DERMATOLOGICAL PHARMACOLOGY

Directly treat D/O of skin Deliver drugs to other tissues Stratum corneum

Major barrier to percutaneous absorption of drugs and loss of water from the body Possesses multiple proteins and lipids

Reversibly/irreversibly bind drugs

Thickest palm and sole Thinnest-facial and post-auricular regions

Dermis and its BV

Superficial capillary plexus between epidermis and dermis

Site of majority of systemic absorption of cutaneous drugs

Cells in dermis-targets for drugs

Mast cells Infiltrating immune cells

Pharmacologic Implications

Dosage Covering skin w/ a topical preparation

Requires 30g of spreadable material

Regional Anatomical Variation

Permeability-inversely proportional to thickness of stratum corneum Higher on face, intertriginous areas and perineum

Altered Barrier Fxn in Disease

Stratum corneum is abnormal Increased percutaneous absorptionsystemic toxicity

Vehicle

Cream

Oil in water emulsion >31% water Leaves concentrated drug at skin surface Spreads and removes easily, no greasy feel

Ointment

Water in oil <25% water Protective oil film on skin Spreads easily Slows water evaporation Gives a cooling effect

Gel/Foam

Water-soluble emulsion Concentrates drug at surface after evaporation Non-staning Greaseless Clear appearance Foams well for scalp and other hairy locations

Lotion/Solution/Foam

Solution-dissolved drug base Lotion-suspended drug Aerosol propellant with drug Foam drug w/ surfactant

May be aqueous or alcoholic Low residue on scalp Children

Age

>ratio of surface area to mass than adults >systemic exposure

Application Frequency

Often applied twice daily

GLUCOCORTICOIDS

Immunosuppressive and anti-inflammatory Topical glucocorticoids

Selected on basis of potency, site of involvement, severity of skin dse Tx uses: Inflammatory skin diseases st Usually use more potent steroid 1

Toxicity:

Chronic use of class 1 Skin atrophy

7 classes in order of decreasing potency Class 1 Betamethasone dipropionate cream, ointment 0.05% Clobetasol propionate Diflorasone diacetate Halobetasol propionate Class 2 Amcinonide Betamethasone dipropionate Desoximetasone Fluocinonide Halcinonide

Class 3 Betamethasone valerate Triamcinolone acetonide Class 4 Amcinonide Flurandrenolide Hydrocortisone valerate Mometasone furoate Class 7 Dexamethasone sodium phosphate

Class 1-most potent

Striae Telangiectasias Purpura Acneiform eruptions

Systemic glucocorticoids

For severe dermatological illnesses Allergic contact dermatitis to plants, lifethreatening vesiculobullous dermatosis Daily morning dosing Side effects: dose dependent Long-term use: psychiatric problems, cataracts, myopathy, osteoporosis, avascular bone necrosis,glucose intolerance, HPN

Retinoids

Natural and synthetic compounds that exhibit vitamin A-like biological activity or bind to nuclear receptors for retinoids 1st generation Retinol (vitamin A) Tretinoin Isotretinoin Alitretinoin 2nd generation Acitretin Methoxsalen

3rd generation Tazarotene Bexarotene adapalene

Topical Retinoids

Acne: caused by Sebaceous gland hyperplasia Follicular hyperkeratosis Propionibacterium acnes colonization Inflammation 1st line therapy for non-inflammatory (comedonal) acne Improves fine wrinkles and dyspigmentation (photoaging)

Toxicity and monitoring Erythema Desquamation Burning Stinging Photosensitivity reactions Decrease w/ time, w/ use of emollients

Exposure avoided during pregnancy

Tretinoin

Applied once nightly for acne and photoaging Not applied together w/ Benzoyl peroxide(inactivates Tretinoin)
3rd generation Psoriasis, photoaging, acne vulgaris OD Side effects: burning, itching, skin irritation

Tazarotene

Alitretinoin Kaposis sarcoma-2-4x daily Bexarotene Early stage (IA,IB) cutaneous T-cell lymphoma

Systemic Retinoids

For Tx of acne, psoriasis and T-cell lymphoma contraIx in pregnant women, contemplating pregnancy or breastfeeding

Highly teratogenic Common malformations

Craniofacial, CVS, thymic CNS

Men-avoid retinoid Tx when trying to father children Cheilitis, xerosis, blepharoconjunctivitis, cutaneous photosensitivity, photophobia, myalgia, arthralgia, headaches, alopecia, nail fragility, > susceptibility to Staph infections Retinoid dermatitis: erythema, pruritus, scaling

Toxicities

Isotretinoin Tx of recalcitrant and nodular acne vulgaris Clinical effects seen w/in 1-3 months Severe acne Induce prolonged remissions after single course of Tx Normalizes keratinization in sebaceous follicle Reduces sebocyte no. w/ dec. sebum synthesis Reduces P. acnes Preteens, males, patients w/ acne conglobata or androgen excess-risk of relapse Usually w/in 3 yrs

Acitretin For cutaneous manifestations of psoriasis Pustular psoriasis Clinical effect: w/in 4-6 weeks Female pts of childbearing age

Avoid pregnancy for 3 yrs after Txavoid retinoid induced embryopathy

Bexarotene Cutaneous T-cell lymphoma

Vitamin analogs

carotene Present in green and yellow vegetables Reduce skin photosensitivity in patients with erythropoietic protoporphyrin Not approved by FDA
Topical vitamin D analog Tx of psoriasis

Calcipotriene

Antimicrobial Agents

Antibiotics Tx of superficial cutaneous infections(pyoderma) Non-infectious diseases Acne rosacea Perioral dermatitis Hidradenitis suppurativa, etc Tx of superficial bacterial infections and acne vulgaris most common D/O treated w/ topical or systemic antibiotics

Commonly used topical antimicrobials Clindamycin Erythromycin Benzoyl peroxide Antibiotic-benzoyl peroxide combinations Also

Sulfacetamide Sulfacetamide/Sulfur Metronidazole Azelaic acid

Tetracyclines Most commonly used Inexpensive, safe and effective 1 g in divided doses Common complication: vaginal candidiasis Pyoderma S. aureus, s. pyogenes Impetigo Topical therapy-Mupirocin Active against staph and strep except D Inactive against normal skin flora

Cutaneous infections

Inhibits protein synthesis Activity enhanced by acid pH of skin surface 2% ointment or cream, applied TID Deeper bacterial infections of skin Folliculitis Erysipelas Cellulitis Necrotizing fasciitiis Penicillins, Cephalosporins-used

Antifungal agents

Most effective agents Griseofulvin Topical and oral imidazoles Triazoles Allylamines Tinea corporis/Tinea pedis Miconazole Naftifine/Terbinafine Localized cutaneous candidiasis/T. versicolor Azoles

T. capitis/follicular-based fungal infections Systemic therapy Oral Griseofulvin Oral Terbinafine-children Onychomycosis Dermatophytes and Candida Griseofulvin for 12-18 months 50% cure rate

Antiviral agents Verrucae (HPV) Herpes simplex virus Condyloma acuminatum Mollusacum contangiosum Chicken pox Acyclovir, Famciclovir, Valacyclovir HSV and VZV infections-systemic Mucocutaneous HSV Acyclovir, Docosanol, Penciclovir Condylomata Podophyllin, Podofilox

Agents used to treat infestations Lice and scabies Permethrin Interferes with insect sodium transport proteins neurotoxicity and paralysis 5% cream-scabies 1% cream, cream rinse, topical solution lice Infants >= 2 mos old Lindane Organochloride Induces neuronal hyperstimulation and eventual paralysis of parasites

2nd line drug in Tx of Pediculosis and scabies Potential for neurotoxicity in children and adults <110 lbs, also in patients with underlying skin D/O sucs as atopic dermatitis and psoriasis contraIx in premature infants and patients w/ seizure D/O Malathion Head lice in children >=6 y.o. Benzyl alcohol Inhibits lice from closing their resp. spiraclesasphyxia

Ivermectin Other less effective Tx 10% crotamiton cream and lotion For patients in whom Lindane pr Permethrin is contraIx

Antimalarial agents Chloroquine Hydroxychloroquine Quinacrine For cutaneous LE Cutaneous dermatomyositis Polymorphous light eruption Porphyria cutanea tarda sarcoidosis

Cytotoxic and Immunosuppressive drugs For psoriasis Auto-immune blistering diseases Leukocytoclastic vasculitis Antimetabolites Methotrexate Moderate to severe psoriasis Suppresses immunocompetent cells in the skin expression of CLA + T cells and endothelial cell E-selectin

Equally effective to oral cyclosporine in achieving partial or complete clearing of psoriasis Used in combination w/ phototherapy and photochemotherapy

Azathioprine Ateroid-sparing agent for auto-immune and inflammatory dermatoses

Pemphigus vulgaris Bullous pemphigoid Dermatomyositis Atopic dermatitis Chronic actinic dermatitis LE Psoriasis Pyoderma gangrenosum Behcets disease

Alkylating agents Cyclophosphamide Cytotoxic and immunosuppressive agent Advanced cutaneous T-cell lymphoma Pemphigus vulgaris Bullous pemphigoid TEN Wegeners granulomatosis 2-3 mg/kg/day 4-6 week delay in onset of action

Calcineurin inhibitors Cyclosporine Inhibits calcineurininhibits T cell activation Present in Langerhans cells, mast cells and keratinocytes Tx of psoriasis Atopic dermatitis, alopecia areata, epidermolysis bullosa acquisita, etc Side effects: hypertension, renal dysfunction

Tacrolimus Available in topical form for Tx of skin disease Atopic dermatitis in adults and children >=2 y.o. Intertriginous psoriasis, vitiligo, mucosal lichen planus, allergic contact dermatitis, rosacea Major benefit compared w/ steroids: Does not cause skin atrophy used safely in the face and intertriginous areas Side effect: transient erythema, burning and pruritusimprove w/ constant Tx

Due to potential for malignancy productiontopical calcineurin inhibitors NOT CONSIDERED 1ST LINE Tx in childhood atopic dermatitis Used only as 2nd line agents for short-term and intermittent Tx of atopic dermatitis (eczema) in pts unresponsive/intolerant to other Tx

Other Immunosuppressive and Anti-inflammatory agents Mycophenolate mofetil Inflammatory and auto-immune diseases in dermatology Imiquimod Immunomodulatory effects For Tx of genital warts

Applied to lesions 2x a week for 16 weeks

Vinblastine Kaposi sarcoma Advanced cutaneous T cell lymphoma

Dapsone Anti-inflammatory in sterile, pustular diseases of skin Dermatitis herpetiformis and leprosy Side effects: methemoglobinemia, hemolysis Thalidomide Anti-inflammatory, immunomodulating, antiangiogenic agent Tx of erythema nodosum leprosum Causes phocomelia

Biologic agents Target specific mediators of immunological reactions For psoriasis 1. T-cell Activation inhibitors Alefacept 1st agent approved for moderate to severe psoriasis Efalizumab Interferes w/ T-cell activation and migration and cytotoxic T-cell function

2.

TNF Inhibitors TNF-prod by macrophages, T cells, dendritic cells, keratinocytes in active psoriasis Reduces inflammation, keratinocyte proliferation, vascular adhesionimprovement in psoriatic lesions risk for serious infection All patients-screened for TB, personal/family Hx of demyelinating D/O, cardiac failure, active infection, malignancy prior to Tx

Etanercept Recombinant, fully human TNF receptor fusion protein For pediatric psoriasis Infliximab Complement fixing antibody that induces complement-dependent and cell-mediated lysis

Sunscreens Chemical agents that absorb incident solar radiation in the UVB and or UVA ranges Provide a broad spectrum of protection Photostable Remain intact for sustained periods on the skin Non-irritating, invisible and non-staining to clothing UVA Sunscreen agents Avobenzone Oxybenzone Titanium dioxide

Zinc oxide Ecamsule UVB Sunscreen Agents PABA esters Cinnamates Octocrylene Salicylates SPF (sun protection factor) Major measurement of sunscreen photoprotection

Ratio of the minimal dose of incident sunlight that will produce erythema or redness (sunburn) on skin w/ the sunscreen in place and the dose that evokes the same reaction on skin w/o the sunscreen

Treatment of Pruritus Symptom unique to skin Occurs in a multitude of dermatological D/O Dry skin/xerosis Atopic eczema Urticaria Infestations

Agents used for the Tx of Pruritus (table 65-11) Pruritoceptive pruritus-due to inflammation or other cutaneous disease Emollients Coolants Capsaicin Antihistamines Topical steroids Topical immunomodulators Phototherapy Thalidomide

Neuropathic pruritus-due to disease of afferent N Carbamazepine Gabapentin Topical anesthetics Neurogenic pruritus-from NS Thalidomide Opioid-receptor antagonists Tricyclic antidepressants SSRIs

Psychogenic pruritus-due to psychological illness Anxiolytics Antipsychotics Tricyclic antidepressants SSRIs Drugs for Hyperkeratotic D/O Keratolytic agents For paoriasis, seborrheic dermatitis, xerosis, ichthyoses, verrucae -Hydroxy acids Glycolic, lactic, malic, citric, hydroxycaprylic, hydroxycapric, and mandelic

Reduce the thickness of stratum corneum by solubilizing components of the desmosome Activating endogenous hydrolytic enzymes Drawing water into stratum corneum Salicylic acid Solubilization of intercellular cement reduced corneocyte adhesionstratum corneum softening Prolonged and widespread use: Salicylism Urea skin absorption and retention of water flexibility and softness of skin

Drugs for Androgenetic Alopecia Male and female pattern baldness Most common cause of hair loss in adults >40 y.o. Tx: reducing hair loss, maintaining existing hair Minoxidil Anti HPN w/ hypertrichosis as side effect Enhances follicular sizethicker hair shafts Stimulates and prolongs anagen phase of hair cyclelonger and inc # of hair Finasteride

Tx of hyperpigmentation Most effective on hormonally or light-induced pigmentation w/in epidermis Hydroquinone st line agent 1 melanocyte pigment production by inhibiting conversion of dopa to melanin thru inhibition of tyrosinase