angioedema and urticaria by nikeborome

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									REVIEW




Angioedema and Urticaria Due to Drugs
Tan Kian Teo MRCP (UK), Malcolm W Greaves MD(Lond) FRCP(Lond)
Dermatology Unit, SGH




         ABSTRACT

         Adverse systemic reactions to drugs often manifest as acute, intermittent or less commonly chronic urticaria and
         angioedema, or urticarial vasculitis. Local skin reactions to contact with drugs may present as contact urticaria and
         this may occasionally be complicated by severe systemic symptoms including angioedema. Reactions to systemically
         and topically administered drugs may be allergic or non-allergic (“pseudoallergic”), but in a given case it is often
         difficult to discriminate between the two. Angioedema presents as a non-allergic reaction to ACE inhibitors, which
         can readily be explained by the molecular mode of action of this class of drugs. NSAIDS cause urticaria and angioedema
         due to redirection of transformation of arachidonic acid down the lipoxygenase pathway leading to leukotriene
         formation, although other mechanisms may also be involved. In contrast, acute urticaria and angioedema due to
         penicillin can usually be ascribed to a straightforward IgE-mediated type 1 reaction (Gel and Coombs). Management
         of acute urticaria and angioedema due to drugs in the emergency room involves management of the airway,
         administration of adrenaline, an H1 antihistamine and hydrocortisone, and admission for 24 hours. In cases due to
         drug allergy, desensitisation protocols are available for certain drugs in exceptional circumstances.

         Keywords: angioedema, desensitisation, drugs, pseudoallergic, urticaria




INTRODUCTION                                                            It is frequently, but incorrectly, believed that drug-
Urticaria and angioedema are common manifestations                      evoked urticaria is normally an “allergic” response.
of exposure to dr ugs, although accurate                                Non-immunological mechanisms are commonplace —
epidemiological data are lacking. Since the cause is                    well-known examples include aspirin and angiotensin-
usually elusive, especially in the chronic forms, it is an              converting enzyme (ACE) inhibitors, which cause
obligation on the part of the physician to consider the                 outbreaks of urticaria and angioedema, respectively.
possibility of a drug as an aetiological agent. Correct                 Nevertheless, many urticarial reactions involve
identification of a culprit drug confers several benefits               genuinely allergic processes, especially in the case of
besides a solution to the patient’s current outbreak.                   acute urticaria and angioedema. In many instances, it
These include alleviation of disability, the possibility                is difficult to be sure whether the outbreak of acute
of avoiding similar outbreaks in the future, and add                    urticaria is allergic or non-allergic in origin.
useful information to the body of knowledge on the                      Like other adverse reactions to drugs, urticarial or
side effects of the drug (if the event is reported to the               angioedematous reactions to drugs tend to be common
appropriate regulatory authority).1 In cases where it is                in the elderly.2 This is in part due to the tendency for
highly likely that a particular drug is responsible for                 older patients to be receiving long-term treatment with
the patient’s urticaria, it is important to notify the                  multiple drugs, and also to pharmacokinetic changes
national drug regulatory body. In Singapore, the                        associated with senescence. Genetic factors are
process involves filling in a form supplied by the                      important at any age, since genetic polymorphisms in
Phar macovigilance Unit of the Health Sciences                          enzymatic pathways for drug metabolism (for example,
Authority. The event can then be documented and                         cytochrome P450 3A or drug acetylation) are common.
added to the national database for this drug. It is also                The emerging science of pharmacogenomics should
important to keep the drug’s manufacturer fully                         eventually lead to rapid laboratory tests to enable
informed on suspected adverse drug events.                              identification of genetically susceptible patients.3

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CLASSIFICATION OF URTICARIAL                                       Table 1. Classification of urticarial reactions to drugs.
REACTIONS TO DRUGS
                                                            Drug-induced Urticaria and Angioedema
Urticaria can be conveniently classified as acute,
intermittent or chronic (Table 1). Acute urticaria is by    Acute Urticaria (including recurrent acute)
far the most common of these, and most of these             Chronic Urticaria
                                                                “Ordinary” Chronic Urticaria
patients never come to the attention of the specialist
                                                                Physical Urticaria*
dermatologist or allergist because the culprit drug is          Urticarial Vasculitis*
evident to patient and doctor alike. Chronic urticaria      Contact Urticaria
is conventionally defined as the occurrence of daily
                                                            *rarely caused by drugs
or almost daily whealing for at least 6 weeks.
Intermittent urticaria may consist of either recurrent
short-lived bouts of acute urticaria, or more prolonged
inter mittent relapses of chronic urticaria. This           Physical urticarias (symptomatic dermographism,
subgroup will not be considered further as a separate       cholinergic urticaria, delayed pressure urticaria, solar
entity. Angioedema is frequently associated with acute      urticaria and cold urticaria are the most common) are
urticaria, and occurs in 50% of patients with chronic       very rarely drug-induced and will not be considered
urticaria.4 In this account, no distinction will be made    further. However, it is worth noting that delayed
between urticaria and angioedema in discussing the          pressure urticaria occurs concurrently with chronic
aetiological role of drugs, unless specifically stated to   urticaria in about 40% of patients and there is no
the contrary. The aetiology, pathogenesis, clinical         reason to suppose that this figure is any different in
features and management have been reviewed by the           instances where a drug is the cause of chronic
author in recent publications. 5,6                          urticaria. 4
Urticaria is due to dermal vasodilation, increased
vasopermeability and increased blood flow. It is almost     DRUGS AS CAUSES OF URTICARIA
invariably associated with itching, and is confined to      As noted above, reactions to drugs are frequently
the skin. Angioedema involves similar                       assumed to be allergic in origin, without good grounds.
pathomechanisms but does not normally itch. It affects      IgE-mediated reactions are well recognised as in
both cutaneous and mucosal epithelia, occurring at a        penicillin-induced urticaria and angioedema. The
deeper location (deep dermal subcutaneous and               pathomechanism involves dimerisation of adjacent
submucosal). In both cases, individual lesions in these     high affinity IgE receptors (FceRI) bearing penicillin-
eruptions normally fade within 24 hours without             specific IgE, by the penicillin antigenic determinant.
leaving any mark in the skin, apart from the effects of     This leads to mast cell activation, degranulation and
r ubbing or scratching. Ver y large swellings of            release of histamine and other mediators. Common in
angioedema may take longer to subside.                      atopic individuals, patients may manifest an acute
                                                            wheal-and-flare reaction to intracutaneous injection of
Urticarial vasculitis is a rare form of chronic urticaria
                                                            penicillin or a penicilloyl determinant.8 However, this
in which histological evidence of vascular damage can
                                                            diagnostic test is risky, and should normally be avoided
be identified on a skin biopsy.7 These patients may have
                                                            in patients with a history of angioedema or systemic
associated systemic symptoms, including evidence of
                                                            symptoms.
multi-system involvement due to circulating immune
complexes. Commonly, distinguishing clinical features       Acute local reactions to drugs directly in contact with
may be evident including purpura, pigmentation, pain        the skin are termed “contact urticaria” and may be
and tenderness (rather than itching) and prolonged          immunologically, or non-immunologically, driven. 9
duration of individual lesions (greater than 24 hours).     They may be complicated by acute anaphylactoid
It is important to recognise drug-induced urticarial        symptoms.
vasculitis, to appreciate that it may commonly be
clinically indistinguishable from “ordinary” chronic        It is possible that many exanthematous mucocutaneous
urticaria and angioedema, and to insist on confirmation     reactions to drugs are also immunologically-based. In
by skin biopsy. The diagnosis should prompt thorough        some instances immune complexes may be involved,
work-up for evidence of renal, cardiovascular,              and in this case the rash may present clinically as
pulmonary and neurological involvement. Drug-               urticarial vasculitis. In others such as maculopapular,
induced urticarial vasculitis is however uncommon and       morbillifor m, scarlatinifor m, the underlying
will not be discussed in detail here.                       immunopathology may be of the delayed type and
                                                            therefore non-urticarial.


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                                                                                           Angioedema and Urticaria Due to Drugs




Fig. 1. Angioedema due to aspirin in a 14-year-old girl.   Fig. 2. Angioedema due to enalapril in a 70-year-old woman.




More commonly, at least in drug-induced urticaria, the     assumed to be due to an IgE-mediated mechanism. As
underlying mechanism is non-allergic.10 Two varieties      indicated earlier, the diagnosis can be cautiously
of non-allergic reactions are conventionally recognised:   confirmed by challenge-testing by intracutaneous
drug intolerance (sometimes called “pseudoallergic”)       injection of minute amounts of penicillin G or the
and idiosyncratic.                                         derivative penicilloyl polylysine. These determinants
                                                           will pick up most cases of penicillin hypersensitivity
Urticarial reactions involving drug intolerance are        including reactions to penicillin degradation products.
usually indistinguishable from the allergic variety and    However, diagnostic skin testing for penicillin allergy
are frequently associated with systemic, even              is at best a high risk procedure and, if done at all,
anaphylactoid symptoms. Mast cell activation without       should only be carried out in a well-equipped clinic
IgE involvement is similar. It follows that                with personnel experienced in dealing with acute
immunologically-based investigations, including            allergic reactions. In any case radio allergosorbent tests
intradermal prick-testing, also yield negative or normal   (RAST) are available for serological diagnosis of IgE-
results in most patients.                                  mediated penicillin allergy, although they are less
The underlying molecular mechanisms in idiosyncratic       specific than skin testing. Cross-reactions may occur
urticarial or angioedematous reactions to drugs are also   with penicillin congeners such as penicillamine and the
often obscure. However, some reactions can be              newer penicillin analogues. 12 The use of RAST in this
explained on the basis of the known molecular actions      context has recently been reviewed. 13 Whilst a positive
of the drugs. Examples include angioedema developing       skin test or RAST test is helpful in management of
in patients receiving angiotensin converting enzyme        patients suspected of penicillin allergy, it is a bold
inhibitor therapy for hypertension or in urticarial        clinician who will prescribe penicillin in a patient with
reactions to drugs known to be mast cell-activating        a suggestive history of penicillin-induced urticaria and
agents. 11 Drugs which cause urticaria and angioedema      angioedema, but with negative prick skin test or RAST.
due to mast cell activation are morphine and congeners,
codeine, muscle relaxants, polymyxin and dextran.          URTICARIAL REACTIONS DUE TO DRUG
These drugs can also exacerbate the symptoms in            INTOLERANCE
mastocytosis. A number of important examples of            As a group, the non-steroidal anti-inflammatory drugs
these broad categories of drug-induced urticarial          (NSAIDS) are the most common cause.
reactions will be briefly outlined below.
                                                           Aspirin
ACUTE URTICARIA DUE TO PENICILLIN                          Aspirin sensitivity plays a role in the pathogenesis of
This common drug-induced acute allergic urticaria has      chronic urticaria in 21 to 75% of patients.14-16 Aspirin-
been the subject of numerous detailed studies. 12 It is    induced urticaria is especially common in females with


SGH PROCEEDINGS • VOL 14 • NO 1 • 2005                                                                                      77
Review




         Fig. 3. ACE inhibitors reduce bradykinin degradation to inactive products* thereby increasing tissue and plasma levels.
         Bradykinin is active against b2 receptors causing increased cGMP, nitric oxide formation and angioedema. Bradykinin then
         undergoes slow metabolism to an octapeptide which acts on b1 receptors.




nasal polyposis and asthma (“asthma triad”).17 While                    has been reported (Fig. 2).28 ACE inhibitors have been
some aspirin-sensitive patients develop urticaria and                   developed from peptides found in the venom of the
angioedema denovo after aspirin ingestion, more                         snake, Bothrops jararaca, known to potentiate the
commonly aspirin evokes exacerbation of pre-existing                    vasoactive effects of bradykinin. Thus, ACE inhibitors
urticaria (Fig. 1).18 Proposed mechanisms have included                 have a dual action at a molecular level: they reduce
inborn errors of acetyl salicylic acid esterification or                conversion of angiotensin I to angiotensin II (thus
an effect on transformation of arachidonic acid to its                  lowering blood pressure) and they suppress the
cyclooxygenase and lipoxygenase products. 19-21 These                   enzymatic transformation of bradykinin to its inactive
patients may develop reactions to NSAIDS.22 Although                    degradation products leading to elevated levels of
aspirin must be avoided, and other NSAIDS only                          bradykinin. Bradykinin, a potent vasoactive
prescribed with great caution in these patients, dietary                nonapeptide, and kinin-like peptides including
restrictions on salicylate ingestion are of no proven                   bradykinin are present in increased amounts in plasma
value, despite claims to the contrary.23 Although aspirin               of patients with angioedema due to ACE inhibitors. 29
avoidance is the mainstay of treatment, a role for                      The proposed molecular basis of ACE inhibitor-
leukotriene antagonists and 5-lipoxygenase inhibitors                   induced angioedema is illustrated in Figure 3.
has been proposed. 24 However, aspirin-sensitive
urticaria has been reported to be provoked by a                         Angioedema occurs in about 0.5% of patients receiving
leukotriene receptor antagonist. 25 Desensitisation has                 ACE inhibitor treatment and is more common in Afro-
also been tried. 26 Other drugs which may cause aspirin                 Americans. The reaction is truly idiosyncratic, and there
intolerance-like reactions include other NSAIDS, radio                  is no convincing evidence of a dose-response
contrast media, and local anaesthetics. Diagnosis of                    relationship. It is possible that those patients receiving
drug intolerance reactions is by careful history taking                 ACE inhibitors who develop angioedema have a
and documentation of clinical signs and drug records.                   genetic polymorphism in carboxypeptidase enzymes.
Oral challenge testing is rarely justifiable, given the                 Angioedema can occur within hours of first exposure
potential severity of reactions. Reliable skin and                      but may be delayed by as much as several years after
serological tests are unavailable at the present time.                  commencing treatment. 30 The head, neck and
                                                                        oropharynx are the sites of predilection; and abdominal
                                                                        angioedema may occasionally occur. 31 A previous
DRUG REACTIONS DUE TO IDIOSYNCRASY
                                                                        histor y of idiopathic or hereditary angioedema
Amines such as morphine and codeine are recognised                      represents predisposing factors and ACE inhibitors
mast cell-degranulating agents and it is perhaps                        should be avoided in these patients.32 Patients should
surprising that they do not cause urticarial reactions                  be admitted overnight. Treatment measures include
more often. Other drugs which fall into the category                    withdrawal of the ACE inhibitor (which may be
of causes of idiosyncratic urticarial reactions include                 sufficient in mildly affected patients) and for acute
ACE inhibitors. A review of the causes of angioedema,                   episodes, parenteral adrenaline, and corticosteroids.
including drugs, has previously been published.27                       Antihistamines are of little or no value. Intubation or
                                                                        even tracheostomy may be necessary in patients with
ACE Inhibitors                                                          severe oropharyngeal angioedema. Occasionally,
These drugs cause angioedema; urticaria is rarely a                     recurrent episodes of angioedema may continue for
manifestation of an idiosyncratic reaction to ACE-                      some weeks or even months after the ACE inhibitor
inhibitors, although urticaria together with angioedema                 has been withdrawn. Recently a dual vasopeptidase



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                                                                                               Angioedema and Urticaria Due to Drugs

  Table 2. Drugs and other agents which cause contact urticaria.   be due to an autoimmune reaction to endogenous
                                                                   progesterone and is a component of a spectrum of
      Presumed Allergic                 Probably Allergic          manifestations ranging from erythema multiforme to
        Promethazine                        Menthol                eczema. 36,37 Progesterone urticaria is confirmed by
          Oestrogen                    Polyethylene Glycol         carrying out serial estimation of plasma progesterone
           Penicillin                 Cetyl/Stearyl Alcohol
                                                                   levels in relation to onset and regression of skin lesions,
          Gentamicin
          Neomycin                                                 and intradermal testing with progesterone. This
           Bactrim                                                 condition may respond to tamoxifen or a
        Benzophenone                                               gonadotrophin hormone-releasing hormone analogue.
            Latex
         Progesterone
                                                                   Radio Contrast Media
                                                                   Urticarial reaction to radio contrast media is common,
                                                                   with incidence lying at around 5 to 8% of procedures.
inhibitor, omapatrilat, has been introduced.33 The drug            It is usually non-allergic, although occasionally IgE-
is both an ACE and neutral endopeptidase inhibitor,                mediated urticarial or angioedematous reactions may
and along with its congeners, carries a higher risk of             occur. The subject has been well-reviewed recently.38
life-threatening angioedema than ACE inhibitors alone.             Besides urticaria and angioedema, these patients
                                                                   frequently suffer severe systemic symptoms. The
DRUG INDUCED CONTACT URTICARIA                                     ur ticaria may persist for days or weeks after
                                                                   administration of the product.
Probably the most common form of contact urticaria
is non-allergic and due to stinging nettles (Urtica dioica)        Drug Desensitisation
the surface hairs of which contain histamine.34 Contact
urticaria is defined as immediate, or near-immediate               Dermatologists are frequently asked for advice on
whealing and itching reaction at sites of penetration              “desensitisation” of patients with rashes deemed to
of substances through the skin or mucous membranes.                be due to a drug. Desensitisation can be considered in
It needs to be distinguished from contact physical                 patients who have experienced IgE-mediated reactions
urticarias in which the skin reacts to local stimulation           to penicillin and who require penicillin for treatment
by a physical stimulus (such as dermographism, cold                of severe infections such as bacterial endocarditis. Oral
urticaria). Contact urticaria may be due to a non-allergic         desensitisation protocols are available but their
usually histamine-releasing action of a chemical such              performance should be under experienced specialist
as ammonium persulphate being applied to the skin                  supervision.
(often to broken skin) or more commonly allergic such
as contact with peanuts, latex, or foods as in the “oral           TREATMENT
allergy syndrome”. 35
                                                                   Treatment of mild or moderate urticaria with or
Allergic contact urticaria occurs more commonly in                 without angioedema requires H1 antihistamine
atopic individuals. Systemic symptoms may occur in                 together with withdrawal of the suspected culprit(s).
highly sensitive, especially peanut-allergic, patients.            A combination of low sedation antihistamine such as
Drugs known to cause contact urticaria, probably                   fexofenadine or desloratidine in the morning and a first
allergic, are listed in Table 2. Latex present in rubber           generation compound such as hydroxyzine at night is
gloves, tubing and a wide range of other medical                   usually adequate, though off-label dosages of the
equipment is a major occupational cause of contact                 former may be required. Occasionally, short tapering
urticaria in health care personnel. The diagnosis of               courses of oral steroids may be necessary.
allergic contact urticaria is usually confirmed by patch
                                                                   For severely affected patients with respiratory difficulty
or scratch tests.
                                                                   the first priority is to secure an airway and administer
                                                                   oxygen. Occasionally, intubation or even tracheostomy
SOME MISCELLANEOUS CAUSES OF DRUG-                                 may be required. An intravenous line should be
INDUCED URTICARIA
                                                                   established. Subcutaneous adrenaline is the treatment
Progesterone Urticaria                                             of choice, given at 10-minute intervals until relief is
                                                                   evident. Chlorpheniramine and hydrocortisone can be
Exacerbation of chronic urticaria premenstrually is not            given parenterally. Although the latter takes several
uncommon and is, in most cases, non-specific.                      hours to work, it prevents relapses. Because of the risk
However, urticaria related to the menstrual cycle may              of relapse, patients should be admitted for 24 hours



SGH PROCEEDINGS • VOL 14 • NO 1 • 2005                                                                                          79
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for observation. If the culprit drug can be identified,                   17. Samter M, Beers RF. Intolerance to aspirin. Ann Int Med 1968;
                                                                              68:975-82.
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                                                                          18. Warin RP. The effect of aspirin in chronic urticaria. Br J
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                                                                              Dermatol 1960; 72:350-1.
                                                                          19. Williams FM, Asad SI, Lessof MH, Rawlins MD. Plasma
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                                                                              urticaria. Br J Dermatol 1987; 33:387-90.
Urticaria and angioedema represent potentially serious
                                                                          20. Stevenson DD. Proposed mechanism of aspirin sensitivity
clinical manifestations of adverse drug reactions. Non-                       reactions. J Allergy Clin Immunol 1987; 80:788-90.
allergic or allergic mechanisms may be involved,                          21. Szczeklik A. Aspirin induced asthma: new insights into
although in many cases the precise pathomechanism                             pathogenesis and clinical presentation of drug intolerance. Int
is unclear. However, in others, for example angioedema                        Arch Allergy 1989; 90 Suppl 1:70-5.
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Emergency treatment of acute reactions follows the
                                                                              104:5-13.
same guidelines as for acute angioedema from any
                                                                          23. Ros A-M, Juhlin L, Michaelsson G. A follow-up of patients
cause. Drug desensitisation is possible in selected cases.                    with recurrent urticaria and hypersensitivity to aspirin,
                                                                              benzoates and azo dyes. Br J Dermatol 1976; 95:19-24.
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