Approach to and
Management of Adverse
Drug Reactions
Mercedes E. Arroliga
Adverse reactions to drugs are unintended or undesired effects of a
drug therapy that may significantly influence management deci-
sions.1 The incidence may be as high as 15% in hospitalized patients.2,3
Budnitz and colleagues, in a study of emergency department visits
for outpatient adverse drug reactions, reported that such reactions
accounted for 2.5% for all unintentional injury and 0.6% of the
estimated visits for all causes.4
Predictable adverse drug reactions are common. These reactions
are dose dependent or related to the pharmacology of the drug and
include overdose, side effects, secondary or indirect effects, second-
ary effects related to underlying disease, and drug-drug interac-
tions.1,5 Unpredictable drug reactions are less common and occur in
a small subset of patients. These reactions are not related to the dose
or the pharmacology of the drug. Unpredictable reactions include
drug intolerance, idiosyncratic reactions, pseudoallergic reactions,
and immunologic reactions.1,5
Based on the mechanism involved, immunologic reactions can be
classified as immunoglobulin E (IgE)-mediated (type 1) and non–
IgE-mediated reactions. IgE-mediated reactions usually develop
within minutes following the administration of the drug but can
occur up to 72 hours later. These reactions include but are not
limited to anaphylaxis, urticaria, asthma, angioedema, and hypoten-
sion. Non–IgE-mediated reactions can be further classified into
antibody-mediated (type 2), immune complex-mediated (type 3),
and T-lymphocyte-mediated (type 4) reactions. Non–IgE-mediated
reactions include erythema multiforme, serum sickness, hemolytic
anemia, drug fever, Stevens-Johnson syndrome, thrombocytopenia,
and toxic epidermal necrolysis.6
This chapter summarizes current understanding of drug reac-
tions, with emphasis on IgE-mediated reactions to penicillins and
cephalosporins, adverse reactions to local anesthetics, and angio-
edema due to angiotensin-converting enzyme (ACE) inhibitors and
angiotensin receptor blockers (ARBs).
PENICILLIN
Penicillin is commonly prescribed because of its effectiveness and
low toxicity.7 However, adverse reactions to penicillin are common
and often complicate medical therapy. Up to 20% of patients admit-
ted to the hospital claim to have penicillin allergy.1 These patients
are usually treated with more expensive, more toxic, and sometimes
less effective antibiotics. Although the exact prevalence of allergic
reactions to penicillin is unknown, allergic reactions are estimated to
occur in approximately 2% of patients treated with penicillin.1 Most
of these reactions are skin rashes, such as maculopapular or urti-
carial eruptions.1 However, the penicillins are one of the most
common causes of drug-induced anaphylactic reactions,8 and fatali-
ties have been reported.9
Penicillin is a chemical hapten, with a low molecular weight of
300 daltons, that needs to bind to a tissue macromolecule, usually a
protein, to become immunogenic.7 The major breakdown product
of penicillin is the penicilloyl group (approximately 85%-90%),
known as the major determinant.7 The reminder of the breakdown
products are minor determinants, so called because they are formed
in smaller quantities.7 The minor determinants include penicilloate,
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and Nicola M. Vogel
S E C T I O N  1 
penicilloylamine, penilloate, and other simple chemical products of
penicillin.7 Immediate reactions following penicillin administration
ALLERGY AND IMMUNOLOGY
are mediated through IgE antibodies against the major determinants,
the minor determinants, or both.
Risk Factors
The risk of penicillin sensitization is increased with multiple short
courses of antibiotics and can occur with any route of administra-
tion.7 Anaphylactic reactions to penicillin occur most commonly in
persons between 20 and 49 years old. However, they can occur in
children and in the elderly. Race, gender, personal or family history
of atopic disease, and allergy to other drugs or to the mold Penicil-
lium are not predisposing factors.7
Testing for Penicillin Allergy
The presence of IgE antibodies to penicillin can be detected through
a skin test to penicillin, a radioallergosorbent test (RAST) to penicil-
lin, or the enzyme-linked immunosorbent assay (ELISA). The skin
test for penicillin is the most reliable way to demonstrate the presence
or absence of specific IgE antibodies to major and minor penicillin
determinants. However, it does not predict the future development
of IgE-mediated reactions during subsequent courses of penicillin or
the development of non-IgE-mediated reactions caused by other
immune mechanisms, such as cytotoxic antibody-mediated reac-
tions, antibody-antigen immune complex-mediated reactions, and
delayed-type cell-mediated reactions.10
Penicillin skin testing is performed using benzylpenicilloyl poly-
lysine (Pre-Pen), penicillin G, and minor determinants (if available)
to detect the presence of IgE antibodies to the major and minor
determinants. Because the minor determinant mixture is not com-
mercially available, penicillin G at a concentration of 10,000 U/mL
has been recommended as a partial source of minor determinants.
Methods of preparation of the minor determinants have been pub-
lished elsewhere.11,12 Unfortunately, Pre-Pen, the source of major deter­
­minants, has been withdrawn from the market and is not available.
Both percutaneous and intradermal tests are performed using
diluted penicillin G at a concentration of 10,000 U/mL, Pre-Pen at
full strength, and minor determinant mixture (if available). Hista-
mine and saline skin tests are used as positive and negative controls,
respectively. Percutaneous testing is done, and the results are read at
15 minutes. If the percutaneous test findings are negative, intrader-
mal testing is performed. The skin test is positive if it produces a
wheal more than 3 mm larger than the wheal produced by the nega-
tive saline control (Fig. 1).
Up to 99% of patients tolerate penicillin if skin testing is negative
for penicillin using major determinants (benzylpenicilloyl) and a
mixture of minor determinants and penicillin G. Approximately
97% of patients tolerate penicillin if skin testing is negative using
benzylpenicilloyl and penicillin G (as the sole source of minor deter-
minants).13 However, a few patients who are at risk for anaphylactic
reaction are missed with this testing method because penicillin G
does not contain all the minor determinants.13 Patients with a history
of penicillin allergy and negative penicillin skin test have a low risk
43
 44 Approach to and Management of Adverse Drug Reactions
ALLERGY AND IMMUNOLOGY
S E C T I O N  1 
Figure 1  Positive skin test to Pre-Pen.  Gindicates penicillin G result;
P indicates Pre-Pen result; S indicates saline result; H indicates histamine
result.
of developing an IgE-mediated reaction following administration of
penicillin. At our institution, we found a reaction rate of 1.7% in a
group of 596 patients with a history of penicillin allergy and negative
skin tests.14 Similar to the findings in our study, low rates of adverse
reactions also have been reported by other clinicians.15-17
The RAST and the ELISA detect only IgE antibodies to the major
penicillin determinant. Therefore, these tests are less sensitive than
the skin test.13 If a patient has a positive history and a positive skin test
to penicillin, there is a 50% or greater chance of an immediate IgE-
mediated reaction if penicillin is received again.13 Similarly, a positive
RAST or ELISA demonstrates the presence of IgE antibodies to peni-
cillin, and these patients should be considered at risk for immediate
IgE-mediated reactions to penicillin.15 These patients should receive
an equally efficacious alternative antibiotic or be desensitized.
The detection of IgE antibodies to penicillin by a skin test is
affected by the amount of time between the original allergic drug
reaction and the skin test. Many patients with documented IgE anti-
bodies to penicillin by skin test lose the sensitivity with time. It is
estimated that up to 80% of patients with a history of immediate
reactions to penicillin will have a negative skin test at 10 years.18
However, these patients may be at increased risk of sensitization to
penicillin on subsequent administration compared with the rest of
the population.17
Safety of the Skin Test
If done properly, the skin test is safe, with a rate of systemic reaction
of less than 1%.14,19 Nevertheless, severe reactions such as anaphylaxis
and death have occurred. Serious reactions to the penicillin skin test
are usually a result of violations of the skin test protocol, such as
administering a dose that is too high or performing intracutaneous
testing without prick or puncture testing beforehand.13
Additional Uses of the Penicillin Skin Test
Penicillin skin testing can also serve as a way to decrease the necessary
dose of broad-spectrum antibiotics such as vancomycin and fluoro-
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quinolones.20,21 These antibiotics, when used extensively, are associ-
ated with the emergence of multidrug-resistant pathogens and
increased morbidity and mortality.
Evaluation
Most patients labeled allergic to penicillin do not have penicillin-
specific IgE antibodies as detected by skin test and can safely be given
penicillin. However, patients with a history of penicillin allergy are
more likely to experience a reaction on subsequent courses than
those without such history.10
The evaluation of adverse drug reactions begins with a detailed
history. However, many patients do not clearly recall the drug to
which they reacted, the type of reaction that occurred, or the dura-
tion of drug exposure. In addition, up to 33% of patients with a vague
history of penicillin allergy have a positive penicillin skin test.18
Therefore, it is recommended that even patients who have a vague
history of penicillin allergy and who require penicillin have skin
testing to determine the presence of penicillin-specific IgE antibodies
before it is assumed that the patient will tolerate penicillin.13 Some
clinicians suggest that the penicillin skin test needs to be repeated
before each course of penicillin, especially for patients with a history
of IgE-mediated reaction who received intravenous penicillin,
because of the risk of resensitization.1 However, Solensky and col-
leagues have reported that none of 46 patients with a history of
penicillin allergy and a negative penicillin skin test were resensitized
after receiving three courses of oral penicillin V.22
Because of the lack of commercially available penicillin minor
determinants for skin testing, some authorities recommend a test-
dose challenge in patients with a history of penicillin allergy and
negative skin tests to major determinants and penicillin G.6 A test-
dose challenge might be done using 0.01 of the therapeutic dose
(0.001 of the therapeutic dose if the previous reaction was severe),
followed by 0.1 of the dose, and then the full therapeutic dose if there
is no reaction.6 If a reaction occurs during the test-dose challenge
and the drug is essential for treatment, penicillin desensitization is
recommended.6
Treatment
If the penicillin skin test is positive and the treatment with a penicil-
lin antibiotic is essential, desensitization is needed. Oral and intrave-
nous protocols for penicillin desensitization have been published.5,6,8,23
Oral desensitization is safer than parenteral desensitization.23
The basic principle for oral or parenteral (intravenous) desensi-
tization is similar. The initial dose is very small, usually 0.0001 of the
recommended dose. The dose is usually doubled every 15 minutes
until the full therapeutic dose is achieved.
Adverse reactions can occur during and after the desensitization
procedure.22 Most of these reactions are mild, such as pruritus,
rhinitis, wheezing, and urticaria.23 These reactions require symp-
tomatic treatment, and the dose of penicillin should be repeated until
tolerated. Severe reactions, such as laryngeal edema, require rapid
treatment until the patient is stable and a reduction of the next
penicillin dose by one third or more of the previous provoking
dose.6 When desensitization is achieved, continuous treatment with
penicillin is required to avoid the return of the IgE-sensitive state. A
time lapse greater than 12 to 48 hours can allow such sensitivity to
return.6
CEPHALOSPORINS
Like penicillins, cephalosporins are commonly used. Cephalosporins
share a common beta-lactam ring with the penicillin (Fig. 2).
However, they have a dihydrothiazide ring instead of the thiazolide
ring of the penicillin molecule. Various adverse reactions to cepha-
losporin have been described including eosinophilia, serum sickness,
febrile reactions, interstitial nephritis, and hemolytic anemia.24 Urti-

S CH3
J
R NH
JJ
N CH3
O
O COOH
A losporin antibiotic, the following approaches have been recom-
RJNH S administration of a cephalosporin (preferably second or third gen-
N
O JOJR1
OH O on the diagnosis and management of drug hypersensitivity.10 Finally,
B perform a penicillin skin test. If the skin test is negative, the patient
Figure 2  A, Penicillin molecule. B, Cephalosporin molecule.
caria, rash, exanthema, and pruritus are estimated to occur in
approximately 1% to 2.8%.24 Although anaphylactic reactions after
cephalosporin administration are rare,25 death has been reported.26,27
Unlike penicillin, cephalosporin determinants have not been well
identified or studied. Therefore, the positive and negative predictive
values of cephalosporin skin testing are unknown. A negative skin test
does not rule out the presence of IgE antibodies to these drugs. On the
other hand, a positive skin test suggests the presence of drug-specific
IgE antibodies. These patients should be considered at increased risk
for IgE-mediated reaction on administration of the specific drug.
They should receive an alternative antibiotic or undergo desensitiza-
tion. Nonirritant concentrations of commonly used antimicrobial
drugs that can be used for skin testing have been published.8,28
If the patient needs a cephalosporin and has a history of cepha-
losporin allergy, the treating physician can choose one of the follow-
ing approaches: choose a non–beta-lactam antibiotic, give a graded
dose challenge with a cephalosporin with a different side chain from
the one to which the patient reacted, or perform a cephalosporin skin
test with a nonirritating concentration.24 If the skin test is positive,
the patient can be desensitized or tested for another cephalosporin
with a different structure.1 Protocols for cephalosporin desensitiza-
tion are published elsewhere.24 Because the negative predictive value
of a cephalosporin skin test is unknown, it is preferable that a nega-
tive skin test be followed by a provocative graded-dose challenge, if
a challenge is favorable from a risk-to-benefit standpoint.1
CROSS-REACTIVITY BETWEEN PENICILLINS   of nerve impulses by decreasing the permeability of excitable mem-
AND CEPHALOSPORINS
The rate of cross-reactivity between penicillins and cephalosporins
is unknown. Clinical cross-reactivity between penicillins and cepha-
losporins appears to be low, especially for second- and third-
generation cephalosporins.10 However, patients with a history of
penicillin allergy appear to be at increased risk for severe IgE-
mediated reactions to cephalosporin, including anaphylaxis.
A penicillin skin test can help to determine which patients are at
increased risk for severe IgE-mediated reactions when receiving a
cephalosporin. A review of 11 studies concluded that the risk for
reaction when receiving cephalosporin in a patient with a positive
skin test to penicillin was approximately 4.4%.25 Pumphrey and
David reported that 3 of 12 anaphylactic deaths following adminis-
tration of cephalosporin occurred in patients known to be allergic to
penicillin.29
Some patients who react to beta-lactam antibiotics other than
penicillin have antibodies directed to side-chain structures rather
than to the beta-lactam ring, and cross-reactivity among cephalospo-
rins could be explained by the presence of these antibodies.1 Such
antibodies can cause anaphylaxis.13 Figure 3 shows an extensive list
of cephalosporins and their structures, including similarities and
differences of side-chain structures (indicated by R1 and R2).30 Cefa-
mandole, cefalothin, cepaloridine, cephalotin, and penicillin G have
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Approach to and Management of Adverse Drug Reactions 45
similar side chains. Similar side chains are present in cefadroxil and
amoxicillin, ceftazidime and aztreonam, and cephalexin and amoxi-
cillin.24 It can be appreciated that reactions to cephalosporin can
occur even with a negative penicillin skin test.
If a patient has a history of penicillin allergy and needs a cepha-
mended10: First, use a non–beta-lactam antibiotic. Next, consider
S E C T I O N  1 
eration) if the patient has a history of mild reaction. Although the
risk of life-threatening reaction is low, severe adverse reactions can
occur. This approach has been discouraged in published guidelines
may receive the cephalosporin with a low risk of developing an aller-
gic reaction.
ALLERGY AND IMMUNOLOGY
If a patient in need of a penicillin antibiotic has a history of a
cephalosporin allergy, the penicillin skin test can identify those at
risk for IgE-mediated reaction to penicillin. If the skin test is nega-
tive, penicillin may be given. If the skin test is positive and penicillin
is needed, the patient should undergo desensitization.
Carbapenems (e.g., imipenem) should be considered cross-
reactive with penicillin and cephalosporin because of the presence of
a similar beta-lactam ring.10,13 On the other hand, aztreonam (a
monobactam) rarely cross-reacts with penicillin, possibly because
of the lack of a second nuclear ring structure.10,13 However, ceftazi-
dime and aztreonam share the same side chains, and clinical cross-
reactivity can occur.1
The presence of IgE antibodies to penicillin can be determined by
the use of the penicillin skin test. This test can help us to identify
patients who have a history of penicillin allergy and can receive
penicillin or cephalosporin with a low risk for immediate hypersen-
sitivity reactions, and it can identify patients who should avoid using
these drugs. In spite of the importance of penicillin skin testing,
Pre-Pen was withdrawn from the market because of manufacturing
problems. Without this preparation, a reliable diagnostic test for
managing drug hypersensitivity has been lost.
ALLERGIC REACTIONS TO LOCAL ANESTHETICS
Local anesthetics have been used worldwide in different medical
procedures since procaine (Novocaine), the first synthetic local anes-
thetic agent, was developed.
Local anesthetics reversibly block the generation and conduction
branes to sodium through interaction with one or more specific
binding sites within sodium channels.31 The duration of anesthesia
depends on plasma protein binding and the addition of vasoconstric-
tors such as epinephrine. Vasoconstrictors decrease the rate of
absorption of local anesthetics, localizing the anesthetic to the desired
site and allowing its rate of destruction to keep pace with its rate of
absorption into the circulation.31
The structure of local anesthetics has three segments: a lipophilic
or aromatic group, an intermediate chain linkage, and a hydrophilic
or amine group. Based on their intermediate chain linkage, local
anesthetics are classified into two major groups: the benzoic acid
esters or group 1 and the amides and miscellaneous or group 2.
Group 1 anesthetics include benzocaine, butamben picrate, cocaine,
procaine, tetracaine, proparacaine. Group 2 anesthetics include
bupivacaine, dibucaine, dyclonine, etiodocaine, levobupivacaine,
lidocaine, mepivacaine, prilocaine).31,32
Different types of adverse reactions to local anesthetics have been
reported. Most of these appear to be vasovagal, anxiety, and toxic
reactions.33 Case reports have suggested that adverse reactions to the
preservatives in local anesthetics, including methylparaben and sul-
fites, can also occur.34,35
Following absorption, local anesthetics may be associated with
central stimulation manifested by restlessness, tremor, and seizures.
Central stimulation is followed by depression, and death is due to
 46 Approach to and Management of Adverse Drug Reactions

H H
S
R1-CONH
N
OK R2
COOH
R1− −R2 R1− −R2
Ceftizoxime N C H
ALLERGY AND IMMUNOLOGY

Cephalexin

K
CH CH3 H2N
S N-OCH3
NH2
Cefotaxime N C CH2OCOCH3

K
Cefaclor H2N
CH Cl S N-OCH3

NH2 Cefpodoxime N C CH2OCH3

K
Cefadroxil H2N
S N-OCH3
HO CH CH3 H3C Na
Ceftriaxone N C N N
NH2
KO

K
H2N CH2S
S N-OCH3
Cephaloglycin N

K
CH CH2OCOCH3 O
Ceftazidime N C CH3
NH2

K
H2N
N-O-C-COCH
 

S CH2–N+
Cephalothin
S E C T I O N  1 

CH2 CH2OCOCH3 CH3

S
Cefamandole CH3
CH
Cefoxitin1 N N
CH2 CH2OCONH2

K
OH CH2-S
S
N N
Cefuroxime
Cefmetazole1 CH3
C CH2OCONH2
K

O N N
N C-CH2-S-CH2
N-OCH3

K
CH2-S
N N
Cefazolin N N N Cefotetan1 CH3
N N CH2 CH2S CH3 H2NCO S
N S CK N N
HOOC S

K
CH2-S
N N
1Cephamycin with an α-methoxy group (-OCH3) at the 7-position.

Figure 3  Similarities in the side chains of different cephalosporins.  From Baldo BA: Penicillins and cephalosporins as
allergens-structural aspects of recognition and cross-reactions. Clin Exp Allergy 1999;29(6):744-749. Used with permission.

respiratory failure.33 Palpitations, tachycardia, diaphoresis, and ven-
tricular arrhythmias have also been described.31,32,36
Hypersensitivity reactions to local anesthetics are uncommon.
Contact dermatitis mediated by sensitized lymphocytes is the most
common, and it accounts for up to 80% of reactions reported to local
anesthetics.37 Patch testing is available for patients with a history of
contact dermatitis. Although IgE-mediated reactions to local anes-
thetics are extremely rare, cases have been reported.37 de Shazo and
Nelson evaluated 90 patients with a history of adverse reaction to
local anesthetics, and only one patient had a positive test by the
intradermal method; the other 89 had a negative challenge.38 Gall and
colleagues reported negative skin-test results in 177 patients evalu-
ated for adverse reactions to local anesthetics. Three patients reacted
after a provocative dose challenge with the causative drug, two
patients had immediate-type reactions to articaine and lidocaine, and
one patient had a delayed reaction to mepivacaine.39 In a large series
of 236 patients reported by Berkun and colleagues, all subjects had
negative skin test results, and only one patient had a positive pro-
vocative dose challenge.40
Patients with a history of adverse reactions to local anesthetics are
usually advised to avoid them in the future. When surgery is indi-
cated, they must decide whether to undergo surgery without anes-
thesia, have a procedure with general anesthesia, or forgo benefits of
the surgical procedure.
The role of the allergist or immunologist is to rule out IgE-
mediated (allergic and anaphylactic) potential to group 1 and group
2 agents. Different protocols for evaluating patients with a history of
adverse reactions to local anesthetics have been described.6,32,40,41
Based on the information obtained from patch-test studies, the
benzoic acid esters usually cross-react with each other but not with
the amides and the other agents in group 2. The amides and the other
agents in group 2 do not appear to cross-react with each other.6
One approach to managing these patients begins with identifying
the agent that caused the previous untoward reaction. If the drug is
a benzoic acid ester (group 1), an amide or a drug from group 2 may
be used. If the drug is an amide, another amide may be used and no
further evaluation is needed. If the drug is unknown, skin-prick
testing with the undiluted local anesthetic to be used can be per-
formed. A negative test can be followed by intradermal testing with
0.1 mL of a 1 : 100 dilution of the same agent. If both tests are nega-
tive, the next step is a provocative dose challenge with 1 mL subcu-
taneous injection of the undiluted agent.

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Positive and negative controls should be used with all prick and
intradermal testing. Local anesthetics used for skin testing should not
contain epinephrine, because false-negative results can occur.41 Skin
testing may be performed with preservative-free local anesthetics or
with local anesthetics containing preservatives. However, if the result
is positive with a local anesthetic containing preservative , skin
testing should be repeated with a preservative-free agent. Another
positive skin test might indicate the presence of IgE antibodies, and
a different local anesthetic should be considered.
True IgE-mediated reactions to local anesthetics are extremely
rare. Allergy and immunology evaluation is useful for patients with
suspected local anesthetic allergy, because it can identify local anes-
thetic agents that can be tolerated without elevated risk of IgE-
mediated reaction.
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS
AND ANGIOTENSIN II RECEPTOR BLOCKERS
Adverse drug reactions to ACE inhibitors are common and include
cough in up to 35% of patients and angioedema in approximately
0.1% to 2.2%.42-45 Angioedema has also been reported in association
with angiotensin II receptor blockers (ARBs).
Cough
Cough associated with ACE inhibitors often develops within the first
2 weeks of starting an ACE inhibitor and generally is a dry, nonpro-
ductive cough. Cough may be accompanied by bronchospasm,
although this does not occur more often in asthmatics than in non-
asthmatics.46 Cough is more common in women and nonsmokers.47
The pathogenesis of ACE inhibitor–associated cough is not com-
pletely understood. The mechanism might involve increased levels
of prostaglandins, kinins (including bradykinin), and substance P.
Bradykinin and substance P are degraded by ACE, and prostaglandin
production may be increased by bradykinin. Potential mechanisms
involve bradykinin-induced sensitization of airway sensory nerves or
activation of bradykinin receptors.48,49
Treatment options include discontinuing the medication and
using alternative medications. The American College of Chest Physi-
cians (ACCP) Evidence-Based Clinical Practice Guidelines recom-
mend discontinuing the ACE inhibitor.44 Cough associated with ACE
inhibitors usually resolves within a few days of discontinuing the
medication but can take up to several weeks.44,50 Cough often recurs
with the same or different ACE inhibitor. Cough has not been
reported in association with ARBs, and the ACCP guidelines recom-
mend ARBs as a treatment alternative.44 In patients in whom the
benefits of treatment with an ACE inhibitor outweigh the risks of a
recurrence of the cough, a repeat trial of ACE inhibitor might also
be indicated.44
Angioedema
Although the onset of angioedema associated with ACE inhibitors
often occurs during the first week or first month after initiating treat-
ment in 25% to 60% of patients, it can occur at any time.42,51 This
unpredictable characteristic of ACE inhibitor–associated angio-
edema can lead to a delay in identifying the association. The newer
ARBs, often used as an alternative to ACE inhibitors, have also been
associated with angioedema.51-53 Studies estimate that the incidence
of ARB-associated angioedema varies from 0% to 32% in patients
with a history of ACE inhibitor–associated angioedema.51,54-56
Women, African Americans, and patients with a history of either
idiopathic angioedema or C1 inhibitor deficiency are at higher risk
for angioedema.42,57 Angioedema associated with either ACE inhibi-
tors or ARBs generally affects the head and neck, and pruritis and
urticaria generally do not occur.
Similar to the pathogenesis of ACE inhibitor–induced cough, the
pathogenesis of ACE inhibitor–associated angioedema may be
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Approach to and Management of Adverse Drug Reactions 47
related to the accumulation of bradykinin and other vasoactive pep-
tides. ACE catalyzes the conversion of angiotensin I to angiotensin
II, which is a vasoconstrictor that can increase blood pressure. ACE
also degrades bradykinin, a vasodilator that opposes the effects of
angiotensin II. With ACE inhibition, subsequently increased levels
of bradykinin can induce angioedema through vasodilation and
increased vascular permeability. In some patients with ACE inhibi-
tor–associated angioedema, an active metabolite of bradykinin,
S E C T I O N  1 
des-Arg9-BK, may be abnormally degraded and lead to increased
bioavailability of bradykinin.58 Dipeptidyl peptidase IV might also
play a role in angioedema. Decreased levels of this enzyme can lead
to increased amounts of substance P, which can be associated with
increased vascular permeability and leakage of plasma proteins.59
Evaluation
ALLERGY AND IMMUNOLOGY
The approach to a patient with a history of an adverse reaction to an
ACE inhibitor or ARB should begin with a detailed medical history
including a list of all medications, indication for each medication,
dose, date of initiation, and duration of therapy. The clinical mani-
festations of the reaction, including associated symptoms, should
also be reviewed. Additional history to obtain is whether the patient
had a prior exposure to the same or other ACE inhibitor or ARB
medications, the effect of drug discontinuation, and the treatment of
the prior reaction. Other factors that may be related to the develop-
ment of urticaria and angioedema should be considered, including
infections; collagen vascular diseases; malignancy; physical factors
such as pressure, vibration, or exposure to heat, cold, or sunlight;
and family history of angioedema suggesting C1-inhibitor deficiency.
Treatment
Treatment of angioedema should be tailored to each patient and may
include antihistamines, oral or intravenous corticosteroids, or intra-
muscular or subcutaneous epinephrine for severe airway compromise.
No studies support the effectiveness of treatment with antihistamines
or corticosteroids. Symptoms generally resolve within 48 hours after
treatment is initiated and the ACE inhibitor or ARB is discontinued.
There is no valid skin or blood test to establish a diagnosis of ACE
inhibitor–associated or ARB-associated angioedema. Desensitiza-
tion, a process of administering incremental doses of a drug over
hours to days and conversion of a drug allergy to a state of drug
tolerance, is not indicated for patients who have angioedema associ-
ated with ACE inhibitors or ARB because the reaction is not an
IgE-mediated process.
All ACE inhibitors carry the same risk of developing angioedema.
Patients who experience angioedema related to one ACE inhibitor
are at risk for more severe and frequent episodes with other ACE
inhibitors.60 The best approach for a patient with ACE inhibitor–
associated angioedema is to avoid other ACE inhibitors and use
alternative, equally efficacious, medications.
Although patients with ACE inhibitor–associated angioedema
might tolerate ARBs, ARBs should be used with caution because
these patients can also develop angioedema associated with ARB.
Studies estimate that the incidence of experiencing ARB-associated
angioedema varies from 0% to 32% in patients with a history of ACE
inhibitor–associated angioedema.51,54-56 The largest of these studies
involved more than 2000 patients with congestive heart failure.
Either an ARB (candesartan) or placebo was given to patients with a
history of adverse reaction to ACE inhibitors. In the treatment group,
39 of 1013 patients previously experienced angioedema or anaphy-
laxis from an ACE inhibitor. Of these 39 patients, only 3 (7.6%)
developed angioedema associated with candesartan. More studies are
needed to evaluate the incidence of developing ARB-associated
angioedema in patients with ACE inhibitor–associated angioedema.
Any patient with a history of ACE inhibitor–associated angioedema
prescribed an ARB should be counseled regarding the possible risk
of developing angioedema.
 48 Approach to and Management of Adverse Drug Reactions
Summary
l The incidence of adverse drug reactions may be as high as
15% in hospitalized patients.
l Adverse reactions to penicillins and cephalosporins are
common and complicate medical therapy.
l Penicillin skin testing can reliably identify patients with a
history of penicillin or cephalosporin allergy who can
ALLERGY AND IMMUNOLOGY
safely take penicillin.
l Patients with positive skin tests can use equally
effective alternative antibiotics or undergo Immunology, the American College of Allergy, Asthma and Immunology, and the
desensitization.
l Penicillin skin testing can decrease the use of broad-
spectrum antibiotics such as vancomycin and
fluoroquinolones.
l Hypersensitivity reactions to local anesthetics are
uncommon.
l A board-certified allergist or immunologist can identify
local anesthetics that can be used without elevated risk of
immunoglobulin E-mediated reaction in patients with a
history of allergy to local anesthetics.
l Common adverse drug reactions to ACE and ARBs include
cough and angioedema.
l Alternative medications should be considered.
S E C T I O N  1 
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Further Readings
Alvarez del Real G, Rose ME, Ramirez-Atamoros MT, et al: Penicillin skin testing in
patients with a history of β-lactam allergy. Ann Allergy Asthma Immunol
2007;98:355-359.
Berkun Y, Ben-Zvi A, Levy Y, et al: Evaluation of adverse reactions to local anesthetics:
Experience with 236 patients. Ann Allergy Asthma Immunol 2003;91:342-345.
Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma and
Immunology, the American College of Allergy, Asthma and Immunology, and the
Joint Council of Allergy, Asthma and Immunology: Executive summary of disease
management of drug hypersensitivity: A practice parameter. Ann Allergy Asthma
Immunol 1999;83:665-700.
Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma and
Joint Council of Allergy, Asthma and Immunology: The diagnosis and management
of anaphylaxis. J Allergy Clin Immunol 1998;101 (Pt 2):S465-S528.
Kelkar PS, Li JT: Cephalosporin allergy. N Engl J Med 2001;345:804-809.
Mendelson LM: Adverse reactions to β-lactam antibiotics. Immunol Allergy Clin North
Am 1998;18:745-757.
Sogn DD, Evans R III, Shepherd GM, et al: Results of the National Institute of Allergy
and Infectious Diseases Collaborative Clinical Trial to test the predictive value of
skin testing with major and minor penicillin derivatives in hospitalized adults. Arch
Intern Med 1992;152:1025-1032.
Soto-Aguilar MC, de-Shazo RD, Dawson ES: Approach to the patient with suspected
local anesthetic sensitivity. Immunol Allergy Clin North Am 1998;18:851-865.
References
For a complete list of references, log onto www.expertconsult.com.