UTHSC – P1 Exam 1 – Dermatology – Flashcards

Minimum surface area, lipid-soluble, small molecular weight, non-ionized (non-polar) molecules

Areas of the body - scrotum, face, axilla, scalp (highly vascularized!) Extremes in age - babies - REALLY easily absorbed - Peds skin - THINNER - and more hydrated, more easily absorbed - Elderly skin - thinner, less hydrated, and more friable Broken skin --> i.e. eczema - increased penetration vs. psoriasis (plaques) --> decreased penetration Moves DOWN concentration gradient

Follicular epithelial hyper-proliferation Excess sebum Inflammation Propionibacterium acnes

Regulation of genes involved in inflammation & proliferation, Regulation of pro-inflammatory cytokines & chemokines, Eradication of P. acnes, Etc.

They act in the nucleus of the cell. - Retnoids - Acitretin Adapalene Bexarotene Isotretinoin Tazarotene Tretinoin (ATRA) - Vitamin D analogs - Calcipotriene Calcitriol - Corticosteroids - Hydrocortisone Betamasone validate Fluocinonide Clobetasol propionate

monoclonal antibodies (end in -mab) Adaimumab (humira)* Alefacept Brodalumab Etancercept* Guselkumab Infliximab* Ixekizumab Secukinumab Ustekinumab * - biosimilar available

Benzoyl peroxide Clindamycin-erthromycin Salicylic acid

Stimulated T-cells, macrophages, and dendritic cells release pro-inflammatory cytokines (through vicious cycle), such as TNF-alpha, IL-23, and IL-17 that induce keratinocyte and endothelial cell proliferation (this makes cytokines + their receptors attractive targets for treatment)

Topical retinoids are considered 1st-line treatment: - inhibit precursor lesions - block consequences of P. acnes activation (like TLR-2 receptors) - decrease production of pro-inflammatory cytokines (NFkB, IL-8, IL-12) - inhibit lipo-oxygenase pathway and chemotaxis (along with free radical release from neutrophils) - provide inhospitable environment for P. acnes

They are all DNA binding proteins

RAR: Tissue specific - up or down regulations of genes in charge of inflammation, cellular differentiation, apoptosis, and sebaceous gland activity RXR: specifically induces apoptosis Molecular mechanism of retinoid-induced epidermal hyperplasia retinoic acid receptor/retinoid X receptor (RAR/RXR) heterodimers --> proliferation of basal keratinocytes, thickened epidermis and consequent peeling/flaking of the stratum corneum (basically just proliferates underneath and kicks off the outer layer of skin)

1. Vitamin A alcohol - Stored, less irritating, can be used rapidly 2. Vitamin A aldehyde 3. Vitamin A acid - Cannot be stored, more adverse effects, no way to minimize amount of product

- oral bioavailability greatly enhanced with food - CYP metabolism, hepatic and urinary elimination - Accumulates in liver (when absorption >>> capacity = toxicity!) - Acute toxicity similar to Vit A def (symptoms: dry skin, nosebleeds, dry mucous membranes, conjunctivitis, reduced night vision, alopecia) - must monitor baseline serum lipids (most common abnormality- high level increase cardiovascular risk), serum transaminases, CBC, and pregnancy tests *Monitor Isotretinoin for depression/suicidal ideation

1st line agents for non-inflammatory (comedonal) acne - correct abnormal follicular keratinization, decreases P. acnes counts and inflammation - Effective in reducing fine wrinkles and dyspigmentation associated with photo-again (due to skin tightening) - Adverse Effects: erythema (redness), desquamation, burning, stinging, increase reactivity to UV radiation (more risk for sunburn)

Topical drug; binds to Vitamin D receptor; complex associates with RXR-alpha and binds DNA Vit D response elements - modulation of epidermal differentiation and inflammation, leading to improvement in psoriatic plaques Topical irritant - reduced by concurrent corticosteroids Hypercalcemia (Vit D. regulates calcium ions) - abdominal pain, constipation, depression, fatigue, hypertension, anorexia, weight loss, muscle weakness, N/V, thirst (polydipsia) Increases susceptibility to UV-induced skin cancer

hormonally active form of Vitamin D3 - better tolerated in intertriginous and sensitive areas of the skin - comparable safety data to calcipotriene ointment - when taken normally, no adverse effects

Anti-inflammatory, anti-pruritic (itching), and vasoconstrictive Binds to intracellular glucocorticoid receptor located in cytoplasm, dimerizes then binds to DNA, enters nucleus, activates glucocorticoid response element, regulates transcription - increases production of IkB, an inhibitory partner of NFkB, a major pro-inflammatory transcriptional regulator - localized application (topical, inhalation, intra-articular) helps limit systemic adverse effects - not good for long-term use - extra-hepatic metabolism with renal excretion - increased production of anti-inflame lipocortins (lipoxygenase and cycloxygenase) and decreases formation of endogenous inflammatory mediators

hydrocortisone (available OTC) - betamethasone valerate - fluocinonide - clobetasol propionate (not available OTC)

- Moist skin - Occlusion (Wet pajamas, saran/plastic wrap, bandage, intertriginous areas; Can increases absorption by a factor of 10!) - Thin skin (Face, anterior neck, genitals thinnest skin of body; Palms/soles, back & neck thickest; Debride scale) - Change steroid vehicle to ointment

- Iatrogenic Cushing's syndrome with large quantities and applied extensively (long duration) - Dermal atrophy (shiny skin, often wrinkled appearance with spider veins and tendency of purport & ecchymosis) - Cortcoid rosacea: persistant facial erythema (redness) FLUORINATED TOPICAL STEROIDS SHOULD NOT BE APPLIED TO FACE -Perioral dermatitis, steroid acne, alterations of cutaneous infections, hypo pigmentation, hypertrichosis, increased intraocular pressures, allergic contact dermatitis

Most important adverse effects of retinoids - teratogenicity - cannot become pregnant during treatment or at initiation - become pregnant for 3 years after systemic retinoid is d/c (must use contraception) - cannot ingest alcohol with acitretin - isotretinoin only available via ipledge program - all topical retinoids should be avoided in pregnancy - excessive Vit D during preg could cause birth defects (not likely with topical drugs - safe in preg) - Only use mild/moderate systemic corticosteroids if benefit outweighs risk (can cause fetal HPA-axis suppression: halts production of cortisol, increase risk of stillbirth and spontaneous abortion)

Drugs preventing the effects of inflammatory cytokines TNF-alpha, IL-23, or IL-17 by inhibiting release, binding free ligand or blocking receptor function - IgG based drugs (IgG - long persistence in body due to interaction with FcRn and recycling) - Some products conjugated with PEG (polyethylene glycol) to increase persistence - IV, SC, or IM injection - Absorption via the lymphatic system - lysosomal and cytosolic degradation - Dosing Q 2-3 weeks - EXPENSIVE $$$$

Adalimumab (SC): TNF-alpha IgG monoclonal antibody that binds to the TNF-alpha and blocks its interaction with cell surface receptors Etancercept (SC): extracellular ligand-binding portion of human p75 TNF receptor linked o part of IgG Fc; endogenous p75 acts as a TNF antagonist - it binds to and inactivates TNF-alpha receptor (TNF-a stays in circulation) Infliximab (IV): Chimeric IgG monoclonal antibody against TNF-alpha, it binds and neutralizes both soluble and transmembrane TNF-alpha

- rotate site for SC or IM - immunosuppression --> opp infections --- don't initiate treatment in a patient with an active infection - signs/symptoms of new or reoccurring infection (Hep B, TB) during therapy and months after d/c - avoid live vaccines during treatment - may increase likelihood of lymphoma or other malignancy (report persistent fevers, night sweats, or sign weight loss) - CHF, hypotension/angina/dysrhythemia - demyelination of CNS - autoimmune/non-autoimmune hepatocellular injury or predominantly cholestasis -- d/c drug!!!! ---- some may benefit from course of corticosteroids

Alefacept (IM): recombinant human LFA-3/IgG fusion protein that binds to CD2 on memory effector T-cells, which prevents T-cell activation and promotes apoptosis Brodalumab (SC): Human IgG monoclonal antibody that binds IL-17A receptor, inhibiting release of pro-inflammatory cytokines (monitor for suicidal ideation or behavior - drug only available through risk mitigation strategy REMS - 6 suicides in trial) Ixekizumab (SC): Humanized IgG monoclonal antibody that binds IL-17A, inviting its interaction with IL-17 receptor Secukinumab: Human IgG monoclonal antibody that binds IL-17A, inviting its interaction with IL-17 receptor Ustekinamab: Human IgG monoclonal antibody that binds to the p40 subunits of IL-12 and IL-23 cytokines

- immunosuppression --> opp infections --- don't initiate treatment in a patient with an active infection - signs/symptoms of new or reoccurring infection (Hep B, TB) during therapy and months after d/c - avoid live vaccines during treatment - development or excaberation of Crohn's disease

- topical pro-drug converted to benzoic acid (free radical liberation is lethal to nearby P. acnes) - drying of skin: peeling, redness, irritation --- contact dermatitis includes rash, itching, blistering, crusting, or swelling of skin --- cool compresses or topical corticosteroids to reduce symptoms and increase healing - often formulated with antimicrobials (clindamycin/erythromycin, adapaline) --- helps to prevent antimicrobial resistance - avoid contact with eyes, mucous membranes, fabrics --> its an oxidant (bleaching agent)

- topical keratolytic - cause desquamation of horny layer of skin - can treat hyperkeratotic skin disorders (common and plantar warts, psoriasis, calluses, corns) and acne - may cause contact irritation - prolonged administration over large areas (esp in children and patients with renal or hepatic impairment) increased risk of salicylism - neonatal toxicity via breast milk and contact toxicity from drug applied to chest

topical pimecrolimus (Elidel) or tacrolimus (Protopic) cream - common adv effects: erythema, pruritus, headache, fever, and increased risk of viral infection - rare cases of malignancy (avoid long-term use and apply only to areas affected by atopic dermatitis) ORAL CYCLOSPORINE - CYP3A4 (metabolizing agent) & P-Gyp (transport pump) substrate and inhibitor - extensive drug-drug interactions possible - adv reactions: renal dysfunction, tremor, hirsutism (excessive hair in females), hypertension, and gum hyperplasia

- PDE breaks down cyclic-AMP - sustained cyclic-AMP --> inhibits T-cell activation - Crisaborole (Eucrisa) cream - Rare incidence of: --- application site pain --- contact urticaria, severe pruritus, swelling, or redness at application site or distant site ORAL AGENT - Apremilast (Otezla) - treatment for psoriasis - common adv effects: GI distresss, nausea, headache, weight loss

SC human IgG IL-4Ra antibody for severe adult disease - well tolerated - adv effects: injection site reactions, conjunctivitis, rare herpes simplex infection - increased levels of IL-4 and IL-13 could impact CYP activity --> drug-drug interactions (cytokines control CYP - which this drug interrupts)

Oral therapy - Terbinafine, itraconazole, fluconazole, griseofulvin

Topical therapy - Azoles, terbinafine, naftifine, ciclopirox

Oral therapy - Terbinafine, itraconazole, fluconazole, griseofulvin Topical therapy - Ciclopirox, amorolfine

- Fluconazole - PO and IV - requires acidic environment - low weight and high solubility - penetrate most host tissue (including eye and CNS) - not extensively metabolized; eliminated predominantly unchanged in urine --- dose adjust for RENAL, but not hepatic dysfunction - Itraconazole - PO - capsule & oral solution - capsule: bioavailability improves with gastric acidity (avoid PPIs and H2 antagonist which decrease acidity) - oral sol: improved and consistent bioavailability - HIGHLY PROTEIN BOUND - does not penetrate CNS or eye - concentrates in skin and nail beds - hepatic metabolism; dose reduction in impairment (3A4 Inhibitor - drug-drug interactions) - most common toxicity: hepatic dysfucntion (elevated LFTs) and failure AVOID IN PREGNANCY (for oral azoles) topical azoles - safe in pregnancy - clotrimazole, miconazole, nystatin - cream may be preferred in intertriginous areas; powder preferred if lesions are moist

- well tolerated, esp for topical drug - hepatic metabolism/renal elimination --- long terminal half life --- rare hepatotoxicity reported - lymphopenia and neutropenia with oral drug - avoid in immunosuppressed patients (opp infections) - ROUTINE CBCs needed

- attacks mitotic spindles which stops cell growth - unable to penetrate skin, only in oral dosing - extensive hepatic metabolism - CYP3A4 Inducer (produces CYP by transcriptional regulation) - Pregnancy - teratogen - Hepatotoxic - interferes with porphyrin metabolism - product of penicillum (cross-sensitive to those with this allergy) - photosensitizer

- Topical agent - blocks sterol biosynthesis by inhibiting enzyme squalene 2,3 - e-oxidase - locally bactericidal, gram + and gram- - anti-inflam thru inhibition of mediators (vasoconstriction) - topical agent with limited absorption (no sign drug interactions) - don't combine with azolesS!!!! (both work by inhibiting ergosterol, but this one inhibits sterols at earlier point, and using both diminishes effectiveness)

Topical only - limited absorption - hypersensitive/allergy to drug possible - may irritate if applied to skin abrasions CICLOPIROX ONLY - blocks fungal transmembrane transport, depletes essential substrates, and interferes with RNA and DNA synthesis - high conc permits leakage