dermatological pharmacology lecture

7/27/2019 Dermatological Pharmacology Lecture

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DERMATOLOGICALPHARMACOLOGY


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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

Thickestpalm and sole

Thinnest-facial and post-auricular regions


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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


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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


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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


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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


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May be aqueous or alcoholic

Low residue on scalp

Age

Children

>ratio of surface area to mass than adults

>systemic exposure

Application Frequency

Often applied twice daily


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GLUCOCORTICOIDS

Immunosuppressive and anti-inflammatory

Topical glucocorticoids

Selected on basis of potency, site of involvement,

severity of skin dse

Tx uses: Inflammatory skin diseases

Usually use more potent steroid 1st

Toxicity:

Chronic use of class 1 Skin atrophy


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7 classes in order of decreasing potency

Class 1

Betamethasone dipropionate cream, ointment0.05%

Clobetasol propionate

Diflorasone diacetate

Halobetasol propionate

Class 2

Amcinonide

Betamethasone dipropionate Desoximetasone

Fluocinonide

Halcinonide


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Class 3

Betamethasone valerate

Triamcinolone acetonide

Class 4

Amcinonide

Flurandrenolide

Hydrocortisone valerate

Mometasone furoate

Class 7

Dexamethasone sodium phosphate Class 1-most potent


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Striae

Telangiectasias

Purpura

Acneiform eruptions

Systemic glucocorticoids

For severe dermatological illnesses

Allergic contact dermatitis to plants, life-

threatening vesiculobullous dermatosis

Daily morning dosing Side effects: dose dependent

Long-term use: psychiatric problems, cataracts,

myopathy, osteoporosis, avascular bone

necrosis,glucose intolerance, HPN


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Retinoids

Natural and synthetic compounds that exhibitvitamin A-like biological activity or bind to

nuclear receptors for retinoids

1stgeneration

Retinol (vitamin A) Tretinoin

Isotretinoin

Alitretinoin

2nd generation

Acitretin

Methoxsalen


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3rd generation

Tazarotene Bexarotene

adapalene


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Topical Retinoids

Acne: caused by Sebaceous gland hyperplasia

Follicular hyperkeratosis

Propionibacterium acnes colonization

Inflammation

1stline therapy for non-inflammatory (comedonal)

acne

Improves fine wrinkles and dyspigmentation

(photoaging)


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Toxicity and monitoring

Erythema Desquamation

Burning

Stinging

Photosensitivity reactions Decrease w/ time, w/ use of emollients

Exposure avoided during pregnancy


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Tretinoin

Applied once nightly for acne and photoaging Not applied together w/ Benzoyl

peroxide(inactivates Tretinoin)

Tazarotene

3rd generation

Psoriasis, photoaging, acne vulgaris

OD

Side effects: burning, itching, skin irritation


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Alitretinoin

Kaposis sarcoma-2-4x daily

Bexarotene

Early stage (IA,IB) cutaneous T-cell lymphoma


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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

Toxicities

Cheilitis, xerosis, blepharoconjunctivitis, cutaneous

photosensitivity, photophobia, myalgia, arthralgia,

headaches, alopecia, nail fragility, > susceptibility to

Staph infections

Retinoid dermatitis: erythema, pruritus, scaling


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IsotretinoinTx of recalcitrant and nodular acne vulgaris

Clinical effects seen w/in 1-3 monthsSevere 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 conglobataor androgen excess-risk of relapse

Usually w/in 3 yrs


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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


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Vitamin analogs

carotene Present in green and yellow vegetables

Reduce skin photosensitivity in patients with

erythropoietic protoporphyrin

Not approved by FDA

Calcipotriene

Topical vitamin D analog

Tx of psoriasis


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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

vulgarismost common D/O treated w/ topicalor systemic antibiotics


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Commonly used topical antimicrobials

Clindamycin Erythromycin

Benzoyl peroxide

Antibiotic-benzoyl peroxide combinations

Also Sulfacetamide

Sulfacetamide/Sulfur

Metronidazole

Azelaic acid


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Tetracyclines

Most commonly used Inexpensive, safe and effective

1 g in divided doses

Common complication: vaginal candidiasis

Cutaneous infections Pyoderma

S. aureus, s. pyogenes

Impetigo

Topical therapy-Mupirocin

Active against staph and strep except D

Inactive against normal skin flora


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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


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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


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T. capitis/follicular-based fungal infections

Systemic therapy Oral Griseofulvin

Oral Terbinafine-children

Onychomycosis

Dermatophytes and Candida Griseofulvin for 12-18 months50% cure rate


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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


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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 solutionlice

Infants >= 2 mos old

Lindane

Organochloride

Induces neuronal hyperstimulation and

eventual paralysis of parasites


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2nd line drug in Tx of Pediculosis and scabies

Potential for neurotoxicity in children and adults=6 y.o.

Benzyl alcohol

Inhibits lice from closing their resp.spiraclesasphyxia


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Ivermectin

Other less effective Tx 10% crotamiton cream and lotion

For patients in whom Lindane pr Permethrin is

contraIx


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Antimalarial agents

Chloroquine Hydroxychloroquine

Quinacrine

For cutaneous LE

Cutaneous dermatomyositis Polymorphous light eruption

Porphyria cutanea tarda

sarcoidosis


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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 endothelialcell E-selectin


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Equally effective to oral cyclosporine in achieving

partial or complete clearing of psoriasis

Used in combination w/ phototherapy and

photochemotherapy


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Azathioprine

Ateroid-sparing agent for auto-immune andinflammatory dermatoses

Pemphigus vulgaris

Bullous pemphigoid

Dermatomyositis

Atopic dermatitis

Chronic actinic dermatitis

LE

Psoriasis

Pyoderma gangrenosum Behcets disease


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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


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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


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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


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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


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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


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Dapsone

Anti-inflammatory in sterile, pustular diseases ofskin

Dermatitis herpetiformis and leprosy

Side effects: methemoglobinemia, hemolysis

Thalidomide Anti-inflammatory, immunomodulating, anti-

angiogenic agent

Tx of erythema nodosum leprosum

Causes phocomelia


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Biologic agents

Target specific mediators of immunologicalreactions

For psoriasis

1. T-cell Activation inhibitors

Alefacept 1stagent approved for moderate to severe

psoriasis

Efalizumab

Interferes w/ T-cell activation andmigration and cytotoxic T-cell function


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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


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Etanercept

Recombinant, fully human TNF receptor fusion

protein

For pediatric psoriasis

Infliximab

Complementfixing antibody that inducescomplement-dependent and cell-mediated

lysis


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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


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Zinc oxide

Ecamsule

UVB Sunscreen Agents

PABA esters

Cinnamates

Octocrylene Salicylates

SPF (sun protection factor)

Major measurement of sunscreen

photoprotection


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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


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Treatment of Pruritus

Symptom unique to skin

Occurs in a multitude of dermatological D/O

Dry skin/xerosis

Atopic eczema

Urticaria Infestations


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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


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Neuropathic pruritus-due to disease of afferent N

Carbamazepine

Gabapentin

Topical anesthetics

Neurogenic pruritus-from NS

Thalidomide Opioid-receptor antagonists

Tricyclic antidepressants

SSRIs


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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


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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

reducedcorneocyte adhesionstratum corneum

softening

Prolonged and widespread use: Salicylism

Urea skin absorption and retention of water

flexibility and softness of skin


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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


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Tx of hyperpigmentation

Most effective on hormonally or light-induced

pigmentation w/in epidermis

Hydroquinone

1stline agent

melanocyte pigment production by inhibitingconversion of dopa to melanin thru inhibition

of tyrosinase

dermatological pharmacology lecture

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