Systemic therapy of skin diseases. Gabriella Emri

Transcription

1 Systemic therapy of skin diseases Gabriella Emri

2 Therapy of skin diseases Systemic therapy + topical therapy Aim of systemic therapy: therapy of skin diseases considering the pathogenetic factors diminishing the subjective complaints accompanying the skin symptoms (e.g. pruritus, pain, fever) therapy of the cause of the skin symptoms (e.g in the case of an infection) therapy of the internal disease influencing the skin symptoms (e.g. cardial decompensation, diabetes mellitus, arteriosclerosis, chronic venous insufficiency)

3 Antibiotics Severe impetigo, pyoderma, superinfected atopic dermatitis: beta-lactames or clindamycine, makrolides, microbiological examination if necessary

4 Antibiotics Erysipelas: beta-lactames or clindamycine, makrolides, in combination if necessary: metronidazole, aminoglikozide

5 Antibiotics Acne: tetracyclines, erythromycine, clindamycine, sulfonamide+trimethoprim, microbiological examination if necessary Rosacea: metronidazole, tetracyclines, erythromycine, clindamycine, sulfonamide+trimethoprim, microbiological examination if necessary

6 Antibiotics Lyme-disease: doxycycline, benzylpenicilline, ceftriaxone Syphilis: benzylpenicilline, benzathine benzylpenicilline

7 Antiviral drugs Acyclovir guanozine-analogue, arrests the viral DNA-polymerase HSV-1, -2, VZV, CMV (prophylaxis) 5x mg/day p. o. or 3x5-10 mg/kg/day i. v. dose reduction in CRF herpes simplex prophylaxis: 2-3x200 mg careful application in pregnancy Famcyclovir 3x250 mg p. o. (zoster), 2x125 mg (recurrent herpes genitalis) Inosiplex 50 mg/kg alone not enough

8 Antifungal drugs Itraconazole effective against Dermatophytones, moulds, several yeasts (C. albicans, C. crusei) (inhibits the synthesis of ergosterole) contraindicated: in pregnancy several drug interaction is possible skin mycosis: mg/d for 2-4 ws, onychomycosis: 2x200 mg/day for 7 ds, repeat at the 4 th and the 7 th ws, genital: 2x200 mg for 1 day

9 Antifungal drugs Terbinafine effective against Dermatophytones contraindicated: in renal or hepatic disease skin mycosis: 250 mg/d for 2-4 ws, onychomycosis: 250 mg/day for 6-12 ws

10 Antifungal drugs Fluconazole effective against Dermatophytones and yeasts (less efficient against: T. mentagrophytes, C. glabrata, C. guilliermondii) contraindicated: in severe hepatic disease, in pregnancy, by manifestation of any skin symptoms (TEN!) listen to drug interactions genital: 1x150 mg, invasive: mg/d (for children 3-6 mg/kg/d), dermatophytones: 50 mg/d (1-2 mg/kg/d), onychomycosis: 150 mg/w for 3-6 or 6-12 ms

11 Invazive mycosis: Amphotericin B Antifungal drugs renal toxicity, fever, arthralgia, myalgia, nausea, headache are possible Voriconazole Caspofungin

12 Antihistamines Urticaria, anaphylaxia, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, pruritus, prurigo sedatives: hydroxyzine, promethazine, chloropyramine nonsedatives: (levo)cetirizine, fexofenadine, (des)loratadine after the age of 1 month: dimetindene contraindicated: in pregnancy, glaucoma, urinary retention

13 Corticosteroids Dose-dependent anti-inflammatorical effect (0.3-1 mg/kg prednisolone), immunosuppressive effect (>1 mg/kg) Inhibits the synthesis of cytokines and lipoid mediators of macrophages, the adhesion of neutrophils to the endothel, the synthesis and release of eosinophil and mastocyte mediators (anti-inflammatorical) Inhibits the cytokine-production of T-lymphocytes, the Ig-synthesis of B- cells, the cytokine-production and MHCII-expression of macrophages (immunosuppressive) 5 mg prednisolone = 4 mg methylprednisolone = 0.75 mg dexamethasone

14 Corticosteroids Short-term, intermediate dose therapy (32-48 mg methylprednisolone/d, reduced in 1-2 ws): severe allergic contact dermatitis, drug reactions, erythema nodosum, erythema multiforme, lichen planus, leukocytoclastic vasculitis, Sweet-sy., granulomatous inflammations

15 Corticosteroids High dose therapy (64-96 mg methylprednisolone): angioedema, Jarisch- Herxheimer reaction, lupus erythematosus, pyoderma gangrenosum

16 Corticosteroids Long-term therapy (starting with high dose, maintainance at the minimum effective dose, completing with other immunosuppressive drugs): autoimmune bullous diseases, connective tissue diseases, Sezary-sy., vasculitis

17 Corticosteroids contraindicated: in severe infection, osteoporosis, GI ulcer, myopathies, psychosis, glaucoma, recurrent thrombosis, in the first trimester of pregnancy listen to drug interactions IMPORTANT avoid systemic steroids in the following cases: Atopic dermatitis: fast response, but fast recurrence after stopping the steroid therapy Cutaneous lupus erythematosus: better to keep it for therapy of systemic symptoms Psoriasis: limited effect, after stopping rebound, even psoriasis pustulosa can be developed

18 Corticosteroids Side effects: osteoporosis (after 6 months 50%), hypertension, diabetes mellitus, infections, Cushing-sy. (skin symptoms: acne, folliculitis, furunculus, candida infection, hypertrichosis, effluvium, atrophy, teleangiectasia, purpura, striae, impaired wound healing)

19 Immunosuppressive agents Azathioprine purine-antagonist, decreases the activity of NK, T-, B-cells Bullous autoimmune diseases, LE, DM, vasculitis, Behcet-sy., pyoderma gangrenosum, CAD Contraindicated: in pregnancy, in hepatic disease, in myelosuppression, in the case of an active infection in TPMT-deficiency increased immunosuppression 1-3 mg/kg/d Side effects: leukopenia, thrombocytopenia, pancytopenia, pancreatitis, nausea, vomit, fever, hepatitis, arthralgia, stomatitis, increased skin cancer risk, alopecia, teratogenicity

20 Immunosuppressive agents Cyclophosphamide Alkilating agents Pemphigus vulgaris, LE, vasculitis, Wegener granulomatosis, pyoderma gangrenosum, Behcetsy. contraindicated: in pregnancy, in myelosuppression 1-3 mg/kg/d p. o. or 15 mg/kg p. o. 1x/m or 500 mg-1 g/m 2 i. v. 1x/m with strong hydration or mesna Side effects: cardiotoxicity, hepatotoxicity, myelosuppression, thrombocytopenia, leukopenia, pancytopenia, nausea, vomit, diarrhoea, haemorrhagic cystitis, sterility, azoospermia, amenorrhoea, alopecia

21 Dapsone (diaminodiphenylsulfone) Inhibits the folic acid synthesis, it has anti-neutrophil activity contraindicated: in severe cardiovascular disease, renal failure, pregnancy, sulfonamide allergy side effect: methb-induction, hemolysis (severe in G6PDdeficiency!), agranulocytosis, aplastic anaemia, nephrosis sy., renal papillar necrosis, peripheral motor neuropathy, sulfone sy. Lepra, Mo. Duhring, Pneumocystis carinii prophylaxis, pyoderma gangraenosum, autoimmune bullous diseases, bullous LE, granuloma faciale, erythema elevatum et diutinum, leukocytoclastic vasculitis mg/d max. 200 mg, t 1/2 : 2-4 ds (renal elimination 90%) Alternative: sulfapyridine 1.5-2g/d

22 Immunosuppressive agents Cyclosporine inhibits the T h -cell function severe therapy-resistant psoriasis, atopic dermatitis, pyoderma gangrenosum, autoimmune diseases contraindicated: in cancer, hypertension, renal disease, pregnancy, active infection drug interactions! mg/kg/d, with control of creatinine, potassium, bilirubine, liver enzyme level, uric acid, lipid level, blood pressure side effects: renal failure, leukopenia, hypertension, headache, tremor, gingiva hyperplasia, oral candidiasis, hirsutism Cave: UV-light!

23 Immunosuppressive agents Methotrexate Folic acid-antagonist Severe psoriasis, arthropathia psoriatica, bullous pemphigoid contraindicated: in pregnancy, GI ulcer, liver cirrhosis, renal, hepatic dysfunction, hepatitis, alcoholism, anemia, leukopenia, thrombocytopenia, severe infection Nota bene: avoid alcohol, salicylates, other NSAID, sulfonamide, increase fluid intake, serum procollagene II aminopeptid can be monitored (hepatic fibrosis) mg p. o. 1x/w (3x mg q12 hs) side effects: myelosuppression (leukovorine 12 mg i. m. q6 hs 4-6 doses), hepatotoxicity (after >3 ys therapy and >1.5-2 g total dose liver biopsy may be necessary), pulmonary fibrosis, GI bleeding, anorexia, nausea, vomit, stomatitis, renal failure, seizures, defective spermatogenesis, alopecia, phototoxic dermatitis, skin ulceration

24 Biological therapy cellular immune response (signalisation, activation, citokine production) modifying molecules Nomenclature: mab: monoclonal antibody cept: fusion protein with receptor effect mu: human antibody xi: chimera (mouse-human) antibody zu: humanized mouse antibody li: anti-inflammatorical Examples: infliximab (TNF- inhibitor, Remicade), etanercept (TNFRII+IgG1 Fc domain, Enbrel), efalizumab (anti-cd11a, Raptiva), alefacept (anti-cd2)

25 Retinoids Influence on the keratinocyte differentiation, fibroblast activity, T- cell response Isotretionin acne, rosacea, Gram-negative folliculitis, severe sebaceus hyperplasia, XP, Gorlin-Goltz sy mg/kg/d for 4-10 ms or until 120 mg/kg total dose

26 Retinoids Acitretin psoriasis, Darier, pityriasis rubra pilaris, lichen planus, keratinisation diseases, Reiter, pustular diseases, CLE, epidermodysplasia verruciformis, multiplex keratoacanthoma mg/kg/d for 2-4 ms, in genodermatoses mg/kg

27 Retinoids Bexaroten (Targretin) CTCL 300 mg/m 2 /d, then 200 mg/m 2, then 100 mg/m 2

28 Retinoids Nota bene: draw women s attention to teratogenicity (informed consent), apply it in severe disease forms only, with control of liver enzyme levels and lipid levels Drug interactions: vitamin A (hypervitaminosis), tetracycline (pseudotumor cerebri), methotrexate (hepatotoxicity), alcohol (hepatotoxicity, TG-level increase) Side effects: teratogenicity (AC >6 ms after isotretionin, >2 ys after acitretin), mucous membrane dryness, skin dryness, alopecia, nail deformity, depression, hepatopathia, increased lipid levels, arthralgia, myalgia, hyperostosis, calcification, pseudotumor cerebri, visual dysfunction, hypothyreosis (bexaroten)

29 Cytostatics Alkilating agents: cyclophosphamide, lomustine, fotemustine Antimetabolites: methotrexate Antibiotics: bleomycine Vinca alkaloids: vincristine Other: dacarbazine, cisplatin Side effects: myelosuppression, haemorrhagic cystitis, sterility, teratogenicity, reversible alopecia, pulmonary fibrosis, acutely nausea, vomit, fever

30 Interferon-alfa Melanoma malignum, Kaposi sarcoma, Kaposiform haemangioendothelioma, mycosis fungoides weekly 3x3-10 million NE s. c. acutely fever, headache, arthralgia, myalgia at long-term use leukopenia, thrombocytopenia, hepatopathia, hypertrigliceridemia, weakness, depression, autoimmune disease (thyreoiditis) contraindicated: in autoimmune diseases (thyreoiditis), cardial arrythmias, hepatopathia, depression Immunotherapy

31 Colchicine Inhibits neutrophil functions by inhibiting microtubule function, inhibits collagen-synthesis, inhibits amiloid deposition gout, Behcet-sy., vasculitis, amiloid deposition (familiary mediterranean fever) contraindicated: in pregnancy mg/d Side effects: thrombocytopenia, pancytopenia, agranulocytosis, aplastic anemia, nausea, vomit, diarrhoea, azoospermia, myopathia, alopecia Other

32 Antimalarial drugs Stabilises the membrane of lysosome, decreases the MHC-expression, inhibits the neutrophil and eosinophil migration and function, inhibits the complement system, inhibits the PG-synthesis, etc. LE, RA, PFE, sarcoidosis, PCT contraindicated: in pregnancy, G6PD-deficiency, myasthenia gravis, hematopoietic diseases, hepatotoxic drugs Ophthalmological control q6-12 ms Chloroquine Side effects: agranulocytosis, hemolytic anemia, irreversible retinal damage, ECG-alterations, GI complaints, pigment abnormalities, psoriasis worsening

33 Other Thalidomide Anti-neutrophil activity, anti-tnf, anti-angiogenic Behcet-sy., severe aphtosis, pyoderma gangrenosum, LE (hyperkeratotic cases), prurigo nodularis Side effects: teratogenicity, peripheral neuropathia, nausea, vomit, thrombosis

34 Other Cyproterone Anti-androgenic Acne, hirsutism, androgenic alopecia

35 Medication during pregnancy and nursing contraindicated: azathioprine, colchicine, cyclophosphamide, NSAID, potassium-iodide, tetracyclines Antibiotics first choice: penicilline, cephalosporine, erythromycine alternative: clindamycine, sulfonamides contraindicated: tetracyclines, aminoglikozides Antimycotics best to avoid life-threatening infection: amphotericin B Antihistamines avoid Acyclovir in the case of possible fetal varicella or neonatal herpes, but fetal damage can not be excluded