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ETAS_16 dermatopharm ETAS_16 dermatopharm Document Transcript

  • 16  Dermatopharmacology Erika Gaines Levine, MDC o n t e n t s16.1 Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52116.2 Antivirals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52216.3 Antifungals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52416.4 Topical and Systemic Corticosteroids . . . . . . . . . . 52616.5 Cytotoxic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52616.6 Immunosuppressants . . . . . . . . . . . . . . . . . . . . . . . . . . 52916.7 Dapsone and Sulfapyridine . . . . . . . . . . . . . . . . . . . . . 52916.8 Antimalarials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53016.9 Retinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53116.10 Sunscreens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53216.11 Antiparasitics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53316.12 Antihistamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53416.13 Hormone-related Drugs . . . . . . . . . . . . . . . . . . . . . . . . 53416.14 Miscellaneous Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . 53516.15 Biologic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53616.16 Drugs in Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53716.17 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539 Dermatopharmacology  519
  • Committed to Your Future For practice exam questions and interactive study tools, visit the Dermatology In-Review Online Practice Exam and Study System at DermatologyInReview.com/GaldermaSponsored by
  • 16.1  ANTIBIOTICS The important antibacterial agents in dermatology are the penicillins, cephalosporins, tetra-cyclines, macrolides, and fluoroquinolones. This section will also briefly discuss clindamycin andrifampin.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 anaphylaxis3Cephalosporins • 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- u TIP enterococcal streptococci4 a efaclor has been associated C • 10% of patients allergic to penicillins may also exhibit similar with an increased incidence of serum sickness in children6 allergic reactions to cephalosporins5Tetracyclines • Inhibit protein synthesis by binding to the 30S ribosomal subunit • Effective against both gram-positive and negative organisms, mycoplasma infections, Chlamydia and Rickettsia infections4 • Absorption of tetracycline, unlike minocycline and doxycycline, is impaired by the ingestion of dairy products, calcium, and iron or zinc salts7 • Doxycycline, excreted by the GI tract, is the only tetracycline for use in patients with renal failure8 •  emeclocycline and doxycycline are the most phototoxic of all the tetracyclines. D Onycholysis can accompany tetracycline-induced phototoxicity4 • Tetracyclines are contraindicated in children less than 9 years uTIP of age → risk of brown discoloration of the teeth and delayed aetracycline: most common T bone growth. Pneumonitis, drug-induced lupus and serum cause of fixed drug eruption sickness-like reactions from tetracyclines have been reported • Minocycline has been reported to cause blue-black pigmentation of the nails, skin (especially shins), scars, and sclerae9 • In contrast to tetracycline staining of the teeth, which occurs in childhood and produces a brown discoloration along the gingival third, minocycline stains the permanent teeth in adults, with a gray-green discoloration of the midportion of the tooth10Macrolides • Inhibit the 50S ribosomal subunit during protein synthesis • Azithromycin and clarithromycin are effective in the treatment u TIP of gram-negative soft-tissue infections11 a holestatic hepatitis is associ- C • Erythromycin is effective against acne, pyodermas, erythrasma, ated with the estolate form of and pitted keratolysis erythromycin12 Dermatopharmacology  521
  • • Erythromycin is known to interact with many drugs by inhibiting the cytochrome P-450 system, increasing levels of carbamezapine, warfarin, theophylline, phenytoin, digoxin, and terfenadineFluoroquinolones • Inhibit DNA gyrase • Effective against Mycobacterium species, gram-negative infections, particularly Enterobacteriaceae organisms and multiresistant bacteria13 • Antacids decrease the absorption of fluoroquinolones and should be taken at least two hours after the drug4 • Contraindicated during pregnancy and in children because of evidence of its deposition in cartilage leading to impaired cartilage formation13Rifampin • A rifamycin, inhibits RNA synthesis by inhibiting DNA-dependent RNA polymerase • Effective in tuberculosis and atypical mycobacterial infections • Only drug bactericidal to M. leprae u TIP • Cutaneous leishmaniasis and rhinoscleroma also respond to a ifampin causes orange-red dis- R coloration of urine and tears and rifampin can permanently stain soft contact lenses14Clindamycin • Binds to the 50S ribosomal subunit and inhibits protein synthesis • Particularly effective against anaerobic and gram-positive organisms, particularly those causing deep tissue infections • Pseudomembraneous colitis associated with Clostridium difficile toxin has been reported in up to 10% of treated patients, limiting the dermatologic use of clindamycin to primarily topical application1516.2  ANTIVIRALS This 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 • Relies upon the fact that thymidine kinase (TK) is produced at a higher rate in herpes infected cells than in noninfected cells • A guanosine analog, is preferentially phosphorylated by viral thymidine kinase and inhibits viral DNA polymerase, halting viral DNA synthesis by chain termination • Useful for treatment of herpes simplex infections, u TIP varicella-zoster viral infections, and recurrent erythema a apid intravenous infusion of acyclovir R has been associated with a reversible multiforme eruptions secondary to HSV infection obstructive nephropathy16Valacyclovir • The prodrug of its active metabolite, acyclovir • Has enhanced bioavailability and converts rapidly and u TIP completely into acyclovir aevere and even fatal cases of the S thrombotic thrombocytopenic purpura/ • Valacyclovir has been shown to be superior to acyclovir HUS syndrome reported in AIDS and in shortening the duration of pain from post-herpetic transplant patients taking high doses neuralgia associated with zoster patients17522  2011/2012 Dermatology In-Review l Committed to Your Future
  • Famciclovir and Penciclovir • Famciclovir is the prodrug of penciclovir • Initially phosphorylated by TK • Similar mechanism as acyclovir • Famciclovir taken PO, converted by deacetylation and oxidation in liver and intestine • Longer intracellular half-life than acyclovir • Used for VZV in immunocompetent and for recurrent HSV genital infectionsGancyclovir • Used to treat CMV retinitis in immunocompromised patients and for CMV prophylaxis in transplant patients • Markedly more active against CMV than acyclovir • Initially phosphorylated by viral TK • CMV isolates resistant to ganciclovir on the basis of DNA polymerase mutations; may also be resistant to foscarnet and cidofovir • IV or PO, but PO has very poor bioavailability • Adverse effects: Bone marrow suppression, neutropenia, and thrombocytopenia; worsened by concomitant administration of AZTFoscarnet • Noncompetitive inhibition of viral DNA polymerases at the pyrophosphate-binding site • Does not require phosphorylation for antiviral activity, therefore active against viruses resistant to acyclovir, famciclovir, or ganciclovir on basis of altered kinase activities18 • Given only IV and in dilute solutions u TIP • Major use is for CMV retinitis in AIDS patients aPenile erosions are known to • Useful for HSV or VZV infection resistant to acyclovir and for occur 19 ganciclovir-resistant CMVCidofovir • Nucleotide analogue • Does not require phosphorylation by virus, but is converted by host cell kinases to a diphosphate • Usually active against CMV isolates resistant to ganciclovir and foscarnet • IV use only • Adverse effect: Renal—proteinuria and increased creatinine • Used for CMV retinitis in AIDS patients who have failed treatment with ganciclovir and foscarnet The nucleoside analogs, the nonnucleoside analogs and the protease inhibitors comprise thethree major categories of antiretroviral drugs for treatment of HIV-1 infection.Zidovudine (AZT) • A thymidine analog, is phosphorylated to its active form and preferentially inhibits HIV reverse transcriptase rather than human DNA polymerase • Bone marrow suppression with subsequent anemia and granulocytopenia is the most severe adverse effect16 • Can cause dark streaks in the nails, diffuse and oral hyperpigmented macules, and trichomegaly Dermatopharmacology  523
  • Didanosine • A pyrimidine nucleoside analog, requires a basic environment for enhanced absorption; didanosine cannot be combined with the use of ketoconazole, itraconazole, or quinolone antibiotics because of their requirement of an acidic environment20Abacavir • A nucleoside reverse transcriptase inhibitor • Causes a hypersensitivity reaction in approximately 5% of treated patients → can be fatal upon rechallenge of abacavir21Protease Inhibitors • Block the protease enzyme u TIP responsible for final assembly of new ahe protease inhibitors, especially indinavir, have been associated T with lipodystrophy, which manifests as abnormal fatty deposits viral proteins known as the “buffalo hump” and “protease pouch” • The protease inhibitors, especially a everal HIV medications including indinavir, zidovudine, and lami- S indinavir, have been associated with vudine have been reported to cause periungual/paronychial erup- lipodystrophy, which manifests as tions resulting in PG-like lesions22,23 abnormal fatty deposits known as, the “buffalo hump” and “protease pouch” • Indinavir can cause gynecomastia and periungal pyogenic granulomasOther Agents Interferons • Cytokines with broad antiviral, immunomodulating, and antiproliferative effects • Given IV, IM, IL, or SQ • Side effects: Fever, chills, headache, myalgia, arthralgia, GI symptoms (these are dose-related); granulocytopenia, thrombocytopenia, various neurotoxicities, alopecia, hepatotoxicity, and autoantibody formation • Effective in treatment of chronic hepatitis C and warts Imiquimod • A topical agent • Does not exhibit direct antiviral activity, but instead exerts its action through immunomodulation • Induces cytokines, most notably, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interferon (IFN)-α, and interleukin (IL)-12, leading to stimulation of a cell-mediated immune response24 Podophyllin • A crude cytotoxic extract from the May apple plant, is antimitotic, arresting cells in metaphase by binding to the protein tubulin • Used for treatment of condyloma acuminatum2516.3  ANTIFUNGALSTerbinafine • Allylamine • Fungicidal • Blocks the biosynthesis of ergosterol, a sterol essential to the integrity of the fungal cell membrane; inhibits squalene epoxidase (fungal inhibited 4X more than mammalian)524  2011/2012 Dermatology In-Review l Committed to Your Future
  • • Does not interfere with synthesis of steroid hormones, prostaglandins, and drug metabolism • Extensively biotransformed in liver; patients with liver dysfunction slow elimination by 30% • Clinical use: onychomycosis due to dermatophytes; tinea corporis, pedis, and to a lesser degree, cutaneous candidiasis • Side effects: nausea, dyspepsia, stomach pain; does not inhibit cytochrome p450 superfamilyItraconazole • Triazole • Inhibits 14-α-demethylase, blocking lanosterol conversion to ergosterol • Highly lipophilic • Bioavailability increased postprandially • Clinical use: Blastomycosis, histoplasmosis, aspergillosis, candidiasis, cryptococcosis, coccidioidomycois, sporotrichosis, superficial infections with dermatophytes, onychomycosis • Side effects: Nausea and vomiting, hypertriglyceridemia, edema, hypertension, leukopenia, elevated LFTs, nephrotic syndrome • Drug interactions: Small affinity for cytochrome p450 → elevates digoxin, cyclosporine, triazolam, midazolam • Needs acid environment for absorptionKetoconazole u TIP • Mechanism similar to triazoles a ide effects include gynecomastia and S • Absorption enhanced by food intake impotence, by interfering with androgen and glucocorticoid synthesis30 • Highly lipophilic and keratinophilic • Needs acid environment for absorption • Side effects: Uncommon effects on liver (fulminant hepatitis and transient increases in LFTs) • Inhibits cytochrome P450Fluconazole • Inhibits 14-α-demethylase, blocking lanosterol conversion to ergosterol • Clinical use: Oral, esophageal, vaginal candidiasis, cryptococcal meningitis, candidal prophylaxis in AIDS and transplant recipients, tinea corporis, cruris, pedis, unguium, histoplasmosis, sporotrichosis, tinea versicolor • Side effects: Nausea, vomiting, diarrhea, abdominal pain, dysgeusia • Rarely, elevated LFTs • Alopecia for prolonged use at 400 mg • Drug interactions: Elevates phenytoin, warfarin, nortriptyline, midazolam, triazolam, and tacrolimusGriseofulvin • Disrupts microtubule mitotic spindle formation causing metaphase arrest • Absorption enhanced by fatty meal • Effective against dermatophytes, but not yeast and bacteria • Indicated for tinea capitis, but resistance to Trichophyton • Indicated for onychomycosis, but cure rate is low and relapse rate is high • 20-50% experience severe headaches • Photoallergy occurs, and may precipitate LE and severe skin reactions • Induces cytochrome P450 • Ineffective against candidiasis, systemic mycoses, and Pityrosporum species • Has been reported as a potential exacerbator of acute intermittent porphryia and thus is contraindicated in patients with a history of porphyria Dermatopharmacology  525
  • 16.4  TOPICAL AND SYSTEMIC CORTICOSTEROIDSTopical Corticosteroids • Utilized for their anti-inflammatory, antimitotic, immunosuppressive and vasoconstricitve properties • Most common adverse effects of topical glucocorticoids are atrophy and striae formation, through suppression of collagen cross-linking during synthesisSystemic Corticosteroids • Decrease circulating lymphocytes • Decrease T-cell responsiveness to antigens • Inhibit release of lysosomal enzymes • Decrease response of macrophages to lymphokines • Decrease antibody production • Increase the number of polymorphonuclear leukocytes and diminish the numbers of lymphocytes, eosinophils, and monocytes • Short-acting steroids, cortisone and hydrocortisone, have the greatest mineralcorticoid activity, while cortisone has the lowest glucocorticoid activity • Intermediate and long-acting steroids, methylprednisolone, triamcinalone, dexamethasone, and betamethasone, have virtually no mineralcorticoid activity, while dexamethasone and betamethasone have the highest glucocorticoid activity32 • Risk of HPA axis suppression is minimized in acute disease with single morning dosing, to mimic normal circadian cortisol production • Alternate-day administration of oral steroids is advised during a tapering regimen to reduce complications of systemic therapy •  ll complications are believed to be reduced by alternate-day dosing except the risk of A posterior subcapsular cataracts, osteoporosis, and osteonecrosis32,33 • Other adverse effects from systemic therapy include increased infection risk, hyperglycemia, hypertriglyceridemia, cushingoid appearance, pancreatitis, sodium retention, potassium wasting, open-angle glaucoma, myopathy, and growth retardation in children3416.5  CYTOTOXIC AGENTS The cytotoxic agents include alkylating agents, such as, cyclophosphamide, chlorambucil, andthe anthracyclines (doxorubicin and dactinomycin) and the antimetabolites, such as, methotrex-ate, azathioprine, thioguanine, mycophenolate mofetil, and hydroxyurea. Other cytotoxic agentsinclude 5-FU and bleomycin.Cyclophosphamide • Nitrogen mustard derivative and is cell-cycle nonspecific, producing DNA cross-linkages at any point in the cell cycle • Treatment of choice in Wegener’s granulomatosis • Increased incidence of lymphoma, leukemia, bladder carcinoma, and squamous cell carcinoma, and leukopenia from bone marrow suppression35 •  emorrhagic cystitis is associated with the increased risk of transitional cell carcinoma of H the bladder and can occur in up to 40% of treated patients36,37526  2011/2012 Dermatology In-Review l Committed to Your Future
  • • Risk of cystitis is avoided by adequate fluid intake, u TIP frequent voiding and careful screening for hematuria; a ladder toxicity is due to the acrolein B metabolite of cyclophosphamide; mesna cyclophosphamide must be discontinued if red blood (sodium 2-mercaptoethanesulfonate) has cells are detected in the urine been used to reduce this toxic effect • Azoospermia: Rare but reported adverse reactionChlorambucil • Like cyclophosphamide, is an alkylating agent that is derived from nitrogen mustard • Steroid-sparing agent in the treatment of vasculitis, Behcet’s disease, dermatomyositis, histiocytosis X, and sarcoidosis • Bone marrow suppression with leukopenia, oral ulcers, amenorrhea and azoospermia are notable adverse effects • In children with nephritic syndrome or adults with a seizure history, can cause generalized tonic-clonic seizures36Methotrexate • S-phase specific antimetabolite, which competitively and irreversibly blocks dihydrofolate reductase from catalyzing the formation of tetrahydrofolate, an important cofactor in thymidylate and purine synthesis • Used in the treatment of psoriasis and other proliferative dermatoses and immunobullous diseases38 u TIP • Most common significant adverse effect of a atients with renal disease, those using P methotrexate use is hepatotoxicity NSAIDS or TMP/SMX, and those with no • Excessive alcohol intake, renal insufficiency, diabetes, folate supplementation are at greater risk obesity and higher cumulative doses of methotrexate of pancytopenia; Leukovorin (folinic acid), with its ability to bypass dihydrofolate increase the risk of toxicity reductase in the cell division pathway, is • Cumulative doses at or above 4.0 grams can risk given under conditions of methotrexate- inducing liver fibrosis and cirrhosis; liver biopsy is the induced myelosuppression gold standard diagnostic test for methotrexate-induced hepatic toxicity39 • Uncommonly causes acute pneumonitis and pulmonary fibrosis • Teratogenic affects both egg and sperm production • Trimethoprim, the sulfonamides, and dapsone, which inhibit the folic acid metabolic pathway, can lead to hematologic toxicity when combined with methotrexate • Tetracyclines, phenytoin, phenothiazines, u TIP chloramphenicol, NSAIDS, salicylates, and a auses radiation recall, in which the adminis- C sulfonamides can all increase methotrexate levels by tration of the drug causes either previous sunburn to reappear or previously irradiated displacement of plasma proteins 40 skin to develop a toxic cutaneous reactionAzathioprine • Antimetabolite, is a purine analog that acts only during the S phase of the cell cycle in the formation of adenine and guanine nucleotides; azathioprine is converted into 6-mercaptopurine, which is then converted into the active metabolite 6-thioguanine via the hypoxanthine guanine phosphoribosyltransferase (HGPRT) pathway • Also converted into several inactive metabolites via xanthine oxidase and thiopurine methyltransferase (TPMT) activity Dermatopharmacology  527
  • • Used as a corticosteroid sparing agent in the u TIP treatment of autoimmune bullous diseases, a hen either xanthine oxidase or TPMT activity W is diminished, the HGPRT pathway becomes vasculitides, and other cutaneous inflammatory the primary pathway and excess active diseases41 metabolites, toxic purine analogs, can lead to • Adverse effects include increased risk of bone marrow suppression; can occur either lymphoproliferative malignancies and cutaneous in the setting of concomitant allopurinol use, which inhibits xanthine oxidase or in patients squamous cell carcinomas; risks have only been with genetically low TPMT allele activity documented in patients with rheumatoid arthritis or severe immunosuppression, and not in patients treated for cutaneous disease42 • Hypersensitivity syndrome (fever/shock) can occur at 14 daysMycophenolate Mofetil (MMF) • Inhibits de novo purine synthesis • Noncompetitively inhibits inosine monophosphate dehydrogenase (IMPDH) • Cells dependent on the de novo pathway of purine synthesis rather than the salvage pathway are most affected by inhibition of this enzyme • T- and B- cells are particularly affected by the antiproliferative activity of MMF because these cells lack a purine salvage pathway36 • Mycophenolate mofetil is cleaved to mycophenolic acid after ingestion • Liver inactivates mycophenolic acid • GI tract and epidermis can “reactivate” the inactive form via β-glucoronidase • Gastrointestinal: Nausea, diarrhea, anorexia, abdominal cramps, vomiting, anal tenderness (more common with higher doses) • Genitourinary: Urgency, frequency, dysuria • Reversible bone marrow toxicity (rare)Hydroxyurea • S-phase specific cytotoxic agent, inhibits ribonucleotide reductase, an enzyme responsible for converting ribonucleotides to deoxyribnucleotides in DNA synthesis • Treats psoriasis, scleromyxedema, hypereosinophilic syndrome, pyoderma gangrenosum, Sweet’s syndrome, vasculitis secondary to cryoglobulinemia • Anemia, hepatitis, and renal toxicity are associated adverse effects36 •  oikiloderma of the dorsal hands with a band-like distribution over the fingers and toes, P diffuse hyperpigmentation, and leg ulcers upon withdrawal of the medication have been described • Radiation recall, acral erythema, and dermatomyositis-like reactions are other rare cutaneous reactions43,44Fluorouracil (5-FU) • Cell-cycle specific pyrimidine antagonist, preventing the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) in DNA synthesis • Has the ability to incorporate into RNA, where it has a higher affinity for rapidly proliferating tumor tissue rather than healthy tissue • Effective as a topical therapy for actinic keratoses528  2011/2012 Dermatology In-Review l Committed to Your Future
  • Bleomycin • Effective for dermatologic use as an intralesional therapy for HPV infection • Damages DNA by direct binding during M and G2 phases • Associated with Raynaud’s phenomenon occurring in digits treated with intralesional therapy for periungual and plantar warts45 Several cytotoxic agents such as doxorubicin, dactinomycin, the vinca alkaloids, vincristineand vinblastine, play an important role in dermatology in the treatment of Kaposi’s sarcoma46 Doxorubicin (Adriamycin) • Blocks nucleic acid transcription by intercalation with DNA residues • Cardiac toxicity Dactinomycin (Actinomycin-D) • Forms complexes with DNA, inhibiting DNA, RNA, and protein synthesis Vinblastine • Extract from the periwinkle plant, is a cell-cycle specific cytotoxic agent, that arrests mitosis in metaphase by microtubule linkage • Vincristine is an analog of vinblastine4716.6  IMMUNOSUPPRESSANTSCyclosporin A • Immunosuppressant against T-cell activity → inhibits calcineurin, a phosphatase activated in the presence of calmodulin and calcium, by cyclophilin • Forms a complex with cyclophilin, blocking its ability to activate calcineurin, and thus preventing calcineurin from phosphorylating NFAT-1, a transcription factor. NFAT-1, when phosphorylated can travel into the nucleus of cells and initiate IL-2 production, which causes helper T-cell (CD4) and cytotoxic T-cell (CD8) proliferation48 • Treats psoriasis, autoimmune bullous disorders, lichen planus, severe atopic dermatitis, and pyoderma gangrenosum • Most common electrolyte abnormalities are u TIP hyperkalemia, hyperuricemia, and hypomagnesemia a dverse effects: nephrotoxicity, reversible A hypertension, paresthesias and dysesthesias, • Metabolized by the hepatic cytochrome P-450 3A4 hypertrichosis, gingival hyperplasia, enzyme system, concomitant use of other drugs hyperlipidemia, and electrolyte imbalances49 that inhibit or induce this P-450 isoform, can lead to inappropriate circulating levels of cyclosporine • Aminoglycosides, NSAIDS, amphotericin B, and vancomycin can potentiate renal toxicity when combined with cyclosporine16.7  DAPSONE AND SULFAPYRIDINE • Dapsone, sulfonamide, and sulfapyridine treat leprosy, dermatitis herpetiformis, bullous disease of childhood, bullous SLE, EED, subcorneal pustular dermatosis, Sweet’s syndrome, and pyoderma gangrenosum • Anti-inflammatory activity is most effective against polymorphonuclear leukocytes by inhibiting their myeloperoxidase activity and chemotactic abilities •  emolytic anemia and methemoglobinemia are well known side effects of dapsone, are H dose-related and occur with varying degrees in all individuals Dermatopharmacology  529
  • • Methemoglobinemia → not a major problem for most patients; cyanosis seen after level greater than 3% → symptoms of methemoglobinemia are weakness, tachycardia, nausea, headache, and abdominal pains •  ral methylene blue is used in emergency situations to lower methemoglobin levels O • Hematologic toxicity is related to G6PD function • G6PD-deficient individuals are more sensitive to the oxidative stress of dapsone metabolites • Cimetidine and Vitamin E have both been shown to provide some protection against methemoglobin formation • Agranulocytosis50,51 • Neurologic effects are also idiosyncratic and include a predominantly motor peripheral neuropathy and acute psychosis • Dapsone hypersensitivity syndrome: severe mononucleosis-like reaction, including fever, erythroderma, hepatitis, eosinophilia, and even death52 • Sulfapyridine has a similar but often less severe side effect profile • Sulfapyridine can cause renal toxicity by crystallization in the urine16.8  ANTIMALARIALS • The most commonly used antimalarials are the 4-aminoquinolones, hydroxychloroquine, chloroquine, and quinacrine • Effective in DLE, SLE, dermatomyositis, other photosensitive dermatoses like porphyria cutanea tarda and PMLE, granulomatous dermatoses and lymphocytic infiltrates • Mechanism of action not well understood → may work by intercalating into DNA, blocking further transcription • Chloroquine has immunosuppressive and anti-inflammatory activity by impairing chemotaxis of leukocytes and eosinophils, inhibiting lysosomal function, and inhibiting antigen-antibody complex formation53 • High affinity for melanin-containing tissue, with a tendency to accumulate in ocular tissues such as the choroids and ciliary body • Most severe adverse effect is ocular toxicity with retinopathy, which is potentially irreversible • Premaculopathy associated with changes in visual field without visual loss is reversible if the antimalarial is discontinued • True retinopathy is associated with “bull’s eye” pigment deposition, central scotoma, and diminished visual acuity • Only the 4-aminoquinolones, hydroxychloroquine and chloroquine are associated with ocular toxicity • Risk of retinopathy is greatest with chloroquine and does not exist for quinacrine54 • Chloroquine and hydroxychloroquine should not be given together because of an additive effect on retinotoxicity • Other adverse effects are hemolysis in patients with G6PD-deficiency, GI distress, and infrequent central nervous system effects with confusion, seizures, and restlessness • Cutaneous adverse reactions are a bluish-gray hyperpigmentation over the shins, face, and palate and in the nailbeds as transverse bands → due to both hemosiderin and melanin • Quinacrine frequently produces a yellow discoloration to the sclera and skin, especially over the dorsal hands and feet55530  2011/2012 Dermatology In-Review l Committed to Your Future
  • 16.9  RETINOIDS • All synthetic and natural substances that have Vitamin A-like structure and activity • Vitamin A exists as retinol, a Vitamin A alcohol; retinal, a Vitamin A aldehyde; and retinoic acid, a Vitamin A acid; these three forms are interconvertible • Precursors of Vitamin A (retinal): carotenoids, synthesized by plants and when ingested are oxidized to Vitamin A • Retinol is transported in the serum by retinol binding proteins and transthyretin • Retinol binds to a cytosolic retinol binding protein for translocation to the nucleus56 • First-generation synthetic retinoids: tretinoin (all-trans RA) and isotretinoin (13-cis RA) • Second-generation synthetic retinoids are etretinate, which was replaced by its metabolite acitretin • Third-generation (polyaromatic) retinoids include the arotinoids, tazarotene, adapalene, and bexarotene arotinoids have been developed to interact selectively with specific receptors • Isotretinoin, acitretin, and bexarotene are water- u TIP soluble, with very little lipid deposition57; water-soluble a he recommended period for contraception T retinoids are undetectable in the serum after 1 month after acitretin therapy is 3 years58 of stopping therapy • Etretinate is 50 times more lipophilic than acitretin with increased storage in adipose tissue • Highly lipid-soluble etretinate lasts several years in the fatty tissues; in the presence of ethanol (alcohol), acitretin is reesterified to etretinate • Etretinate has a half-life of 100 days, in contrast to the half-life of acitretin and isotretinoin, which is 50 hours and 20 hours, respectively59 • Tretinoin and isotretinoin down regulate the proliferative keratins, K6 and K16 • Keratinocyte differentiation is enhanced by retinoids with increased filaggrin production, increased keratohyalin granules, keratin filaments and Odland body secretion of lipids • Isotretinoin reduces the size of sebaceous glands and decreases differentiation to mature sebocytes • Retinoids normalize keratinization leading to decreased follicular occlusion • Retinoids directly inhibit ornithine decarboxylase and therefore lessen inflammatory hyperplasia56,57 • Acitretin is used to treat severe, pustular or erythrodermic forms of psoriasis • Isotretinoin is used to treat nodulocystic or recalcitrant, scarring acne • Bexarotene is used to treat mycosis fungoides • Retinoids are used for follicular disorders, such as HIV-associated eosinophilic folliculitis and for disorders of keratinization, such as Darier’s disease or lamellar ichthyosis56 • Retinoid teratogenicity: microtia, hearing loss, microphthalmia, optic nerve atrophy, acral and axial skeletal abnormalities, cardiovascular defects, hydrocephalus, microcephaly, meningomyelocele, thymic aplasia, and anal and vaginal atresia60 • The most common serious side effects from systemic u TIP retinoids include reduced night vision, diffuse interstitial a exarotene has been shown B skeletal hyperostosis (DISH), premature epiphyseal to cause reversible hypothyroidism56,61 closure, elevated serum lipids and transaminases, pseudotumor cerebri (risk increased with concomitant tetracyclines), depression, and myopathy Dermatopharmacology  531
  • Table 16-1. Drug Category Half-life Metabolism Excretion Tretinoin First generation 48 mins Hepatic Bile, urine Isotretinoin First generation 20 hours 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 Table 16-2. Receptor Specificities of Topical Retinoids RAR-α RAR-β RAR-γ RXR-α RXR-β RXR-γ Tretinoin (all-trans-RA) + + + – – – Alitretinoin (9-cis-RA) + + + + + + Adapalene – + + – – – Tazarotene – + + – – – Table 16-3. Receptor Specificities of Systemic Steroids RAR-α RAR-β RAR-γ RXR-α RXR-β RXR-γ Isotretinoin (13-cis-RA) – – – – – – Acitretin – – – – – – Bexarotene – – – + + + 16.10  SUNSCREENS • Two main categories: chemical absorbers and physical blockers • Chemical sunscreens absorb ultraviolet light and, in their conversion from a higher energy state back down to the ground state, convert the absorbed energy into longer lower energy wavelengths • Chemical sunscreens further divided into UVA and UVB absorbers • Most common UVB-absorbing chemicals are padimate O (PABA esters), octylmethoxycinnamate, and octyl salicylate • Most common UVA-absorbing chemicals are the benzophenones, dibenzoylmethanes and methyl anthranilate • Benzophenones, oxybenzone and dioxybenzone, have u TIP the broadest spectrum of absorption of the chemical a llergic contact allergy can occur A sunscreens with UVB and UVA II absorption with PABA and its derivatives, which can cross react with azodyes, • Avobenzone or Parsol 1789 is a dibenzoylmethane with aniline, procaine, benzocaine, UVA I absorption paraphenylenediamine and • Physical blockers, titanium dioxide and zinc oxide, reflect sulfonamides and scatter ultraviolet rays62,63 • There have been increasing reports of photoallergy to benzophenones64 532  2011/2012 Dermatology In-Review l Committed to Your Future
  • Summary of Sunscreens UVA Blockers • Benzophenones (dioxybenzone, oxybenzone, sulisobenzone) • Dibenzoylmethane → avobenzone (Parsol 1789), the best UVA/UVB blocker • Methyl anthranilate • Red veterinary petrolatum UVB Blockers • PABA • Cinnamates • Salicylates • Amyl p-dimethylaminobenzoate (Padimate A, Padimate O → PABA derivatives) Physical Blockers • Titanium dioxide • Zinc oxide16.11  ANTIPARASITICSLindane • An organochloride that blocks neural transmission, inducing respiratory and muscular paralysis in parasites • Effective against scabies, pubic lice, head lice and body lice • Side effects from lindane include irritant contact dermatitis and neurotoxicity, predominantly seizuresPermethrin • Pyrethroid compound that disables sodium transport channels in the nerve cell membrane of the parasite, leading to its paralysis65Ivermectin • Used to treat strongyloidiasis, onchocerciasis and Norwegian scabies • Ivermectin blocks glutamate-gated chloride ion channels, leading to paralysis of the parasite66Malathion • An organophosphate cholinesterase inhibitor • Used for treatment of scabies and head lice • FlammablePrecipitated Sulfur (6%) • Used for treatment of scabies in pregnant women67Thiabendazole • Inhibits fumarate reductase, a helminth-specific enzyme • Used to treat creeping eruption or cutaneous larva migrans and larva currens68 Dermatopharmacology  533
  • 16.12  ANTIHISTAMINES • First generation H1 antihistamines competitively block histamine from binding to histamine receptors; class includes diphenhydramine, promethazine, cyproheptadine, chlorpheniramine, and hydroxyzine • Cyproheptadine is the histamine of choice for treating cold urticaria69 • Adverse effects of first-generation H1 antihistamines are sedation, increased appetite, dry mouth, constipation, tachycardia, dysrhythmias, and blurry vision • Chlorpheniramine is considered one of the safest antihistamines for pregnancy70 • Second-generation H1 antihistamines are also histamine antagonists for receptor binding • These include fexofenadine, loratadine, and cetirizine; fexofenadine has few or no sedative and anticholinergic effects; loratadine is a long-acting, minimally sedating antihistamine; cetirizine is a low sedation metabolite of hydroxyzine • Second generation H1 antihistamines are used for chronic urticaria71 • Cimetidine and ranitidine (H2 antihistamines) are used in dermatology; cimetidine has suppressor T-cell inhibitory activity, by competitive blocking their H2 receptors • Immunomodulatory effects are useful for treating mucocutaneous candidiasis, verrucae vulgaris, and condyloma acuminata • Cimetidine also competitively inhibits dihydrotestosterone at the androgen receptor site; has several anti-androgen side effects including gynecomastia, impotence, and loss of libido72 • Doxepin is a tricyclic antidepressant with H1 and H2 antihistamine activity; topical doxepin cream is used for pruritic disorders, neurotic excoriations and factitial dermatitis; oral doxepin can cause anticholinergic side effects as well as cardiotoxic effects73 • Cromolyn sodium blocks mast cell degranulation and is used for controlling diarrhea in mastocytosis16.13 HORMONE-RELATED DRUGSSpironolactone • Aldosterone antagonist that works as an antiandrogen by blocking the androgen receptor and by inhibiting testosterone and DHT production • Steroid molecule with structure closely resembling mineralocorticoids • Primary metabolite, canrenone, is the active aldosterone antagonist • Treats hirsuitism, acne, and androgenetic alopecia • 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 • Other adverse effect is gynecomastiaFlutamide • Nonsteroidal antiandrogen when converted to 2-OH-flutamide, which competitively inhibits DHT binding • Limited use in dermatology; combined with oral contraceptives to treat hirsuitism • Hepatotoxicity with potentially fulminant liver failure is possible adverse effect534  2011/2012 Dermatology In-Review l Committed to Your Future
  • Finasteride • Specifically inhibits type II 5a-reductase, which converts testosterone to DHT, predominantly in hair follicles from frontal to vertex scalp and in sebaceous gland ducts • Most often dermatologic use is in male pattern androgenetic alopecia • Infrequent reported side effects include decreased libido, erectile dysfunction and decreased ejaculate volume (type II 5a-reductase also largely found in the prostate) • Known teratogen; causes genitourinary defects in male offspring; category XStanozolol and Danazol • Synthetic derivatives of testosterone, attenuated androgens alkylated in the 17-a position, with marked anabolic properties, and diminished androgenic properties • Known to increase concentrations of select hepatic-derived plasma glycoproteins, including the inhibitor of the first component of complement • Effective in preventing angioedema attacks in patients with hereditary angioedema • Also potent fibrinolytic activity used in treatment of cryofibrinogenemia, lipodermatosclerosis, and livedoid vasculitis • Adverse effects include mild alopecia, hirsuitism, acne, and menstrual irregularities in female patients • Other side effects are hypertension, insulin resistance, interference with liver function, and muscle cramps16.14  MISCELLANEOUS DRUGS Miscellaneous drugs, including colchicine, gold, potassium iodide, and thalidomide are importantdermatologic agents to review.Colchicine • Alkaloid used in dermatology for its effects on neutrophils • Has antimitotic activity • Binds to tubulin dimers in neutrophils, preventing microtubule assembly critical for metaphase and neutrophil motility and chemotaxis • Used in the treatment of gout and familial Mediterranean fever, however, there is some evidence to suggest its usefulness in treating Sweet’s syndrome, Behcet’s disease, aphthous stomatitis, dermatitis herpetiformis, linear IgA bullous disease, and vasculitis74 • Most common side effect from colchicine use is gastrointestinal distress with abdominal cramping and watery diarrheaGold • Used in dermatology for its anti-inflammatory activity • Inhibits macrophage and neutrophil phagocytosis, complement activity, and prostaglandin synthesis • Effective in pemphigus by inhibiting degradative epidermal lysosomal enzymes, which contribute to blister formation • Used to treat severe discoid lupus erythematosus and psoriatic arthritis75 • Mucocutaneous side effects, more common with injectable gold, include stomatitis, cheilitis, lichen planus-like eruptions, and pityriasis rosea-like eruptions • Rarely, can cause diffuse pulmonary infiltrates leading to a chronic pulmonary fibrosis •  Nitritoid reaction after gold injection: acute flushing, dizziness, hypotension, and fainting76 Dermatopharmacology  535
  • Potassium Iodide • Mechanism of action not well understood • May inhibit granuloma formation, which may contribute to its efficacy in treating cutaneous sporotrichosis • Suppresses hypersensitivity reactions by mediating the release of heparin from mast cells • Used to treat erythema nodosum, nodular vasculitis and subacute nodular migratory panniculitis, Wegener’s granulomatosis, and in some cases, erythema multiforme, and Sweet’s syndrome • Can cause iododerma, acneiform, or vasculitic eruptions77 • Thyroid function must be thoroughly assessed prior to initiating therapy with potassium iodide •  olff-Chaikoff effect: the inhibition of thyroid hormone synthesis from excess iodides that W 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 initiatedThalidomide • Drug of choice for erythema nodosum leprosum • Inhibits tumor necrosis factor-alpha and suppresses monocyte and neutrophil phagocytosis • Other known uses for thalidomide include HIV-associated mucosal ulceration and apthous stomatitis, chronic cutaneous lupus erythematosus, and chronic GVHD79 • Teratogenicity: Most common birth defect associated with thalidomide is underdevelopment of arms and legs, known as phocomelia; ear malformation, gastrointestinal and urogenital defects are also well documented; peak vulnerability to thalidomide occurs between days 21 to 36 of gestation, during which only a single dose will cause the birth defects to occur80,81 • Peripheral neuropathy, most commonly presenting as proximal muscle weakness and symmetric painful paresthesias of the distal extremities • A very common side effect is sedation, which is additive with other sedatives, such as alcohol and barbiturates8016.15  BIOLOGIC THERAPY • Biologic therapy refers to proteins synthesized through recombinant DNA techniques as immunomodulating agents • Recombinant human cytokines, humanized monoclonal antibodies, or specific molecular receptors • Psoriasis is currently the major target for biologic therapies • With regard to psoriasis therapy, there are three classes of biologics: the T-cell targeting drugs (efalizumab and alefacept), the TNF-inhibiting drugs (etanercept, infliximab, adalimumab) and those directed against interleukins (Ustekinumab and Kineret) Alefacept (Amevive) is an immunoglobulin/receptor fusion protein, and the IL 12/23 inhibi-tor, ustekinumab. It is a human LFA-3/IgG fusion protein, which is designed to block LFA-3 onantigen presenting cells from interacting with CD2 on activated T-cells, thus preventing T-cellstimulation. Further, alefacept eliminates activated memory T-cells, so weekly CD4 T-cell countsare recommended.101,102 Alefacept treats psoriasis. It is given intramuscularly. A primary concern isT-cell depletion, so CD-4 T-cell counts must be monitored.106536  2011/2012 Dermatology In-Review l Committed to Your Future
  •  Efalizumab (Raptiva) is a humanized monoclonal antibody against CD-11a, a component ofLFA-1 on T-cells. It blocks LFA-1 on T-cells from interacting with ICAM-1 on antigen presentingcells, endothelial cells, and cells in the dermis and epidermis.104 Efalizumab blocks the ability ofT-cells from egressing the vasculature and entering the skin. Efalizumab is effective in treatingpsoriasis. It is given subcutaneously. Withdrawn from U.S. market. Etanercept (Enbrel) is an immunoglobulin/receptor fusion protein. It is a human dimeric fusionprotein of the TNF-alpha receptor linked with the Fc portion of human IgG1. It binds to TNF-alphaand blocks receptor binding and subsequent proinflammatory TNF-alpha activity.103 Etanercept iseffective 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 solubleand transmembrane TNF-alpha. It is given subcutaneously every other week. It is effective forpsoriaisis and psoriatic arthritis. Has been associated with reactivation of tuberculosis.106 Infliximab (Remicade) is a chimeric monoclonal antibody directed against TNF-alpha. Itbinds to TNF-alpha, blocking the receptor binding and proinflammatory activity of TNF-alpha.105Infliximab is effective in treating both psoriasis and psoriatic arthritis. It is infused intravenously.Tuberculin skin test is required prior to starting therapy. Rare association with demyelinating diseases.106 Ustekinumab (Stelara) is a human monoclonal antibody that binds to the p40 protein subuniton both IL-12 and IL-23 cytokines. It is administered subcutaneously and is approved for the treat-ment of psoriasis. Kineret (Anakinra) is an IL-1 receptor antagonist indicated for the treatment of Periodic Feversyndromes.16.16  DRUGS IN PREGNANCY The categories for safety of drug use in pregnancy are as follows: 82,83 Category A: Controlled studies in humans show no risk to fetus Category B: ontrolled human studies show no risk to fetus but may show risk to animals, or C no risk in animal studies but no human studies conducted Category C: Risk to human fetus cannot be ruled out, studies are lacking; animal studies are equivocal Category D: Controlled studies show risk to human fetus, but in some instances benefits may outweigh risks Category X: Contraindicated in pregnancy Drugs used in dermatology are listed below by category determined by the FDA.83 Lists are not comprehensive.Category X • Acitretin • Etretinate • Estrogens • Finasteride • 5-fluorouracil • Flutamide • Isotretinoin • Methotrexate • Stanozolol • Tthalidomide • Tazarotene Dermatopharmacology  537
  • Category D • Aspirin • Azathioprine • Bleomycin • Colchicine • Cyclophosphamide • Hydroxyurea • Mechlorethamine • Penicillamine • Potassium iodide • Tetracycline (Griseofulvin and spironolactone are unrated but should be used as cautiously as category D drugs)Category C • Quinolones/ciprofloxacin • Ttrimethoprim-sulfamethoxazole • Cyclosporine (but believed to be safe in pregnancy) • Acyclovir • Fluconazole, ketoconazole, itraconazole • Benzoyl peroxide • Topical tretinoin • Topical and oral steroids • EfalizumabCategory B • Penicillin • Erythromycin (not estolate form due to hepatotoxicity in the mother) • Dimenhydrinate • Cyproheptadine • Azeleic acid • Permethrin • Cephalosporins • Lidocaine • Etanercept, alefacept, and infliximabCategory A • Folic acid • Levothyroxine - Azathioprine and NSAIDS are associated with IUD failure 84,85 - Griseofulvin and rifampin are associated with oral contraceptive failure, by increased estrogen metabolism by hepatic microsomal enzyme induction538  2011/2012 Dermatology In-Review l Committed to Your Future
  • 16.17  DRUG INTERACTIONS The most relevant drug interactions in dermatology involve the hepatic biotransformationpathways catalyzed by the cytochrome P-450 isoenzymes from the subfamilies CYP3A3/4.Drugs that induce CYP3A enzymes may decrease levels of drugs that act as substrates forCYP3A. The CYP3A inhibitors may increase levels and cause toxicity of drugs metabolized bycytochrome P-450.Cytochrome 2B6 • TerbinafineSpecific Drug Eruptions Acute Generalized Exanthematous Pustulosis (AGEP)89 • Beta-lactam antibiotics • Macrolide antibiotics • Mercury • Cephalosporins Lichenoid Eruptions90 u TIP • Hydrochlorothiazide aCytochrome P450 Inhibitors/Inducers • Antimalarials Inhibitors • NSAIDS • Warfarin • Gold • Azoles • Verapamil • D-penicillamine • Erythromycin • Captopril • Sex steroids and methylprednisolone SLE-like Eruption91 • St. John’s wort • Ciprofloxacin • Anticonvulsants • Cimetidine • Isoniazid • Cyclosporine • Hydralazine • Clarithromycin • Minocycline • Diuretics (furosemide and thiazides) • Danazol • Procainamide • Diltiazem • Penicillin • Grapefruit juice • D-penicillamine • Protease inhibitors SCLE-like Eruption92 Inducers • Griseofulvin • Azathioprine • Rifampin • Glyburide • INH • Griseofulvin • Propranolol • Phenytoin • Terbinafine • Phenobarbital • Hydrochlorothiazide • Carbamazepine • Penicillin • Omeprazole • Penicillamine • Retinoids • Tobacco • Piroxicam Fixed Drug Eruptions93 • Tetracyclines • Barbiturates • NSAIDS, naproxen • Sulfonamides • Phenopthalein (in laxatives) Dermatopharmacology  539
  • • Erythromycin • Pseudoephedrine hydrochloride (non-pigmenting FDE)94 Acne-inducing Drugs • ACTH • Steroids • Halogens • Lithium • INH • Dilantin Psoriasis-inducing Drugs • Lithium • Corticosteroid withdrawal • NSAIDS (though not really true) • Antimalarials (though not really true) • Inderal (beta blockers) • Interferons • Interleukin 2Hypersensitivity Syndromes • Seen most often with anticonvulsants and sulfonamides, and less commonly with allopurinol, dapsone, and gold • Reactions present with fever, rash with facial edema, eosinophilia, lymphadenopathy, hepatitis, and nephritis • Pathogenesis of anticonvulsant hypersensitivity is related to the individual’s inability to detoxify arene oxide metabolites of these medications, due to lack of epoxide hydrolase • Diphenylhydantoin, phenobarbital, and carbamazepine are known to cross-react, whereas valproic acid generally does not cross react95Drug-related Pigmentation Side Effects • Amiodarone can cause a slate-gray hyperpigmentation in photo-exposed areas. Histologically, PAS positive yellow-brown granules are seen in macrophages in the dermis; on electron microscopy, membrane-bound structures resembling lysosomes are visualized • Clofazamine can cause a “drug-induced lipofuscinosis” • Skin initially turns pink then red-brown in lesions of patients with Hansen’s disease • Granular pigment thought to be lipofuscin is seen in macrophages • Chlorpromazine, thioridazine, imipramine and clomipramine causes a sun-exposed purple- gray hyperpigmentation, with corneal and lens opacities • Gold, silver, and bismuth can induce a slate-gray hyperpigmentation in sun-exposed areas • Bismuth can cause pigmentation of the gingival margin • Arsenical melanosis causes truncal hyperpigmentation with depigmented raindrop-like macules96Chemotherapy-induced Cutaneous Effects Radiation Enhancement and Recall • Actinomycin D • Methotrexate • Bleomycin • -rubicins (dauna-, doxo-, ida-)540  2011/2012 Dermatology In-Review l Committed to Your Future
  • Acral Erythema, Edema, and Tenderness • Ara C (cytosine arabinoside) • Doxorubicin • 5-fluorouracil (pyridoxine reduces the pain) • MethotrexateNeutrophilic Eccrine Hidradenitis • Ara C • Bleomycin • Neutropenic patients with fever • Erythematous papules, plaques, or nodulesHyperpigmentation – Localized • Bleomycin → flagellate or linear • 5-fluorouracil → serpentine hyperpigmentation overlying the veins proximal to the infusion siteHyperpigmentation – Diffuse • Busulfan • Cyclophosphamide • Hydroxurea • MethotrexateHyperpigmentation – Under Bandages or Adhesives • Thiotepa • Topical carmustine (BCNU)Hyperpigmentation – Nails • Cyclophosphamide, bleomycin and 5-FU → transverse bands • Doxorubicin causes hyperpigmentation of nails, skin, and tongueRaynaud’s Phenomenon • Bleomycin with vinblastineAcral Sclerosis • BleomycinUlceration Over Pressure Areas • Bleomycin • MethotrexateUrticaria • L-asparaginaseFolliculitis • Actinomycin D • Daunarubicin • 5-FU • MethotrexateLinear IgA Dermatosis • Vancomycin • Lithium • Amiodarone • Captopril • Penicillin Dermatopharmacology  541
  • Hair • Methotrexate → flag sign Increased Growth of Eyelashes (Trichomegaly) • Interferons Bullous Pyoderma Gangrenosum and Sweet’s • G-CSF Exacerbation of LCV (Leukocytoclastic Vasculitis) • G-CSF • GM-CSF Exacerbation of Psoriasis • Interferon-alpha • Interferon-gamma • G-CSF • IL-2 Interleukin-2 Effects • Psoriasis exacerbation • Diffuse erythema • Desquamation • Pruritus • Mucositis • Glossitis • Flushing • Erythroderma or TEN-like reaction Pulmonary Fibrosis • Bleomycin • Methotrexate RE F E RE N C E S1. Epstein ME, et al. Antimicrobial agents for the dermatologist. I. β-lactam antibiotics and related compounds. J Am Acad Dermatol 1997; 137: 149-165.2. Neu HC. Penicillins: microbiology, pharmacology, and clinical usage. In BM Kagan, Ed. Antimicrobial therapy. Philadelphia: WB Saunders, 1980; 31-32.3. Romano A, et al. Immediate hypersensitivity to penicillins. Studies on Italian subjects. Allergy 1997; 52: 89-93.4. Sadick, NS. Systemic antibacterial agents. In SE Wolverton, Ed. Comprehensive dermatologic drug therapy. Philadelphia: WB Saunders, 1980; 31.5. Levine, BB. Antigenicity and cross reactivity of penicillins and cephalosporins. J Infect Dis 1973; 128: 364-366.6. Stricker BH, et al. Serum sickness-like reactions to cefaclor. J Clin Epidemiol 1992; 45: 1177.7. Neuvonen PJ, et al. Interference of iron with the absorption of tetracyclines in man. BMJ 1970; 4: 532.8. Klein NC, Cunha BA. Tetracyclines. Med Clin North Am 1995; 79: 789-801.9. Hendrix JD, et al. Cutaneous hyperpigmentation caused by systemic drugs. Int J Dermatol 1992; 3: 458.10. Rosen T, Hoffman TJ. Minocycline-induced discoloration of the permanent teeth. J Am Acad Dermatol 1989; 21: 569.11. Alvarez-Elcoro S, Enzler MJ. The macrolides: erythromycin, clarithromycin, and azithromycin. Mayo Clin Proc 1999; 74: 613-634.12. Wilson WR, Cockerill FR 3rd. Tetracyclines, chloramphenicol, erythromycin, and clindamycin. Mayo Clin Proc 1983; 58: 92-98.542  2011/2012 Dermatology In-Review l Committed to Your Future
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  • NOTES546  2011/2012 Dermatology In-Review l Committed to Your Future