35_623_652 05.11.2005 11:22 Uhr Seite 623 Chapter 35 Topical Drugs 35 Francisco M. Brandão, An Goossens, Antonella Tosti Contents medication habits. Prescribing habits are changing, 35.1 Incidence and Prevalence . 623 and some medicaments that were common allergens 20–30 years ago,such as sulfonamides,penicillin,and 35.2 Factors Predisposing antihistamines, have now been replaced by other al- to Medicament Contact Dermatitis . 624 lergenic drugs, such as nonsteroidal anti-inflamma- 35.3 Clinical Patterns of Contact Reactions . 624 tory drugs (NSAID), and corticosteroids. 35.3.1 Irritant Contact Dermatitis . 624 The real incidence of adverse reactions to topical 35.3.2 Contact Urticaria . 625 medicaments is not known, and most of the data 35.3.3 Other Important Clinical Patterns . 625 about prevalence are quite old. Bandmann et al. [1] 35.3.4 Allergic Contact Dermatitis . 626 found that 14% of 4,000 patients tested in several Eu- 35.4 Allergens . 627 ropean countries were allergic to medicaments.Blon- 35.4.1 Local Anesthetics . 627 deel et al. [2] found a much higher incidence – 54.6%. 35.4.2 Antibiotics and Antimicrobials . 627 Still, in Belgium [3], 17% of 2,025 patients were aller- 35.4.3 Antivirals . 629 gic to the ingredients of pharmaceutical products, 35.4.4 Antimycotics . 629 while in Italy, in the 1980s [4], about 20.5% of 8,230 35.4.5 Corticosteroids . 630 patients were allergic to topical drugs. In Sweden, 35.4.6 Antihistamines . 632 40% of all recorded allergic reactions were due to 35.4.7 Nonsteroidal Anti-Inflammatory Drugs . 632 medicaments [5], which was equivalent to an annual 35.4.8 Ingredients of the Vehicles . 634 incidence of 43/100,000. More recently, in Singapore 35.4.9 Other Allergens . 635 [6], 22.5% of patients tested at a contact dermatitis 35.4.10 Transdermal Therapeutic Systems . 636 clinic had medicament sensitivity.A more recent sur- 35.5 Sites at Risk . 637 vey in Italy (1984–1993) disclosed a prevalence of 35.5.1 Ophthalmic Preparations . 637 13.2% in patients with nonoccupational allergic con- 35.5.2 Vulval and Perianal Dermatoses . 638 tact dermatitis [7], while in Portugal, over a 6-year 35.5.3 Stasis Dermatitis and Leg Ulcer Patients . 638 period (1998–2003), 18.0% of all patch-tested pa- 35.6 Systemic Contact Dermatitis . 639 tients were sensitized to medicaments (Table 1). Such 35.7 Diagnosis and Prognosis . 640 a high figure may be due to the existence and use of several topical medications still containing mercury 35.8 Appendix: Allergens in Medicaments compounds, neomycin, and other common sensitiz- (pet. petrolatum, aq. aqueous, eth. ethanol, o.o.olive oil) . 641 References . 644 Table 1. Incidence of medicament contact allergy in Portugal, 1998–2003 (data from the Portuguese Contact Dermatitis Group) Year Total patients Patch tests positive % 35.1 Incidence and Prevalence patch tested to medicaments Cutaneous adverse drug reactions are usually an iat- 1998 4,154 740 17.8 1999 3,990 755 18.9 rogenic disease induced in patients. More rarely, they 2000 3,625 675 18.6 are an occupational disease, either in health care per- 2001 3,361 635 18.9 sonnel or in pharmaceutical industry employees. 2002 2,681 490 18.3 The incidence of topical reactions to drugs varies 2003 2,849 426 14.9 from one area to another, and from one country to Total 20,660 3,721 18.0 another, depending on local prescribing and self- 35_623_652 05.11.2005 11:22 Uhr Seite 624 624 Francisco M. Brandão, An Goossens, Antonella Tosti ers. However, there is a trend of these figures to de- cidence of medicament allergy [3, 4]. In addition, pa- crease in future. tients with otitis externa, eye problems, perianal and These differences are due not only to geographic vulval dermatoses, and chronic hand and foot der- differences, but also to the type of patient selection – matitis are known to frequently develop secondary leg ulcer patients, anogenital dermatitis, for example medicament allergy. – and to the specific interests of some investigators.A In other chronic dermatological conditions, how- prevalence of allergic reactions to medicaments of ever,such as atopic dermatitis and psoriasis,this pos- about 15%, excluding leg ulcers or other high-risk pa- sibly increased contact allergy seems to be an open tients,seems a realistic figure to be expected in a con- question. In atopic patients, the defective T-cell pop- tact dermatitis clinic. However, this figure does not ulation and the difficulty in sensitizing patients to include other clinical entities, such as irritant contact dinitrochlorobenzene (DNCB) would suggest that dermatitis or contact urticaria, among others. these patients would not develop allergic contact der- matitis as often as nonatopic individuals [10]. This seems to be confirmed in some reports [11, 12], al- Core Message though others consider that atopic patients become sensitized to topical medicaments at least as often as í A prevalence of up to 15% of allergic nonatopic patients [13–15]. contact dermatitis to topical medicaments It has also been suggested that psoriatic patients is, probably, a realistic figure in most are not easily sensitized [16, 17], and that sensitiza- contact clinics. tion could be associated with certain localizations (palmoplantar and flexural [18]), although this could not be confirmed by other authors [19, 20]. Sensitiza- tion was found to be equal in other patients, especial- ly to antipsoriatic medicaments [21–24], although 35.2 Factors Predisposing seemingly less to corticosteroids [19, 25]. to Medicament Contact Dermatitis Many factors may contribute, in various ways, to cu- Core Message taneous drug sensitization. The environment, on the whole, must be considered to be the more important í The use of medicaments under occlusion 35 contributing factor, although there is some individu- or in folds increases its absorption and al predisposition, which mainly depends on genetic allergenic potential. It is not unanimous factors. The intrinsic sensitizing potential of each if atopic and psoriatic patients really drug is by far the most important factor (see Chap.3), do sensitize more or less to topical although sometimes impurities, contaminants, and medicaments. degradation of products may be the allergenic mate- rial [4].Moreover,compound allergy [8] and quench- ing phenomena [9] may interfere with this intrinsic capacity. However, many of the more potent aller- gens, such as sulfonamides and penicillin, have now 35.3 Clinical Patterns of Contact Reactions been almost banished from our prescribing habits and from the market; on the other hand, some weak Allergic contact dermatitis is by far the more com- sensitizers, such as neomycin, are so widely used that mon and more important clinical entity caused by several new cases are seen every year. topical drugs. However, other pathological clinical The use of medicaments in high concentrations entities, through direct cutaneous aggression, by im- or in vehicles that increase skin penetration favors munoallergic mechanisms, or by local or systemic their irritant and sensitizing capacities. The same ap- pharmacological effects, may be caused by medica- plies when medications are used in folds, under oc- ments (Table 2) [26–29]. clusive dressings or in transdermal devices, both of which lead to a much greater skin absorption and, thus, increase the probability of developing contact 35.3.1 Irritant Contact Dermatitis allergy. Damage to the skin barrier is another very impor- There are several medicaments that can irritate the tant factor favoring sensitization. Leg ulcer and stasis skin [26,30] (Table 3).Most are well-known mildly ir- dermatitis patients are known to have a very high in- ritant drugs, and their irritancy is usually expected, 35_623_652 05.11.2005 11:22 Uhr Seite 625 Topical Drugs Chapter 35 625 Table 2. Clinical patterns of eruptions caused by topical medic- repeated contact, the skin becomes dry, erythema- aments [26–29] tous, and scaly, with pruritus or burning sensation, Allergic contact dermatitis usually confined to the application area [26]. If ap- Irritant contact dermatitis plied for a longer time, in higher concentrations, or Photoallergic contact dermatitis in occluded areas, they may cause acute irritant con- Phototoxic contact dermatitis tact dermatitis with edema, erythema, vesicles, or Contact urticaria bullae that may be difficult to differentiate from al- Photocontact urticaria Dermographism lergic contact dermatitis. Airborne allergic contact dermatitis Airborne irritant contact dermatitis predominates Airborne irritant contact dermatitis in exposed areas, but, as opposed to photosensitive Airborne photoallergic contact dermatitis dermatitis, it does not spare areas such as the upper Airborne phototoxic contact dermatitis eyelids, retroauricular folds, or submental area. Erythema-multiforme-like eruptions Lichenoid contact dermatitis The subjective irritant sensation of “stinging” may Purpuric contact dermatitis be immediate or delayed, and may be caused by sev- Skin necrosis eral drugs (see Chap. 15). Dyschromia Pustular contact dermatitis Lymphomatoid contact dermatitis 35.3.2 Contact Urticaria Acne/folliculitis/rosacea Granulomatous eruption Interactions with cutaneous microbial flora Since the first reports [31], the contact urticaria syn- Pharmacological local effects drome (CUS) has been frequently studied. It includes Systemic side-effects the localized cutaneous forms (immunological and nonimmunological), as well as a broad spectrum of noncutaneous involvement (generalized urticaria, Table