Review For reprint orders, please contact:
[email protected]
Clinical work-up of adverse drug reactions Stefan Wöhrl
CONTENTS Pathophysiology The size of the problem (epidemiology) Diagnostic work-up Drug classes Management of the acute drug reaction Expert commentary Five-year view Key issues
Self-reported adverse drug reactions (ADRs) are a frequent problem of the daily clinical praxis. Unevaluated ADRs lead to the prescription of less effective or more expensive alternative drugs. Therefore, a work-up is recommended by current European and American guidelines. The work-up begins with a careful case history. Following this, skin tests or, if available, in vitro tests should be performed. If they remain inconclusive, drug provocation tests with the suspicious or alternative drugs should be performed. The results must be given to the patient in a written form, such as by issuing ‘allergy passes’. ADRs are multifactorial diseases and, hence, a lot of medical specialities are involved. Therefore, this interdisciplinary clinical review compiles recent advances in immunological, as well as nonimmunological ADRs (‘hypersensitivity reactions’). First, it begins with an introduction to the definitions (e.g., type B reaction, hypersensitivity reaction, drug allergy). A compilation of new data about the epidemiology of ADRs will be followed by a review on guidelines explaining how these tests shall be performed. This is done with respect to the most relevant classes of drugs causing ADRs, namely antibiotics, nonsteroidal anti-inflammatory drugs, muscle relaxants, local anesthetics and radio contrast media. Current knowledge about the management of acute ADRs will be evaluated. As a future perspective, the possible value of genetic testing prior to prescription for avoiding ADRs will also be discussed.
References
Expert Rev. Dermatol. 2(2), 217–231 (2007)
Affiliation
According to the WHO definition, adverse drug reactions (ADRs) are defined as ‘a response to a drug, which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for the modification of physiological function’ [1]. The original terminology, proposed by Rawlins and Thompson, groups ADRs into two main classes (TABLE 1) [2]. Type A reactions (augmented reactions) can be explained pharmacologically and are common, predictable, dose dependent and can occur in any individual. They are usually already known in prelicensing times [3], for example sedation by first-generation antihistamines. Type A reactions comprise more than 80% of all drug reactions [4] and are usually documented in common prescription manuals. Type B (bizarre reaction) are uncommon, unpredictable, cannot be explained pharmacologically and occur in susceptible individuals
Medical University of Vienna, Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases (DIAID), Währinger Gürtel 18–20, A-1090 Wien, Austria Tel.: +43 140 400 7704 Fax: +43 140 400 7574
[email protected] KEYWORDS: adverse drug event, diagnosis, drug allergy, drug hypersensitivity, drug provocation challenge, drug provocation test, drug reaction, drug re-exposure, skin test
www.future-drugs.com
10.1586/17469872.2.2.217
only [4]. According to Hunziker and colleagues, 13% of ADRs belong to type B [4]. Following the new World Allergy Organization (WAO) nomenclature [5], the term ‘drug allergy’ should remain restricted to patients with a proven immunological cause. The terms ‘immediate’ and ‘delayed drug allergy’ should be used to describe the onset of symptoms and the probable responsible immunological mechanism (immunoglobulin [Ig]E- and T-cell mediated, rarely IgG-mediated [6]). The enhanced classification for allergic drug reactions according to Pichler is depicted in TABLE 2 [6]. Drug hypersensitivity is an umbrella term for all kinds of type B reactions neglecting the exact pathophysiology. Hence, all ADRs without involvement of the immune system, such as reactions caused by enzyme polymorphism, should be termed ‘hypersensitivity reaction’, for example, aspirin hypersensitivity. These reactions are also known as ‘pseudoallergies’.
© 2007 Future Drugs Ltd
ISSN 1746-9872
217
Wöhrl
Table 1. Classification of adverse drug reactions. Type of reaction Definition
Features
Examples
A
Dose related
Toxicity of digitoxin
Common
Sedation by first-generation antihistamines
Predictable
Angioedema to angiotensin-converting enzyme inhibitors
Augmented
Related to the pharmacological action of the drug Low mortality B
Bizarre
Nondose related
Immunological reactions: Type I, III, IV reactions (e.g., drug rash)
Uncommon
Hypersensitivity reactions (e.g., radio contrast media hypersensitivity, aspirin hypersensitivity)
Unpredictable Not related to the pharmacological action of the drug Mortality possible C
Chronic
Dose and time related
Suppressing effect of corticosteroids on the adrenal gland
D
Delayed
Uncommon
Teratogenesis
Time related
Carcinogenesis
Uncommon
Myocardial ischemia after β-blocker withdrawal
E
End of use
Withdrawal F
Failure of therapy
Common
Low dosage of oral contraceptive when used with enzyme inducer
Dose related Modified from [1].
Four other classes have been added to the original scheme [1] and are defined by long-term side effects, for example, teratogenic or carcinogenic properties (type D, delayed) or the adrenal–cortex suppression of corticosteroids (type C, chronic). Type E (end of treatment) considers side effects upon withdrawal of a drug, for example, myocardial ischemia after cessation of β-blockers. Finally, type F defines not an adverse reaction per se, but a ‘failure of therapy’. The rest of this review will focus exclusively on type B reactions. Pathophysiology Genetics & the environment
Drug hypersensitivity is a complex process depending on multiple interactions between gene products and the environment [7]. One of the earliest examples of a complex genetic susceptibility was the two gene loci with an increased risk for hydralazine-induced systemic lupus erythematosus (SLE): slow acetylation (deficiency in the N-acetyl transferase type 2 [8]) and the presence of the human leukocyte antigen (HLA)-DR4 haplotype [9]. This already leads us to the two major systems
218
involved in ADRs: metabolism and the immune system. Naisbitt and colleagues divide the genes involved in ADRs into four categories [10]: • Drug bioactivation, for example, the mostly hepatic cytochrome P450 enzymes • Drug inactivation • Immune responses, for example, the major histocompatibility complex (MHC) loci • Tissue injury and tissue repair, for example, cytokines In addition, environmental cofactors, such as inflammation, which deliver unspecific ‘danger’ signals [11], are associated with an increased risk of developing an ADR, for example, infection with HIV or Epstein–Barr viruses. Another example is the frequent exposition to antibiotics in patients with cystic fibrosis [12]. Models
There are only a few well-established animal models to study ADRs, such as penicillamin-induced autoimmunity in the Brown Norway rat or nevirapine-induced skin rash, also in the rat [13]. We are facing a lack of prospective clinical studies owing
Expert Rev. Dermatol. 2(2), (2007)
Clinical work-up of adverse drug reactions
Table 2. Enhanced classification of allergic drug reactions. Extended classification Pathophysiology
Clinical symptoms
Onset of symptoms after
I
IgE
Urticaria/angioedema
Minutes to several hours
Activates mast cells and basophils
Rhinoconjunctivitis
Allergic bronchial asthma
Anaphylaxis Allergic shock
II
IgG
Cytopenia
5–15 days
IgG and IgM immune complexes
Vasculitis
7–21 days
Deposition of immune complexes activates complement
Urticaria vasculitis
Lysis of cells binding the Fcγ-receptor III
Serum sickness
7–8 days
Allergic hepatitis IV a
Th1
Eczema
IFN-γ production
Skin reaction to tuberculin
5–21 days
Monocyte activation IV b
Th2
Maculopapular exanthema
IL-5 and IL-4
Bullous exanthema
2–6 weeks
Eosinophilic inflammation IV c
IV d
Cytotoxic T cells
Maculopapular exanthema
Perforin and granzyme B
Pustular exanthema
CD4- and CD8-mediated killing of keratinocytes
Hepatitis
2 days (fixed drug eruption)
Bullous exanthema
7–21 days (Stevens–Johnson syndrome and toxic epidermal necrolysis)
T cells
Pustular exanthema
