Angiotensin Converting Enzyme Inhibitors

Properties and Side Effects

HARALAMBOS GAVRAS AND IRENE GAVRAS

SUMMARY The purpose of this brief review is to separate the characteristic properties and side
effects attributable to the pharmacology of the whole class of angiotensin converting enzyme (ACE)
inhibitors from those attributable to the chemical structure and kinetics of each particular ACE
inhibitor. The former would be predictable and probably similar for all agents and, therefore, would
be expected to recur with each agent, whereas the latter are likely to be characteristic of individual
compounds and may be avoidable by changing to another compound with similar pharmacology but
different molecular structure. (Hypertension 11 [Suppl II]: H-37-II-41, 1988)

KEY WORDS * angiotensin converting enzyme Inhibition * class effects * toxic effects
pharmacodynamics kinetics
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A NGIOTENSIN converting enzyme (ACE) inhi-
/ \ bition is the newest approach in the treatment
X \ . of hypertension, and in the last few years, it
has become increasingly popular as the first choice in
the pharmacotherapy of this disease. As with other
classes of antihypertensive drugs, such as thiazide
diuretics and /3-adrenergic blockers, the pharmacody-
namics of this mode of treatment have been most ex-
tensively investigated using the first agent of this class
that became available, captopril. '2 After the effective-
ness of this treatment was established for hyperten-
sion, congestive heart failure, and other indications,
the search continued for the production of the second
generation of such drugs with similar pharmacological
actions but different chemistry, kinetics, and ancillary
properties. The aim here was at reducing side effects,
improving convenience of administration, etc., while
maintaining efficacy. The first drug to become avail-
able from this second generation is enalapril, 34 with
several others currently being investigated in clinical
trials.
The purpose of this brief review is to separate the
properties, effects, and adverse reactions attributable
to the pharmacological action of this class of drugs,
that is, the ACE inhibition, from those attributable to
the particular chemical structure, kinetics, and ancil-
lary characteristics of each individual agent.
Effects of ACE Inhibition
All ACE inhibitors share the same mode of action,
that is, elimination of the production of angiotensin II
From the Department of Medicine, Boston City Hospital, and
Boston University School of Medicine, Boston, Massachusetts.
Supported in part by United States Public Health Service Grant
HL 18318 and National Institutes of Health Grant RR-533.
Address forreprints:Haralambos Gavras, M.D., Boston Univer-
sity School of Medicine, 80 East Concord Street, Boston, MA
02218.
and inhibition of the degradation of bradykinin. Ac-
cordingly, all lead to suppression of angiotensin II with
1) decrease of blood pressure, which may be normal-
ized in over 50% of an unselected population with mild
to moderately severe hypertension when the ACE in-
hibitor is used as monotherapy and in about 85% when
a diuretic is combined with ACE inhibition5-6; 2) vaso-
dilation varying in degree in various tissues (depend-
ing on the sensitivity of each organ's vascular tree to
angiotensin) and leading to increase in cardiac output
and redistribution of regional blood flows in favor of
vital organs at the expense of the less-sensitive muscu-
loskeletal tissues7; 3) partial suppression of aldoster-
one production by the adrenal zona glomerulosa
(though stimulation of aldosterone production contin-
ues to be exerted by the other two major mechanisms,
that is, plasma K + and adrenocorticotropin); 4) in-
crease in circulating levels of plasma renin due to inter-
ruption of the negative feedback control exerted nor-
mally by angiotensin II on the release of renin; 5)
potentiation of the vasodilatory effect of bradykinin
(although the physiological significance of this effect
has not been fully evaluated); and 6) in the long run,
decrease of the activity of the sympathetic nervous
system with diminished levels of plasma catechol-
amines as well as other hormones whose secretion is
partly dependent upon the stimulus of angiotensin II
(e.g., vasopressin).
As a result, all ACE inhibitors share the same hemo-
dynamic and metabolic effects,8 that is, a blood pres-
sure fall due to decreased peripheral vascular resis-
tance, increased cardiac output, relatively increased
renal, cerebral, and coronary blood flow (provided
there is no local anatomic obstruction or excessive fall
of perfusion pressure), and tendency toward increased
elimination of fluid and sodium with retention of po-
tassium by the kidneys (due to partial suppression of
aldosterone). Moreover, by changing intrarenal hemo-

11-37
 11-38 ANTIHYPERTENSIVE DRUG EFPECTS SUPPL II HYPERTENSION, VOL 11, No 3, MARCH 1988
dynamics9 (i.e., reducing to a large extent the tone of
both the afferent and the efferent arterioles so that
glomerular capillary pressure is usually maintained un-
changed despite either fall of systemic arterial pressure
or increase in renal blood flow), ACE inhibitors tend to
maintain glomerular filtration rate and decrease the
preexisting proteinuria associated with parenchymal
renal diseases or diabetes mellitus.10
Since their antihypertensive effects are obtained
mostly by alteration in the peripheral action of hor-
mones, all ACE inhibitors are free of the common side
effects originating from the central nervous system that
have been associated with other classes of antihyper-
tensive drugs." For example, drowsiness, fatigue, loss
of mental acuity, depression, impotence, vague weak-
ness, and loss of energy are not associated with ACE
inhibition. In fact, patients who have lived for long
periods of time under the influence of such side effects
and who are subsequently relieved of them when
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switched to an ACE inhibitor sometimes experience an
intense feeling of well being on which they comment
spontaneously.
By the same token, all ACE inhibitors share a num-
ber of potential adverse reactions that are inherent in
their mechanism of action. Excessive hypotension is
always a possibility, especially in patients with ma-
lignant hypertension who may have intense renin-
dependent vasoconstriction, in patients with hypona-
tremia and congestive heart failure, or in patients who
are already being treated with diuretics or who may be
dehydrated or volume depleted for other reasons.l2 Hy-
potension is more profound and abrupt with the fast-
acting captopril, which frequently produces a "tripha-
sic response" characterized by an immediate blood
pressure drop occurring within 20 to 30 minutes that is
followed by an intermediate rise and a subsequent,
more gradual fall over the next few days. The long-
acting agents like enalapril can produce a gradual but
more protracted and persistent hypotension. In either
case, the excessive blood pressure response to ACE
inhibition can easily be corrected by salt repletion (by
i.v. saline on symptomatic cases or by oral salt supple-
mentation in milder cases).
Other symptoms attributable to hypotension may
also arise in such cases and may become severe or lead
to other complications in elderly arteriosclerotic pa-
tients with coexisting vascular occlusive disease.
Tachycardia, coronary ischemia with angina, cerebral
ischemia with syncopal episodes, and decreased renal
perfusion ranging from mild azotemia to acute renal
failure with transient oliguria or anuria have all been
described as adverse reactions after initiation of ACE
inhibition; however, all are reversible and should in
fact be preventable by cautious assessment of the pa-
tient's clinical condition, coexisting diseases, and con-
current treatment, and they are no different from what
might be expected from any potent vasodilator.
On the other hand, the functional renal insufficiency
that has been described in patients with bilateral renal
artery stenoses or with stenosis of the renal artery of a
solitary kidney appears to be characteristic of ACE
inhibition and not simply the result of overall de-
creasedrenalperfusion. The postulated mechanism for
this side effect is the diminished renal blood flow due
to anatomic obstruction in combination with the alter-
ation in intrarenal hemodynamics occurring from the
elimination of angiotensin's constrictor effect on the
renal arterioles, in this case the efferent ones whose
tone is necessary for the maintenance of adequate glo-
merular filtration rate.9'l3 Though clearly functional
and totallyreversibleupon discontinuation of the ACE
inhibitor, this adverse reaction may become particular-
ly detrimental in patients with kidney transplant who
develop stenosis at the site of the arterial anastomosis;
it has been described as causing deterioration of the
graft's function14'l5 and can pose diagnostic problems
if confused with a rejection reaction.
Hyperkalemia is another potential side effect of
ACE inhibition, attributable to some decrease of aldos-
terone secretion after elimination of angiotensin II.
Normally, the small rise in plasma K+ levels itself can
again stimulate the secretion of aldosterone so that a
new homeostasis is achieved without reaching hyper-
kalemic levels. However, in patients with advanced
renal insufficiency, in elderly diabetics, in patients
treated with nonsteroid anti-inflammatory drugs, in
those using salt substitutes, or in those receiving con-
comitantly potassium-sparing diuretics, a potentially
dangerous hyperkalemia can develop.16
Two other peculiar and rare reactions seem to be
particular, although ill-defined, side effects of ACE
inhibition: angioedema17'18 and a persistent dry cough
sometimes accompanied by wheezing.1920 Angio-
edema has been reported to have an incidence of 0.2%
with enalapril and 0.1% with captopril17 and is self-
limited and reversible upon discontinuation of the
drug. Although triggering of previously dormant asth-
ma has been described with ACE inhibitors,21 in our
experience, chronic asthma is not necessarily exacer-
bated by ACE inhibition. In fact, many hypertensive
patients whose asthma had worsened by the use of
sympatholytic agents (e.g.,reserpine)reportedsignifi-
cant improvement when switched to an ACE inhibitor
(H. Gavras and I. Gavras, unpublished observations).
However, a chronic dry cough has lately been reported
with increasing frequency since it was first recognized
as a side effect of ACE inhibitors.
Dilutional hyponatremia has been described in pa-
tients with congestive heart failure treated with multi-
ple drugs including ACE inhibition22; however, other
studies have reported correction of this condition by
the use of an ACE inhibitor,23 which may be explained
by the suppressing effect of ACE inhibition on vaso-
pressin release.
Additional Side Effects of ACE Inhibitors
In addition to the side effects attributable to their
mechanism of action (i.e., the so-called "class ef-
fects," which would be expected to occur more or less
with any one drug from the same class), individual
ACE inhibitors may display different adverse reactions
 ACE INfflBITORS/Gavraj and Gavras
attributable to their particular chemical structure or
kinetics.
Captopril contains a modified proline molecule with
a mercapto moiety that binds with the zinc atom of the
metalloenzyme ACE, thus inactivating it. It is easily
absorbed by mouth in the active form, provided it is
taken on an empty stomach (because food has been
reported to diminish its bioavailability,24 although this
may not always be the case). Its onset of action is
apparent within 20 to 30 minutes, and its duration of
action is probably in the range of 12 hours, usually
requiring twice-daily administration. Within the body,
it undergoes constant interconversion with its active
metabolites, which are excreted in the urine.23
Enalapril and the other second-generation ACE in-
hibitors that are presently undergoing clinical trials
differ from captopril in that they compete with the
renin substrate for binding sites of the ACE; therefore,
their effect does not depend on the chelating action of a
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mercapto moiety on the zinc atom of the ACE.3
The lack of a mercapto group should theoretically
render these agents free of several side effects. Indeed,
because these adverse reactions (listed below) are
common to all sulfhydryl-containing drugs, regardless
of their particular pharmacological actions (drugs as
disparate as heavy metal antagonists and antithyroid
agents26), it is speculated that they are attributable to
this structure.
Enalapril (and several other second-generation ACE
inhibitors) is a prodrug, the ethylester of the active
diacid compound. It is easily absorbed after oral ad-
ministration, not hindered by the presence of food, but
must be deesterified in the liver, which acts as a reser-
voir and gradually releases the active diacid. There-
fore, it has a delayed onset of action of about 2 hours, a
peak at 4 to 12 hours, and usually lasts for 24 hours,
thus permitting once-daily administration. The active
drug is not further metabolized but is excreted in the
urine unchanged. 2728 These different kinetics explain
some of the differences in pharmacological properties
between the two drugs.
The most common adverse effect with any chemical
is the possibility of an allergic reaction, with a maculo-
papular pruritic rash, that may be accompanied by
eosinophilia. Both captopril and enalapril have been
described to cause such reactions, but their incidence is
higher in the former (ranging between 2.5 and 10% in
various reports depending on the dosage used12'13) than
in the latter (1.2% 17 ). These are usually mild, self-
limiting reactions that are more likely to occur in
patients receiving higher doses and having underlying
conditions that place them at risk, such as renal
insufficiency.
In addition, captopril has also been reported to cause
a wide variety of more severe skin conditions some-
times accompanied by drug fever, including lichenoid
eruption,29 a bullous pemphigus-like rash, 3031 rosa-
cea,32 erythroderma with exfoliative dermatitis,33
tongue ulcers, 3433 necrotizing blepharitis,3* and fatal
Stevens-Johnson syndrome.37
Bone marrow suppression is another potentially
11-39
serious reaction associated with captopril. Neutrope-
nia with agranulocytosis, 3839 ' 40 thrombocytopenia,41
aplastic anemia,42 and pancytopenia43 have all been
encountered with this agent. Although at least three
fatal cases have been reported to date, 44 ' 43 ' ** these re-
actions should be reversible upon discontinuation of
the drug, provided they are diagnosed before causing
other complications. Again, as with other side effects,
the probability of blood reactions rises from 0.02% in
otherwise healthy hypertensive patients receiving
small doses of the drug to 0.4% in those with serum
creatinine over 2 mg/dl to 7.2% in those with coexist-
ing collagen disease concurrently receiving immuno-
suppressive drugs.47
It should also be pointed out that the incidence of
drug-induced leukopenia may be exaggerated because
many perfectly healthy subjects, especially from cer-
tain racial or ethnic groups, have an idiopathic tenden-
cy to wide cyclic changes of white blood cell counts,
which, if previously unnoticed, could be mistaken for
a drug effect.48
There is one case of reversible neutropenia reported
to occur 6 hours after administration of the first 0.6-mg
dose of enalapril.49 No other blood reactions have been
reported with the usual 5 to 20 daily doses of this drug,
even in patients with renal failure. In fact, in a multi-
center trial, most of the adverse reactions associated
with enalapril had an incidence similar to that observed
with a placebo.50
A nephrotic syndrome, presenting with intermittent
proteinuria and accompanied by immune-complex
neuropathy with pathological changes suggestive of
membranous glomerulonephritis or acute interstitial
nephritis, is also one of the potential adverse effects of
captopril. 5152
This nephrotic reaction should be differentiated
from the reversible acute renal failure attributable
to ACE inhibition as mentioned earlier, which is
characterized by absence of such pathological
changes.53'** 35> x It is also possible that some degree
of subclinical glomerulonephritis may exist in the hy-
pertensive population without being necessarily drug
related.57 These side effects of captopril, that is, the
bone marrow suppression, the nephrotic syndrome,
the severe skin reactions, and taste alterations17 rang-
ing from transient or persistent loss of taste to peculiar
sulfuric or metallic taste, have been attributed to the
molecular structure of the drug and, in particular, to its
sulfhydryl moiety. In support of this view is the fact
that they appear to be equally common to drugs with
different pharmacological properties but similar mo-
lecular structure, such as penicillamine and thio-
ureas. 26 ' 50 In fact, there are cases in the literature of
patients developing the same reactions to more than
one drug from these different classes, for example,
captopril and methimazol.59
On the other hand, the majority of patients with
previous adverse reactions to captopril could be un-
eventfully treated with enalapril.17'w> 61 There are also
reports of patients with allergic reaction to enalapril
(mild skin rash with eosinophilia) treated successfully
 11-40 ANTIHYPERTENSIVE DRUG EFFECTS SUPPL II HYPERTENSION, VOL 11, No 3, MARCH 1988
with captopril,62 indicating that it is clinically impor-
tant to separate class effects that could be expected to
recur with any ACE inhibitor from idiosyncratic reac-
tions to a particular compound.
Rare and isolated reports with a questionable causa-
tive relationship to captopril include cholestatic jaun-
dice,6364 toxic hepatitis,65 pericarditis and parkin-
sonism,66 psychotic reactions,67 neuropathy,68 and
development of positive antinuclear antibodies69 some-
times accompanying a lupus-like syndrome.70 The pos-
sibility of zinc deficiency has also been raised as a
result of long-term treatment with captopril.71
Side effects peculiar to enalapril include the possi-
bility of renal glucosuria72 and the potential for dimin-
ished bioavailability73 of this agent when administered
concurrently with propranolol. It should also be kept in
mind that enalapril has been used less extensively, and
therefore, there may still be other rare adverse reac-
tions that have not yet been observed or associated
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with the drug to date.
A number of publications have reported adverse ef-
fects on the fetus when the mother was treated with
captopril during pregnancy. Such effects ranged from
increased fetal loss74 to fetal or neonatal renal fail-
ure7576 and other abnormalities.77 At this point, it is
unclear whether they are specific to captopril or wheth-
er they should be attributed to ACE inhibition. Howev-
er, patency of the ductus arteriosus may well be related
to release of prostaglandins enhanced by potentiation
of bradykinin.
In conclusion, all ACE inhibitors appear to be equal-
ly effective in the treatment of hypertension, conges-
tive heart failure, and other indications where ACE
inhibition is beneficial. They all share the same small
probability of more or less predictable side effects due
to their common pharmacological properties, but each
one has a number of additional characteristics and po-
tential adverse reactions due to its particular chemis-
try, kinetics, or other ancillary properties that should
be considered separate from the class effects. Several
new compounds with different potency, route of ab-
sorption and excretion, and different toxicity profiles
are currently in earlier stages of clinical development78
and will probably become available in the near future.
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H Gavras and I Gavras

Hypertension. 1988;11:II37
doi: 10.1161/01.HYP.11.3_Pt_2.II37
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