Phototoxicity
Photoallergy
Incidence
High
Low
Amount of agent required for photosensitivity
Large
Small
Onset after exposure to photosensitizer and light
Minutes to hours
24 h or more
Occurs after first exposure
Yes
No
Clinical presentation
Exaggerated sunburn: erythema, edema, vesicles, and bullae; burning, stinging
Distribution: exposed skin only
Acute, subacute, or chronic dermatitis; usually pruritic
Distribution: exposed skin; may spread to unexposed skin
Pigmentary changes
Frequently resolves with hyperpigmentation
Infrequent
Histopathologic features
Epidermal necrosis, dermal edema, sparse inflammatory infiltrate
Epidermal spongiosis; dermal mononuclear cell infiltrate
Cross-reactions to related agents
No
Yes
Phototoxicity
Epidemiology
The exact prevalence of phototoxicity in the general population is unknown; however, frequency in photodermatology referral centers ranges from 5 to 15 %.
Pathogenesis
There are substantial differences in the pathogenesis of phototoxicity compared to photoallergy. All patients exposed to sufficient amounts of a phototoxic drug should, theoretically, develop signs and symptoms of a phototoxic reaction upon light exposure. In contrast, as described later in the chapter, photoallergy occurs only in individuals who have been immunologically sensitized to the photoallergen. Various factors prevent the reaction from occurring in everyone exposed to a particular phototoxic agent. For example, the quantity of drug present within the skin will depend on the route of administration and on individual rates of gastrointestinal absorption along with drug distribution and metabolism. On the other hand, the amount of radiation reaching the skin will depend on a person’s pigmentation, coverage by hair, and thickness of the stratum corneum.
In phototoxic reactions, light interacts with the photosensitizing chemicals in the skin. The interaction excites electrons in the photosensitizer, leading to unstable singlet or triplet states. Energy is transferred from these unstable compounds as they return to ground state. The transferred energy damages cellular components and organelles, and generates reactive oxygen species. Superoxide anion is considered to be the major oxygen species to cause a phototoxic response. Membrane lipids are most readily oxidized, resulting in disruption of the cellular membrane.
Phototoxic reactions can be classified as being photodynamic (oxygen dependent) or non-photodynamic (oxygen independent). Photodynamic chemicals cause damage by reacting with oxygen in their triplet states to form radicals (type I reaction) or by producing singlet oxygen and oxidizing cell components (type II reactions). Quinolones, NSAIDs, tetracyclines, amitriptyline, imipramine, sulfonylureas, hydrochlorothiazide, furosemide, porphyrins, and chlorpromazine are examples of agents that cause photodynamic phototoxic reactions. Nonphotodynamic chemicals cause damage without oxygen requirements. Photoaddition of 8-methoxypsoralen to pyrimidine bases in DNA is an example of a non-photodynamic reaction.
With either mechanism, a photosensitizing agent interacts with UV to produce a biological change at the cellular or subcellular level. Cellular targets of phototoxic responses depend on the distribution of the drug. Topical agents are more likely to cause damage to keratinocytes. Oral or parenteral agents are more likely to damage mast cells or dermal endothelial cells. Lipid solubility affects subcellular targets of phototoxic agents. Hydrophilic substances are more likely to damage the cell membrane, whereas hydrophobic agents are more likely to diffuse into the cell and damage cytoplasmic or nuclear components.
Clinical Features
Exposure to a systemic or topical phototoxic drug in conjunction with exposure to appropriate UVR can produce phototoxicity. One form of phototoxic response is characterized by delayed erythema and edema 8–24 h after radiation exposure and lasts 2–4 days. Psoralens cause this type of phototoxic response. Alternatively, a more rapid, transient erythema, starting within 30 min of light exposure and lasting 1–2 days can occur, as seen with demeclocycline. For the majority of these drugs, phototoxicity occurs with exposure in the UVA spectrum. The most common clinical presentation of phototoxicity is an exaggerated sunburn, with erythema and edema in sun-exposed areas. Vesicle and bullae formation followed by desquamation may occur in more severe cases. The exaggerated sunburn can be followed by localized areas of hyperpigmentation, which can persist for several months after discontinuation of the drug. While some drugs cause hyperpigmentation by causing melanocyte proliferation and migration, such as psoralens, other drugs produce a slate-gray or golden-brown pigmentation from deposition of the drug or its photoproducts in the skin, such as amiodarone.
Agents That Cause Phototoxicity
Many drugs, both topical and systemic, can cause phototoxic response. This section discusses the most common (see Tables 10.2 and 10.3).
Table 10.2
Common topical phototoxic agents
Topical phototoxic agents | Use |
|---|---|
Fluorouracil | Treatment of actinic keratoses |
Furocoumarins (i.e. psoralens) | Topical photochemotherapy |
Retinoids | Treatment of acne and photoaging |
Table 10.3
Common systemic phototoxic agents
Class | Generic names |
|---|---|
Antiarrhythmics | Amiodarone Quinidinea |
Antibiotics | Sulfonamides Tetracyclines Demeclocycline Doxycycline Minocycline Trimethoprim Quinolones Ciprofloxacin Enoxacina Gemifloxacin Lomefloxacina Moxifloxacin Nalidixic acida Norfloxacin Ofloxacin Sparfloxacin |
Antifungals | Griseofulvin Itraconazole Ketoconazole Voriconazole |
Antimalarials | Chloroquine Quininea |
Antineoplastics | Dacarbazine Docetaxelb Fluorouracilb Methotrexateb Paclitaxel Vandetanib Vinblastine |
Calcium Channel Blockers | Amlodipine Nifedipine Diltiazem |
Diuretics | Furosemide Thiazides Bendroflumethiazide Chlorothiazide Hydrochlorothiazide |
Furocoumarins | Psoralens 5-Methoxypsoralen 8-Methoxypsoralen |
Hypoglycemics | Sulfonylureas Acetohexamide Chlorpropamide Glipizide Glyburide Tolazamide Tolbutamide |
NSAIDs | Alkanone derivative Nabumetone Anthranilic acid derivative Mefenamic acid Cyclooxygenase-2 inhibitor Celecoxib Rofecoxib Enolic acid derivative Piroxicama Proprionic acid derivatives Ibuprofen Ketoprofen Naproxen Oxaprozin Tiaprofenic acid Salicylic acid derivative Diflunisal |
Photodynamic therapy | Porfimer Verteporfin |
Psychiatric medications | Clozapine Phenothiazines Chlorpromazine Thioridazine Tricyclics Amitriptyline Desipramine Imipramine |
Other | Dapsone Hypericin (St. John’s Wort) |
Psoralens
Psoralens are well-known drugs with inherent photosensitizing properties that have been utilized for the treatments of diseases such as psoriasis, vitiligo, mycosis fungoides, and atopic dermatitis. Psoralens are used therapeutically with UVA (PUVA) as either systemic preparations or topical agents. Acute adverse side effects of PUVA include erythema, vesicles, pruritus, and nausea; whereas, long-term PUVA therapy is associated with an increased risk of nonmelanoma skin cancer and cataract formation. Other adverse effects include xerosis, pigment changes, actinic damage, premature skin aging, and exacerbation of underlying skin disease. The psoralen-induced phototoxic reaction targets DNA, which is different from most other phototoxic agents, and peaks from 48 to 72 h after exposure to UVA. This timeline is the rationale for administering PUVA photochemotherapy doses 48–72 h apart. The phototoxic response resolves with varying degrees of hyperpigmentation.
Berloque dermatitis is a type of psoralen phototoxicity that occurred more often in the past with the use of perfumes with high concentration of psoralens, usually 5-methoxypsoralen (5-MOP). It was often seen on the lateral neck and preauricular areas.
Tar Products
Tar and tar-based products cause a unique phototoxic response with burning and stinging almost immediately on exposure to sunlight, called “tar smarts.” Although no longer commonly administered, tar-based products such as creams, soaks, and shampoos have been used in some dermatology treatment regimens. Patients treated with these agents should be reminded that sun exposure can cause skin irritation.
Antimicrobials
Antibiotics are a common source of phototoxic reactions. The tetracyclines, a family of anti-inflammatory antibiotics, are one of the most frequent culprits because of the prevalence of their use. Dimethylchlortetracycline (DMCT) was the first tetracycline to be recognized for phototoxicity, which follows a sunburn pattern. Of the two commonly used tetracyclines, doxycycline is a more potent photosensitizer, whereas minocycline has less of a phototoxic effect. The phototoxic response of doxycycline is dose-dependent, with phototoxicity more common at the higher dose of 200 mg/day or above.
The fluoroquinolones, a group of broad-spectrum antibiotics, are also capable of producing a phototoxic reaction. In the late 1980s, the first generation of fluoroquinolones were marketed and labeled as weak photosensitizers. Development of more potent fluoroquinolones has also increased the photosensitivity potential of the antibiotics. Degree of phototoxicity ranges widely among fluoroquinolones due to chemical differences in a side chain in position 8. Levofloxacin and moxifloxacin, two commonly used respiratory fluoroquinolones, have low phototoxic potential, whereas lomefloxacin and sparfloxacin, which have halogens (i.e. fluorine or chlorine) in their side chains, have the greatest phototoxic potential.
The action spectrum of fluoroquinolones-induced phototoxicity is primarily in the UVA range, with some extension into the visible light range. Many fluoroquinolones are rapidly eliminated and do not undergo significant metabolism. For this reason, photosensitivity may be reduced by evening dosing, thus limiting exposure during peak sunlight times. Cystic fibrosis patients have been reported to have a higher incidence of phototoxicity due to ciprofloxacin, perhaps due to their often prolonged courses of therapy.
Voriconazole, a systemic triazole antifungal, can be prescribed for months to years in immunocompromised patients with allogeneic hematopoietic stem cell transplants and chronic graft-versus-host disease. In addition to causing a classic phototoxic reaction, it is noted to increase the risk of hypertrophic actinic keratoses, aggressive cutaneous squamous cell carcinomas and possibly melanoma. Itraconazole has also been reported to cause phototoxic response.
Other phototoxic antimicrobials include ceftazidime, griseofulvin, ketoconazole, and trimethoprim.
Non-steroidal Anti-inflammatory Drugs (NSAIDs)
NSAIDs, although designed to reduce inflammation, are a frequent cause of phototoxicity. Benoxaprofen (no longer on the market due to its cholestatic hepatitis side effect) and piroxicam are commonly reported phototoxic agents in the literature. Benoxaprofen and piroxicam undergo photodecarboxylation to produce a photoproduct. This photoproduct then combines with the parent compound, which results in damage to cell membranes, particularly in mast cells and leukocytes. Ibuprofen, ketoprofen, meclofenamide sodium, naproxen, nabumetone, oxaprozen, sulindac, and tiaprofenic acid are implicated agents. A recent report of naproxen-induced phototoxicity describes a lichenoid reaction in a patient with sunbed exposure. Phototoxicity to naproxen is possibly due to irradiation of extracellular naproxen resulting in oxidative and replicative stress to cells. Singlet oxygen, superoxide radical anion, and peroxyl radical species are thought to be formed through photodegradation pathways of naproxen and nabumetone, leading to cellular effects such as lipid peroxidation.
Psychiatric Medications
Chlorpromazine, a phenothiazine antipsychotic less commonly used than in the past, is known as both a phototoxic and photoallergic drug. Chlorpromazine-induced phototoxicity is dependent on UVA in a dose-dependent manner and quickly resolves following drug cessation. Thioridazine, also a phenothiazine antipsychotic, causes photosensitivity less commonly than chlorpromazine. Long-term, high-dose therapy with either drug can result in slate-gray to violaceous hyperpigmentation in photo-distributed areas.
St. John’s wort (Hypericum perforatum), an over-the-counter agent sometimes used to treat depression, contains the phototoxic agent hypericin.
Antimalarials
Quinine, like chlorpromazine, has also been reported to cause both phototoxic and photoallergic reactions. Quinine, although no longer a first-line agent for malaria, is sometimes used for the treatment of night cramps. The agent occasionally produces an idiosyncratic photodistributed leukomelanoderma. Phototesting demonstrates sensitivity to UVB and UVA in these patients. Uncommonly, hydroxychloroquine also appears to cause phototoxic and photoallergic reactions. A report of phototoxic eruption that progressed to Stevens-Johnson syndrome has been described after ingestion of a combination of antimalarials chloroquine and sulfadoxine pyrimethamine.
Amiodarone
Amiodarone is an antiarrhythmic drug often used when more conventional drug therapy has failed. It has been reported to cause phototoxic reactions in over 50 % of patients taking amiodarone; however, a more recent study found photosensitivity to occur in only 7 of 98 patients. Amiodarone phototoxicity is dose-related and presents as an immediate burning or prickling sensation combined with erythema that rapidly resolves, and then reemerges in 24 h. The phototoxic response is thought to be dependent on UVA and visible light. Elimination half-life is over 200 days, so even if the drug is discontinued, the patient may continue to have problems for months. Its typical phototoxic reaction can often be managed with dose reduction rather than cessation of treatment. Amiodarone phototoxicity frequently is associated with slate-gray pigmentation on sun-exposed areas, which has been shown to be secondary to deposition of a drug metabolite.
Dronedarone is a newer antiarrhythmic drug approved by the U.S. Food and Drug Administration in 2009 for treatment of patients with atrial fibrillation or atrial flutter. It is chemically related to amiodarone but is less lipophilic and has a shorter serum half-life (24 h versus several weeks for amiodarone). These properties limit its potential for adverse effects typically seen with amiodarone. Dronedarone has a substantially lower incidence of phototoxicity (1 %) compared to amiodarone (50 %).
Antihypertensives
Phototoxic antihypertensive agents include diuretics such as hydrochlorothiazide, bendroflumethiazide, and furosemide. The phototoxic dermatitis in thiazides sometimes presents years after starting to take the drug. There are reports of photoleukomelanoderma following thiazide-induced phototoxicity in the Asian population. Bullous photo-eruptions have rarely been reported in association with furosemide. Dihydropyridines calcium channel blockers, (i.e. nifedipine and amlodipine) in addition to an erythematous phototoxicity, can cause an unusual form of phototoxicity with telangiectasias on photo-exposed sites. Phototoxic reactions to quinapril, an angiotensin converting enzyme (ACE) inhibitor, have been reported in the literature. Although ACE inhibitors are considered to be relatively more tolerable anti-hypertensives, the incidence of adverse effects to ACE inhibitors is estimated at 28 %, half of which occurs in the skin.
Retinoids
Isotretinoin and etretinate have been noted to cause phototoxicity, although photo-testing in patients taking these retinoids or applying topical tretinoin have typically been normal. Retinoid-induced thinning of the stratum corneum, allowing for penetration of a larger quantity of UV into the skin, is the likely cause for the development of phototoxicity in these patients. There may be residual photosensitivity after cessation of systemic retinoids due to their longer half-life.
Anti-neoplastic Agents
5-Fluorouracil is an antineoplastic agent used topically to treat actinic keratoses and systemically for a variety of cancers. It causes phototoxicity in the form of erythema and hyperpigmentation. Methotrexate occasionally produces a “recall” of previous UVR-induced erythema; specifically, the patient develops erythema upon taking methotrexate on sites of previous erythema (such as photo-test sites) but no longer exposed to UV. However, photo-testing of patients taking methotrexate has been normal. The mechanism of the “recall” phenomenon remains unclear. Rare reports of a “recall” phenomenon have also been reported with 5-fluorouracil.
Dacarbazine and vinblastine are other antineoplastic agents implicated in photoxic reactions. Recently, UVA-dependent phototoxicity secondary to vemurafenib, a B-RAF inhibitor used for treatment of metastatic melanoma, has been reported. Paclitaxel and docetaxel belong to the taxane class of chemotherapeutics. By stabilizing and preventing breakdown of microtubules, taxanes interfere with cell division. Both agents have been reported to cause phototoxic reactions in conjunction with trastuzumab (a humanized monoclonal antibody against human epidermal growth factor receptor-2) in patients being treated for metastatic breast cancer. Elevation of urinary porphyrin levels suggests an association with porphyrin biosynthesis. A photo-recall phenomenon has been observed with docetaxel.
Phototoxicity followed by hyperpigmentation has been observed with vandetanib. Vandetanib is a multikinase inhibitor of epidermal growth factor receptor, vascular endothelial growth factor receptor, and the RET (rearranged during transfection) kinases currently being tested in cancer treatments. It has been shown to have a number of photosensitive effects in patients treated for metastatic thyroid cancer. Photosensitization was observed in 37 % of patients after a median treatment duration of 8 weeks. Phototoxic reactions ranged from an exaggerated sunburn after moderate sun exposure to severe photodistributed erythematous eruption. Lichenoid eruption, subacute cutaneous lupus erythematosus, erythema multiforme, and positive photopatch test results were also reported.
Porfimer sodium is an intravenous photosensitizer used therapeutically to induce phototoxic damage of systemic tumors. It is associated with a visible wavelength-dependent and persistent photosensitivity that can be severe. Following intravenous injection, patients who have been administered porfimer sodium are advised to avoid bright sunlight and incandescent light for 4–6 weeks. Some patients may develop severe phototoxicity within the infusion arm beyond this period of time, which suggests that the drug persists at a higher concentration, for a longer period of time at the site of injection than elsewhere on the body.
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