Drug-Induced Photosensitivity

Updated: Jun 12, 2018
  • Author: Alexandra Y Zhang, MD; Chief Editor: Dirk M Elston, MD  more...
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Overview

Background

Drug-induced photosensitivity refers to the development of cutaneous disease as a result of the combined effects of a chemical and light. [1] Exposure to either the chemical or the light alone is not sufficient to induce the disease; however, when photoactivation of the chemical occurs, one or more cutaneous manifestations may arise. These include phototoxic and photoallergic reactions, a planus lichenoides reaction, pseudoporphyria, and subacute cutaneous lupus erythematosus. Photosensitivity reactions may result from systemic medications and topically applied compounds (see Table 1 below).

UV-A–associated phototoxicity is also common with vemurafenib, [2, 3, 4] with reduced UV-A minimal erythema dose in 94% of those tested. [2]

Wavelengths within the UV-A (320-400 nm) range and, for certain compounds, within the visible range, are more likely to cause drug-induced photosensitivity reactions, although occasionally UV-B (290-320 nm) can also be responsible for such effects. UV-B wavelengths are most efficient at causing sunburn and nonmelanoma skin cancer. In patients who present with photosensitivity, it is often difficult to differentiate phototoxic from photoallergic reactions. However, they have a number of distinguishing characteristics (see Table 2 below).

Table 1. Common Photosensitizing Medications (Open Table in a new window)

Class

Medication

Photo-toxic Reaction

Photo-allergic Reaction

Lichenoid Reaction

Pseudo-porphyria

Subacute Cutaneous Lupus Erythematosus

Antibiotics

Tetracyclines (doxycycline, tetracycline)

Yes

No

Yes

Yes

No

Fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin) [5]

Yes

No

No

No

No

Sulfonamides

Yes

No

No

No

No

Nonsteroidal anti-inflammatory drugs [6]

Ibuprofen

Yes

No

Yes

No

No

Ketoprofen [7]

Yes

Yes

No

No

No

Naproxen [8]

Yes

No

Yes

Yes

No

Celecoxib [9]

No

Yes

No

Yes

No

Diuretics

Furosemide

Yes

No

No

Yes

No

Bumetanide

No

No

No

Yes

No

Hydro-chlorothiazide

Yes

No

No

No

Yes

Retinoid

Isotretinoin

Yes

No

No

No

No

Acitretin

Yes

No

No

No

No

Hypoglycemics

Sulfonylureas (glipizide, glyburide) [5]

No

Yes

Yes

Yes

No

HMG-CoA* reductase inhibitors

Statins (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin) [10]

Yes

Yes

Yes

Yes

No

Epidermal growth factor receptor inhibitors

Cetuximab, panitumumab, erlotinib, gefitinib, lapatinib, vandetanib [11]

Yes

Yes

Yes

Yes

No

BRAF inhibitors Vemurafenib, [2, 3, 4, 12] sorafenib Yes No No No Yes

Photodynamic therapy prophoto-sensitizers

5-Aminolevulinic acid [13]

Yes

No

No

No

No

Methyl-5-aminolevulinic acid

Yes

No

No

No

No

Verteporfin [14]

Yes

No

No

No

No

Photofrin [15]

Yes

No

No

No

No

Neuroleptic drugs [16]

Phenothiazines (chlorpromazine, fluphenazine, perazine, perphenazine, thioridazine) [17]

Yes

Yes

Yes

No

No

Thioxanthenes (chlorprothixene, thiothixene)

Yes

No

No

No

No

Antifungals

Terbinafine

No

No

No

No

Yes

Itraconazole

Yes

Yes

No

No

No

Voriconazole [18, 19, 20, 21]

Yes

No

No

Yes

No

Griseofulvin

Yes

Yes

No

No

Yes

Other drugs

Para-aminobenzoic acid

Yes

Yes

No

No

No

5-Fluorouracil

Yes

Yes

Yes

Yes

No

Paclitaxel [6, 22]

Yes

No

No

No

Yes

Amiodarone

Yes

No

No

Yes

No

Diltiazem

Yes

No

No

No

Yes

Quinidine

Yes

Yes

Yes

No

No

Hydroxychloroquine

No

No

Yes

No

No

Coal tar

Yes

No

No

No

No

Enalapril

No

No

No

No

Yes

Dapsone

No

Yes

Yes

Yes

No

Oral contraceptives [23, 24]

No

Yes

No

Yes

No

Sunscreens [25]

Para-aminobenzoic acid

No

Yes

No

No

No

Cinnamates

No

Yes

No

No

No

Benzophenones

No

Yes

No

No

No

Salicylates

No

Yes

No

No

No

Fragrances

Musk ambrette

No

Yes

No

No

No

6-Methylcoumarin

No

Yes

No

No

No

*3-Hydroxy-3-methylglutaryl coenzyme A.

Phototoxic reactions occur because of the damaging effects of light-activated compounds on cell membranes and, in some instances, DNA. By contrast, photoallergic reactions are cell-mediated immune responses to a light-activated compound. Phototoxic reactions develop in most individuals if they are exposed to sufficient amounts of light and drug. Typically, they appear as an exaggerated sunburn response, as shown in the image below.

Phototoxic reaction. Phototoxic reaction.

Photoallergic reactions resemble allergic contact dermatitis, with a distribution limited to sun-exposed areas of the body. However, when the reactions are severe or prolonged, they may extend into covered areas of skin.

Table 2. Distinguishing Characteristics of Phototoxic and Photoallergic Reactions (Open Table in a new window)

Feature

Phototoxic Reaction

Photoallergic Reaction

Incidence

High

Low

Amount of agent required for photosensitivity

Large

Small

Onset of reaction after exposure to agent and light

Minutes to hours

24-72 hours

More than one exposure to agent required

No

Yes

Distribution

Sun-exposed skin only

Sun-exposed skin, may spread to unexposed areas

Clinical characteristics

Exaggerated sunburn

Dermatitis

Immunologically mediated

No

Yes; Type IV

 

Photoallergic reactions develop in only a minority of individuals exposed to the compound and light; they are less prevalent than phototoxic skin reactions. The amount of drug required to elicit photoallergic reactions is considerably smaller than that required for phototoxic reactions. Moreover, photoallergic reactions, as shown in the image below, are a form of cell-mediated immunity; their onset often is delayed by as long as 24-72 hours after exposure to the drug and light. By contrast, phototoxic responses often occur within minutes or hours of light exposure.

Photoallergic reaction. Photoallergic reaction.
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Pathophysiology

Phototoxicity

Phototoxic reactions result from direct damage to tissue caused by a photoactivated compound. Many compounds have the potential to cause phototoxicity. Most have at least one resonating double bond or an aromatic ring that can absorb radiant energy. Most compounds are activated by wavelengths within the UV-A (320-400 nm) range, although some compounds have a peak absorption within the UV-B or visible range.

In most instances, photoactivation of a compound results in the excitation of electrons from the stable singlet state to an excited triplet state. As excited-state electrons return to a more stable configuration, they transfer their energy to oxygen, leading to the formation of reactive oxygen intermediates. Reactive oxygen intermediates such as an oxygen singlet, superoxide anion, and hydrogen peroxide damage cell membranes and DNA. Signal transduction pathways that lead to the production of proinflammatory cytokines and arachidonic acid metabolites are also activated. The result is an inflammatory response that has the clinical appearance of an exaggerated sunburn reaction.

The exception to this mechanism of drug-induced phototoxicity is psoralen-induced phototoxicity. Psoralens intercalate within DNA, forming monofunctional adducts. Exposure to UV-A radiation produces bifunctional adducts within DNA. Exactly how bifunctional adducts cause photosensitivity is unknown.

Photoallergic reactions

Photoallergic reactions are cell-mediated immune responses in which the antigen is a light-activated drug. Photoactivation results in the development of a metabolite that can bind to protein carriers in the skin to form a complete antigen. The reaction then proceeds exactly as other cell-mediated immune responses do. Specifically, Langerhans cells and other antigen-presenting cells take up the antigen and then migrate to regional lymph nodes. In those locations, the Langerhans cells present the photoallergen to T lymphocytes that express antigen-specific receptors. The T cells become activated and proliferate, and they return to the site of photoallergen deposition. In the skin, the T cells orchestrate an inflammatory response that usually has an eczematous morphology if the photoallergen is applied topically or the characteristics of a drug eruption if the photoallergen is administered systemically.

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Etiology

Most phototoxic reactions result from the systemic administration of drugs. Photoallergic reactions can be caused by either topical or systemic administration of the chemical. Compounds that commonly cause phototoxic and/or photoallergic reactions are listed in Table 1 in Background.

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Epidemiology

Frequency

United States

The incidence of drug-induced photosensitivity in the United States is uncertain. Phototoxic reactions are considerably more common than photoallergic reactions.

International

The incidence of drug-induced photosensitivity is unknown.

Race

The racial incidence of drug-induced photosensitivity reactions is unknown. Photosensitivity reactions can occur in races with heavily pigmented skin.

Sex

Men are more likely to have photoallergic reactions than women.

Age

Drug-induced photosensitivity reactions can occur in persons of any age.

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Prognosis

In most patients, the prognosis is excellent once the offending agent is removed. However, complete resolution of the photosensitivity may take several weeks to months with some compounds. Occasionally, patients have persistent light reactivity for which the prospects for resolution are poor.

Drug-induced photosensitivity is associated with death only in rare individuals who are exposed to large amounts of sunlight after taking large doses of psoralens. Although mortality is rare, drug-induced photosensitivity can cause significant morbidity in some individuals, who must severely limit their exposure to natural or artificial light.

Voriconazole photosensitivity is associated with a risk of skin cancer. [26, 27] The changes that occur with long-term exposure resemble accelerated photo-aging. Acute photosensitivity occurs in 1–2% or more of patients taking voriconazole for more than 12 weeks. It appears to be UV-A induced, but it is not strictly dose-dependent. Cheilitis and facial erythema are typical initial manifestations.

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Patient Education

Patients need to be counseled regarding the possible photosensitizing properties of both prescription and nonprescription medications. Most often, appropriate sun protection measures prevent drug-induced photosensitivity reactions.

For patient education resources, see the Burns Center, as well as Sunburn.

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