Why tetracycline cause photosensitivity

The clinical phototoxicity, the rates of photochemical degradation, and the in vitro phototoxicity of the TCs were qualitatively but not quantitatively correlated. Phototoxicity in vitro was partially oxygen-dependent and possibly singlet oxygen is involved. The contribution of photoproducts to the phototoxic process may be the basis for the reported differences between the in vivo action spectrum and the absorption spectrum of demethylchlorotetracycline.

A mechanistic model for in vivo phototoxicity is proposed where the absorption of UVA radiation by TC leads to at least two main processes: i photosensitization by the drug of biologic molecules to cause phototoxicity; ii production of one or more photoproducts which photosensitize by absorption of visible radiation.

Photoallergic reactions are usually delayed in onset and appear sometime after 24 hours of drug administration as a superficial dermatitislike reaction. These reactions may occur even after only one dose. Phototoxic reactions, however, manifest as a more severe burn reaction and may arise within a few hours after the drug is taken.

They usually involve a higher drug dosage than photoallergic reactions do. In these cases, destabilization of the drug structure results in an accumulation of free radicals and localized cell damage. This effect is more extensive than the superficial photoallergic reaction and leads to cell damage at multiple levels of the dermis and epidermis.

People complain of a hot sensation in the affected area and often display redness. In some, this symptom progresses to blistering or peeling. With prolonged use of the drug, some people actually develop skin thickening and skin darkening or a loss of pigment in the area.

Physical sunscreens such as those containing zinc or titanium oxide are preferred because chemical sunscreen may exacerbate the reaction. Cool, wet dressings may help soothe the irritated skin. Oral antihistamines such as diphenhydramine and topical corticosteroids such as hydrocortisone may also provide symptomatic relief.

In extreme cases, corticosteroid therapy with prednisone, an oral tablet, may be required. An important lesson is that every patient should ask their health care provider questions when they receive a prescription for a new drug. Review of the written information provided by your pharmacist or other health care provider should be a careful one.

A limited number of chemicals, for instance fleroxacin, depend mainly on UV-B activation. Although the precise pathogenesis of drug-induced photosensitivity is not completely understood for all of the photosensitizing compounds reported in the literature, several mechanisms play varying roles. Two principal types of reactions are generally accepted, regardless of the route of administration of the photosensitizer: phototoxicity and photoallergy.

In a third category of reaction, photosensitizing drugs may induce or exacerbate disorders such as lupus erythematosus in which photosensitivity plays a prominent role. Phototoxic reactions result from direct cellular damage produced by the photoproducts, provided enough of the chemical and radiation are present.

No immunologic mechanisms are involved in phototoxic reactions, so they can manifest themselves during an initial exposure. Phytophotodermatitis caused by bergamot oil, parsley, celery, dates, and other plants containing the furocoumarins is a classic example of phototoxic reaction Figure 1.

At a molecular level, most phototoxic reactions eg, in the case of acriflavine, porphyrins, chlorothiazide, tetracyclines, nonsteroidal anti-inflammatory agents, quinolones, and certain dyes, such as methylene blue develop in the presence of oxygen, in which free radicals resulting from photo-oxidation and peroxidation processes cause injury to cell nuclei, cytoplasm, and cellular membrane components. Phototoxicity reactions to psoralens, although rarely requiring molecular oxygen, are for the most part oxygen independent.

In those cases, UV-A—induced covalent binding formation of cyclobutane dimers between the chemical and the molecules of DNA occurs. Similar dimers are formed between chlorpromazine and RNA molecules. Most phototoxic eruptions clinically resemble exaggerated sunburns and are characterized by rapid onset of a burning sensation, erythema, edema, and sometimes vesiculation Figure 2. Eruptions develop shortly after exposure to light with intensity increasing in a dose-dependent manner.

Persons with light skin types I and II seem to be more prone to develop phototoxic reactions, whereas in darker skins melanin offers some degree of protection. A distinct type of phototoxic eruption consisting in diffuse pigmentation on light-exposed areas is reported in relation to several drugs, including amiodarone, chlorpromazine, minocycline, and quinine.

The phototoxic effect of some drugs on nails is a well-known phenomenon referred to as photo-onycholysis. The latter may be the only manifestation of photosensitivity.

Pseudoporphyria, a condition clinically similar to porphyria cutanea tarda but lacking abnormalities in porphyrin metabolism, has been described as a variant of a phototoxic reaction in conjunction with sulfonamides, griseofulvin, nalidixic acid, and the tetracyclines. Photoallergy refers to immunologically mediated photosensitivity reactions, in which immediate humoral-mediated hypersensitivity, delayed cell-mediated hypersensitivity, or both develop to a photoactivated compound a drug or chemical transformed into a hapten or a complete antigen during radiation.

Photoallergic drug responses develop only in sensitized persons and are not dose dependent, although a sensitized person is likely to get a stronger reaction with a much higher dose.

The delayed type of photoallergy is more frequent. The pathogenetic mechanisms of photoallergic reactions are quite similar to those seen in allergic dermatitis, ie, the photoantigen hapten is presented by epidermal Langerhans cells to T lymphocytes with all the subsequent features of delayed skin hypersensitivity response of lymphocytic infiltration, release of lymphokines, activation of mast cells, and increased cytokine expression. According to the mode of administration of the photosensitizer, photoallergic reactions can be classified as either contact photoallergic dermatitis or photoallergy induced by systemic agents.

Clinically, drug-induced photoallergic reactions can appear as solar urticaria or as eczematous or lichenoid dermatitis on predominantly light-exposed areas.

In rare instances, however, photosensitivity may persist longer and relapse with minimal UV radiation, despite the lack of contact with the photosensitizing substance. This condition, defined as persistent light reaction, is observed in relation to topical photosensitizers and, more rarely, through systemic photosensitization.

Determining the exact mechanism of a photosensitivity reaction is important because phototoxins can be manipulated and rendered harmless by decreasing the dose or the amount of radiation, whereas photoallergic reactions do not significantly change with alterations in these parameters. These include the phenothiazines, quinolone derivatives, sulfonamides, and thiazide diuretics.

More than 70 drugs have been reported as causing symptoms and serologic markers of lupus erythematosus. Subacute cutaneous lupus erythematosus is the subtype of lupus erythematosus most frequently associated with photosensitivity. Symptoms of subacute cutaneous lupus erythematosus include widespread symmetric superficial lesions, often of the shoulders, upper part of the chest, back, and neck, which evolve into psoriasiform or annular plaques.

There is epidermal-dermal separation because of severe injury to the basal keratinocytes. Those that have include hydrochlorothiazide, griseofulvin, 26 and, more rarely, sulphasalazine. The mechanism of photosensitivity reactions in drug-induced lupus is not well understood. It has been suggested that a drug may interact chemically with self molecules to enhance the immunogenic susceptibility of self antigens and also that these drugs or their metabolites may alter the functioning of immune active cells.

This same antibody system is highly associated with photosensitive lupus erythematosus syndromes, 30 suggesting that photoactive drugs may be synergistic with these antibodies in producing the cutaneous lesions of subacute cutaneous lupus erythematosus. To date, no single method of assaying drug photosensitivity has emerged as the ideal yardstick for establishing photosensitivity.

A panel of in vitro and in vivo assay systems has been established for studying photosensitivity reactions, which taken together have proven useful either to predict or to confirm the photosensitizing hazards of a new compound.

In vitro methods used in preliminary screening for photosensitivity include measurement of UV and visible light absorption spectra of the drug; quantification of its ability to photo-oxidize histidine, to induce photohemolysis, and to inhibit yeast growth and mitogen-induced lymphocytic blast transformation; testing on skin equivalents; mutagenicity testing on different organisms and strains; and ability to bind to a protein carrier, such as serum albumin.

Hairless mouse skin, guinea pig, albino mice, and rat auricular skin and retina are most commonly used for experimentally reproducing human skin response to drugs and UV exposure. Under clinical conditions, the epidemiological data and clinical features are usually conclusive enough for the diagnosis of a photosensitivity drug eruption. Histological findings can be hardly decisive in differentiating phototoxic from photoallergic reactions, but they may be relevant for the diagnosis of lichenoid eruptions, porphyria cutanea tarda, and pseudoporphyria from other idiopathic photosensitivity disorders.

In porphyria cutanea tarda and pseudoporphyria, the direct immunofluorescence testing reveals a characteristic deposition of IgG at the basement membrane zone and around dermal blood vessels Figure 3.

A provisional diagnosis of photoallergic contact is confirmed by the technique of photopatch testing, in which the photosensitizing drug is simultaneously applied at 2 sites, 1 of which is subsequently irradiated. A number of standard photopatch test series exist for screening chemically induced photoallergy.

The ability to cause photosensitivity reactions is a common adverse effect of several anti-infective agents and their derivatives. Most of them are cyclic and tricyclic hydrocarbons, frequently containing an alternative double-bond isoprene or naphthyridine nucleus.

The epidemic incidence of photocontact allergic dermatitis and persistent light eruption they caused in the s rapidly led to their withdrawal from the market in most countries. Since when Epstein 40 first reported photoallergic contact dermatitis following intradermal injection of sulfanilamide, sulfa-derived drugs, including sulfonamide antibacterials, hypoglycemics, and diuretics, have been well-known causes of photosensitivity reactions. A case of phototoxic eruption progressing to Stevens-Johnson syndrome was recently reported 41 after prophylactic ingestion of the antimalarial combination product containing chloroquine and sulfadoxine-pyrimethamine Fansidar , the latter component being incriminated as the cause of this unusual adverse reaction.

Other sulfonamides, such as sulfamethoxazole and the trimethoprim-sulfamethoxazole combination, although known to induce Steven-Johnson syndrome and toxic epidermal necrolysis, are relatively safe in regard to photosensitivity. Sulfasalazine salazopyrin , used in the treatment of rheumatoid arthritis, chronic bowel disease, and other inflammatory diseases, is reported to produce a diffuse hyperpigmentation of the skin in light-exposed areas.

Dapsone formerly diaminodiphenylsulfone , a sulfone antibacterial known for years for its antilepromatous action and currently prescribed in the treatment of several noninfectious dermatoses, was identified in the s as causing photosensitivity.

Sulfonamides should be also considered among drugs capable of exacerbating preexisting hepatic porphyrias and inducing sporadic porphyria cutanea tarda. Several cases of drug-induced porphyria cutanea tarda have been reported in association with the sulfonylurea hypoglycemic drugs tolbutamide and chlorpropamide, which are chemically related to sulfonamide compounds. For many years, griseofulvin has been persistently listed among the systemic photosensitizing drugs. The precise mechanisms of the various photosensitivity reactions it causes are not completely clarified; however, UV-A radiation is responsible for eliciting griseofulvin photosensitivity.

In animal models, griseofulvin in high doses interferes with porphyrin metabolism to cause phototoxic reactions. In humans, griseofulvin has been shown to inhibit heme synthesis, which results in increased urinary porphyrin excretion and appearance of acute hepatic porphyrias, especially in susceptible individuals.

There are also reports of cases of subacute cutaneous lupus erythematosus induction by oral administration of griseofulvin. Tetracycline antibiotics serve as an excellent example of the phototoxic hazards of antibacterial agents.

Among them, chlorderivatives are most frequently reported to cause phototoxicity. In a double-blind crossover study with doxycycline mg twice daily , lymecycline mg twice daily , and placebo, run-in combination with UV-A radiation in a series of 15 healthy volunteers, doxycycline was found to have greater phototoxic potency than lymecycline which is available abroad. The phototoxic reaction was dependent on the dose of doxycycline and the UV-A intensity. Bjellerup and Ljunggren 52 recommend that therapy with doxycycline be avoided during summertime and in sunny climates.

There are differences in the phototoxic potential of tetracycline derivatives in vitro as well. Minocycline did not show hemolytic effect. Common clinical manifestations of tetracycline photosensitivity include sunburn, sometimes with blistering, papular eruption, or both. Photo-onycholysis is a common feature with many tetracyclines, occurring 3 to 6 weeks after drug administration on the distal portion of 1 or several nails. In addition, chromonychia with white, yellow, or brown discoloration of nail plates may be observed Figure 5.

Tetracycline and oxytetracycline have also been reported to cause pseudoporphyria, which manifests with skin fragility, traumatic bullae, scarring and milia formation on sun-exposed areas, and normal porphyrin levels. The effective wavelengths for eliciting phototoreactivity fall in the long UV-A and short visible range nm.

Clinical phototoxicity, the rates of photochemical degradation, and the in vitro phototoxicity of the tetracyclines are qualitatively correlated. The precise mechanisms of tetracycline phototoxicity are not fully understood. In vitro studies have shown that they are dependent on oxygen and complement. The chromophores in the skin are cell membranes, ribosomal proteins, and DNA. The first quinolone drug, nalidixic acid, was introduced as a uroantiseptic in