Download University of Groningen Merits and demerits of the converting

University of Groningen
Merits and demerits of the converting-enzyme inhibitor captopril in antihypertensive
treatment
Hoorntje, Steven Jan
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1981
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Hoorntje, S. J. (1981). Merits and demerits of the converting-enzyme inhibitor captopril in antihypertensive
treatment s.n.
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Chapter 6
Summ?,rftconclusionsand
look toward the future
6.1 Summary
TheJoint National Committee on Detection,Evaluationand Treatment
of High Blood Pressurehas recently advisedthat diastolic BP readingsof
examinationsshouldbe regardedascon90 mmHg or more on 2 successive
firmation of hypertension and should be an indication for therapy. Most
hypertensivepatients can be controlled with dietary regimensalone or in
combination with currently availableantihypertensiveagents.However,
the number of patientswho are moderateor poor respondersto antihypertensivetherapywill increasewith the rigorousrequirementsfor BP control.
There will be, therefore, an increasingneed for potent antihypertensive
agents.One of these might be the converting-enzymeinhibitor captopril.
This antirenin drug is the product of intensive researchwhich was started
in the sixtieswhen the influenceof the renin systemin initiating and sustaining hypertension was increasinglyrecognized.Preliminary studies with
captopril have shown that its antihypertensiveproperties exceedthe results
with other currently available therapeutics.
The aim of the present investigation was to stud.vthe efficary ol captryt-:,r
in a large groupof hypertensivepatients. The studiesdescribedarein part a
continuationof Prins's studies. However, in this thesis the effects of
captoprilon blood pressureand the cardiovascularsystemhave especially
beendescribedduring prolonged rrearmenr. In addidon, the vasalar and
rena,lresponsesto the drug were srudiedin order to gain a betterinsight into
capropril'sBP lowering effecrs.Finally, specialattention hasbeenpaid to the
roxrciryof captopril since rhis might limit cli,nica| appticabiliry (chaprer 1).
This studyestablishedthat captopril is a potent antihypertensiveagent.
A sustainedlowering of BP for periods up to rg months was observedin a
groupof 89 patients.These results are the more impressiveas this group
consisted
predominantlyof severeor previously uncontrollablecases.The
combinationof captopril and dietary sodium restriction - with an additional
diureticin 30-40per cenr of all cases- resultedin an adequateBp response
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(SDBP ( 95 mmHg accordingto \7HO-criteria) in 93 per cent of all patients after one year of treatment. Additional advantageswere the rapid
occurring BP-responseand the absenceof reflex tachycardiaas well as the
absenceof posturalhypotension.Secondaryresistanceto the drug developed
only in 10 per cent of the patientsand was characterizedby markedresponsivenessto diuretics.Finally, fluid retention did not occurto the sameextent
as occurring with comparablypotent vasodilators.
The therapeuticeffect of captopril was objectivatedby studyingchanges
in those organs that can be consideredtarget orlans for elevatedarterial
pressure.A significant improvement was observedin fundoscopic,electrocardiographicand roentgenologicparametersof hypertensivedamageof
arterial vesselsand heart.Thesechangeswere most dramaticin the first few
months of therapy. Therefore,the casualBP readingsalso most probably
indicatedadequateBP control (chapter 2).
The way in which captopril lowers BP is incompletelyunderstood.Most
investigatorsagreethat blockadeof the RAS by CE inhibition playsan important part in the decreasein BP. However, the evidencefor this is mainly
circumstantial.Our studiesdisclosedthat inhibition of the pressoreffectsof
exogenousA I ran parallel to the decreasein BP. Captopril showedno depressoractivity in two different hypertensivestatesassociated
with little or
no renin. Though there is every reasonto concludefrom thesedata that
decreased
formation of A II playsan important part in the captopril-induced
decreasein BP, it appearedthat continuousBP control wasachieveddespite
intermittent resumption of normal CE activiry.This indicatesthat the specific effect of captopril administration (inhibition of A II generation)acts
togetherwith other mechanismsto control BP throughout the day (chapter
J).
I7ith regardto the renal responseto captopril,we observeda decrease
in
renal vasoconstrictionaod an increasein renalbloodflow. Thestrongcorrelation between the percentagechangeof GFR and of the producr of MAP and
ERPF during captopril treatment comparedwith baselinevaluesjustifies
the conclusionthat GFR is maintainedby the increasein renal blood flow
in BP. Though the meanGFR did not change,
despitea considerabledecrease
the individual patient mostly reactedwith either an increaseor a decrease
in
GFR. No differencescould be detectedin the RVH patients having these
different renal responses.However, patients with EH who showedan increasein GFR appearedto be youngerthan the patientswho reactedwith a
decreasein GFR. The probableexplanationfor this is that youngerpatients
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have functional,i.e. reversible,changesof the renal vessels,often in combination with an activatedRAS. Ageing patientshaveanaromicalchangesof
the renal vasculature,often in combination with a suppressedRAS. It is
therefore no surprise that thesecategoriesof patients with EH showeda
different renal responseto captopril. No conclusiveanswer can be supplied
as to whether changesin renal function contributeto the hypotensiveaction
of the drug (chapter 4;.
Beforea final conclusioncan be drawn as to the placeof captopril in anrihyperrensivetreatment, the toxicity of the drug has ro be considered.We
observedone or more side effectsin 30 per cent of our patients. Theseincluded rash, sometimesin associationwith arthralgia and fever, ageusia,
proteinuria and anaemia.The drug had to be withdrawn in 8 patients.
However, most events were transient and did not prejudicerhe conrinued
treatment with captopril. The characterof side effects, in combination
with a parallel increasein auto-antibodies,favours an immunologically
mediatedpathogenesis.Their high incidencemay be a consequenceof a
specialfearureof the patients enrolled in this study to developsideeffects,
the designof the study,or both. !7ith regard to the patients,recenrstudies
have shown an increaseof immune reactivity in patients with malignant
hypertension. Since many patients with severe, therapy-resisrant or
malignant hypertensionwere includedin this studv,it may well be that the
high incidenceof side effects is a consequenceof our patienr selection
(chapter2).
Undoubtedly,the most seriouscomplicationswere renal (nephrotic syndrome) and haematological(agranulocytosis).
Nfith regard to the former,
we reviewedall availabledataon deveiopmentof proteinuria during captopril therapy.It appearedthat proteinuria occurredin a frequenryoI7 .4 7oin
a singlecenter studyin New York whereaswe found in our own study4.) %.
Membranousglomerulopathy at an early stagewas unvariablyestablished
in all patients who underwent a renal biopsy having captopril-associated
proteinuria. However, proteinuria seemsto be an unreliablemarker for the
presenceof MGP sinceurinary protein loss may be transienteven without
discontinuing the drug. The way in which captopril induces MGP is
unknown. It is possible that auto-antibodies,which result from immunodysregulation,play a part in the pathogenesis.As for the clinical impact
of the histologicallesions,it is asyet unknown whether MGP will progress
to renal function loss by the development of a thickened GBM or,
alternatively,may heal completely.
81
Our studies indicated that patchy immunoglobulin deposition and
atypical,small, very densedepositsin EM are found in most patientswith
hypertension before captopril rreatment.The arypicalparticles were also
seen in biopsiesof a control group (transplant biopsies).No differences
could be established between pre- and post-captopril biopsies. These
observationsare conclusiveevidencethat captopril is not associated
with the
developmentof these ultrastructuralabnormalities (chapter 5).
l
6.2 Conclusion
Captopril is highly effective in lowering blood pressure,especiallyin
combination with sodium restriction. The main mechanismof captopril's
BP lowering-actionis inhibition of the RAS. The drug increasesrenalblood
flow and decreases
renalvasoconstrictionwhile GFR is maintaineddespitea
fall
considerable of BP. Though captopril is an antihypertensiveagentwith
undoubtedpotency,its associatedside effects,some of them serious,limit
unlimited clinical applicabiliry.
Our presentknowledgesuggeststhat captopril shouldbe reservedfor the
treatment of hypertensionwhich is untreatableby other currentlyavailable
drugs.
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6.3 Look toward the furure
So far, no studieshavecome to hand that dealwith optimum dosagingof
captopril. Furure studiesshould focuson this important issueand should
pay attention to the relative significanceof dietary sodium restrictionand
diureticsin obtaining the maximum effectof captopril in the lowestdosages.
The questionas to whether lower dosagesthan currentlyusedwill diminish
the frequencyof side effects,may be answeredin thesestudies.
The remarkable efficacyof captopril (i.e. the principle of convertingenzymeinhibition) hasstimulatedmany pharmaceuticalindustriesto develop orally activeCE inhibitors. Sinceir wasrhoughtthat the SH group might
be responsiblefor the sideeffectsof captopril,the designof this researchhas
been focussedon the developmentof a CE inhibitor without a mercaptogroup210.
One must be aware,however,that no conclusiveevidenceisavailable at the presenttime that it is only this mercapto-groupwhich is involved
in the range of captopril-associated
side effects.It should not be forgotten
that the principle of CE inhibition per se is by no meansbeyondsuspicionof
playing a part in the pathogenesisof side effects.
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t