Allergic Reactions to Drugs

770 Pages·1983·21.23 MB·English

by  C. H. Schneider (auth.)

Handbook of
Experimental Pharmacology
Continuation of Handbuch der experimentellen Phannakologie
Vol. 63
Editorial Board
G. V. R Born, London· A. Farah, Rensselaer, New York
H. Herken, Berlin· A. D. Welch, Memphis, Tennessee
Advisory Board
S. Ebashi . E. G. Erdos· V Erspamer . U. S. von Euler· W S. Feldberg
G. B. Koelle· M. Rocha e Silva· J. R. Vane· P. G. Waser
Allergic Reactions
to Drugs
Contributors
M. Alexander· H. E. Amos· K. E. Andersen· A. Arnaud
E. S. K.Assem . J. Aubert· H. Bundgaard . J. Charpin
M. C. Conroy· A. L. de Week· J. Dewdney . L. DostaIova
A.A. Fisher· L. Gamba· J.-P. Girard· H. Hedin· R. Hoigne
L. Juhlin· D. Kraft . H. 1. Maibach . P. Middleton . C. W Parker
J. Pepys . W Richter· W Schalch . C. H. Schneider
K. H. Schulz· F. Stocker· A. Szczeklik . S. Zawodnik
Editors
A.L. de Week and H. Bundgaard
Springer-Verlag Berlin Heidelberg New York Tokyo 1983
Professor Dr. ALAIN L. DE WEeK
Institut fur klinische Immunologie, Inselspital,
CH-3010 Bern
Professor Dr. HANS BUNDGAARD
The Royal Danish School of Pharmacy,
Department of Pharmaceutical Chemistry AD, 2, Universitetsparken,
DK-2100 Copenhagen
With 96 Figures
ISBN-13: 978-3-642-69090-7 e-ISBN-13: 978-3-642-69088-4
DOl: 10.1007/978-3-642-69088-4
Library of Congress Cataloging in Publication Data. Main entry under title: Allergic reactions to drugs. (Handbook
of experimental pharmacology; v. 63) Bibliography: p. Includes index. I. Drug allergy-Addresses, essays, lectures.
I. Alexander, M. (Meta), 1924-. II. Weck, Alain L. de. III. Bundgaard, Hans. IV. Series. [DNLM: I. Drug
hypersensitivity-Congresses. WI HA51L v. 63fWD 320A434] QP905.H3 vol. 63 [RC594.D7] 615'.s [616.97'5]83-4756
This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned,
specifically those of translation, reprinting, re-use of illustrations, broadcasting, reproduction by photocopying
machine or similar means, and storage in data banks. Under § 54 of the German Copyright Law where copies are
made for other than private use, a fee is payable to "Verwertungsgesellschaft Wort", Munich.
© by Springer-Verlag Berlin Heidelberg 1983.
Softcover reprint of the hardcover 15t edition 1983
The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific
statement, that such names are exempt from the relevant protective laws and regulations and therefore free for
general use.
Product liability: The publisher can give no guarantee for information about drug dosage and application thereof
contained in this book. In every individual case the respective user must check its accuracy by consulting other
pharmaceutical literature.
2122/3130-543210
Preface
According to most studies, allergic reactions represent 35%-50% of all untoward
reactions to drugs, yet the pharmacological literature concerning the clinical
aspects, diagnosis, and pathophysiological mechanisms of drug allergy is markedly
less extensive than reports dealing with the toxicological or pharmacological effects
of drugs. The main reasons for this state of affairs may be on the one hand that until
a few years ago the pathophysiological mechanisms of the various types of allergic
reactions were not well understood, and on the other hand that objective diagnosis
of a drug allergy is still fraught with serious difficulties. Drug allergy is still an
unpopular topic for most allergologists and pharmacologists; this is reflected by the
fact that despite their frequency, allergic reactions to drugs still occupy a relatively
small proportion of space in most pharmacology handbooks and in classical books
devoted to the side effects of drugs.
There has recently been considerable progress in research into the immunologi
cal and pathophysiological events occurring in allergic reactions, and on that basis
investigations of various drug allergies have also yield~d new objective findings.
Consequently, it was natural to attempt a review of the most frequent and
important drug allergies in the form of a handbook. We originally intended to
present a comprehensive review of all drug allergies, but the realization of this goal
soon became more difficult than we had at first imagined. Whereas for some
frequent allergies to drugs that have been in clinical use for over 20 years, such as
the beta-Iactam antibiotics, the clinical forms as well as the pathophysiological and
immunological features have been thoroughly studied by numerous investigators,
the reports concerning other drugs are often limited to clinical descriptions and to
hypothetical considerations without objective elements that permit a secure
diagnosis and an understanding of the mechanisms.
Accordingly, the level and extent of information contained in this volume have
become somewhat unbalanced, since for many drugs causing allergic reactions,
little can be said about the pathogenic and immunological or para-immunological
mechanisms involved. An additional complicating factor is the recent finding that
many "allergic" reactions to drugs are in fact "pseudoallergic," i.e., they may be
due to the same inflammatory mediators but are not initially triggered by an
immunological reaction and are not dependent on specific sensitization to the drug
implicated.
For the compilation of this book, which reflects the still fragmentary state of
our knowledge, we owe particular gratitude to the authors, who have continued
their collaboration despite a fairly long gestation period. Special thanks also go to
the publisher and his competent staff.
Bern A. L. DE WEeK
Copenhagen H. BUNDGAARD
List of Contributors
M. ALEXANDER, Abteilung fUr Innere Medizin mit Schwerpunkt Infektions
krankheiten, Freie UniversiHit Berlin, Klinikum Charlottenburg, Spandauer
Damm 130, D-I000 Berlin 19
H. E. AMOS, Pharmaceuticals Division, Imperial Chemical Industries, PLC,
Mereside Alderley Park, GB-Macc1esfield, Cheshire SKIO 4TG
K. E. ANDERSEN, K0benhavns Amts Sygehus i Gentofte, Dermatology, Afdeling,
Niels Andersens vej 65, DK-2900 Hellerup
A. ARNAUD, Hopital Sainte-Marguerite, B.P. 29, F-13274 Marseille Cedex 2
E. S. K. ASSEM, Department of Pharmacology, University College London,
Gower Street, GB-London WCIE 6BT
J. AUBERT, Service de Pneumologie, Hopital Saint-Joseph, 26, Bd. de Louvain,
B.P. 265, F-13285 Marseille Cedex 8
H. BUNDGAARD, The Royal Danish School of Pharmacy, Department of
Pharmaceutical Chemistry AD, 2, Universitetsparken, DK-2100 Copenhagen
J. CHARPIN, Universite Aix-Marseille, Faculte de Medecine, Clinique de
Pneumo-Phtisiologie, Allergologie, Hopital Sainte-Marguerite, B.P. 29,
F-13277 Marseille Cedex 9
M. C. CONROY, Institut fur klinische Immunologie, Inselspital, CH-3010 Bern
A. L. DE WEeK, Institut fur klinische Immunologie, Inselspital, CH-3010 Bern
J. DEWDNEY, Research Division, Beecham Pharmaceuticals, Biosciences Research
Centre, Great Burgh, Yew Tree Bottom Road, GB-Epsom, Surrey KTl8 5XQ
L. DOSTALOVA, Abteilung VF (Department of Vitamin and Nutrition Research),
Hoffmann-La Roche & Co., Ltd., Grenzacher Strasse 124, CH~4002 Basel
A. A. FISHER, 45-14 48 th Street, Woodside, Long Island, NY 11377 jUSA
L. GAMBA, Division of Immunology and Allergology, Department of Medicine,
Hopital Cantonal Universitaire, CH-1211 Geneva 4
VIII List of Contributors
J.-P. GIRARD, Division of Immunology and Allergology, Department of Medicine,
Hopital Cantonal Universitaire, CH-1211 Geneva 4
H. HEDIN, Department of Biomedical Research, Pharmacia AB, Box 181,
S-751 04 Uppsala 1
R. HOIGNE, Medizinische Abteilung, Zieglerspital, Postfach 2600, CH-3001 Bern
L. JUHLIN, Centre International de Recherches Dermatologiques, Sophia
Antipolis, F-06565 Valbonne Cedex
D. KRAFT, Institut fur Allgemeine und Experimentelle Pathologie der Universitat
Wien, Wahringer Strasse 13, A-1090 Wien
H.1. MAIBACH, Department of Dermatology, School of Medicine, University of
California, San Francisco, CA 94143jUSA
P. MIDDLETON, II St. Anne's Court, Northenden Road, GB-SalejCheshire
M333HB
c. W. PARKER, Department of Medicine, Washington University School of
Medicine, 650 South Euclid, St. Louis, MO 63110jUSA
J. PEPYS, Clinical Immunology, University of London (Cardiothoracic Institute),
34 Ferncroft Avenue, GB-Hampstead, London NW3 7PE
W. RICHTER, Department of Biomedical Research, Pharmacia AB, Box 181,
S-751 04 Uppsala I
W. SCHALCH, Abteilung VF (Department of Vitamin and Nutrition Research),
Hoffmann-La Roche & Co., Ltd., Grenzacher Strasse 124, CH-4002 Basel
C. H. SCHNEIDER, Institut fUr klinische Immunologie, Inselspital, CH-3010 Bern
K. H. SCHULZ, Universitats-Hautklinik, Martinistrasse 52, D-2000 Hamburg 20
F. STOCKER, Comprehensive Hospital Drug Monitoring, Zieglerspital, CH-3007
Bern
A. SZCZEKLIK, Instytut Medycyny Wewnetrznei, Klinika Alergii i Immunologii,
ul. Skawinska 8, PL-31-066 Krakow
S. ZAWODNIK, Division ofImmunology and Allergology, Department of Medicine,
Hopital Cantonal Universitaire, CH-1211 Geneva 4
Contents
Section I: General Aspects of Drug Allergies
CHAPTER 1
Immunochemical Basis of Allergic Reactions to Drugs
C. H. SCHNEIDER
A. Introduction. . . . . . . . . . . . . . . 3
I. Definitions . . . . . . . . . . . . . 3
II. Miscellaneous Parameters in Sensitization 4
1. Chemical Characteristics of the Antigen 5
2. Antigen Metabolism . . . . . . . . . 6
3. Genetic Aspects . . . . . . . . . . . 7
B. Cellular and Immunochemical Elements in Antigenicity 8
I. Cellular Aspects . . . . . . . . . . . . . . 8
II. Antigenic Determinants Reacting with Antibody 9
III. Antigenic Determinants in Cellular Reactions 13
C. Antigenicity and Drugs . . . . . . . . . . . . 14
I. Agents of Intrinsic Immunogenicity. . . . . 14
II. Low Molecular Weight Drugs as Immunogens 16
1. The Formation of Antigenic Determinants 16
2. The Formation of Complete Immunogens. 20
III. Immunogenic Complexes not Involving Covalent Linkage Between
Hapten and Carrier. . . . . . . . . . . . . . . . . .. 21
IV. Molecular Parameters in Elicitation and Inhibition of Allergic
Reactions . 24
References . . . . . . . . . . . . . . . . . . . . . . . . . . 27
CHAPTER 2
Chemical and Pharmaceutical Aspects of Drug Allergy
H. BUNDGAARD. With 23 Figures
A. Introduction: Routes of Formation of Drug Antigens. . . . . .. 37
B. Immunologically Active Macromolecular Contaminants of Penicillins 39
C. Polymerization of fJ-Lactam Antibiotics . . . 41
I. Penicillin Polymers. . . . . . . . . . 41
I. Formation and Structure of Polymers 42
x Contents
2. Immunologic Effects of Polymers . . 52
3. Prevention of Penicillin Polymerization 54
II. Cephalosporin Polymers . . . . . . . 55
D. Reactions Between Penicillins and Pharmaceutical Adjuvants. 56
E. Chemically Reactive Impurities and Degradation Products . 59
I. Acetylsalicylic Acid. 60
II. Phenindione. . 62
III. Phenylbutazone 63
IV. Corticosteroids. 64
V. Penicillins . 65
References . 67
CHAPTER 3
Immunopathological Mechanisms and Clinical Aspects
of Allergic Reactions to Drugs
A. L. DE WEeK. With 4 Figures
A. Introduction. . . . . . . . . . . . . . . . . . . . . . . . 75
B. Chemical Properties Involved in the Allergenic Potential of Drugs 77
I. Formation of Immunogenic Conjugates . . . . . . . . . 78
II. Reactive Derivatives and Metabolites . . . . . . . . . . 79
III. Requirements for Allergens Eliciting Antibody-Mediated Reactions 80
IV. Requirements for Allergens Eliciting Cell-Mediated
(Delayed-Type) Allergic Reactions . . . . . . . . . . . 81
V. Impurities and Galenic Factors Involved in Sensitization . . 81
C. Induction of Immune Responses to Drugs: Main Factors Involved 82
I. Factors Involving the Sensitizing Drug. 82
1. Chemical Structure and Reactivity . . . . . . . . 82
2. Cross-Sensitization . . . . . . . . . . . . . . . 83
3. Dose, Duration, and Number of Courses of Therapy 83
4. Mode of Administration. . . . . . . . . . . . . 83
II. Factors Involving the Patient. . . . . . . . . . . . 84
1. The Immune System and the Regulation of Immune Responses
to Drugs . . . 84
2. Age and Sex. . . . 85
3. Genetic Factors . . 85
4. Underlying Diseases 86
5. Variable Relationship Between the Immune Response to a Drug
and the Incidence of Clinical Allergic Symptoms . . . . 87
D. Immunopathological Mechanisms of Allergic Reactions to Drugs. 89
I. Antibody-Mediated Reactions 89
1. Anaphylactic Reactions . . . 89
2. Cytotoxic Reactions . . . . 92
3. Immune Complex Reactions. 93
II. Cell-Mediated (Delayed-Type) Reactions. 94
III. Reactions by Photosensitivity. 96
IV. Pseudoallergic Reactions. . . . . . . . 97
Contents XI
1. Mast Cell and Basophil Degranulation by Complement
Components (Anaphylatoxins) . . . . . . . . . . 97
2. Liberation of Histamine Through Nonimmunologic
Mechanisms. . . . . . . . . . . . . . . . . 98
3. Pseudoallergic Reactions to Drugs Interfering with
Prostaglandin Synthesis . . . . . . 99
E. Clinical Forms of Allergic Reactions to Drugs 100
I. Anaphylactic Shock . 100
II. Serum Sickness. . . . 103
III. Fever . . . . . . . . 105
IV. Hematologic Reactions 106
1. Hemolytic Anemia 107
2. Agranulocytosis . 109
3. Thrombocytopenia III
4. Eosinophilia. . 112
V. Hepatic Disorders. . 113
VI. Renal Diseases . . . 114
VII. Reactions Affecting the Respiratory Tract 116
1. Asthma. . . . . . . . . . . . . . 116
2. Infiltrative and Fibrotic Pulmonary Reactions 116
VIII. Drug-Induced Autoimmunity. . . . . . 118
IX. Vasculitis . . . . . . . . . . . . . . 120
X. Digestive Tract and Other Manifestations 120
XI. Skin Manifestations. 121
References . . . . . . . . . . . . . . . . . . 121
CHAPTER 4
Cutaneous Manifestations of Drug Allergy
K.H.SCHULZ
A. Pathogenesis and Classification. . . . 136
I. Anaphylaxis, Urticaria, Angioedema. 137
II. Late Urticarial Reactions 138
III. Serum Sickness. . . . . . . . . . 139
IV. Maculopapular Rashes . . . . . . 139
V. Erythema Multiforme and Stevens-Johnson Syndrome 140
VI. Allergic Vasculitis. . 141
VII. Erythema Nodosum ..... . 143
VIII. Purpura. . . . . . . ... . 143
IX. Purpura Pigmentosa Progressiva 144
X. Fixed Eruptions . . . . . . . 145
XI. Lyell's Syndrome (Toxic Epidermal Necrolysis) 148
XII. Drug-Induced Lupus Erythematosus. . . . . 151
XIII. Allergic and Photo allergic Contact Dermatitis 152
B. Diagnosis of Allergic Drug Reactions Involving the Skin 154
References . . . . . . . . . . . . . . . . . . . . . . 156
XII Contents
CHAPTER 5
Allergy of the Respiratory Tract to Low Molecular Weight Chemical Agents
J. PEPYS
A. Introduction. . . . . . . . . . . . 163
B. Inorganic Chemicals . . . . . . . . 164
I. Halide Complex Salts of Platinum 164
1. Allergy to Complex Platinum Salts. 165
2. Immunochemical Analysis of Allergenicity of Platinum Salts. 165
3. Inhalation Tests with Platinum Salts 169
4. Serological Findings . . . . . . . . . . 170
II. Nickel Sulphate . . . . . . . . . . . . . 172
III. Allergy to Potassium and Sodium Persulphate 172
C. Chemical Organic Dusts. . . . 173
I. Amprolium Hydrochloride 173
II. Chloramine-T . . . . . . 173
III. Piperazine Hydrochloride . 174
IV. Antibiotic Dusts: Ampicillin, Benzylpenicillin, 6-Aminopenicillanic
Acid and Related Substances 174
V. Salbutamol . . . . . . . . . . 176
VI. Azo and Anthraquinone Dyes . . 176
D. Organic Chemical Fumes and Vapours 176
I. Aminoethylethanolamine . . . . 177
II. Diisocyanates . . . . . . . . . 177
1. Reactions to Diisocyanates Other than TDI . 178
2. Modes of Action of TDI . . . . . 178
3. Antibodies to Other Diisocyanates. . . . 179
III. Epoxy Resin System Activating Agents . . . 179
1. Phthalic Anhydride-Specific IgE Antibodies 180
2. Trimellitic Acid-Specific IgE and IgG Antibodies 181
IV. Miscellaneous Agents. 181
E. General Comments . 181
References . 182
CHAPTER 6
Epidemiology of Drug Allergy: Drug Monitoring
R. HOIGNE, F. STOCKER, and P. MIDDLETON. With 3 Figures
A. Introduction. . . . . . . . . . . . . . . . . . . 187
B. Methods of Epidemiology and Drug Monitoring . . . 188
I. Comprehensive Inpatient (Intensive) Drug Monitoring 189
1. Euler-Venn Diagram. . . 189
2. Weighted Attributions . . . . . . . . . . . . . 191
II. Outpatient Drug Monitoring. . . . . . . . . . . . 192
III. Spontaneous Reporting of Adverse Reactions to Drugs 192
IV. Use of Record Linkage for Drug Surveillance 192
C. The Patient . . . . . . . . . . . . . . . . . . . . . 193