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Topic 28. Systemic therapy in dermatology

Is systemic therapy indicated?Indicated1. Severe disease2. Widespread symptoms3. Rapid effect required4. Bad complicance5. 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. Corticosteroids2. Anabolic steroids3. 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↓

Cell regulation :

Not indicated1. Would heal anyway2. Localised symptoms3. Heals on local thx

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1. Macrophage and lymphocyte functions↓2. Monocytopenia, lymphopenia3. Diabetogenic effect4. 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 - Sarcoidosis5. 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

2) Anti infection drugs Antibiotics

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Antivirals Antimycotics Antiparazites

AntibioticsMostly 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 zoster2. Eczema herpeticum3. Pustulosis varicelliformis (Kaposi)4. HIV/AIDS

Mechanism of action: 1. Nucleotide analogues2. 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

Antimycotic Mechanism of action:

- Specific inhibition of fungal cell wall synthesis

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- 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) Kaposi’s sarcoma Other (sarcomas, Merkel cell tumor, etc)

Antimycotic - indi cations Widespread superficial mycosis Resistent / recurrent superficial

mycosis Onychomycosis Genital mycosis Immunosuppression

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Cytostatic drugs usage DTIC

1. Curative/adjuvant thx of melanoma2. 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 54. 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 α 2b - indications Melanoma malignum

- Only FDA approved adjuvant treatment for melanoma- 3-10 IU/week s.c. for 12 months

CTCL Kaposi’s sarcoma

Side effects Flu-like symptoms (paracetamol!) Autoimmune diseases (diabetes, SLE)

4) Immun o modul ators 1. Anti infectious agents 2. Citotoxic agents 3. Macrolide immunosuppressants 4. Biologicals

Anti infectious agents Dapsone (sulphapiridine, 1 00-200 mg )

- Antibacterial + antiinflammatory - Lepra, DHD, erythema elevatum - Side effect: methemoglobinaemia

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Aminoquinolin es (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

5) Retinoids

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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) Antihistamin es 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)