Diuretics & anti diuretics

Diuretics & Anti-Diuretics drugs

1. DIURETICS &
ANTI-DIURETICS AGENT
By:-Dr. Manish Pal Singh,
Associate Professor
1
AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA

2. General Physiology of Urine Formation
❑Themainfunctionofkidneystomaintainahomeostasisbalanceof
electrolytesandwater.
❑Urineformationstartsfromglomerularfiltration(g.f.).
❑Normally180Loffluideverydayfiltered;butmorethan99%oftheg.f.is
reabsorbedinthetubules,onlyabout1.5Lurineisproducedin24hr.
❑Thediureticsmainlyinhibitthereabsorptionattubularside.
AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
2
Source*
-
http%3A%2F%2Fpathwaymedicine.org%2Furine
-
formation
-
mechanisms

3. AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
3
➢Each kidney contains approximately one million nephrons and is
capable of forming urine independently.
The nephrons are composed of glomerulus, proximal tubule, loop of
henle, distal tubule.
Loop of Henle
Source*
-
https%3A%2F%2Fwww.unmc.edu%2Felearning%2Fegallery%2Fthe
-
main
-
processes
-
of
-
the
-
nephron

4. AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
4

5. Mechanism of Tubular Reabsorption
➢It’sanenergydependenttransmembranepumpsaswellaschannelsinbetween
theloosefittingcellsofproximaltubule(PT).
➢AllNa+thatentersthroughcellsviaNa+K+ATPase-energisedNa+-K+
antiporter.
AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
5
Source*-l=https%3A%2F%2Fcourses.lumenlearning.com%2Fsuny-
ap2%2Fchapter%2Ftubular-reabsorption-

6. Stages of Tubular Reabsorption
AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
6
Site-4
(Distal Tubule {DT})
Site-3
(Cortical diluting
segment of
loop)
Site-2
(Loop of
Henle)
Site-1
(PT)

7. AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
7
Heart
•Pumping action of heart control renal blood flow.
•Relative dimensions of glomerular vessels.
RAS
•Distal Tubular reabsorption of Na+ & Secretion of K+/H+
•AT-II-effect on intracellular beds & Na+/H2O reabsorption.
Prostaglandins &
Atrial natriuretic
factors (ANP)
•PG’s-direct renin release & inhibits the action of anti-diuretic
hormone (ADH)
•Atrial natriuretic peptide produced by atrium & inducing ‘Natriuresis’
in response to salt & water overload.
Regulation of Renal Function (GFR)

8. DIURETICS
❑ThesearedrugswhichcauseanetlossofNa+&waterinurine.
❑Theyarepopularlyusedinthemanagementofhypertensionastheirusedin
edema.
“Diuretics (“water pills”) are the drugs which increase the urine out put
(or) urine volume” .
Natriuresis-“Any drug when introduce into the body
increases the out put of sodium
ie., loss of sodium in urine”.
AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
8
The first oral diuretics ‘Chlorthiazide’
(1957)-Thiazidediuretics

9. AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
9Source*-https%3A%2F%2Fwww.ctdt.co.in

10. AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
10
Source*-https%3A%2F%2Fslideplayer.com

11. High Ceiling (Loop) Diuretics:-{Frusemide}
➢Theseagentsproduceapeakdiuresismuchgreaterthanobservedwith
othercommonlyuseddiuretics.
➢TheyactbyinhibitingtheluminalNa/K/2Clsymporter.
➢Ithasbroaderdoseresponsecurve.
➢Itismoreconvenientfori.v.use.
➢Itsmaximalnatriureticeffectismuchgreaterthanthatofotherclasses.
➢Theonsetofaction-i.v.(2-5min);oral(20-40min)&i.m(10-20min).
AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
11

12. Mechanism Of Action
✓Loopdiuretics(ferusemide)primarilytargeton‘Site-II’(thickAscLH).
✓WhereitisinhibitNa+-K+-2Cl-cotransport.
✓ItsminoractioncomponentofactiononPT.
✓K+-excretionincreasedueto-highNa+loadreachingDT.
AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
12
Source*-
https%3A%2F%2Fwww.youtube.com%2Fwatch%3Fv%3D5k5btYZTKhQ&psig

13. AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
13
➢Itcauseschangesin
renal& systemic
hemodynamics.
➢Itcancausesincreases
Ca++excretionaswellas
Mg++excretion
➢Molecularactionofit
canbindwithCl-binding
siteofcotransporterpump
proteintoinhibitits
transportfunction.
Source*-http%3A%2F%2Ftmedweb.tulane.edu%2Fpharmwiki%2Fdoku.php%2Floop_diuretics

14. AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
14
Indications:-
➢Edema-incardiac;hepaticorrenal.
➢HighlypreferredinCHF
➢Acutepulmonaryedema(LVF);followingMI
➢Cerebraledema
➢Hypertension
➢Hypercalcaemia
Source*-https://encrypted-tbn0.gstatic.com/images?

15. ThiazideDiuretics
❑Thesedrugscompeteforthechloridebindingsiteofthesodium/chloride
symporterandinhibitthere-absorptionofsodium&chloride.
❑Thesearemediumefficacydiureticswithprimary‘Site-III’(inthecortical
dilutingsegmentortheearlyDT).
❑AsaresultthesedrugsincreasetheconcentrationofNaandClinthetubular
fluidandincreaseitsexcretion.
❑Reducebloodvolume decreaseG.F.R
❑DecreaseB.P.inhypertensives.
❑ThiazidereduceurinevolumeinbothpituitaryoriginaswellasrenalDI
(diabeticinsipidus)byanunknownmechanism.
AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
15

16. AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
16
➢Theybindtospecificreceptors
locatedontheluminal
membrane.
➢Itcancauseincreasedamount
ofNa+ispresentedtodistal
nephron;urinaryK+-excretionis
increasedinparalleltothe
natriureticresponse.
Source*-https%3A%2F%2Fwww.memorangapp.com

17. AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
17
ADR’s:-
•Potassiumdepletion
•Hyperuricemia
•Hypercalcemiaandhypomagnesemia
•Nausea,vomiting,diarrhea
•Orthostatichypotension
•Inhibitionofinsulinsecretion
Indications:-
✓DI-theyreduceurinevolume
✓Hypercalciuria
✓Edema
✓Reducestheintraocularpressure-usedintreatmentofGlaucoma.
Source*-https%3A%2F%2Fwww.indiamart.com%2Fproddetail%2Fhydrochlorothiazide-ip-25mg-21465357162.html

18. Comparison Between
Loop Diuretics
➢TheyinhibitNa/K/2Clsymporter.
➢Actsatthickascendingloopof
henle.
➢TheseareCa+wastingdrugs.
➢Theycauseheavydiuresis.
➢Para thyroid hormone
independentCaabsorption.
➢Itcanreabsorb25%to30%of
Na.
ThiazideDiuretics
➢TheyactbyinhibitingNa/Cl
symporter.
➢Actsatdistalconvolutedtubule.
➢TheseareCa+retainingdrugs.
➢Theycausemilddiuresis.
➢ParathyroidhormonedependentCa
absorption.
➢Itcanreabsorb8%ofNa.
AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
18

19. Carbonic Anhydrase (CAse) Inhibitors
(Acetazolamide):
➢CAse-isanenzymewhichcatalysesthereversiblereactionH2O+CO2-------
H2CO3.
➢TransportinH+-ionsecretionfromtubuleside,helptoNa+Reabsorption
intubularcells.
➢Acetazolamideisasulfonamidederivativewhichisanoncompetitive
reversibleinhibitorof“carbonicanhydraseenzyme”.
➢ResultingslowingofhydrationofCO2-decreasedavailabilityofH+to
exchangewithluminalNa+throughtheNa+-H+antiporter.
AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
19

20. AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
20
CAs-enzymeisresponsiblefor
catalyticreversiblehydrationof
carbondioxideanddehydrationof
carbonicacid.
Theneteffectisinhibitionof
HCO3-(withNa+)reabsoprtionin
PT---promptbutmildalkaline
diuresisensues.
Source*-https%3A%2F%2Fwww.youtube.com

21. ➢ADR’s:-
➢Hypokalemia
➢Acidosis
➢Drowsiness
➢Renalcalculi.
➢Nausea,lossofhearing,lossofappetite.
➢Uses:-(Selflimitingusedasdiuretics)
➢Glaucoma
➢Toalkalineurine-forurinarytractinfectionortopromoteexcretionofcertainacidic
drugs.
➢Epilepsy-inabsenceseizures
➢Acutemountainsickness
➢DIAMOX;IOPAR;SYNOMAX-(Brands)
AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
21

22. Potassium Sparing Diuretics
(Spironolactone):{Aldosterone Antagonist}
➢TheseareeitheraldosteroneantagonistordirectlyinhibitNa+channelsin
DT&CDcellstoindirectlyconverseK+.
➢Theyactbyinhibitingsodiumreabsoprtioninthelatedistaltubuleandthus
indirectlysparepotassiumexcretion.
➢Spironolactoneisasteroid,chemicallyrelatedtothemineralocorticoid
aldosterone.
➢Aldosterone,bybindingtoitsreceptor-{Aldosteroneinducedproteins-
(AIPs)}inthecytoplasmincreasesexpression&functionofNachannel
andsodiumpump{K+secretion}.
AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
22

23. AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
23
➢Competitiveandreversibleinhibition
ofthealdeosteronepresentinthe
cytoplasmofprincipalcells(locatedin
lateDCTandcorticalCT).
➢Formation of inactive
spironoloactone-receptorcomplex
whichcannotgettraslocatedintothe
nucleustobindtoDNA.
➢Failuretoproduce“aldosterone-
inducedproteins”whichnormally
promoteNa+reabsoprtionviaENac
andasaresultofwhichK+secretion
viaK+channelisfacillated.
➢DecreasedNa+reabsorptionand
decreasedK+secretion.
Source*-https%3A%2F%2Fhealthjade.net%2Fpotassium-sparing-
diuretics

24. ADR’s:-
▪Gynaecomastiaandimpotenceinmale;hirsutism
▪breastdiscomfortandmenstrualirregularitiesinfemale.
▪GIupset–cancausepepticulcer.
▪Hyperkalemia.
Uses:-
▪Fluidretentionofhyperaldosteronism
▪ResistantHTN(usedonlyasadjuvanttothiazidetopreventhypokalemia).
▪TocounteractK+lossduetothiazideandloopdiuretics
▪Hypokalemiaandhypomagnesemia
▪Heartfailure
AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
24

25. Osmotic Diuretics
(Mannitol):
➢Osmoticdiureticsactonproximaltubuleandalsoatloopofhenle.where
theypreventwaterreabsoprtionbyincreasingosmolalityoftubularfluid.
➢Mannitolisanonelectrolyteoflowmolecularweight;freelyfilteredatthe
glomerulus&undergoeslimitedreabsorption;thereforeexcellentlysuited
tobeusedasosmoticdiuretic.
AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
25
increase
urine volume
flow rate
Decreasecontacttimebetween
fluidandtubularepithelium
Decrease Na+ reabsorption

26. AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
26
Uses:-
▪Increased intracranial or intraocular tension(acute
congestive
▪glaucoma,headinjury,storke,etc.)
▪To maintain g.f.r. and urine flow in impending acute
renal Failure
▪To counteract low osmolarity of plasma/e.c.f.due
to rapid Haemodialysis.
ADR’s:-
▪ It is contraindicated in acute tubular necrosis
▪ Anuria
▪ Pulmonary edema
▪ Acute LVF
▪ CHF
▪ Cerebral haemorrhage
Source*-htpp/:OsmoseIt%2Fposts%2Fwhat-are-some-side-effects-of-osmotic-diuretics-
share-your-answers-in-the-commen

27. Anti-Diuretics
➢Antidiuretics(inhibitthewaterexcretionwithoutaffectingsaltexcretion)
aredrugsthatreduceurinevolume,particularlyindiabetesinsipidus(DI).
AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
27
Anti-Diuretics
Miscellaneous:-
Indomethacin;
Chlorpropamide
ADH
(Vasopressin)
Thiazide
diuretics

28. ADH {Anti-diuretics hormone}:
➢ANTIDIURETICHORMONE (ADH)issecretedbytheposteriorpituitary
gland.
➢It’sanonpeptidesecretedalongwith‘Oxytocin’.
➢TherateofADHreleasegovernedbybodyhydration.
AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
28
ADH-release
Contraction of e.c.f.
volume
Rise in plasma
osmolarity

29. ADH-Receptors:
AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
29
•Located on vascular & other smooth muscles, platelets etc.
•Follow IP3/DAG-Ca+ release-ACTH release, vasoconstriction
etc.V1
•Located primarily on the CD cells in the kidney
•Regulate their water permeability-CAMP production
•Its more sensitive to ADH than V1-receptors.V2
ADH-receptors-‘G-protein coupled’-receptors

30. MAO-ADH (Kidney cells):
➢ADHenhanceswaterreabsorptionbyactingonthecollectingduct.
➢ADHactivatestheV2receptorspresentonthecellmembraneofthe
collectingductandincreasesthewaterpermeabilityofthesecells.
➢ADHcausesvasoconstrictionandraisesBPmediatedbyV1receptors.
➢VasopressinisgivenparentallyasinjectionofSC,IM,IV.
➢WhenADHisabsent,CDcellsremainimpermeabletowater---diluteurine
(producedbythedilutingsegments)ispassedassuch.
➢ActivationofV2-receptorbyADH–increasedCAMPdependentprotien
kinaseA-whichpromote“aquaporin-2”waterchannelcontainingvesicles.
AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
30

31. AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
31
➢Thewaterpermeabilityof
CDcellsisincreasedin
proportiontothepopulationof
aquaporin-2channelsinthe
apicalmembraneatanygiven
time.
➢WhileV1-receptors
activationconstrictsvasarecta
todiminishbloodflowtoinner
medullawhichwillhelpin
maintaininghighosmolarityin
thisregionandthus
contributingtoantidiuresis.
Source*-https%3A%2F%2Fwww.qsstudy.com

32. VasopressinAnalogues:-
❑Lypressin:-{20IU,10IU-IMorSCor20IUdilutedin100-200mlofdextrose
solutionandinfusedIVin10-20min}.
❑Terlipressin:-{2mg,repeat1-2mgevery4-6hr}
❑Desmopressin:-{IVorSC;2-4Ug/day}
AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA 32
Uses:-
✓Diabetesinsipidusofpituitaryorigindesmopressinisthe
preparationused.
✓Itshouldbeusedlifelong.
✓Bleedingesophagealvarices-ADHconstrictsmesenteric
bloodvessels(v1receptors)andmayhelp.
✓Beforeabdomonalradiography-expelsgasesfromthe
bowel.
✓Hemophiliaandvonwillebrand’sdisease-ADHmay
releasefactorVIIIandpreventbleeding.
Source*-https%3A%2F%2F1.bp.blogspot.com

33. ADR’s& Contraindication of ADH-Analogues
▪WhenusedintranasallyADHcancausenasalirritation,allergy,rhinitisand
atrophyofnasalmucosa's.
▪Othereffectsincludenausea,abdominalcrampsandbackache(dueto
constrictionoftheuterus).
▪Patientsufferingfromvasculardisease,especiallydiseaseofcoronaryarteries.
▪V2-selectivelydesmopressinproducesfeweradverseeffectsthanvasopressin,
lypressinorterlipressin.
▪Itscontraindicatedinpatientswithischemicheartdisease.
AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
33

34. Miscellaneous Anti-Diuretics:
Chlorpropamide---has a long duration of action oral hypoglycemic, found to
reduce urine volume in DI of pituitary origin
➢ButnotinrenalDIissensitizethekidneytoADHactionitsefficacydependson
smallamountofthecirculatinghomeone.
➢ItisnotactivewhenADHistotallyabsent.
➢ItalsodirectlypronesaltreabsorptionintheascendinglimbC-maycontributetoits
antidiureticaction.
Carbamazepine---is an antiepileptic anticonvulsant, drug which, reduces urine
volume in DI of pituitary origin.
➢IthasbeenshowntostimulateADHsecretion.Howeveritisnotvaluableinthe
treatmentofDI.
➢Contraindications-Abnormalitiesinliverfunction
AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA
34