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Drug-Induced Photosensitivity
Drug-Induced Photosensitivity By Edward Stempel and Rina Stempel
An
article on suntan preparations in Consumer Reports evaluated some sun-protective preparations and . provided suntan precautions by indicating that certain drugs and chemicals can increase the skin's sensitivity to solar radiation. Precaution against solar · radiation while using . certain drugs was also indicated in the July 5, 1971, issue of Drug Topics through the use of a picture of a huge sign which was posted on the window of a Buffalo, New York, pharmacy stating, "Certain Drugs Cause Sensitivity · to Sunlight." Articles in pharmacy journals have not publicized the drugs which induce photosensitivity although the lay press and medical journals have; therefore, the following provides the pharmacist with some information.
L'\.. the July 1971
Photosensitization A photodynamic action implies all forms of change which are evoked by the energy of light. Photosensitivity refers to a reaction in which a foreign substance in a biological system initiates an observable change by means of its absorption of light. The foreign substance is known as a photosensitizer! or photosensitizing-drug molecule.
and vesiculation. These investigators also believe that the majority of drugs that cause phototoxic reactions are resonating aromatic rings with a molecular weight ranging from 200 to 500. Usually, within 24 to 48 hours after administration of a phototoxic drug and adequate exposure to the proper wavelengths of light, the toxic response is erythematous and sunburn-like ·and is accompanied by coincident or isolated dermal injury revealed by urticaria. 5 A photoallergic reaction results when the photosensitizing-drug molecule absorbs quantity of light of a specific wavelength and leads to a photochemical change in the drug which then results in the formation of an allergenic compound;6 . Burkhardt7 likewise postulated that photons of electromagnetic energy react with the ingested drug to create a "new" molecule, but more specifically indicated that it acts as a haptene to form a unit with antigenic potential by probably combining with cutaneous proteins. The compounds
metabolized or conjugated with a protein form a photosensitizing substance with an absorption spectrum different from that of the administered drug. 8 Photoallergic reactions occur only after an incubation period of sensitization, may occur at unexposed sites distant from the site of light exposure and may result in cross-photosensitivity to immunochemkally related allergens. 9 The clinical manifestations are likely to be eczematous, urticarial, lichen planuslike or may resemble a sunburn; furthermore, hypersensitivity to light may continue months after the drug itself has been withdrawn. 8 Baer and Harber7 have illustrated their concept of the mechanisms of photosensitization through the use of a schematic presentation (Figure 1, below), and Daniels!O has provided a summary in table form of some factors regarding phototoxic and photoallergic dermatoses (Table I, page 201). A comprehensive listing of photosensitizing agents appears in Table II, (page 202).11 Table III (page 203)
FIGURE 1
Mechanisms of Photosensitization PHOTOSENSITIZING DRUG
I
.Absorption of Electromagnetic Energy (f hotons)
Phototoxic vs. Photo-allergic Skin Reactions PHOTOTOXIC
A photosensitizer which is ingested or applied topically can alter the reactivity of the skin to cause either a photo toxic or photoallergic reaction. In 1905 Albert Einstein proposed that light is propagated through space· as photons, each of which has a quantum of energy.2 Blum indicated that the absorbed photons of light give the absorbing molecules a higher energy content. 3 Baer and Harber 4 believe that the absorbed energy may be re-emitted in the form of harmless fluorescent or phosphorescent radiation or become part of a photochemical reaction that results in the transfer of energy to adjacent cells to cause a phototoxic reaction or biological change ranging from heating of tissue to severe cellular damage manifested by erythema, edema 200
PHOTOALLERGIC
{-
1-
Change in photosensitizer from ground energy state to excited singlet or triplet energy state
Oxidative formation of "new" compound (haptene)
Transfer of energy
Formation of full antigen (Conjugation of haptene with protein)
~
!
Formation of free radicals, peroxides, and heat
tell
Alteration in membrane, cytoplasm and/or nucleus
1 t
Antigen engenders formation of cellular or humoral antibodies Antigen-antibodt reaction upon reexposure to drug plus light
~~ cell ular damage Sunburn-type
re~
~n
of varied
morphology
Source: Baer, R. L. and Harber, L. C., "Photosensitivity Induced by Drugs," JAMA, 192,990 (1965)
Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION
Edward Stempel is professor and chairman of the pharmacy department of Brooklyn College of Pharmacy. He received his BS cum laude from Brooklyn College of Pharmacy, his MS from Columbia University college of pharmaceutical sciences, and his MA and EdD from Teachers College, Columbia University. Stempel practices community and hospital pharmacy. He was a contributing author for the fifth and sixth editions of Husa's Pharmaceutical Dispensing and the seventh edition of Dispensing of Medication. He has written numerous articles on pharmacy and pharmaceutical education and is listed in American Men of Science, Dictionary of International Biography, Who's Who in American Education, and Who's Who in the East.
indicates the type of photosensitivity reaction as well as the route of exposure. 4 Tetracyclines
DeVeber and Lepper indicated that photosensitivity as a side effect of chlortetracycli"ne was considered for a long time to be dependent, at least in part, on the substitution of chlorine in the tetracycline nucleus; however, the photosensitivity due to the nonchlorinated forms upset that theory.12 The use of 500 mg of oxytetracycline q.i.d. for three days was reported to cause redness, swelling and itching in the skin areas exposed to sunlight. Since the patient remained photosensitive for at least one-half year after the cessation of therapy, Tromovitch and Jacobs 13 believe that the photosensitive reaction is probably photoallergic rather than phototoxic. Photosensitivity has also been reported for tetracycline; however, more photosensitivity reactions have been reported following the use of demethylchlortetracycline (DMCT). A letter from Lederle, published in JAMA (172, 1196, 1960), reported 40 patients (in a total of 2,682 reports from 1,354 physicians) in whom dermatitis developed from DMCT following exposure to bright sunlight. 14 Kligman,15,16 in a 1962 report from the same manufacturer, indicated that a one-hour midday exposure to sunlight produced mild to severe evidence of phototoxicity in 43 of 89 subjects who received 150 mg of DMCT q.i.d. for seven to ten days, and subsequent studies showed that reduced dosage produced fewer phototoxic reactions. Discontinuance of the drug resulted in a milder phototoxic reaction within 24 hours, and complete remission occurred in two more days. Since 23 of the DMCT phototoxic subjects show no reaction with either tetracycline or chlortetracycline (i.e., no cross-photosensitization), it was construed that the reaction was phototoxic and not photoallergic. For a period of one week, Blank et a/. l7 gave 30 volunteers 600 mg of DMCT per day, 200 mg of doxycycline (Vibramycin) per day, or a placebo each day. Then he took them on a voyage designed to maximize sun exposure; nine of the ten receiving DMCT developed photosensitive eruptions, two of the ten receiving doxycycline were also positive, while one volunteer receiving the placebo was doubtful. The results supported the concept that DMCT was a powerful photo toxicant and suggested that doxycycline in the doses used will cause a lower incidenc.e of this annoying side effect. An unusual form of phototoxic reaction seen in a small number of persons who take large doses of DMCT is
Rina Stempel received her BS and MS degrees from Brooklyn College. She is presently assistant principal (supervision), health and physical education, at Samuel J. Tilden High School in Brooklyn, New York. Besides conducting methods of teaching courses for the New York City Board of Education and Brooklyn College, she has conducted and coordinated drug abuse programs, and is also active in health and educational organizations.
fingernail changes described as photoonycholysis which manifests itself about four weeks subsequent to combined ingestion of the drug and adequate exposure of the fingernails to sunlight. However, improvement occurs spontaneously two to three months after
avoidance of both the drug and sunlight. 18 Nail discoloration and onycholysis have also been reported as a result of the combination of sunlight and either tetracycline or chlortetracycline. 14 In 1965, it was reported 19 that FDA
TABLE I
Spontaneous and Drug-Induced Photo toxic and Photoallergic Dermatoses ...
Population
Exposure
Morphology
Pigment
Photopatch Tests Flare
Specificity
Spectroscopic Characteristics of the Photosensitizer
Clinical Features
Phototoxic
Photoallergic
Elicited in all persons receiving adequate dose of chemical and active wavelengths of radiation. May occur on first combined drug and light exposure.
Occurs in only a small percentage of those exposed to drug and sunlight. Occurs only after an incubation period of com bined drug and exposure (with exception of cross reaction with an earlier similar chemical). Often has morphology of other allergic reactions including eczema. Melanin equal to or less than expected for the same degree of erythema seen in sunburn.
Often resembles an exaggerated sunburn but may be urticarial or consist of a persistent erythema. Several of the phototoxic reactions produce intense melanization in relationship to degree of earlier erythema. Reproduce phototoxic reaction. Reactions confined to the area of combined chemical and light exposure. Reaction produced only by chemicals producing direct photosensitization effects. Chemical usually has an absorption spectrum in ultraviolet longer than 0.32 microns or in visible spectrum. These reactions occur at wavelengths where tissue is transparent and photosensitizer may be assumed to be the chromophore (initial absorber).
Erythema, dermatitis or bullae followed by pigmentation and depigmentation. May have no pain or itch. Generally fills area of combined chemical and light exposure uniformly.
Lesions with characteristics of allergic reactions. Flare-ups can occur in unexposed areas distant from the site of light exposure. Photo-cross sensitization to chemically related allergens may be found. Many of the reactions are produced by wavelengths shorter than 0.32 microns, i.e., the sunburn spectrum. Since these reactions occur where tissue as well as chemicals absorb radiations, the chemicals may act in any part of the reaction as well as trigger different photochemical events. Often dermatitis without pigmentation and with severe pruritus. Most prominent in exposed areas, but intensity often irregular as in papular and nodular types.
Source: Daniels, F., Jr., "Diseases Caused or Aggravated by Sunlight," Medical Clinics of N. A ., 49, 571 (1965)
Vol. NS13, No.4, April 1973
201
Glossary Cross Sensitivity-Susceptibility to sensitivity to a substance which is structurally related to another substance which causes a sensitizing reaction. Furocoumarins-Naturally occurring photosensitizers which are found in some plants allover the world. Photoallergic-A reaction which is initiated by an allergenic compound which is formed when a foreign substance absorbs light of a specific wavelength . Photochemical-The influence of light in causing a chemical change. Photon-A bundle of light-energy or a particle of light analogous to an electron. Photo-onycholysis-Loosening or separation of a nail from its bed due to sensitivity to light. Photosensitivity-A reaction in which a foreign substance in a biological system initiates an observable change due to absorption of light of a specific wavelength. Phototoxicity-A reaction initiated by a photochemical change and resulting in transfer of energy to adjacent cells. The result is heating of tissue to severe cellular damage. Phytodermatitis-A skin reaction caused by a combination of external contact to plants or plant products and exposure to light of a specific wavelength.
TABLE II
Photosensitizing Agents of Interest to the Dermatologist (Adapted from a list of photosensitizing agents prepared by Capt. James W. Young, USAF (MC)-Bull. Assn. Mil. Dermal., 13, 33, 1964) I. DRUGS 1. Antidiabetic agents (oral): including carbutamide, tolbutamide, chlorpropamide (Nadisan, Diabinese, Orinase, Ora betic) 2. Anesthetics: the procaine group of local anesthetics 3. Antibiotics: including tetracyclines and their derivatives: chlortetracycline (Aureomycin), oxytetracycline (Terramycin), demethylchlortetracycline (Declomycin) and griseofulvin (a penicillium derivative) 4. Antihistaminics: including diphenhydramine hydrochloride (Benadryl), promethazine (Phenergan), tripyrathiazine hydrochloride (Pyrrolazote), isothipendyl (Theruhistin) 5. Anticonvulsants: Tridione and Dilantin 6. Arsenicals 7. Barbiturates 8. Hormonal substances: including estrone and diethylstilbestrol 9. Topical antibacterial agents (antiseptics): Bithional, hexachlorophene, tetrachlorsalicylanilide (TCSA), tribromsalicylanilide (TBS) 10. Phenothiazine derivatives: including chlorpromazine (Thorazine), prochlorperazine (Compazine), mepazine (Pacatal), perphenazine (Trilafon), trimeprazine (Temaril), triflupromazine (Vesprin), promazine (Sparine), thiopropazote dihydrochloride (Dartal) 11. Psoralens: Furocoumarin derivatives, including 5-methoxypsoralen, 8-methoxypsoralen, and others 12. Sulfonamides: including sulfacetamide, sulfadiazine, sulfaguanidine, sulfamerazine, sulfamethazine, sulfapyridine, sulfathiazole, sulfadimethoxine 13. Sulfonylureas: see oral antidiabetic drugs above 14. Thiazide diuretics (aromatic sulfonamide preparations): chlorothiazide (Diuril) and hydrochlorothiazide (Hydrodiuril) 15. Heavy metals: gold and silver salts 16. Porphyrins: hematoporphyrin (used to treat melancholia), chlorophyll 17. Miscellaneous: digalloy I trioleate, monoglycerol para-amino benzoa te, p-dimethylaminoazobenzene, phenylbutazone, quinine, stilbamidine, salicylates, Lantinin, PerIoline, dicyanine-A, 5-fluorouracil, triethylene melamine (TEM), 9-aminoacridine II. DYES: 1. Acridine dyes-including acridine, trypaflavine and others 2. "Blankophores" (optical brighteners- mainly sulfa derivatives) 3. Dibenzopyran derivatives-eosin, fluorescein dyes, rose bengal and others 4. Paraphenylenediamine 5. Phenothiazine dyes (methylene blue, toluidine blue, others) 6. Phenoxazine dyes 7. Phenazine dyes 8. Trypan blue III. COAL TAR PRODUCTS AND PETROLEUM PRODUCTS: crude coal tar and its derivatives (benzene, anthracene, xylene, naphthalene, toluene, phenanthrene, thiophene, phenolic compounds, pyridine, and others). Pitch and pitch fumes. IV. ESSENTIAL OILS AND OTHERS: including, oil of bergamot, oil of cedar, oil of citron, oil of lavender, lime oil, vanillan oils, other agents included in various perfumes and cologne water. V. PLANTS: mainly members of the Umbelliferae family including: parsnips, carrots (wild and garden types), celery, yarrow, angelica, fennel, dill and parsley. Members of the Rutaceae (rue, bergamot and lime, wafer ash) meadow grass, clover mustards, agrimony, bavachi (corylifolia) Agave lechiguilla-a perennial flowering plant of the Amaryllis family, related to A. belladonna Lantana: a shrub of the Verbenae family Lady's thumb and smartweed: flower herbs of the buckwheat family Source: (1964)
202
Kirshbaum, B. A., and Beerman, H., "Photosensitization Due To Drugs," Amer. J. Med. Sc., 248, 450
Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION
would require package inserts for all tetracyclines to carry a warning that hypersensitive persons may develop photodynamic reactions from exposure to natural or artificial sunlight while using these drugs, and that persons with a history of a photosensitivity reaction should be instructed to avoid direct exposure to sunlight while under treatment with tetracycline drugs. Most package inserts thereafter indicated either a phototoxic or photoallergic reaction even though it was not until September 2, 1970, that the Federal Register indicated the requirement of a warning regarding "photosensitivity." Sulfonamides
After the introduction of sulfanilamide in the mid-1930's, a number of reports of its photosensitizing activity appeared. 20 Sams 21 indicated there are nearly 40 sulfanilamide preparations which have been used for their chemotherapeutic effects, and many of them have been found to have a photosensitizing action when used topically or systemically. Cross-photosensitivity has been demonstrated in some patients who have shown photosensitization due to compounds chemically related to the sulfonamide group - p-aminobenzoic acid (sometimes used as a sun-screen agent), local anesthetics of the procaine group, p-phenylenediamine,20 and monoglyceryl p-aminobenzoate 22 (sometimes used as a sunburn preventive). Sulfonylurea Hypoglycemics
The oral hypoglycemic sulfonylureas were introduced for the control and treatment of diabetes. The three sulfonylurea derivatives which have been popular are chlorpropamide (Diabinese), tolbutamide (Orinase) and tolazamide (Tolinase). Patients who take these drugs over an extended period may feel that the drugs cannot be the cause of subsequent reactions on the skin; therefore, they may fail to inform the examining physician of these medicaments which they take routinely. 21 It appears probable that chlorpropamide is metabolized or conjugated with protein to form a photosensitizing substance having a different absorptive spectrum than that of chlorpropamide. 23 Further evidence of a photoallergic mechanism is that ingestion of tolbutamide may be responsible for crossphotosensitization to chlorpropamide. 24 Thiazides
The thiazides- chlorothiazide and hydrochlorothiazide-are aromatic sulfonamide-type preparations with closely related structural formulas. They have a diuretic effect and have been used in edema, hypertension and
in reducing the weight of obese patients. Reports indicate that they are potent photo sensitizers, and both a photo toxic and photoallergic mechanism are involved in the production of various types of dermatitis. 25 Harber, Lashinsky and Baer 26 indicated that their clinical study showed that the photosensitivity reaction to either diuretic has many features in favor of a photoallergic mechanism. However, the possibility cannot be excluded that metabolism of the drug after ingestion results in a phototoxic compound that is not formed on the skin after topical application or in the skin after intracutaneous injection. Baer and Harber 27 believe that the biochemical mechanism of photoallergic sensitivity of the chlorothiazide in man may be due to (1) formation of other oxidation products of chlorothiazide in the skin or (2) photochemical precursors produced elsewhere than in the skin. 27
Phenothiazines The phenothiazine derivatives have been used (1) as a sedative, (2) as an antihistaminic, (3) for the control of nausea and motion sickness and (4) for the management of patients with psychiatric disorders. Phenothiazine was first noted in 1940 to cause intolerance to sunlight in agricultural workers who were using it as an insecticide as a spray to destroy the coddling moth. 28 A number of cross-sensitivities have been demonstrated between compounds included in the phenothiazine group; these are denoted in Table IV (right). 29 Many of the photosensitizing compounds consist of three aromatic rings in a linear configuration, and substitutions in the center ring with sulfur or nitrogen lead to an increase in photosensitizing capacity as seen with methylene blue and the phenothiazine compounds. 30 Like methylene blue, phenothiazine has both a sulfur and nitrogen substituted for two carbons in the center ring of anthracene. In two cases of photosensitivity to a water-insoluble chlorphenothiazine, Jung et al. 31 demonstrated that the allergic effect of this compound is not entirely dependent on the substitution at the nitrogen ring but also has a relation to the heterocyclic ring structure of phenothiazine. Chlorpromazine manifests two different reactions to sunlight-photoallergic and phototoxic. The photoallergic reaction manifests itself as an urticarial maculopapular eruption or eczematous reaction of the skin of the exposed areas of the body after an incubation period, and can occur in persons taking small amounts of medication. The phototoxic reaction can occur in most indi-
TABLE III
Drugs and Other Agents That Produce Photosensitivity Reactions
Photosensitizer Coal tar derivatives Anthracene, Acridine, Phenanthrene, Pyridine Antiseptics Bithionol (bisphenol) Tetrachlorsalicylanilide (Impregon) Diuretics Thiazides and related sulfonamide compounds Tranquilizers Chlorpromazine (Thorazine) Antibiotics Demethylchlortetracycline hydrochloride (Declomycin) Sunscreening agents Digalloyl trioleate (Neo-A-Fil) Amino benzoic acid Antijunga!s Griseofulvin (Fulvicin, Fulvicin VIF, Grifulvin, Grifulvin V, Grisactin, Griseoful yin) N-butyl-4 chlorosalicylamide (jadit) Antihistamines Promethazine Hydrochloride (Phenergan Hydrochloride) Antibacterials Sulfonamides Oral hypoglycemic agents Chlorpropamide (Dia binese) Tolbutamide (Orinase) Miscellaneous agents Furocoumarins t
Probable Mechanism of Action
Usual Route of Exposure
Phototoxic
Topical
Photoallergic Photoallergic
Topical
Photoallergic
Oral
Photo toxic, * Photoallergic
Oral
Phototoxic* (Photoallergic ?)
Oral
Photoallergic Photoallergic
Topical
Photoallergic
Oral
Photoallergic
Photoallergic
Topical Oral
Phototoxic, * Photoallergic
Oral Topical
(Photoallergic ?)
Oral
Phototoxic
Topical
* Protection
t
usually afforded by window glass. Found in fruits, perfumes; used to treat vitiligo.
Source:
Baer, R. L., and Harber, L. C., "Photosensitivity Induced by Drugs," JAMA, 192, 989 (1965)
viduals provided there is an adequate concentration of the photosensitizer in the living epidermal cells, an exposure to a specific band of light and the presence of oxygen. 32 Ayd 33 stated in 1956 that there is apparently no relationship between the incidence of photosensitivity and the dosage of chlorpromazine. Satanove 34 reported in 1965 that 78 out of thousands of patients at a specific mental hospital developed pigmentary changes (ranging from tan to slate blue to a deep blue-black or purple color) after high doses of chlorpromazine and related phenothiazines over long periods of time and after exposure to sunlight. The two factors in the production of pigment are an increase in melanin and the presence of a purplish-colored substance in the skin. The increase in melanin can be explained by the action of ultraviolet light on a photosensitizing drug such as the chlorpromazine in the skin. 35 The serious photosensitivity of pigmentation due to the phenothiazines is considered irreversible but evidence suggests that in some cases it can be
TABLE IV
Phenothiazines Showing CrossSensitivity Trade Name
Generic Name
Compazine Dartal Pacatal Phenergan Pyrrolazote Temaril Theruhistin Thorazine Trilafon Vesprin
prochlorperazine thiopropazate dihydrochloride mepazine promethazine hydrochloride pyrathiazine hydrochloride trimeprazine isothipendyl chlorpromazine perphenazine trifl upromazine
reversed by confining the patient in a dark room or by the use of a chelating agent such as d-penicillamine (Cuprimine-Merck, Sharp & Dohme).36 Patients who developed reactions of photosensitivity after the oral administration of prochlorperazine, promazine or mepazine showed improvement in a few weeks after withdrawal. 25 Promethazine was extensively used topically and orally as an antipruritic and antihistaminic, respectively, and Vol. NS13, No.4, April 1973
203
contact and photocontact dermatitis were described with exacerbations of sensitized individuals after subsequent oral ingestion and exposure to sunlight; however, Sams utilized it for at least five years as an antihistaminic without encountering a case of photosensitivity. Therefore he suggests that the topical use of the drug was a factor in the development of photosensitivity. 25 Furocoumarins The furocoumarins are a group of naturally occurring photosensitizers which are found in some plants all over the world. Some of these plants areparsnips, carrots, celery, yarrow, angelica, fennel, dill, parsley, rue, bergamot and lime. The hazards of exposure to such plants or their derivatives conjointly with sun exposure has been known for some time. 37 The term "phytodermatitis" was suggested for skin reactions caused by a combination of external contact with plants or plant products and subsequent exposure to light. 38 The dermatitis that develops is known by a variety of names---=-berlock dermatitis, perfume dermatitis, meadow-grass dermatitis, fig dermatitis, phytophotodermatitis and dermatitis bullosa striata pratensis. 37 Since perfumes and colognes may contain furocoumarins, particular caution should be the advice of pharmacists regarding exposure to sunlight after dabbing or spraying these products onto the skin. Berlock (or berlocque) dermatitis is an irregular discd'loration of the skin which appears occasionally upon exposure to the sun of a skin previously dabbed or sprayed with eau de cologne. Bergamot oil, an ingredient of eau de cologne, was first held responsible for this phenomenon; however, the following essential oils also were implicatedlavender, lemon, lime, orange and rosemary. A similar reaction has been produced experimentally by the application of any of the aforesaid oils when followed by irradiation. The psoralens were found to be furocoumarins 39 and experimental results published in 1953 indicated that the psoralens present in a variety of natural oils (including the oils of bergamot and other citrus fruits) were responsible. 40 Burdick 41 indicated that the element in perfumes that causes skin reactions when women wear perfumes in bright sunlight is photo toxic rather than photoallergic. The reactions start as reddened areas and then turn to darkened skin spots which may last for several months. Some women do not react because the outer layer of the skin does not allow the perfume to penetrate; however, when the outer skin layer was removed, the rash appeared in all 10 of some experimental volunteers, was typical of the f urocoumarins and tests 204
indicated that the material in the perfume was a furocoumarin. The psoralens are presumed to enhance tanning and increase resistance to sunburn; however, Becker has indicated that 8-methoxypsoralen (8-MOP) can protect patients with light allergy, but, conversely, may precipitate light allergy in susceptible individuals. When a patient describes a peculiar reaction to sunlight such as redness of the "butterfly area" of the face, hives, headache or upset stomach, 8-MOP should not be given. Furthermore, known photosensitizers should be avoided by patients who are taking 8-MOP.42 Halogenated Salicy lanilides About 1960 an outbreak of photosensitive dermatitis occurred in England and was found to be due to tetrachlorsalicylanilide (TCSA) which had been added to soaps as an antimicrobial agent. Recently, related compounds like tribromsalicylanilide and two isomers of dibromsalicylanilide were added to soaps in the United States as antimicrobial agents, and several cases of photodermatitis were reported. 43 Bithionol Bithionol is chemically known as 2,2 'thiobis(4,6-dichlorophenol). It is a local anti-infective and has been used widely in proprietary soaps, shampoos, antiseptic creams and acne preparations. On October 31, 1967, the Federal Register indicated that clinical experience and the use of photopatch tests show that the use of bithionol may cause photosensitivity, and the photosensitivity may in some instances persist for prolonged periods as severe reactions without further contact with sensitizing articles. Furthermore, cross-photosensitization may be produced by bithionol to other commonly used chemicals such as certain halogenated salicylanilides and hexachlorophene. Therefore, as of October 24, 1967, all drugs for human use containing any bithionol are to be regarded as new drugs for which no approval is in effect. Effective March 15, 1968, FDA banned cosmetics containing bithionol because they maintained that the ingredient caused photosensitivity and that they were enforcing the earlier FDA ban against new drugs containing bithionol. 44 Recommendation Before dispensing medication, the pharmacist should inquire whether the patient has a history of allergy and/or photosensitivity. Furthermore, the pharmacist should take due cognizance of solar radiation on patients using certain pharmaceuticals and should judiciously advise such patients to avoid sunlight. •
Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION
Acknowledgment The authors express their appreciation to J. Lemansky, assistant professor of library science at the Brooklyn College of Pharmacy, for his cooperation.
References 1. Kirshbaum, B.A., and Beerman, H ., "Photosensitization Due to Drugs," Amer. J . M ed. Sc., 248,446 (1964) 2. Osol, A., Jr., in Chapter 30 of Remington's Pharmaceutical Sciences, 13th ed., Martin, E.W., editor-inchief, Mack Publishing Co., Easton, Pa., 408 (1965) 3. Knox, J .M., "Sunlight and Man," J. Chronic Dis., 13, 396 (1961), citing Blum, H .F., Photodynamic Action and Diseases Caused by Light, Reinhold Publishing Corp., New York (1941). 4. Baer, R.L., and Harber, L.C ., "Photosensitivity Induced by Drugs," JAMA, 192, 989 (1965) 5. Kirshbaum and Beerman, op. cit., 447 6. Baer, R.L., "Newer Knowledge of Cutaneous Drug Eruptions," N.Y. State J. Med., 63, 3221 (1963) 7. Ba er and Harber, op. cit., 990 8 . Kirshbaum and Beerma n, op. cit., 448, citing Therapeutic Notes , 173 (1963) 9. Kirshbaum and Beerman, op. cit., 448 10. Daniels, F., Jr., "Diseases Caused or Aggravated by Sunlight," Med. Clin. oj N. A., 49, 571 (1965) 11. Kirshbaum and Beerman, op . cit., 450, citing Young, J.W., Bull. Assn. Mil. Dermat. , 13, 33 (1964) 12. Kirshbaum and Beerman, op. cit., 456 13. Kirshbaum and Beerman, op. cit., 457, citing Tromovitch, T.A., a nd Jacobs, P.H., Ann. Int. Med., 58, 529 (1963) 14. Kirshbaum and Beerman, op. cit., 457 15. Sams, W.M., "Photosensitivity to Thera peutic Agents," JAMA, 174, 2046 (1960) 16 . Kirshbaum a nd Beerman, op. cit., 457, citing Kligman, A .M., Declomycin Compendium, Lederle Labs, Pea rl River, N .Y., 49 (1962) 17. Blank, H., et al., "Photosensitivity Studies With Demethylchlortetracycline and Doxycycline," Arch. Derm. , 97, 1 (1968) 18 . Baer, op . cit., 63,3221 (1963), citing Orentreich, N., et al., Arch. Derm., 83, 730 (1961) 19. "Drug Reactions," Medical Letter, Drug & Therapeutic Information, Inc., 305 E. 45th St., New York, 7, 39 (May 1965) 20. Kirshbaum and Beerman, op. cit., 451 21. Sa ms, op. cit., 2044 22. Klarmann, E.G., "Sunburn and its Control,', Drug & Cos. Ind., 81, 522 (1957), citing Sa tulsky' E.M., Arch. Derm . & Syphilol., 62, 711 (1950) 23 . Hitselberger, J.F., and Fosnaugh, R.P., "Photosensitivity Due to Chlorpropamide," JAMA, 180, 62 (1962) 24 . Ibid., 63 25 . Sa ms, op . cit ., 2045 26. Harber, L.C ., et al., "Photosensitivity Due To Chlorothiazide and Hydrochlorothiazide," New Eng. J. Med., 261, 1380 (1959) 27. Kirshbaum and Beerman, op. cit., 453, citing Baer, R.L., and Harber, L.C., Arch. Derm., 83, 7 (1961) 28 . Kirshbaum and Beerman, op. cit. , 453, citing DeEds, F ., et al., JAMA, 86, 168 (1962) 29. Kirshbaum and Beerman, op. cit., 453 30. Daniels, op. cit., 573, citing Fowlks, W.L., J. Invest. Dermat., 32, 233 (1959), and Shelley, W.B. in Rees, R.B., Dermatoses Due To Environmental & Physical Factors , Charles C Thomas, Springfield, IlL , 88 (1959) 31. Kirshbaum and Beerman, op. cit., 456, citing Jung, E.G., et al., Schweiz. Med. Wchnschr., 93,249 (1963) 32. Satanove, A., "Pigmentation Due to Phenothiazines in High and Prolonged Dosage," JAMA, 19, 266 (1964), citing Shelley, W.B., as in ref. 30 33 . Kirshbaum and Beerman, op. cit., 454, citing Ayd, F.J., Jr., J. Nerv . & Mental Dis., 124,84 (1956) 34. Satanove, op. cit., 263 35. Ibid., 266 36. " Drug Reactions," op . cit., citing Greiner, A.C., et al., Canad. Med. Assoc. J. , 91, 627 and 636 (1964) 37. Kirshbaum and Beerman, op. cit., 460 38. Klarmann, op. cit., 522, citing Klaber, R. , Brit . J. Dermatol., 64, 193 (1942) 39. Kirshbaum and Beerman, op. cit., 460, citing Fahmy, I.R., a nd Abu-Shady, H., Quart. J. Pharm. and Pharmacol., 20, 281 (1947) 40. Klarmann, op. cit., 522 41. Burdick, K.H., "Phototoxicity of Shalimar Perfume," Arch. Derm ., 93,424 (1954) 42 . Becker, S.W., Jr. , "Prevention of Sunburn and Light Allergy With Methoxsalen," Gen. Practitioner, 19,117 (1959) 43 . Ison, A .E., and Tucker, J .B., "Photosensitive Derma titis From Soaps," New Eng. J. A1ed., 278, 81 (1968) 44. Drug & Cos . Ind., 168 (March 1968)
An
article on suntan preparations in Consumer Reports evaluated some sun-protective preparations and . provided suntan precautions by indicating that certain drugs and chemicals can increase the skin's sensitivity to solar radiation. Precaution against solar · radiation while using . certain drugs was also indicated in the July 5, 1971, issue of Drug Topics through the use of a picture of a huge sign which was posted on the window of a Buffalo, New York, pharmacy stating, "Certain Drugs Cause Sensitivity · to Sunlight." Articles in pharmacy journals have not publicized the drugs which induce photosensitivity although the lay press and medical journals have; therefore, the following provides the pharmacist with some information.
L'\.. the July 1971
Photosensitization A photodynamic action implies all forms of change which are evoked by the energy of light. Photosensitivity refers to a reaction in which a foreign substance in a biological system initiates an observable change by means of its absorption of light. The foreign substance is known as a photosensitizer! or photosensitizing-drug molecule.
and vesiculation. These investigators also believe that the majority of drugs that cause phototoxic reactions are resonating aromatic rings with a molecular weight ranging from 200 to 500. Usually, within 24 to 48 hours after administration of a phototoxic drug and adequate exposure to the proper wavelengths of light, the toxic response is erythematous and sunburn-like ·and is accompanied by coincident or isolated dermal injury revealed by urticaria. 5 A photoallergic reaction results when the photosensitizing-drug molecule absorbs quantity of light of a specific wavelength and leads to a photochemical change in the drug which then results in the formation of an allergenic compound;6 . Burkhardt7 likewise postulated that photons of electromagnetic energy react with the ingested drug to create a "new" molecule, but more specifically indicated that it acts as a haptene to form a unit with antigenic potential by probably combining with cutaneous proteins. The compounds
metabolized or conjugated with a protein form a photosensitizing substance with an absorption spectrum different from that of the administered drug. 8 Photoallergic reactions occur only after an incubation period of sensitization, may occur at unexposed sites distant from the site of light exposure and may result in cross-photosensitivity to immunochemkally related allergens. 9 The clinical manifestations are likely to be eczematous, urticarial, lichen planuslike or may resemble a sunburn; furthermore, hypersensitivity to light may continue months after the drug itself has been withdrawn. 8 Baer and Harber7 have illustrated their concept of the mechanisms of photosensitization through the use of a schematic presentation (Figure 1, below), and Daniels!O has provided a summary in table form of some factors regarding phototoxic and photoallergic dermatoses (Table I, page 201). A comprehensive listing of photosensitizing agents appears in Table II, (page 202).11 Table III (page 203)
FIGURE 1
Mechanisms of Photosensitization PHOTOSENSITIZING DRUG
I
.Absorption of Electromagnetic Energy (f hotons)
Phototoxic vs. Photo-allergic Skin Reactions PHOTOTOXIC
A photosensitizer which is ingested or applied topically can alter the reactivity of the skin to cause either a photo toxic or photoallergic reaction. In 1905 Albert Einstein proposed that light is propagated through space· as photons, each of which has a quantum of energy.2 Blum indicated that the absorbed photons of light give the absorbing molecules a higher energy content. 3 Baer and Harber 4 believe that the absorbed energy may be re-emitted in the form of harmless fluorescent or phosphorescent radiation or become part of a photochemical reaction that results in the transfer of energy to adjacent cells to cause a phototoxic reaction or biological change ranging from heating of tissue to severe cellular damage manifested by erythema, edema 200
PHOTOALLERGIC
{-
1-
Change in photosensitizer from ground energy state to excited singlet or triplet energy state
Oxidative formation of "new" compound (haptene)
Transfer of energy
Formation of full antigen (Conjugation of haptene with protein)
~
!
Formation of free radicals, peroxides, and heat
tell
Alteration in membrane, cytoplasm and/or nucleus
1 t
Antigen engenders formation of cellular or humoral antibodies Antigen-antibodt reaction upon reexposure to drug plus light
~~ cell ular damage Sunburn-type
re~
~n
of varied
morphology
Source: Baer, R. L. and Harber, L. C., "Photosensitivity Induced by Drugs," JAMA, 192,990 (1965)
Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION
Edward Stempel is professor and chairman of the pharmacy department of Brooklyn College of Pharmacy. He received his BS cum laude from Brooklyn College of Pharmacy, his MS from Columbia University college of pharmaceutical sciences, and his MA and EdD from Teachers College, Columbia University. Stempel practices community and hospital pharmacy. He was a contributing author for the fifth and sixth editions of Husa's Pharmaceutical Dispensing and the seventh edition of Dispensing of Medication. He has written numerous articles on pharmacy and pharmaceutical education and is listed in American Men of Science, Dictionary of International Biography, Who's Who in American Education, and Who's Who in the East.
indicates the type of photosensitivity reaction as well as the route of exposure. 4 Tetracyclines
DeVeber and Lepper indicated that photosensitivity as a side effect of chlortetracycli"ne was considered for a long time to be dependent, at least in part, on the substitution of chlorine in the tetracycline nucleus; however, the photosensitivity due to the nonchlorinated forms upset that theory.12 The use of 500 mg of oxytetracycline q.i.d. for three days was reported to cause redness, swelling and itching in the skin areas exposed to sunlight. Since the patient remained photosensitive for at least one-half year after the cessation of therapy, Tromovitch and Jacobs 13 believe that the photosensitive reaction is probably photoallergic rather than phototoxic. Photosensitivity has also been reported for tetracycline; however, more photosensitivity reactions have been reported following the use of demethylchlortetracycline (DMCT). A letter from Lederle, published in JAMA (172, 1196, 1960), reported 40 patients (in a total of 2,682 reports from 1,354 physicians) in whom dermatitis developed from DMCT following exposure to bright sunlight. 14 Kligman,15,16 in a 1962 report from the same manufacturer, indicated that a one-hour midday exposure to sunlight produced mild to severe evidence of phototoxicity in 43 of 89 subjects who received 150 mg of DMCT q.i.d. for seven to ten days, and subsequent studies showed that reduced dosage produced fewer phototoxic reactions. Discontinuance of the drug resulted in a milder phototoxic reaction within 24 hours, and complete remission occurred in two more days. Since 23 of the DMCT phototoxic subjects show no reaction with either tetracycline or chlortetracycline (i.e., no cross-photosensitization), it was construed that the reaction was phototoxic and not photoallergic. For a period of one week, Blank et a/. l7 gave 30 volunteers 600 mg of DMCT per day, 200 mg of doxycycline (Vibramycin) per day, or a placebo each day. Then he took them on a voyage designed to maximize sun exposure; nine of the ten receiving DMCT developed photosensitive eruptions, two of the ten receiving doxycycline were also positive, while one volunteer receiving the placebo was doubtful. The results supported the concept that DMCT was a powerful photo toxicant and suggested that doxycycline in the doses used will cause a lower incidenc.e of this annoying side effect. An unusual form of phototoxic reaction seen in a small number of persons who take large doses of DMCT is
Rina Stempel received her BS and MS degrees from Brooklyn College. She is presently assistant principal (supervision), health and physical education, at Samuel J. Tilden High School in Brooklyn, New York. Besides conducting methods of teaching courses for the New York City Board of Education and Brooklyn College, she has conducted and coordinated drug abuse programs, and is also active in health and educational organizations.
fingernail changes described as photoonycholysis which manifests itself about four weeks subsequent to combined ingestion of the drug and adequate exposure of the fingernails to sunlight. However, improvement occurs spontaneously two to three months after
avoidance of both the drug and sunlight. 18 Nail discoloration and onycholysis have also been reported as a result of the combination of sunlight and either tetracycline or chlortetracycline. 14 In 1965, it was reported 19 that FDA
TABLE I
Spontaneous and Drug-Induced Photo toxic and Photoallergic Dermatoses ...
Population
Exposure
Morphology
Pigment
Photopatch Tests Flare
Specificity
Spectroscopic Characteristics of the Photosensitizer
Clinical Features
Phototoxic
Photoallergic
Elicited in all persons receiving adequate dose of chemical and active wavelengths of radiation. May occur on first combined drug and light exposure.
Occurs in only a small percentage of those exposed to drug and sunlight. Occurs only after an incubation period of com bined drug and exposure (with exception of cross reaction with an earlier similar chemical). Often has morphology of other allergic reactions including eczema. Melanin equal to or less than expected for the same degree of erythema seen in sunburn.
Often resembles an exaggerated sunburn but may be urticarial or consist of a persistent erythema. Several of the phototoxic reactions produce intense melanization in relationship to degree of earlier erythema. Reproduce phototoxic reaction. Reactions confined to the area of combined chemical and light exposure. Reaction produced only by chemicals producing direct photosensitization effects. Chemical usually has an absorption spectrum in ultraviolet longer than 0.32 microns or in visible spectrum. These reactions occur at wavelengths where tissue is transparent and photosensitizer may be assumed to be the chromophore (initial absorber).
Erythema, dermatitis or bullae followed by pigmentation and depigmentation. May have no pain or itch. Generally fills area of combined chemical and light exposure uniformly.
Lesions with characteristics of allergic reactions. Flare-ups can occur in unexposed areas distant from the site of light exposure. Photo-cross sensitization to chemically related allergens may be found. Many of the reactions are produced by wavelengths shorter than 0.32 microns, i.e., the sunburn spectrum. Since these reactions occur where tissue as well as chemicals absorb radiations, the chemicals may act in any part of the reaction as well as trigger different photochemical events. Often dermatitis without pigmentation and with severe pruritus. Most prominent in exposed areas, but intensity often irregular as in papular and nodular types.
Source: Daniels, F., Jr., "Diseases Caused or Aggravated by Sunlight," Medical Clinics of N. A ., 49, 571 (1965)
Vol. NS13, No.4, April 1973
201
Glossary Cross Sensitivity-Susceptibility to sensitivity to a substance which is structurally related to another substance which causes a sensitizing reaction. Furocoumarins-Naturally occurring photosensitizers which are found in some plants allover the world. Photoallergic-A reaction which is initiated by an allergenic compound which is formed when a foreign substance absorbs light of a specific wavelength . Photochemical-The influence of light in causing a chemical change. Photon-A bundle of light-energy or a particle of light analogous to an electron. Photo-onycholysis-Loosening or separation of a nail from its bed due to sensitivity to light. Photosensitivity-A reaction in which a foreign substance in a biological system initiates an observable change due to absorption of light of a specific wavelength. Phototoxicity-A reaction initiated by a photochemical change and resulting in transfer of energy to adjacent cells. The result is heating of tissue to severe cellular damage. Phytodermatitis-A skin reaction caused by a combination of external contact to plants or plant products and exposure to light of a specific wavelength.
TABLE II
Photosensitizing Agents of Interest to the Dermatologist (Adapted from a list of photosensitizing agents prepared by Capt. James W. Young, USAF (MC)-Bull. Assn. Mil. Dermal., 13, 33, 1964) I. DRUGS 1. Antidiabetic agents (oral): including carbutamide, tolbutamide, chlorpropamide (Nadisan, Diabinese, Orinase, Ora betic) 2. Anesthetics: the procaine group of local anesthetics 3. Antibiotics: including tetracyclines and their derivatives: chlortetracycline (Aureomycin), oxytetracycline (Terramycin), demethylchlortetracycline (Declomycin) and griseofulvin (a penicillium derivative) 4. Antihistaminics: including diphenhydramine hydrochloride (Benadryl), promethazine (Phenergan), tripyrathiazine hydrochloride (Pyrrolazote), isothipendyl (Theruhistin) 5. Anticonvulsants: Tridione and Dilantin 6. Arsenicals 7. Barbiturates 8. Hormonal substances: including estrone and diethylstilbestrol 9. Topical antibacterial agents (antiseptics): Bithional, hexachlorophene, tetrachlorsalicylanilide (TCSA), tribromsalicylanilide (TBS) 10. Phenothiazine derivatives: including chlorpromazine (Thorazine), prochlorperazine (Compazine), mepazine (Pacatal), perphenazine (Trilafon), trimeprazine (Temaril), triflupromazine (Vesprin), promazine (Sparine), thiopropazote dihydrochloride (Dartal) 11. Psoralens: Furocoumarin derivatives, including 5-methoxypsoralen, 8-methoxypsoralen, and others 12. Sulfonamides: including sulfacetamide, sulfadiazine, sulfaguanidine, sulfamerazine, sulfamethazine, sulfapyridine, sulfathiazole, sulfadimethoxine 13. Sulfonylureas: see oral antidiabetic drugs above 14. Thiazide diuretics (aromatic sulfonamide preparations): chlorothiazide (Diuril) and hydrochlorothiazide (Hydrodiuril) 15. Heavy metals: gold and silver salts 16. Porphyrins: hematoporphyrin (used to treat melancholia), chlorophyll 17. Miscellaneous: digalloy I trioleate, monoglycerol para-amino benzoa te, p-dimethylaminoazobenzene, phenylbutazone, quinine, stilbamidine, salicylates, Lantinin, PerIoline, dicyanine-A, 5-fluorouracil, triethylene melamine (TEM), 9-aminoacridine II. DYES: 1. Acridine dyes-including acridine, trypaflavine and others 2. "Blankophores" (optical brighteners- mainly sulfa derivatives) 3. Dibenzopyran derivatives-eosin, fluorescein dyes, rose bengal and others 4. Paraphenylenediamine 5. Phenothiazine dyes (methylene blue, toluidine blue, others) 6. Phenoxazine dyes 7. Phenazine dyes 8. Trypan blue III. COAL TAR PRODUCTS AND PETROLEUM PRODUCTS: crude coal tar and its derivatives (benzene, anthracene, xylene, naphthalene, toluene, phenanthrene, thiophene, phenolic compounds, pyridine, and others). Pitch and pitch fumes. IV. ESSENTIAL OILS AND OTHERS: including, oil of bergamot, oil of cedar, oil of citron, oil of lavender, lime oil, vanillan oils, other agents included in various perfumes and cologne water. V. PLANTS: mainly members of the Umbelliferae family including: parsnips, carrots (wild and garden types), celery, yarrow, angelica, fennel, dill and parsley. Members of the Rutaceae (rue, bergamot and lime, wafer ash) meadow grass, clover mustards, agrimony, bavachi (corylifolia) Agave lechiguilla-a perennial flowering plant of the Amaryllis family, related to A. belladonna Lantana: a shrub of the Verbenae family Lady's thumb and smartweed: flower herbs of the buckwheat family Source: (1964)
202
Kirshbaum, B. A., and Beerman, H., "Photosensitization Due To Drugs," Amer. J. Med. Sc., 248, 450
Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION
would require package inserts for all tetracyclines to carry a warning that hypersensitive persons may develop photodynamic reactions from exposure to natural or artificial sunlight while using these drugs, and that persons with a history of a photosensitivity reaction should be instructed to avoid direct exposure to sunlight while under treatment with tetracycline drugs. Most package inserts thereafter indicated either a phototoxic or photoallergic reaction even though it was not until September 2, 1970, that the Federal Register indicated the requirement of a warning regarding "photosensitivity." Sulfonamides
After the introduction of sulfanilamide in the mid-1930's, a number of reports of its photosensitizing activity appeared. 20 Sams 21 indicated there are nearly 40 sulfanilamide preparations which have been used for their chemotherapeutic effects, and many of them have been found to have a photosensitizing action when used topically or systemically. Cross-photosensitivity has been demonstrated in some patients who have shown photosensitization due to compounds chemically related to the sulfonamide group - p-aminobenzoic acid (sometimes used as a sun-screen agent), local anesthetics of the procaine group, p-phenylenediamine,20 and monoglyceryl p-aminobenzoate 22 (sometimes used as a sunburn preventive). Sulfonylurea Hypoglycemics
The oral hypoglycemic sulfonylureas were introduced for the control and treatment of diabetes. The three sulfonylurea derivatives which have been popular are chlorpropamide (Diabinese), tolbutamide (Orinase) and tolazamide (Tolinase). Patients who take these drugs over an extended period may feel that the drugs cannot be the cause of subsequent reactions on the skin; therefore, they may fail to inform the examining physician of these medicaments which they take routinely. 21 It appears probable that chlorpropamide is metabolized or conjugated with protein to form a photosensitizing substance having a different absorptive spectrum than that of chlorpropamide. 23 Further evidence of a photoallergic mechanism is that ingestion of tolbutamide may be responsible for crossphotosensitization to chlorpropamide. 24 Thiazides
The thiazides- chlorothiazide and hydrochlorothiazide-are aromatic sulfonamide-type preparations with closely related structural formulas. They have a diuretic effect and have been used in edema, hypertension and
in reducing the weight of obese patients. Reports indicate that they are potent photo sensitizers, and both a photo toxic and photoallergic mechanism are involved in the production of various types of dermatitis. 25 Harber, Lashinsky and Baer 26 indicated that their clinical study showed that the photosensitivity reaction to either diuretic has many features in favor of a photoallergic mechanism. However, the possibility cannot be excluded that metabolism of the drug after ingestion results in a phototoxic compound that is not formed on the skin after topical application or in the skin after intracutaneous injection. Baer and Harber 27 believe that the biochemical mechanism of photoallergic sensitivity of the chlorothiazide in man may be due to (1) formation of other oxidation products of chlorothiazide in the skin or (2) photochemical precursors produced elsewhere than in the skin. 27
Phenothiazines The phenothiazine derivatives have been used (1) as a sedative, (2) as an antihistaminic, (3) for the control of nausea and motion sickness and (4) for the management of patients with psychiatric disorders. Phenothiazine was first noted in 1940 to cause intolerance to sunlight in agricultural workers who were using it as an insecticide as a spray to destroy the coddling moth. 28 A number of cross-sensitivities have been demonstrated between compounds included in the phenothiazine group; these are denoted in Table IV (right). 29 Many of the photosensitizing compounds consist of three aromatic rings in a linear configuration, and substitutions in the center ring with sulfur or nitrogen lead to an increase in photosensitizing capacity as seen with methylene blue and the phenothiazine compounds. 30 Like methylene blue, phenothiazine has both a sulfur and nitrogen substituted for two carbons in the center ring of anthracene. In two cases of photosensitivity to a water-insoluble chlorphenothiazine, Jung et al. 31 demonstrated that the allergic effect of this compound is not entirely dependent on the substitution at the nitrogen ring but also has a relation to the heterocyclic ring structure of phenothiazine. Chlorpromazine manifests two different reactions to sunlight-photoallergic and phototoxic. The photoallergic reaction manifests itself as an urticarial maculopapular eruption or eczematous reaction of the skin of the exposed areas of the body after an incubation period, and can occur in persons taking small amounts of medication. The phototoxic reaction can occur in most indi-
TABLE III
Drugs and Other Agents That Produce Photosensitivity Reactions
Photosensitizer Coal tar derivatives Anthracene, Acridine, Phenanthrene, Pyridine Antiseptics Bithionol (bisphenol) Tetrachlorsalicylanilide (Impregon) Diuretics Thiazides and related sulfonamide compounds Tranquilizers Chlorpromazine (Thorazine) Antibiotics Demethylchlortetracycline hydrochloride (Declomycin) Sunscreening agents Digalloyl trioleate (Neo-A-Fil) Amino benzoic acid Antijunga!s Griseofulvin (Fulvicin, Fulvicin VIF, Grifulvin, Grifulvin V, Grisactin, Griseoful yin) N-butyl-4 chlorosalicylamide (jadit) Antihistamines Promethazine Hydrochloride (Phenergan Hydrochloride) Antibacterials Sulfonamides Oral hypoglycemic agents Chlorpropamide (Dia binese) Tolbutamide (Orinase) Miscellaneous agents Furocoumarins t
Probable Mechanism of Action
Usual Route of Exposure
Phototoxic
Topical
Photoallergic Photoallergic
Topical
Photoallergic
Oral
Photo toxic, * Photoallergic
Oral
Phototoxic* (Photoallergic ?)
Oral
Photoallergic Photoallergic
Topical
Photoallergic
Oral
Photoallergic
Photoallergic
Topical Oral
Phototoxic, * Photoallergic
Oral Topical
(Photoallergic ?)
Oral
Phototoxic
Topical
* Protection
t
usually afforded by window glass. Found in fruits, perfumes; used to treat vitiligo.
Source:
Baer, R. L., and Harber, L. C., "Photosensitivity Induced by Drugs," JAMA, 192, 989 (1965)
viduals provided there is an adequate concentration of the photosensitizer in the living epidermal cells, an exposure to a specific band of light and the presence of oxygen. 32 Ayd 33 stated in 1956 that there is apparently no relationship between the incidence of photosensitivity and the dosage of chlorpromazine. Satanove 34 reported in 1965 that 78 out of thousands of patients at a specific mental hospital developed pigmentary changes (ranging from tan to slate blue to a deep blue-black or purple color) after high doses of chlorpromazine and related phenothiazines over long periods of time and after exposure to sunlight. The two factors in the production of pigment are an increase in melanin and the presence of a purplish-colored substance in the skin. The increase in melanin can be explained by the action of ultraviolet light on a photosensitizing drug such as the chlorpromazine in the skin. 35 The serious photosensitivity of pigmentation due to the phenothiazines is considered irreversible but evidence suggests that in some cases it can be
TABLE IV
Phenothiazines Showing CrossSensitivity Trade Name
Generic Name
Compazine Dartal Pacatal Phenergan Pyrrolazote Temaril Theruhistin Thorazine Trilafon Vesprin
prochlorperazine thiopropazate dihydrochloride mepazine promethazine hydrochloride pyrathiazine hydrochloride trimeprazine isothipendyl chlorpromazine perphenazine trifl upromazine
reversed by confining the patient in a dark room or by the use of a chelating agent such as d-penicillamine (Cuprimine-Merck, Sharp & Dohme).36 Patients who developed reactions of photosensitivity after the oral administration of prochlorperazine, promazine or mepazine showed improvement in a few weeks after withdrawal. 25 Promethazine was extensively used topically and orally as an antipruritic and antihistaminic, respectively, and Vol. NS13, No.4, April 1973
203
contact and photocontact dermatitis were described with exacerbations of sensitized individuals after subsequent oral ingestion and exposure to sunlight; however, Sams utilized it for at least five years as an antihistaminic without encountering a case of photosensitivity. Therefore he suggests that the topical use of the drug was a factor in the development of photosensitivity. 25 Furocoumarins The furocoumarins are a group of naturally occurring photosensitizers which are found in some plants all over the world. Some of these plants areparsnips, carrots, celery, yarrow, angelica, fennel, dill, parsley, rue, bergamot and lime. The hazards of exposure to such plants or their derivatives conjointly with sun exposure has been known for some time. 37 The term "phytodermatitis" was suggested for skin reactions caused by a combination of external contact with plants or plant products and subsequent exposure to light. 38 The dermatitis that develops is known by a variety of names---=-berlock dermatitis, perfume dermatitis, meadow-grass dermatitis, fig dermatitis, phytophotodermatitis and dermatitis bullosa striata pratensis. 37 Since perfumes and colognes may contain furocoumarins, particular caution should be the advice of pharmacists regarding exposure to sunlight after dabbing or spraying these products onto the skin. Berlock (or berlocque) dermatitis is an irregular discd'loration of the skin which appears occasionally upon exposure to the sun of a skin previously dabbed or sprayed with eau de cologne. Bergamot oil, an ingredient of eau de cologne, was first held responsible for this phenomenon; however, the following essential oils also were implicatedlavender, lemon, lime, orange and rosemary. A similar reaction has been produced experimentally by the application of any of the aforesaid oils when followed by irradiation. The psoralens were found to be furocoumarins 39 and experimental results published in 1953 indicated that the psoralens present in a variety of natural oils (including the oils of bergamot and other citrus fruits) were responsible. 40 Burdick 41 indicated that the element in perfumes that causes skin reactions when women wear perfumes in bright sunlight is photo toxic rather than photoallergic. The reactions start as reddened areas and then turn to darkened skin spots which may last for several months. Some women do not react because the outer layer of the skin does not allow the perfume to penetrate; however, when the outer skin layer was removed, the rash appeared in all 10 of some experimental volunteers, was typical of the f urocoumarins and tests 204
indicated that the material in the perfume was a furocoumarin. The psoralens are presumed to enhance tanning and increase resistance to sunburn; however, Becker has indicated that 8-methoxypsoralen (8-MOP) can protect patients with light allergy, but, conversely, may precipitate light allergy in susceptible individuals. When a patient describes a peculiar reaction to sunlight such as redness of the "butterfly area" of the face, hives, headache or upset stomach, 8-MOP should not be given. Furthermore, known photosensitizers should be avoided by patients who are taking 8-MOP.42 Halogenated Salicy lanilides About 1960 an outbreak of photosensitive dermatitis occurred in England and was found to be due to tetrachlorsalicylanilide (TCSA) which had been added to soaps as an antimicrobial agent. Recently, related compounds like tribromsalicylanilide and two isomers of dibromsalicylanilide were added to soaps in the United States as antimicrobial agents, and several cases of photodermatitis were reported. 43 Bithionol Bithionol is chemically known as 2,2 'thiobis(4,6-dichlorophenol). It is a local anti-infective and has been used widely in proprietary soaps, shampoos, antiseptic creams and acne preparations. On October 31, 1967, the Federal Register indicated that clinical experience and the use of photopatch tests show that the use of bithionol may cause photosensitivity, and the photosensitivity may in some instances persist for prolonged periods as severe reactions without further contact with sensitizing articles. Furthermore, cross-photosensitization may be produced by bithionol to other commonly used chemicals such as certain halogenated salicylanilides and hexachlorophene. Therefore, as of October 24, 1967, all drugs for human use containing any bithionol are to be regarded as new drugs for which no approval is in effect. Effective March 15, 1968, FDA banned cosmetics containing bithionol because they maintained that the ingredient caused photosensitivity and that they were enforcing the earlier FDA ban against new drugs containing bithionol. 44 Recommendation Before dispensing medication, the pharmacist should inquire whether the patient has a history of allergy and/or photosensitivity. Furthermore, the pharmacist should take due cognizance of solar radiation on patients using certain pharmaceuticals and should judiciously advise such patients to avoid sunlight. •
Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION
Acknowledgment The authors express their appreciation to J. Lemansky, assistant professor of library science at the Brooklyn College of Pharmacy, for his cooperation.
References 1. Kirshbaum, B.A., and Beerman, H ., "Photosensitization Due to Drugs," Amer. J . M ed. Sc., 248,446 (1964) 2. Osol, A., Jr., in Chapter 30 of Remington's Pharmaceutical Sciences, 13th ed., Martin, E.W., editor-inchief, Mack Publishing Co., Easton, Pa., 408 (1965) 3. Knox, J .M., "Sunlight and Man," J. Chronic Dis., 13, 396 (1961), citing Blum, H .F., Photodynamic Action and Diseases Caused by Light, Reinhold Publishing Corp., New York (1941). 4. Baer, R.L., and Harber, L.C ., "Photosensitivity Induced by Drugs," JAMA, 192, 989 (1965) 5. Kirshbaum and Beerman, op. cit., 447 6. Baer, R.L., "Newer Knowledge of Cutaneous Drug Eruptions," N.Y. State J. Med., 63, 3221 (1963) 7. Ba er and Harber, op. cit., 990 8 . Kirshbaum and Beerma n, op. cit., 448, citing Therapeutic Notes , 173 (1963) 9. Kirshbaum and Beerman, op. cit., 448 10. Daniels, F., Jr., "Diseases Caused or Aggravated by Sunlight," Med. Clin. oj N. A., 49, 571 (1965) 11. Kirshbaum and Beerman, op . cit., 450, citing Young, J.W., Bull. Assn. Mil. Dermat. , 13, 33 (1964) 12. Kirshbaum and Beerman, op. cit., 456 13. Kirshbaum and Beerman, op. cit., 457, citing Tromovitch, T.A., a nd Jacobs, P.H., Ann. Int. Med., 58, 529 (1963) 14. Kirshbaum and Beerman, op. cit., 457 15. Sams, W.M., "Photosensitivity to Thera peutic Agents," JAMA, 174, 2046 (1960) 16 . Kirshbaum a nd Beerman, op. cit., 457, citing Kligman, A .M., Declomycin Compendium, Lederle Labs, Pea rl River, N .Y., 49 (1962) 17. Blank, H., et al., "Photosensitivity Studies With Demethylchlortetracycline and Doxycycline," Arch. Derm. , 97, 1 (1968) 18 . Baer, op . cit., 63,3221 (1963), citing Orentreich, N., et al., Arch. Derm., 83, 730 (1961) 19. "Drug Reactions," Medical Letter, Drug & Therapeutic Information, Inc., 305 E. 45th St., New York, 7, 39 (May 1965) 20. Kirshbaum and Beerman, op. cit., 451 21. Sa ms, op. cit., 2044 22. Klarmann, E.G., "Sunburn and its Control,', Drug & Cos. Ind., 81, 522 (1957), citing Sa tulsky' E.M., Arch. Derm . & Syphilol., 62, 711 (1950) 23 . Hitselberger, J.F., and Fosnaugh, R.P., "Photosensitivity Due to Chlorpropamide," JAMA, 180, 62 (1962) 24 . Ibid., 63 25 . Sa ms, op . cit ., 2045 26. Harber, L.C ., et al., "Photosensitivity Due To Chlorothiazide and Hydrochlorothiazide," New Eng. J. Med., 261, 1380 (1959) 27. Kirshbaum and Beerman, op. cit., 453, citing Baer, R.L., and Harber, L.C., Arch. Derm., 83, 7 (1961) 28 . Kirshbaum and Beerman, op. cit. , 453, citing DeEds, F ., et al., JAMA, 86, 168 (1962) 29. Kirshbaum and Beerman, op. cit., 453 30. Daniels, op. cit., 573, citing Fowlks, W.L., J. Invest. Dermat., 32, 233 (1959), and Shelley, W.B. in Rees, R.B., Dermatoses Due To Environmental & Physical Factors , Charles C Thomas, Springfield, IlL , 88 (1959) 31. Kirshbaum and Beerman, op. cit., 456, citing Jung, E.G., et al., Schweiz. Med. Wchnschr., 93,249 (1963) 32. Satanove, A., "Pigmentation Due to Phenothiazines in High and Prolonged Dosage," JAMA, 19, 266 (1964), citing Shelley, W.B., as in ref. 30 33 . Kirshbaum and Beerman, op. cit., 454, citing Ayd, F.J., Jr., J. Nerv . & Mental Dis., 124,84 (1956) 34. Satanove, op. cit., 263 35. Ibid., 266 36. " Drug Reactions," op . cit., citing Greiner, A.C., et al., Canad. Med. Assoc. J. , 91, 627 and 636 (1964) 37. Kirshbaum and Beerman, op. cit., 460 38. Klarmann, op. cit., 522, citing Klaber, R. , Brit . J. Dermatol., 64, 193 (1942) 39. Kirshbaum and Beerman, op. cit., 460, citing Fahmy, I.R., a nd Abu-Shady, H., Quart. J. Pharm. and Pharmacol., 20, 281 (1947) 40. Klarmann, op. cit., 522 41. Burdick, K.H., "Phototoxicity of Shalimar Perfume," Arch. Derm ., 93,424 (1954) 42 . Becker, S.W., Jr. , "Prevention of Sunburn and Light Allergy With Methoxsalen," Gen. Practitioner, 19,117 (1959) 43 . Ison, A .E., and Tucker, J .B., "Photosensitive Derma titis From Soaps," New Eng. J. A1ed., 278, 81 (1968) 44. Drug & Cos . Ind., 168 (March 1968)