Lecture 4 & 6 Acne Vulgaris Miller & Klassen Acne Vulgaris: common inflammation of the pilosebaceous unit (sebaceous glands & hair follicles) Acne lesions Closed comedone (1-2 mm): whiteheads o First clinical sign, high tendency to rupture Open comedone (2-5 mm): blackheads o Visible keratin plug, oxidized melanin & oil = black, stable Papules/pustules/nodules: inflammatory lesions (bacteria) Acne severity Comedonal: closed & open comedones Mild-moderate papulopustular: superficial inflammatory lesions & comedones Severe: deep pustules/nodules (cysts) that extend over large areas tissue destruction (scars) o May be painful NOTE: <50 lesions = mild; >100 = severe Precipitating or risk factors for acne vulgaris Hormones: androgens (puberty both genders), anabolic steroids, oral contraceptives (levonorgestrel, progestin) Family hx & environment (tropical climate, diet, exposure) Habits: oil products, cosmetics, local friction, improper cleansing of hair & skin Drugs: phenytoin, phenobarbital, lithium, haloperidol, bromides, iodides Other: stress, premenstrual flares Pathophysiology 1. Inflammatory cytokine release: promote PRISH hyperkeratinisation and microcomedone (plug) 2. Hyperkeratosis: follicular epidermal hyperproliferation clumping of keratinocytes plugging hair follicle 3. Excess sebum production secondary to androgens: hormones cause oil glands to increase size & production (hypersecretion) sebum becomes trapped solidifies behind keratin plug 4. Bacterial growth & colonization: Propionibacterium acnes proliferation metabolize oil to fats fatty acids induce inflammation Drugs in acne vulgaris Goals of therapy To prevent new lesions from forming, heal existing lesions & minimize permanent scarring o Reduce keratinization, decrease sebum production, reduce microbial flora decrease enzymes Prevent psychological distress Pharmacotherapy for acne Comedonal (mild) acne: re-assess at 2-3 mo Topical retinoid (most effective) or benzoyl peroxide (alone or in combo) Add topical abx (clindamycin) to retinoid if inflammatory lesions present Last resort: add combined oral contraceptive for females Moderate acne: assess 2 mo for tolerability; 3 mo for efficacy Topical agents (BPO faster; all retinoids equally effective) Combinations: clinda + BPO or adapalene + BPO or clinda + tretinoin Oral abx for inflammatory lesions not responsive to topical or if involves other areas (limit to 6 mo) Severe acne: isotretinoin if other therapies have failed; hormonal therapy for women
General principles of topical txt Cornerstone of acne treatment Must treat ALL skin areas daily (not just current lesions) Acne may worsen for first few wks o Optimal effect delayed up to 12 weeks o Maintenance essential to prevent recurrence Initiate with lowest strengths in water-based products or apply every second or third night for adaptation to occur If using two different therapies, apply one in morning & one in evening Benzoyl peroxide MOA: antibacterial against P. acnes Penetrates the stratum corneum or follicular openings unchanged Converts metabolically to benzoic acid by cysteine within skin o Liberates free oxygen radicals that oxidize bacterial proteins Skin peeling & comedolytic effects 5% absorbed from skin in 8 hrs : Mild acne (alone) Adjunct for all acne (reduce abx resistance) ADRs Dryness & irritation (redness) for first 1-2 weeks Contact dermatitis (patch-test advised) o Avoid contact w/ eyes & mucus membranes Bleaches fabrics & hair Oxidizes tretinoin (need to separate treatment) Azelaic acid MOA: not fully determined Antimicrobial against P. acnes Inhibits conversion of testosterone to dihydrotestosterone o DHT promotes formation of acne Acne vulgaris Acne rosacea Reduces inflammatory lesions & erythema ADR: mild irritation with redness & dryness of skin; hypopigmentation General principles for abx therapy Don t use topical & oral abx together Use in combo with benzoyl peroxide to prevent bacterial resistance Use judiciously for inflammatory acne Restrict to < 6 mo Dapsone 5% gel (bid) MOA: anti-inflammatory & antimicrobial Inhibits bacterial dihydropterase synthase in folic acid pathway ADRs Dryness Rash, erythema, pruritis Sunburn, burning Aggravation of acne & peeling * No evidence of drug-induced hemolytic anemia in patients with G6PD deficiency (compared to oral) Sulfonamide-allergic patients Patients exhibiting sensitivity or intolerance to conventional antiacne agents LOW REPSONSE RATE & EXPENSIVE Exfoliants: phenol, resorcinol, sulfur, salicylic acid, glycolic (alpha-hydroxy) acid, azelaic acid Limited evidence for safety & efficacy Salicylic acid washes useful in young pts with recent onset acne Azelaic acid also antibacterial o Hypopigmentation risk in dark complexions
Retinoic acid for acne Topical: acne vulgaris & wrinkles (age/sun damage) Systemic: severe cystic acne Effects of retinoids on skin Stabilization of lysosomes (less inflammation) Increase RNAP activity Decrease cohesion b/w epidermal cells Increased epidermal cell turnover Cause expulsion of open comedones Transform closed comedones into open Decrease sebaceous gland size & function Decreases number of cell layers in stratum corneum (from 14 5) Prolonged use promotes dermal collagen synthesis, new blood vessel formation & thickening of epidermis decrease appearance of wrinkles Vitamin A derivatives: non-selective Retinoic acid (tretinoin, trans-retinoic acid) Allitretinoin (9-cis retinoic acid) Isotretinoin (13-cis-retinoic acid) Selective retinoic receptor antagonists more effective than tretinoin Adapalene: derivative of naphtoic acid o Selective for RAR-γ o Also inhibits arachidonic acid metabolism (less inflammation) Tazarotene: pro-drug hydrolyzed to active tazoratenic acid o Selective for RAR-β/γ o Anti-inflammatory and antiproliferative actions ADRs of topical retinoids Burning/stinging sensation Peeling, erythema, edema Photosensitizing (less with adapalene) Alopecia Allergic dermatitis Tazarotene absorbed = teratogenic Mechanism: steroid hormone receptors Retinoic Acid Receptor Retinoid X Receptor Natural ligands: trans retinoic acid, 9-cis-retinoic acid After ligand activation, RAR forms heterodimer with RXR Bind to retinoic acid response elements on DNA alter transcription of target genes RAR-α Lipid elevation Promoter of acute promyelocytic leukemia RAR-β Modulates solid tumor development RAR-γ Keratinocyte differentiation & irritation Bone tenderness/abnormal bone growth Teratogenicity Natural ligand: 9-cis-retinoic acid Binds to retinoid X response elements of DNA Modulation of cell growth, apoptosis, and differentiation Isotretinoin: decreases sebum production by 70%; decreased P. acnes & inflammation; normalizes keratinization Should follow two 8 week courses of different antibiotics where there is less than 50% improvement in acne Dose: 0.5 mg/kg/day for 2-4 wks increase to 1 mg/kg/day with a 120-150 mg/kg cumulative dose (over 5-6 mos) ADRs of systemic retinoids Similar to vitamin A-induced toxicity Dry lips, dryness & desquamation of face Headache Corneal opacities Decreased night vision Increased intracranial pressure Inflammatory bowel disease & anorexia Muscle & joint pain (calcification) Cholesterol & triglyceride elevation Hepatotoxicity Teratogenicity Monitoring CBC, LFT, lipids: baseline, 4 and 8 weeks Pregnancy: 2 wk before & wk after
Topical antibiotics for acne MOA: eliminates P. acnes from follicle decreased free fatty acid production and subsequent inflammation Concentrates medication in affected area & reduces risk of systemic SEs : mild to moderate acnes (inflammatory lesions) Not as effective on trunk as face Apply twice daily P. acne resistance with prolonged use Choices Topical erythromycin o Safest in pregnancy, greatest resistance risk o Combo products Topical clindamycin o Equal efficacy to topical erythromycin o Rare cases of pseudomembranous colitis o Disagreeable taste with topical use Both have combo products with retinoic acid or BPO Systemic antibiotics for acne MOA: reduce P. acne from follicle Use: moderate-severe inflammatory acne Disadvantages GI upset Vaginal candidiasis Gram ve folliculitis (proteus, kleibsella) Refractoriness due to resistant P. acnes (esp. erythromycin) Warning If no response in 6 wk, switch to different abx Discontinue once acne has improved Always combine with BPO Limit use to 6 months Clindamycin: refractory acne SEs: pseudomembranous colitis (C. difficile) diarrhea Dose: 150 mg od or bid SMX/TMP: for severe refractory acne Dose: 1 DS tab od (800/160 mg) o TMP alone 300 mg bid SE: skin rashes (Stevens Johnson) Tetracycline: 1 st choice (effective, low cost & less resistance) Also inhibits chemotaxis, phagocytosis, complement activation & cell-mediated immunity = anti-inflammatory Contraindicated in pregnancy (2 nd or 3 rd trimester) & in children <9 yo SEs: photosensitivity reactions; NVD; vaginal candidiasis, esophageal ulcerations, benign intracranial hypertension (pseudotumor cerebri) Starting dose: 250 mg qid or 500 mg bid empty stomach for 2-3 weeks reduce to 250 or 500 mg od once new lesions stopped forming o Doxycycline (more lipid soluble): 50 100 mg od Minocycline: equal efficacy In patients unresponsive to tetracycline (expensive) SEs: dizziness (vestibular irritation), drug-induced lupus (reversible), hypersensitivity reactions o Hypersensitivity: brown or blue-gray pigmentation first occurs on mucus membranes of mouth, appears after months-years (may not fade after DC) Dose: 50 mg bid or 100 mg od (200 mg daily max) Erythromycin Used in females contemplating pregnancy SEs: causes GI distress (cramps) motilin-like effect Drug interactions: P450 inhibition (anticoagulants, digoxin, carbamazepine, statins, theophylline) More P. acnes resistance (greatest risk) Dose: 250 mg qid (or 500 mg bid) decrease with response to 250-500 mg daily
Lecture 6 Acne Vulgaris Miller Oral contraceptives for acne OCs (estrogen) decrease amount of circulating androgens and increase serum binding hormone globulin Approved OCs for acne o Yasmin o Tricyclen o Alesse or Aviane o Diane-35 or CyEstra-35 OCs equal efficacy in acne Max effectiveness seen 4-6 mo Acne in pregnancy Avoid o Topical & oral retinoids o Tetracyclines, SMX/TMP o Anti-androgens (spironolactone) o Hormones (oral contraceptives) Select erythromycin (topical or oral) but not estolate salt Topical benzoyl peroxide is safe Spironolactone for acne Androgen-receptor blockade Dose: 50 mg daily or 100 mg bid (when contraception is not required) SEs: diuresis, hyperkalemia, irregular menstrual periods Avoid in pregnancy (feminization of male fetus) Pediatric acne Neonatal acne (birth-4 wk) Infantile acne (6 wk 1 yr) Mid-childhood acne (1-7 yr) Preadolescent (7-12 yr or menarche in girls) Self-limited No comedones Self-limited Comedones Papules, pustules Very uncommon Gently txt with topical abx Txt similar to adults Avoid tetracyclines <9 yo Avoid OCs until 1 yr after menarche