Upload
derma202
View
782
Download
0
Embed Size (px)
Citation preview
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
For practice exam questions and interactive study tools, visit the Dermatology In-Review Online
Practice Exam and Study System at
DermatologyInReview.com/Galderma
Committed to Your Future
Sponsored by
Dermatopharmacology 521
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
Dermatopharmacology 523
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
524 2011/2012DermatologyIn-Reviewl Committed to Your Future
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
Dermatopharmacology 525
• 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
526 2011/2012DermatologyIn-Reviewl Committed to Your Future
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
Dermatopharmacology 527
• 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
528 2011/2012DermatologyIn-Reviewl Committed to Your Future
• 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
Dermatopharmacology 529
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
530 2011/2012DermatologyIn-Reviewl Committed to Your Future
• 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
Dermatopharmacology 531
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
532 2011/2012DermatologyIn-Reviewl Committed to Your Future
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
Dermatopharmacology 533
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
534 2011/2012DermatologyIn-Reviewl Committed to Your Future
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
Dermatopharmacology 535
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
536 2011/2012DermatologyIn-Reviewl Committed to Your Future
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
Dermatopharmacology 537
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
538 2011/2012DermatologyIn-Reviewl Committed to Your Future
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
Dermatopharmacology 539
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
540 2011/2012DermatologyIn-Reviewl Committed to Your Future
• 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-)
Dermatopharmacology 541
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
542 2011/2012DermatologyIn-Reviewl Committed to Your Future
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
REFERENCES1. EpsteinME,etal.Antimicrobialagentsforthedermatologist.I.β-lactam antibiotics and related compounds.
J Am Acad Dermatol1997;137:149-165.2. NeuHC.Penicillins:microbiology,pharmacology,andclinicalusage.InBMKagan,Ed.Antimicrobial therapy.
Philadelphia:WBSaunders,1980;31-32.3. RomanoA,etal.Immediatehypersensitivitytopenicillins.StudiesonItaliansubjects.Allergy1997;52:89-93.4. Sadick,NS.Systemicantibacterialagents.InSEWolverton,Ed.Comprehensive dermatologic drug therapy.
Philadelphia:WBSaunders,1980;31.5. Levine,BB.Antigenicityandcrossreactivityofpenicillinsandcephalosporins.J Infect Dis1973;128:364-366.6. Stricker BH, et al. Serum sickness-like reactions to cefaclor. J Clin Epidemiol 1992;45:1177.7. NeuvonenPJ,etal.Interferenceofironwiththeabsorptionoftetracyclinesinman.BMJ1970;4:532.8. KleinNC,CunhaBA.Tetracyclines. Med Clin North Am1995;79:789-801.9. HendrixJD,etal.Cutaneoushyperpigmentationcausedbysystemicdrugs. Int J Dermatol1992;3:458.10. RosenT,HoffmanTJ.Minocycline-induceddiscolorationofthepermanentteeth.J Am Acad Dermatol 1989;
21: 569.11. Alvarez-ElcoroS,EnzlerMJ.Themacrolides:erythromycin,clarithromycin,andazithromycin.Mayo Clin Proc
1999;74:613-634.12. WilsonWR,CockerillFR3rd.Tetracyclines,chloramphenicol,erythromycin,andclindamycin.Mayo Clin Proc
1983;58:92-98.
Dermatopharmacology 543
13. WalkerRC,WrightAJ.Thefluoroquinolones.Mayo Clinic Proc 1991;66:1249-59.14. TsankovN,AngelovaI.Rifampinindermatology.Clin Dermatol2003;21:50-55.15. BartlettJG.AntimicrobialagentsimplicatedinClostridiumdifficiletoxinassociateddiarrheaandcolitis.Johns
Hopkins Med J1981;149:6-9.16. EvansTY,TyringSK.Advancesinantiviraltherapyindermatology.Dermatol Ther 1998;16:409-420.17. Baker DA. Valacyclovir in the treatment of genital herpes and herpes zoster. Expert Opin Pharmacother
2002;3(1):51-58.18. SallRK,etal.Successfultreatmentofprogressiveacyclovir-resistantherpessimplexvirusinfectionusing
intravenousfoscarnetinapatientwithacquiredimmunodeficiencysyndrome1989;125(11):1548-1550.19. EvansLM,GrossmanME.Foscarnet-inducedpenileulcer.J Am Acad Dermatol1992;27(1):124-126.20.EvansTY,etal.SystemicAntiviralAgents.InSEWolverton,Ed.Comprehensive Dermatologic Drug Therapy.
Philadelphia:WBSaunders,2001;97.21. Hetherington S, et al. Hypersensitivity reaction during therapy with the nucleoside reverse transcriptase
inhibitor abacavir. Clin Ther2001;23(10):1603-1614.22.WardHA,etal.Cutaneousmanifestationsofantiretroviraltherapy. J Am Acad Dermatol2002;46(2):284-
293.23. Calista D, Booschini A. Cutaneous side effects induced by indinavir. Eur J Dermatol2000;10(4):292-296.24. Stanley MA. Imiquimod and the imidazoquinolones: mechanism of action and therapeutic potential. Clin Exp
Dermatol 2002;27(7):571-577.25.TyringS,etal.Safetyandefficacyof0.5%podofiloxgelinthetreatmentofanogenitalwarts.Arch Dermatol
1998;134:33-38.26.GuptaAK,ShearNH.Terbinafine:anupdate.J Am Acad Dermatol1997;37:979-988.27. Haria M, et al. Itraconazole. A reappraisal of its pharmacological properties and therapeutic use in the man-
agement of superficial fungal infections. Drugs1996;51:585-620.28.GuptaAKetal.Druginteractionswithitraconazole,fluconazole,andterbinafineandtheirmanagement.J Am
Acad Dermatol 1999;41:237-248.29.ElewskiBE.Tineacapitis:acurrentperspective. J Am Acad Dermatol2000;42:1-20.30.EilC.Ketoconazolebindstothehumanandrogenreceptor.Horm Metab Res1992;24(8):367-370.31. BarnesPJ.Anti-inflammatoryactionsofglucocorticoids:molecularmechanisms.Clin Sci 1998;94:557-572.32.WolvertonSE.SystemicCorticosteroids.InWolvertonSE,Ed.Comprehensive Dermatologic Drug Therapy.
Philadelphia:WBSaunders,2001;109-138.33.ReichlingGH,KligmanAM.Alternate-daycorticosteroidtherapy.Arch Dermatol 1961;83:980-983.34.LesterRS,etal.Therisksofsystemiccorticosteroiduse. Dermatol Clin1998;16:277-288.35.AhmedAR,HombalSM.Cyclophosphamide(Cytoxan):Areviewonrelevantpharmacologyandclinicaluses.
J Am Acad Dermatol 1984;11(6):1115-1126.36.PanTD,McDonaldCJ.CytotoxicAgents.InSEWolverton,Ed.Comprehensive Dermatologic Drug Therapy.
Philadelphia:WBSaunders,2001;180-204.37.StillwellTJ,etal.Cyclophosphamide-inducedbladdertoxicityinWegener’sgranulomatosis.Arthritis Rheum
1988;31(4):465-470.38.OlsonEA.Thepharmacologyofmethotrexate.J Am Acad Dermatol1993;25:300-318.39.RoenigkHH,etal.Methotrexateinpsoriasis:revisitedguidelines.J Am Acad Dermatol 1998;38:478-485.40.CallenJP,etal.Methotrexate.InSEWolverton,Ed.Comprehensive Dermatologic Drug Therapy. Philadelphia:
WBSaunders,2001;147-164.41. YoungerIR,etal.Azathioprineindermatology.J Am Acad Dermatol1991;25(2Pt1):281-286.42. Cockburn I. Assessment of the risks of malignancy and lymphoma developing in patients using Sandimmune.
Transplant Proc 1987;19:1804-1807.43.BestPJ,etal.Hydroxyurea-inducedlegulcerationin14patients.Ann Intern Med 1998;128:29-32.44.KennedyBJ,etal.Skinchangessecondarytohydroxyureatherapy.Arch Dermatol 1975;111:183-187.45.EpsteinE.IntralesionalbleomycinandRaynaud’sphenomenon.J Am Acad Dermatol 1991;24:785-786.46.GelmannEP,etal.CombinationchemotherapyofdisseminatedKaposi’ssarcomainpatientswiththe
acquired immune deficiency syndrome. Am J Med1987;82(3)456-462.
544 2011/2012DermatologyIn-Reviewl Committed to Your Future
47.BleyerWA.Cancerchemotherapyininfantsandchildren.Pediatr Clin North Am1985;32(3):557-574.48.SchreiberSL,CrabtreeGR.ThemechanismofactionofcyclosporineandFK506. Immunol Today1992;13:
136-142.49.LebwohlM,etal.Cyclosporineconsensusconference:withanemphasisonthetreatmentofpsoriasis.J Am
Acad Dermatol1998;39:464-475.50.ColemanMD.Dapsonetoxicity:somecurrentperspectives.Gen Pharmacol 1995;26:1461-1467.51. Coleman MD. Dapsone: modes of action, toxicity and possible strategies for increasing patient tolerance. Br J
Dermatol1993;129:507-513.52.PrussickR,ShearNH.Dapsonehypersensitivitysyndrome.J Am Acad Dermatol1996;35:346-349.53.CallenJP,CamisaC.AntimalarialAgents.InSEWolverton,Ed.Comprehensive Dermatologic Drug Therapy.
Philadelphia:WBSaunders,2001;251-268.54.JonesSK.Oculartoxicityandhydroxychloroquine:guidelinesforscreening.Br J Dermatol1999;140:3-7.55.KorandaFC.Antimalarials.J Am Acad Dermatol 1981;4(6):650-655.56.NguyenEH,WolvertonSE.Systemicretinoids.InSEWolverton,Ed.Comprehensive Dermatologic Drug
Therapy.Philadelphia:WBSaunders,2001;269-310.57.DickenCH.Retinoids:areview. J Am Acad Dermatol1984;11:541-552.58.Acitretin(Soriatane)packageinsert.Nutley,NJ.RocheLaboratories,1997.59.LucekRW,ColburnWA.Clinicalpharmacokineticsoftheretinoids.Clin Pharmacokinet 1985;10(1):38-62.60.LammerEJ,etal.Retinoicacidembryopathy.N Engl J Med1985;313:837-841.61. David M. Adverse effects of retinoids. Med Toxicol Adverse Drug Exp1988;3(4):273-288.62. Patel NP, et al. Properties of topical sunscreen formulation. A review. J Dermatol Surg Oncol 1992;18(4): 316-320.63.LevySB.Sunscreens.InSEWolverton,Ed.Comprehensive Dermatologic Drug Therapy.Philadelphia:WB
Saunders,2001;632-646.64.LeniqueP,eal.Contactandphotocontactallergytooxybenzone. Contact Dermatitis 1992;26:177-181.65. Narahashi T. Nerve membrane Na+ channels as targets of insecticides. Trends Pharmacol Sci1992;13:236-241.66. Burkhart CN. IvermectIn an assessment of its pharmacotherapy, microbiology, and safety. Vet Hum Toxicol
2000;42(1):30-35.67.GurevitchAW.Scabiesandlice.Pediatr Clin North Am1985;32(4):987-1018.68.LiuLX,etal.Antiparasiticdrugs.N Engl J Med 1996;334:11178-1184.69.SiglerRW.Theroleofcyproheptadineinthetreatmentofcoldurticaria.J Allergy Clin Immunol 1980;65(4):
309-312.70.BlaissMS.Managementofrhinitisandasthmainpregnancy.Ann Allergy Asthma Immunol 2003;90:16-22.71. SimonsFER,SimonsKJ.ThepharmacologyanduseofH1-receptorantagonists.N Engl J Med1994;330:
1663-1670.72. Scheinfeld N. Cimetidine: a review of the recent developments and reports in cutaneous medicine. Dermatol
Online J 2003;9(2):4.73.GoldsobelAB,etal.Efficacyofdoxepininthetreatmentofchronicidiopathicurticaria.J Allergy Clin
Immunol 1986;78:867-873.74. Sullivan TP, et al. Colchicine in dermatology. J Am Acad Dermatol 1998;39:993-999.75.ThomasI.Goldtherapyanditsindicationsindermatology.J Am Acad Dermatol1987;16:845-854.76. Arthur AB, et al. Nitritoid reactions: case reports, review, and recommendations for management. J
Rheumatol 2001;28(10):2209-2212.77. SterlingJB,HeymannWR.Potassiumiodideindermatology:a19thcenturydrugforthe21stcentury-uses,
pharmacology, adverse effects, and contraindications. J Am Acad Dermatol 2000;43:691-697.78. HeymannWR.PotassiumiodideandtheWolff-Chaikoffeffect:relevancetothedermatologist.J Am Acad
Dermatol 2000;42:490-492.79.BarnhillRL,McDougallAC.Thalidomide:Useandpossiblemodeofactioninreactionallepromatousleprosy
and in various other conditions. J Am Acad Dermatol1982;7:317-323.
Dermatopharmacology 545
80.TsengS,etal.Rediscoveringthalidomide:Areviewofitsmechanismofaction,sideeffects,andpotentialuses. J Am Acad Dermatol 1996;35:969-979.
81. StirlingD,etal.Thalidomide—asurprisingrecovery.J Am Pharm Assoc(Wash.)1997;NS37:306-313.82. Physicians’ desk reference,Montvale,NJ,1998,MedicalEconomicsDataProductionCompany.83.ReedBR.Dermatologicdrugsduringpregnancyandlactation.InSEWolverton,Ed.Comprehensive
Dermatologic Drug Therapy.Philadelphia:WBSaunders,2001;817-847.84.ZernerJ,etal.Intrauterinecontraceptivedevicefailuresinrenaltransplantpatients. J Repro Med1981;26: 99-102.85.PapiernikE,etal.Intra-uterinedevicefailure:relationwithdruguse.Eur J Obstet Gynecol Reprod Biol 1989;
32:205-212.86. Hansten PD. Pharmacokinetic drug interaction mechanisms and clinical characteristics. Appl Ther 1997; 499-517.87.RendicS.SummaryofinformationonhumanCYPenzymes:humanCYP-450metabolismdata.Drug Metab
Rev 2002;34(1-2):83-448.88.ShapiroLE,ShearNH.Druginteractions.InSEWolverton,Ed. Comprehensive Dermatologic Drug Therapy.
Philadelphia:WBSaunders,2001;848-871.89.RoujeauJC,etal.Acutegeneralizedexanthematouspustulosis.Arch Dermatol 1991;127:1333.90.HalevyS,ShaiA.Lichenoiddrugeruptions.J Am Acad Dermatol1993;29(2Pt1):249-255.91. KnowlesSR,etal.Reactivemetabolitesandadversedrugreactions:clinicalconsiderations.Clin Rev Allergy
Immunol 2003;24(3):229-238.92.CallenJP.Drug-inducedcutaneouslupuserythematosus,adistinctsyndromethatisfrequentlyunrecog-
nized. J Am Acad Dermatol 2001;45(2):315-316.93.ShuklaSR.Drugscausingfixeddrugeruptions.Dermatologic1981;163(2):160-163.94. Vidal C, et al. Nonpigmenting fixed drug eruption due to pseudoephedrine. Ann Allergy Asthma Immunol
1998;80(4):309-310.95.KnowlesSR,ShearNH.DrugHypersensitivitySyndromes.InSEWolverton,Ed.Comprehensive Dermatologic
Drug Therapy.Philadelphia:WBSaunders,2001;872-884.96.GransteinRD,SoberAJ.Drugandheavymetal-inducedhyperpigmentation.J Am Acad Dermatol 1981;5(1):
1-18.97.BaackBR,BurgdorfWH.Chemotherapy-inducedacralerythema.J Am Acad Dermatol 1991;249(3):457-461.98.BaileyDL.Neutrophiliceccrinehidradenitis:acasereportandreviewoftheliterature.Pediatr Dermatol1989;
6(1): 33-38.99. Duhra P. Bleomycin-induced flagellate erythema. Clin Exp Dermatol 1991;16:216-217.100.VukeljaSJ,etal.Unusualserpentinehyperpigmentationassociatedwith5-fluorouracil.Casereportand
review of cutaneous manifestations associated with systemic 5-fluorouracil. J Am Acad Dermatol1991;25(5Pt2):905-908.
101.EllisCN,KruegerGG.TreatmentofchronicplaquepsoriasisbyselectivetargetingofmemoryeffectorTlym-phocytes. NEJM2001;345:248-255.
102.KruegerGG,CallisKP.Developmentanduseofalefacepttotreatpsoriasis.J Am Acad Dermatol 2003;49: S87-97.103.GoffeB,CatherJC.Etanercept:anoverview.J Am Acad Dermatol 2003;49:S105-111.104.CallenJP.Newpsoriasistreatmentsbasedonadeeperunderstandingofthepathogenesisofpsoriasisvul-
garis and psoriatic arthritis: a personal appraisal of their use in practice. J Am Acad Dermatol 2003;49:351-356.105.GottliebAB.Infliximabforpsoriasis.J Am Acad Dermatol 2003;49:S112-117.106.BoehnekeW,PrinzJ,GottliebAB.BiologicTherapyforPsoriasis:AsystematicReview.J Rheumatol2006;
33:1447-51.107.HelfmanT,FalangaV.Stanozolasanoveltherapeuticagentindermatology. J Am Acad Dermatol
1995;33:254-258.108.SawayaME,HordinskyMK.Theantiandrogens.Whenandhowtheyshouldbeused.Dermatol Clin
1993;11(1):65-72.108.ShawJC.Spironolactoneindermatologictherapy.J Am Acad Dermatol1991;24:236-243.
546 2011/2012DermatologyIn-Reviewl Committed to Your Future
NOTES