ETAS_16 dermatopharm

16 Dermatopharmacology

Erika Gaines Levine, MD

C o n t e n t s

16.1 Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521

16.2 Antivirals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 522

16.3 Antifungals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524

16.4 Topical and Systemic Corticosteroids . . . . . . . . . 526

16.5 Cytotoxic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526

16.6 Immunosuppressants . . . . . . . . . . . . . . . . . . . . . . . . . . 529

16.7 Dapsone and Sulfapyridine . . . . . . . . . . . . . . . . . . . . 529

16.8 Antimalarials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530

16.9 Retinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531

16.10 Sunscreens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532

16.11 Antiparasitics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533

16.12 Antihistamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 534

16.13 Hormone-related Drugs . . . . . . . . . . . . . . . . . . . . . . . 534

16.14 Miscellaneous Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . 535

16.15 Biologic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536

16.16 Drugs in Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . 537

16.17 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539

Dermatopharmacology 519

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16.1 ANTIBIOTICSThe important antibacterial agents in dermatology are the penicillins, cephalosporins, tetra-

cyclines, macrolides, and fluoroquinolones. This section will also briefly discuss clindamycin and rifampin.

Penicillins • Inhibit bacterial cell wall synthesis by blocking the transpeptidation step1 • Active against a broad spectrum of organisms: group A beta-hemolytic streptococci,

Neisseria species, Treponema pallidum, and Erysipelothrix rhusiopathae2 • Most common adverse effects: hypersensitivity reactions ranging from mild morbilliform

eruptions, to urticaria and angioedema, to severe anaphylaxis3

Cephalosporins• Structure resembles the penicillins, possessing a β-lactam ring • Block bacterial cell wall synthesis through inhibition of penicillin-binding proteins that

catalyze transpeptidation • Treat soft tissue infections caused by staphylococci and non-

enterococcal streptococci4

• 10%ofpatientsallergictopenicillinsmayalsoexhibitsimilarallergic reactions to cephalosporins5

Tetracyclines • Inhibitproteinsynthesisbybindingtothe30Sribosomalsubunit• Effectiveagainstbothgram-positiveandnegativeorganisms,mycoplasmainfections,

Chlamydia and Rickettsia infections4 • Absorptionoftetracycline,unlikeminocyclineanddoxycycline,isimpairedbytheingestion

of dairy products, calcium, and iron or zinc salts7 • Doxycycline,excretedbytheGItract,istheonlytetracyclineforuseinpatientswithrenal

failure8 • Demeclocyclineanddoxycyclinearethemostphototoxicofallthetetracyclines.

Onycholysis can accompany tetracycline-induced phototoxicity4

• Tetracyclinesarecontraindicatedinchildrenlessthan9yearsof age → risk of brown discoloration of the teeth and delayed bone growth. Pneumonitis, drug-induced lupus and serum sickness-like reactions from tetracyclines have been reported

• Minocyclinehasbeenreportedtocauseblue-blackpigmentationofthenails,skin(especially shins), scars, and sclerae9

• Incontrasttotetracyclinestainingoftheteeth,whichoccursinchildhoodandproducesa brown discoloration along the gingival third, minocycline stains the permanent teeth in adults, with a gray-green discoloration of the midportion of the tooth10

Macrolides • Inhibitthe50Sribosomalsubunitduringproteinsynthesis• Azithromycinandclarithromycinareeffectiveinthetreatment

of gram-negative soft-tissue infections11

• Erythromyciniseffectiveagainstacne,pyodermas,erythrasma,and pitted keratolysis

uTIPa�Cefaclor has been associated

with an increased incidence of serum sickness in children6

uTIPa�Tetracycline: most common

cause of fixed drug eruption

uTIPa�Cholestatic hepatitis is associ-

ated with the estolate form of erythromycin12

522 2011/2012DermatologyIn-Reviewl Committed to Your Future

• ErythromycinisknowntointeractwithmanydrugsbyinhibitingthecytochromeP-450system, increasing levels of carbamezapine, warfarin, theophylline, phenytoin, digoxin, and terfenadine

Fluoroquinolones • Inhibit DNA gyrase • EffectiveagainstMycobacterium species, gram-negative infections, particularly

Enterobacteriaceae organisms and multiresistant bacteria13

• Antacidsdecreasetheabsorptionoffluoroquinolonesandshouldbetakenatleasttwohours after the drug4

• Contraindicatedduringpregnancyandinchildrenbecauseofevidenceofitsdepositionincartilage leading to impaired cartilage formation13

Rifampin• Arifamycin,inhibitsRNAsynthesisbyinhibitingDNA-dependentRNApolymerase• Effectiveintuberculosisandatypicalmycobacterialinfections• OnlydrugbactericidaltoM. leprae• Cutaneousleishmaniasisandrhinoscleromaalsorespondto

rifampin

Clindamycin• Bindstothe50Sribosomalsubunitandinhibitsprotein

synthesis• Particularlyeffectiveagainstanaerobicandgram-positiveorganisms,particularlythose

causing deep tissue infections • PseudomembraneouscolitisassociatedwithClostridium difficile toxin has been reported inupto10%oftreatedpatients,limitingthedermatologicuseofclindamycintoprimarilytopical application15

16.2 ANTIVIRALSThis section will focus on the agents for human herpes virus infections and HIV-1 infection.

Imiquimod and podophyllin will briefly be discussed for their use in the treatment of HPV infections.

Acyclovir • Reliesuponthefactthatthymidinekinase(TK)isproducedatahigherrateinherpes

infected cells than in noninfected cells • Aguanosineanalog,ispreferentiallyphosphorylatedbyviralthymidinekinaseandinhibits

viral DNA polymerase, halting viral DNA synthesis by chain termination • Usefulfortreatmentofherpessimplexinfections,

varicella-zoster viral infections, and recurrent erythema multiforme eruptions secondary to HSV infection

Valacyclovir• Theprodrugofitsactivemetabolite,acyclovir• Hasenhancedbioavailabilityandconvertsrapidlyand

completely into acyclovir• Valacyclovirhasbeenshowntobesuperiortoacyclovir

in shortening the duration of pain from post-herpetic neuralgia associated with zoster patients17

uTIPaRifampincausesorange-reddis-

coloration of urine and tears and can permanently stain soft contact lenses14

uTIPaRapidintravenousinfusionofacyclovir

has been associated with a reversible obstructive nephropathy16

uTIPa�Severe and even fatal cases of the

thromboticthrombocytopenicpurpura/HUSsyndromereportedinAIDSandtransplant patients taking high doses


Famciclovir and Penciclovir• Famcicloviristheprodrugofpenciclovir• InitiallyphosphorylatedbyTK• Similarmechanismasacyclovir• FamciclovirtakenPO,convertedbydeacetylationandoxidationinliverandintestine• Longerintracellularhalf-lifethanacyclovir• UsedforVZVinimmunocompetentandforrecurrentHSVgenitalinfections

Gancyclovir • UsedtotreatCMVretinitisinimmunocompromisedpatientsandforCMVprophylaxisin

transplant patients • MarkedlymoreactiveagainstCMVthanacyclovir• InitiallyphosphorylatedbyviralTK• CMVisolatesresistanttoganciclovironthebasisofDNApolymerasemutations;mayalso

be resistant to foscarnet and cidofovir• IVorPO,butPOhasverypoorbioavailability• Adverseeffects:Bonemarrowsuppression,neutropenia,andthrombocytopenia;worsenedbyconcomitantadministrationofAZT

Foscarnet • NoncompetitiveinhibitionofviralDNApolymerasesatthepyrophosphate-bindingsite• Doesnotrequirephosphorylationforantiviralactivity,thereforeactiveagainstviruses

resistant to acyclovir, famciclovir, or ganciclovir on basis of altered kinase activities18

• GivenonlyIVandindilutesolutions• MajoruseisforCMVretinitisinAIDSpatients• UsefulforHSVorVZVinfectionresistanttoacyclovirandfor

ganciclovir-resistant CMV

Cidofovir• Nucleotideanalogue• Doesnotrequirephosphorylationbyvirus,butisconvertedbyhostcellkinasestoa

diphosphate• UsuallyactiveagainstCMVisolatesresistanttoganciclovirandfoscarnet• IVuseonly• Adverseeffect:Renal—proteinuriaandincreasedcreatinine• UsedforCMVretinitisinAIDSpatientswhohavefailedtreatmentwithganciclovirand

foscarnet The nucleoside analogs, the nonnucleoside analogs and the protease inhibitors comprise the threemajorcategoriesofantiretroviraldrugsfortreatmentofHIV-1infection.

Zidovudine (AZT)• Athymidineanalog,isphosphorylatedtoitsactiveformandpreferentiallyinhibitsHIV

reverse transcriptase rather than human DNA polymerase • Bonemarrowsuppressionwithsubsequentanemiaandgranulocytopeniaisthemost

severe adverse effect16

• Cancausedarkstreaksinthenails,diffuseandoralhyperpigmentedmacules,andtrichomegaly

uTIPa Penile erosions are known to

occur19


Didanosine• Apyrimidinenucleosideanalog,requiresabasicenvironmentforenhancedabsorption;

didanosine cannot be combined with the use of ketoconazole, itraconazole, or quinolone antibiotics because of their requirement of an acidic environment20

Abacavir• Anucleosidereversetranscriptaseinhibitor• Causesahypersensitivityreactioninapproximately5%oftreatedpatients→ can be fatal

upon rechallenge of abacavir21

Protease Inhibitors • Blocktheproteaseenzyme

responsible for final assembly of new viral proteins

• Theproteaseinhibitors,especiallyindinavir, have been associated with lipodystrophy, which manifests as abnormal fatty deposits known as, the “buffalo hump” and “protease pouch”

• Indinavircancausegynecomastiaandperiungalpyogenicgranulomas

Other Agents

Interferons• Cytokineswithbroadantiviral,immunomodulating,andantiproliferativeeffects• GivenIV,IM,IL,orSQ• Sideeffects:Fever,chills,headache,myalgia,arthralgia,GIsymptoms(thesearedose-related);granulocytopenia,thrombocytopenia,variousneurotoxicities,alopecia,hepatotoxicity, and autoantibody formation

• EffectiveintreatmentofchronichepatitisCandwarts

Imiquimod • Atopicalagent• Doesnotexhibitdirectantiviralactivity,butinsteadexertsitsactionthrough

immunomodulation • Inducescytokines,mostnotably,tumornecrosisfactor(TNF)-α, interferon (IFN)-γ,

interferon (IFN)-α,andinterleukin(IL)-12,leadingtostimulationofacell-mediatedimmune response24

Podophyllin• AcrudecytotoxicextractfromtheMayappleplant,isantimitotic,arrestingcellsin

metaphase by binding to the protein tubulin • Usedfortreatmentofcondylomaacuminatum25

16.3 ANTIFUNGALSTerbinafine

• Allylamine• Fungicidal• Blocksthebiosynthesisofergosterol,asterolessentialtotheintegrityofthefungalcellmembrane;inhibitssqualeneepoxidase(fungalinhibited4Xmorethanmammalian)

uTIPa�The protease inhibitors, especially indinavir, have been associated

with lipodystrophy, which manifests as abnormal fatty deposits known as the “buffalo hump” and “protease pouch”

a Several HIV medications including indinavir, zidovudine, and lami-vudinehavebeenreportedtocauseperiungual/paronychialerup-tionsresultinginPG-likelesions22,23


• Doesnotinterferewithsynthesisofsteroidhormones,prostaglandins,anddrugmetabolism• Extensivelybiotransformedinliver;patientswithliverdysfunctionsloweliminationby30%• Clinicaluse:onychomycosisduetodermatophytes;tineacorporis,pedis,andtoalesser

degree, cutaneous candidiasis• Sideeffects:nausea,dyspepsia,stomachpain;doesnotinhibitcytochromep450superfamily

Itraconazole• Triazole• Inhibits14-α-demethylase, blocking lanosterol conversion to ergosterol• Highlylipophilic• Bioavailabilityincreasedpostprandially• Clinicaluse:Blastomycosis,histoplasmosis,aspergillosis,candidiasis,cryptococcosis,

coccidioidomycois, sporotrichosis, superficial infections with dermatophytes, onychomycosis• Sideeffects:Nauseaandvomiting,hypertriglyceridemia,edema,hypertension,leukopenia,elevatedLFTs,nephroticsyndrome

• Druginteractions:Smallaffinityforcytochromep450→ elevates digoxin, cyclosporine, triazolam, midazolam

• Needsacidenvironmentforabsorption

Ketoconazole• Mechanismsimilartotriazoles• Absorptionenhancedbyfoodintake• Highlylipophilicandkeratinophilic• Needsacidenvironmentforabsorption• Sideeffects:Uncommoneffectsonliver(fulminanthepatitisandtransientincreasesinLFTs)• InhibitscytochromeP450

Fluconazole• Inhibits14-α-demethylase, blocking lanosterol conversion to ergosterol• Clinicaluse:Oral,esophageal,vaginalcandidiasis,cryptococcalmeningitis,candidal

prophylaxis in AIDS and transplant recipients, tinea corporis, cruris, pedis, unguium, histoplasmosis, sporotrichosis, tinea versicolor

• Sideeffects:Nausea,vomiting,diarrhea,abdominalpain,dysgeusia• Rarely,elevatedLFTs• Alopeciaforprolongeduseat400mg• Druginteractions:Elevatesphenytoin,warfarin,nortriptyline,midazolam,triazolam,and

tacrolimus

Griseofulvin• Disruptsmicrotubulemitoticspindleformationcausingmetaphasearrest• Absorptionenhancedbyfattymeal• Effectiveagainstdermatophytes,butnotyeastandbacteria• Indicatedfortineacapitis,butresistancetoTrichophyton• Indicatedforonychomycosis,butcurerateislowandrelapserateishigh• 20-50%experiencesevereheadaches• Photoallergyoccurs,andmayprecipitateLEandsevereskinreactions• InducescytochromeP450• Ineffectiveagainstcandidiasis,systemicmycoses,andPityrosporum species• Hasbeenreportedasapotentialexacerbatorofacuteintermittentporphryiaandthusis

contraindicated in patients with a history of porphyria

uTIPa Side effects include gynecomastia and

impotence, by interfering with androgen and glucocorticoid synthesis30


16.4 TOPICAL AND SYSTEMIC CORTICOSTEROIDSTopical Corticosteroids

• Utilizedfortheiranti-inflammatory,antimitotic,immunosuppressiveandvasoconstricitveproperties

• Mostcommonadverseeffectsoftopicalglucocorticoidsareatrophyandstriaeformation,through suppression of collagen cross-linking during synthesis

Systemic Corticosteroids• Decreasecirculatinglymphocytes• DecreaseT-cellresponsivenesstoantigens• Inhibitreleaseoflysosomalenzymes• Decreaseresponseofmacrophagestolymphokines• Decreaseantibodyproduction• Increasethenumberofpolymorphonuclearleukocytesanddiminishthenumbersof

lymphocytes, eosinophils, and monocytes• Short-actingsteroids,cortisoneandhydrocortisone,havethegreatestmineralcorticoid

activity, while cortisone has the lowest glucocorticoid activity• Intermediateandlong-actingsteroids,methylprednisolone,triamcinalone,dexamethasone,

and betamethasone, have virtually no mineralcorticoid activity, while dexamethasone and betamethasone have the highest glucocorticoid activity32

• RiskofHPAaxissuppressionisminimizedinacutediseasewithsinglemorningdosing,tomimic normal circadian cortisol production

• Alternate-dayadministrationoforalsteroidsisadvisedduringataperingregimentoreducecomplications of systemic therapy

• All complications are believed to be reduced by alternate-day dosing except the risk of posterior subcapsular cataracts, osteoporosis, and osteonecrosis32,33

• Otheradverseeffectsfromsystemictherapyincludeincreasedinfectionrisk,hyperglycemia,hypertriglyceridemia, cushingoid appearance, pancreatitis, sodium retention, potassium wasting, open-angle glaucoma, myopathy, and growth retardation in children34

16.5 CYTOTOXIC AGENTSThe cytotoxic agents include alkylating agents, such as, cyclophosphamide, chlorambucil, and

the anthracyclines (doxorubicin and dactinomycin) and the antimetabolites, such as, methotrex-ate, azathioprine, thioguanine, mycophenolate mofetil, and hydroxyurea. Other cytotoxic agents include5-FUandbleomycin.

Cyclophosphamide • Nitrogenmustardderivativeandiscell-cyclenonspecific,producingDNAcross-linkagesat

any point in the cell cycle• TreatmentofchoiceinWegener’sgranulomatosis• Increasedincidenceoflymphoma,leukemia,bladdercarcinoma,andsquamouscell

carcinoma, and leukopenia from bone marrow suppression35

• Hemorrhagic cystitis is associated with the increased risk of transitional cell carcinoma of the bladder and can occur in up to 40% of treated patients36,37


• Riskofcystitisisavoidedbyadequatefluidintake,frequentvoidingandcarefulscreeningforhematuria;cyclophosphamide must be discontinued if red blood cells are detected in the urine

• Azoospermia:Rarebutreportedadversereaction

Chlorambucil• Likecyclophosphamide,isanalkylatingagentthatisderivedfromnitrogenmustard• Steroid-sparingagentinthetreatmentofvasculitis,Behcet’sdisease,dermatomyositis,histiocytosisX,andsarcoidosis

• Bonemarrowsuppressionwithleukopenia,oralulcers,amenorrheaandazoospermiaarenotable adverse effects

• Inchildrenwithnephriticsyndromeoradultswithaseizurehistory,cancausegeneralizedtonic-clonic seizures36

Methotrexate • S-phasespecificantimetabolite,whichcompetitivelyandirreversiblyblocksdihydrofolate

reductase from catalyzing the formation of tetrahydrofolate, an important cofactor in thymidylate and purine synthesis

• Usedinthetreatmentofpsoriasisandotherproliferativedermatosesandimmunobullousdiseases38

• Mostcommonsignificantadverseeffectofmethotrexate use is hepatotoxicity

• Excessivealcoholintake,renalinsufficiency,diabetes,obesity and higher cumulative doses of methotrexate increase the risk of toxicity

• Cumulativedosesatorabove4.0gramscanriskinducingliverfibrosisandcirrhosis;liverbiopsyisthegold standard diagnostic test for methotrexate-induced hepatic toxicity39

• Uncommonlycausesacutepneumonitisandpulmonaryfibrosis• Teratogenicaffectsbotheggandspermproduction• Trimethoprim,thesulfonamides,anddapsone,whichinhibitthefolicacidmetabolic

pathway, can lead to hematologic toxicity when combined with methotrexate• Tetracyclines,phenytoin,phenothiazines,

chloramphenicol, NSAIDS, salicylates, and sulfonamides can all increase methotrexate levels by displacement of plasma proteins40

Azathioprine• Antimetabolite,isapurineanalogthatactsonlyduringtheSphaseofthecellcycleintheformationofadenineandguaninenucleotides;azathioprineisconvertedinto6-mercaptopurine, which is then converted into the active metabolite 6-thioguanine via the hypoxanthineguaninephosphoribosyltransferase(HGPRT)pathway

• Alsoconvertedintoseveralinactivemetabolitesviaxanthineoxidaseandthiopurinemethyltransferase (TPMT) activity

uTIPa Patients with renal disease, those using

NSAIDSorTMP/SMX,andthosewithnofolate supplementation are at greater risk ofpancytopenia;Leukovorin(folinicacid),with its ability to bypass dihydrofolate reductase in the cell division pathway, is given under conditions of methotrexate-induced myelosuppression

uTIPa Causes radiation recall, in which the adminis-

tration of the drug causes either previous sunburn to reappear or previously irradiated skin to develop a toxic cutaneous reaction

uTIPa�Bladder toxicity is due to the acrolein

metaboliteofcyclophosphamide;mesna(sodium 2-mercaptoethanesulfonate) has been used to reduce this toxic effect


• Usedasacorticosteroidsparingagentinthetreatment of autoimmune bullous diseases, vasculitides, and other cutaneous inflammatory diseases41

• Adverseeffectsincludeincreasedriskoflymphoproliferative malignancies and cutaneous squamouscellcarcinomas;riskshaveonlybeendocumented in patients with rheumatoid arthritis or severe immunosuppression, and not in patients treated for cutaneous disease42

•Hypersensitivitysyndrome(fever/shock)canoccurat14days

Mycophenolate Mofetil (MMF) • Inhibitsdenovopurinesynthesis• Noncompetitivelyinhibitsinosinemonophosphatedehydrogenase(IMPDH)• Cellsdependentonthedenovopathwayofpurinesynthesisratherthanthesalvage

pathway are most affected by inhibition of this enzyme • T-andB-cellsareparticularlyaffectedbytheantiproliferativeactivityofMMFbecause

these cells lack a purine salvage pathway36

• Mycophenolatemofetiliscleavedtomycophenolicacidafteringestion• Liverinactivatesmycophenolicacid• GItractandepidermiscan“reactivate”theinactiveformviaβ-glucoronidase• Gastrointestinal:Nausea,diarrhea,anorexia,abdominalcramps,vomiting,analtenderness

(more common with higher doses)• Genitourinary:Urgency,frequency,dysuria• Reversiblebonemarrowtoxicity(rare)

Hydroxyurea• S-phasespecificcytotoxicagent,inhibitsribonucleotidereductase,anenzymeresponsible

for converting ribonucleotides to deoxyribnucleotides in DNA synthesis• Treatspsoriasis,scleromyxedema,hypereosinophilicsyndrome,pyodermagangrenosum,Sweet’ssyndrome,vasculitissecondarytocryoglobulinemia

• Anemia,hepatitis,andrenaltoxicityareassociatedadverseeffects36

• Poikiloderma of the dorsal hands with a band-like distribution over the fingers and toes, diffuse hyperpigmentation, and leg ulcers upon withdrawal of the medication have been described

• Radiationrecall,acralerythema,anddermatomyositis-likereactionsareotherrarecutaneous reactions43,44

Fluorouracil (5-FU)• Cell-cyclespecificpyrimidineantagonist,preventingtheconversionofdeoxyuridinemonophosphate(dUMP)todeoxythymidinemonophosphate(dTMP)inDNAsynthesis

• HastheabilitytoincorporateintoRNA,whereithasahigheraffinityforrapidlyproliferatingtumor tissue rather than healthy tissue

• Effectiveasatopicaltherapyforactinickeratoses

uTIPa WheneitherxanthineoxidaseorTPMTactivity

isdiminished,theHGPRTpathwaybecomesthe primary pathway and excess active metabolites, toxic purine analogs, can lead to bonemarrowsuppression;canoccureitherin the setting of concomitant allopurinol use, which inhibits xanthine oxidase or in patients with genetically low TPMT allele activity


Bleomycin • EffectivefordermatologicuseasanintralesionaltherapyforHPVinfection• DamagesDNAbydirectbindingduringMandG2phases• AssociatedwithRaynaud’sphenomenonoccurringindigitstreatedwithintralesional

therapy for periungual and plantar warts45 Several cytotoxic agents such as doxorubicin, dactinomycin, the vinca alkaloids, vincristine

andvinblastine,playanimportantroleindermatologyinthetreatmentofKaposi’ssarcoma46

Doxorubicin (Adriamycin) • BlocksnucleicacidtranscriptionbyintercalationwithDNAresidues• Cardiactoxicity

Dactinomycin (Actinomycin-D) • FormscomplexeswithDNA,inhibitingDNA,RNA,andproteinsynthesis

Vinblastine• Extractfromtheperiwinkleplant,isacell-cyclespecificcytotoxicagent,thatarrests

mitosis in metaphase by microtubule linkage• Vincristineisananalogofvinblastine47

16.6 IMMUNOSUPPRESSANTSCyclosporin A

• ImmunosuppressantagainstT-cellactivity→ inhibits calcineurin, a phosphatase activated in the presence of calmodulin and calcium, by cyclophilin

• Formsacomplexwithcyclophilin,blockingitsabilitytoactivatecalcineurin,andthuspreventing calcineurin from phosphorylating NFAT-1, a transcription factor. NFAT-1, when phosphorylatedcantravelintothenucleusofcellsandinitiateIL-2production,whichcauses helper T-cell (CD4) and cytotoxic T-cell (CD8) proliferation48

• Treatspsoriasis,autoimmunebullousdisorders,lichenplanus,severeatopicdermatitis,andpyoderma gangrenosum

• Mostcommonelectrolyteabnormalitiesarehyperkalemia, hyperuricemia, and hypomagnesemia

• MetabolizedbythehepaticcytochromeP-4503A4enzyme system, concomitant use of other drugs thatinhibitorinducethisP-450isoform,canleadtoinappropriate circulating levels of cyclosporine

• Aminoglycosides,NSAIDS,amphotericinB,andvancomycincanpotentiaterenaltoxicitywhen combined with cyclosporine

16.7 DAPSONE AND SULFAPYRIDINE• Dapsone,sulfonamide,andsulfapyridinetreatleprosy,dermatitisherpetiformis,bullousdiseaseofchildhood,bullousSLE,EED,subcornealpustulardermatosis,Sweet’ssyndrome,and pyoderma gangrenosum

• Anti-inflammatoryactivityismosteffectiveagainstpolymorphonuclearleukocytesbyinhibiting their myeloperoxidase activity and chemotactic abilities

• Hemolytic anemia and methemoglobinemia are well known side effects of dapsone, are dose-related and occur with varying degrees in all individuals

uTIPa Adverse effects: nephrotoxicity, reversible

hypertension, paresthesias and dysesthesias, hypertrichosis, gingival hyperplasia, hyperlipidemia, and electrolyte imbalances49


• Methemoglobinemia→notamajorproblemformostpatients;cyanosisseenafterlevelgreaterthan3%→ symptoms of methemoglobinemia are weakness, tachycardia, nausea, headache, and abdominal pains

• Oral methylene blue is used in emergency situations to lower methemoglobin levels• HematologictoxicityisrelatedtoG6PDfunction• G6PD-deficientindividualsaremoresensitivetotheoxidativestressofdapsonemetabolites• CimetidineandVitaminEhavebothbeenshowntoprovidesomeprotectionagainst

methemoglobin formation• Agranulocytosis50,51

• Neurologiceffectsarealsoidiosyncraticandincludeapredominantlymotorperipheralneuropathy and acute psychosis

• Dapsonehypersensitivitysyndrome:severemononucleosis-likereaction,includingfever,erythroderma, hepatitis, eosinophilia, and even death52

• Sulfapyridinehasasimilarbutoftenlessseveresideeffectprofile• Sulfapyridinecancauserenaltoxicitybycrystallizationintheurine

16.8 ANTIMALARIALS• Themostcommonlyusedantimalarialsarethe4-aminoquinolones,hydroxychloroquine,

chloroquine, and quinacrine• EffectiveinDLE,SLE,dermatomyositis,otherphotosensitivedermatoseslikeporphyriacutaneatardaandPMLE,granulomatousdermatosesandlymphocyticinfiltrates

• Mechanismofactionnotwellunderstood→ may work by intercalating into DNA, blocking further transcription

• Chloroquinehasimmunosuppressiveandanti-inflammatoryactivitybyimpairingchemotaxis of leukocytes and eosinophils, inhibiting lysosomal function, and inhibiting antigen-antibody complex formation53

• Highaffinityformelanin-containingtissue,withatendencytoaccumulateinoculartissuessuch as the choroids and ciliary body

• Mostsevereadverseeffectisoculartoxicitywithretinopathy,whichispotentiallyirreversible• Premaculopathyassociatedwithchangesinvisualfieldwithoutvisuallossisreversibleifthe

antimalarial is discontinued • Trueretinopathyisassociatedwith“bull’seye”pigmentdeposition,centralscotoma,and

diminished visual acuity • Onlythe4-aminoquinolones,hydroxychloroquineandchloroquineareassociatedwith

ocular toxicity • Riskofretinopathyisgreatestwithchloroquineanddoesnotexistforquinacrine54

• Chloroquineandhydroxychloroquineshouldnotbegiventogetherbecauseofanadditiveeffect on retinotoxicity

• OtheradverseeffectsarehemolysisinpatientswithG6PD-deficiency,GIdistress,andinfrequent central nervous system effects with confusion, seizures, and restlessness

• Cutaneousadversereactionsareabluish-grayhyperpigmentationovertheshins,face,andpalate and in the nailbeds as transverse bands → due to both hemosiderin and melanin

• Quinacrinefrequentlyproducesayellowdiscolorationtothescleraandskin,especiallyoverthe dorsal hands and feet55


16.9 RETINOIDS • AllsyntheticandnaturalsubstancesthathaveVitaminA-likestructureandactivity• VitaminAexistsasretinol,aVitaminAalcohol;retinal,aVitaminAaldehyde;andretinoicacid,aVitaminAacid;thesethreeformsareinterconvertible

• PrecursorsofVitaminA(retinal):carotenoids,synthesizedbyplantsandwheningestedareoxidized to Vitamin A

• Retinolistransportedintheserumbyretinolbindingproteinsandtransthyretin• Retinolbindstoacytosolicretinolbindingproteinfortranslocationtothenucleus56

• First-generationsyntheticretinoids:tretinoin(all-transRA)andisotretinoin(13-cisRA)• Second-generationsyntheticretinoidsareetretinate,whichwasreplacedbyitsmetabolite

acitretin• Third-generation(polyaromatic)retinoidsincludethearotinoids,tazarotene,adapalene,and

bexarotene arotinoids have been developed to interact selectively with specific receptors• Isotretinoin,acitretin,andbexarotenearewater-

soluble, with very little lipid deposition57;water-solubleretinoids are undetectable in the serum after 1 month of stopping therapy

• Etretinateis50timesmorelipophilicthanacitretinwithincreasedstorageinadiposetissue• Highlylipid-solubleetretinatelastsseveralyearsinthefattytissues;inthepresenceof

ethanol (alcohol), acitretin is reesterified to etretinate• Etretinatehasahalf-lifeof100days,incontrasttothehalf-lifeofacitretinandisotretinoin,whichis50hoursand20hours,respectively59

• Tretinoinandisotretinoindownregulatetheproliferativekeratins,K6andK16• Keratinocytedifferentiationisenhancedbyretinoidswithincreasedfilaggrinproduction,

increased keratohyalin granules, keratin filaments and Odland body secretion of lipids• Isotretinoinreducesthesizeofsebaceousglandsanddecreasesdifferentiationtomature

sebocytes• Retinoidsnormalizekeratinizationleadingtodecreasedfollicularocclusion• Retinoidsdirectlyinhibitornithinedecarboxylaseandthereforelesseninflammatory

hyperplasia56,57

• Acitretinisusedtotreatsevere,pustularorerythrodermicformsofpsoriasis• Isotretinoinisusedtotreatnodulocysticorrecalcitrant,scarringacne• Bexaroteneisusedtotreatmycosisfungoides• Retinoidsareusedforfolliculardisorders,suchasHIV-associatedeosinophilicfolliculitisandfordisordersofkeratinization,suchasDarier’sdiseaseorlamellarichthyosis56

• Retinoidteratogenicity:microtia,hearingloss,microphthalmia,opticnerveatrophy,acraland axial skeletal abnormalities, cardiovascular defects, hydrocephalus, microcephaly, meningomyelocele, thymic aplasia, and anal and vaginal atresia60

• Themostcommonserioussideeffectsfromsystemicretinoids include reduced night vision, diffuse interstitial skeletal hyperostosis (DISH), premature epiphyseal closure, elevated serum lipids and transaminases, pseudotumor cerebri (risk increased with concomitant tetracyclines), depression, and myopathy

uTIPa The recommended period for contraception

after acitretin therapy is 3 years58

uTIPa� Bexarotene has been shown

to cause reversible hypothyroidism56,61


Table 16-1.

Drug Category Half-life Metabolism Excretion

Tretinoin First generation 48 mins Hepatic Bile, urine

Isotretinoin First generation 20hours Hepatic Bile, urine

Etretinate Second generation 4 months Hepatic Bile, urine

Acitretin Second generation 2 days Hepatic Bile, urine

Bexarotene Third generation 7 hours Hepatic Hepatobiliary

Table16-2.ReceptorSpecificitiesofTopicalRetinoids

RAR-α RAR-β RAR-γ RXR-α RXR-β RXR-γ

Tretinoin(all-trans-RA) + + + – – –

Alitretinoin(9-cis-RA) + + + + + +

Adapalene – + + – – –

Tazarotene – + + – – –

Table16-3.ReceptorSpecificitiesofSystemicSteroids

RAR-α RAR-β RAR-γ RXR-α RXR-β RXR-γ

Isotretinoin(13-cis-RA) – – – – – –

Acitretin – – – – – –

Bexarotene – – – + + +

16.10 SUNSCREENS• Twomaincategories:chemicalabsorbersandphysicalblockers• Chemicalsunscreensabsorbultravioletlightand,intheirconversionfromahigherenergy

state back down to the ground state, convert the absorbed energy into longer lower energy wavelengths

• ChemicalsunscreensfurtherdividedintoUVAandUVBabsorbers• MostcommonUVB-absorbingchemicalsarepadimateO(PABAesters),

octylmethoxycinnamate, and octyl salicylate• MostcommonUVA-absorbingchemicalsarethebenzophenones,dibenzoylmethanesand

methyl anthranilate • Benzophenones,oxybenzoneanddioxybenzone,have

the broadest spectrum of absorption of the chemical sunscreenswithUVBandUVAIIabsorption

• AvobenzoneorParsol1789isadibenzoylmethanewithUVAIabsorption

• Physicalblockers,titaniumdioxideandzincoxide,reflectand scatter ultraviolet rays62,63

• Therehavebeenincreasingreportsofphotoallergytobenzophenones64

uTIPa Allergic contact allergy can occur

with PABA and its derivatives, which can cross react with azodyes, aniline, procaine, benzocaine, paraphenylenediamine and sulfonamides


Summary of Sunscreens

UVA Blockers• Benzophenones(dioxybenzone,oxybenzone,sulisobenzone)• Dibenzoylmethane→ avobenzone(Parsol1789),thebestUVA/UVBblocker• Methylanthranilate• Redveterinarypetrolatum

UVB Blockers• PABA• Cinnamates• Salicylates• Amylp-dimethylaminobenzoate(PadimateA,PadimateO→ PABA derivatives)

Physical Blockers• Titaniumdioxide• Zincoxide

16.11 ANTIPARASITICSLindane

• Anorganochloridethatblocksneuraltransmission,inducingrespiratoryandmuscularparalysis in parasites

• Effectiveagainstscabies,pubiclice,headliceandbodylice• Sideeffectsfromlindaneincludeirritantcontactdermatitisandneurotoxicity,

predominantly seizures

Permethrin• Pyrethroidcompoundthatdisablessodiumtransportchannelsinthenervecellmembrane

of the parasite, leading to its paralysis65

Ivermectin• Usedtotreatstrongyloidiasis,onchocerciasisandNorwegianscabies• Ivermectinblocksglutamate-gatedchlorideionchannels,leadingtoparalysisofthe

parasite66

Malathion• Anorganophosphatecholinesteraseinhibitor• Usedfortreatmentofscabiesandheadlice• Flammable

Precipitated Sulfur (6%)• Usedfortreatmentofscabiesinpregnantwomen67

Thiabendazole • Inhibitsfumaratereductase,ahelminth-specificenzyme• Usedtotreatcreepingeruptionorcutaneouslarvamigransandlarvacurrens68


16.12 ANTIHISTAMINES• FirstgenerationH1antihistaminescompetitivelyblockhistaminefrombindingtohistaminereceptors;classincludesdiphenhydramine,promethazine,cyproheptadine,chlorpheniramine, and hydroxyzine

• Cyproheptadineisthehistamineofchoicefortreatingcoldurticaria69

• Adverseeffectsoffirst-generationH1antihistaminesaresedation,increasedappetite,drymouth, constipation, tachycardia, dysrhythmias, and blurry vision

• Chlorpheniramineisconsideredoneofthesafestantihistaminesforpregnancy70 • Second-generationH1antihistaminesarealsohistamineantagonistsforreceptorbinding• Theseincludefexofenadine,loratadine,andcetirizine;fexofenadinehasfewornosedativeandanticholinergiceffects;loratadineisalong-acting,minimallysedatingantihistamine;cetirizine is a low sedation metabolite of hydroxyzine

• SecondgenerationH1antihistaminesareusedforchronicurticaria71 • Cimetidineandranitidine(H2antihistamines)areusedindermatology;cimetidinehas

suppressor T-cell inhibitory activity, by competitive blocking their H2 receptors • Immunomodulatoryeffectsareusefulfortreatingmucocutaneouscandidiasis,verrucae

vulgaris, and condyloma acuminata• Cimetidinealsocompetitivelyinhibitsdihydrotestosteroneattheandrogenreceptorsite;

has several anti-androgen side effects including gynecomastia, impotence, and loss of libido72

• DoxepinisatricyclicantidepressantwithH1andH2antihistamineactivity;topicaldoxepincreamisusedforpruriticdisorders,neuroticexcoriationsandfactitialdermatitis;oraldoxepin can cause anticholinergic side effects as well as cardiotoxic effects73

• Cromolynsodiumblocksmastcelldegranulationandisusedforcontrollingdiarrheainmastocytosis

16.13 HORMONE-RELATED DRUGSSpironolactone

• Aldosteroneantagonistthatworksasanantiandrogenbyblockingtheandrogenreceptorand by inhibiting testosterone and DHT production

• Steroidmoleculewithstructurecloselyresemblingmineralocorticoids• Primarymetabolite,canrenone,istheactivealdosteroneantagonist• Treatshirsuitism,acne,andandrogeneticalopecia

• Most common and serious side effect is hyperkalemia, most likely to occur when taken with a thiazide diuretic, potassium supplements, or angiotensin-converting enzyme inhibitors or in individuals with severe renal insufficiency

• Otheradverseeffectisgynecomastia

Flutamide• Nonsteroidalantiandrogenwhenconvertedto2-OH-flutamide,whichcompetitivelyinhibits

DHT binding• Limiteduseindermatology;combinedwithoralcontraceptivestotreathirsuitism• Hepatotoxicitywithpotentiallyfulminantliverfailureispossibleadverseeffect


Finasteride• SpecificallyinhibitstypeII5a-reductase,whichconvertstestosteronetoDHT,

predominantly in hair follicles from frontal to vertex scalp and in sebaceous gland ducts• Mostoftendermatologicuseisinmalepatternandrogeneticalopecia• Infrequentreportedsideeffectsincludedecreasedlibido,erectiledysfunctionanddecreasedejaculatevolume(typeII5a-reductasealsolargelyfoundintheprostate)

• Knownteratogen;causesgenitourinarydefectsinmaleoffspring;categoryX

Stanozolol and Danazol• Syntheticderivativesoftestosterone,attenuatedandrogensalkylatedinthe17-aposition,

with marked anabolic properties, and diminished androgenic properties• Knowntoincreaseconcentrationsofselecthepatic-derivedplasmaglycoproteins,including

the inhibitor of the first component of complement• Effectiveinpreventingangioedemaattacksinpatientswithhereditaryangioedema• Alsopotentfibrinolyticactivityusedintreatmentofcryofibrinogenemia,lipodermatosclerosis,

and livedoid vasculitis• Adverseeffectsincludemildalopecia,hirsuitism,acne,andmenstrualirregularitiesinfemale

patients • Othersideeffectsarehypertension,insulinresistance,interferencewithliverfunction,and

muscle cramps

16.14 MISCELLANEOUS DRUGSMiscellaneous drugs, including colchicine, gold, potassium iodide, and thalidomide are important

dermatologic agents to review.

Colchicine• Alkaloidusedindermatologyforitseffectsonneutrophils• Hasantimitoticactivity• Bindstotubulindimersinneutrophils,preventingmicrotubuleassemblycriticalfor

metaphase and neutrophil motility and chemotaxis• UsedinthetreatmentofgoutandfamilialMediterraneanfever,however,thereissomeevidencetosuggestitsusefulnessintreatingSweet’ssyndrome,Behcet’sdisease,aphthousstomatitis, dermatitis herpetiformis, linear IgA bullous disease, and vasculitis74

• Mostcommonsideeffectfromcolchicineuseisgastrointestinaldistresswithabdominalcramping and watery diarrhea

Gold• Usedindermatologyforitsanti-inflammatoryactivity• Inhibitsmacrophageandneutrophilphagocytosis,complementactivity,andprostaglandin

synthesis• Effectiveinpemphigusbyinhibitingdegradativeepidermallysosomalenzymes,which

contribute to blister formation• Usedtotreatseverediscoidlupuserythematosusandpsoriaticarthritis75

• Mucocutaneoussideeffects,morecommonwithinjectablegold,includestomatitis,cheilitis,lichen planus-like eruptions, and pityriasis rosea-like eruptions

• Rarely,cancausediffusepulmonaryinfiltratesleadingtoachronicpulmonaryfibrosis

• Nitritoid reaction after gold injection: acute flushing, dizziness, hypotension, and fainting76


Potassium Iodide• Mechanismofactionnotwellunderstood• Mayinhibitgranulomaformation,whichmaycontributetoitsefficacyintreatingcutaneous

sporotrichosis • Suppresseshypersensitivityreactionsbymediatingthereleaseofheparinfrommastcells• Usedtotreaterythemanodosum,nodularvasculitisandsubacutenodularmigratorypanniculitis,Wegener’sgranulomatosis,andinsomecases,erythemamultiforme,andSweet’ssyndrome

• Cancauseiododerma,acneiform,orvasculiticeruptions77

• Thyroidfunctionmustbethoroughlyassessedpriortoinitiatingtherapywithpotassiumiodide

• Wolff-Chaikoff effect: the inhibition of thyroid hormone synthesis from excess iodides that block organic iodides from binding in the thyroid; in patients with normal thyroid function, autoregulatory mechanisms allow for appropriate escape from the Wolff-Chaikoff effect; in patients with impaired autoregulatory mechanisms, the Wolff-Chaikoff effect can lead to hypothyroidism78. TSH should also be checked a month after therapy is initiated

Thalidomide • Drugofchoiceforerythemanodosumleprosum• Inhibitstumornecrosisfactor-alphaandsuppressesmonocyteandneutrophilphagocytosis• OtherknownusesforthalidomideincludeHIV-associatedmucosalulcerationandapthousstomatitis,chroniccutaneouslupuserythematosus,andchronicGVHD79

• Teratogenicity:Mostcommonbirthdefectassociatedwiththalidomideisunderdevelopmentofarmsandlegs,knownasphocomelia;earmalformation,gastrointestinalandurogenitaldefectsarealsowelldocumented;peakvulnerabilitytothalidomide occurs between days 21 to 36 of gestation, during which only a single dose will cause the birth defects to occur80,81

• Peripheralneuropathy,mostcommonlypresentingasproximalmuscleweaknessandsymmetric painful paresthesias of the distal extremities

• Averycommonsideeffectissedation,whichisadditivewithothersedatives,suchasalcohol and barbiturates80

16.15 BIOLOGIC THERAPY• BiologictherapyreferstoproteinssynthesizedthroughrecombinantDNAtechniques

as immunomodulating agents• Recombinanthumancytokines,humanizedmonoclonalantibodies,orspecificmolecular

receptors • Psoriasisiscurrentlythemajortargetforbiologictherapies• Withregardtopsoriasistherapy,therearethreeclassesofbiologics:theT-celltargeting

drugs (efalizumab and alefacept), the TNF-inhibiting drugs (etanercept, infliximab, adalimumab) andthosedirectedagainstinterleukins(UstekinumabandKineret)

Alefacept(Amevive)isanimmunoglobulin/receptorfusionprotein,andtheIL12/23inhibi-tor, ustekinumab. ItisahumanLFA-3/IgGfusionprotein,whichisdesignedtoblockLFA-3onantigen presenting cells from interacting with CD2 on activated T-cells, thus preventing T-cell stimulation. Further, alefacept eliminates activated memory T-cells, so weekly CD4 T-cell counts are recommended.101,102 Alefacept treats psoriasis. It is given intramuscularly. A primary concern is T-cell depletion, so CD-4 T-cell counts must be monitored.106


Efalizumab(Raptiva)isahumanizedmonoclonalantibodyagainstCD-11a,acomponentofLFA-1onT-cells.ItblocksLFA-1onT-cellsfrominteractingwithICAM-1onantigenpresentingcells, endothelial cells, and cells in the dermis and epidermis.104EfalizumabblockstheabilityofT-cellsfromegressingthevasculatureandenteringtheskin.Efalizumabiseffectiveintreatingpsoriasis. It is given subcutaneously. WithdrawnfromU.S.market.

Etanercept(Enbrel)isanimmunoglobulin/receptorfusionprotein.ItisahumandimericfusionproteinoftheTNF-alphareceptorlinkedwiththeFcportionofhumanIgG1.ItbindstoTNF-alphaand blocks receptor binding and subsequent proinflammatory TNF-alpha activity.103Etanerceptiseffective in treating both psoriasis and psoriatic arthritis. It is given subcutaneously.

Adalimumab (Humira) is a human monoclonal antibody to TNF-alpha. It binds to both soluble and transmembrane TNF-alpha. It is given subcutaneously every other week. It is effective for psoriaisis and psoriatic arthritis. Has been associated with reactivation of tuberculosis.106

Infliximab(Remicade)isachimericmonoclonalantibodydirectedagainstTNF-alpha.Itbinds to TNF-alpha, blocking the receptor binding and proinflammatory activity of TNF-alpha.105 Infliximab is effective in treating both psoriasis and psoriatic arthritis. It is infused intravenously. Tuberculinskintestisrequiredpriortostartingtherapy.Rareassociationwithdemyelinatingdiseases.106

Ustekinumab(Stelara)isahumanmonoclonalantibodythatbindstothep40proteinsubunitonbothIL-12andIL-23cytokines.Itisadministeredsubcutaneouslyandisapprovedforthetreat-ment of psoriasis.

Kineret(Anakinra)isanIL-1receptorantagonistindicatedforthetreatmentofPeriodicFeversyndromes.

16.16 DRUGS IN PREGNANCYThe categories for safety of drug use in pregnancy are as follows: 82,83

Category A: Controlled studies in humans show no risk to fetusCategory B: Controlled human studies show no risk to fetus but may show risk to animals, or

no risk in animal studies but no human studies conductedCategory C: Risktohumanfetuscannotberuledout,studiesarelacking;animalstudiesare

equivocalCategory D: Controlled studies show risk to human fetus, but in some instances benefits may

outweigh risks Category X: Contraindicated in pregnancyDrugs used in dermatology are listed below by category determined by the FDA.83Listsarenot comprehensive.

Category X• Acitretin• Etretinate• Estrogens• Finasteride• 5-fluorouracil• Flutamide• Isotretinoin• Methotrexate• Stanozolol• Tthalidomide• Tazarotene


Category D• Aspirin• Azathioprine• Bleomycin• Colchicine• Cyclophosphamide• Hydroxyurea• Mechlorethamine• Penicillamine• Potassiumiodide• Tetracycline(GriseofulvinandspironolactoneareunratedbutshouldbeusedascautiouslyascategoryDdrugs)

Category C• Quinolones/ciprofloxacin• Ttrimethoprim-sulfamethoxazole• Cyclosporine(butbelievedtobesafeinpregnancy)• Acyclovir• Fluconazole,ketoconazole,itraconazole• Benzoylperoxide• Topicaltretinoin• Topicalandoralsteroids• Efalizumab

Category B• Penicillin• Erythromycin(notestolateformduetohepatotoxicityinthemother)• Dimenhydrinate• Cyproheptadine• Azeleicacid• Permethrin• Cephalosporins• Lidocaine• Etanercept,alefacept,andinfliximab

Category A• Folicacid• Levothyroxine- AzathioprineandNSAIDSareassociatedwithIUDfailure84,85 - Griseofulvinandrifampinareassociatedwithoralcontraceptivefailure,byincreased

estrogen metabolism by hepatic microsomal enzyme induction


16.17 DRUG INTERACTIONSThe most relevant drug interactions in dermatology involve the hepatic biotransformation

pathwayscatalyzedbythecytochromeP-450isoenzymesfromthesubfamiliesCYP3A3/4.Drugs that induce CYP3A enzymes may decrease levels of drugs that act as substrates for CYP3A. The CYP3A inhibitors may increase levels and cause toxicity of drugs metabolized by cytochromeP-450.

Cytochrome 2B6• Terbinafine

Specific Drug EruptionsAcute Generalized Exanthematous Pustulosis (AGEP)89

• Beta-lactamantibiotics• Macrolideantibiotics• Mercury• CephalosporinsLichenoid Eruptions90

• Hydrochlorothiazide• Antimalarials• NSAIDS• Gold• D-penicillamine• Captopril

SLE-like Eruption91

• Anticonvulsants• Isoniazid• Hydralazine• Minocycline• Procainamide• Penicillin• D-penicillamine

SCLE-like Eruption92

• Azathioprine• Glyburide• Griseofulvin• Terbinafine• Hydrochlorothiazide• Penicillin• Penicillamine• Piroxicam

Fixed Drug Eruptions93

• Tetracyclines• Barbiturates• NSAIDS,naproxen• Sulfonamides• Phenopthalein(inlaxatives)

uTIPaCytochrome P450 Inhibitors/Inducers

Inhibitors• Warfarin• Azoles• Verapamil• Erythromycin• Sexsteroidsandmethylprednisolone• St.John’swort• Ciprofloxacin• Cimetidine• Cyclosporine• Clarithromycin• Diuretics(furosemideandthiazides)• Danazol• Diltiazem• Grapefruitjuice• Proteaseinhibitors

Inducers• Griseofulvin• Rifampin• INH• Propranolol• Phenytoin• Phenobarbital• Carbamazepine• Omeprazole• Retinoids• Tobacco


• Erythromycin• Pseudoephedrinehydrochloride(non-pigmentingFDE)94

Acne-inducing Drugs• ACTH• Steroids• Halogens• Lithium• INH• Dilantin

Psoriasis-inducing Drugs• Lithium• Corticosteroidwithdrawal• NSAIDS(thoughnotreallytrue)• Antimalarials(thoughnotreallytrue)• Inderal(betablockers)• Interferons• Interleukin2

Hypersensitivity Syndromes • Seenmostoftenwithanticonvulsantsandsulfonamides,andlesscommonlywith

allopurinol, dapsone, and gold• Reactionspresentwithfever,rashwithfacialedema,eosinophilia,lymphadenopathy,

hepatitis, and nephritis• Pathogenesisofanticonvulsanthypersensitivityisrelatedtotheindividual’sinabilityto

detoxify arene oxide metabolites of these medications, due to lack of epoxide hydrolase• Diphenylhydantoin,phenobarbital,andcarbamazepineareknowntocross-react,whereas

valproic acid generally does not cross react95

Drug-related Pigmentation Side Effects• Amiodaronecancauseaslate-grayhyperpigmentationinphoto-exposedareas.Histologically,PASpositiveyellow-browngranulesareseeninmacrophagesinthedermis;on electron microscopy, membrane-bound structures resembling lysosomes are visualized

• Clofazaminecancausea“drug-inducedlipofuscinosis”• Skininitiallyturnspinkthenred-browninlesionsofpatientswithHansen’sdisease• Granularpigmentthoughttobelipofuscinisseeninmacrophages• Chlorpromazine,thioridazine,imipramineandclomipraminecausesasun-exposedpurple-

gray hyperpigmentation, with corneal and lens opacities • Gold,silver,andbismuthcaninduceaslate-grayhyperpigmentationinsun-exposedareas• Bismuthcancausepigmentationofthegingivalmargin• Arsenicalmelanosiscausestruncalhyperpigmentationwithdepigmentedraindrop-like

macules96

Chemotherapy-induced Cutaneous EffectsRadiation Enhancement and Recall• ActinomycinD• Methotrexate• Bleomycin• -rubicins(dauna-,doxo-,ida-)


Acral Erythema, Edema, and Tenderness• AraC(cytosinearabinoside)• Doxorubicin• 5-fluorouracil(pyridoxinereducesthepain)• Methotrexate

Neutrophilic Eccrine Hidradenitis• AraC• Bleomycin• Neutropenicpatientswithfever• Erythematouspapules,plaques,ornodules

Hyperpigmentation – Localized • Bleomycin→ flagellate or linear• 5-fluorouracil→ serpentine hyperpigmentation overlying the veins proximal to the infusion

site

Hyperpigmentation – Diffuse• Busulfan• Cyclophosphamide• Hydroxurea• Methotrexate

Hyperpigmentation – Under Bandages or Adhesives• Thiotepa• Topicalcarmustine(BCNU)

Hyperpigmentation – Nails • Cyclophosphamide,bleomycinand5-FU→ transverse bands• Doxorubicincauseshyperpigmentationofnails,skin,andtongue

Raynaud’s Phenomenon• Bleomycinwithvinblastine

Acral Sclerosis• Bleomycin

Ulceration Over Pressure Areas• Bleomycin• Methotrexate

Urticaria• L-asparaginase

Folliculitis• ActinomycinD• Daunarubicin• 5-FU• Methotrexate

Linear IgA Dermatosis• Vancomycin• Lithium• Amiodarone• Captopril• Penicillin


Hair• Methotrexate→ flag sign

Increased Growth of Eyelashes (Trichomegaly)• Interferons

Bullous Pyoderma Gangrenosum and Sweet’s• G-CSF

Exacerbation of LCV (LeukocytoclasticVasculitis)• G-CSF• GM-CSF

Exacerbation of Psoriasis• Interferon-alpha• Interferon-gamma• G-CSF• IL-2

Interleukin-2 Effects• Psoriasisexacerbation• Diffuseerythema• Desquamation• Pruritus• Mucositis• Glossitis• Flushing• ErythrodermaorTEN-likereaction

Pulmonary Fibrosis• Bleomycin• Methotrexate

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NOTES

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