Dermatologic Pharmacology

Topical Glucocorticoids: Actions, Uses, and Potency

Primary Actions and Clinical Uses
- These agents are primarily utilized to relieve inflammation and itching associated with various skin conditions.
- They are commonly prescribed for:
  - Insect bites
  - Dermatitis
  - Psoriasis
  - Eczema
  - Pemphigus
Therapeutic Vehicles and Penetration
- The vehicle, such as a cream, ointment, or gel, significantly affects the penetration of the drug into the skin and its subsequent therapeutic effect.
Potency Classifications and Influencing Factors
- Relative potency ranges from low-potency to super-high-potency agents.
- Factors that influence the overall potency include:
  - The concentration of the drug.
  - The specific vehicle used.
  - The method of application.
  - The use of occlusive dressings, which can increase drug absorption by up to $10\text{-fold}$ .

Topical Glucocorticoids: Absorption and Adverse Effects

Systemic Absorption Dynamics
- Drugs in this class are absorbed into the systemic circulation.
- Increased Absorption Factors:
  - Prolonged duration of use.
  - Application to a large surface area.
  - Application to highly permeable skin areas, including the face, neck, eyelids, and genitalia.
  - Application to inflamed skin.
  - Use of occlusive dressings.
- Decreased Absorption Factors:
  - Application to thick-skinned areas such as the palms of the hands and soles of the feet.
Local Adverse Effects
- Skin irritation.
- Increased risk of localized infection.
- Skin thinning (atrophy), striae (stretch marks), purpura, and telangiectasias (spider veins).
- Development of acne and hypertrichosis (excessive hair growth).
Systemic Adverse Effects
- Growth delay in pediatric populations.
- Adrenal suppression across all age groups.
- The risk of systemic effects increases with high-potency agents, application to large surface areas, prolonged use, and occlusion.

Acne Overview and Pathophysiology

Epidemiology and Economic Impact
- Acne is recognized as the most common dermatologic condition.
- It affects approximately $85\%$ of teenagers and may persist well into adulthood.
- This condition accounts for the highest volume of dermatology visits.
- The annual cost in the United States exceeds $1 billion, including approximately $100 million spent on over-the-counter (OTC) products.
Pathophysiology and Lesion Types
- Acne is a chronic condition that typically starts at puberty and is often more severe in males.
- Common sites of occurrence include the face, neck, chest, shoulders, and back.
- Types of Lesions:
  - Open comedones, also known as blackheads.
  - Closed comedones, also known as whiteheads.
  - Severe lesions, which include abscesses and inflammatory cysts.
- Mechanisms of Development:
  - Triggered by increased androgen levels, leading to increased sebum production and skin cell turnover.
  - Propionibacterium acnes bacteria exacerbate inflammation by converting sebum into irritant fatty acids and releasing chemotactic factors.
  - Contributing factors include oily skin and genetics.

Acne Treatment Overview and General Therapy

Treatment Goals and Nature
- Because acne is a chronic condition, it requires long-term treatment strategies.
- The primary goals are to prevent permanent scarring, reduce the duration of the condition, and minimize the psychological impact on the patient.
Nonpharmacologic Therapy
- Gentle cleansing should be performed with nonirritant soap twice daily ( $2\times/\text{day}$ ).
- Scrubbing and the use of abrasive products must be avoided.
- Oil-based makeup and moisturizers should be avoided.
- Optional interventions include comedo extraction and dermabrasion.
- Dietary changes have no proven benefit in the treatment of acne.
Drug Therapy Selection by Severity
- Mild Acne: Treated with topical antibiotics and topical retinoids.
- Moderate Acne: Treated with oral antibiotics (e.g., doxycycline) combined with comedolytics.
- Severe Acne: Treated with the oral retinoid isotretinoin.
- Hormonal therapy: Oral contraceptives (OCs) or spironolactone may be used for resistant cases in young women.

Topical Antibiotics for Acne

Benzoyl Peroxide
- Considered a first-line treatment for mild to moderate acne.
- Possesses dual action as both an antibacterial and a keratolytic agent.
- Mechanism: Releases active oxygen species to kill P. acnes; also reduces inflammation and promotes peeling of the stratum corneum.
- Notably, it does not cause bacterial resistance.
- Side Effects: Drying, peeling, and severe irritation (burning, blistering, or swelling). If severe irritation occurs, the frequency of application should be reduced.
- Rarely, hypersensitivity reactions occur, particularly in patients with asthma. Health Canada issued a warning in 2015 regarding these allergic reactions.
Clindamycin and Erythromycin
- These agents suppress P. acnes and reduce localized inflammation.
- Bacterial resistance develops rapidly if these are used as monotherapy.
- They are typically combined with benzoyl peroxide to prevent resistance.
- Fixed-dose combinations:
  - Clindamycin/benzoyl peroxide (e.g., Acanya, BenzaClin).
  - Erythromycin/benzoyl peroxide (e.g., Benzamycin).
Dapsone (Aczone)
- Provides a modest reduction in inflammation and lesion count.
- Common Side Effects: Oiliness, peeling, dryness, and erythema (largely attributed to the gel base).
- There is a slight risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase ( $\text{G6PD}$ ) deficiency.
- Unlike oral dapsone, the topical form carries no risk of peripheral neuropathy.
- May cause a yellow or orange skin discoloration when used in combination with benzoyl peroxide.

Topical Retinoids for Acne and Wrinkles

General Characteristics
- Retinoids are derivatives of Vitamin A and serve as a cornerstone of acne therapy.
- They work by unplugging existing comedones and preventing the formation of new ones.
- They reduce inflammation and enhance the penetration of other topical therapeutic agents.
Tretinoin
- Used for mild to moderate acne as well as fine wrinkles.
- Acne Brands: Atralin, Avita, Retin-A, Retin-A Micro.
- Wrinkle Brands: Refissa, Renova.
- Mechanism: Normalizes epithelial cell turnover and thins the stratum corneum.
- Side Effects: Local irritation (blistering, peeling, burning, edema) and increased risk of sunburn.
- Patient Education: Use sunscreen with SPF $15+$ and protective clothing. Avoid abrasive soaps or other keratolytics.
Adapalene (Differin)
- Modulates inflammation and follicular cell differentiation.
- Reduces both comedones and inflammatory lesions.
- Approved for OTC use in individuals aged $12$ and older since 2016.
- Onset: Benefits typically appear in $8\text{--}12$ weeks.
- Initial Effect: May initially worsen acne by bringing hidden lesions to the surface.
- It is considered more effective than tretinoin for reducing total and inflammatory lesions.
Tazarotene (Avage, Fabior, Tazorac)
- Used for acne, wrinkles, and psoriasis.
- Avage is specifically approved for wrinkles and pigmentation, rather than acne treatment.

Topical Keratolytic Agents

Salicylic Acid
- Used for mild to moderate acne.
- Common side effects include local irritation and peeling.
- Salicylate Toxicity (Salicylism): Possible if applied over large areas (e.g., the trunk or back).
- Symptoms of Toxicity: Hyperpnea, tinnitus, nausea, vomiting, and mental status changes.
Azelaic Acid (Azelex, Finacea)
- Used for mild to moderate acne and rosacea.
- Mechanism: Suppresses P. acnes growth and decreases keratinocyte proliferation, thereby thinning the stratum corneum.
- Adverse Effects: Pruritus, burning, stinging, tingling, and erythema.
- Clinical Note: There is a risk of hypopigmentation in dark-skinned individuals; these patients must be monitored closely.

Oral Antibiotics for Acne

Primary Indications and Agents
- Reserved for moderate to severe acne.
- These agents suppress P. acnes and reduce inflammation; they are frequently combined with topical retinoids.
- Preferred Drugs: Doxycycline (Vibramycin) and Minocycline (Minocin).
- Onset and Maintenance: The onset of action is $3\text{--}6$ months. Once improvement is achieved, patients should be switched to topical antibiotics for maintenance therapy.

Isotretinoin (Accutane, Amnesteem, Claravis)

Therapeutic Intent
- A Vitamin A derivative used for severe nodulocystic acne that is unresponsive to other treatments.
- Often highly effective after a single course of treatment.
Mechanisms of Action
- Decreases sebum production and the physical size of sebaceous glands.
- Reduces inflammation and keratinization.
- Indirectly reduces P. acnes by limiting its nutrient source (sebum).
Common Physical Adverse Effects
- Mucocutaneous: Nosebleeds ( $80\%$ ), lip inflammation ( $90\%$ ), eye inflammation ( $40\%$ ), and dryness or itching of the skin, nose, and mouth ( $80\%$ ).
- Musculoskeletal: Joint and muscle pain ( $15\%$ ) and back pain in children ( $30\%$ ). There is a significant risk of premature epiphyseal closure.
- Other: Rash, headache, hair loss, skin peeling, and reduction in night vision.
- Serious Risks: Pseudotumor cerebri, pancreatitis, hearing loss, bone loss, and erectile dysfunction.
Mental Health and Metabolic Risks
- Potential risk of depression and suicidal ideation; patients must be monitored for mood changes.
- May elevate triglycerides; patients should avoid alcohol to mitigate hypertriglyceridemia.
Drug Interactions
- Tetracyclines: Increased risk of pseudotumor cerebri.
- Vitamin A Supplements: Intensifies retinoid toxicity.
Teratogenicity and Pregnancy Contraindication
- Isotretinoin is a known teratogen carrying a Black Box Warning.
- Causes major fetal abnormalities: hydrocephalus, microcephaly, facial malformations, cleft palate, and cardiovascular/ear defects.
- Increases the risk of miscarriage.

Patient Education and the iPLEDGE Program

Isotretinoin Patient Education
- Potential impairment of night vision; avoid driving at night if affected.
- Increased sun sensitivity; use sunscreen and avoid tanning beds.
- Regular blood tests are mandatory.
- Do not donate blood during treatment or for $1$ month after completion.
- Avoid cosmetic skin procedures (waxing, laser) during and for $6$ months after treatment.
- Immediate Reporting Requirement: Severe headaches, vision changes, vomiting, seizures, mood changes, or erectile dysfunction.
The iPLEDGE Program
- A strict risk management program designed to prevent pregnancy during treatment.
- Requirements:
  - Two negative pregnancy tests before initiation.
  - Monthly pregnancy tests for prescription refills.
  - The use of two forms of birth control beginning $1$ month before treatment and continuing for $1$ month after.
  - Patient registration and monthly check-ins to confirm adherence.
Baseline Data Requirements before Starting Isotretinoin
- Complete blood count ( $\text{CBC}$ ) with differential.
- Glucose and Lipid panel.
- Liver function tests.
- Vision and mental health assessments.
- Height measurement for patients under the age of $18$ .

Hormonal Agents for Acne

Oral Contraceptives (OCs)
- Approved Agents: Estrostep, Ortho Tri-Cyclen, Beyaz, and YAZ.
- Indications: Females $\ge 15$ years old who have reached menarche, desire contraception, and have not responded to topical therapy.
- Mechanism: Suppress ovarian androgen production and increase sex hormone-binding globulin, which inactivates androgens and decreases sebum production.
- Clinical Note: Improvement may take $6$ or more months. Estrogen is the primary active component.
Spironolactone (Aldactone)
- Blocks androgen receptors to reduce sebum.
- Typically added if OCs fail.
- Warning: It is teratogenic; contraception is required before use.
- Adverse Effects: Menstrual irregularities, breast tenderness, and hyperkalemia.

Sunscreens and UV Protection

Dermatologic Effects of UV Radiation
- UVB: Penetrates the epidermis; responsible for sunburn and tanning.
- UVA: Penetrates the deeper dermis; responsible for photoaging (wrinkles, yellowing), immunosuppression, and photosensitivity drug reactions.
- Shared Risks: Both UVA and UVB damage DNA and can cause skin cancers (basal cell carcinoma, squamous cell carcinoma, melanoma) and actinic keratoses.
Types of Sunscreens
- Organic (Chemical): Absorb UV radiation and convert it to heat. Only $6$ of the $15$ FDA-approved organic agents absorb UVA. Only avobenzone absorbs $\text{UVA}1$ .
- Inorganic (Physical): Reflect and scatter UV radiation. Includes titanium dioxide and zinc oxide. Best for sensitive areas like the nose, lips, and ears.
Sun Protection Factor (SPF)
- Measures protection against UVB only.
- Scale:
  - SPF 15: Blocks $93\%$ of UVB.
  - SPF 30: Blocks $96.7\%$ of UVB.
  - SPF 40: Blocks $97.5\%$ of UVB.
  - SPF 50+: FDA designation for any product with an SPF greater than $50$ .
Labeling Regulations
- Highly Protective: Broad-spectrum + SPF $\ge 15$ (protects against sunburn, cancer, and photoaging).
- Moderately Protective: Broad-spectrum + SPF $2\text{--}14$ (protects against sunburn only).
- Least Protective: UVB-only protection (protects against sunburn only).
- Water Resistance: Products can claim resistance for either $40$ or $80$ minutes; the terms "waterproof" and "sweatproof" are prohibited.

Drugs for Atopic Dermatitis (Eczema)

Condition Overview
- A chronic inflammatory condition characterized by dry, scaly skin and intense pruritus.
- Continuous scratching leads to erythema, abrasions, and lichenification.
- The condition is caused by abnormal T lymphocyte activity.
Treatment Options
- First-Line: Moisturizers (e.g., Cetaphil, Eucerin), topical glucocorticoids, and sedating antihistamines.
- Topical Immunosuppressants (Calcineurin Inhibitors):
  - Tacrolimus (Protopic): For moderate to severe eczema in adults ( $0.03\%$ or $0.1\%$ ) and children aged $2\text{--}16$ ( $0.03\%$ ). Suppresses T-cell activity. Common side effects include burning and pruritus. Carries a cancer risk concern (lymphoma, skin cancer).
  - Pimecrolimus (Elidel): For mild to moderate eczema. Similar profile to tacrolimus.
- PDE4 Inhibitor:
  - Crisaborole (Eucrisa): Reduces cytokines and inflammation. Used for mild to moderate dermatitis. Common side effects include burning and stinging at the application site.

Management of Warts

Common Warts (Verruca Vulgaris)
- Benign papules caused primarily by HPV types $1$ , $2$ , and $3$ .
Provider-Applied Treatments
- Podophyllin: Inhibits DNA synthesis and mitosis. Must be washed off after $1\text{--}4$ hours. Risks include systemic toxicity (neuropathy, kidney damage) and is contraindicated in pregnancy.
- Trichloroacetic Acid (TCA) and Bichloroacetic Acid (BCA): Used in $80\text{--}90\%$ concentrations to destroy warts via chemical coagulation.
Patient-Applied Treatments
- Imiquimod (Aldara, Zyclara): Stimulates internal immune response. Applied at bedtime and washed off in the morning.
- Podofilox (Condylox): Inhibits mitosis ( $0.5\%$ gel or solution). Used in cycles of $3$ days on and $4$ days off.
- Kunecatechins (Veregen): Green tea extract applied $3\times/\text{day}$ for up to $16$ weeks.
Physical Removal Methods
- Cryotherapy (liquid nitrogen), electrodesiccation (electric current), curettage (surgical cutting), and laser therapy.

Miscellaneous Skin Conditions and Treatments

Botox (OnabotulinumtoxinA)
- Neurotoxin that blocks acetylcholine release. Used for cosmetic (glabellar lines) and therapeutic (migraines, cervical dystonia) purposes.
- Black Box Warning: Risk of toxin spread to unintended areas.
Seborrheic Dermatitis and Dandruff
- Caused by Malassezia yeast infection.
- Treatment: Ketoconazole (antifungal), topical glucocorticoids, and maintenance shampoos containing pyrithione zinc or selenium sulfide.
Hair Loss Treatment
- Topical Minoxidil: Stimulates hair follicles. Hair regrowth is typically lost within $3\text{--}4$ months of discontinuation.
- Oral Finasteride (Propecia): Used for male-pattern baldness at $1\,mg/\text{day}$ . Inhibits dihydrotestosterone ( $\text{DHT}$ ) production. Teratogenic and should not be handled by pregnant women.
Unwanted Facial Hair
- Eflornithine (Vaniqa): $13.9\%$ topical cream that slows hair growth. Effects begin in $4\text{--}8$ weeks and are lost within $8$ weeks of stopping.
Impetigo
- Common bacterial infection (usually S. aureus) in children. Types include bullous and nonbullous (crusted, with honey-colored crusts). Treatment involves topical or oral antibiotics.
Topical Local Anesthetics
- Agents like benzocaine, lidocaine, and pramoxine are used to relieve pain and itching from sunburn, plant poisoning, or eczema.

Questions & Discussion

What are the primary factors that influence the potency of topical glucocorticoids?
- Potency is determined by the concentration of the drug, the vehicle (cream, ointment, or gel) used, the method of application, and whether occlusive dressings are utilized, as they can increase absorption by ten times ( $10\times$ ).
What are the strict requirements for the iPLEDGE program regarding isotretinoin?
- Patients must undergo two negative pregnancy tests before starting and monthly tests for refills. They must use two forms of birth control starting one month before and continuing for one month after treatment, and they must register with the iPLEDGE program.