1.1.3.1 Drug Reactions

Cutaneous drug reactions are the most frequently occurring adverse reactions to drugs. Among hospitalized patients, their incidence ranges from 0.1 to 5%. Predisposing factors include advanced age, gender (more frequent in women), underlying diseases, viral infections, genetic factors and the use of multiple drugs.

Anti-infective, antipyretic/anti-inflammatory analgesics and anticonvulsant agents are among the drugs most commonly associated with muco-cutaneous adverse reactions.

Drug reactions may arise as a result of immunological allergy directed against the drug itself, or a reactive metabolite or by non-immunological mechanisms (pseudoallergic reactions) caused by non- immune-mediated degranulation of mast cells and basophils.

Immunologic mechanisms can involve type I (immunoglobulin E [IgE]-mediated), type II (cytotoxic), type III (immune complex), type IV (cell-mediated immunity), or a combination of multiple mechanisms.

Common causes:

• Antibiotics (sulphonamides, ampicillin, penicillins, cephalosporins).

• Anti-inflammatory drugs (NSAIDs).

• Anticonvulsant medications (phenytoin, barbiturates).

• Diuretics (thiazides).

• Alllopurinol

An extensive number of clinicopathological presentations may develop secondary to drugs. Most (but not all) drug reactions appear 5–15 days after the drug administration. Several drugs may cause any particular reaction, although certain drugs are more likely than others to give a particular pattern.

The most common reactions produced by drugs are exanthematous/morbilliform rashes, followed by urticaria and angioedema.

Exanthematous drug reactions (80%):

Symmetrically distributed erythematous macules or papules appearing from 4 to 14 days after the onset of treatment. The lesions are often pruritic and appear first on the trunk and then spread to the extremities. The eruption usually lasts for 1-2 weeks and clears with cessation of the drug. Occasionally the exanthem may be urticarial or haemorrhagic.

Related drugs: Acetaminophen, allopurinol, anticonvulsants, antidepressants, antipsychotics, antibiotics (penicillins, tetracyclines, macrolides, sulphonamides), NSAIDs and monoclonal antibodies, carbamazepine.

Urticarial eruptions, angioedema (5%): Rapid onset (first few hours after drug ingestion)

Evanescent, raised intensely itchy plaques (wheals). Generalized distribution. Angioedema is more persistent and may be observed as an isolated manifestation or in association with urticarial lesions.

Related drugs: ACE inhibitors (angioedema), penicillins, sulphonamides, NSAIDs (aspirin, diclofenac, ibuprofen, naproxen), amphotericin B, tartrazine, codeine, vacomycin.

Fixed drug eruption: Onset within 2 days of initiation of drug therapy. Limited number of lesions. Well-demarcated round or oval itchy/burning erythematous/edematous plaques becoming dusky violaceous or brown, and sometimes vesicular or bullous. Cutaneous and/or mucosal involvement. After re-exposure to the responsible drug the lesions recur at the same location, although new lesions in different areas may develop.

Related drugs: Acetaminophen, antibiotics (sulphonamides (cotrimoxazole), tetracyclines, penicillins), NSAIDs (aspirin, oxyphenbutazone, phenazone/ antipyrine, metamizole), paracetamol, barbiturate derivatives, anticonvulsants, antidepressants, antimalarials, antipsychotics.

Acute generalized exanthematous pustulosis (AGEP): Febrile drug reaction often seen within 1 - 2 days of starting offending drug. Multiple punctate non-follicular sterile pustules in a background of edematous erythema. Face or intertriginous areas and spread to trunk and upper extremities. Edema of face and hands. Resolves within 1–2 weeks with desquamation.

Related drugs: Antibiotics (pristinamycin, amino-penicillins, quinolones, sulfonamides, macrolides), hydroxy) chloroquine, terbinafine, diltiazem, calcium channel blockers, carbamazepine, paracetamol, iodinated contrast media.

Other less common clinicopathological patterns: Purpura, photosensitivity eruptions, neutrophilic dermatoses, erythema nodosum, vasculitis, drug-induced pemphigus and pemphigoid, acneiform eruptions, lichenoid eruptions, sclerodermoid, pseudolymphomatous reactions, granulomatous eruptions, erythroderma, necrosis of the skin, hypertrichosis, alopecia, etc. Possible mucosal involvement.

The most severe drug reactions are Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN), DRESS syndrome, exfoliative dermatitis and anaphylaxis (with or without angioedema). Severe cutaneous drug eruptions may be accompanied by fever, chills, lymphadenopathy, arthralgias and wheezing.

Stevens-Johnson syndrome and TEN: Life-threatening disorders. Fever and constitutional symptoms precede 1 to 3 days the onset of cutaneous lesions. Extensive symmetrical erythematous macular eruption upper trunk of the body and the face, that subsequently result in flaccid bullae or frank epidermal detachment due to necrosis of the epidermis, erythema with painful mucosal erosions/ ulcerations, involving genital, buccal, and ocular mucosa. Stevens-Johnson syndrome affects less than 10% of the body while TEN causes large areas of peeling affecting over 30% of the body. Involvement of more than 10% to 30% is considered an overlap. (see chapter 1.1.3.4).

Related drugs: Anticonvulsants (carbamazepine, lamotrigine, phenytoin), penicillins, allopurinol, sulphonamides, antiretrovirals, barbiturates, NSAIDs.

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS). “Hypersensitivity syndrome”; appearing 2 – 6 weeks after starting offending drug. Maculo-papular (morbilliform) generalized skin eruption. Edematous with occasional blisters and bullae. Upper trunk and extremities. Facial edema. Fever, lymph node enlargement. Eosinophilia, elevated liver enzymes, interstitial nephritis, etc.

Related drugs: Sulphonamides, phenobarbital, carbamazepine, phenytoin, lamotrigine, allopurinol, dapsone, abacavir.

A single drug may be associated with numerous forms of skin eruption. Drug eruptions may be classified in terms of both their clinical morphology and the presumed mechanism of action (Immediate-type and delayed-type Immune-mediated drug eruptions).

In general, the skin findings of one of the clinico-morphological patterns define the histological pattern.

Examples:

• Exanthematous drug reactions: Mild spongiosis, vacuolar changes involving the basal layer. Occasional apoptotic keratinocytes. Discrete perivascular lymphocytic infiltrate. Mild dermal edema. Some eosinophils

• Pustular drug reactions: epidermotropic non-follicular subcorneal neutrophilic and eosinophilic infiltration.

• Lichenoid drug eruptions: interface dermatitis with attack against basal cell layer of epidermis.

In severe muco-cutaneous drug reactions: Liver, renal and hematologic abnormalities may be present. Anaphylactic reaction.

Careful history (time course fits with drug exposure), clinical features, associated symptoms, histology and laboratory studies, examples from drug bank literature. Cessation of the suspected drug (re-challenge).

If possible, identification of the responsible drug. Databases: Potential responsible drugs for particular clinicopathological patterns. No reliable specific confirmatory tests. In some drugs patch, or other skin, tests could be useful. Re-challenge (ethical considerations).

Depending on the observed clinical picture or clinicopathological pattern. In exanthematous drug reactions, other generalised exanthems, depending on lesion morphology, such as viral exanthems, secondary syphilis and lupus erythematosus. In pustular variants: subcorneal pustular dermatosis (Sneddon–Wilkinson disease), pustular vasculitis.

Take care of multimedication and comorbidities promoting drug reactions.

Discontinue the suspected medication, antihistamines, topical and even systemic corticosteroids.

Antihistamines are sometimes helpful for pruritus.