Excerpt from Drug-Induced Photosensitivity

Synonyms, Key Words, and Related Terms: phototoxicity, phototoxic reactions, photoallergic reactions, photosensitivity reaction, sun exposure, sunburn, UV-A, UVA, UV-B, UVB

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Background

Drug-induced photosensitivity refers to the development of cutaneous disease as a result of the combined effects of a chemical and light. 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).

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

Class	Medication	Phototoxic Reaction	Photoallergic Reaction	Planus Lichenoides Reaction	Pseudoporphyria	Subacute Cutaneous Lupus Erythematosus (SCLE)
Antibiotics	Tetracyclines (doxycycline, tetracycline)	Yes	No	Yes	Yes	No
	Fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin)	Yes	No	No	No	No
	Sulfonamides	Yes	No	No	No	No
Nonsteroidal anti- inflammatory drugs (NSAIDs)	Ibuprofen	Yes	No	Yes	No	No
	Ketoprofen	Yes	Yes	No	No	No
	Naproxen	Yes	No	Yes	Yes	No
	Celecoxib	No	Yes	No	Yes	No
Diuretics	Furosemide	Yes	No	No	Yes	No
	Bumetanide	No	No	No	Yes	No
	Hydrochlorothiazide	Yes	Yes	Yes	No	Yes
Retinoid	Isotretinoin	Yes	No	No	No	No
Retinoid	Acitretin	Yes	No	No	No	No
Hypoglycemics	Sulfonylureas (glipizide, glyburide)	No	Yes	Yes	Yes	No
PDT Pro- photosensitizers	5-aminolevulinic acid	Yes	No	No	No	No
	Methyl-5-aminolevulinic acid	Yes	No	No	No	No
	Verteporfin	Yes	No	No	No	No
	Photofrin	Yes	No	No	No	No
Neuroleptic drugs	Phenothiazines (chlorpromazine, fluphenazine, perazine, perphenazine, thioridazine)	Yes	Yes	Yes	No	No
Neuroleptic drugs	Thioxanthenes (chlorprothixene, thiothixene)	Yes	No	No	No	No
Anti-Fungals	Terbinafine	No	No	No	No	Yes
	Itraconazole	Yes	Yes	No	No	No
	Voriconazole	Yes	No	No	Yes	No
Other drugs	Para-aminobenzoic acid (PABA)	Yes	Yes	No	No	No
	5-FU	Yes	Yes	Yes	Yes	No
	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	No	Yes	No	Yes	No
Sunscreens	Para-aminobenzoic acid (PABA)	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
Fragrances	6-Methylcoumarin	No	Yes	No	No	No

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. 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

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 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.

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.

Frequency

United States

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

International

The incidence is unknown.

Mortality/Morbidity

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. The carcinogenic potential due to prolonged exposure to these photosensitizing drugs has been suggested; its clinical relevance remains to be determined.

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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