- Identify common and serious drug eruptions.
- The majority of drug eruptions arise within three weeks of starting a new medication.
- Mechanisms may be immunologically mediated, or non-immunologic.
- Drug eruptions generally improve within days of discontinuing the responsible drug, but resolution may take much longer.
- There is a wide range of clinical presentations that may be characteristic of drug eruption or mimic exanthemas due to infection or other skin diseases.
- Life threatening adverse cutaneous drug reactions include anaphylaxis, toxic epidermal necrolysis and drug hypersensitivity syndrome.
- Exanthematous drug eruption is adverse hypersensitivity reaction characterised by a measles-like exanthem with minimal systemic involvement.
- Drug hypersensitivity syndrome begins within 2 months of initiation of a drug and is characterised by fever, exfoliative dermatitis, haematological and organ involvement.
- Drug-induced urticaria and angioedema may due to several mechanisms and in some cases are accompanied by systemic anaphylaxis.
- Fixed drug eruption is characterised by solitary or multiple plaques or bullae that reappears in the same site within hours of rechallenge with the same drug.
- Drug-induced purpura may be due to coagulation abnormality or vasculitis.
- Drug-induced Stevens-Johnson syndrome / toxic epidermal necrolysis are moderately severe / severe mucocutaneous and systemic reactions.
Think carefully before you prescribe an unnecessary drug! In hospital patients, rashes are commonly attributed to and often caused by medications.
About 3% of patients admitted to hospital have rashes due to adverse drug reactions but in others the cutaneous signs are due to the underlying or intercurrent illness (e.g. viral or bacterial exanthemas or internal disease), non-specific reactions to treatment (e.g. sweat-rash due to prolonged bed rest with plastic sheeting) or independent skin disease that has not been recognised by hospital staff. True drug reactions may mimic other skin diseases. In general, the rash improves when the drug is withdrawn. This may occur quickly but in some cases takes weeks or longer.
Adverse drug eruptions can be dangerous, especially toxic epidermal necrolysis (TEN) and drug hypersensitivity syndrome.
Features indicating a potentially serious reaction include:
- Facial and/or mucous membrane involvement
- Widespread confluent erythema or erythroderma
- Skin pain
- Blistering, purpura or necrosis
- Urticaria that includes tongue or throat swelling
- High fever
- Lymphadenopathy, arthralgias or arthritis
- Abnormal blood count, hepatic or renal dysfunction
- Shortness of breath, wheezing, hypotension
TEN due to allopurinol
TEN due to lamotrigine
TEN due to lamotrigine
Mechanisms of cutaneous reactions to drugs
Immunological hypersensitivities (true allergy)
- Type I anaphylactic reactions: anaphylaxis, anaphylactoid, urticaria, angioedema
- Type II cytotoxic reactions: thrombocytopaenia, TEN
- Type III immune complex mediated reactions: serum sickness, vasculitis
- Type IV cell mediated reactions: morbilliform rash, TEN
Non-immunologic drug eruptions may be due to idiosyncratic reaction, hereditary enzyme deficiency, dose dependent cumulation, irritancy or toxicity. Examples include:
- Eczema craquelé aggravated by diuretics
- Cutaneous atrophy, striae and telangiectasia due to topical or systemic steroids
- Drug-induced alopecia from cytotoxic medications
- Erosions due to topically applied 5-fluorouracil
- Cheilitis, xerosis and dermatitis due to lack of sebum on retinoids
- Lithium-induced psoriasis (mechanism unknown)
- Psoriasis aggravated by Interleukin II, which induces pro-inflammatory cytokines
- Pigmentation due to accumulation of amiodarone within skin
The patient may need to be coaxed to report their drug history. Although adverse reactions are less likely to arise from drugs that the patient has been on for a long period of time, this is not always the case. Suggest these are brought to the clinic for inspection.
Ask about all medications taken in the last three months:
- Prescribed and unprescribed
- Oral, injected, patches, creams, ointments
- Household remedies: laxatives, hypnotics, analgesics
- Herbals, vitamins, homeopathic remedies
It is not possible to memorise all possible causes of all possible drug eruptions. Standard reference handbooks such as the New Ethicals Catalogue and manufacturers’ data sheets include “rash” in the list of potential adverse effects for nearly every drug.
Exanthematous drug reactions
These are often also described as toxic erythema. Features include:
- Abrupt onset 5-10 days after new drug prescribed (or 1-3 days after its reintroduction);
- May be associated with fever and malaise;
- Most often morbilliform i.e. symmetrical erythematous macules and papules, but the rash may be scarlatiniform (tiny red spots) or confluent lesions presenting as large erythematous patches or urticated plaques;
- More likely in patients with infectious mononucleosis, leukaemia or human immunodeficiency virus infection and in those also taking allopurinol (especially to ampicillin and derivatives);
- Can progress to erythroderma or toxic epidermal necrolysis.
Patient with leukaemia and reaction to ampicillin
The suspected drug or drugs should be discontinued, and the rash usually subsides within a week. Unfortunately there are no useful in vitro or in vivo tests to confirm hypersensitivity reactions and re-challenge is not recommended (although it sometimes occurs inadvertently at a later date). May cross-react with other drugs in the same class. Sometimes the rash clears despite continuing the responsible drug or re-challenge is tolerated without adverse reaction.
Drugs that cause exanthematous rashes in >1%
- Record the suspected drug allergy in the drug chart (follow specific hospital procedures)
- Inform the patient, care giver and family doctor
- Complete a CARM adverse drug reactions form. You can download the form from NZ Pharmacovigilance Centre.
- Treat the patient with emollients, hydrocortisone lotion and if very itchy, a sedative oral antihistamine such as promethazine
Exfoliative dermatitis / erythroderma
A morbilliform rash or intertriginous eruption may progress to exfoliative dermatitis (generalised peeling) or erythroderma (red all over), a potentially dangerous reaction. Drugs most often implicated are sulphonamides, penicillin, antimalarials, anticonvulsants and allopurinol.
Drug hypersensitivity syndrome due to allopurinol
Severe reaction to penicillin
Papular eruption due to hydroxychloroquine
Internal organ involvement and fever indicates possible drug hypersensitivity syndrome. This has a mortality rate of about 10%.
Urticaria may occur with or without angioedema.
- Onset arises up to three weeks after first exposure (or minutes on re-challenge).
- May be due to type 1hypersensitivity (e.g. penicillin), sometimes in association with anaphylaxis and constitutional symptoms (respiratory distress, vascular collapse and shock).
- May be due to direct release of inflammatory mediators from mast cells on first exposure to the drug (e.g. opiates, aspirin, NSAID, muscle relaxants).
- ACE inhibitors such as captopril and enalapril may cause recurrent angioedema without urticaria, rarely commencing months or years after the drug was first prescribed.
- Serum sickness is combination of urticaria, fever and arthralgia (sometimes lymphadenopathy, nephritis, endocarditis) and may be due to antibiotics especially cefaclor.
Drugs that cause urticaria in >1%
- Cytostatic agents
- ACE inhibitors
- Calcium channel blockers
Fixed drug eruption
Fixed drug eruption (FDE) refers to solitary or multiple oval plaques that arise over a few hours and may have central blisters. May affect mucosal surfaces such as the genitals and lips. Frequently resolves in a few days leaving purplish hyperpigmentation, then re-erupts in the same site on re-exposure to the causative drug, which is usually a medication taken intermittently such as paracetamol or antibiotics but may also be a food dye.
FDE due to tetracycline
FDE due to cotrimoxazole
Purpuric FDE: cause unknown
Drug-related bleeding into the skin includes:
- Allergic or cytotoxic thrombocytopaenia (platelet count <30x109/l)
- Capillary fragility due to systemic, inhaled or topical corticosteroids
- Capillaritis (unknown mechanism)
- Overdose of anticoagulants often because of drug interaction
- Coumarin necrosis (cutaneous infarction especially in patients deficient in protein C)
- Leukocytoclastic vasculitis (purpura most often affecting lower legs and feet)
Photosensitivity may be due to toxic or immunological mechanisms or both, from systemic or topical exposure to the medication. The rash affects sites of light exposure (UVA), but may spare habitually exposed areas such as the face and hands. Phototoxic reactions will affect everyone if the dose is high enough, and appears like sunburn (e.g. doxycycline, chlorpromazine). Photoallergic eruptions are generally eczematous or lichenoid (e.g. quinine).
Onycholysis may be due to drug-induced photosensitivity.
Photo-onycholysis due to doxycycline
Postinflammatory hypopigmentation due to photosensitivity reaction to quinine
Severe sunburn in a patient taking isotretinoin
Several drugs may slowly induce hyperpigmentation of the skin and mucosal surfaces, due to the deposition of melanin (e.g. ACTH, oestrogen/progesterone, phenytoin), haemosiderin (minocycline), exogenous pigment (minocycline) or unknown mechanisms,
- Pigmentary changes occur on exposed sites in 75% of patients on long-term amiodarone.
- Clofazimine causes a reddish brown pigmentation on light exposed areas and excretions (sweat, urine and faeces).
- Carotenaemia due to ingestion of large quantities of red or orange coloured vegetables causes yellow-orange discolouration most obvious on palms and soles.
- Pigmentation is not uncommon due to antimalarials, bleomycin, cyclophosphamide, busulphan, phenothiazines, silver (argyria), gold (chrysiasis) and iron.
Flagellate pigmentation due to bleomycin (secondary to excoriation)
Blue-black pigmentation minor trauma due to minocycline
Slate-grey pigmentation due to melanin and lipofuscin deposited in patient on amiodarone
Carotenaemia (with normal palm for comparison)
Other patterns of cutaneous reaction to drugs
Pustular psoriasis induced by systemic steroids
Pseudoporphyria bulla due to frusemide in patient with chronic renal failure