Skin

• Skin as a Barrier

  • Protects the body against external insults, thus maintaining homeostasis
  • Participates in thermal, electrolyte, hormonal, metabolic, antimicrobial, and immune regulation
  • May react to noxious physical agents with various defensive mechanisms preventing its widespread cutaneous and/or internal injuries
• If an insult is severe or sufficiently intense to overwhelm the protective function of the skin, acute or chronic injury becomes manifest
• Interfollicular epidermis


  • Stratified squamous epithelium consisting primarily of keratinocytes
• Melanocytes


  • Stimulated by ultraviolet light in the epidermis to produce melanin granules which are extruded and taken up by the surrounding keratinocytes and become pigmented
• Langerhans cells


  • Dendritic, antigen presenting cells involved in the immune response of skin to foreign xenobiotics
• Stratum corneum


  • Formed during program of terminal differentiation, is the primary barrier to percutaneous absorption
  • Once compromised can permit greatly increased uptake of poorly permeable substances
  • Having hydrophobic properties, it prevents water loss from underlying tissues by evaporation
  • Is ordinarily hydrated (typically 20% water) or the moisture residing in corneocyte protein
• Percutaneous absorption


  • The degree of uptake through the skin depends on the details of exposure conditions
  • Proportional to solute concentration, time, and the amount of skin surface exposed
• Factors affecting percutaneous absorption

  • Hydrophobicity - affects ability to partition into epidermal lipid
  • Rate of diffusion through the barrier - inverse function of molecular weight (MW) or molecular volume
• Diffusion through the epidermis is considerably faster at some anatomical sites than others
• Transdermal drug delivery


  • Provides a steady infusion of drug over extended periods, thereby avoiding large variations in plasma concentrations
  • Prevents exposure to the acidic pH of the stomach, thus preventing biodegradation
  • Avoids biotransformation in the gastrointestinal tract from first pass removal by the liver
• For risk assessment and pharmaceutical design, the most useful subject for experimentation is human skin
• Biotransformation in the skin

  • Major sites: epidermis and pilosebaceous units
  • Enzymes participating: cytochrome P450, epoxide hydrolase, UDPglucuronosyltransferase, quinone reductase, and glutathione transferases
  • Other metabolic enzyme activities: sulfatases, βglucuronidase, Nacetyltransferases, esterases, and reductases
  • The intercellular region of the stratum corneum has catabolic activities (e.g., proteases, lipases, glycosidases, and phosphatase)
• Contact dermatitis


  • Falls into two major categories: irritant and allergic, which may co-exist
  • Both involve inflammatory processes and can have indistinguishable clinical characteristics of erythema, induration, scaling, and vesiculation in areas of direct contact with the chemical
• Irritant dermatitis


  • Arises from the direct action of agents on the skin on a high concentration and long exposure
  • Certain chemicals at sufficient concentration produce an acute irritation/second degree chemical burn
  • Strong acids, alkalis, and powerful oxidizing or reducing agents can produce cytotoxicity directly
  • Contact with a variety of plants can also have irritant effects, resulting in the production of proinflammatory cytokines (IL1α, IL1β, and TNFα) from keratinocytes
• Response to exposure varies depending on the sensitivity of the anatomic site and individuals also vary greatly in sensitivity to irritant dermatitis
• Chemical burns (corrosion)


  • Extremely corrosive and reactive chemicals may produce immediate coagulative necrosis that results in substantial tissue damage, with ulceration and sloughing
  • Necrotic tissue can act as a chemical reservoir resulting in either continued cutaneous damage or percutaneous absorption and systemic injury after exposure
• Allergic contact dermatitis


  • A delayed (T-cell mediated) hypersensitive reaction
  • To induce sensitization, chemical haptens must penetrate the skin and become attached to carrier proteins
  • Complete antigens are processed by Langerhans cells and presented to type 1 T-helper cells in regional lymph nodes
  • Subsequent exposure to the same antigen results in an amplified immune response characterized by dermal infiltration and spongiosis
• Common contact allergens


  • Antibiotics (Bacitracin, Neomycin, Polymyxin, aminoglycosides sulfonamides, benzocaine, corticostroids)
  • Personal care products (Formaldehyde, formaldehyde releasers, Methylchloroisothiazolone/Methylisothiazolinone (MCI/MI), Ethylenediamine, Lanolin, p-Phenylenediamine, Propylene glycol, Fragrances)
  • Antiseptics (Chlorhexidine, Chloroxylenol, Dichlorophene, Glutaraldehyde, Thimerosal (Merthiolate), Mercurials, Triphenylmethane dyes)
• Photosensitivity - Adverse responses to electromagnetic radiation


  • Erythema (redness or sunburn) - the most evident acute feature of UV radiation exposure
  • Environmental conditions that affect UV-induced injury: duration of exposure, season, altitude, body site, skin pigmentation, and previous exposure
• Chronic exposure to radiation


  • Induces a variety of characteristic skin changes like pigmentary changes, wrinkling, telangiectasias, actinic keratoses, and malignant skin lesions such as basal and squamous cell carcinomas and malignant melanoma
• Phototoxicity


  • Phototoxic reactions may be produced either by systemic or topical exposures
  • In acute reactions, the skin can become red and blistered within minutes to hours following ultraviolet light exposure, typically UVA (320 to 400 nm)
  • Chronic phototoxic responses may result in hyperpigmentation and thickening of the affected areas
• Photoallergy


  A type IV delayed hypersensitivity reaction
• Chronic exposure to radiation


  • Induces a variety of characteristic skin changes like pigmentary changes, wrinkling, telangiectasias, actinic keratoses, and malignant skin lesions
• Phototoxicity


  Phototoxic reactions may be produced either by systemic or topical exposures
• In acute phototoxic reactions


  The skin can become red and blistered within minutes to hours following ultraviolet light exposure, typically UVA (320 to 400 nm)
• In chronic phototoxic responses


  May result in hyperpigmentation and thickening of the affected areas, UVA (320 to 400 nm) is the most commonly responsible, UVB(290 to 320 nm) may occasionally be involved
• Photoallergy


  A type IV delayed hypersensitivity reaction, leading typically to eczema, requires prior sensitization to the chemical
• Urticaria


  May develop for those allergens to which IgE antibodies have been elicited by previous or ongoing exposure, through an immediate type I hypersensitivity reaction, hives are raised wheals that usually itch or sting and may appear reddish
• Hyperpigmentation


  Results from increased melanin production or deposition of endogenous or exogenous pigment in the upper dermis
• Hypopigmentation


  A loss of pigmentation from melanin loss, melanocyte damage, or vascular abnormalities, leukoderma (vitiligo) and depigmentation denote complete loss of melanin from the skin imparting porcelain-white appearance
• Acne


  • Comedogenic chemicals induce comedone lesions, which may be open or closed, additionally papules, pustules, cysts, and scars may complicate the process, hair follicles and associated sebaceous glands become clogged with compacted keratinocytes that are bathed in sebum
• Chloracne


  One of the most disfiguring forms of acne in humans, caused by exposure to polyhalogenated aromatic hydrocarbons, typically comedones and strawcolored cysts are present behind the ears, around the eyes, and on the shoulders, back, and genitalia, in addition to acne, hypertrichosis, hyperpigmentation, brown discoloration of the nail, conjunctivitis, and eye discharge may be present
• Granulomatous disease


  • Occurs infrequently toward a variety of agents introduced into the skin through injection or after laceration or abrasion, persistent lesions with abundant inflammatory cells can be produced, resembling chronic infectious condition and present diagnostic challenges, many substances can produce granulomatous reactions
• Toxic epidermal necrolysis (TEN)


  A rare life-threatening skin disease involving detachment of ≥30% of the epidermal surface from the dermis, commonly accompanied by severe erosions of the mucous membranes, can result in gastrointestinal hemorrhage, respiratory failure, ocular abnormalities, and genitourinary complications
• Toxic epidermal necrolysis (TEN) represents one of the most lifethreatening dermatologic diseases that is caused by drugs and chemicals
• At the most severe end of a spectrum, TEN involves detachment of ≥ 30% of the epidermal surface from the dermis, commonly accompanied by severe erosions of mucous membranes, and has a fatality rate ≈30%
• TEN commonly resembles an upper respiratory tract infection in the first several days (fever, cough, sore throat, and malaise), but prompt diagnosis when the cutaneous lesions become evident several days later improves survival chances
• Drugs that have been reported to cause TEN

  • Anticonvulsants
  • Nonsteroidal anti-inflammatories
  • Antibacterial sulfonamides
  • Allopurinol
  • Nevirapine
• Mechanisms leading to this idiosyncratic drug reaction are under scrutiny and current hypotheses identify HLA genotype and ethnic background as contributing factors
• Radiation-induced skin cancer


  • Radiation from ionizing wavelengths to ultraviolet wavelengths has been shown to cause skin cancer, shortly after the discovery of radioactive elements at the turn of the twentieth century, it was observed that X-rays could cause severe burns, squamous cell carcinoma, and basal cell carcinomas, X-ray induced nonmelanoma skin cancers (NMSC) continued to be observed throughout the twentieth century, as X-rays were used therapeutically until the midtwentieth century for a variety of skin diseases