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University of Groningen Merits and demerits of the converting-enzyme inhibitor captopril in antihypertensive treatment Hoorntje, Steven Jan IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 1981 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Hoorntje, S. J. (1981). Merits and demerits of the converting-enzyme inhibitor captopril in antihypertensive treatment s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 12-08-2017 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 79 (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 80 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. I I a I , t 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. 82 t