thr renal blood flow by enhancing thr intra renal release of vasodilatory intra renal release of vasodilatory prostaglandins.prostaglandins.

Decrease the lumen-positive Decrease the lumen-positive transepithelial voltage which transepithelial voltage which interferes the Ca transportinterferes the Ca transport

Classification Classification OrganomercurialsOrganomercurials 5-sulfamoyl-2-aminobenzoic Acid5-sulfamoyl-2-aminobenzoic Acid FurosemideFurosemide

AzosemideAzosemide 5-sulfamoyl-3-aminobenzoic Acid5-sulfamoyl-3-aminobenzoic Acid BumetanideBumetanide PiretanidePiretanide 4-amino-3-pyridinesulfonylureas4-amino-3-pyridinesulfonylureas TorsemideTorsemide TriflocinTriflocin Phenoxyacetic AcidsPhenoxyacetic Acids Ethacrynic AcidEthacrynic Acid Miscellaneous site 2 diureticsMiscellaneous site 2 diuretics Etozoline,MK-447,CRE 10904Etozoline,MK-447,CRE 10904

Substitusion at position 1 must Substitusion at position 1 must be acidic(carboxyl gps –max be acidic(carboxyl gps –max activity)activity)

5 position always bear the 5 position always bear the sulfomyl gpssulfomyl gps

4 th position – substitution 4 th position – substitution with Cl /CF3with Cl /CF3

R-must be R-must be

Furfuryl > benzyl > thienylmethylFurfuryl > benzyl > thienylmethyl

X NH

COOHH2NO2S

R

5- Sulfamoyl-2-aminobenzoic Acid`5- Sulfamoyl-2-aminobenzoic Acid`

X NH

COOHH2NO2S

R

Cl NH

COOHH2NO2S

CH2O

Cl NH

H2NO2S

CH2O

N

N

N

NH

FurosemideFurosemide AzosemideAzosemide

Substitusion at position Substitusion at position 1 must be 1 must be acidic(carboxyl gps –acidic(carboxyl gps –max activity)max activity)

5 position always bear 5 position always bear the sulfomyl gpsthe sulfomyl gps

4 th position – 4 th position – substitution with Cl substitution with Cl /CF3/CF3

R-must be R-must be a wide variety of alkyl a wide variety of alkyl

groupgroup

COOHH2NO2S

X

N. .

R

5- Sulfamoyl-2-aminobenzoic Acid`5- Sulfamoyl-2-aminobenzoic Acid`

NH

O

H2NO2S COOH

CH2-CH2-CH2-CH3

N

O

H2NO2S COOH

COOHH2NO2S

X

N. .

R

BumetanideBumetanidePiretanidePiretanide

PharmacokineticsPharmacokinetics Bumetanide is more potent than furosemide Bumetanide is more potent than furosemide Bumetanide produces equieffective diuresis in about 1/4Bumetanide produces equieffective diuresis in about 1/4 thth dose dose Bioavailability of furosemide 60-69%Bioavailability of furosemide 60-69% Bioavailability of bumetanide 80-90%Bioavailability of bumetanide 80-90% Both having rapid onset of action( 3-5 min) after parentral admBoth having rapid onset of action( 3-5 min) after parentral adm Duration of action(parentral adm) furosemide -2hrsDuration of action(parentral adm) furosemide -2hrs bumetanide -3.5-4hrsbumetanide -3.5-4hrs Oral adm :-30-60min furosemide -6-8hrsOral adm :-30-60min furosemide -6-8hrs bumetanide -4-6hrsbumetanide -4-6hrs Extensive plasma protein binding for bothExtensive plasma protein binding for both Furosemide 88% excreted by kidneyFurosemide 88% excreted by kidney smal % by glucuronide conjugationsmal % by glucuronide conjugation Bumetanide undergo extensive biotransformation --Bumetanide undergo extensive biotransformation --81% in urine81% in urine

45%45% as unchanged drugas unchanged drug

N

NH

SO2

CH3

NH C

O

NH HC

CH3

CH3

N

NH

COOH

CH3

Torsemide:-Torsemide:-1-isopropyl-3-(4-(3-methyl phenyl amino)1-isopropyl-3-(4-(3-methyl phenyl amino)pyridine)-3 sulfonyl)ureapyridine)-3 sulfonyl)urea

TriflocinTriflocin

4-AMINO-3-PYRIDINE SULFONYL UREAS4-AMINO-3-PYRIDINE SULFONYL UREAS

PHARMACOKINETICSPHARMACOKINETICS TORSEMIDETORSEMIDE-quick absorption & 80% bioavailability after -quick absorption & 80% bioavailability after

oral admoral adm 98-99%plasma protein binding98-99%plasma protein binding t1/2 =3-4hrst1/2 =3-4hrs Peak serum conc. Attained with in 1hrsPeak serum conc. Attained with in 1hrs Metabolism by hepatic Cy P450 system by oxidation of Metabolism by hepatic Cy P450 system by oxidation of

aromatic methyl group to hydroxy & carboxyl derivative & aromatic methyl group to hydroxy & carboxyl derivative & para hydroxylation of methyl phenyl amino moietypara hydroxylation of methyl phenyl amino moiety

ADRADR Fatigue , dizziness ,muscles crampsFatigue , dizziness ,muscles cramps Nausea , orthostatic hypotensionNausea , orthostatic hypotension OtotoxicityOtotoxicity USEUSE Mild & moderate hypertensionMild & moderate hypertension

ClCl

CH5C2

H2C

OCH2COOH

O

Ethacrynic acidEthacrynic acid2,3-dichloro-4-(2-2,3-dichloro-4-(2-methylene-methylene-1-oxobutyl)phenoxy 1-oxobutyl)phenoxy Acetic acidAcetic acid

Oxyacetic acid gp on the 1Oxyacetic acid gp on the 1stst positionof the benzene positionof the benzene A sulfhydryl reactive acryloyl moeity is located para to the A sulfhydryl reactive acryloyl moeity is located para to the

oxyacetic acid gpoxyacetic acid gp Activating (gp:Cl/CH3) occupy either the 3 position or 2 or 3 Activating (gp:Cl/CH3) occupy either the 3 position or 2 or 3

positionposition Alkyl substituents of 2-4 C atoms in length occupy the position Alkyl substituents of 2-4 C atoms in length occupy the position

άά to the carbonyl on the acryloyl moeity to the carbonyl on the acryloyl moeity H atom occupy the terminal position of the C=C of the H atom occupy the terminal position of the C=C of the

acryloylacryloyl moeitymoeity

SARSAR

PHARMACOKINETICS OF ETHACRYNIC ACIDPHARMACOKINETICS OF ETHACRYNIC ACID

Excellent oral absorptionExcellent oral absorption Rapid onset of action for both oral( 2-3hrs) & I V(3-5hrs)Rapid onset of action for both oral( 2-3hrs) & I V(3-5hrs) >95% of plasma protein binding>95% of plasma protein binding Metabolism to its cysteine adduct after oral administration has Metabolism to its cysteine adduct after oral administration has

much greater activity than parent compound.much greater activity than parent compound. Ethacrynic acid alkylated the thio gp of glutathione & the Ethacrynic acid alkylated the thio gp of glutathione & the

resulting conjugate is converted to the ethacrynic acid-cysteine resulting conjugate is converted to the ethacrynic acid-cysteine &ethacrynic acid-N-acetyl cysteine conjugates&ethacrynic acid-N-acetyl cysteine conjugates

Excreated by kidney in the form of cysteine adduct, small Excreated by kidney in the form of cysteine adduct, small amount through bile.amount through bile.

ADR-Ototoxicity, GI haemorrhage.ADR-Ototoxicity, GI haemorrhage.

O

Cl

OHOOC

IndacrinonIndacrinonee

Is a derivative of ethacrynic acidIs a derivative of ethacrynic acid Both enantiomers have uricosuric activityBoth enantiomers have uricosuric activity (-) enantiomer is more potent diuretic(-) enantiomer is more potent diuretic

OH

CH2 OCH2 F

O

CH2 OCH2 F

SO3-

C CH2

OH

I

NH2

CH3

CH3

CH3

C CH2

O

I

NH2

CH3

CH3

CH3

SO3-

CRE10904CRE10904

MK-MK-447447

These compounds undergo bioconversion to a sulphated active These compounds undergo bioconversion to a sulphated active metabolitemetabolite

Secreted by OATS in proximal tubular & hence attains high Secreted by OATS in proximal tubular & hence attains high levels in luminal fluidlevels in luminal fluid

Highly –vely charged sulfate moiety binds to Cl- binding site Highly –vely charged sulfate moiety binds to Cl- binding site on luminal membrane- bound 1Na/K/Cl co transport system of on luminal membrane- bound 1Na/K/Cl co transport system of thick ascending limb & macula densathick ascending limb & macula densa

Etozoline undergo hydrolyzed to ozolinone, which acts the Etozoline undergo hydrolyzed to ozolinone, which acts the transport process in the cells of the thick ascending limb, of transport process in the cells of the thick ascending limb, of Henle’s loop. Ozolinone secreted actively into proximal Henle’s loop. Ozolinone secreted actively into proximal tubule luminal fluid by the OATStubule luminal fluid by the OATS

The high conc. Of ozolinone delivered to thick ascending limb The high conc. Of ozolinone delivered to thick ascending limb & inhibit the luminal membrane-bound1Na/1K/2Cl- co & inhibit the luminal membrane-bound1Na/1K/2Cl- co transport systemtransport system

N

SN

O

CCH3

H

H

C

O

O CH2CH3

N

SN

O

CCH3

H

H

C

O

O-

EtozolineEtozoline OzolinoneOzolinone

Adverse effectsAdverse effects Hypokalemic alkalosisHypokalemic alkalosis Short term- tubuloglomerular feedback mechanismShort term- tubuloglomerular feedback mechanism long term-reduce the plasma volumelong term-reduce the plasma volume Gout- b’coz diuretic induce plasma volume reduction Gout- b’coz diuretic induce plasma volume reduction

leads to increased reabsorbtion of solutes by proximal leads to increased reabsorbtion of solutes by proximal tubule( uric acid) tubule( uric acid)

Hypersensitivity reaction – urticaria , drug fever , Hypersensitivity reaction – urticaria , drug fever , intertitial nephritis intertitial nephritis

USE USE Pulmonary edema associated with heart failurePulmonary edema associated with heart failure Edema by cirrhosis of liver , nephrotic syndromesEdema 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 DIURETICSTHIAZIDE DIURETICS

CLASSESCLASSES

1.1. Thaiazides/BenzothiadiazinesThaiazides/Benzothiadiazines

2.2. HydrothiazidesHydrothiazides

3.3. Thiazide like diureticsThiazide like diuretics1.1. Substituted m-disulfamoyl benzeneSubstituted m-disulfamoyl benzene

2.2. SalicylanilideSalicylanilide

3.3. BenzhydrazidesBenzhydrazides

4.4. TetrahydroquinazolinonesTetrahydroquinazolinones

5.5. 1-oxoisoindolines1-oxoisoindolines

6.6. PhthalimidinesPhthalimidines

THIAZIDE DIURETICSTHIAZIDE DIURETICS Weakly acidicWeakly acidic 22ndnd position –small alkyl gps (CH3), position –small alkyl gps (CH3),↓es ↓es

polaritypolarity 33rdrd position-determine the potency & position-determine the potency &

duration of actionduration of action (lipophilic gps -↑es diuretic ) eg:-(lipophilic gps -↑es diuretic ) eg:-

haloalkyl,arylalkyl or thioether gps haloalkyl,arylalkyl or thioether gps benzothiazide.>>chlorthiazidebenzothiazide.>>chlorthiazide

Saturation of C=N b/w 3&4 ↑es the Saturation of C=N b/w 3&4 ↑es the potency 3-10 timespotency 3-10 times

Substitution at 4,5,8 with alkyl ↓es Substitution at 4,5,8 with alkyl ↓es 66thth position with activating gp ↑es position with activating gp ↑es 77thth position with sulfamoyl-diuretic position with sulfamoyl-diuretic

NH

N

S

O O

H2NO2S

R1R2

Benzothiadiazine-1,Benzothiadiazine-1,1-dioxide nucleus1-dioxide nucleus

NH

N

S

O O

H2NO2S

Cl

NH

N

S

O O

H2NO2S

Cl CH2SCH2

ChlorthiazideChlorthiazide

BenzthiazideBenzthiazide

HYDROTHIAZIDESHYDROTHIAZIDES Saturation of C=N-Saturation of C=N-↑es the ↑es the

potencypotency 66thth position with Cl, Br or position with Cl, Br or

CF3-↑es with H or –CF3-↑es with H or –NH2 ,weakly active NH2 ,weakly active

33rdrd position with alkyl, position with alkyl, cycloalkyl, haloalkyl -- ↑es cycloalkyl, haloalkyl -- ↑es action (hydrophobic)action (hydrophobic)

77thth position with sulfamoyl position with sulfamoyl gives diuretic action gives diuretic action

N

NH

S

R1

H2NO2S

O O

H

R2

R3

N

NH

S

Cl

H2NO2S

O O

R3

CH2 HC

CH3

CH3

N

NH

S

Cl

H2NO2S

O O

R3

CH2 C5H9

ButhiazideButhiazide

CyclopenthiazideCyclopenthiazide

S

NHO

Cl

H2NO2S CH3

O O

C

NH

Cl

H2NO2S

O

CH3

CH3

OH

MefrusideMefruside-substitution -substitution m- disulfamoyl benzenem- disulfamoyl benzene

XipamideXipamide -salicylanilide -salicylanilide

THIAZIDE LIKE DIURETICSTHIAZIDE LIKE DIURETICS

C

NH

N

Cl

H2NO2S

O

CH3

CH3

C

NH

N

Cl

H2NO2S

O

CH3

IndapamideIndapamide

ClopamideClopamide-Benhydrazides-Benhydrazides

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 forceThe driving force PC –PC –the deficit of the deficit of

intracellular Na+ created by intracellular Na+ created by the Na+-K+ATPasethe Na+-K+ATPase

3Na PC3Na PC ININ

2K+ IN PC2K+ IN PC Creates lumen –Creates lumen –negative negative

transepithelial voltagetransepithelial voltage Cl moves paracellularlyCl moves paracellularly K+-potassium channelsK+-potassium channels

H+ -H+ATPaseH+ -H+ATPase

Mineralocorticoids Na reabsorbedMineralocorticoids Na reabsorbed K+ & H+ excreatedK+ & H+ excreated

Luminal fluid flow rate & % of the filtered load of Na present to 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 the exchange site the greater the flow rate & the load of Na the greater the amount of exchangegreater the amount of exchange

Acid –Base states of the indivitualAcid –Base states of the indivitualacidosis favours exchange of Na & H ionacidosis favours exchange of Na & H ionalkalosis favours exchange of Na & K ionalkalosis favours exchange of Na & K ion

7ά-acetylothio-17β hydroxy-3-oxopregn-4-ene-21-carboxilyic acid-γ-lactones

PharmacokineticsPharmacokinetics Well oral absorption- bioavailability >90%Well oral absorption- bioavailability >90% Biotransformation by liver ~80% -CanrenoneBiotransformation by liver ~80% -Canrenone

Site of actionSite of action Inhibition of aldosterone Inhibition of aldosterone Action is slow-12-72hrs(last for 2 or 3 days) Action is slow-12-72hrs(last for 2 or 3 days)

O

CH3

O

O

HH

S C CH3

O

CH3

Spironolacton -Aldosterone antagonist –Steroidal group

O

CH3

O

O

HH

S C CH3

O

CH3

OH2

O

CH3

O

O

HH

CH3

Spironolactone

Canrenone

metabolite

FATE OF SPIRONOLACTONE

N

N

N

NNH2H2N

H2N2,4,7-TRIAMINO-6-PHENYLPTERIDINE

2,4,7-Triamino-6-arylpteridinesTriamterene

SARSAR Pteridine analoguesPteridine analogues Structural similarities to Structural similarities to

folic acid & dihydrofolate reductasefolic acid & dihydrofolate reductase

AA-gastrointestinal tract-gastrointestinal tract DD-bound to plasma protein-bound to plasma protein M-M-under biotransformation in liverunder biotransformation in liver EE- biliary route & renal route- biliary route & renal route

Site of actionSite of action Plugs the Na+ channels in luminal membrane Plugs the Na+ channels in luminal membrane

of principal cellsof principal cells

Adverse effectsAdverse effects HyperkalemiaHyperkalemia Kidney stone.Kidney stone.

N

N NH2

Cl

H2N

C NH

O

C

-ClH2N+

NH2

Amiloride. HCl 3,5-diamino-N-

(aminoiminomethyl)-6-chloropyrazinecarboxamide monohydrochloride dehydrate

Pyrazinoylguanidines

SARSAR 6 position-with Cl optimal activity6 position-with Cl optimal activity Amino gps in 3 &5 are unsubstitutedAmino gps in 3 &5 are unsubstituted The guanidino nitrogen are not multiply substituted The guanidino nitrogen are not multiply substituted

with alkyl gpswith alkyl gps

PharmacokineticsPharmacokinetics

AAbsorbed incompletely & erracticalybsorbed incompletely & erracticaly Passive diffusion of uncharged drugsPassive diffusion of uncharged drugs Contains the stronger basic guanidine moiety,pKa Contains the stronger basic guanidine moiety,pKa

value-8.7value-8.7 Bound with the plasma proteins no biotransformationBound with the plasma proteins no biotransformation Action with in 2hrs,last for 24hrsAction with in 2hrs,last for 24hrs

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

into the principal cells of CT & Cortical collecting into the principal cells of CT & Cortical collecting tubule by plugging the Na channel in the luminal tubule by plugging the Na channel in the luminal membranemembrane

USEUSE Mild edema associated with congestive heart Mild edema associated with congestive heart

failure, cirrhosis of the liverfailure, cirrhosis of the liver Combination with other diureticsCombination with other diuretics

O

CH3

CH3

H

C O CH3

O

O

O

O

Eplerenone

New drug

A specific aldrosterone antagonist

XXANTHINE DIURETICS Theophylline is a weak diuresis Theophylline is a weak diuresis

by stimulation of cardiac function by stimulation of cardiac function & by direct action on the nephron& by direct action on the nephron

Adenosine receptor Adenosine receptor antagonism( adenosin produces antagonism( adenosin produces antidiuretics & antinatriuretic antidiuretics & antinatriuretic respons )respons )

Renal action of adenosine is due Renal action of adenosine is due to the stimulation of adenosine to the stimulation of adenosine A1 receptorA1 receptor

N+

NN

NH

CH3

O

CH3

O

N

NNH

O

CH3

O

H3CH2CH2C

N

N

NNH

O

H3CH2CH2C

O

H3CH2CH2C

N

8-Cyclopentyl-8-Cyclopentyl-1-3-dipropyl xanthine1-3-dipropyl xanthine

8-(dicyclopropyl 8-(dicyclopropyl methyl)methyl)-1,3-dipropylxanthine-1,3-dipropylxanthine

A1 receptor antagonistsA1 receptor antagonists

Osmotic DiureticsOsmotic Diuretics Undergo passive filtration at glomerulusUndergo passive filtration at glomerulus

Undergo limited reabsorbtion in the renal Undergo limited reabsorbtion in the renal tubulestubules

Metabolically & pharmacologically inertMetabolically & pharmacologically inert

This agents hinders salt & water reabsorbtion This agents hinders salt & water reabsorbtion from the proximal tubulesfrom the proximal tubules

MannitolMannitol Non electrolyte of low molecular weightNon electrolyte of low molecular weight Rise osmolarity of plasma &Rise osmolarity of plasma & tubular fluidtubular fluid Freely filtered through the Freely filtered through the glomerulus & undergo limited reabsorbtionglomerulus & undergo limited reabsorbtion Expands extracellular fluid Expands extracellular fluid volume—increase g.f.r & inhibits renin releasevolume—increase g.f.r & inhibits renin release Increases renal blood flow, specially to the medulla—Increases renal blood flow, specially to the medulla—

medullary hypertonicity is reduced—corticomedullary osmotic medullary hypertonicity is reduced—corticomedullary osmotic gradient is dissipated—passive salt reabsorption is reducedgradient is dissipated—passive salt reabsorption is reduced

Retains water isoosmotically in PT—dilutes luminal fluid Retains water isoosmotically in PT—dilutes luminal fluid which opposes NaCl reabsorptionwhich opposes NaCl reabsorption

Inhibits transport prosses in the thick AscLH by an unknown Inhibits transport prosses in the thick AscLH by an unknown mechanismmechanism

CH2OH

CH2OH

OH .

OH .

OH.

OH.

USEUSE In prophylaxis of acute renal failure---500-1000mlIn prophylaxis of acute renal failure---500-1000ml To low intraocular pressure in ophthalmologic proceduresTo low intraocular pressure in ophthalmologic procedures

(increase intra cranial or intraocular tension—acute congestive (increase intra cranial or intraocular tension—acute congestive glaucoma ,head injury , stroke etc.)---1-1.5g/kgglaucoma ,head injury , stroke etc.)---1-1.5g/kg

To counteract low osmolarity of plasma/e.c.f due to rapid To counteract low osmolarity of plasma/e.c.f due to rapid haemodialysis or peritoneal dialysishaemodialysis or peritoneal dialysis

Eg:- isosorbide}Eg:- isosorbide}

glycerol} 1.5g/kg as oral solutionglycerol} 1.5g/kg as oral solution

Class Class Adverse Side Adverse Side Effects Effects

Drug InteractionsDrug Interactions

Thiazide Thiazide hypokalemia hypokalemia metabolic alkalosis metabolic alkalosis dehydration (hypovolemia), dehydration (hypovolemia), leading to hypotension leading to hypotension hyponatremia hyponatremia hyperglycemia in diabetics hyperglycemia in diabetics hypercholesterolemia; hypercholesterolemia; hypertriglyceridemia hypertriglyceridemia increased low-density increased low-density lipoproteins lipoproteins hyperuricemia (at low doses) hyperuricemia (at low doses) azotemia (in renal disease azotemia (in renal disease

patients)patients)

hypokalemia potentiates hypokalemia potentiates digitalis toxicity digitalis toxicity non-steroidal anti-non-steroidal anti-inflammatory drugs: inflammatory drugs: reduced diuretic efficacy reduced diuretic efficacy beta-blockers: potentiate beta-blockers: potentiate hyperglycemia, hyperglycemia, hyperlipidemias hyperlipidemias corticosteroids: enhance corticosteroids: enhance

hypokalemiahypokalemia

Adverse Side Effects and ContraindicationsAdverse Side Effects and Contraindications

Loop Loop hypokalemia hypokalemia metabolic alkalosis metabolic alkalosis hypomagnesemia hypomagnesemia hyperuricemia hyperuricemia dehydration dehydration (hypovolemia), leading to (hypovolemia), leading to hypotension hypotension dose-related hearing loss dose-related hearing loss (ototoxicity) (ototoxicity)

hypokalemia potentiates hypokalemia potentiates digitalis toxicity digitalis toxicity non-steroidal anti-non-steroidal anti-inflammatory drugs: inflammatory drugs: reduced diuretic efficacy reduced diuretic efficacy corticosteroids: enhance corticosteroids: enhance hypokalemia hypokalemia aminoglycosides: enhance aminoglycosides: enhance

ototoxicity, nephrotoxicityototoxicity, nephrotoxicity

K+-sparing K+-sparing hyperkalemia hyperkalemia metabolic acidosis metabolic acidosis gynecomastia (aldosterone gynecomastia (aldosterone antagonists) antagonists) gastric problems including gastric problems including

peptic ulcerpeptic ulcer

ACE inhibitors: potentiate ACE inhibitors: potentiate hyperkalemia hyperkalemia non-steroidal anti-non-steroidal anti-inflammatory drugs: inflammatory drugs: reduced diuretic efficacy reduced diuretic efficacy

Carbonic Carbonic anhydrase anhydrase inhibitors inhibitors

HypokalemiaHypokalemia metabolic acidosismetabolic acidosis

ANP Clearance Receptor Blocker & Neutral ANP Clearance Receptor Blocker & Neutral Endopeptidase InhibitorsEndopeptidase Inhibitors

ANPANP Atrial Natriuretic Peptides is a 28-amino acid peptides that Atrial Natriuretic Peptides is a 28-amino acid peptides that

released into circulation from the heart aterial distensionsreleased into circulation from the heart aterial distensions

ANP exerts natriuretic , diuretic , vasorelaxant & suppresses ANP exerts natriuretic , diuretic , vasorelaxant & suppresses renin & aldosterone levelsrenin & aldosterone levels

ANP increases the GFR significantly by vasodialation of ANP increases the GFR significantly by vasodialation of afferent arterioles & vasoconstriction of efferent vesselsafferent arterioles & vasoconstriction of efferent vessels

ANP also inhibits Na reabsorption in collecting tubulesANP also inhibits Na reabsorption in collecting tubules ANP is eliminated from circulation by enzymatic degradationANP is eliminated from circulation by enzymatic degradation

NEP—Neutral Endo PeptidaseNEP—Neutral Endo Peptidase NEP is a zinc-metallopeptidase that NEP is a zinc-metallopeptidase that

cleaves cleaves αα-amino bond of -amino bond of hydrophobic amino acids—is a hydrophobic amino acids—is a major degradative enzymemajor degradative enzyme

ANP Clearance Receptor BlockersANP Clearance Receptor Blockers——

SC46542—is a biologically inactive SC46542—is a biologically inactive analogue of ANP that has similar analogue of ANP that has similar affinity for c-receptor as ANP, thus affinity for c-receptor as ANP, thus prolong the t1/2 of the ANP.prolong the t1/2 of the ANP.

Both R & S enantiomers of Both R & S enantiomers of thiorphan have same enzyme thiorphan have same enzyme inhibitory potencyinhibitory potency

NHSH

O

COOH

ThiorphanThiorphan

Why thiazide diuretics are used for diabetes Why thiazide diuretics are used for diabetes insipidus?insipidus?

They reduce urine volumeThey reduce urine volume Thiazide diuretics alone or Thiazide diuretics alone or ββ-blockers impair glucose -blockers impair glucose

metabolisms in hypertensive patients with abdominal metabolisms in hypertensive patients with abdominal obesity.obesity.

The metabolic analogue of thiazide –act on the The metabolic analogue of thiazide –act on the pituitary—ADH releases--pituitary—ADH releases--anti diuretic effectanti diuretic effect

Increase the cell permiability of the collecting duct Increase the cell permiability of the collecting duct & reabsorbtion of water& reabsorbtion of water

A synthetic analogue-(immuno cyto chemical A synthetic analogue-(immuno cyto chemical charaterization) 1-3-mercaptopropionic acid)-8-D-charaterization) 1-3-mercaptopropionic acid)-8-D-arginin vasopressin monoacetate trihydrate acts the arginin vasopressin monoacetate trihydrate acts the pituitary gland--ADHpituitary gland--ADH

DIURETIC SITE OF ACTIONDIURETIC SITE OF ACTION

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.

CONCLUSIONCONCLUSION

ReferencesReferences

Burger’s Medicinal chemistry-6Burger’s Medicinal chemistry-6thth edition volume-3 pg edition volume-3 pg no:55-142no:55-142

Text Book of Organic Medicinal & Pharmaceutical Text Book of Organic Medicinal & Pharmaceutical Chemistry(Wilson & Gisvold’s)-10Chemistry(Wilson & Gisvold’s)-10 thth edition pg edition pg no:553-579no:553-579

Foye’s principles of medicinal chemistry pg no:Foye’s principles of medicinal chemistry pg no: Essentials of medical pharmacology5th

edition-KD Tripathi pg no:525-542 Sites:-Medicap,wikepedia,Science direct.comSites:-Medicap,wikepedia,Science direct.com