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Gelerstein 2011

Topic 28. Systemic therapy in dermatology Is systemic therapy indicated? Indicated 1. Severe disease 2. Widespread symptoms 3. Rapid effect required 4. Bad complicance 5. Technical causes Systemic drugs in dermatology: 1. Hormones 2. Anti infectious drugs 3. Antitumoral drugs 4. Immunmodulators 5. Retinoids 6. Antihistamines 1) Hormones: Produced by an endocrine organ Reaches the target cell via blood Fine regulation of cell function Mechanism of action: Cell membrane diffusion intracellular receptor gene regulation Groups (used in dermatology): 1. Corticosteroids 2. Anabolic steroids 3. Antiandrogenes Corticosteroids Structure: steran skeleton Natural form: - Cortisol - Hypothalamic pituitary adrenal cortex - 15-30 mg/day - Daily peak: 8 a.m. Corticosteroids mechanism of action Rapidly penetrated the cell membrane picked up by intracellular receptors into the nucleus influence many cellular functions of the immune system: Gene regulation: 1. Proinflammatory cytokines 2. Phospholipase A2 PG synthesis

Not indicated 1. Would heal anyway 2. Localised symptoms 3. Heals on local thx

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Cell regulation: 1. Macrophage and lymphocyte functions 2. Monocytopenia, lymphopenia 3. Diabetogenic effect 4. Protein degradation, Ca+ loss (bones) 5. Na+ retention, K+ loss (oedema, hypertension)

Corticosteroids indication: 1. Severe allergy Anaphylaxis Angioedema Erythroderma 2. Autoimmune diseases Polysystemic (SLE, PSS, Dermatomyositis) Bullous disease (pemphigus, pemphigoid) 3. Inflammatory dermatoses Erythema multiforme Erythema nodosum 4. Granulomatous diseases - Sarcoidosis 5. Tumors Cutaneous T cell lymphoma (CTCL) Melanoma Corticosteroids usage: 1. Oral Morning, in a single dose. High starting (induction) dose symptoms dose. Gradual tapering Lower maintenance dose Intermittent dosage if possible important for the natural cortisol reduction 2. I.V in case of large doses Corticosteroids Side effects: Important because Corticosteroids are widely used K and Ca+ loss can appear in 2-3 days hypokalemia severe cardiac dysfunction death Na+ retention, edema, hypertension Diabetogenic effect, Ulcerogenic effect Acne, Psychosis, Hypertrichosis Infection

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2) Anti infection drugs Antibiotics Antivirals Antimycotics Antiparazites Antibiotics Mostly used indication and their treatment: 1. Pyodermas Folliculitis, furuncle, carbuncle, impetigo, erysipelas, cellulitis,fasciitis necrotisans Penicillin (2x1-6 ME), cephalosporine, macrolides I.M or I.V. Targeted treatment (based on culture) In case of failure: change (after 2-3 days!) At least 8-10 days 2. Acne is not a bacterial disease, although presented with pustule Is a disease of young with bacterial involvement (Not a pyogenic disease) Antibiotics have a strong anti-inflammatory effect in acne Tetracycline (250 mg/day), Doxycyclin (100 mg/day) Metronidazole 2x100 mg Long term treatment (months) 3. Tuberculosis, Lepra 4. STD - Syphilis, NGU, GU 5. Others Borreliosis, Tularaemia, Actinomycosis Antibiotics Side effects: Allergic reaction Elimination of normal bacterial flora Enteritis, Candida vaginitis Photosensitivity e.g. tetracyclines in acne Antiviral Indications: 1. Herpes simplex / Herpes zoster 2. Eczema herpeticum 3. Pustulosis varicelliformis (Kaposi) 4. HIV/AIDS Mechanism of action: 1. Nucleotide analogues 2. Viral RNA/DNA polimerase inhibition Dosing (acyclovir) 1. Herpes simplex PO 5x200 mg/day 5 days 2. Herpes zoster PO 5x800 mg/day 7 days 3. Immunosuppression IV 3x500-1000 mg

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Antimycotic Mechanism of action: - Specific inhibition of fungal cell wall synthesis - Accumulation in keratin structures - If someone is allergic to it long time side effects Always according to culture! fungal culture takes 2-3 weeks - Candida itraconazole, fluconazole, ketoconazole - Dermatophytes terbinafin, griseofulvin Dosage: - Based on the indication - Usually requires prolonged treatment Side effects: - Eliminated through the CYP system - Allergic reactions (severe, prolonged) 3) Anti-tumour drugs Used mostly for melanoma patient Group of anti-tumour drugs: 1. Cytostatic drugs - Dacarbazin (DTIC) - B.O.L.D. 2. Biological response modifiers - Interferon - Interleukines - Retinoids Cytostatic drugs Goal of therapy (cost / benefit): Curative Adjuvant / neo-adjuvant Palliation Indications: Melanoma malignum CTCL Non-melano+ma skin tumor (mainly SCC) Kaposis sarcoma Other (sarcomas, Merkel cell tumor, etc)

Antimycotic - indications Widespread superficial mycosis Resistent / recurrent superficial mycosis Onychomycosis Genital mycosis Immunosuppression

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Cytostatic drugs usage DTIC 1. Curative/adjuvant thx of melanoma 2. 200 mg/m2/day i.v. 5 days 7 cycles B.O.L.D. 1. Curative/adjuvant thx of melanoma 2. Bleomycin 7.5-15 IU s.c. on day 1 and 4 3. Vincristine 1 mg/m i.v. on day 1 and 5 4. Lomustine 80 mg/m p.o. on day 1 5. Dacarbazine 200 mg/m/die i.v. on day 1-5 Cytostatic drugs Side effects Rapidly deviding cells: - Bone marrow depression - Hair loss - Gonadal cell damage - Teratogenity Cells involved in elimination Hepatotoxicity, Nephrotoxicity General side effects Nausea, vomiting, fatigue Interferon 2b - indications Melanoma malignum - Only FDA approved adjuvant treatment for melanoma - 3-10 IU/week s.c. for 12 months CTCL Kaposis sarcoma Side effects Flu-like symptoms (paracetamol!) Autoimmune diseases (diabetes, SLE) 4) Immunomodulators 1. Anti infectious agents 2. Citotoxic agents 3. Macrolide immunosuppressants 4. Biologicals Anti infectious agents Dapsone (sulphapiridine, 100-200 mg) - Antibacterial + antiinflammatory - Lepra, DHD, erythema elevatum - Side effect: methemoglobinaemia

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Aminoquinolines (antimalarial drugs) - Chloroquin, Delagil - Inhibition of PG synthesis, chemotaxis, DNA-binding, membrane stabilizing effect - Indications: SLE, DLE, SCLE, scleroderma - Side effects: cataract, retinopathy

Cytotoxic drugs Methotrexate Azathioprine antimetabolites Hydroxyurea Cyclophosphamide alkilating agents Methotrexate (MTX) Inhibition of DHF-THF and DNA synthesis Immunosuppressive in low doses Indication: psoriasis Usage: 3-4 x 2.5-5 mg/week Side effects: - Acute: marrow depression, mucous membrane ulcers - Cumulative: hepatotoxicity (over 5 g) Azathioprine (Imuran) 6-mercaptopurine inhibition of purine synthesis Immunosuppressive in low doses Indications SLE, pemphigus, pemphigoid, dermatomyositis Usage - Monotherapy or steroid spare - 2-3x50-100 mg/day Side effects - Marrow depression - infections Macrolide immunosuppressants Cyclosporine Tacrolimus Cyclosporine Inhibitor of calcineurine and IL-2 synthesis T-cell specific Indications: - Psoriasis / Atopic dermatitis - Pyoderma gangrenosum Dosage 2-5 mg/day Side effects Nephrotoxicity

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5) Retinoids Mechanism of action Retinoids: vitamine A derivates (lipofilic) Modification of proliferation, differentiation, and keratinisation of epithelial cells Regulation of cellular and humoral immune response, inflammatory processes Side effects Teratogenic Dryness of skin and eyes Desquamation of palms and soles Vitamin A derivaties - inrterfere with proliferation and differentiation DO NOT GIVE IT TO PREGANANT WOMEN Indications and usage: Pustulosus psoriasis Etretinate 25-50 mg/day, decrease dose thereafter Plaque, guttate psoriasis combination therapy Acne conglobata, inversa Isotretinoin 120 mg/kg total dose (napi 20-60 mg) Control: Monthly: pregnancy test (women, childbearing age) CBC, lipids, liver and kidney function, creatinine and phosphokinase Contraindications: Absolute: pregnancy, not reliable anticonception Relative: women of child-bearing age, liver and kidney abnormality, hyperlipidaemia 6) Antihistamines H1 receptors: vasculature (vasodilation, permeability) H2 receptors: gastric secretion H3 receptors: CNS Indications: Type I. hypersensitivity reactions Sedative effect Generations: I. generation Chloropyramide (Suprastin) Dimetindene (Fenistil) II. generation Cetirizine (Zyrtec, Parlazin, Cetirizin-Ratiopharm) Loratadine (Claritine, Erolin, Loratadine-Ratiopharm) Fexofenadine (Telfast) III. generation Levocetirizine (Xyzal) Desloratadine (Aerius)