The phenomenon of phototoxicity and long-term risks of commonly prescribed and structurally diverse drugs

Abstract

Photosensitivity to structurally diverse drugs is a common but under-reported adverse cutaneous reaction and can be classified as phototoxic or photoallergic. Phototoxic reactions occur when the skin is exposed to sunlight after administering topical or systemic medications that exhibit photosensitizing activity. These reactions depend on the dose of medication, degree of exposure to ultraviolet light, type of ultraviolet light, and sufficient skin distribution volume. Accurate prediction of the incidence and phototoxic response severity is challenging due to a paucity of literature, suggesting that phototoxicity may be more frequent than reported. This paper reports an extensive literature review on phototoxic drugs; the review employed pre-determined search criteria that included meta-analyses, systematic reviews, literature reviews, and case reports freely available in full text. Additional reports were identified from reference sections that contributed to the understanding of phototoxicity. The following drugs and/or drug classes are discussed: amiodarone, voriconazole, chlorpromazine, doxycycline, fluoroquinolones, hydrochlorothiazide, nonsteroidal anti-inflammatory drugs, and vemurafenib. In reviewing phototoxic skin reactions, this review highlights drug molecular structures, their reactive pathways, and, as there is a growing association between photosensitizing drugs and the increasing incidence of skin cancer, the consequential long-term implications of photocarcinogenesis.

Keywords: Drug reaction; Photosensitizing medications; Phototoxicity; Reactive oxygen species; Skin cancer; Ultraviolet light.

Fig. 1.. Clinical photographs of doxycycline-induced phototoxicity.

A 60-year-old male with a chief complaint of a burning and pruritic rash in photo-exposed areas after several weeks of limited sun exposure while on 100 mg doxycycline taken twice a day orally. A & B. The photos show scaly pink to violaceous plaques on the photoexposed aspects of the forearm (A) and neck and upper chest (B) with evidence of excoriations and erosions proximal to the elbow. There is sparing of sun-protected sites, including the folds on the neck and the areas covered by t-shirts of the upper arms and upper chest. (Photos are courtesy of Roswell Park Comprehensive Cancer Center Department of Dermatology).

Fig. 2.

UVA radiation (320–400 nm) is less potent than UVB but is known to reach the dermis due to its longer wavelength, allowing it to interact with medications that deposit in deeper tissue layers. UVB radiation (290–320 nm) has a shorter wavelength and is well-known to induce sunburns. It predominantly penetrates the epidermal layer and is significantly more cytotoxic, with a stronger role in carcinogenesis. The Fig. was created with BioRender.

Fig. 3.. Chemical structure of phototoxic drugs.

Structures of phototoxic drugs: Amiodarone, Chlorpromazine, Doxycycline, Hydrochlorothiazide, Lomefloxacin, Naproxen, Vemurafenib, and Voriconazole. Each of these molecules contains chemical unsaturation – double bonds and aromatic moieties or both – that facilitate the absorption of UV light, producing reactive singlet and triplet electronic states that ultimately lead to the phototoxic reaction in the skin.

Fig. 4.. Mechanisms of phototoxicity.

1) a single electron can be passed to the activated photosensitizer, which leads to the free radical formation and subsequent cellular damage alone, or free radicals can further react with oxygen to generate hydroxyl or peroxyl radicals; 2) the activated photosensitizer transfers energy to oxygen and forms a singlet oxygen, a radical that oxidizes lipids, proteins, and DNA; 3) generation of a photoproduct that acts as a new photosensitizer or cytotoxin. The figure was created with BioRender.

Fig. 5.

Study flowchart.

Fig. 6.. Structure-activity relationships among fluoroquinolones, after Rubinstein, 2001 [177].

The presence in the quinolone nucleus of an ethyl or a cyclopropyl group on the nitrogen at position 1 has the effect of increasing phototoxicity, whereas other organic moieties (aminodifluorophenyl or an isoxazolyl group) yields a drug that has less severe phototoxicity [178]. A methyl group at position 5 increases phototoxicity; an amino group reduces phototoxicity while increasing stability to photoirradiation [179]. Phototoxicity is well known in fluoroquinolones with fluorine or chlorine at position 8, while substitution of a methoxy group is associated with reduced incidence of phototoxicity [–177].