Dermatology Drugs Mechanisms of Action PDF

DERMATOLOGY DRUGS Mechanisms of Action Prof Bronwen Connor, Dept Pharmacology [email protected] Adobe Stock  Objectives To understand the mechanism of action of: 1. Corticosteroids (Topical & Oral) 2. Vitamin A Derivatives (Topical & Or...

DERMATOLOGY DRUGS Mechanisms of Action Prof Bronwen Connor, Dept Pharmacology [email protected] Adobe Stock  Objectives To understand the mechanism of action of: 1. Corticosteroids (Topical & Oral) 2. Vitamin A Derivatives (Topical & Oral) 3. Vitamin D analogues (Topical) 4. Immunomodulators (Topical & Systemic agents) 5. Acne medication Anti-androgens Anti-bacterial Miscellaneous topical anti-inflammatories  Steroid Hormone Receptor Complex (SHRC) Kulkrani, Siddharth. 2014. Steroid Hormones O Increase / decrease mRNA transcription → increase / decrease protein production  1: Use of Corticosteroids O Inflammatory conditions of skin: O Eczema O Contact dermatitis O Insect bites www.Eczemalife.com www.NHS.UK  Corticosteroids O Topical: O Hydrocortisone = mild O Clobetasone (Eumovate®) = moderate O Diflucortolone (Nerisone®) = potent O Betamethasone (Betnovate®) = potent O Clobetasol (Dermol®) = very potent O Sometimes combined with antibacterial/ antifungal agents O Daktacort® = Hydrocortisone 1% / clotrimazole 1%  Corticosteroids O Oral: O Prednisone O Occasionally used in short-course in very severe eczema / dermatitis. O Receptors: O Glucocorticoid receptor (GR) = cortisol Corticosteroids MOA GR = Glucocorticoid receptor Barnes PJ. Inhaled corticosteroids. Pharmaceuticals 2010. 3: 514-540.  Corticosteroids MOA 1. Anti-inflammatory effect: O Binds to intracellular steroid receptor  SHRC translocated to the nucleus.  Binds to DNA and increases the production of Annexin 1.  Annexin 1 suppresses the conversion of phospholipids to arachidonic acid  Suppresses production of inflammatory mediators. Corticosteroids MOA Annexin 1 University of Auckland  Corticosteroids MOA 2. Reduced inflammation O Binds to intracellular steroid receptor  SHRC translocated to the nucleus.  Forms a complex with CBP and NFκ-B  Inhibits activation of NFκ-B  Reduces production of cytokines, chemokines, inflammatory proteins, enzymes and receptors CBP = CREB binding protein  Adverse Effects O Care with systemic absorption, especially potent agents (children). O Suppression of HPA axis O May worsen infection of the skin, skin thinning and striae O May worsen acne 2. Vitamin A derivatives (Retinoids) O Used for treatment of acne iStock; ttsz  Vitamin A derivatives (Retinoids) O Topical: O Tretinoin O Isotretinoin O Adapelene O Used for mild – moderate acne O Very effective Vitamin A derivatives (Retinoids) O Oral O Isotretinoin (Roaccutane® / Accutane ®) O Analog of retinoic acid (Vit A) O Used in systemic treatment of acne American Academy of Dermatology O Reserved for severe cases and/or if not responsive to other agents. O Occasionally used in psoriasis / severe eczema O Acitretin (Neotigason®) O Used in severe psoriasis (resistant to other therapies)  Vitamin A derivatives (Retinoids) MOA O Isotretinoin is a pro-drug O little / no ability to bind to retinol binding protein (RBP) or cellular retinol binding proteins (CRBP). O converted to Retinol (R) and taken up into cell. O Retinol is then converted to retinoic acid (RA). O Binds to cellular retinoic acid binding proteins (CRABP) and transported to nucleus. O RA is the agonist for the retinoic acid receptor (RAR) and the retinoid X receptor (RXR). Afornali A et al 2013. http://dx.doi.org/10.1590/abd1806-4841.20132208 O Regulates gene expression via retinoic acid responsive element (RARE)  Vitamin A derivatives (Retinoids) MOA O A complex forms between (RA-RAR) and (RA-RXR), which in turn binds to specific DNA sequences. 1.. of the retinoic acid Inactivation responsive element (RARE). 2. Repression of the transcription factor AP-1  AP-1 regulates gene expression in response to stimuli such as RARE cytokines, bacterial and viral https://clinicalgate.com/retinoids-2/ infections  Control proliferation, differentiation and apoptosis of keratinocytes.  Vitamin A derivatives (Retinoids) MOA O The final result is a promotion of cellular differentiation and an inhibition of cellular proliferation = modulate epidermal cell growth = reduce sebum gland activity and sebum production = anti-inflammatory effect.  Adverse Effects O Topical agents: O Very “drying” and may cause redness/skin peeling O Sensitivity to UV light O Dry/flaky skin O redness/soreness of skin/mucous membranes O myalgia/joint pain O psychiatric changes – depression, suicidal thoughts, psychosis. O many other effects. O Main caution is that these agents are teratogenic: must not be given to women of child-bearing age unless they have adequate contraception.  3. Vitamin D Analogues O Vitamin D are a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, iron, magnesium, phosphate and zinc. O In humans, the most important compounds in this group are vitamin D3 (also known as cholecalciferol; sun) and vitamin D2 (ergocalciferal; diet). O Dermal synthesis of vitamin D3 is the major natural source of the vitamin. O Dependent on sun exposure (specifically UVB radiation). O Vitamin D has complex roles in calcium/phosphate metabolism and bone formation and complex regulatory actions on the immune system.  Vitamin D Analogues O Topical: O calcipotriol (Daivonex®) O calcitriol O tacalcitol O Used in most forms of plaque psoriasis. O They should be avoided in patients with calcium metabolism disorders. O Local skin reactions (itching, erythema etc.) are common.  Vitamin D Analogues MOA O Not completely understood. O Vit D analogues act through the Vit D Vitamin D Receptor (VDR). VDR O Activates VDRE (Vit D Responsive Cell nucleus Element) RXR O SHRC in keratinocytes and other cells cytosol including sebaceous gland cells. VDR O Activates a number of gene pathways RXR to reduce proliferation, induce apoptosis and inhibit T-cell activation. VDRE Gene coding region  Vitamin D Analogues MOA Szyszka P et al. Expert Rev Anticancer Ther 2012. 12: 585-599 doi:10.1586/era.12.40 5 MIN  4. Immunomodulators O A diverse range of agents used topically or systemically to reduce inflammation by modifying the immune response. O Cytokines: O Released by cells and affect the behaviour of other cells. O Cytokines can also be involved in autocrine signalling. O TNFα O Interleukins O IFN O TGFβ O chemokines  Immunomodulators O Cytokines are produced by a broad range of cells, including immune cells like macrophages, B lymphocytes, and mast cells, endothelial cells, fibroblasts and various stromal cells O a given cytokine may be produced by more than one type of cell. O They act through receptors, and are especially important in the immune system O cytokines modulate the balance between humoral and cell- based immune responses O Cytokines use several downstream pathways to mediate their effects O The two most important pathways are the JAK-STAT pathway and the NF-kB pathway  Immunomodulators O Cytokines play an important role in cellular communication. O They regulate immunity, inflammation, cell activation, cell migration, cell proliferation, apoptosis, and haematopoiesis. O However, when released persistently they can produce chronic disease  Immunomodulators O Topical agents: O Pimecrolimus (Elidel®) O Tacrolimus (Protopic®) O used in psoriasis, eczema and acne O Pimecrolimus and Tacrolimus (FK506) are ascomycin macrolactam derivatives. O bind to macrophilin-12 (FKBP) and inhibits calcineurin (CaN).  Inhibits T-cell activation of NFAT  Inhibits the synthesis and release of cytokines from T- cells. http://www.Researchgate.net  Immunomodulators O Infliximab O Adalumimab O Methotrexate O Cyclosporin O Etanercept O Used in treatment of severe refractory eczema and severe psoriasis.  Immunomodulators O Systemic Agents O Infliximab O Adalumimab (Humira®) O Chimeric monoclonal antibody biologic drug that works against TNFα. O Binds to TNFα and prevents TNFα from binding to its receptor. O Used in the treatment of psoriasis and psoriasis arthritis.  Immunomodulators O Systemic agents: O Methotrexate O MOA unclear. O Likely to involve a number of pathways including: O inhibition of the activity of enzymes involved in the metabolism of purines (leading to the accumulation of adenosine) leading to suppression of T cell activation. O Decreasing the synthesis of a range of proinflammatory cytokines such as tumour necrosis factor α (TNF-α) and interleukin-1 (IL-1).  Immunomodulators O Pregnant women do not take methotrexate, and women of childbearing age should not become pregnant while taking methotrexate O The incidence of adverse reactions associated with methotrexate treatment of psoriasis is estimated at approx. 78%. O Adverse symptoms occur with varying severity. The most common complaints include nausea and vomiting. O Systemic agents O Cyclosporin O Calcineurin inhibitor O It is a prodrug - it is inactive until bound to its cytoplasmic receptor, known as cyclophilin (CpN).  Inhibits T-cell activation of NFAT  Inhibits the synthesis and http://www.Researchgate.net release of cytokines from T- cells.  Immunomodulators SM Stepkowski. 2004. Expert Reviews in Molecular Medicine 2: 1-23. CpN = cyclophylin CaN = calcineurin  Immunomodulators O Etanercept O Etanercept inhibits TNFα activity by competitively binding to it and preventing interactions with its cell surface receptors.  5. Acne Treatments O Antibacterial agents: O used to control Propionibacterium acnes (P acnes = causative organism) O also some anti-inflammatory effects O Topical: O clindamycin and erythromycin O Oral: O oxytetracycline, doxycycline, minocycline O bacterial protein synthesis inhibitors by inhibiting ribosomal translocation O Antibacterial resistance of P.acnes is increasing  Acne Treatments O Anti-androgens O Cyproterone (CPA) O Androgens stimulate acne via sebum production O Anti-androgens alter the androgen pathway by blocking the androgen receptors or affecting androgen production.  Acne Treatments O Benzoyl peroxide O MOA?? O Antibacterial activity against Propionibacterium acnes is thought to be a major mode of action. O In addition, patients treated with benzoyl peroxide show a reduction in lipids and free fatty acids, and mild desquamation (drying and peeling activity) with simultaneous reduction in acne lesions. O Azaleic acid O MOA??? O Antibacterial activity against Propionibacterium acnes is thought to be a major mode of action. Any Questions