Antihypertensive Drugs & Diuretics|Pharmacology Assignment 3.1.pdf

Antihypertensive Drugs & Diuretics|Pharmacology Assignment 3.1.pdf Antihypertensive Drugs & Diuretics|Pharmacology Assignment 3.1.pdf

1. MawlanaBhashaniScienceandTechnologyUniversity
Santosh,Tangail-1902
DepartmentofPharmacy
AssignmentNo:02
Assignment
on
AntihypertensiveDrugs&Diuretics
CourseCode:PHAR3107
CourseTittle:PharmacologyII
SubmittedBy SubmittedTo
Md.ShakilSarker
StudentID:PHA-20008
3
rd
Year,1
st
Semester
Session:2019-2020
DepartmentofPharmacy
MawlanaBhashaniScienceandTechnology
University
Santosh,Tangail-1902
SayemaArefin
AssistantProfessor
DepartmentofPharmacy
MawlanaBhashaniScienceandTechnology
University
Santosh,Tangail-1902
DateofSubmission:October10,2022

2. AntihypertensiveDrugs
Overview
Bloodpressureiselevatedwhensystolicbloodpressureexceeds120mmHganddiastolic
bloodpressureremainsbelow80mmHg.Hypertensionoccurswhensystolicbloodpressure
exceeds130mmHgordiastolicbloodpressureexceeds80mmHgonatleasttwooccasions.
Hypertensionresultsfromincreasedperipheralvasculararteriolarsmoothmuscletone,which
leadstoincreasedarteriolarresistanceandreducedcapacitanceofthevenoussystem.Inmost
cases,thecauseoftheincreasedvasculartoneisunknown.Elevatedbloodpressureisa
commondisorder,affectingapproximately30%ofadultsintheUnitedStates.Although
manypatientshavenosymptoms,chronichypertensioncanleadtoheartdiseaseandstroke,
thetoptwocausesofdeathintheworld.Hypertensionisalsoanimportantriskfactorinthe
developmentofchronickidneydiseaseandheartfailure.Theincidenceofmorbidityand
mortalitysignificantlydecreaseswhenhypertensionisdiagnosedearlyandisproperly
treated.Thedrugsusedinthetreatmentofhypertensionareshowninclassificationtable.In
recognitionoftheprogressivenatureofhypertension,hypertensionisclassifiedintofour
categories.Themajorityofcurrentguidelinesrecommendtreatmentdecisionsbasedon
goalsofantihypertensivetherapy,ratherthanthecategoryofhypertension.
Classificationofbloodpressure
Symptomsofhypertension
Hypertensionisgenerallyasilentcondition.Manypeopledonotexperienceanysymptoms.
Symptomsofseverehypertensioncaninclude:
●Headaches
●dizziness
●shortnessofbreath
●chestpain
●nosebleeds
●visualchange
●flushing
●bloodintheurine.
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3. CausesofHypertension
Althoughhypertensionmayoccursecondarytootherdiseaseprocesses,morethan90%of
patientshaveessentialhypertension(hypertensionwithnoidentifiablecause).
●Afamilyhistoryofhypertensionincreasesthelikelihoodthatanindividualwill
develophypertension.
●Theprevalenceofhypertensionincreaseswithagebutdecreaseswitheducationand
incomelevel.
●Non-Hispanicblackshaveahigherincidenceofhypertensionthandoboth
nonHispanicwhitesandHispanicwhites.
●Personswithdiabetes,obesity,ordisabilitystatusareallmorelikelytohave
hypertensionthanthosewithouttheseconditions.
●Inaddition,environmentalfactors,suchasastressfullifestyle,highdietaryintakeof
sodium,andsmoking,mayfurtherpredisposeanindividualtohypertension.
ClassificationofAntihypertensivedrugs
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4. MechanismsforControllingBloodPressure
Arterialbloodpressureisregulatedwithinanarrowrangetoprovideadequateperfusionof
thetissueswithoutcausingdamagetothevascularsystem,particularlythearterialintima
(endothelium).Arterialbloodpressureisdirectlyproportionaltocardiacoutputand
peripheralvascularresistance.Cardiacoutputandperipheralresistance,inturn,arecontrolled
mainlybytwooverlappingmechanisms:thebaroreflexesandthe
reninangiotensin–aldosteronesystem.Mostantihypertensivedrugslowerbloodpressureby
reducingcardiacoutputand/ordecreasingperipheralresistance.
A.Baroreceptorsandthesympatheticnervoussystem
Baroreflexesactbychangingtheactivityofthesympatheticandparasympatheticnervous
system.Therefore,theyareresponsiblefortherapid,moment-to-momentregulationofblood
pressure.Afallinbloodpressurecausespressure-sensitiveneurons(baroreceptorsinthe
aorticarchandcarotidsinuses)tosendfewerimpulsestocardiovascularcentersinthespinal
cord.Thispromptsareflexresponseofincreasedsympatheticanddecreasedparasympathetic
outputtotheheartandvasculature,resultinginvasoconstrictionandincreasedcardiacoutput.
Thesechangesresultinacompensatoryriseinbloodpressure.
B.Renin–angiotensin–aldosteronesystem
Thekidneyprovideslong-termcontrolofbloodpressurebyalteringthebloodvolume.
Baroreceptorsinthekidneyrespondtoreducedarterialpressure(andtosympathetic
stimulationofβ1-adrenoceptors)byreleasingtheenzymerenin.Low-sodiumintakeand
greatersodiumlossalsoincreasereninrelease.Reninconvertsangiotensinogento
angiotensinI,whichisconvertedinturntoangiotensinII,inthepresenceofangiotensin
convertingenzyme(ACE).AngiotensinIIisapotentcirculatingvasoconstrictor,constricting
botharteriolesandveins,resultinginanincreaseinbloodpressure.AngiotensinIIexertsa
preferentialvasoconstrictoractionontheefferentarteriolesoftherenalglomerulus,
increasingglomerularfiltration.Furthermore,angiotensinIIstimulatesaldosteronesecretion,
leadingtoincreasedrenalsodiumreabsorptionandincreasedbloodvolume,whichcontribute
toafurtherincreaseinbloodpressure.TheseeffectsofangiotensinIIaremediatedby
stimulationofangiotensinIItype1(AT1)receptors.
TreatmentStrategies
Thegoalofantihypertensivetherapyistoreducecardiovascularandrenalmorbidityand
mortality.Formostpatients,thebloodpressuregoalwhentreatinghypertensionisasystolic
bloodpressureoflessthan130mmHgandadiastolicbloodpressureoflessthan80mmHg.
Currentrecommendationsaretoinitiatetherapywithathiazidediuretic,ACEinhibitor,
angiotensinreceptorblocker(ARB),orcalciumchannelblocker.However,initialdrug
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5. therapychoicemayvarydependingontheguidelineandconcomitantdiseases.Ifblood
pressureisinadequatelycontrolled,aseconddrugshouldbeadded,withtheselectionbased
onminimizingtheadverseeffectsofthecombinedregimenandachievinggoalblood
pressure.Patientswithsystolicbloodpressuregreaterthan20mmHgabovegoalordiastolic
bloodpressuremorethan10mmHgabovegoalshouldbestartedontwoantihypertensives
simultaneously.Combinationtherapywithseparateagentsorafixed-dosecombinationpill
maylowerbloodpressuremorequicklywithminimaladverseeffects.Avarietyof
combinationformulationsofthevariouspharmacologicclassesareavailabletoincreaseease
ofpatientadherencetotreatmentregimensthatrequiremultiplemedications.
Individualizedcare:Hypertensionmaycoexistwithotherconditionsthatcanbeaggravated
bysomeoftheantihypertensivedrugsorthatmaybenefitfromtheuseofsome
antihypertensivedrugsindependentofbloodpressurecontrol.Insuchcases,itisimportantto
matchantihypertensivedrugstotheparticularpatient.Inadditiontothechoiceoftherapy,
bloodpressuregoalsmayalsobeindividualizedbasedonconcurrentdiseasestatesandage.
Antihypertensivestobeavoidedduringpregnancy
ACEinhibitors,ARBs:Riskoffoetaldamage,growthretardation.
Diuretics:Thereissomeevidencethatbyreducingbloodvolume,diureticstendtoaccentuate
uteroplacentalperfusiondeficit(oftoxaemia)—increaseriskoffoetalwastage,placental
infarcts,miscarriage,stillbirth.
Nonselectiveβblockers:Propranololhasbeenimplicatedtocauselowbirthweight,
decreasedplacentalsize,neonatalbradycardiaandhypoglycaemia.
Sod.nitroprusside:Contraindicatedineclampsia.
Antihypertensivesforuseduringpregnancy
Labetalol
Thiscombineda+badrenergicblockergivenorallyiseffectiveinmajorityofcases,andis
mostwidelyusednow.
Nifedipine(sustainedrelease)
ThisdihydropyridineCCBisavasodilatorthathasbeenusedinpreeclampsiawithgood
results.How-ever,itshouldbestoppedbeforelabourbegins,becauseitmayweakenuterine
contractions.
Methyldopa
Ithasthelongestrecordofuseduringpregnancywithsafety,andisstillused.Apositive
Coomb’stestmayoccur,buthasnoadverseimplication.
Hydralazine
Thisoldvasodilatorhasbeensafelyusedduringpregnancy,butisnotfavourednow.
HypertensiveEmergency
Hypertensiveemergencyisararebutlife-threateningsituationcharacterizedbysevere
elevationsinbloodpressure(systolicgreaterthan180mmHgordiastolicgreaterthan120
mmHg)withevidenceofimpendingorprogressivetargetorgandamage(forexample,
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6. stroke,myocardialinfarction).[Note:Asevereelevationinbloodpressurewithoutevidence
oftargetorgandamageisconsideredahypertensiveurgency.]Hypertensiveemergencies
requiretimelybloodpressurereductionwithtreatmentadministeredintravenouslytoprevent
orlimittargetorgandamage.Avarietyofmedicationsareused,includingcalciumchannel
blockers(nicardipineandclevidipine),nitricoxidevasodilators(nitroprussideand
nitroglycerin),adrenergicreceptorantagonists(phentolamine,esmolol,andlabetalol),the
vasodilatorhydralazine,andthedopamineagonistfenoldopam.Treatmentisdirectedbythe
typeoftargetorgandamageand/orcomorbiditiespresent.
ResistantHypertension
Resistanthypertensionisdefinedasbloodpressurethatremainselevated(abovegoal)despite
administrationofanoptimalthree-drugregimenthatincludesadiuretic.Themostcommon
causesofresistanthypertensionarepoorcompliance,excessiveethanolintake,concomitant
conditions(diabetes,obesity,sleepapnea,hyperaldosteronism,highsaltintake,and/or
metabolicsyndrome),concomitantmedications(sympathomimetics,nonsteroidal
antiinflammatorydrugs,orcorticosteroids),insufficientdoseand/ordrugs,anduseofdrugs
withsimilarmechanismsofaction.
Diuretics
Forallclassesofdiuretics,theinitialmechanismofactionisbasedupondecreasingblood
volume,whichultimatelyleadstodecreasedbloodpressure.Routineserumelectrolyte
monitoringshouldbedoneforallpatientsreceivingdiuretics.
A.Thiazidediuretics
Thiazidediuretics,suchashydrochlorothiazideandchlorthalidone,lowerbloodpressure
initiallybyincreasingsodiumandwaterexcretion.Thiscausesadecreaseinextracellular
volume,resultinginadecreaseincardiacoutputandrenalbloodflow.Withlong-term
treatment,plasmavolumeapproachesanormalvalue,butahypotensiveeffectpersiststhatis
relatedtoadecreaseinperipheralresistance.Thiazidediureticscanbeusedasinitialdrug
therapyforhypertensionunlesstherearecompellingreasonstochooseanotheragent.
Thiazidesareusefulincombinationtherapywithavarietyofotherantihypertensiveagents,
includingβ-blockers,ACEinhibitors,ARBs,andpotassium-sparingdiuretics.Withthe
exceptionofmetolazone,thiazidediureticsarenoteffectiveinpatientswithinadequate
kidneyfunction(estimatedglomerularfiltrationratelessthan30mL/min/m2).Loopdiuretics
mayberequiredinthesepatients.Thiazidediureticscaninducehypokalemia,hyperuricemia,
and,toalesserextent,hyperglycemiainsomepatients.
B.Loopdiuretics
Theloopdiuretics(furosemide,torsemide,bumetanide,andethacrynicacid;)actpromptlyby
blockingsodiumandchloridereabsorptioninthekidneys,eveninpatientswithpoorrenal
functionorthosewhohavenotrespondedtothiazidediuretics.Loopdiureticscause
decreasedrenalvascularresistanceandincreasedrenalbloodflow.Likethiazides,theycan
causehypokalemia.However,unlikethiazides,loopdiureticsincreasethecalciumcontentof
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7. urine,whereasthiazidediureticsdecreaseit.Theseagentsarerarelyusedalonetotreat
hypertension,buttheyarecommonlyusedtomanagesymptomsofheartfailureandedema.
C.Potassium-sparingdiuretics
Amilorideandtriamtereneareinhibitorsofepithelialsodiumtransportatthelatedistaland
collectingducts,andspironolactoneandeplerenonearealdosteronereceptorantagonists.All
oftheseagentsreducepotassiumlossintheurine.Aldosteroneantagonistshavethe
additionalbenefitofdiminishingthecardiacremodelingthatoccursinheartfailure.
Potassium-sparingdiureticsaresometimesusedincombinationwithloopdiureticsand
thiazidestoreducetheamountofpotassiumlossinducedbythesediuretics.
β-Adrenoceptor–BlockingAgents
β-Blockersareatreatmentoptionforhypertensivepatientswithconcomitantheartdiseaseor
heartfailure.
A.Actions
Theβ-blockersreducebloodpressureprimarilybydecreasingcardiacoutput.Theymayalso
decreasesympatheticoutflowfromthecentralnervoussystem(CNS)andinhibittherelease
ofreninfromthekidneys,thusdecreasingtheformationofangiotensinIIandthesecretionof
aldosterone.Theprototypeβ-blockerispropranolol,whichactsatbothβ1andβ2receptors.
Selectiveblockersofβ1receptors,suchasmetoprololandatenolol,areamongthemost
commonlyprescribedβ-blockers.Nebivololisaselectiveblockerofβ1receptors,whichalso
increasestheproductionofnitricoxide,leadingtovasodilation.Theselectiveβ-blockersmay
beadministeredcautiouslytohypertensivepatientswhoalsohaveasthma.Thenonselective
β-blockersarecontraindicatedinpatientswithasthmaduetotheirblockadeofβ2mediated
bronchodilation.β-Blockersshouldbeusedcautiouslyinthetreatmentofpatientswithacute
heartfailureorperipheralvasculardisease.
Figure:Actionsofβ-adrenoceptor–blockingagents.
B.Therapeuticuses
Theprimarytherapeuticbenefitsofβ-blockersareseeninhypertensivepatientswith
concomitantheartdisease,suchas
●supraventriculartachyarrhythmia(forexample,atrialfibrillation),
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8. ●previousmyocardialinfarction,
●stableischemicheartdisease,
●andchronicheartfailure.
Conditionsthatdiscouragetheuseofβ-blockersincludereversiblebronchospasticdisease
suchas
●asthma,
●second-andthird-degreeheartblock,
●andsevereperipheralvasculardisease.
C.Pharmacokinetics
Theβ-blockersareorallyactiveforthetreatmentofhypertension.Propranololundergoes
extensiveandhighlyvariablefirst-passmetabolism.Oralβ-blockersmaytakeseveralweeks
todeveloptheirfulleffects.Esmolol,metoprolol,andpropranololareavailablein
intravenousformulations.
D.Adverseeffects
1.Commoneffects
Someoftheadverseeffectsofβ-blockers.
●Hypertension
●Bradycardia
●Fatigue
●Insomnia
●Sexualdysfunction
Theβ-blockersmaydecreaselibidoandcauseerectiledysfunction,whichcanseverely
reducepatientcompliance.
2.Alterationsinserumlipidpatterns:Noncardioselectiveβ-blockersmaydisturblipid
metabolism,decreasinghigh-densitylipoproteincholesterolandincreasingtriglycerides.
3.Drugwithdrawal:Abruptwithdrawalmayinduceseverehypertension,angina,myocardial
infarction,andevensuddendeathinpatientswithischemicheartdisease.Therefore,these
drugsmustbetaperedoverafewweeksinpatientswithhypertensionandischemicheart
disease.
ACEInhibitors
ACEinhibitorssuchascaptopril,enalapril,andlisinoprilarerecommendedasfirst-line
treatmentofhypertensioninpatientswithavarietyofcompellingindications,includinghigh
coronarydiseaseriskorhistoryofdiabetes,stroke,heartfailure,myocardialinfarction,or
chronickidneydisease.
A.Actions
TheACEinhibitorslowerbloodpressurebyreducingperipheralvascularresistancewithout
reflexivelyincreasingcardiacoutput,heartrate,orcontractility.Thesedrugsblockthe
enzymeACE,whichcleavesangiotensinItoformthepotentvasoconstrictorangiotensinII.
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9. ACEisalsoresponsibleforthebreakdownofbradykinin,apeptidethatincreasesthe
productionofnitricoxideandprostacyclinbythebloodvessels.Bothnitricoxideand
prostacyclinarepotentvasodilators.Vasodilationofbotharteriolesandveinsoccursasa
resultofdecreasedvasoconstriction(fromdiminishedlevelsofangiotensinII)andenhanced
vasodilation(fromincreasedbradykinin).ByreducingcirculatingangiotensinIIlevels,ACE
inhibitorsalsodecreasethesecretionofaldosterone,resultingindecreasedsodiumandwater
retention.ACEinhibitorsreducebothcardiacpreloadandafterload,therebydecreasing
workloadontheheart.
B.Therapeuticuses
●ACEinhibitorsslowtheprogressionofdiabeticnephropathyanddecrease
albuminuriaand,thus,haveacompellingindicationforuseinpatientswithdiabetic
nephropathy.
●Beneficialeffectsonrenalfunctionmayresultfromdecreasingintraglomerular
pressures,duetoefferentarteriolarvasodilation.
●ACEinhibitorsareastandardinthecareofapatientfollowingamyocardial
infarctionandfirst-lineagentsinthetreatmentofpatientswithsystolicdysfunction.
●ChronictreatmentwithACEinhibitorsachievessustainedbloodpressurereduction,
regressionofleftventricularhypertrophy,andpreventionofventricularremodeling
afteramyocardialinfarction.
●ACEinhibitorsarefirst-linedrugsfortreatingheartfailure,hypertensivepatientswith
chronickidneydisease,andpatientsatincreasedriskofcoronaryarterydisease.
●AlloftheACEinhibitorsareequallyeffectiveinthetreatmentofhypertensionat
equivalentdoses.
C.Pharmacokinetics
AlloftheACEinhibitorsareorallybioavailableasadrugorprodrug.Allbutcaptopriland
lisinoprilundergohepaticconversiontoactivemetabolites,sotheseagentsmaybepreferred
inpatientswithseverehepaticimpairment.FosinoprilistheonlyACEinhibitorthatisnot
eliminatedprimarilybythekidneys.Therefore,itdoesnotrequiredoseadjustmentinpatients
withrenalimpairment.Enalaprilatistheonlydruginthisclassavailableintravenously.
D.Adverseeffects
SomeofthecommonadverseeffectsofACEinhibitors.
●Drycough
●Hyperkalemia
●Skinrash
●Hypotension
●Alteredtaste
Thedrycough,whichoccursinupto10%ofpatients,isthoughttobeduetoincreasedlevels
ofbradykininandsubstancePinthepulmonarytree,anditoccursmorefrequentlyin
women.Thecoughresolveswithinafewdaysofdiscontinuation.Angioedemaisararebut
potentiallylife-threateningreactionthatmayalsobeduetoincreasedlevelsofbradykinin.
PotassiumlevelsmustbemonitoredwhileonACEinhibitors,andpotassiumsupplements
andpotassium-sparingdiureticsshouldbeusedwithcautionduetotheriskofhyperkalemia.
8

10. Serumcreatininelevelsshouldalsobemonitored,particularlyinpatientswithunderlying
renaldisease.However,anincreaseinserumcreatinineofupto30%abovebaselineis
acceptableandbyitselfdoesnotwarrantdiscontinuationoftreatment.ACEinhibitorscan
inducefetalmalformationsandshouldnotbeusedbypregnantwomen.
AngiotensinIIReceptorBlockers
Mechanismofaction
TheARBs,suchaslosartanandirbesartan,blocktheAT1receptors,decreasingtheactivation
ofAT1receptorsbyangiotensinII.TheirpharmacologiceffectsaresimilartothoseofACE
inhibitorsinthattheyproducearteriolarandvenousdilationandblockaldosteronesecretion,
thusloweringbloodpressureanddecreasingsaltandwaterretention.ARBsdonotincrease
bradykininlevels.
Therapeuticuses
Theymaybeusedasfirst-lineagentsforthetreatmentofhypertension,especiallyinpatients
withacompellingindicationofdiabetes,heartfailure,orchronickidneydisease.
Adverseeffects
AdverseeffectsaresimilartothoseofACEinhibitors,althoughtherisksofcoughand
angioedemaaresignificantlydecreased.
●Drycough
●Hyperkalemia
●Skinrash
●Hypotension
●Alteredtaste
ARBsshouldnotbecombinedwithanACEinhibitorforthetreatmentofhypertensiondueto
similarmechanismsandadverseeffects.Theseagentsarealsoteratogenicandshouldnotbe
usedbypregnantwomen.
ReninInhibitor
Aselectiverenininhibitor,aliskiren,isavailableforthetreatmentofhypertension.Aliskiren
directlyinhibitsreninand,thus,actsearlierintherenin–angiotensin–aldosteronesystemthan
ACEinhibitorsorARBs.AliskirenshouldnotbecombinedwithanACEinhibitororARBin
thetreatmentofhypertension.Aliskirencancausediarrhea,especiallyathigherdoses.Italso
causescoughandangioedemabutlessoftenthanACEinhibitors.AswithACEinhibitors
andARBs,aliskireniscontraindicatedduringpregnancy.Aliskirenismetabolizedby
CYP3A4andissubjecttomanydruginteractions.
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11. CalciumChannelBlockers
Calciumchannelblockersarearecommendedfirst-linetreatmentoptioninblackpatients.
Theymayalsobeusefulinhypertensivepatientswithdiabetesorstableischemicheart
disease.Highdosesofshort-actingcalciumchannelblockersshouldbeavoidedbecauseof
increasedriskofmyocardialinfarctionduetoexcessivevasodilationandmarkedreflex
cardiacstimulation.
A.Classesofcalciumchannelblockers
Thecalciumchannelblockersaredividedintothreechemicalclasses,eachwithdifferent
pharmacokineticpropertiesandclinicalindications.
1.Diphenylalkylamines
VerapamilistheonlymemberofthisclassthatisavailableintheUnitedStates.Verapamil
hassignificanteffectsonbothcardiacandvascularsmoothmusclecells.Itisalsousedto
treatanginaandsupraventriculartachyarrhythmiasandtopreventmigraineandcluster
headaches.
2.Benzothiazepines
DiltiazemistheonlymemberofthisclassthatiscurrentlyapprovedintheUnitedStates.
Likeverapamil,diltiazemaffectsbothcardiacandvascularsmoothmusclecells,butithasa
lesspronouncednegativeinotropiceffectontheheartcomparedtothatofverapamil.
Diltiazemhasafavorablesideeffectprofile.
3.Dihydropyridines
Thisclassofcalciumchannelblockersincludesnifedipine(theprototype),amlodipine,
felodipine,isradipine,nicardipine,andnisoldipine.Theseagentsdifferinpharmacokinetics,
approveduses,anddruginteractions.Alldihydropyridineshaveamuchgreateraffinityfor
vascularcalciumchannelsthanforcalciumchannelsintheheart.Theyare,therefore,
particularlybeneficialintreatinghypertension.Thedihydropyridineshavetheadvantagein
thattheyshowlittleinteractionwithothercardiovasculardrugs,suchasdigoxinorwarfarin,
whichareoftenusedconcomitantlywithcalciumchannelblockers.
B.Actions
Theintracellularconcentrationofcalciumplaysanimportantroleinmaintainingthetoneof
smoothmuscleandinthecontractionofthemyocardium.Calciumchannelantagonistsblock
theinwardmovementofcalciumbybindingtoL-typecalciumchannelsintheheartandin
smoothmuscleofthecoronaryandperipheralarteriolarvasculature.Thiscausesvascular
smoothmuscletorelax,dilatingmainlyarterioles.Calciumchannelblockersdonotdilate
veins.
C.Therapeuticuses
●Inthemanagementofhypertension,CCBsmaybeusedasaninitialtherapyoras
add-ontherapy.
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12. ●Theyareusefulinthetreatmentofhypertensivepatientswhoalsohaveasthma,
diabetes,and/orperipheralvasculardisease,becauseunlikeβ-blockers,theydonot
havethepotentialtoadverselyaffecttheseconditions.
●AllCCBsareusefulinthetreatmentofangina.
●Inaddition,diltiazemandverapamilareusedinthetreatmentofatrialfibrillation.
D.Pharmacokinetics
Mostoftheseagentshaveshorthalf-lives(3to8hours)followinganoraldose.
Sustained-releasepreparationsareavailableandpermitonce-dailydosing.Amlodipinehasa
verylonghalf-lifeanddoesnotrequireasustained-releaseformulation.
E.Adverseeffects
●Flushing
●Dizziness
●Headache
●Hypotension
●Peripheraledema
First-degreeatrioventricularblockandconstipationarecommondose-dependentsideeffects
ofverapamil.Verapamilanddiltiazemshouldbeavoidedinpatientswithheartfailureorwith
atrioventricularblockduetotheirnegativeinotropic(forceofcardiacmusclecontraction)
anddromotropic(velocityofconduction)effects.Dizziness,headache,andafeelingof
fatiguecausedbyadecreaseinbloodpressurearemorefrequentwithdihydropyridines.
Peripheraledemaisanothercommonlyreportedsideeffectofthisclass.Nifedipineandother
dihydropyridinesmaycausegingivalhyperplasia.
α-ADRENOCEPTOR–BLOCKINGAGENTS
α-Adrenergicblockersusedinthetreatmentofhypertensionincludeprazosin,doxazosin,and
terazosin.
Mechanismofaction
Theseagentsproduceacompetitiveblockofα1-adrenoceptors.Theydecreaseperipheral
vascularresistanceandlowerarterialbloodpressurebycausingrelaxationofbotharterial
andvenoussmoothmuscle.Thesedrugscauseonlyminimalchangesincardiacoutput,renal
bloodflow,andglomerularfiltrationrate.
Adverseeffect
●saltandwaterretention
●Reflextachycardia
●posturalhypotension
●Sexualdysfunction
●Dizziness,headache,fatigue,nasalcongestion
Therapeuticuses
●hypertension
●benignprostatichyperplasia
●Raynaud'sdisease
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13. Contraindications
●Hypotension
●Allergytothedrug
a-/b-Adrenoceptor–blockingAgents
Labetalolandcarvedilolblockα1,β1,andβ2receptors.Carvedilolisindicatedinthe
treatmentofheartfailureandhypertension.Ithasbeenshowntoreducemorbidityand
mortalityassociatedwithheartfailure.Labetalolisusedinthemanagementofgestational
hypertensionandhypertensiveemergencies.
CentrallyActingAdrenergicDrugs
A.Clonidine
Clonidineactscentrallyasanα2agonisttoproduceinhibitionofsympatheticvasomotor
centers,decreasingsympatheticoutflowtotheperiphery.Thisleadstoreducedtotal
peripheralresistanceanddecreasedbloodpressure.Clonidineisusedprimarilyforthe
treatmentofhypertensionthathasnotrespondedadequatelytotreatmentwithtwoormore
drugs.Clonidinedoesnotdecreaserenalbloodfloworglomerularfiltrationand,therefore,is
usefulinthetreatmentofhypertensioncomplicatedbyrenaldisease.Clonidineiswell
absorbedafteroraladministrationandisexcretedbythekidney.Itisalsoavailableina
transdermalpatch.Adverseeffectsincludesedation,drymouth,andconstipation.Rebound
hypertensionoccursfollowingabruptwithdrawalofclonidine.Thedrugshould,therefore,be
withdrawnslowlyifdiscontinuationisrequired.
B.Methyldopa
Methyldopaisanα2agonistthatisconvertedtomethylnorepinephrinecentrallytodiminish
adrenergicoutflowfromtheCNS.Themostcommonsideeffectsofmethyldopaaresedation
anddrowsiness.Itsuseislimitedduetoadverseeffectsandtheneedformultipledailydoses.
Itismainlyusedformanagementofhypertensioninpregnancy,whereithasarecordof
safety.
Vasodilators
Thedirect-actingsmoothmusclerelaxants,suchashydralazineandminoxidil,arenotusedas
primarydrugstotreathypertension.Thesevasodilatorsactbyproducingrelaxationof
vascularsmoothmuscle,primarilyinarteriesandarterioles.Thisresultsindecreased
peripheralresistanceand,therefore,bloodpressure.Bothagentsproducereflexstimulationof
theheart,resultinginthecompetingreflexesofincreasedmyocardialcontractility,heartrate,
andoxygenconsumption.Theseactionsmaypromptanginapectoris,myocardialinfarction,
orcardiacfailureinpredisposedindividuals.Vasodilatorsalsoincreaseplasmarenin
concentration,resultinginsodiumandwaterretention.Theseundesirablesideeffectscanbe
blockedbyconcomitantuseofadiuretic(todecreasesodiumretention)andaβ-blocker(to
12

14. balancethereflextachycardia).Together,thethreedrugsdecreasecardiacoutput,plasma
volume,andperipheralvascularresistance.Hydralazineisanacceptedmedicationfor
controllingbloodpressureinpregnancy-inducedhypertension.Adverseeffectsofhydralazine
includeheadache,tachycardia,nausea,sweating,arrhythmia,andprecipitationofangina.A
lupus-likesyndromecanoccurwithhighdosages,butitisreversibleupondiscontinuationof
thedrug.Minoxidiltreatmentcauseshypertrichosis(thegrowthofbodyhair).Thisdrugis
usedtopicallytotreatmalepatternbaldness.
Hydralazine/Dihydralazine
Introducedinthe1950s,itisadirectlyactingarteriolarvasodilatorwithlittleactionon
venouscapacitancevessels.Hydralazinereducest.p.r.andcausesgreaterdecreaseindiastolic
thaninsystolicBP.Reflexcompensatorymechanismsareevokedwhichcausetachycardia,
increaseinc.o.andreninrelease→increasedaldosterone→Na+andwaterretention.
Pharmacokinetics
Hydralazineiswellabsorbedorally,andissubjectedtofirstpassmetabolisminliver.
Hydralazineiscompletelymetabolizedbothinliverandplasma;themetabolitesareexcreted
inurine.
Dose:25–50mgOD–TDS.
Adverseeffects
•Facialflushing,conjunctivalinjection,throbbingheadache,dizziness,palpitation,nasal
stuffiness,fluidretention,edema,CHF.
•AnginaandMImaybeprecipitatedinpatientswithcoronaryarterydisease.
•Posturalhypotensionisnotprominentbecauseoflittleactiononveins.
•Paresthesias,tremor,musclecramps,rarelyperipheralneuritis.Gastrointestinaldisturbances
arefrequent.
Use
Hydralazineisnowrarelyusedasasecondlinealternativeonlyincombinationwitha
diureticand/orβblockerforpatientsnotachievingtargetBPwithfirstlinedrugs.Itisoneof
theantihy-pertensivesthathasbeenusedduringpregnancy,especiallyforpreeclampsia.
Injectedhydralazineisoccasionallyemployedinhypertensiveemergen-cies.Itis
contraindicatedinolderpatientsandinthosewithischaemicheartdisease.
13

15. Diuretics
Overview
Diureticsaredrugsthatincreasethevolumeofurineexcreted.Mostdiureticagentsare
inhibitorsofrenaliontransportersthatdecreasethereabsorptionofNa+atdifferentsitesin
thenephron.Asaresult,Na+andotherionsentertheurineingreaterthannormalamounts
alongwithwater,whichiscarriedpassivelytomaintainosmoticequilibrium.Diuretics,thus,
increasethevolumeofurineandoftenchangeitspH,aswellastheioniccompositionofthe
urineandblood.Thediureticeffectofthedifferentclassesofdiureticsvariesconsiderably
withthesiteofaction.Inadditiontotheiontransportinhibitors,othertypesofdiuretics
includeosmoticdiuretics,aldosteroneantagonists,andcarbonicanhydraseinhibitors.While
diureticsaremostcommonlyusedformanagementofexcessivefluidretention(edema),
manyagentswithinthisclassareprescribedfornon-diureticindicationsorforsystemic
effectsinadditiontotheiractionsonthekidney.Examples,whicharediscussedbelow,
includeuseofthiazidesinhypertension,useofcarbonicanhydraseinhibitorsinglaucoma,
anduseofaldosteroneantagonistsinheartfailure.
Figure:Summaryofdiureticdrugs.
Classificationofdiureticsaccordingtositeofaction
Site-I(PCT):2types
Osmoticdiureticse.gmannitol,urea
carbonicanhydraseinhibitorse.gAcetazolamide,ethoxazolamide
Site-II(ALLH):Highceilingdiureticse.gfrusemide,bumetamide
Site-III(DCT):moderateefficacydiureticse.gthiazide
Site-IV(collectingduct):potassiumsparingdiureticse.gspironolactone,amiloride
14

16. Classificationofdiureticsaccordingtopotency
A.Highceilingdiureticse.gfrusemide,bumetamide
B.moderateefficacydiureticse.gthiazide
C.lowefficacydiuretics
●Osmoticdiureticse.gmannitol,urea
●potassiumsparingdiureticse.gspironolactone,amiloride
●carbonicanhydraseinhibitorse.gAcetazolamide,ethoxazolamide
NormalRegulationofFluidandElectrolytesbytheKidneys
Approximately16%to20%ofthebloodplasmaenteringthekidneysisfilteredfromthe
glomerularcapillariesintoBowman'scapsule.Thefiltrate,althoughnormallyfreeofproteins
andbloodcells,containsmostofthelowmolecularweightplasmacomponentsin
concentrationssimilartothatintheplasma.Theseincludeglucose,sodiumbicarbonate,
aminoacids,andotherorganicsolutes,aswellaselectrolytes,suchasNa+,K+,andCl−.The
kidneyregulatestheioniccompositionandvolumeofurinebyactivereabsorptionor
secretionofionsand/orpassivereabsorptionofwateratfivefunctionalzonesalongthe
nephron:
1)theproximalconvolutedtubule,
2)thedescendingloopofHenle,
3)theascendingloopofHenle,
4)thedistalconvolutedtubule,and
5)thecollectingtubuleandduct.
Figure:Majorlocationsofionandwaterexchangeinthenephron,showingsitesofactionof
thediureticdrugs.
15

17. A.Proximalconvolutedtubule
Intheproximalconvolutedtubulelocatedinthecortexofthekidney,almostalltheglucose,
bicarbonate,aminoacids,andothermetabolitesarereabsorbed.Approximately65%ofthe
filteredNa+(andwater)isreabsorbed.Giventhehighwaterpermeability,about60%of
waterisreabsorbedfromthelumentothebloodtomaintainosmolarequality.Chlorideenters
thelumenofthetubuleinexchangeforananion,suchasoxalate,aswellasparacellularly
throughthelumen.TheNa+thatisreabsorbedispumpedintotheinterstitiumbythe
Na+/K+adenosinetriphosphatase(ATPase)pump.Carbonicanhydraseintheluminal
membraneandcytoplasmoftheproximaltubularcellsmodulatesthereabsorptionof
bicarbonate.DespitehavingthehighestpercentageoffilteredNa+thatisreabsorbed,
diureticsworkingintheproximalconvolutedtubuledisplayweakdiureticproperties.The
presenceofahighcapacityNa+andwaterreabsorptionarea(loopofHenle)distaltothe
proximalconvolutedtubuleallowsreabsorptionofNa+andwaterkeptinthelumenby
diureticsactingintheproximalconvolutedtubule,andlimitseffectivediuresis.
Figure:Proximalconvolutedtubulecell.
Theproximaltubuleisthesiteoftheorganicacidandbasesecretorysystems.Theorganic
acidsecretorysystem,locatedinthemiddle-thirdoftheproximaltubule,secretesavarietyof
organicacids,suchasuricacid,someantibiotics,anddiuretics,fromthebloodstreamintothe
proximaltubularlumen.Theorganicacidsecretorysystemissaturable,anddiureticdrugsin
thebloodstreamcompetefortransferwithendogenousorganicacidssuchasuricacid.A
numberofotherinteractionscanalsooccur.Forexample,probenecidinterfereswith
penicillinsecretion.Theorganicbasesecretorysystem,locatedintheupperandmiddle
segmentsoftheproximaltubule,isresponsibleforthesecretionofcreatinineandcholine.
B.DescendingloopofHenle
Theremainingfiltrate,whichisisotonic,nextentersthedescendinglimboftheloopofHenle
andpassesintothemedullaofthekidney.Theosmolarityincreasesalongthedescending
portionoftheloopofHenlebecauseofthecountercurrentmechanismthatisresponsiblefor
16

18. waterreabsorption.Thisresultsinatubularfluidwithathree-foldincreaseinNa+andCl−
concentration.Osmoticdiureticsexertpartoftheiractioninthisregion.
C.AscendingloopofHenle
Thecellsoftheascendingtubularepitheliumareuniqueinbeingimpermeabletowater.
ActivereabsorptionofNa+,K+,andCl−ismediatedbyaNa+/K+/2Cl−cotransporter.Both
Mg2+andCa2+arereabsorbedviatheparacellularpathway.Thus,theascendingloopdilutes
thetubularfluidandraisestheosmolarityofthemedullaryinterstitium.Approximately25%
to30%ofthefilteredsodiumchlorideisabsorbedhere.BecausetheascendingloopofHenle
isamajorsiteforsaltreabsorptionandnosegmentsdistallyarecapableofsignificantNa+
andwaterreabsorption,drugsaffectingthissite,suchasloopdiuretics,havethegreatest
diureticeffect.
ThickAscendinglimpofloopofHenleiscalleddilutingsegmentforfollowingreasons:
Thethickascendinglimb,whichfollowsthethinlimbofHenle,activelyreabsorbsodium
chloridefromthelumenbutunliketheproximaltubuleandthethindescendinglimbof
Henle's,itisnearlyimpermeabletowater.SaltreabsorptionintheTAL,thereforedilutesthe
tubularfluidandforthisreason,theTALiscalledadilutingsegment.
Figure:AscendingloopofHenlecell.
D.Distalconvolutedtubule
Thecellsofthedistalconvolutedtubulearealsoimpermeabletowater.About5%to10%of
thefilteredsodiumchlorideisreabsorbedviaaNa+/Cl−transporter,thetargetofthiazide
diuretics.Calciumreabsorption,undertheregulationofparathyroidhormone,ismediatedby
anapicalchannelandthentransportedbyaNa+/Ca2+-exchangerintotheinterstitialfluid.
17

19. Figure:Distalconvolutedtubulecell.
E.Collectingtubuleandduct
TheprincipalcellsofthecollectingtubuleandductareresponsibleforNa+,K+,andwater
transport,whereastheintercalatedcellsaffectH+secretion.Approximately1%to2%ofthe
filteredsodiumenterstheprincipalcellsthroughepithelialsodiumchannelsthatareinhibited
byamilorideandtriamterene.Onceinsidethecell,Na+reabsorptionreliesona
Na+/K+-ATPasepumptobetransportedintotheblood.Aldosteronereceptorsintheprincipal
cellsinfluenceNa+reabsorptionandK+secretion.Aldosteroneincreasesthesynthesisof
epithelialsodiumchannelsandoftheNa+/K+-ATPasepumptoincreaseNa+reabsorption
andK+excretion.Antidiuretichormone(ADH;vasopressin)bindstoV2receptorsto
promotethereabsorptionofwaterthroughaquaporinchannels.
Figure:Collectingtubuleandductcells.ENachannel=Epithelialsodiumchannel.
18

20. Thiazides
Chlorothiazidewasthefirstorallyactivethiazide,althoughhydrochlorothiazideand
chlorthalidonearenowusedmorecommonlyduetobetterbioavailability.
Hydrochlorothiazideismorepotent,sotherequireddoseisconsiderablylowerthanthatof
chlorothiazide,buttheefficacyiscomparabletothatoftheparentdrug.Inallotheraspects,
hydrochlorothiazideresembleschlorothiazide.Chlorthalidoneisapproximatelytwiceas
potentashydrochlorothiazide.Chlorthalidone,indapamide,andmetolazonearereferredtoas
thiazide-likediureticsbecausetheylackthecharacteristicbenzothiadiazinechemical
structure;however,theirmechanismofaction,indications,andadverseeffectsaresimilarto
thoseofhydrochlorothiazide.
1.Mechanismofaction
Thethiazideandthiazide-likediureticsactmainlyinthedistalconvolutedtubuletodecrease
thereabsorptionofNa+byinhibitionofaNa+/Cl−cotransporter.Asaresult,thesedrugs
increasetheconcentrationofNa+andCl−inthetubularfluid.Thiazidesmustbeexcreted
intothetubularlumenattheproximalconvolutedtubuletobeeffective.Therefore,
decreasingrenalfunctionreducesthediureticeffects.Theantihypertensiveeffectsof
thiazidesmaypersistevenwhentheglomerularfiltrationrateisbelow30mL/min/1.73m
2
.
However,hypertensionatthislevelofrenaldysfunctionisoftenexacerbatedby
hypervolemia,requiringachangetoloopdiureticsforvolumestatusand,therefore,blood
pressurecontrol.Theefficacyofthiazidesmaybediminishedwithconcomitantuseof
nonsteroidalanti-inflammatorydrugs(NSAIDs),suchasindomethacin,whichinhibit
productionofrenalprostaglandins,therebyreducingrenalbloodflow.
2.Actions
a.IncreasedexcretionofNa+andCl−
Thiazideandthiazide-likediureticscausediuresiswithincreasedNa+andCl−excretion,
whichcanresultintheexcretionofveryhyperosmolar(concentrated)urine.Thislattereffect
isunique,astheotherdiureticclassesareunlikelytoproduceahyperosmolarurine.
b.Decreasedurinarycalciumexcretion
Thiazideandthiazide-likediureticsdecreasetheCa2+contentofurinebypromotingthe
reabsorptionofCa2+inthedistalconvolutedtubulewhereparathyroidhormoneregulates
reabsorption.
c.Reducedperipheralvascularresistance
Aninitialreductioninbloodpressureresultsfromadecreaseinbloodvolumeand,therefore,
adecreaseincardiacoutput.Withcontinuedtherapy,bloodvolumereturnstobaseline.
However,antihypertensiveeffectscontinue,resultingfromreducedperipheralvascular
resistancecausedbyrelaxationofarteriolarsmoothmuscle.
19

21. 3.Therapeuticuses
a.Hypertension
Clinically,thiazidesareamainstayofantihypertensivetreatment,becausetheyare
inexpensive,convenientto
administer,andwelltolerated.Bloodpressurecanbeloweredwithadailydoseofthiazide.
Atdosesequipotenttohydrochlorothiazide,chlorthalidoneisconsideredapreferredoption
bysomecliniciansbecauseofitslongerhalflife(50to60hours)andimprovedcontrolof
bloodpressureovertheentireday.However,currenttreatmentguidelinesforhypertensiondo
notrecommendanythiazidepreferentially.
b.Heartfailure
Loopdiuretics(notthiazides)arethediureticsofchoiceinreducingextracellularvolumein
heartfailure.However,thiazidediureticsmaybeaddedinpatientsresistanttoloopdiuretics,
withcarefulmonitoringforhypokalemia.Metolazoneismostfrequentlyutilizedasan
additiontoloopdiuretics,althoughthereisalackofevidencethatitismoreeffectivethan
otherthiazidesforthisindicationwhenadministeredatequipotentdoses.Historically,
thiazideswereprescribedtobeadministered30minutespriortoloopdiureticstoallowthe
thiazidetimetoreachthesiteofactionwhencombinedtoaugmentdiuresisindiuretic
resistance.Thispracticeisunnecessaryandnotsupportedbycurrentevidence.
c.Hypercalciuria
Thethiazidescanbeusefulintreatingidiopathichypercalciuriaandcalciumoxalatestonesin
theurinarytract,becausetheyinhibiturinaryCa2+excretion.
d.Diabetesinsipidus
Thiazideshavetheuniqueabilitytoproduceahyperosmolarurine.Thiazidescanbeutilized
asatreatmentfornephrogenicdiabetesinsipidus.Theurinevolumeofsuchindividualsmay
dropfrom11toabout3L/dwhentreatedwiththiazides.
4.Pharmacokinetics
Asaclass,thiazidesareeffectiveorally,withabioavailabilityof60%to70%.Chlorothiazide
hasamuchlowerbioavailability(15%to30%)andistheonlythiazidewithanintravenous
dosageform.Mostthiazidestake1to3weekstoproduceastablereductioninbloodpressure
andexhibitaprolongedhalf-life(approximately10to15hours).Indapamidediffersfromthe
classbecauseitundergoeshepaticmetabolismandisexcretedinboththeurineandbile.
Mostthiazidesareprimarilyexcretedunchangedintheurine.
5.Adverseeffects
Thesemainlyinvolveproblemsinfluidandelectrolytebalance.
a.Hypokalemia
Hypokalemiaisthemostfrequentproblemwiththethiazidediuretics.Becausethiazides
increaseNa+inthefiltratearrivingatthedistaltubule,moreK+isalsoexchangedforNa+,
resultinginacontinuallossofK+fromthebodywithprolongeduseofthesedrugsThus,
serumK+shouldbemeasuredperiodically(morefrequentlyatthebeginningoftherapy)to
monitorforthedevelopmentofhypokalemia.Potassiumsupplementationorcombination
withapotassium-sparingdiureticmayberequired.Low-sodiumdietsbluntthepotassium
depletioncausedbythiazidediuretics.
20

22. b.Hypomagnesemia
Urinarylossofmagnesiumcanleadtohypomagnesemia.
c.Hyponatremia
HyponatremiamaydevelopduetoelevationofADH,aswellasdiminisheddilutingcapacity
ofthekidneyandincreasedthirst.
d.Hyperuricemia
Thiazidesincreaseserumuricacidbydecreasingtheamountofacidexcretedthrough
competitionintheorganicacidsecretorysystem.Beinginsoluble,uricaciddepositsinthe
jointsandmayprecipitateagoutyattackinpredisposedindividuals.Therefore,thiazides
shouldbeusedwithcautioninpatientswithgoutorhighlevelsofuricacid.
e.Hypovolemia
Thiscancauseorthostatichypotensionorlight-headedness.
f.Hypercalcemia
ThiazidesinhibitthesecretionofCa2+,sometimesleadingtohypercalcemia(elevatedlevels
ofCa2+intheblood).
g.Hyperglycemia
Therapywiththiazidescanleadtomildelevationsinserumglucose,possiblyduetoimpaired
releaseofinsulinrelatedtohypokalemia.Patientswithdiabetesstillbenefitfromthiazide
therapy,butshouldmonitorglucosetoassesstheneedforanadjustmentindiabetestherapyif
thiazidesareinitiated.
6.Contraindications
Excessiveuseofanydiureticisdangerousinpatientswithhepaticcirrhosis,borderlinerenal
failure,orheartfailure.
7.DosesofThiazidesandrelateddiuretics.
21

23. LoopDiuretics
Bumetanide,furosemide,torsemide,andethacrynicacidhavetheirmajordiureticactionon
theascendinglimboftheloopofHenle.Ofallthediuretics,thesedrugshavethehighest
efficacyinmobilizingNa+andCl−fromthebody,producingcopiousamountsofurine.
Similartothiazides,loopdiureticsdonotgenerallycausehypersensitivityreactionsin
patientswithallergiestosulfonamideantimicrobialssuchassulfamethoxazolebecauseof
structuraldifferencesintheirsulfonamidederivative.Furosemideisthemostcommonlyused
ofthesedrugs.Theuseofbumetanideandtorsemideisincreasing,astheseagentshavebetter
bioavailabilityandaremorepotentcomparedtofurosemide.Ethacrynicacidisused
infrequentlyduetoitsadverseeffectprofile.
Loopdiureticsarecalledhighceilingdiureticsforthefollowingreasons.
1.Theyareverypotent
2.Progressiveincreasesindosesismatchedbyincreasingindiuresis
3.Canactinsevererenalandheartfailurewhereotherdiureticsfail
4.Rapidonstateofaction
5.Shortdurationofaction
6.Noneedofcombinationtopotentialitsaction
A.Bumetanide,furosemide,torsemide,andethacrynicacid
1.Mechanismofaction
LoopdiureticsinhibitthecotransportofNa+/K+/2Cl−intheluminalmembraneinthe
ascendinglimboftheloopofHenle.Therefore,reabsorptionoftheseionsintotherenal
medullaisdecreased.Byloweringtheosmoticpressureinthemedulla,lesswateris
reabsorbedfromwaterpermeablesegments,likethedescendingloopofHenle,causing
diuresis.Theseagentshavethegreatestdiureticeffectofallthediureticsbecausethe
ascendinglimbaccountsforreabsorptionof25%to30%offilteredNaClanddownstream
sitesareunabletocompensatefortheincreasedNa+load.Loopdiureticsmustbeexcreted
intothetubularlumenattheproximalconvolutedtubuletobeeffective.NSAIDsinhibit
renalprostaglandinsynthesisandcanreducethediureticactionofloopdiuretics.
2.Actions
a.Diuresis
Loopdiureticscausediuresis,eveninpatientswithpoorrenalfunctionorlackofresponseto
otherdiuretics.Loopdiureticsdisplayasigmoidal(“S”-shaped)dose-responsecurvewith
threeparts:athresholdeffect,arapidincreaseindiuresiswithsmallchangesindrug
concentration,andaceilingeffect.Adosemustbeselectedtocrosstheresponsethreshold,
whichispatient-specific.Reducingtheeffectivedosewiththeintentofareductionin
diuresiscanresultinnodiuresis,iftheconcentrationofloopdiureticdropsbelowthe
responsethreshold.Likewise,increasingtheeffectivedosemaynotcausemorediuresis
becauseoftheceilingeffect.Thus,afterdeterminationofaneffectivediureticdose,the
22

24. clinicianshouldmodifythefrequencyofadministrationtoincreaseordecreasethedaily
diuresis.
b.Increasedurinarycalciumexcretion
Unlikethiazides,loopdiureticsincreasetheCa2+contentofurine.Inpatientswithnormal
serumCa2+concentrations,hypocalcemiadoesnotresult,becauseCa2+isreabsorbedinthe
distalconvolutedtubule.
c.Venodilation
Priortotheirdiureticactions,loopdiureticscauseacutevenodilationandreduceleft
ventricularfillingpressuresviaenhancedprostaglandinsynthesis.
3.Therapeuticuses
a.Edema
Loopdiureticsarethedrugsofchoicefortreatmentofpulmonaryedemaandacute/chronic
peripheraledemacausedfromheartfailureorrenalimpairment.Becauseoftheirrapidonset
ofaction,particularlywhengivenintravenously,thedrugsareusefulinemergencysituations
suchasacutepulmonaryedema.
b.Hypercalcemia
Loopdiuretics(alongwithhydration)arealsousefulintreatinghypercalcemia,becausethey
stimulatetubularCa2+excretion.
c.Hyperkalemia
Loopdiureticscanbeusedwithorwithoutreplacementintravenousfluidforthetreatmentof
hyperkalemia.
4.Pharmacokinetics
Loopdiureticsareadministeredorallyorparenterally.Furosemidehasunpredictable
bioavailabilityof10%to90%afteroraladministration.Bumetanideandtorsemidehave
reliablebioavailabilityof80%to100%,whichmakestheseagentspreferredfororaltherapy.
Thedurationofactionisapproximately6hoursforfurosemideandbumetanide,and
moderatelylongerfortorsemide,allowingpatientstopredictthewindowofdiuresis.
5.Effects
Fluidandelectrolyteissuesarethepredominantadverseeffects.
a.Acutehypovolemia
Loopdiureticscancauseasevereandrapidreductioninbloodvolume,withthepossibilityof
hypotension,shock,andcardiacarrhythmias.
b.Hypokalemia
TheheavyloadofNa+presentedtothecollectingtubuleresultsinincreasedexchangeof
tubularNa+forK+,leadingtohypokalemia,themostcommonadverseeffectoftheloop
diuretics.ThelossofK+fromcellsinexchangeforH+leadstohypokalemicalkalosis.Use
ofpotassium-sparingdiureticsorsupplementationwithK+canpreventthedevelopmentof
hypokalemia.
c.Hypomagnesemia
Urinarylossofmagnesiumcanleadtohypomagnesemia.
23

25. d.Ototoxicity
Reversibleorpermanenthearinglossmayoccurwithloopdiuretics,particularlywhen
infusedintravenouslyatfastrates,athighdoses,orwhenusedinconjunctionwithother
ototoxicdrugs(forexample,aminoglycosideantibiotics).Withcurrentdosingand
appropriateinfusionrates,ototoxicityisarareoccurrence.Ethacrynicacidisthemostlikely
tocauseototoxicity.Althoughlesscommon,vestibularfunctionmayalsobeaffected,
inducingvertigo.
e.Hyperuricemia
Loopdiureticscompetewithuricacidfortherenalsecretorysystems,thusblockingits
secretionand,inturn,maycauseorexacerbategoutyattacks.
6.Typicaldosagesofloopdiuretics.
Potassium-SparingDiuretics
Potassium-sparingdiureticsactinthecollectingtubuletoinhibitNa+reabsorptionandK+
excretion.Potassiumlevelsmustbemonitoredinpatientstreatedwithpotassium-sparing
diuretics.Thesedrugsshouldbeusedcautiouslyinmoderaterenaldysfunctionandavoided
inpatientswithsevererenaldysfunctionbecauseoftheincreasedriskofhyperkalemia.
Withinthisclass,therearedrugswithtwodistinctmechanismsofactionwithdifferent
indicationsforuse:aldosteroneantagonistsandepithelialsodiumchannelblockers.
A.Aldosteroneantagonists:spironolactoneandeplerenone
1.Mechanismofaction
Spironolactoneandeplerenonearesyntheticsteroidsthatantagonizealdosteronereceptors.
Thispreventstranslocationofthereceptorcomplexintothenucleusofthetargetcell,
ultimatelyresultinginalackofintracellularproteinsthatstimulatetheNa+/K+-exchange
sitesofthecollectingtubule.Thus,aldosteroneantagonistspreventNa+reabsorptionand,
therefore,K+andH+secretion.Eplerenoneismoreselectiveforaldosteronereceptorsand
causeslessendocrineeffects(gynecomastia)thanspironolactone,whichalsobindsto
progesteroneandandrogenreceptors.
2.Actions
Spironolactoneandeplerenoneantagonizealdosteronereceptorsatrenalsites,whichcauses
diuresis,andnonrenalsites,whichcausesothereffects.Inmostedematousstates,blood
24

26. levelsofaldosteronearehigh,causingretentionofNa+.Spironolactoneantagonizesthe
activityofaldosterone,resultinginretentionofK+andexcretionofNa+.
3.Therapeuticuses
a.Edema
Aldosteroneantagonistsareparticularlyeffectivediureticswhenusedinhighdosesfor
edemaassociatedwithsecondaryhyperaldosteronism,suchashepaticcirrhosisandnephrotic
syndrome.Spironolactoneisthediureticofchoiceinpatientswithhepaticcirrhosiswithfluid
intheperitonealcavity(ascites).Bycontrast,inpatientswhohavenosignificantcirculating
levelsofaldosterone,thereisminimaldiureticeffectwithuseofthisdrug.
b.Hypokalemia
AlthoughthealdosteroneantagonistshavealowefficacyinmobilizingNa+fromthebodyin
comparisonwiththeotherdiuretics,theyhavetheusefulpropertyofcausingtheretentionof
K+.TheseagentsareoftengiveninconjunctionwiththiazideorloopdiureticstopreventK+
excretionthatoccurswiththosediuretics.
c.Heartfailure
Aldosteroneantagonistsareemployedatlowerdosestopreventmyocardialremodeling
mediatedbyaldosterone.Useoftheseagentshasbeenshowntodecreasemortalityassociated
withheartfailure,particularlyinthosewithreducedejectionfraction.
d.Resistanthypertension
Resistanthypertension,definedbytheuseofthreeormoremedicationswithoutreachingthe
bloodpressuregoal,oftenrespondswelltoaldosteroneantagonists.Thiseffectcanbeseenin
thosewithorwithoutelevatedaldosteronelevels.
e.Polycysticovarysyndrome
Spironolactoneisoftenusedoff-labelforthetreatmentofpolycysticovarysyndrome.It
blocksandrogenreceptorsandinhibitssteroidsynthesisathighdoses,therebyhelpingto
offsetincreasedandrogenlevelsseeninthisdisorder.
4.Pharmacokinetics
Bothspironolactoneandeplerenonearewellabsorbedafteroraladministration.
Spironolactoneisextensivelymetabolizedandconvertedtoseveralactivemetabolites,which
contributetothetherapeuticeffects.EplerenoneismetabolizedbycytochromeP4503A4.
5.Adverseeffects
a.Hyperkalemia
Themostcommonsideeffect,hyperkalemia,isdose-dependentandincreaseswithrenal
dysfunctionoruseofotherpotassium-sparingagentssuchasangiotensin-convertingenzyme
inhibitorsandpotassiumsupplements.
b.Gynecomastia
Spironolactone,butnoteplerenone,mayinducegynecomastiainapproximately10%ofmale
patientsandmenstrualirregularitiesinfemalepatients.
c.HyperchloremicMetabolicAcidosis
d.AcuteRenalFailure
e.KidneyStones
25

27. B.Triamtereneandamiloride
Triamtereneandamilorideblockepithelialsodiumchannels,resultinginadecreasein
Na+/K+exchange.AlthoughtheyhaveaK+-sparingdiureticactionsimilartothatofthe
aldosteroneantagonists,theirabilitytoblocktheNa+/K+-exchangesiteinthecollecting
tubuledoesnotdependonthepresenceofaldosterone.Likethealdosteroneantagonists,
theseagentsarenotveryefficaciousdiuretics.Bothtriamtereneandamiloridearecommonly
usedincombinationwithotherdiuretics,almostsolelyfortheirpotassium-sparingproperties.
DosesofPotassium-sparingdiureticsand
combinationpreparations.
Contraindications
Potassium-sparingagentscancausesevere,evenfatal,hyper-kalemiainsusceptiblepatients.
Patientswithchronicrenalinsuf-ficiencyareespeciallyvulnerableandshouldrarelybe
treatedwiththesediuretics.OralK+administrationshouldbediscontinuedifK+-sparing
diureticsareadministered.Concomitantuseofotheragentsthatblunttherenin-angiotensin
system(βblockers,ACEinhibitors,ARBs)increasesthelikelihoodofhyperkalemia.Patients
withliverdiseasemayhaveimpairedmetabolismoftri-amtereneandspironolactone,so
dosingmustbecarefullyadjusted.
CarbonicAnhydraseInhibitor
Acetazolamideandothercarbonicanhydraseinhibitorsaremoreoftenusedfortheirother
pharmacologicactionsthanfortheirdiureticeffect,becausetheyaremuchlessefficacious
thanthethiazideorloopdiuretics.
26

28. A.Acetazolamide
1.Mechanismofaction
Acetazolamideinhibitscarbonicanhydraselocatedintracellularly(cytoplasm)andonthe
apicalmembraneoftheproximaltubularepithelium.[Note:Carbonicanhydrasecatalyzesthe
reactionofCO2andH2O,leadingtoH2CO3,whichspontaneouslyionizestoH+and
HCO3−(bicarbonate).]ThedecreasedabilitytoexchangeNa+forH+inthepresenceof
acetazolamideresultsinamilddiuresis.Additionally,HCO3−isretainedinthelumen,with
markedelevationinurinarypH.ThelossofHCO3−causesahyperchloremicmetabolic
acidosis.
2.Therapeuticuses
a.Glaucoma
Oralacetazolamidedecreasestheproductionofaqueoushumorandreducesintraocular
pressureinpatientswithchronicopen-angleglaucoma,probablybyblockingcarbonic
anhydraseintheciliarybodyoftheeye.Topicalcarbonicanhydraseinhibitors,suchas
dorzolamideandbrinzolamide,havetheadvantageofnotcausingsystemiceffects.
Carbonicanhydraseinhibitorsusedorallyinthetreatmentofglaucoma.
b.Altitudesickness
Acetazolamidecanbeusedintheprophylaxisofsymptomsofaltitudesickness.
Acetazolamidepreventsweakness,breathlessness,dizziness,nausea,andcerebralaswellas
pulmonaryedemacharacteristicofthesyndrome.
c.Urinaryalkalization
d.Metabolicalkalosis
e.AcuteMountainsickness
f.Others:carbonicanhydraseinhibitorshavebeenusedasadjuvantsinthetreatmentof
epilepsy.Itisalsousedinthetreatmentofparalysis,CSFleakage,Hyperphosphatemia.
FinallyAcetazolamidemayhavearoleinthetreatmentofMeniere'sdisease,diabetes
insipidus,hypertension,Kleine-Levinsyndrome.
3.Pharmacokinetics
Acetazolamidecanbeadministeredorallyorintravenously.Itisapproximately90%protein
boundandeliminatedrenallybybothactivetubularsecretionandpassivereabsorption.
4.Adverseeffects
Metabolicacidosis(mild),potassiumdepletion,renalstoneformation,drowsiness,and
paresthesiamayoccur.Thedrugshouldbeavoidedinpatientswithhepaticcirrhosis,because
itcouldleadtoadecreasedexcretionofNH4+.
●HyperchloremicMetabolicAcidosis
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29. ●RenalStones
●RenalPotassiumWasting
5.Contraindications
Carbonicanhydraseinhibitor–inducedalkalinizationoftheurinedecreasesurinaryexcretion
ofNH4+(byconvertingittorapidlyreabsorbedNH3)andmaycontributetothe
developmentofhyperammonemiaandhepaticencephalopathyinpatientswithcirrhosis.
OsmoticDiuretics
Anumberofsimple,hydrophilicchemicalsubstancesthatarefilteredthroughthe
glomerulus,suchasmannitol,resultindiuresis.Filteredsubstancesthatundergolittleorno
reabsorptionresultinahigherosmolarityofthetubularfluid.Thispreventsfurtherwater
reabsorptionatthedescendingloopofHenleandproximalconvolutedtubule,resultingin
osmoticdiuresiswithlittleadditionalNa+excretion(aquaresis).Therefore,theseagentsare
notusefulfortreatingconditionsinwhichNa+retentionoccurs.Theyareusedtomaintain
urineflowfollowingacutetoxicingestionofsubstancescapableofproducingacuterenal
failure.Osmoticdiureticsareamainstayoftreatmentforpatientswithincreasedintracranial
pressure.[Note:Mannitolisnotabsorbedwhengivenorallyandshouldbegiven
intravenously.]
Pharmacokinetics
MannitolispoorlyabsorbedbytheGItract,andwhenadministeredorally,itcausesosmotic
diarrhearatherthandiuresis.Forsystemiceffect,mannitolmustbegivenintravenously.
Mannitolisnotmetabolizedandisexcretedbyglomerularfiltrationwithin30–60minutes,
withoutanyimportanttubularreabsorptionor
secretion.Itmustbeusedcautiouslyinpatientswithevenmildrenalinsufficiency.
Mechanismofaction
OsmoticDiuretics>increasenonabsorbablesolutesinthePCT>decreasespassivewater
reabsorption>decreasesodiumreabsorption>diuresis.
Therapeuticuses
●Intracranialpressure
●IncreaseofUrineVolume
Adverseeffects
Adverseeffectsincludedehydrationandextracellularwaterexpansionfromtheosmotic
effectsinthesystemiccirculation.Theexpansionofextracellularwateroccursbecausethe
presenceofmannitolintheextracellularfluidextractswaterfromthecellsandcauses
hyponatremiauntildiuresisoccurs.
●ExtracellularVolumeExpansion
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30. ●Dehydration,Hyperkalemia,andHypernatremia
●Hyponatremia
DIURETICCOMBINATIONS
Inmanyclinicalpracticediureticscombinationisusedtotherationalofdiuretics
combinationasfollows
1.Tominimisetheadverseeffectse.g.Frusemide/Thiazideproduceshypokalemiaand
spironolactonepreventsK+loss.Sosimultaneousapplicationsofbothtypesof
diureticsremainsserumK+withinnormallimit.
2.Toincreasethedurationofdiureticaction.
3.Toachievepharmacologicalsynergism.e.gtheuseoftwodrugsfrusemide+Thiazide
actingatdifferentnephronsitesexhibitsynergisticdiureticsresponses.
4.Toavoidrefractorytosingleagente.gthecombinationofloopdiureticsandThiazide
canmobilizelargeamountsoffluid.
References
1.BasicandClinicalPharmacology-BertramG.Katzung,McHillCompanies.
2.Lipponcott'sIllustratedReviewsPharmacology:RA.HarveyandP.C.Champe
3.EssentialsofMedicalPharmacology:K.D.Tripathi
4.Internetsources:https://en.m.wikipedia.org/;https://www.britannica.com/;
https://www.webmd.com/;https://www.rxlist.com/
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