Topical Drugs & Skin Anatomy PDF

3.1 Topical Drugs: Reasons for Topical Application ○ Protecting injured skin from the environment. ○ Treating various skin conditions like eczema and psoriasis. ○ Relieving joint pain, as seen with diclofenac gel (Voltaren). ○ Systemic drug...

3.1 Topical Drugs: Reasons for Topical Application ○ Protecting injured skin from the environment. ○ Treating various skin conditions like eczema and psoriasis. ○ Relieving joint pain, as seen with diclofenac gel (Voltaren). ○ Systemic drug delivery via transdermal patches, such as nicotine and fentanyl patches. Dosage Forms for Topical Administration ○ Liquids: Solutions, lotions, tinctures, collodions, and medicated shampoos. ○ Semisolids: Ointments, creams, pastes, and gels. ○ Solids: Powders and sticks. ○ Others: Aerosols, foams, dressings, tapes, and plasters. Skin Anatomy and Physiology ○ The skin, the largest organ, varies in thickness and weighs about 3-4 kilograms in adults. ○ Protective Barrier: The skin serves as a barrier against various external factors, including microorganisms, chemicals, radiation (like UV rays), electrical shocks, and mechanical injuries. ○ Physiological Roles: Regulates temperature through sweating, excretes substances, and plays a role in drug absorption. ○ Complex Structure: The skin is intricate both physiologically and biochemically. Skin Layers and Appendages ○ ○ The skin comprises three primary layers: the epidermis, the dermis, and the subcutaneous fat layer. ○ It also includes appendages, such as sweat glands (apocrine and eccrine) and hair follicles. The Epidermis in Detail  Composition: The epidermis, the outermost layer, is a stratified squamous epithelium constantly renewing itself. ○ Its thickness varies across different body areas. ○ It mainly consists of keratinocytes, cells containing the protein keratin. ○ Other cell types interspersed within the epidermis include: Langerhans cells: Macrophages involved in the skin's immune defense. Melanocytes: Produce melanin, protecting against UV radiation and contributing to skin color. Merkel cells: Involved in fine touch sensation. Layers of the Epidermis: ○ Stratum corneum: Outermost layer; dead cells, no nucleus or organelles; relatively dry but contains 10–20% water; loaded with keratin and filaggrin, acting as the primary protective barrier. Natural Moisturizing Factor (NMF): Low molecular weight polar compounds, including amino acids, that help retain water in the stratum corneum Hydrophilic compounds attract water from the dermis below, keeping the stratum corneum hydrated. ○ Stratum lucidum: A thin layer found mainly on the palms and soles. ○ Stratum granulosum: Crucial for producing lipids contributing to the skin's barrier properties. ○ Stratum spinosum: Found throughout the body. ○ Stratum basale (or stratum germinativum): The deepest layer responsible for generating new keratinocytes. ○ Keratinocytes: ○ Make up 80% of the epidermis. ○ Named for their high content of keratin, a structural protein providing strength and toughness to skin, hair, and nails. ○ Organized into layers, or strata, which contribute significantly to the skin's barrier properties. ○ Classified as either viable (living) or non-viable (dead).  Viable epidermis includes all layers except the stratum corneum. Non-viable epidermis solely consists of the stratum corneum, composed of dead cells. Focus on the Stratum Corneum Primary Barrier: The stratum corneum is the most critical barrier to drug penetration, with its structure and composition playing a key role in this function. Brick and Mortar Structure: ○ The stratum corneum is organized like a wall, with corneocytes (dead keratinocytes) acting as bricks and intercellular lipids serving as mortar. ○ ○ Corneocytes: The end product of keratinocyte differentiation, flat, enlarged, overlapping, and interspersed with lipid sheets. Dead cells lacking a nucleus and organelles. Contain 10-20% water, a crucial factor in preventing dryness and maintaining skin health.  Rich in keratin and filaggrin, structural proteins providing the stratum corneum's skeleton. Contain low molecular weight polar compounds, primarily polar amino acids, collectively known as the Natural Moisturizing Factor (NMF). NMF attracts water from the underlying dermis, maintaining hydration. ○ Intercellular Lipids: Composed of ceramides, free fatty acids, and cholesterol, mimicking the composition of CeraVe moisturizing products. Produced by the stratum granulosum. Crucial for holding corneocytes together, limiting permeation of substances (both inward and outward), and preventing excessive transepidermal water loss. Functions of the intercellular lipids: Hold corneocytes together, contributing to the structural integrity of the stratum corneum. Limit permeation of substances through the skin in both directions (outside to inside and inside to outside). Limit transepidermal water loss, preventing excessive water loss through the skin. Desmosomes: ○ Specialized junctions acting like spot welds to bind corneocytes together. ○ Contribute to the structural integrity and barrier function of the stratum corneum. ○ Breakdown of desmosomes can lead to excessive desquamation, resulting in skin flaking.  ○ Continuous Renewal: ○ Corneocytes slough off after about 14 days in the stratum corneum, a process referred to as molting. ○ Skin shedding is continuous, with individual cells being replaced by new cells from the basale layer. ○ Turnover time varies across different body regions (e.g., 6 days on the forehead, 21 days on the back of the hand). Deeper Layers and Appendages: The Dermis: ○ Located beneath the epidermis and significantly thicker (about 40 times). ○ Composed of a connective tissue matrix, providing support and strength to the epidermis. ○ Responsible for skin structure and elasticity; alterations in the dermis lead to wrinkles and scars. ○ Contains a matrix of connective tissue, primarily collagen, that strengthens the epidermis ○ Contains nerves, appendages (sweat glands and hair follicles), and blood and lymphatic vessels. ○ Drugs reaching the dermis can be absorbed into systemic circulation via these blood and lymphatic vessels. ○ Drug absorption: Drugs applied to the skin can reach the dermis and be absorbed into the bloodstream. Even drugs intended for topical effects can be absorbed systemically. ○ Subcutaneous Fat: ○ The deepest layer, primarily composed of adipose tissue.  ○ Can act as a reservoir for certain drugs, especially lipophilic ones, potentially delaying absorption or serving as a depot for slow release. ○ Skin Appendages: ○ Include: Sweat glands: Eccrine: Widely distributed and responsible for thermoregulation via sweating. Apocrine: Secrete into hair follicles. Sebaceous glands: Associated with hair follicles. Produce sebum, a lipid mixture forming a film on the skin surface. Sebum provides waterproofing, lubrication, and contributes to the acid mantle. The Acid Mantle: ○ An acidic environment on the skin surface with a pH ranging from 4.5 to 6.2.  ○ Created by fatty acids present in sebum. ○ Protective Functions: Antimicrobial: Inhibits the growth of certain pathogens. Orderly Desquamation: Ensures proper shedding of individual skin cells. Lipid Lamellae Formation: Supports the creation of the protective lipid layers between corneocytes. ○ pH Dependence: The functions of the acid mantle are pH-dependent, relying on the optimal activity of specific enzymes. ○ Disruptions in the acid mantle's pH can impair these functions, potentially leading to issues like flaky skin or increased permeability. ○ Hair Follicles: ○ Present throughout the body except for lips, palms, soles, and certain areas of the sex organs. ○ Like sweat glands, hair follicles can act as pathways for drug penetration, bypassing the stratum corneum to some extent. Drug Transport Mechanisms Topical Drug Action: ○ Some topical drugs act on the skin surface (e.g., Vaseline, Neosporin, DEET-containing insect repellents, moisturizers, exfoliants). ○ Others must penetrate various skin layers to reach their target sites. ○ Examples of drugs targeting different skin layers:  Stratum Corneum: Exfoliants targeting clogged hair follicles. Appendages: Antiperspirants targeting sweat glands, antimicrobials for follicular infections, and depilatories. Deeper Layers: Topical corticosteroids for anti-inflammatory effects. Dermis: Drugs requiring transdermal delivery for systemic absorption. Drug Permeation Steps: ○ Drug application to the skin. ○ Drug dissolution and release from the dosage form (e.g., cream, ointment). ○ Entry into appendages or penetration through the stratum corneum and deeper layers. Drug Permeation Challenges: ○ The skin's primary function is protection, creating a significant barrier to drug penetration. ○ Drug permeation is typically slow, taking hours to permeate the epidermis, especially through the stratum corneum. ○ Damaged skin allows for faster drug penetration, and specialized formulations can temporarily disrupt the stratum corneum to enhance permeation. Routes of Drug Permeation: ○ Transepidermal: The primary route, involving passage through the epidermal layers, including the stratum corneum.  ○ Transappendageal: A less significant route due to the limited surface area covered by appendages (hair follicles and sweat glands). Allows for bypassing the stratum corneum to some extent, potentially leading to faster diffusion. Transepidermal Transport Most important route Stratum Corneum as the Major Barrier: ○ Drugs must cross the stratum corneum and viable layers to reach the dermis. ○ The stratum corneum presents the most significant obstacle due to its brick and mortar structure. Pathways Through the Stratum Corneum:  ○ Transcellular: Passage through corneocytes, requiring permeation across protein-lipid cell membranes. A relatively polar pathway due to the partially hydrated protein matrix within corneocytes. ○ Paracellular: The dominant route for most drugs, involving movement around corneocytes and through the lipid lamellae. Requires navigating multiple layers of lipid sheets, contributing to the slow permeation rate. A relatively non-polar pathway due to the prevalence of lipids. ○ Lipophilicity Favored: ○ The stratum corneum's lipophilic nature favors the permeation of lipophilic drugs. ○ Lipophilicity is a key consideration for drug selection and formulation development for topical applications. Viable Layers: ○ Once a drug crosses the stratum corneum, it usually diffuses rapidly through the viable epidermal layers. ○ Viable layers, especially compared to the stratum corneum, don't offer significant resistance to drug penetration. Systemic Absorption: ○ Upon reaching the dermis, systemic absorption of the drug typically occurs quickly. ○ Transappendageal Transport Appendages as Bypasses: ○ Sweat glands and hair follicles allow drugs to circumvent the stratum corneum to some degree, potentially facilitating faster entry into the viable epidermis and dermis. Limited Contribution: ○ Despite bypassing the stratum corneum, transappendageal transport is a minor pathway for drug delivery. ○ The reason for this limited contribution is the small surface area covered by appendages compared to the total skin surface. Regional Variations: ○ The density of appendages varies across body regions, influencing the extent of transappendageal drug transport. ○ Areas with a higher concentration of appendages may exhibit faster drug absorption. Factors Influencing Drug Permeation: Biological Factors: ○ Interpatient Variability: Permeability can differ tenfold between individuals at the same site. ○ Sources of Variability: Region of the body: Epidermal thickness and lipid composition variations affect permeability. This variation is particularly important for transdermal patches, which must be applied to specific, manufacturer-approved sites for optimal drug delivery. Skin condition: A healthy epidermis is crucial for barrier function. Diseased, damaged, or compromised skin can significantly alter drug penetration. For example, individuals with eczema have a less effective skin barrier. Drug metabolism: Viable epidermis contains drug-metabolizing enzymes like CYPs and esterases, leading to a cutaneous first-pass effect. This effect is generally less pronounced than hepatic first-pass metabolism. Examples of cutaneous metabolism: Nitroglycerin: Up to 15-20% can be metabolized in the skin, for angina.  Tazarotene: A prodrug for psoriasis, metabolized by skin esterases to its active form. Drug binding: Binding to components within the stratum corneum (proteins and lipids) can impact drug availability. Drug binding can delay the onset of action by slowing down drug release and penetration. It can also create a drug reservoir, prolonging drug effects even after removing the drug source (e.g., a transdermal patch). Patient's age: Premature infants have an underdeveloped stratum corneum, making them highly susceptible to drug penetration. Extreme caution is needed when applying medications to their skin. Aged skin can thicken and become less hydrated, making the effects on permeation less predictable. These changes can be further complicated by alterations in dermal microcirculation, affecting drug removal. Physical-Chemical Factors (Modifiable by Formulation): ○ Hydration state of the skin: Normal stratum corneum water content is low (10-20%) but essential for its function. Stratum corneum can absorb significant amounts of water, up to 75%, leading to swelling and softening. This water uptake occurs within the cells and interlamellar spaces. Hydration typically enhances drug permeation by expanding the pathways within the stratum corneum. ○ Occlusion: Blocking transepidermal water loss (TEWL), achieved through occlusive dressings, greasy ointments, or patches, increases skin hydration and drug permeation at the site of application. Occlusion expands the pathways within the stratum corneum for drug penetration by trapping moisture. ○ Drug properties:  Lipophilic (non-polar) drugs are favored over hydrophilic (polar) drugs due to the stratum corneum's lipid-rich nature. Non-ionized drug forms, being more lipophilic, permeate more readily than ionized forms. ○ Dosage form properties: Drug release: The dosage form must effectively release the drug for it to be absorbed. Occlusion: Different dosage forms vary in their occlusive properties (e.g., Vaseline is highly occlusive, while lotions are less so). Occlusive properties impact skin hydration and drug permeation.