Diuretics.ppt

Diuretics for Pharm. D 3 year Medicinal Chemistry

1. Diuretics
Dr. Rakam Gopi Krishna,
Associate Professor,
M. Pharm. Ph.D.,
Pharmaceutical Chemistry,
Marri Laxman Reddy Institute of Pharmacy,
Hyderabad.

2. Diuretics
Adiureticisdefinedasachemicalthatincreasestherateofurine
formation.
Theprimaryactionofmostofthediureticsisthedirectinhibitionof
sodiumreabsorptionatoneormoreanatomicalsitesofnephron.
Mainorganinvolvedindiuresisiskidney.
AdiureticusuallypossesssomecombinationofNatriuretic,
Chloruretic,Saluretic,Kaliuretic,Bicarbonaturetic,andCalciuretic
propertiesdependingonincreaseintherenalexcretionofSodium,
Chlorine,Sodiumchloride,Potassium,BicarbonateOrCalcium
respectively.

3. Diuretics
•Diureticsaredrugsthatincreasesecretionof
excesswaterandsaltthataccumulatesintissues
andurine.
•Anexcessquantityofintercellularfluidisformed
intheorganismasaresultofaninabilityofthe
kidneystoreleasesodiumionsfastenoughto
ensurethatasufficientquantityofwateris
excretedalongwiththem

4. Diuretics
•Theprimarytherapeuticuseofdiureticsisto
reducetheoverallswelling,correctspecificion
imbalance,lowerbloodpressure,lowertherateof
intraocularfluidformationandtolowerpressure
onpulmonaryvessels.

5. Diuretics
•Diureticsarewidelyusedinmedicineforvery
diversepathologies,primarilyforrelieving
Edema,treatingHypertension,Cardiac
Insufficiency,Hypercalcinuria,Glaucoma,anda
fewformsofEpilepsy,LiverCirrhosis,and
Nephrosis.

6. Anatomy and Physiology of
Nephron
ThefunctionalunitofkidneyisNephronwithits
accompanyingglomerulus.
Thereareapproximatelyonemillionnephronsin
eachkidney.

7. NephronconsistsofBowman’scapsule,Proximalconvolutedtubule,
DescendingloopofHenle,loopofHenle,AscendingloopofHenle,
DistalconvolutedtubuleandaCollectingduct.

8. Sites of Nephron
•Therearefourmajorsitesalongthenephron
whichinvolveinactiveabsorptionofsodium
whichinclude
Site 1: The convoluted and straight part of
proximal tubule
Site 2: the thick ascending limb of Henle loop
Site 3: Distal convoluted tubule and
Site 4: The collecting tubule.

10. Classification of Diuretics
Theagentswhichinvolveintheinhibitionofsodium
reabsorptionareclassifiedonthebasisofthesiteofactioninto.
Site 1 Diuretics: Carbonic
anhydrase inhibitors.
Site 2 Diuretics: High-
Ceiling or Loop diuretics.
Site 3 Diuretics: Thiazide
and Thiazide like diuretics.
Site 4 Diuretics: Potassium-
Sparing diuretics and
Miscellaneous diuretics.

11. Site 1 Diuretics: Carbonic anhydrase inhibitors
Thesediureticshadevolvedfromsulfanilamideandsulfonamide
antibiotics.Aftertheadministrationofsulfanilamideforbacterialinfection
milddiuresiswasobserved,thiswascharacterizedbythepresenceof
urinarysodiumandasubstantialamountofbicarbonate.Itwas
subsequentlyshownthatitinducesthiseffectthroughinhibitionofrenal
carbonicanhydrase.Buttheeffectwasminimumandbystructural
modificationofsulfanilamideeffectivedrugswereprepared.

12. Carbonic anhydrase inhibitors
•Carbonicanhydraseisanenzymefoundinvarious
segmentsofthenephronespeciallyinthecellsof
theproximalconvolutedtubule(PCT).
•Carbonicanhydrasefunctionstocatalyzethe
reversiblereactioninvolvedtheformationof
carbonicacid(H
2CO
3)fromwaterand
carbondioxide.

13. •ThiscarbonicaciddissociatestoformH
+
andHCO
3
-
ions.
•Carbonicanhydraseinhibitorsinhibitthis
reactionleadingtourinaryexcretionof
Na+,K+andHCO3-ions.

14. Carbonic anhydrase inhibitors

15. Synthesis of Acetazolamide
Acetazolamideissynthesizedbythereactionof
ammoniumthiocyanateandhydrazine,forming
hydrazino-N,N-bis-(thiourea)whichcyclesinto
thiazole(9.7.2)uponreactionwithphosgene.
Acylationofthiazolewithaceticanhydridegives2-
acetylamino-5-mercapto-1,3,4-thiadiazol(9.7.3).

16. Synthesis of Acetazolamide
•Theobtainedproductischlorinatedtogive2-
acetylamino-5-mercapto-1,3,4-thiadiazol-5-
sulfonylchloride(9.7.4),whichistransformedinto
acetazolamideuponreactionwithammonia

17. Synthesisof Acetazolamide
Ammonium
thiocyanate
Hydrazine
1,2-bis (thiocarbamoyl) hydrazine
Thiazole
Acetylation
2-acetylamino-5-mercapto
-1,3,4-thiadiazol
Acetazolamide
2-acetylamino-5-mercapto-1,3,4-
thiadiazol-5-sulfonylchloride

18. SAR of carbonic anhydrase inhibitors
•Afterseveralefforts,twogroupsofcarbonic
anhydraseinhibitorsweresynthesized.
•Theyareheterocyclicsulphonamidesand
derivativesofm-disulphamoylbenzene.
•Boththesegroupofcompoundsretainthe
essentialsulphamoyl(-SO2NH2)group.

19. SAR
•SothegeneralSARofcarbonicanhydrase
inhibitorswouldbestudiedundertwo
headings.

20. Structural Activity Relationship (SAR)
AsthesecompoundsareevolvedfromSulfanilamidethebasic
structuretobeconsideredissulfanilamide.
Maximumdiureticactivityisobservedwhen3
rd
positionis
substitutedwith–Cl,-Br,-CF
3
or–NO
2
.
Anunsubstitutedsulfamoylgroupat4
th
positionisamustfor
diureticactivity.
Substitutionat1
st
positionwith–NH
2
groupincreasessaluretic
(sodiumchlorideexcretion)activity,butdecreasescarbonic
anhydraseinhibitoryactivity.
Sulfamoylgroupat6
th
positionincreasesactivityandifitis
replacedwithotherelectrophilicgroupslikecarboxylorcarbamoyl
mayincreasediureticpotencywhiledecreasingcarbonic
anhydraseinhibitoryactivity.

21. For Heterocylic agents
Sulfamoylgroupat2
nd
position
isessentialfordiureticactivity.
Substitutionwithmethylgroupat4
th
positionyielded
methazolamidewhichexhibitsappreciablecarbonic
anhydraseinhibitoryactivity,butisnotsuperiorto
theprototypedrug.
Anacetaminogroupat5
th
positionismustfor
diureticactivity.

22. SAR
•Diureticpotencyandcarbonic
anhydraseinhibitoryactivityisentirely
duetothesulphamoylgrouppresentat
C-5.

23. Mechanism of Action
TheseagentsinhibitCarbonicanhydrasewhichis
essentialfortheproductionofH
+
.
WhentherearenoH
+
theexchangeofH
+
with
sodiumispreventedwhichleadstodiuresis.
Sulphamoyl(-SO
2NH
2)groupisentirelyresponsible
fortheirinhibitoryeffectoncarbonicanhydrase
enzyme.

24. USES
Usedinthetreatmentofglaucoma,
motionsickness,asadjuvantfor
treatmentofepilepsy,andtocreate
alkalineurinetodissolvecertainpoorly
watersolubleendogenousweakacids
likeuricacid.

25. Adverse Effects
Carbonic anhydrase inhibitors are associated with
Developmentofmetabolicacidosisduetorenallossof
bicarbonate.
Hypokalemia due to renal loss of potassium.
Typicalsulfonamideassociatedhypersensitivityreactionslike
urticaria,fever,andintestinalnephritis.
Symptomsassociatedwithlivercirrhosisandhepatic
encephalopathyareseen.
Drowsiness,fatigue,anorexia,gastrointestinaldisturbances
andrenalcaliculi.

26. Site 2 Diuretics: High-Ceiling or Loop Diuretics
Thoseagentswhichpreventthereabsorptionofsodiumonthick
ascendingloopofHenle’sareconsideredasloopdiuretics.
Previouslyorganomercurialswereusedandbecauseofseveralserious
limitationslikepoororalabsorption,timelaginonsetofactionafter
parentraladministrationandnephroandcardiotoxicities,thesewere
replacedbyotheragentslike1.Aminobenzoicacidderivatives
(Bumetanide,Furosemide),2.Phenoxyaceticacidderivative(Ethacrynic
acid),and3.Pyridinesulfonylureas(Torsemide,Triflocin).
1. Aminobenzoic acid derivatives:

27. High-ceiling diuretics
•Loopdiureticsarethemostpotentand
efficaciousdiuretics.
•Theyarealsotermedashigh-ceilingdiureticsas
theyexhibitasteepdoseresponsecurve.
•Innormaldosesloopdiureticsarecapableof
inducingupto20-30%ofNatriuresisandon
increasingthedoseupto30-40%natriuresiscan
beachieved.

28. high-ceiling diuretics
Suchanexcretionisnotexhibitedbyanyother
diureticslikethiazides(only10-12%natriuresis)
orK
+
sparingdiuretics(5-6%natriuresis).
Thesiteofactionforloopdiureticsisthethick
ascendinglimbofloopofHenle.

29. Furosemide
•Furosemide:Furosemide,4-chloro-N-furfuryl-5-
sulfamoylanthranylicacid.
•SynonymsofthisdrugareLasix,Lazizix,Franil,
Urosemide,

30. Synthesis of Furosemide
•Itissynthesizedinarelativelysimplemanner
from2,4-dichlorobenzoicacid,whichis
converted into 3-aminosulfonyl-4,6-
dichlorobenzoicacid(21.4.10)during
subsequentreactionwithChlorosulfonicAcid
andAmmonia.
•Reactingthiswithfurfurylaminegives
Furosemide.

31. Synthesisof Furosemide
2,4-dichlorobenzoic acid
3-aminosulfonyl-4,6-
dichlorobenzoic acid
Chlorosulfonic
Acid
furfurylamine
Furosemide

32. SAR of High-ceiling diuretics
•Thelooporhighceilingdiureticsaredivided
intotwoclassesbasedontheirstructure.
•Thefirstclassofdrugsarederivativesof5-
sulfamoyl-2-aminobenzoicacid
(Eg:-Furosemide,Azosemide).
•Thesecondclasscomprisesof5-sulfamoyl-3-
aminobenzoicacidderivatives.(Eg:-
Bumetanide,Piretanide).

33. SAR of High-ceiling diuretics

34. Structural Activity Relationship
–COOHgroupisessentialatposition1fordiureticactivity.
–SO
2NH
2groupatposition5isalsoessentialfordiureticactivity
Compoundswithhalogengrouporbenzoylgroupat4thposition
shownmaximumactivity.
Aminogroupmaybeat3rdor2ndpositionandthesubstituenton
aminogroupmaybeFurfuroylorn-butylformaximumactivity.

35. SAR
Compoundswithhalogengrouporbenzoyl
groupat4
th
positionshownmaximum
activity.
Theheterocyclicaromaticmoietiesare
bettersubstituentsthanhalogenand
substitutedhalogenderivativeat4
th
position.

36. Mechanism of Action
Alltheloopdiureticspreventthe
reabsorptionofsodiuminexchangeofH
+
or
K
+
andalsoinhibittheNa
+
/K
+
/Cl
−
cotransportsystemlocatedintheluminal
membraneofcellsinthethickascending
limbofHenle’sloop.

37. Uses
•Inanumberofcases,furosemidehasproven
moreeffectivethanotherdiuretics.
•Besidesadiureticeffect,italsodilates
peripheralvessels.
•Itisfrequentlyusedincombinationwithother
antihypertensivedrugs

38. UsedinthetreatmentofOedema,
Symptomatic hypercalcemiaand
hypertension.

39. Adverse Effects
Hypokalemicalkalosis,Electrolytelosses,
Hyperuricemia,Utricaria,Drugfever,Blood
dyscrasiasandintestinanephritisarethe
common sideeffectsassociatedwith
aminobenzoicacidcompoundsofloop
diuretics.

40. Thiazide Diuretics
•Thiazide Diuretics are a group of moderately efficacious
diuretics which has vast clinical applications.
•Mostofthediureticsofthethiazideclassarestructurally
relatedtoantibacterialdrugsofthesulfonamideclass;
however,thesecompoundsexhibitnoantibacterialactivity.
•Drugsofthisgrouparederivativesofbenzothiadiazine,and
asaruletheyaresubstitutedatC7ofthebenzylringbya
sulfonamidegroupandachlorineatom,orbyanother
electron-acceptinggroup(trifluoromethyl)atC6.

41. Thiazide Diuretics
•Allthethiazidediureticsareinhibitorsof
Na
+
-Cl
-
symporter
•Themajorsiteofactionbeingtheearly
segmentoftheDistalconvolutedtubule
(DCT).
•Theirsecondarysiteofactionisthoughtto
beProximalconvolutedtubule(PCT).

42. •TheNa-K-Clcotransporter(NKCC)isa
proteinthataidsintheactivetransportof
sodium,potassium,andchlorideintoand
outofcells.

43. Thiazide Diuretics
•TheNa
+
-Cl
-
symporterisassociatedwiththe
reabsorptionofbothNa
+
andCl
-
ions.
•Thiazidediureticsinhibitthissymporterresulting
inurinaryexcretionofbothNa
+
ionsandwater.

44. Site 3 Diuretics: Thiazide and Thiazide like Diuretics
Thethiazideswerethefirstorallyeffectivesalureticagentsandtheir
activitywasnotinfluencedbytheacid-basestatusoftheindividual.
Examples: Thiazide Diuretics includes Chlorthiazide and Benzthiazide
Hydrothiazides includes Hydrochlorthiazide,
Hydroflumethiazide’ Trichlormethiazide
Thiazide Diuretics-H
2
C-S-H
2
C
Name of the Compound R R
1
Chlorthiazide -Cl -H
Benzthiazide -Cl

45. Structures

46. Hydrochlorothiazide
•Hydrochlorothiazideisoneofthemostwidely
useddrugsofthisseries,anditisusedforthe
sameindications,asisChlorothiazide.
•Hydrochlorothiazidecauseslessinhibitionof
Carbonicanhydrase,butcauses5–10timesmore
diuresisofsodiumionsthanchlorothiazideusing
thesamedose.

47. Synonyms
•SynonymsofthisdrugareChlorozide,
Diaqua,Esidrix,Hydrodiuril,Hydrozide,
Hypothiazide,Novohydrazide,Urozide,and
others.

48. Synthesis of Hydrochlorthiazide
•Hydrochlorothiazide:1,1-dioxide6-chloro-3,4-
dihydro-2H-1,2,4-benzothiadiazin-7-sulfonamideis
synthesizedbycyclizationof4,6-sulfonamido-3-
chloroaniline(21.3.2)usingparaformaldehyde,
duringwhichsimultaneousreductionofthedouble
bondoccursatpositionC3–C4.

49. Synthesis of Hydrochlorthiazide
Hydrochlorthiazide4,6-sulfonamido-3-chloroaniline
Paraformaldehyde
1,1-dioxide 6-chloro-3,4-dihydro-
2H-1,2,4-benzothiadiazin-7-
sulfonamide

50. Structural Activity Relationship
Smalleralkylgrouplikemethylgrouppresentonposition2increasesthe
activity.
Substitutiononthe3
rd
positionplaysanimportantroleindeterminingthe
potencyanddurationofactionofthiazidediuretics.
Lossofdoublebondbetween3
rd
and4
th
positionasinthecaseof
hydrothiazideincreasesdiureticactivity.
Substitutionon4th,5thand8thpositiondecreasesactivity.
Substitutionatthe6
th
positionwithactivatinggroupslike–Cl,-Br,-CF
3
,
and–NO
2
groupsincreasesactivity.
Asulfamoylgroupat7
th
positionismustfordiureticactivity.

51. Name of the Compound R R
1
R
2
Hydrochlorthiazide -Cl -H -H
Hydroflumethiazide -CF
3
-H -H
Trichlormethiazide -Cl -CHCl
2
-H

52. Mechanism of action
Theexactmechanismofactionisnotknown;
Theeffectorregionsofthiazidediureticsarethe
distalnephrontubules.
Drugsofthisgroupinhibitreabsorptionof
Sodium,Chloride,Magnesium,andCalciumions
andcauseincreasedexcretionfromtheorganism
alongwithanosmoticallyequivalentamountof
water.

53. Mechanism of action
Theseagentsblockthereabsorptionofsodiumin
thedistalconvolutedtubulebyinhibitingthe
luminalboundNa
+
/Cl
-
co-transportsystem,there
byeliminatessodiumintheformofsodium
chloride.

54. Uses
Theseareusedinthetreatmentofedemaassociatedwithmildor
moderatecongestiveheartfailure,cirrhosisofliver,ornephroticsyndrome.
Theyarealsousedinthetreatmentofhypertension,diabetesinsipidus,
typeIIrenaltubularacidosisandhypercalciuria.

55. Uses
•Thiazidesarealsoeffectiveinacidosisor
alkalosis,inhibitingcarbonicanhydraseinvitro,
andloweringarterialpressureinhypertensive
patients.

56. Adverse Effects
Theseagentsareassociatedwith
hypersensitivityreactionssuchasutricaria,
drugfever,blooddyscrasiasandintestinal
nephritis.
TheymayalsocauseHypokalemia,
HypotensionandoccasionalHypocalcemia.

57. Blood dyscrasias
•Thepathologicconditionsordisorderssuch
asleukemiaorhemophiliainwhichthe
constituentsofthebloodareabnormalor
arepresentinabnormalquantity.
•blooddyscrasiasapathologicconditionof
theblood,usuallyreferringtoadisorderof
thecellularelementsoftheblood.

58. Urticaria
•commonlyreferredtoashives,isakindof
skinrashnotableforpalered,raised,itchy
bumps.
•Hivesmaycauseaburningorstinging
sensation.Theyarefrequentlycausedby
allergicreactions

59. Interstitial nephritis
•Interstitialnephritisisakidneydisorderin
whichthespacesbetweenthekidney
tubulesbecomeswollen(inflamed).

60. Site 4 Diuretics: Potassium-
Sparing Diuretics
•Theseagentsincreasesodiumandchlorine
excretionwithoutincreasingtherateof
potassiumexcretion.
•Astheseagentsdonotaffecttherateof
excretionofpotassiumthesearecalled
PotassiumSparingDiureticsOrAntikaliuretic
Agents.Theseagentsactontheconnecting
andcollectingtubuleofnephron.

61. Examples:Aldosteroneantagonist–Spironolactone,Arylpteridines–
TriamtereneandPyrazinoylguanidine–Amiloride.
Structural Activity Relationship
Forspironolactone–SCOCH
3
at6
th
positionisessentialfordiureticactivity.
Fortriamtereneanunsubstituted2,4,7-triamineisessentialfordiuretic
activity.
Foramiloridean–Clat6
th
positionandunsubstituted–NH
2
groupsat3
rd
and
5
th
positionismustforincreasedactivity.

62. Mechanism of Action
Aldosteroneincreasesthesodiumreabsorption
intotheluminalfluid.
Spironolactoneinhibitstheactionsof
aldosteroneandpreventsthesodium
reabsorption.

63. MOA
TriamtereneandAmiloridedoesnotrequires
thepresenceofaldosteronetoproduce
diuresis.
TheydecreasetheNa
+
-K
+
ATPaseactivity
andpreventthelossofK
+
inexchangeof
sodium.

64. Uses
Alltheseagentsareusedtoremovetheedema
fluidinindividualswithcongestiveheartfailure,
heartfailure,cirrhosis,nephriticsyndromeand
withhypertension.
However,itsprimaryuseistobegivenin
combinationwithotherdiureticstoprevent
potassiumloss.

65. Adverse Effects
Themajoradverseeffectsofspironolactoneinclude
hyperkalemiaandmildmetabolicacidosis.Inaddition,
spironolactonemayproducegynecomastiainmenand
breasttendernessandmenstrualdisturbancesin
women.
Triamtereneproduceshyperkalemia,nausea,
vomiting,legcrampsanddizziness.
Amilorideisassociatedwithhyperkalemia,nausea,
vomiting,diarrheaandheadache.

66. Miscellaneous Diuretics
Theseagentsactbydifferentways.ExamplesincludeMannitoland
Theophylline.N
N
N
H
N
O
O
H
3
C
CH
3 Theophylline
Theosmoticeffectinducedbythemannitolpreventsthereabsorption
ofwateralongwithsodiumandtheophyllinepromotesweakdiuresisby
stimulationofcardiacfunctionandbyadirectactiononnephron.