The manifestations of drug reactions are very diverse. The following are some types of
drug reactions that cause various types of pigmentation or purpura:
1. Vasculitis (palpable purpura)
• Usually 1–3 weeks after starting drug, but interval may be longer.
• Palpable purpura (small-vessel cutaneous vasculitis) initially on legs but may become
widespread. Purpuric papules may evolve into haemorrhagic blisters or purpuric plaques.
• Other signs may include urticaria, ulcers, and nodules.
• Vasculitis may affect the kidney, liver, GIT, and/or nervous system.
• Consider other causes of a small-vessel cutaneous vasculitis, including infection.
• Common causes: penicillins and other antibiotics, allopurinol, phenytoin, thiazides, and
thiouracils.
• Cocaine, adulterated by levamisole, may induce retiform purpura on the body and
tender purpura of the ears, nose, cheeks, lips, and hard palate, sometimes with necrosis
(vasculitis and/or occlusive vasculopathy).
2. Macular purpura: may be pigmented
• Aspirin, anticoagulants, calcium channel blockers, ACE inhibitors, analgesics.
3. Anticoagulant-induced purpura fulminans and skin necrosis
• Rare, but life-threatening, complication of treatment with warfarin.
• Risk greatest in obese female patients with heterozygous deficiency of protein C or
protein S. Warfarin inhibits protein C and protein S, inducing a hypercoagulable state.
• 3 to 5 days after starting warfarin, painful, erythematous, indurated plaques develop on
fatty areas—breasts, hips, and buttocks. the large, irregularly outlined plaques become
haemorrhagic, bullous, and eventually necrotic. Biopsy shows microthrombin in
capillaries, venules, and veins.
• 3 treatment: stop warfarin; administer vitamin K and/or fresh frozen plasma to restore
levels of protein C/S. use another anticoagulant, e.g. heparin.
• Heparin necrosis is rare. Presents 5–14 days after starting heparin. Erythema at injection
sites (rarely distant sites) progresses to painful necrosis. Platelet aggregation is secondary
to antibodies to heparin–platelet factor 4 complex. Platelets may fall. Stop heparin. Use
non-heparin anticoagulant.
4. Cutaneous hyperpigmentation
• Mechanisms of hyperpigmentation include increased melanin synthesis and deposition
of drug or drug metabolites in the skin.
• Photosensitivity may contribute to the colour change.
• Ask if the colour change was preceded by erythema or itching to differentiate drug-
induced pigmentation from post-inflammatory hyperpigmentation, e.g. after dermatitis,
lichenoid rashes, or fixed drug eruptions, particularly in individuals with dark skin.
• What is the colour and distribution of the change, e.g. is it predominantly in scars or on
light-exposed skin?
• Increased melanin (brown pigmentation) maybe caused by drugs such as cytotoxics,
hydroxycarbamide (hydroxyurea), pegylated IFN (in chronic hepatitis C infection),
ACTH, oral contraceptives (melasma on the face), and some antiretroviral agents
(zidovudine and lamivudine).
• Flagellate brown hyperpigmentation is caused by bleomycin.
• Bluish grey pigmentation (may be worse on light-exposed skin) is caused by drugs such
as minocycline (often in scars or on the shins), phenothiazines, antimalarials, ezogabine
(anti- epileptic), vandetanib, gold, and amiodarone (facial pigmentation with
photosensitivity).
• Orange pigmentation is caused by the antimalarial mepacrine.
• Pink discoloration is caused by clofazimine.
• Facial hyperpigmentation caused by skin-lightening creams containing hydroquinone
(acquired ochronosis).
• Resolution of pigmentation may be very slow (months or years) or pigment may persist,
despite drug withdrawal. Photoprotection is often an important part of management.
5. Oral mucosal pigmentation
• Changes are often seen along the gingival margins but may develop on the lip, tongue,
or palate.
• May be caused by drugs such as oral contraceptives (general darkening), minocycline
(grey-blue), antimalarial drugs (grey-blue), phenothiazines (grey-blue), and ezogabine
(blue-grey).
• Pigmented macules or patches may develop on the tongue in heroin addicts who inhale
smoke.
• A black hairy tongue may be caused by drugs such as oral antibiotics (cephalosporins,
chloramphenicol, clarithromycin, penicillins, sulfonamides), as well as corticosteroids
and antidepressants.
