Angiotensin-Converting Enzyme Inhibitors Sideeffects

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THE JOURNAL OF CLINICAL HYPERTENSION VOL. VI NO. VII JULY 2004410

Angiotensin-converting enzyme (ACE) inhibitorsare increasingly recognized as having an impor-tant role in the treatment of hypertension and/orend-organ disease. The sheer number of ACEinhibitors in the United Statesnow numbering10 different chemical entitieshas created a senseof comfort with these compounds, which is par-ticularly evident when these compounds are usedin the patient with essential hypertension; con-versely, when comorbid conditions are present inthe ACE inhibitor-treated patient, circumstances

change and physician vigilance becomes more of anecessity. ACE inhibitor therapy in patients witheither cardiac and/or renal disease is as much anart as it is a science, and even in the most skilledhands can prove a challenging undertaking. Thisreview discusses the physiologic and non-physi-ologic basis for side effects with ACE inhibition.(J Clin Hypertens. 2004;6:410416)2004 Le Jacq Communications, Inc.

In addition to their antihypertensive properties,angiotensin-converting enzyme (ACE) inhibitorshave been widely accepted for their capacity to slowprogressive renal, cardiac, and/or vascular disease.1,2Outcome studies with a variety of ACE inhibitorshave resulted in usage indications in conditions, suchas congestive heart failure, post-myocardial infarc-tion, and diabetic nephropathy (Table).1,2 Mostrecently, a treatment indication has been granted tothe ACE inhibitor ramipril for reducing cardiovascu-lar events in the high-risk cardiac patient without evi-

dent left ventricular dysfunction.3

In consideration ofthese successes with ACE inhibitor therapy, it comesas no great surprise that the market for this drug classis as expansive as it is. At present there are 10 ACEinhibitors available in the United States and severalmore to be had worldwide.

ACE INHIBITOR SIDE EFFECTSACE inhibition is a sufficiently well accepted treat-ment modality, and most of the guidelines address-ing treatment of hypertension, renal disease, and/orcardiovascular disease have this therapeutic optionprominently positioned in the treatment hierar-

chy.46Despite the universality of such recommen-dations, issues remain as to how to most safelyutilize these compounds. There remains an art asmuch as a science to the use of these drugs. Thescience behind ACE inhibitor use is well accepted,the art, however, is a work in progress, with manysubtleties to use that only become evident afterextensive usage experience.

Both physiologic and non-physiologic side effectscan be the basis for ACE inhibitor intolerance;

Angiotensin-Converting Enzyme InhibitorsSide EffectsPhysiologic andNon-Physiologic Considerations

Domenic A. Sica, MD

From the Departments of Medicine and Pharmacology,

Section of Clinical Pharmacology and Hypertension,Division of Nephrology, Virginia CommonwealthUniversity, Richmond, VAAddress for correspondence:Domenic A. Sica, MD, Professor of Medicine andPharmacology, Chairman, Clinical Pharmacologyand Hypertension, Division of Nephrology, VirginiaCommonwealth University, MCV Station Box 980160,Richmond, VA 23298-0160E-mail: [email protected]

C u r r e n t C o n c e p t s o fP h a r m a c o t h e r a p y i n H y p e r t e n s i o nD o m e n i c A . S i c a , M D , S e n i o r E d i t o r

www.lejacq.com ID: 2866


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VOL. VI NO. VII JULY 2004 THE JOURNAL OF CLINICAL HYPERTENSION 411

however, what constitutes true ACE inhibitorintolerance is highly subjective, and even whenextreme physiologic change (such as an excessiveincrease in serum creatinine concentration) is thebasis for drug discontinuation, there are differingopinions on when to stop (and/or restart) a medi-cation in this class. Alternatively, with the readyavailability of a drug class such as the angioten-sin-receptor blockers (ARBs), which offer similarbenefits for both blood pressure (BP) control andevent protection, the decision is simplified as tohow long to tolerate a non-physiologic side effectsuch as cough. As of yet, the available information

is less than convincing that ARBs are better toler-ated than ACE inhibitors relative to physiologicside effects.7

Although certain ACE inhibitor side effects canprove life threatening (such as angioedema) themajority fall into the category of being no morethan discomforting; however, in certain instances,ACE inhibitor side effects (such as a suppression inred blood cell production in the setting of erythrocy-tosis) can prove beneficial. Most ACE inhibitor sideeffects can be viewed as a class effect.8The conceptof an intraclass switch to alleviate a side effect hasbeen most commonly applied to the issue of ACE

inhibitor-related cough.9,10In most instances, a less-than-rigorous trial design proves to be the unmak-ing of a superiority claim for one ACE inhibitor(over another) for less frequent cough. As such,simply switching from one ACE inhibitor to anotherwill not alleviate the side effect per se.

PHYSIOLOGIC SIDE EFFECTSThe site of ACE inhibitor activity (within the reninangiotensin aldosterone axis) can be pinpointed at

the pluripotent ACE, an enzyme known to catalyzethe conversion of angiotensin-I to angiotensin-II,as well as to facilitate the degradation of bradyki-nin to assorted vasoactive peptides.2,3The basis forphysiologic side effects with ACE inhibitors relatesto these aforementioned changes in angiotensin-II(and possibly the increase in bradykinin) and isparticularly prominent when the effected systemcardiovascular and/or renalis heavily dependenton the presence of angiotensin-II for maintenanceof function. ACE inhibitor side effects of a physi-ologic nature are typically worsened when patientsare volume depleted, but even in the face of an

overly sodium restricted diet, such side effects candevelop.11

Blood PressureHypotension is not a specific side effect with ACEinhibitors; rather, it is a broadening of the physi-ologic action of these drugs that occurs most com-monly when a patient becomes volume contracted.In the setting of ACE inhibitor-related hypotension,circumstances have evolved in such a way thatperipheral resistance (and thereby BP) is dependenton angiotensin-II. As angiotensin-II is subtractedfrom this hemodynamic equation, there can be a

precipitous fall in BP, which is only worsened bythe actions of the vasodilator bradykinin.

ACE inhibitor hypotension can present as afirst-dose phenomenon or anytime in the courseof chronic therapy.12Hypotension observed in thefirst days of treatment with an ACE inhibitor maybe best managed with a dose reduction or tem-porary discontinuation of the drug. Hypotensiondeveloping in the course of chronic therapy canbe anticipatedsuch as in heart failurewhere

Table. United States Food and Drug Administration-Approved Indications for Angiotensin-Converting Enzyme Inhibitors

DG HTN CHF D NOY HG-RK P WO

L V DYO

Captopril (post-MI) *

Benazepril

Enalapril **

Fosinopril Lisinopril (post-MI) *

Moexipril

Perindopril

Quinapril

Ramipril (post-MI)

Trandolapril (post-MI)

HTN=hypertension; CHF=congestive heart failure; MI=myocardial infarction; *captopril and lisinopril are indicated for CHFtreatment both post-MI and as adjunctive therapy in general heart failure therapy; **enalapril is indicated for asymptomatic, leftventricular dysfunction


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intention is there to become pregnant in the nearfuture.19 If ACE inhibitors or ARBs are requiredor are being incidentally used when a women isnursing, there will be minimal entry of these com-pounds into breast milk. Although not all ACEinhibitors or ARBs have been submitted to formal

study, in most cases breast milk selectively restrictsthe passage of these drugs.20

HyperkalemiaHyperkalemia is an additional ACE inhibitor-asso-ciated side effect that has a strong physiologicbasis.2125 ACE inhibitor-related hyperkalemia, likeall forms of hyperkalemia, is highly definitional innature. Once a specific definitional threshold valuehas been reached during ACE inhibitor therapy, aspecific criterion for hyperkalemia will be satisfiedand the patient then counts as an affected case. In

reality, ACE inhibitors will increase the serum potas-sium value in virtually all treated subjects but to adegree (0.10.2 mEq/L) that is clinically undetectableand never reaches (or even approaches) an assign-ment criterion for the diagnosis of hyperkalemia.

Thus, it is axiomatic in the use of an ACEinhibitor to always anticipate an increase in serumpotassium values. The frequency with which serumpotassium values should be monitored in an ACEinhibitor-treated patient should be based on pre-

therapy serum potassium value and level of renalfunction, as well as the presence of diabetes andwhether concomitant medications are being giventhat might also influence systemic potassium bal-ance.1,2,24 Potassium supplements or potassium-sparing diuretics, when given with ACE inhibi-

tors, not suprisingly increase the probability ofdeveloping hyperkalemia.24To this end, two othercommon drug causes of hyperkalemia (when giventogether with an ACE inhibitor) exist: first, saltsubstitutes (60 mEq/tsp of potassium chloride)and second, non-steroidal anti-inflammatory drugsand cyclooxygenase inhibitor therapy. These lattertwo drug classes decrease potassium excretion byreducing aldosterone concentrations, and throughthis mechanism interact with ACE inhibitors in thedevelopment of hyperkalemia.

It is uncommon even under the most extreme cir-cumstances to see more than a 2.0-mEq/L increase

in serum potassium values with an ACE inhibitor.When such extreme changes occur, it is generallyin conjunction with a sudden fall in GFReitherprompted by the ACE inhibitor (as is the case withrenal artery stenosis) or as a consequence of inter-current illness having lead to volume contraction.Conversely, ACE inhibitors will cut the potassiumloss ordinarily occurring with diuretic therapy. ACEinhibitor hyperkalemia appears to be class-specificwith very little experimental evidence supportingone ACE inhibitor over another in lessening the riskof hyperkalemia. If differences between ACE inhibi-tors in the incidence of hyperkalemia do existas

has been suggested for fosinoprilthey are prob-ably coupled to the pattern of drug accumulationfor these drugs in chronic kidney disease.12,26A finalconsideration on this topic is whether ARB therapyis associated with a lesser rate of hyperkalemiadevelopment than is the case for ACE inhibition.Although there are few data to support this notionrelative to hyperkalemia per se, the degree of changein serum potassium with an ARB (in an absolutesense) can be somewhat less than what is observedwith an ACE inhibitor.25

NON-PHYSIOLOGIC SIDE EFFECTSCoughA dry, irritating, nonproductive cough is a commoncomplication with ACE inhibitors, with an inci-dence between 0% and 44%.27The wide variabili-ty in cough relates to the differing representation insurveyed populations for variables associated withan increased cough incidence, which include: age,gender, ethnicity, and geographic location of thestudies. Cough is a class phenomenon with ACE

Figure. Schematic illustration of settings wherein angio-tensin-converting enzyme (ACE) inhibitor therapymay worsen renal function. Conditions causing renalhypoperfusion include systemic hypotension, high-graderenal artery stenosis, extracellular fluid volume contrac-tion (simplified as dehydration in the Figure), andadministration of vasoconstrictor agents (non-steroidalanti-inflammatory drugs or cyclosporine, not shown),and congestive heart failure. These conditions typicallyincrease renin secretion and angiotensin-II production.

Angiotensin-II constricts the efferent arteriole to agreater extent than the afferent arteriole, such that glo-merular hydrostatic pressure and glomerular filtrationrate (GFR) can be maintained despite hypoperfusion.When these conditions occur in ACE-inhibitor treated

patients, angiotensin-II formation and effect are dimin-ished, and GFR may decrease. Adapted with permis-sion from Circulation. 2001;104:19851991.13


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inhibitors and has been attributed to an increase inbradykinin and/or other vasoactive peptides, suchas Substance P, which may play a second messen-ger role in setting off the cough reflex. Althoughnumerous therapies have been tried, few have hadany lasting success in eliminating ACE inhibitor-

induced cough.28,29

The sensible clinical approachfor suspected ACE inhibitor-related cough is tore-assess the patient several weeks after drug dis-continuation. Disappearance of the cough can thenbe taken as proof of an ACE inhibitor etiology.In most cases it is not necessary to re-challenge apatient with an ACE inhibitor to obtain absoluteproof of a cause-and-effect relationship for cough.

AngioedemaAngioneurotic edema is a potentially life-threaten-ing complication of ACE inhibitors that is morecommon in blacks.30 Angioedema can be quite

subtle in its early presentation with non-specificoral, lingual, and lip symptoms. In its early presen-tation it is often attributed to food or other concur-rent medication; however, early nonlife-threaten-ing episodes of angioedema presage episodes witha more extreme presentation. Angioedema can beeffectively managed in the long-term with simplediscontinuation of the offending ACE inhibitor.31Angioedema can occasionally recur with ARBtherapy in a patient having previously experiencedit with an ACE inhibitor, but it is generally mildand not life-threatening.32 Angioedema of theintestine (more common in women) can also occur

with ACE inhibitor therapy with a typical presen-tation being one of abdominal pain/diarrhea withor without facial and/or oropharyngeal swelling.33This process can be intermittent in nature develop-ing even several years after ACE inhibitor therapyhas been initiated.34 However, the use of ACEinhibitors is not associated with a significantlyincreased risk of acute pancreatitis.35

AnemiaAnother side effect consideration with ACE inhibi-tors is that of anemia. ACE inhibitors suppress the

production of erythropoietin in a dose-dependentmanner, which presents a particular problem whenACE inhibitors are administered in the presenceof renal failure.36 ACE inhibitor-related anemiais at least, in part, related to N-acetyl-seryl-aspar-tyl-lysyl-proline accumulation. This substance isa potent natural inhibitor of hematopoietic stemcell proliferation as well as an antifibrotic moiety,which is degraded mainly by ACE.37 Because ofthe increase in N-acetyl-seryl-aspartyl-lysyl-pro-

line concentrations with ACE inhibitor therapy,these compounds may possibly be better suitedfor suppression of red bloodcell production whenit is a desired clinical goal. Such settings includepost-transplant erythrocytosis38,39 and high-alti-tude polycythemia with as much as a 4.5-g/dL fall

in hemoglobin concentration being observed withACE inhibitor therapy.40

NON-SPECIFIC SIDE EFFECTSNon-specific side effects with ACE inhibitors aregenerally uncommon with the exception of tastedisturbances, leucopenia, and dysgeusia, whichare largely seen in captopril-treated patients.Although skin rashes are seen with captopril,cutaneous reactions including life-threateningangioedema, pruritus, bullous eruptions, urticar-ia, other generalized rashes, photosensitivity, andhair loss can occur with any of the ACE inhibi-

tors. ACE inhibitor skin reactions thus mimic abroad variety of skin diseases, and these drugsshould be considered when sudden, unexplain-able skin eruptions occur.41Whereas a number ofantihypertensives have headache as an accompa-nying side effect with their use, this is not so withACE inhibitors. In fact, ACE inhibitors have beenused for migraine prophylaxis42; moreover; theyhave been proven effective in reducing the risk ofheadache with nitrate therapy.43

CANCER AND ACE INHIBITORSIt went largely unnoticed in the prospective Studies

of Left Ventricular Dysfunction (SOLVD)44studythat enalapril-treated patients with left ventricu-lar dysfunction showed a slightly higher incidenceof malignancy than those receiving placebo (oddsratio, 1.59; confidence interval, 0.902.82). Sincethe SOLVD study, several case reports have linkedACE inhibitors to the development of malignan-cies. For example, pemphigus vulgaris, which canbe seen in association with internal malignancies,is found in association with the use of captopril.One case report has linked enalapril to pemphigusvegetans with a simultaneously occurring internal

malignancy.

45

In another case report, Kaposissarcoma appeared in a 70 year-old female 8months after starting captopril. Upon stoppingthe captopril there was a marked reduction inboth the cutaneous and gastric lesions of thisdisease, suggesting a cause-and-effect relationshipbetween the captopril and the malignancy.46 Asubsequent study disputed these findings in thatit was shown that captopril inhibited angiogenesisin Kaposis sarcoma.47


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These limited data contrast with a greater bodyof evidence supporting the absence of a cancerrisk with ACE inhibitors. In the Heart OutcomesProtection Study (HOPE) trial, a total of 9297high-risk patients treated either with ramipril orplacebo for a mean of 5 years had similar num-

bers of deaths from noncardiovascular causes inboth groups. In addition, several other retrospec-tive studies investigating the possible associationbetween various antihypertensives and cancer riskhave been unable to detect such a relationship withthe use of ACE inhibitors.4850Finally, the Scottishretrospective cohort study (between January 1,1980, and December 31, 1995) by Lever et al.,51who compared 1599 patients taking ACE inhibi-tors and 3648 on other antihypertensive drugs,demonstrated a risk reduction for female sex-spe-cific malignancies and lung cancers. In this cohortstudy, the reduced relative risk of cancer in patients

on ACE inhibitors was greatest with follow-up oflonger than 3 years. Thus, the evidence availableto date suggests that ACE inhibitors have a neutralcancer risk in hypertension52 and might conceiv-ably decrease the risk.53

CLASS AND AGENT-SPECIFICDRUG INTERACTIONSSeveral class-specific drug interactions occur withACE inhibitors. For example, the concurrent admin-istration of lithium with an ACE inhibitor increasesthe likelihood of lithium toxicity.54This seems torelate to two renal processes associated with ACE

inhibitor therapy: first, a reduction in GFR andsecond, an increase in proximal reabsorption, bothof which can decrease lithium renal clearance. Thisappears to be a class-specific phenomenon and onethat is more apt to occur when an ACE inhibitoris combined with a diuretic and some degree ofvolume contraction has occurred. Finally, combin-ing an ACE inhibitor with allopurinol is associatedwith a higher risk of hypersensitivity reactions withseveral reports of the Stevens-Johnson syndromedescribed with the combination of captopril andallopurinol.55Quinapril reduces the absorption of

tetracycline by

35%, which may be due to thehigh magnesium content of quinapril tablets.

CONCLUSIONSACE inhibitor therapy is now a mainstay of clini-cal practice. The ease with which these compoundscan be used in most subjects is reassuring; however,numerous considerations arise when these drugs areused in certain patient types, including the elderlyand/or volume contracted patient and/or those

with comorbid conditions of a renal or cardiacnature. ACE inhibitor side effects are either physi-ologic or non-physiologic. Physiologic side effectswith an ACE inhibitor are to a degree correctableand often allow a restart of the medication undermore strictly controlled circumstances (liberalized

intake of sodium or a decrease in diuretic dose).Non-physiologic side effects are unpredictable intheir occurrence and can go unrecognized; how-ever, when recognized, the decision to discontinuean ACE inhibitor (other than for angioedema)is one of some subjectivity. Alternatively, certainACE inhibitor properties (such as suppressing redblood cell production) can be taken advantage ofas in the case of erythrocytosis.

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