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Classes of Dermatologic Medications What is that?! Common Dermatologic Conditions and ● Topical Immune Suppressants ● Immune Suppressants How to Treat Them ● Vitamin D Derivatives ● Antibiotics, Antivirals, Antiparasitic Matthew Fox, MD ● Retinoids ● Antimalarials Assistant Professor, Division of Dermatology ● Biologic Agents Dell Medical School, University of Texas at Austin Director of Dermatologic Surgery, Seton Healthcare Family ● Chemotherapeutic agents

Learning Objectives Approach to Dermatologic Conditions • Know the clinical subtypes of acne *Know the mechanism and recommended dosing of topical retinoids, oral antibiotics and oral retinoids in the management of acne Acne • Understand the clinical presentation cutaneous dermatophyte infection Infectious diseases of the Skin *Know the classes and recommended dosing of antifungal treatments • Recognize the clinical manifestations of dermatitis Eczema *Know the relative potencies, side effects and indications of topical steroids Psoriasis • Describe the classic clinical findings for psoriasis *Know the mechanism of action and side effects of systemic antipsoriatic medications Sun Damage / Actinic Keratoses • Know the pertinent history and physical exam findings associated with a diagnosis of skin cancer, including the ABCDEs of melanoma

Fundamentals Words to the wise…

• All medications have side effects If you advise the patients of side effects ahead of time, you are informing the • Always consider drug interactions, patient. including with food and supplements If you did not tell the patient about a known • Always consider pregnancy and lactation side effect until after they experience status that side effect, it is an excuse

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Reference: Approach to Dermatologic Conditions

• Wolverton SE, ed. Acne Comprehensive Infectious diseases of the Skin Dermatologic Drug Eczema nd Therapy, 2 Ed. Psoriasis Elsevier, 2007. Sun Damage / Actinic Keratoses

Topical Retinoids

Retinoid RAR-α RAR-β RAR-γ RXR-α RXR-β RXR-γ • Small molecule hormones that activate All-trans retinol ------nuclear receptors and regulate gene All-trans retinoic acid ++ ++ ++ - - - Adapalene Weak ++ ++ - - - transcription Tazarotenic acid + +++ ++ - - - Alitretinoin +++ +++ +++ ++ ++ ++ Bexarotene - - - +++ +++ +++

Retinoids: Clinical Effects Adapalene

• Affect pathways involved in: • Mild comedonal acne – Inflammation – Cellular differentiation • 0.1% gel – Apoptosis • Apply QHS – Sebaceous gland differentiation • OTC (2016) ***NORMALIZATION OF FOLLICULAR EPITHELIAL • Pregnancy: C DIFFERENTIATION AND KERATINIZATION***

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Tretinoin Tazarotene

• Supplied as 0.025%, 0.05%, 0.1% cream • 0.05% and 0.1% cream and gel or as 0.01 - 0.1% gel • Apply QHS • Apply QHS • For female patients, begin during menses • May need to start with lesser frequency • Pregnancy: X • Pregnancy: C

Topical Antibiotics Clindamycin Name Comments • Reversibly binds 50s subunit of ribosomal Benzoyl Beneficial effects can be neutralized with simultaneous tretinoin peroxide No association with induction of bacterial resistance RNA subunit à inhibition of protein synthesis Clindamycin Good gram + and anaerobic coverage • Broad spectrum(S. aureus, streptococci, P. Erythromycin Resistance to some P. acnes; most benefit is via anti-inflammatory effec ts acnes)

Metronidazole Coverage of both aerobic and anaerobic bacteria (more for rosacea) • 1% lotion or solution, applied daily to BID

Azelaic ac id Broad coverage; good for pigmentary disorders; OK during pregnancy • Pustules, inflammatory acne >> non-

Sodium Broad coverage and multiple indications inflammatory lesions sulfac etamide

Azelaic acid Sodium sulfacetamide

• Commonly incorporated in formulation with • Activity against tyrosinase sulfur • Safe during pregnancy (B) • Inhibition pro-inflammatory enzymes • Supplied as 15% gel • Supplied as lotion for BID application

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Benzoyl peroxide Combination products

• Keratolytic and comedolytic properties • Improved patient adherence • Bactericidial, broad spectrum • Better results that individual agents alone • Broad range of concentrations (2.5-10%) • Many combinations: and vehicles (washes, lotion, gel, cream) – BPO/Clindamycin combinations • Little to no induction of bacterial resistance – Clindamycin/retinoid combinations • Peeling, erythema, dryness

Oral antibiotics Tetracyclines

• Tetracyclines • Bacteriostatic, inhibit bacterial protein synthesis • Trimethoprim/sulfonamide • Bind 30S ribosomal subunit • Clindamycin • Do not give to children < 9 – bone, teeth development • Pregnancy category D

Minocycline Doxycycline

• Supplied: 50, 75, 100 mg • Supplied: 20, 50, 75, 100 mg • Dosage: 50-200 mg per day (dosed daily or BID) • Dosage: 50-200 mg per day (dosed daily or BID) • Common SEs: • Common SEs: – Dizziness – GI (burning, discomfort, nausea, vomiting) – Headache (pseudotumor cerebri) • Relieved if taken with food (NON DAIRY) – GI – Photosensitivity – Photosensitivity – Headache – Pigmentation change – Pigmentary change – Hepatotoxic – Hepatotoxic • Not to be used in pregnancy, kids • Not to be used in pregnancy, kids • Not to be used with isotretinoin: increased risk of • Not to be used with isotretinoin: increased risk of pseudotumor cerebri (applies to all tetracyclines) pseudotumor cerebri (applies to all tetracyclines)

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Oral retinoids - Isotretinoin Isotretinoin

• Approved for severe recalcitrant nodular • Dosage: acne – Weight based dosing – Inflammatory lesions greater than 5mm in – 0.5-1 mg/kg daily, until a total cumulative dose diameter of 120-150 mg/kg is reached – Unresponsive to conventional tx (oral abx) • Rate of success approx 70% • Consider impact of disease on patient! – Relapses more likely to respond to conventional treatment

ADVERSE EFFECTS Alternative acne treatment Teratogenicity Hepatic -Retinoic acid embryopathy -Elevated transaminases Ocular Other Endocrine • For ‘hormonal’ acne, may consider -Reduced night vision -Hypothyroidism -Dry eyes, infection – Spironolactone Bone Hematologic -Diffuse skeletal hyperostosis -Leukopenia • SE: Teratogenic, K+ monitoring -Premature epiphyseal closure -Agranuloc ytosis – OCPs Lipids Neuro/Psych -Elevated cholesterol, TG -Depression, pseudotumor Gastrointestinal Muscle -Inflammatory bowel disease flare -Myalgias -Pancreatitis

Acne Pearls Approach to Dermatologic Conditions • For acne on the trunk, it is difficult for patients to apply lotions, gels. Use washes and oral Acne antibiotics. • For medications to work, it takes time. Advise Infectious diseases of the Skin that the earliest they will see improvement is Eczema 6-8 weeks. Psoriasis • Often need combination of products • May need oral retinoids sooner than later! Sun Damage / Actinic Keratoses

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Warts Impetigo

Treatment Comments

Salicylic Ac id Keratolytic; consider 40% plaster under occlusion • Mupirocin

Podophyllin Antimitotic agent; contraindicated in pregnanc y; applied in offic e • Staph directed antibiotic coverage

Cantharidin Vesic ulating agent; applied in office – Bactrim

Imiquimod Immunostimulatory (activates TLR-7); apply at bedtime three times – Clindamycin weekly on non-consecutive days (genital warts) – Doxycycline Candida Immunostimulatory, injec ted into lesion Antigen – Cephalosporins

Mupirocin Acyclovir / valacyclovir • Inhibits bacterial isoleucyl-tRNA synthetase à inhibits bacterial RNA and cell wall • Guanosine analog synthesis • Requires phosphorylation by herpes • Excellent coverage against S. aureus, S. epidermidis, S.pyogenes, B-hemolytic specific thymidine kinase Streptococci • Once active, inhibits viral DNA polymerase • ? Resistance • Valacyclovir is oral prodrug • 2% ointment, to be applied BID • Exceptionally safe and well tolerated • SE: burning, itching, contact dermatitis

Herpes viruses Scabies Treatments

• Topical acyclovir • Permethrin: – Supplied as 5% ointment for limited disease – low efficacy – MOA: acts on arthropod cell wall by disabling sodium – applied Q3 hours, 6x/day for 7 days transport à mite paralysis • Acyclovir – Supplied as oral suspension – Applied from neck to, not just visibly affected sites – Example doses: – Two overnight applications separated by one week • Cold sore: 400 mg 5x/day for 5 days • Shingles: 800 mg 5x/day for 7-10 days – All partners and close contacts should be treated • Valacyclovir – Reasonable to wash clothes and linens concurrent – Easier dosing, possible benefit for PHN • Cold sore: 2g twice daily for one day with treatment • Shingles: 1g TID x 7 days – Pruritus may last for up to 1 month after treatment!

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Scabies Treatments Azole antifungals • Sulfur: MOA: Inhibition of 14α-demethylase, leading to decreased ergosterol formation – time honored Examples include: – 6% precipitated sulfured, compounded, applied daily until improved • Ketoconazole – 2% cream, applied BID until improved • Ivermectin: – 1-2% shampoo, used in seborrheic dermatitis – MOA: blocks glutamate gated chloride ion channels à paralysis of arthropod/helminth • Econazole – 1% cream, applied BID until improved – Off label: single 100-200 μg/kg dose or two full doses separated by one week • Efinaconazole – 10% topical solution, painted topically to nails once daily for 48 weeks!

Te rb i n a fi n e Oral terbinafine

• Allylamine, disrupts fungal cell wall via • Severe or resistant fungal infection • 250 mg daily for: inhibition of squalene epoxidase – 2 weeks (tinea corporis) – 6 weeks (fingernails) • Highly lipophilic (high concentration in – 12 weeks (toenails) stratum corneum, hair follicles, sebum) • Common SEs: HA, GI • 1% gel, cream, spray – applied daily to • Baseline LFTs and 6wks after rx starts • Needs dose adjustment in renal/liver disease BID • Pregnancy category: B

Regimens for tinea versicolor Approach to Dermatologic Conditions

• Topical zinc pyrathione wash Acne • Topical ketoconazole wash Infectious diseases of the Skin • Topical selenium sulfate wash Eczema • Oral ketoconazole option Psoriasis – Take 400mg, work up a sweat, don’t shower Sun Damage / Actinic Keratoses for at least 4 hours

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Eczema/Dermatitis Approach to Dermatitis

• Nonspecific term for a histologic finding • Liberal application of emollients • Remove allergens and avoid – Acute—e.g. poison ivy, contact dermatitis sensitizers – Subacute—e.g. atopic dermatitis • Topical / oral antibiotics to – Chronic—e.g. lichen simplex chronicus reduce secondary infection & colonization • Usually ill-defined scaly papules and • Topical immune suppression plaques, except for contact dermatitis • Systemic immune suppression

Dermatitis NOS Treatment Topical steroids • Ranked according to • To p i c a l immune suppression is the mainstay of strength, based on treatment vasoconstrictor – Topical steroids assays and blinded – Topical CNIs studies • For severe cases, can consider wet wraps, UV – Class 7 (least potent) light, immunomodulators to – Class 1 (ultra potent)

Topical steroids Topical steroids – Base

• Common SEs: Thinning of skin, atrophy, • Ointment vs. Cream vs. Solution vs. Gel vs. spray striae, telangiectasia, ecchymosis, may • Ointments are greasy, but penetrate better and burn/sting on application (fades after 10 min) have fewer potential irritants • Creams rub in better and are often preferred for • Don’t use every day for months and months! small areas; creams bases have potential irritants • Commonly used as: BID x 2 weeks then BID • Solutions are used for the scalp (seborrheic on weekends only dermatitis, scalp psoriasis) • Gels are like thick solutions; Gels and alcohol- – Emphasize intermittent therapy to avoid based sprays evaporate and concentrate tachyphylaxis, atrophy etc. medications

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Topical steroids Topical calcineurin inhibitors Tacrolimus and pimecrolimus • Low potency: • Block T cell activation and proliferation – desonide, – FKBP/NFAT pathway hydrocortisone 2.5% In general, applied BID for • Often used in eczema • Medium potency: up to 2-3 weeks as needed, then tapered… • Particularly good for thin-skinned areas: face, eyelids, – triamcinolone 0.1% axillae, groin • High potency: • Can combine with topical steroid use – clobetasol, – Example: use steroid BID on weekends and TCI Monday- betamethasone Friday • However….

Possible adverse events Oral steroids

• Possible risk of lymph node or skin • Produce apoptosis of T cells, eosinophils, cancer: The potential for systemic immunosuppression is unknown and the role of TCI in the downregulation of pro-inflammatory development of the cancer-related events in the individual patient reports is also uncertain at this. Animal studies have showed that skin tumors formed faster in cytokines animals treated with tacrolimus, the active ingredient in Protopic, and exposed to light. Because of this, you should limit exposure to natural or artificial sunlight, such as sunlamps or tanning beds. • Often used for acute dermatitis flares • Example: Poison Ivy • Viral infections: TCI use may increase the chance of getting chicken pox, shingles, or other viral – Prednisone 1 mg/kg (generally 40-60 mg), infections. tapered slowly over 2-3 weeks

Side effects Oral steroids • HPA axis suppression • Ocular – Ster oid w ithdr aw al – Cataracts – Addis onian c r is is – Glaucoma • Also used for rarer dermatoses quite frequently • Metabolic Effects – Infec tion – Hyperglycemia • Psychiatric – Pemphigus – Inc r eas ed appetite – Ps y c hos is – Pemphigoid – Hypertension – Agitation – Cushingoid changes – Per s onality c hange – Vasculitis – Weight gain – Depression – Connective tissue disease (lupus, DM) • Bone • Neurologic – Osteoporosis – Ps eudotumor – Pyoderma gangrenosum – Osteonecrosis – Neuropathy – Lichen planus • GI • Infectious – Ulcers – TB reactivation • Higher doses, longer duration, more monitoring for – Bow el per for ation – Fungal disease side effects – Fatty liver • Muscular

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Caution Steroid sparing agents • Use caution in starting steroids for patients with history of: • Methotrexate – diabetes • Mycophenelate Mofetil – hypertension – psychiatric disease • Azathioprine – osteoporosis • Cyclosporine – gastric ulcer – chronic infections (eg. TB, systemic fungal)

Seborrheic Dermatitis Seborrheic Dermatitis Treatment • Shampoo as scalp and face wash • Common, 2-5% of population, M and F – Zinc pyrathione • Commonly Called “Dandruff” – Selenium sulfide – Ketoconazole – Erythematous patches and plaques with overlying yellowish dry or greasy scales. • Creams – Ketoconazole cream BID to affected areas, or – Commonly over oil producing areas such as scalp, eyebrows, nasolabial folds, chest / – Sodium sulfacetamide BID – If erythema is a significant component, consider sternal area (sebaceous glands) HC 2.5% cream BID PRN (short duration)

Approach to Dermatologic Conditions Psoriasis Vulgaris

Acne • Common, 1-2% of general population Infectious diseases of the Skin • Round, well-demarcated, dry, scaly Eczema papules and plaques Psoriasis • Scalp, nails, extensor surfaces of the Sun Damage / Actinic Keratoses limbs, umbilicus, and sacral region.

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Psoriasis Treatment Vitamin D analogues • To p i c a l S t e r o i d s • Calcipotriene • Topical Vitamin D analogues – Comparable to potent topical steroids at 8 weeks • UV light of treatment • Methotrexate – Applied twice daily • Retinoids – May be used in combination with topical steroids, • Biologics often ‘in-regimen’ – Can cause hypercalcemia • Recommended application is 100g/week or less

Methotrexate Methotrexate • MANY SE’s, but well known, including but not limited to: – GI • Inhibitor of dihydrofolate reductase and thymidylate – Oral ulcers synthetase à blocks DNA synthesis (S phase specific) – Liver toxicity – My elos uppres s ion • Ultimate action is to inhibit cell division – Radiation recall – Pneumonitis – Pulmonar y fibr os is – Infer tility MOA (psoriasis): – Abor tion – Blocks migration of T cells • Required meticulous lab monitoring before and during therapy – Decreased proliferation of lymphocytes • Folate 1mg qd – Immunosuppression • Start with test dose of 2.5mg before increasing to target • METHOTREXATE IS A Q WEEK DRUG!!!!

Cyclosporine Cyclosporine SE • Varied and many, including: – Renal dysfunction • MOA not fully understood, but involves: – Hypertension – Decreased T cell proliferation – Headache – Hypertrichosis – Inhibition of pro-inflammatory cytokines – Gingival hyperplasia – Nausea • FDA approved for psoriasis – Diarrhea • Requires meticulous lab and BP monitoring – Myalgia – Hyperkalemia • Weight based dosing, with short term (3-6 – Hypomagnesemia months) use ideal – Hyperlipidemia

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• Common SEs: Acitretin – dry skin/mucous membranes – alopecia (50-75%) – cheilitis • Oral retinoid • Generally not given to women – peeling skin/sticky skin/fragile nails of childbearing potential – decreased night vision • Like all retinoids, acts – Two negative pregnancy tests – Joint aches before initiation – Photosensitivity to normalize epithelial – Pregnancy prevention differentiation and • Limit alcohol use during • SERIOUS SEs keratinization treatment – elevated liver transaminases – Long lasting (years) metabolite – pancreatitis • Dosed orally produced – pseudotumor cerebri • Requires meticulous • No blood donation during – hypertriglyceridemia/hypercholesterolemia, decreased HDL lab monitoring before treatment and for 3 years after – depression (aggressive feelings or thoughts of self-harm) and during treatment – Teratogenicity – IBD flare

Biologics Biologics • TNF alpha modulation – Certolizumab (Cimzia) • Increase risk of infection – Etanercept (Enbrel) – Adalimumab (Humira) • Common SE – Remicade (Infliximab)* - IV Infusion – Respiratory infection – Golimumab (Simponi) – Flu-like illness – Injection site reaction • IL12/23 modulation – Ustekinumab (Stelara)* - In-office injection • Serious SE – Nervous system disorders • IL-17 modulation – Cancer (lymphoma) – Secukinumab (Cosentyx) – Blood dyscrasia – Ixekizumab (Talz) – Reactivation of past infections (Hepatitis, TB, Fungal)

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Apremilast Approach to Dermatologic Conditions

• Inhibits phosphodiesterase 4 (PDE4) enzyme Acne • Orally dosed Infectious diseases of the Skin – Starts at 30 mg, titrates to 30 mg BID • SE: Eczema – Diarrhea Psoriasis – Nausea Sun Damage / Actinic Keratoses – Headache – Weight loss

5-fluorouracil

• Antimetabolite • Use 5% cream BID for 2 weeks • Patients may use triamcinolone 0.1% ointment bid during the last 5 days to help www.seton.net/derm relieve the irritation • Warn the patients! They will look terrible when it starts working – show them the pictures!

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