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1. Duane C. Hombrebueno
DRUGS ACTING ON THE RENAL SYSTEM
Chapter Overview
 Describesthe role renin-angiotensinsystemplaysinregulatingthe cardiovascular
system
 Critical role inthe mechanismof hypertensionandcongestive heartfailure
 Developmentof therapeuticagentsthatact on the variousenzymesandreceptors
associatedwiththe renin-angiotensinsystem
 Renin-angiotensinsysteminfluencesnormal physiological function
 Componentsof the systemsuchasrenin,angiotensinIandII,and angiotensin-
convertingenzyme
 Renin-AngiotensinSystemandHypertension
Renin-Angiotensinsystem–isa hormonal systemthatplaysa central role in the control of sodium
excretionandbodyfluidvolume.Interactscloselywiththe sympatheticnervous systemandaldosterone
secretioninthe regulationof bloodpressure.
Renin– a kidneyextractproducedapotentvasopressorresponse.
- Anaspartyl protease (MW 35,000 – 40,000).
- Primarysource iskidney.
- Cleavesthe Leu-Valbondfromthe asparticacidendof the angiotensinogenpolypeptide
molecule toreleasethe decapeptideangiotensinI
Angiotensin– hypertensive substance isolatedandidentifiedasdecapeptide
- isa glycoprotein(MW58,000 – 61,000).
- synthesizedprimarilyinthe liverandbroughtintothe circulatorysystem
 Biochemical Conversion
The Cleavage of a dipeptide(His-Leu) fromthe carboxyl terminal of angiotensinconverting
enzyme toformoctapeptide whichisangiotensinII(apotentvasoconstrictor)
AngiotensinIIIisformedbyremoval of the N-terminal aspartate residue of angiotensinIIa
reactioncatalyzedbyglutamyl aminopeptidase

2. In contrastto angiotensinII,angiotensinIIIhasa lesspotentbutsignificantregulatoryeffecton
sodiumexcretionbythe renal tubules
Thisis primarilyresultingfromthe effectangiotensinIIIhasinstimulatingaldosterone secretion,
a potentmineralcorticoid.
 Vasoconstrictive effectsofangiotensinII
AngiotensinII– stimulatesthe release of vasopressinfromthe hypothalamus.
Vasopressin– alsoknownas antidiuretichormone (ADH)
- Thispeptidichormone istypicallyreleasedtoconserve waterwhenbodyisdehydrated.
Endothelin– a 21 aminoacidpeptide thatisproducedinthe vascularendotheliumandplaysarole in
the regulationof smoothmuscle contractionandcontributestobloodpressure regulation.
Aldosterone – secretedbyadrenal cortex andelicitsitseffectsatvarioussites.Responsibleforthe
absorptionof sodiuminthe bloodstream
 Regulatory action of the renin-angiotensinsystem,
- In controllingsodiumandpotassiumbalance andarterial bloodpressure ismodifiedby
vasodilatorscalledkinins.
Kallikrein– is activatedinplasmabynoxiousinfluencestoacton a kinin,callidin,whichisconvertedto
bradykinin bytissue enzymes.
Bradykinin – enhancesrelease of the prostaglandinsPGE2and PGI2 withincertaintissuestoproduce a
vasodilatoryeffect.
- Convertedtoinactive productsbyACEand othercarboxypeptidases.
ACE – a membrane boundenzyme anchoredtothe cell membranethroughasingle transmembrane
domain.
- Zinccontainingglycoprotein(MW130,000)
- A nonspecificpeptidyldipeptide hydrolase,widelydistributedinmamaliantissues.
- Is a tripeptide withafree carboxylate group.
 Active sitesof ACE
Importantbindingpoints
- Cationicsite toattract a carboxylate ion

3. - Zincion thatcan polarize acarbonyl groupof an amide functiontomake itmore susceptible to
hydrolysis.
In the active site,there isanucleophilic attackof the amide carbonyl bythe y-carbonyl groupof a
glutamicacidresidue tocause hydrolysisof peptide.
 Important role of reninangiotensinsystem
-Regulatingkidneyfunction
-Aldosterone release
-Electrolyte balance
-Bloodvolume
 Renin-AngiotensinSystemInhibitors
Captopril – 1-[(2S)-3-mercapto-2-methyl-1-oxopropionyl]proline(Capoten)
- Blocksthe conversionof angiotensinItoangiotensinIIbyinhibitingthe convertingenzyme.
- Was designedwithacarboxyl groupona proline anda thiol groupwasintroducedtoenhance binding
to zincionof ACE.
Lisinopril – 1-[N2-[S-1-carboxy-3-phenylpropyl]-L-lysyl]-L-prolinedihydrate(Privinil,Zestril)
- A lysine derivative of enalaprilat,active metabolite of enalapril.
- Like all ACE inhibitors,itisanactive site-directedinhibitorof the enzyme,withthe zincionusedinan
effectivebindinginteractionatastoichiometricratioof 1:1
- Pharmacological effectare similartothose of captopril andenalapril.
 ACE-InhibitorsProDrugs
- Availableforthe treatmentof hypertensionfollowingthe clinical effectivenessof enalapril
- These drugs,like the prototypical drugcaptopril,are usedinthe treatmentof mildtomoderate
hypertension,eitheraloneorinconjunctionwithdiuretics orcalciumchannel blockers
Enalapril Maleate - 1-[N[(S)-1-carboxy-3-phenylpropyl]-L-alanyl]-L-proline 1-ethyl estermaleate
(Vasotec)
- Is a long-actingACEinhibitor.
- Is devoidof the side effectsof rashandlossof taste seenwithcaptopril
- The absence of the thiol groupin enalapril maleate mayfree itfromthese side effects.

4. - The half-lifeis11 hours.
Benazepril Hydrochloride - (3S)-3-[[(1S)-1-carbethoxy-3-phenylpropyl]amino]-2,3,4,5-tetrahydro-2-oxo-
1H-1-benzazepine-1-aceticacid 3-ethylesterhydrochloride(Lotensin)
- Metabolizedrapidlytothe active diacidbenazaprilat.
- Nomutagenicityhasbeenfound,eventhoughthesedrugscrossthe placenta.
Quinapril Hydrochloride - (S)-[(S)-N-[(S)21-carboxy3-phenylpropyl]alanyl]-1,2,3,4- tetrahydro-3-
isoquinolinecarboxylicacid1-ethyl esterhydrochloride(Acuretic)
- formsthe diacidquinaprilate inthe body.Itismore potentthancaptopril andequipotenttothe active
formof enalapril.
Ramipril - (2S, 3aS, 6aS)-1-[(S)-N-[(S)-1-carboxy-3phenylpropyl]alanyl] octahydrocyclopenta[b]-pyrrole-
2-carboxylicacid1-ethyl ester(Altace)
- Is hydrolyzedtoramiprilat,itsactive diacidform, fasterthanenalapril ishydrolyzedtoitsactive diacid
form.
- Peakserumconcentrationsfromasingle oral dose are achievedbetween1.5and 3 hours.
- ramiprilate formedcompletelysuppressesACEactivityforupto 12 hours,with80% inhibitionof the
enzyme still observedafter24 hours.
Fosinopril Sodium- (4S)-4-cyclohexyl-1-[[[(RS)-1-hydroxy-2-methylpropoxy](4-phenylbutyl)
phosphinyl]acetyl]-L-proline sodiumsalt(Monopril)
- Phosphorus-containingACEinhibitor.
- It isinactive butservesasa prodrug,beingcompletelyhydrolyzedbyintestinal andliverenzymesto
the active diacidfosinoprilat
Trandolapril - 1-[2-(1-ethoxycarbonyl-3-phenylpropylamino)propionyl]octahydroindole-2-carboxylicacid
(Mavik)
- an indole-containingACEinhibitorthatisstructurallyrelatedtomostof the precedingagents
- VerysimilartoEnalapril withthe primarydifference occurringinthe heterocyclicsystems
- mustbe hydrolyzedtotranolaprilate,whichisthe bioactivespecies