Acne And Drug Induced Dermatological Disorders

I ACNE AND DRUG INDUCED DERMATOLOGICAL DISORDERS G . M or a t aya , P h a r mD Assoc ia te P rofe ssor We st Coa st Un ive r sit y 1 DEFINITIONS ¡ SCAR: Severe Cutaneous Adver se Reaction ¡ ADR: Adver se Reaction ¡ DHS: Drug Hyper sensitivity Syndrome ¡ DRESS: Drug Reaction with Eosinophilia and Systemic Symptoms ¡ AGEP: Acute Generalized Exanthematous Pustulosis ¡ SJS: Stevens-Johnson’s Syndrome ¡ TEN: Toxic Epidermal Necrolysis ¡ EM: Er ythema Multiforme ¡ Derm: Dermatological 3 Common ACNE VULGARIS • Acne “eruption” Vulgaris “common” (blocking of hair follicle) • Chronic inflammatory skin disease, mainly in adolescents and young adults • No mortality, but often psychological comorbidities— direct cost of the disease burden is about 3 billion dollars a year • Open comedones- white heads, black heads • Closed comedones- papules, pustules or nodules (or cysts) PATHOPHYSIOLOGY Oxygenà black P. Acnes Increase sebum production (Testostrone) Hyperkertonization closing hair follicle CLASSIFICATIONS Type 1 Mild No scaring, some small comedones Type 2 Moderate No scarring, Large closed comedones Type 3 Moderately, severe acne Some scarring, papular & pustular acne Type 4 Severe acne Severe Scarring, nodulocystic acne No universal grading/classifying system can be recommended DIAGNOSTICS Culture Testing for bacteria rarely done Androgen Levels prepubertal children: with early-onset body odor, axillary or pubic hair, accelerated growth, advanced bone age, and genital maturation (hyperandrogenism) postpubertal females: infrequent menses, hirsutism, androgenic alopecia, infertility, polycystic ovaries, clitoromegaly, and truncal obesity warrant further hormonal testing Ed EXACERBATING FACTORS OF ACNE • • • • • Genetics Diet: chocolate, high glycemic index, dairy Stress Medications: Steroids, testosterone, lithium Friction or pressure on skin (cell phones, head bands, backpacks) • Oil based cosmetics • Hormones Kucharska A., Postepy Dermatol Alergol. 2016 Apr; 33(2):81–86. BENZYL PEROXIDE Dose Benzyl Peroxide 2.5-10% creams, gels, topical wash, foam used once daily MOA Antibacterial through release of oxygen radicals – no resistance reported mildly comedolytic a Blackheads whiteheads AE Clinical Pearls Concentration dependent irritation Stain/ bleach fabric - Wash off and water based agents are better tolerated - Can start to see results in as soon as 5 days SALICYLIC ACID Dosing 0.5%- 2%, wash, gel, can apply 1-3 times daily and gradually increase MOA Keratolytic, increases turnover of epithelial cells AE Data Well tolerated, dryness and erythema, photosensitivity Limited trials showing efficacy Counseling - Many dosage forms to fit patient’s preference - Start low dose and gradually increase as tolerated - Caution in patients with ASAallergy TOPICAL ANTIBIOTICS Drugs Data AE Clinical Pearls Clindamycin 1% gel (preferred) Erythromycin 2% cream, gel, lotion or pledget Eton Erythro/BP BID in two trials showed greater efficacy over vehicle Clinda daily > vehicle; Clinda/BP > clinda or BP alone Excellent tolerance Rare case reports of C. diff - Erythro has reduced efficacy compared to clinda (due to resistance) - Monotherapy NOT recommended, always in combination with BP - Combo products with BP increase compliance Benyproide TOPICAL DAPSONE Dose Dapsone 5% gel, apply BID MOA Not well understood: possibly antibacterial, most likely anti-inflammatory Data Modest to moderate efficacy Clinical Pearls - Can be inactivated by BP, Separate timing - G6PD not required (topical) kidney TOPICAL RETINOID Drugs Tretinoin 0.025-1% crm, gel (indicated >10 yo) Tazatotene 0.05% cream, gel, or foam (>12 yo) Adapalene 0.1-0.3% cream, or 0.1% lotion (indicated >9 yo) MOA Vitamin A derivative- antiimmflatory, thought to cause keratolytic activity & decrease sebum secretion AE Data Clinical Pearls Concentration dependent dryness, peeling, erythema, irritation, photosensitivity Has several RCTs to support efficacy: Tazarotene> adapalene> tretinoin - Reduced frequency of use to reduce SE Tretinoin Can be inactivated by BP, separate timing Not recommended in pregnancy Can initially worsen acne, takes weeks to work ORAL ANTIBIOTICS Drugs AE Data Clinical Pearls Tetracyclines (first line): Tetracycline, Minocycline, Doxycycline sulfamethoxazole/ trimethoprim; amoxillcin; cephalexin Off Label: erythromycin, azithromycin Review them. All can be associated with C. diff and vulvovaginal candidiasis No difference between tetracyclines (have most evidence) - Should be used in combo with BP and retinoid - For moderate to severe acne - Should limit the use to 3-4 months, topical can help maintain efficacy ORAL CONTRACEPTION Drugs Ethinyl estradiol/norgestimate, Ethinyl estradiol/ norethindrone acetate, ethinyl estradiol/drospirenone, ethinyl estradiol/ drospirenone/levomefonone MOA Reduce alpha 5 reductase activity, increase sex hormone binding globulin which bind to free testosterone, decrease androgen production AE Data Clinical pearls Review common SE Several RCTs proving efficacy, there is probably no difference between different COC - Treatment of acne in women who also want contraception Can be used in combo with other agents COC CONTRAINDICATIONS • • • • • • • • Pregnancy, breast feeding <6 weeks postpartum Current breast cancer style Age > 35 years and heavy smoker (>15 cigarettes per day) Hypertension: systolic, >160 mm Hg or diastolic, > 100 mm Hg Diabetes with end-organ damage or DM > 20 years duration History of or current deep vein thrombosis or pulmonary embolism Major surgery with prolonged immobilization Ischemic heart disease (history or current); valvular heart disease with complications • History of cerebrovascular accident • migraine with focal neurologic symptoms at any age, or without aura if >35 years) SPIRONOLACTONE EIN Dose Spironolactone 50-100 mg PO daily MOA Aldosterone receptor antagonist, Anti-androgen, decrease testosterone production AE Data Clinical Pearls Diuresis, hyperkalemia, increase BUN, metabolic acidosis gynecomastia, regular menses, erectile dysfunction Two placebo controlled trials—reduction in acne and sebum production - Used in women and men, but one trial d/c in men due to gynecomastia - Testing K in young healthy patients is unnecessary ORAL ISOTRETINOIN Drugs Data AE Clinical Pearls Accutane®; Amnesteem®; Claravis®; Sotret® , ***Absorica® 0.5-2 mg/kg/day (TBW) PO divided BID x 15-20 weeks (take with food) Target dose 1 mg/kg/day (up to 2mg/kg/day) 1 mg/kg/day results lower relapse and lower retreatment, cumulative dose goal: 120-150 mg/kg Dryness (lips, skin, eyes), fatigue, headache, photosensitivity, vision changes, joint and muscle pain, birth defects - Can repeat 2nd course of therapy after >2 months off - Growing evidence of IBD with use (UC and CD) - Possible suicidal ideation/ mood disturbances/ depression • 100s of cases reported when drug released in 1982 • Men and women required to enroll in iPLEDGE, must use 2 contraceptive methods • Still approximately 150 isotretinoin pregnancies per year IPLEDGE REMS • Computer-based mandatory risk management program for isotretinoin • The pharmacist must obtain authorization from the iPLEDGE system via site or phone prior to dispensing each prescription for both male and female patients • Female patients must continue birth control for 1 month after discontinuation of medication • Patients must not donate or share blood for up to 1 month after discontinuing therapy • Patients are only eligible to receive 1 month of treatment at a time, must fill Rx within 7 days of completing requirements BIRTH CONTROL OPTIONS Primary Forms • • • • Tubal sterilization Partner’s vasectomy Intrauterine device Hormonal combination - Oral contraceptives - Transdermal patch - Injectables - Implantables - Vaginal ring • Other - Abstinence Secondary forms • Barrier - Male latex condom with or without spermicide - Diaphragm with spermicide - Cervical cap with spermicide • Other - Vaginal sponge with spermicide If abstinence 1st choice, then a 2nd choice doesn’t need to be entered in iPLEDGE TREATMENT Mild First Line: Benzyl peroxide (BP) or topical retinoid, BP + antibiotic (abx) or topical retinoid, Or all three Second line: Consider alternate retinoid or topical dapsone Moderate First Line: Topical combination therapy (BP + abx or topical retinoid, or all three), OR BP+ oral abx +topical retinoid, OR BP+ oral abx + topical retinoid +topical antibiotic Severe First Line: Oral abx +Topical combination therapy (BP + abx or topical retinoid, or all three), OR Oral isotretinoin OTHER TREATMENTS • Corticosteroids can be used temporarily to bridge to other therapies • Topical AzelaicAcid • Flutamide- anti-androgen • Intralesional triamcinolone acetonide for nodular acne • Glycolic acid and salicylic acid peels • Resorcinol/salicylic acid patches OTHER TREATMENTS ¡ Sarecycline (Seysara) Approved for Treatment of Acne Vulgaris: In October 201 8, the FDA approved sarecycline (Seysara), a once-daily oral tablet for treatment of inflammator y lesions of non-nodular moderate to severe acne vulgaris in persons aged 9 years and older. Sarecycline is a tetracycline derivative with a narrower spectrum of activity than other tetracyclines, which may result in lower rates of bacterial resistance. 26 NON-PHARMACOLOGICAL • • • • • • Diet modification Stress reduction Increase Omega-6, Omega-3 fatty acid Increase antioxidants, zinc (in deficient patients) Vitamin A Apple cider vinegar, tea tree oil, green tea applied to skin Kucharska A., Postepy Dermatol Alergol. 2016 Apr; 33(2):81–86. DRUG INDUCED DERM DISORDERS • The skin is among the most common organs of manifestation for adverse reactions (ADR) and accounts for at least 15% to 20% of all ADRs 28 DRUG INDUCED DERM DISORDERS • Some patients more prone to developing hypersensitivity ADRs and risk factors may include the following: • Prior drug reaction (inducing drug-specific antibodies), multiple drug therapy or intermittent/repeated use of the same drug (vs continuous therapy), some concurrent illnesses (eg, HIV, Epstein-Barr virus, and CMV), dosage/serum drug level increases (eg, IV vancomycin administration rate), topical route of administration (more immunogenic than subcutaneous > intramuscular > oral > IV), certain genetic factors (eg, certain HLA-B alleles predispose for drug allergies), and certain comorbidities (eg, asthma). 29 DRUG INDUCED DERM DISORDERS Drug-induced skin reactions can be irritant or allergic in origin. • Irritant reactions are localized. • Examples include chemical vaginitis, such as those resulting from vaginal douches, spermicides, and imidazoles; and vesication, produced by drug extravasation, as with agents such as anthracyclines. • Allergic reactions depend on inducing an immune response from the host; thus, the reaction may be systemic rather than limited to skin manifestations. 30 Types of cutaneous drug eruptions. (AGEP, acute generalized exanthematous pustulosis; SJS, Stevens-Johnson’s syndrome; TEN, toxic epidermal necrolysis.) (Adapted from Knowles, S. Drug-Induced Skin Reactions, Table 3, Description of Drug Eruptions. In: Compendium of Therapeutic Choices for Minor Ailments, 2nd ed. Ottawa (ON): Canadian Pharmacists Association; © 2016.) Citation: Dermatologic Drug Reactions and Common Skin Conditions, DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. Pharmacotherapy: A Pathophysiologic Approach, 10e; 2017. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=1861§ionid=146079670 Accessed: March 07, 2020 31 Copyright © 2020 McGraw-Hill Education. All rights reserved DRUG INDUCED DERM DISORDERS • Drug hypersensitivity syndrome (DHS) is an exanthematous eruption accompanied by fever, lymphadenopathy, and multiorgan involvement (including the kidneys, liver, lung, bone marrow, heart, and brain). • Signs and symptoms usually begin 1 to 4 weeks after starting the offending drug, and the reaction may be fatal if not promptly treated. 32 DRUG INDUCED DERM DISORDERS • This condition is also known as drug reaction with eosinophilia and systemic symptoms (DRESS). • It is more commonly referred to by the acronym DRESS, although DHS is also used. 33 DRUG INDUCED DERM DISORDERS • Usual drug culprits include • Allopurinol • Sulfonamides • Some Anticonvulsants (barbiturates, phenytoin, carbamazepine, and lamotrigine) • Dapsone. • For patients taking allopurinol, several factors increase the risk of serious skin reactions: • Renal impairment • Hypertension • Use of thiazide diuretics or excessive allopurinol doses (ie, not dose adjusted for renal impairment). 34 DRUG INDUCED DERM DISORDERS • Stevens-Johnson’s syndrome (SJS) and toxic epidermal necrolysis (TEN) are complex blistering eruptions that, together with erythema multiforme (EM), are known as acute bullous disorders. They are histologically similar and have been considered part of an “EM spectrum of diseases.” • SJS and TEN are immune complex or cell-mediated allergic responses to offending agents, including drugs. 35 DRUG INDUCED DERM DISORDERS • Because of their histologic similarity, in the past SJS and TEN have been considered either distinct disorders or progressions of the same disorder based on the percentage of skin area involved. • They are now considered variants of the same disorder but distinct from EM, and these two entities are often discussed together as SJS/TEN 36 DRUG INDUCED DERM DISORDERS • Genetic associations between some drug causes of SJS/TEN and HLA alleles have been identified. • For example, carbamazepine-induced SJS/TEN is associated with HLA-B*15:02, with this allele being specific for the carbamazepine-induced activation of cytotoxic T cells that release granulysin, a mediator responsible for the epidermal sloughing in SJS/TEN 37 DRUG INDUCED DERM DISORDERS • SJS/TEN: are rare, severe, and life-threatening conditions with an acute onset (within 7-14 days of drug exposure). • Patients present with generalized tender or painful bullous formation with accompanying systemic signs and symptoms, including fever, headache, and respiratory symptoms, that rapidly deteriorate. 39 DRUG INDUCED DERM DISORDERS • Lesions show rapid confluence and spread, resulting in extensive epidermal detachment and sloughing 40 DRUG INDUCED DERM DISORDERS • This may result in: • Marked loss of fluids • Drop in blood pressure • Electrolyte imbalances • And secondary infections, including Staphylococcus epidermidis and methicillin-resistant Staphylococcus aureus (MRSA). 41 DRUG INDUCED DERM DISORDERS • Usual drug culprits include: • Sulfonamides • Penicillins • Some anticonvulsants (hydantoins, carbamazepine, barbiturates, and lamotrigine) • NSAIDs • Allopurinol 42 DRUG INDUCED DERM DISORDERS Etsy • Other Drug-Induced Skin Reactions • Hyperpigmentation • Photosensitivity Nats ayyy 43 DRUG INDUCED DERM DISORDERS • If a drug-induced skin reaction is suspected, the most important treatment in nearly all cases is discontinuing the suspected drug as quickly as possible and avoiding the use of potential crosssensitizers. • In most instances, that is the only specific treatment required. • In severe cases, a short course of systemic corticosteroids may be needed. • In a few instances, it may be possible to continue the offending drug and “treat through” the reaction (eg, ampicillin-associated maculopapular skin rash) 44 DRUG INDUCED DERM DISORDERS • The next step is to control symptoms associated with the drug reaction (eg, pruritus). • Furthermore, any signs or symptoms of a systemic or generalized reaction may require additional supportive therapies specific to the severity and type of signs and symptoms seen. • For high fevers, an antipyretic such as acetaminophen is more appropriate than aspirin or an NSAID because these may exacerbate skin lesions for some reactions. • Depending on the type of skin reaction, the affected skin condition may take days to weeks or months to resolve. 45 DRUG INDUCED DERM DISORDERS • For patients with life-threatening SJS/TEN, supportive measures such as maintenance of adequate blood pressure and fluid and electrolyte balance, use of broad-spectrum antibiotics and vancomycin for secondary infections, and IV immunoglobulin (IVIG) may all be appropriate. 46 DRUG INDUCED DERM DISORDERS • The use of corticosteroids for SJS/TEN is somewhat controversial; • Although they may curb disease progression, they may also increase the risk of infection and thus contribute to increased mortality. • If used, relatively high initial doses followed by rapid tapering as soon as disease progression halts is indicated. 47 DRUG INDUCED DERM DISORDERS • Patient education should be provided. • Advice to the patient should include information about the suspected drug and potential drugs to avoid in the future and which drugs may be used. • Potential cross-sensitizers should be identified. • For patients with photosensitivity reactions, information should be provided about preventive measures such as the use of sunscreens and sun avoidance • For patients with severe reactions (eg, anaphylaxis), information about MedicAlert programs may be appropriate. 48 DRUG INDUCED DERM DISORDERS • Genetic predisposition has not been established for most drug-induced reactions, but for SCARs such as SJS/TEN or DRESS, the risk may be higher in first-degree relatives of affected patients. 49