Derm Asynchronous- pharm

what are the two reasons medication is applied to skin?

1. to directly treat a skin disorder

2. to deliver drugs to other tissue

what begins the keratinocyte life cycle?

it begins to proliferates in the stratum basale.

how long does it take for the keratinocyte to mature and reach the stratum corneum?

2 weeks

stratum corneum

outermost layer of epidermis

The keratinocytes present in which layer acquire the highest degree of maturity and gradually lose viability?

stratum corneum

what happens to the keratinocyte 2 weeks after reaching the stratum corneum?

it moves through the cornified layer to be eliminated by flaking

this layer of the skin is the "major barrier" where percutaneous absorption of drugs and the loss of water from the body occur; considered "non-living"

stratum corneum

a drug may partition into the stratum corneum and form a reservoir - what will this result in?

it will diffuse into the rest of skin even after topical application of the drug has ceased

densely packed and contain keratin filaments and filaggrin

corneocytes

what is the intracellular matrix of the stratum corneum made of?

lipids and fatty acids that seal spaces between corneocytes

what does the cornified lipid envelope do within the stratum corneum?

replaces the keratinocyte plasma membrane

what is the surface of the cornified lipid envelope bound to?

intercellular lipids

filament-associated protein that binds to keratin fibers in epithelial cells

Filaggrin

what type of keratin is found in vertebrates?

alpha-keratin

key structural material making up scales, hair, nails, feathers, horns, claws, hooves, and the outer layer of skin among vertebrates

alpha keratin

what are the "living layers" of the epidermis? (3)

- stratum basale

- stratum spinosum

- stratum granulosum

what cells are in the "living" epidermis?

melanocytes, Merkel cells, APCs, Langerhans cells, immune cells

Merkel cells

touch receptors (neuroendocrine cells)

located in the basal layer of the epidermis, is a highly differentiated cell that produces a pigment melanin inside melanosomes

melanocyte

other than providing color to skin, hair, and eyes, what other functions do melanocytes have in the body? (2)

- absorb scattered light in the eye

- protect against ROS

what layer provides mechanical strength and flexibility to the skin?

the dermis

What is the dermis primarily composed of?

of fibroblasts and an extracellular matrix, including collagen, proteoglycans, glycoproteins, and elastic fibers in the upper dermis.

what are some cells in the dermis that are targeted by drugs?

mast cells and cytokine-producing immune cells

where does the majority of the systemic absorption of cutaneous drugs occur?

the superficial capillary plexus between the epidermis and dermis

what happens to skin tissue as a person ages?

- flattening of dermoepidermal junction

- increased variability in epidermal cells

- loss of melanocytes

- ineffective water and chemical barriers

- loss of dermal thickness and fat

- sebaceous and sweat gland malfunction (dryness)

when is collagen content maximal?

between 2nd-3rd decade

The loss of _________ is clearly correlated with changes to appearance attributes which are typically referred to as fines lines and wrinkles.

collagen

how does percutaneous absorption occur?

mainly through a tortuous intercellular route

what is the rate limiting step for percutaneous absorption?

passage through the stratum corneum

what molecular mass is preferable for topical drugs?

<500 Da

what kind of solubility should a topical drug have?

solubility in both oil and water

topical drugs should have a high _____________ so the drug will partition from the vehicle to the skin

coefficient

what does not penetrate through the stratum corneum?

water-soluble ions and polar molecules

what will allow for more percutaneous absorption through the stratum corneum?

hydration

how are drugs formulated to allow for more percutaneous absorption through hydration of the stratum corneum?

they are formulated in occlusive vehicles such as ointments and through physical occlusive measures

What is a key advantage of transdermal drug delivery regarding metabolism?

It bypasses hepatic first-pass metabolism, allowing drugs to directly enter systemic circulation.

Despite bypassing first-pass metabolism, what metabolic process still occurs in the epidermis?

The epidermis contains enzymes capable of metabolizing drugs, including CYP26A1, which metabolizes retinoic acid.

What are the two main types of transporter proteins present in keratinocytes, and what do they influence?

OATP (Organic Anion-Transporting Polypeptide) → Influences drug influx

MDR (Multidrug Resistance Transporter)/P-glycoprotein → Influences drug efflux

What is the role of P-glycoprotein in transdermal drug delivery?

it's an efflux transporter, reducing the intracellular concentration of certain xenobiotics by pumping them out of keratinocytes.

The same amount of topical drug can result in __________ systemic exposure in children. Why?

greater because children have a greater ratio of surface area to mass than adults do

what is the concern with topical drugs on preterm infants?

Preterm infants have a markedly impaired barrier function until the epidermis keratinizes completely.

an inflammatory skin disorder of the pilosebaceous units of the skin

acne vulgaris

The development of acne lesions results from four pathogenic factors:

excess sebum production

Keratinization

bacterial growth

inflammation

what bacterium is responsible for acne vulgaris?

Cutibacterium acnes

Gram positive bacteria

The _________________ unit of the skin consists of a hair follicle and the surrounding sebaceous glands.

pilosebaceous

what naturally maintains hair and skin hydration?

sebum

what can cause an increased size of the sebaceous gland and production of abnormally high levels of sebum within it?

increased androgen levels

what occurs in acne that results in an increased adhesiveness of the sloughed cells?

hyperkeratinization

An initial acne lesion invisible to the naked eye, called a _____________, forms as a result of the increased cell division and cohesiveness.

microcomedo

what forms a microcomedo?

increased cell division and cohesiveness

precursor to comedos

subclinical microcomedo

"whitehead"

closed comedo

accumulation of epithelial cells and sebum partially obstruct the follicular opening

closed comedo or "whitehead"

"blackhead"

open comedo

follicular opening is dilated, the keratin buildup can darken and form

open comedo

relatively slow-growing, typically aerotolerant anaerobic, gram-positive bacterium

Cutibacterium acnes

clogged hair follicle, filled with skin, bacteria, and sebum

comedone

inhibits formation of comedones

comedolytic

removes/lyses keratinocytes to remove part of epidermal layer

keratinolytic

__________ therapy is considered the first line for mild acne, with _________ therapies added on in moderate-to-severe acne

topical; oral

treatment with what is more effective, reduces adverse effects, and minimizes treatment resistance in acne?

treatment with multiple topical agents that target different aspects of acne pathogenesis

condition in which exposure to an offending substance produces inflammation, erythema, and pruritus of the skin.

contact dermatitis

how can contact dermatitis be divided?

irritant or allergic

__________ results from first-time exposure to irritating substances, such as soaps, plants, cleaning solutions, or solvents.

irritant dermatitis

is irritant dermatitis an immunologic process?

no, a result of direct injury to skin

symptoms of ICD occur within ____________ of exposure and begin to heal soon after the removal of the offending substance.

minutes to hours

delayed hypersensitivity reaction that occurs after an initial exposure to an allergen results in sensitization.

allergic contact dermatitis

symptoms of ACD are similar to those of the irritant type but may take ____________- to develop following reexposure.

several hours to several days

commonly referred to as eczema, is a chronic inflammatory skin disorder characterized by dry and itchy skin.

atopic dermatitis

initial and second treatment for contact dermatitis

•Identifying the causative substance and eliminating its exposure is the initial treatment goal for contact dermatitis.

•The second treatment goal is symptom relief.

atopic triad

atopic dermatitis, allergic rhinitis, asthma

Epidermal barrier dysfunction and increased ______ cell activity, leading to increased ______production, are characteristic pathophysiologic features of atopic dermatitis.

TH-2, IgE

what type of hypersensitivity reaction is atopic dermatitis?

Type I

atopic derm treatment goals

- controlling pruritus

- healing skin lesions

- maintaining skin integrity

- identifying and removing triggers

- preventing flare-ups

ABSSSIs

Skin and skin structure infections, also known as acute bacterial skin and skin structure infections

most common causative bacteria of ABSSSIs

gram-positive pathogens, primarily Staphylococcus aureus and Streptococcus species

Conditions predisposing patients to ABSSSIs

- trauma to the skin

- alterations in vascularization

- changes innoxygenation

impetigo, folliculitis, furuncles, carbuncles, cellulitis, erysipelas, necrotizing fasciitis, diabetic foot infections (DFIs), infected bite wounds

Skin and skin structure infections (ABSSSIs)

treatment of mycoses

use of azole and allylamine antifungal agents, either topically or orally

whether symptomatic or asymptomatic, refers to an infection in women whose vaginal cultures are positive for Candida species.

Vulvovaginal candidiasis (VVC)

primary pathogen responsible for VVC, accounting for 66% of cases

C. albicans

_________________ VVC infections occur sporadically cause mild-to-moderate symptoms, and occur in nonimmunocompromised women

uncomplicated

______________ VVC infections, including recurrent, severe infections, and those in women with uncontrolled diabetes, debilitation, or immunosuppression, may be caused by non-albicans or azole-resistant fungal organisms.

complicated

________________ are superficial fungal infections in which the pathogen remains within the keratinous layers of the skin or nails.

Tinea infections

Fungal skin infections are primarily caused by dermatophytes such as ______________

Trichophyton, Microsporum, and Epidermophyton

what is the primary mode of transmission of tinea infections?

direct contact with other persons or surface reservoirs

a chronic inflammatory condition exhibits a cyclical pattern of relapse and remission, an autoimmune disorder

psoriasis

is there a cure for psoriasis?

no

what are some factors that can exacerbate psoriasis?

stress, environmental factors including seasonal changes, and certain medications

what medications can exacerbate psoriasis?

lithium, NSAIDs, antimalarials, β-adrenergic blockers, and corticosteroid withdrawal

what type of immunity is involved in psoriasis?

innate and adaptive

what activates the innate immunity in psoriasis?

Antigenic stimuli are thought to activate the innate immune response, leading to the production of cytokines, such as interferon, tumor necrosis factor (TNF), interleukin-23 (IL-23), and IL-12, by macrophages, dendritic cells, and neutrophils.

in psoriasis, activated innate immunity leads to the attraction, activation, and differentiation of T cells which produce cytokines leading to ____________

epidermal hyperplasia (keratinocyte activation and proliferation), recruitment of inflammatory cells (neutrophils)

4 major processes of inflammation in psoriasis

The presentation of putative autoantigens to T cells and the release of interleukin-23 by dermal dendritic cells (I)

The production of proinflammatory mediators such as tumor necrosis factor α (TNF-α) and nitric oxide by TNF-α and inducible nitric oxide synthase-produced by (TIP) dendritic cells (II)

The production of interleukin-17A, interleukin-17F, and interleukin- 22 by Th17 and Tc17 cells and interferon-γ and TNF-α by Th1 and cytotoxic T cells. (III)

These mediators act on keratinocytes, leading to the activation, proliferation, and production of antimicrobial peptides (e.g., LL-37 cathelicidin and β-defensins), chemokines (e.g., CXCL1, CXCL9 through CXCL11, and CCL20), and S100 proteins (e.g., S100A7-9) by keratinocytes. (IV)

what happens when psoriasis is triggered by nonspecific factors?

Stimulated dendritic cells release pro-inflammatory factors (IL-23, TNF-α and IL-12).

These cytokines activate the IL-23 and/or IL-22 pathway to induce T-cell differentiation, resulting in the production of numerous psoriatic cytokines, such as TNF-α, IFN-γ, IL-17 and IL-22, which act on keratinocytes to amplify psoriatic inflammation.

what are the psoriatic cytokines?

TNF-α, IFN-γ, IL-17 and IL-22

treatment for psoriasis is ______________ as there is no "cure"

individualized