Antihypertensive drugs PCI.pdf

Anti-hypertensive Agents for T Y B Pharm (Sem V) as per PCI curriculum

1. Antihypertensive Agents
For TY B Pharm (Sem V, PCI)
By
Prof. Jayshree Patil
Department of P’ceuticalChemistry
AIKTC School of Pharmacy,
New Panvel

2. Contents:
❖ACE inhibitors: Captopril, Lisinopril, Enalapril, Benazepril hydrochloride, Quinapril
hydrochloride,
❖Nonselective β-blockers (First generation): Timolol
❖α-Adrenergic receptor agonists : Methyldopate hydrochloride,* Clonidine hydrochloride,
Guanethidine monosulphate, Guanabenz acetate, Reserpine
❖Vasodilators: Sodium nitroprusside, Diazoxide, Minoxidil, Hydralazine hydrochloride

3. ✓Drugsactingontherenalsystemdescribestheroleofrenin–angiotensinsysteminregulatingthe
cardiovascularsystem.Thissystemplaysacriticalroleinthemechanismsofhypertensionand
heartfailure(formallyrecognizedascongestiveheartfailure[CHF].
✓Therenin-angiotensinsystemisacomplex,highlyregulatedpathwaythatisintegralinthe
regulationofbloodvolume,electrolytebalance,andarterialbloodpressure.
✓Itconsistsoftwomainenzymes,reninandangiotensinconvertingenzyme(ACE),theprimary
purposeofwhichistoreleaseangiotensinIIfromitsendogenousprecursor,angiotensinogen.
Angiotensin II is a potentvasoconstrictorthataffectsperipheralresistance,renalfunction,and
cardiovascularstructure
✓Therenin–angiotensinsystemisahormonalsystemthatplaysacentralroleinthecontrolof
sodiumexcretionandbodyfluidvolume.
✓Itinteractscloselywiththesympatheticnervoussystemandaldosteronesecretioninthe
regulationof blood pressure.

4. https://en.wikipedia.org/wiki/Renin%E2%80%93angiotensin_system

5. ▪Theprecursorofangiotensin,angiotensinogen,isa
glycoproteinofmolecularweight(MW)58,000to
61,000,synthesizedprimarilyintheliverandbrought
intothecirculatorysystem.
▪Renin,anaspartylprotease(MW35,000–40,000),whose
primarysourceisthekidney,cleavestheLeu-Valbond
fromtheasparticacidendoftheangiotensinogen
polypeptidemoleculetoreleasethedecapeptide
angiotensin I.
▪The biochemical conversion continueswiththecleavage
ofadipeptide(His-Leu)fromthecarboxylterminalof
angiotensinIbyangiotensinconvertingenzyme(ACE)to
formtheoctapeptideangiotensinII, a potent
vasoconstrictor.
▪Angiotensin III is formedbyremovaloftheN-terminal
aspartateresidueofangiotensinII,areactioncatalyzed
byglutamylaminopeptidase.
▪IncontrasttoangiotensinII,angiotensinIIIhasaless
potentbutsignificantregulatoryeffectonsodium
excretionbytherenaltubules.Thisisprimarilyresulting
fromtheeffectangiotensinIIIhasinstimulating
aldosteronesecretion,a potent mineralocorticoid.

6. Angiotensin-converting
Enzyme Inhibitors
(ACE Inhibitors)

7. ➢Currently,thereare11ACEinhibitorsapprovedfortherapeuticuseintheUnitedStates.
➢Thesecompoundscanbesubclassifiedintothreegroupsbasedontheirchemicalcomposition:
sulfhydryl-containing inhibitors (exemplifiedbycaptopril),
dicarboxylate-containinginhibitors(exemplifiedbyenalapril),and
phosphonate-containinginhibitors(exemplifiedbyfosinopril).
➢Captoprilandfosinoprilarethelonerepresentativesoftheirrespectivechemicalsubclassifications,
whereasthemajorityoftheinhibitorscontainthedicarboxylatefunctionality.
➢AllofthesecompoundseffectivelyblocktheconversionofangiotensinItoangiotensinIIandhave
similartherapeuticandphysiologiceffects.Thecompoundsdifferprimarilyintheirpotencyand
pharmacokineticprofiles.
➢Additionally,thesulfhydrylgroupincaptoprilisresponsibleforcertaineffectsnotseenwiththe
otheragents.

10. Angiotensin-convertingenzyme(ACE)isacarboxypeptidasehavingazincionasacofactorandisinvolvedin
therenin-angiotensincascadeofbloodpressurecontrol.
TheseincludedtheknowledgethatACEwassimilarinitsenzymaticmechanismtocarboxypeptidaseA,
exceptthatACEcleavedoffadipeptidewhereascarboxypeptidaseAcleavedsingleaminoacidresiduesfrom
thecarboxylendoftheprotein;thediscoveryofL-benzylsuccinicacidasapotentinhibitorof
carboxypeptidaseA.
BenzylsuccinicacidhasbeendescribedasabiproductinhibitorofcarboxypeptidaseA,whereinitsdesignwas
basedonthecombinationoftheproductsofthepeptidasereaction(i.e.,thetwopeptidefragments,onewitha
freecarboxylendthatcoordinatesthezincionoftheproteaseandtheotherwithafreeaminoterminus).Inthe
caseofbenzylsuccinicacid,theamino(–NH2)functionalityisreplacedbytheisostericmethylene(–CH2–
)group.
Usingtheaboveconcepts,itwasrationalizedthatsuccinylaminoacidscouldsimilarlybehaveasabiproduct
inhibitorsofACE.Startingwithasuccinyl-prolinemoiety,thestructuralactivitydevelopmentaleffortfinally
resultedincaptoprilwiththesubstitutionofthestrongerzinccoordinatingmercaptofunctionalityin
placeofthecarboxylicresidue(ofsuccinicacid)andastereospecificRmethylgrouponthesuccinyl
functiontorepresentthemethylgrouponthenaturalL-AlaresidueinAla-Pro(thedipeptidefragmentthat
hadpreviouslyshowninhibitoryactivity).
Captoprilsoonbecamehighlysuccessfulintheclinicasanantihypertensiveagentand,incombinationwith
diuretics,hasprovedtobethetreatmentofchoiceincontrollinghypertension.
FollowingontheheelsofcaptoprilwasanotherbyproductACEinhibitor,enalaprilat.Enalaprilatincorporated
aphenylethylmoietywiththeS-configurationandmadeuseofahydrophobicbindingpocketinACE.

11. TheN-ringmustcontaina
carboxylicacidtomimictheC-
terminalcarboxylateofACE
substrates.
Large hydrophobic heterocyclic
rings (i.e., the N-ring) increase
potency and alter
pharmacokinetic parameters.
Thesulfhydrylgroupshowssuperior
bindingtozinc(thesidechain
mimickingthePheincarboxylate
andphosphinicacidcompounds
partiallycompensatesforthelackof
asulfhydrylgroup).
Sulfhydryl-containingcompoundsproducehighincidenceofskinrashandtastedisturbances
Sulfhydryl-containingcompounds
canformdimersanddisulfides,
whichmayshortendurationof
action.
Compoundsthatbindtozincthrough
eitheracarboxylateorphosphinate
mimicthepeptidehydrolysis
transitionstateandenhancebinding.
Esterificationofthecarboxylateor
phosphinateproducesanorally
bioavailableprodrug.
Xisusuallymethyltomimicthe
sidechainofalanine.Withinthe
dicarboxylateseries,whenXequals
n-butylamine(lysinesidechain),
thisproducesacompoundthatdoes
notrequireprodrugfororalactivity.
Optimumactivityoccurswhen
stereochemistryofinhibitoris
consistentwithL-aminoacid
stereochemistrypresentinnormal
substrates.

13. Sulfhydryl-Containing Inhibitors
CaptoprilCaptopril,1-[(2S)-3-mercapto-2-methyl-
1-oxopropionyl]prolineblockstheconversionof
angiotensinItoangiotensinIIbyinhibitingthe
convertingenzyme.
Byuseofthissmallmoleculeasaprototype,captoprilwasdesignedwithacarboxylgrouponaproline
andathiolgroupwasintroducedtoenhancethebindingtothezincionofACE.
TheimportantbindingpointsattheactivesiteofACEarethoughttobeanarginineresidue,which
providesacationicsitethatattractsacarboxylateion,andazincion,whichcanpolarizeacarbonyl
groupofanamidefunctiontomakeitmoresusceptibletohydrolysis.
Hydrophobicpocketsliebetweenthesegroupsintheactivesite,asdoesafunctionalgroupthatformsa
hydrogenbondwithanamidecarbonyl.showsthehypotheticalbindingofcaptoprilintheactivesiteof
ACE.
TherationaldevelopmentofcaptoprilasaninhibitorofACEwasbasedonthe
hypothesisthatACEandcarboxypeptidaseAfunctionedbysimilarmechanisms.
Itwasnotedthatd-2-benzylsuccinicacidwasapotentinhibitorof
carboxypeptidaseA,butnotACE.

14. Thesulfhydrylgroupofcaptoprilprovedtoberesponsiblenotonlyfortheexcellentinhibitory
activityofthecompoundbutalsoforthetwomostcommonsideeffects,skinrashesandtaste
disturbances(e.g.,metallictasteandlossoftaste).
Thesesideeffectsusuallysubsidedondosagereductionordiscontinuationofcaptopril.Theywere
attributedtothepresenceofthesulfhydrylgroup,becausesimilareffectshadbeenobservedwith
penicillamine,asulfhydryl-containingagentusedtotreatWilsondiseaseandrheumatoidarthritis.
Metabolism:

15. Carboxylate Containing Drug
Lisinopril
Lisinopril, 1-[N2-[S-1-carboxy-3-phenylpropyl]-L-lysyl]-L-proline
dihydrate(Prinivil,Zestril),isalysinederivativeofenalaprilat,the
activemetaboliteofenalapril.
LikeallACEinhibitors,itisanactivesite-directedinhibitorofthe
enzyme,withthezincionusedinaneffectivebindinginteractionata
stoichiometricratioof1:1.
Thepharmacologicaleffectsoflisinoprilaresimilartothoseofcaptopril
and enalapril.
Lisinopril

16. ACE-INHIBITOR PRODRUGS
ManynewACEinhibitorsbecameavailableforthetreatmentofhypertensionfollowingthe
clinicaleffectivenessofenalapril.Enalaprilisanon–thiol-containingACEinhibitordevoidof
thesideeffectsofrashandlossofthesenseoftastecharacteristicofthethiol-containing
compoundcaptopril.
Withtheexceptionofthephosphoruscontainingfosinopril,theseantihypertensiveagents
havea2-(S)-aminophenylbutyricacidethylestermoietydifferingonlyinthesubstituentson
theaminogroup.
Theyhavethecommonpropertyofactingasprodrugs,beingconvertedtotheactiveenzyme
inhibitorfollowingabsorptionandmetabolismbyliverandintestinalenzymes.
Thesedrugsliketheprototypicaldrugcaptopril,areusedinthetreatmentofmild-to-moderate
hypertension,eitheraloneorinconjunctionwithdiureticsorcalciumchannelblockers.

17. Enalapril Maleate
1-[N[(S)-1-carboxy- 3-phenylpropyl]-L-alanyl]-L-proline 1-
ethyl ester maleate,isalong-actingACEinhibitor.
Itrequiresactivationbyhydrolysisofitsethylestertoform
thediacidenalaprilat.
Enalaprilisdevoidofthesideeffectsofrashandlossoftaste
seenwithcaptopril.Thesesideeffectsaresimilartothoseof
themercapto-containingdrugpenicillamine.Theabsenceof
thethiolgroupinenalaprilmaleatemayfreeitfromthese
sideeffects.Thehalf-lifeis11 hours.
Hepatic
Esterase
Enalapril
Enalaprilat

18. Benazepril Hydrochloride
(3S)-3-[[(1S)-1-carbethoxy-3phenylpropyl]amino]
-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-
acetic acid 3-ethyl esterhydrochlorideis
metabolizedrapidlytotheactivediacid
benazaprilat.
AswiththeACEprodrugs,nomutagenicityhas
beenfound,eventhoughthesedrugscrossthe
placenta.
Quinapril Hydrochloride
(S)-[(S)-N-[(S)21-carboxy3-phenylpropyl]
alanyl]-1,2,3,4-tetrahydro-3-isoquinoline -
carboxylic acid 1-ethyl ester hydrochloride
formsthediacidquinaprilateinthebody.
Itismorepotentthancaptopriland
equipotenttotheactive form of enalapril.

19. Propranolol(Inderal,others)istheprototypicalandnonselectiveβ-blocker.
Itblockstheβ1-andβ2-receptorswithequalaffinity,lacksISA,anddoesnotblockα-
receptors.
Timololfindsuseintheprophylaxisofmigraineheadachesandinthetherapyfollowing
myocardialinfarction.
Nonselective β-blockers (First generation)
Propranolol

20. ➢Methyldopate
➢Clonidine,
➢Guanabenz,
α-ADRENERGIC RECEPTOR
AGONISTS

21. Methyldopa(L-α-methyldopa)differsstructurallyfromL-
DOPAonlyinthepresenceofaα-methylgroup.
OriginallysynthesizedasanAADCinhibitor,methyldopa
ultimatelydecreasestheconcentrationofDA,NE,E,and
serotoninintheCNSandperiphery.
However,itsmechanismofactionisnotcausedbyits
inhibitionofAADCbut,rather,byitsmetabolisminthe
CNStoitsactivemetabolite(α-methylnorepinephrine).
Methyldopaisusedonlybyoraladministrationbecauseitszwitterioniccharacterlimitsits
solubility.
Theesterhydrochloridesaltofmethyldopa,methyldopate,wasdevelopedasahighlywater-
solublederivativethatcouldbeusedtomakeparenteralpreparations.Itisconvertedto
methyldopainthebodythroughtheactionofesterases.

22. Methyldopaistransported
activelyintoCNSviaan
aromaticamino acid
transporter,whereitis
decarboxylatedbyAADCin
thebrainto(1R,2S)-α-
methyldopamine. This
intermediate,inturn,is
stereospecifically β-
hydroxylatedbyDBHtogive
the (1R,2S)- α-
methylnorepinephrine.This
activemetaboliteisaselective
α2-agonistbecauseithas
correct(1R,2S)configuration.
Itiscurrentlypostulatedthatα-methylnorepinephrineactsonα2-receptorsintheCNSinthesamemanneras
clonidine,todecreasesympatheticoutflowandlowerbloodpressure.
Absorptioncanrangefrom8%to62%andappearstoinvolveanaminoacidtransporter.Absorptionisthusaffected
byfood,andabout40%ofthatabsorbedisconvertedtomethyldopa-O-sulfatebytheintestinalmucosalcells.

23. 2-aminoimidazolines(centrallyactingalpha-agonisthypotensiveagents)
Clonidinediffersfrom2-arylimidazolineα1-agonistsmainlybythepresenceofo-chlorinegroupsand
aNHbridge.Theo-chlorinegroupsaffordbetteractivityatα2sites.
Importantly,clonidinecontainsaNHbridge(aminoimidazolines).
Clonidineisanexampleofa(phenylimino)imidazolidinederivativethatpossessescentralα2-
selectivity.Theα1:α2ratiois300:1.
Theunchargedformofclonidineexistsasapairoftautomers.

24. Chemistry:
Theabilityofclonidineanditsanalogstoexertanantihypertensiveeffectdependsontheabilityofthese
compoundsnotonlytointeractwiththeα2-receptorinthebrainbutalsotogainentryintotheCNS.
Forexample,inthecaseofclonidine,thebasicityoftheguanidinegroup(typicallypKa=13.6)is
decreasedto8.0(thepKaofclonidine)becauseoftheinductiveandresonanceeffectsofthe
dichlorophenylring.Thus,atphysiologicalpH,clonidinewillexisttoasignificantextentinthe
nonionizedformrequiredforpassageintotheCNS.Ithasanoralbioavailabilityofmorethan90%.
SAR
Althoughvarioushalogenandalkylsubstitutionscanbeplacedatthetwoorthopositionsofthe
(phenylimino)imidazolidinenucleuswithoutaffectingtheaffinityofthederivativesforα2-receptors,
methylanalogsaremuchmorereadilymetabolizedtothecorrespondingacids(inactive)andthushave
shortDOA.
Halogensubstituentssuchaschlorineseemtoprovidetheoptimalcharacteristicsinthisregard.
Oneofthemetabolitesofclonidine,4-hydroxyclonidine,hasgoodaffinityforα2-receptors,butbecauseit
istoopolartogetintotheCNS,itisnotaneffectiveantihypertensiveagent.

25. Stimulationoftheseα2-receptorsbringsaboutadecreaseinsympatheticoutflowfromthe
CNS,whichinturnleadstodecreasesinperipheralvascularresistanceandbloodpressure.
Bradycardiaisalsoproducedbyclonidineasaresultofacentrallyinducedfacilitationofthe
vagusnerveandstimulationofcardiacprejunctionalα2-receptors.
Thesepharmacologicalactionshavemadeclonidinequiteusefulinthetreatmentof
hypertension.

26. Guanabenz(Open-RingImidazolidines)
StudiesonSARofcentralα2-agonistsshowedthattheimidazolineringwasnotnecessaryforα2-
activity.Clonidineanalog,guanabenz(pKa=8.1)iscloselyrelatedchemicallyandpharmacologically,
arealsousedasantihypertensivedrugs.
Inthesecompounds,the2,6-dichlorophenylmoietyfoundinclonidineisconnectedtoaguanidinogroup
byatwo-atombridge.Inthecaseofguanabenz,thisbridgeisa–CH=N-group.
ConjugationoftheguanidinomoietywiththebridgingmoietyhelpstodecreasethepKaofthebasic
group,sothatatphysiologicalpHasignificantportionofeachdrugexistsinitsnonionizedform.This
accountsfortheirCNSpenetrationandhighoralbioavailability(70%–80%forguanabenz)
Clonidine
DifferencesbetweenclonidineandGuanabenzis
seenintheireliminationhalf-lifevaluesandintheir
metabolismandurinaryexcretionpatterns.
Theeliminationhalf-lifeofclonidinerangesfrom20
to25hours,whereasGuanabenzhastheshortestDOA
ofthesethreeagents,withahalf-lifeofabout6hours.
Clonidineisexcretedunchangedintheurinetothe
extentof60%.Verylittleofguanabenzisexcreted
unchangedintheurine.

27. AGENTS DEPLETING
NEUROTRANSMITTER STORES
➢Reserpine
➢Guanethidine

28. Reserpine
Reserpine depletes catecholamines andserotoninfrom
centralandperipheralneuronsbyinterferingwiththe
uptakeoftheseaminesfromthecytosolintothe
vesiclesandgranules.
Asaconsequence,norepinephrinecannotbestored
intraneuronallyinadrenergicneurons,andmuchofthe
norepinephrineinthecytosolismetabolizedby
monoamineoxidase(MAO).
Thebindingofreserpinetothestoragevesicle
membraneisfirm,andasaresult,thestoragegranuleis
destroyed,reducingtheabilityofthenerveto
concentrateandstorenorepinephrine.
Becausereserpineactsonbothcentralandperipheral
adrenergicneurons,itsantihypertensiveeffectsmay
resultfromneurotransmitterdepletionfrombothof
these sites.
Folk remedies from
species of Rauwolfia,
a plant belonging to
the Apocynaceae
family

29. Guanethidine
Guanethidinehasbeenclassifiedtraditionallyasanadrenergicblockingagentbecauseitcan
preventthereleaseofnorepinephrinefrompostganglionicneuronsinresponsetoadrenergic
stimulation.
Guanethidinehaveotheractionsoncatecholaminemetabolismandcancausesignificantdepletion
oftheseaminesinadrenergicneurons.
Theydonotinterferewithreleaseofepinephrinefrom the adrenal medulla.

30. Guanethidinemonosulfateismetabolizedby
microsomal enzymes to 2-(6
carboxyhexylamino)ethylguanidine and
guanethidineN-oxide.Bothmetaboliteshavevery
weakantihypertensiveproperties.
Guanethidinemonosulfateistakenupbythe
aminepumplocatedontheneuronalmembrane
andretainedinthenerve,displacing
norepinephrinefromitsstoragesitesinthe
neuronalgranules.
Thedisplacednorepinephrineismetabolizedto
homovanillicacidbymitochondrialMAO,
depletingthenerveendingoftheneurotransmitter.
The usefulness of guanethidine monosulfatealso resides in the fact that once it is taken up by the nerve, it
produces a sympathetic blockade by inhibiting release of nonepinephrinethat would occur on neuronal
membrane response to stimulation by the nerve action potential.

31. VASODILATORY DRUGS ACTING
ON SMOOTH MUSCLE
➢Hydralazine
➢Sodium Nitroprusside

32. Antihypertensiveagentsthatproducevasodilationofsmoothmusclecanbedividedintotwo
categories:
Directactingand
Indirect-actingvasodilators.
Indirect-actingvasodilatorsmaybedistinguishedfromdirect-actingvasodilators,inthatthey
producetheireffectbyinterferingwiththevasoconstrictorstimuli,andtheirprimarysiteof
actionisnotnecessarilythevascularsmoothmuscleitself.
Indirect-acting Direct-acting
➢Sympatholytic drugs,
➢α-adrenergic antagonists;
➢ACE inhibitors; and
➢Angiotensin II receptor antagonists
➢Hydralazine hydrochloride,
➢Sodium nitroprusside,
➢Potassium channel openers,
➢Calcium channel-blocking agents.

33. Hydralazine Hydrochloride (1-hydrazinophthalazine monohydrochloride)
Itisusefulinthetreatmentofmoderate-to-severehypertension.Itisoften
usedinconjunctionwithlesspotentantihypertensiveagents,becauseside
effectsoccurfrequentlywhenitisusedaloneinadequatedoses.In
combinations,itcanbeusedinlowerandsaferdoses.
Itsactionappearstobecenteredonthesmoothmuscleofthevascularwalls,
withadecreaseinperipheralresistancetobloodflow.Thisresultsin
increasedbloodflowthroughtheperipheralbloodvessels.Italsohasthe
uniquepropertyofincreasingrenalbloodflow,animportantconsideration
inpatientswithrenalinsufficiency.
Hydralazine hydrochloride acts on vascular smooth muscle tocauserelaxation.Itsmechanism
ofactionisunclear.ItinterfereswithCa
2+
entryandCa
2+
releasefromintracellularstoresand
reportedlycausesactivationofguanylatecyclase,resultinginincreasedlevelsofcGMP.Allof
thesebiochemical events can cause vasodilation.

34. Hydralazine hydrochloride undergoes benzylic oxidation, glucuronideformation,andN-
acetylationbythemicrosomalenzymes in the tissues.

35. Sodium Nitroprusside
sodium nitroferricyanide, disodium pentacyanonitrosylferrate
Na2[Fe(CN)5NO],isoneofthemostpotentbloodpressure–
loweringdrugs.Itsuseislimitedtohypertensiveemergencies
becauseofitsshortdurationofaction.
Theeffectivenessofsodiumnitroprussideasanantihypertensivehasbeenknownsince1928,but
notuntil1955wasitsefficacyasadrugestablished.
Thedrugdiffersfromothervasodilators,inthatvasodilationoccursinbothvenousandarterial
vascularbeds.
Sodiumnitroprussideisareddishbrownwater-solublepowderthatisdecomposedbylightwhen
insolution.
ThehypotensiveeffectofthechemicalisaresultoftheformationofNOinsitu,elevating
cellularlevelsofcGMP.
Sodiumnitroprussideismetabolizedbytheliver,yieldingthiocyanate.Becausethiocyanateis
excretedbythekidneys,patientswithimpairedrenalfunctionmaysufferthiocyanatetoxicity.

36. POTASSIUM CHANNEL
AGONISTS
➢Diazoxide
➢Minoxidil

37. Thetwoagentsthatcanbeclassifiedinthiscategoryarediazoxideandminoxidil.Thesedrugs
arealsocalledpotassiumchannelopeners.
TheseagentsactivateATP-sensitivepotassiumchannels,whichleadstoadecreaseof
intracellularCa2andreducestheexcitabilityofsmoothmuscle.
Theprimaryactionofthesedrugsistoopenpotassiumchannelsintheplasmamembraneof
vascularsmoothmuscle.
Aneffluxofpotassiumfromthecellfollows,resultinginhyperpolarizationofthemembrane,
whichproducesaninhibitoryinfluenceon membrane excitation and subsequent vasodilation.

38. Diazoxide
Itisusedasthesodiumsaltof7-chloro-3-methyl-2H-1,2,4-
benzothiadiazine 1,1-dioxide. Diazoxide lowers peripheral vascular
resistance, increasescardiacoutput,anddoesnotcompromiserenal
blood flow.
Thisisades-sulfamoylanalogofthebenzothiazinediureticsandhasa
closestructuralsimilaritytochlorothiazide.Itwasdeveloped
intentionallytoincreasetheantihypertensiveactionofthethiazidesand
tominimizethediureticeffect.
Itisusedbyintravenousinjectionasarapidlyactingantihypertensiveagentforemergency
reductionofbloodpressureinhospitalizedpatientswithacceleratedormalignanthypertension.
Morethan90%isboundtoserumprotein,andcautionisneededwhenitisusedinconjunction
withotherprotein-bounddrugsthatmaybedisplacedbydiazoxide.

39. Minoxidil, 2,4-diamino-6-piperidinopyrimidine-3-oxide
Itwasdevelopedasaresultofisostericreplacementofatriaminotriazine
moietybytriaminopyrimidine.
Thetriaminotriazineswereinitiallyobservedtobepotentvasodilatorsin
catsanddogs,followingtheirformationofN-oxidesintheseanimals.
ThetriazineswereinactiveinhumansbecauseoftheirinabilitytoformN-
oxidemetabolites;thisledtothediscoveryofminoxidil.
Minoxidilistheonlydirect-actingvasodilatorthat
requiresmetabolicactivationtoproduceits
antihypertensiveeffect.Itisconvertedtominoxidil
sulfateintheliverbya sulfotransferase enzyme.

40. Theantihypertensivepropertiesofminoxidilaresimilartothoseofhydralazinehydrochloride,
inthatminoxidilcandecreasearteriolarvascularresistance.Minoxidilexertsitsvasodilatory
actionbyadirecteffectonarteriolarsmoothmuscleandappearstohavenoeffectontheCNS
orontheadrenergicnervoussysteminanimals.
Minoxidilisusedforseverehypertensionthatisdifficulttocontrolwithotherantihypertensive
agents.
Thedrughassomeofthecharacteristicsideeffectsofdirectvasodilatorydrugs.Itcauses
sodiumandwaterretentionandmayrequirecoadministrationofadiuretic.Minoxidilalso
causesreflextachycardia,whichcanbecontrolledbyuseofa–adrenergicblocking agent.
Minoxidiltopicalsolutionisusedtotreatalopecia
androgenitica(male-patternbaldness).Althoughthe
mechanismisnotclearlyunderstood,topicalminoxidilis
believedtoincreasecutaneousbloodflow,whichmay
stimulatehairgrowth.Thestimulationofhairgrowthis
attributedtovasodilationinthevicinityofapplicationofthe
drug,resultinginbetternourishmentofthelocalhairfollicles.

41. REFERENCE BOOKS:
1.Foye’s Principles of Medicinal Chemistry, Thomas L. Lemke, David A Williams, Lippincott
Williams & Wilkins.
2.Wilson and Gisvold’sTextbook of Organic Medicinal and Pharmaceutical Chemistry, John M.
Beale, John H. Block, Lippincott Williams & Wilkins.

42. Thank you