Pharmacology of Dermatological Agents

1. Introduction/Overview

The pharmacology of dermatological agents encompasses a diverse array of therapeutic compounds administered both topically and systemically to manage diseases of the skin, hair, nails, and mucous membranes. The skin, as the largest organ of the human body, presents a unique therapeutic challenge and opportunity due to its function as a protective barrier. Effective dermatological therapy requires a thorough understanding of the principles of percutaneous absorption, the pathophysiology of cutaneous diseases, and the specific pharmacodynamic actions of drugs applied to or acting upon the skin. The clinical relevance of this field is substantial, given the high prevalence of dermatological conditions, which range from common ailments like acne and eczema to severe, life-altering diseases such as psoriasis and cutaneous T-cell lymphoma.

Mastery of dermatological pharmacology is essential for rational prescribing, optimizing therapeutic outcomes, and minimizing adverse effects, particularly since many agents possess narrow therapeutic indices or significant systemic toxicity when absorbed. This chapter provides a systematic examination of the major classes of dermatological drugs, integrating fundamental pharmacological principles with clinical application.

Learning Objectives

• Classify major dermatological agents based on their chemical structure, mechanism of action, and primary therapeutic indications.
• Explain the mechanisms of action for key drug classes, including corticosteroids, retinoids, antimicrobials, and immunomodulators, at molecular and cellular levels.
• Analyze the pharmacokinetic principles governing topical drug delivery, including factors influencing percutaneous absorption and bioavailability.
• Evaluate the therapeutic applications, major adverse effect profiles, and significant drug interactions for common dermatological agents.
• Apply knowledge of special population considerations, including use in pregnancy, pediatrics, and hepatic or renal impairment, to clinical prescribing decisions.

2. Classification

Dermatological agents can be classified according to several schemata, including route of administration, therapeutic use, chemical structure, and mechanism of action. A functional classification based on primary pharmacodynamic action and clinical indication is most clinically relevant.

Topical Anti-inflammatory and Immunomodulatory Agents

• Corticosteroids: Grouped by potency (Classes I-VII), chemical structure (e.g., halogenated vs. non-halogenated), and duration of action.
• Calcineurin Inhibitors: Tacrolimus and pimecrolimus.
• Phosphodiesterase-4 (PDE4) Inhibitors: Crisaborole.
• Retinoids: Tretinoin, adapalene, tazarotene.
• Vitamin D Analogues: Calcipotriene, calcitriol.

Antimicrobial and Antiseptic Agents

• Topical Antibiotics: Clindamycin, erythromycin, metronidazole, mupirocin.
• Topical Antifungals: Azoles (e.g., ketoconazole, clotrimazole), allylamines (e.g., terbinafine), polyenes (e.g., nystatin).
• Topical Antivirals: Acyclovir, penciclovir.
• Antiseptics and Disinfectants: Chlorhexidine, povidone-iodine, hydrogen peroxide.

Acne Therapeutics

• Retinoids: Topical (tretinoin, adapalene) and systemic (isotretinoin).
• Antimicrobials: Topical and oral antibiotics (e.g., doxycycline, minocycline).
• Anti-androgens: Spironolactone, oral contraceptives.
• Other Agents: Benzoyl peroxide, azelaic acid, salicylic acid.

Systemic Immunomodulators and Biologics

• Conventional Systemic Agents: Methotrexate, cyclosporine, azathioprine, mycophenolate mofetil.
• Biologic Response Modifiers:
  • Tumor Necrosis Factor-alpha (TNF-α) inhibitors: Adalimumab, etanercept, infliximab.
  • Interleukin inhibitors: Ustekinumab (IL-12/23), secukinumab (IL-17A), ixekizumab (IL-17A), dupilumab (IL-4/13).
  • Other: Rituximab (anti-CD20).
• Small Molecule Inhibitors: Janus kinase (JAK) inhibitors (e.g., tofacitinib, upadacitinib).

Other Important Classes

• Local Anesthetics: Lidocaine, prilocaine (often as eutectic mixture, EMLA).
• Antipruritics: Doxepin, capsaicin, menthol.
• Keratolytics: Salicylic acid, urea, alpha-hydroxy acids (e.g., glycolic acid).
• Depigmenting Agents: Hydroquinone, monobenzone.
• Photosensitizers and Photoprotectants: Psoralens, sunscreens (chemical and physical blockers).

3. Mechanism of Action

The mechanisms of action for dermatological agents are as varied as the conditions they treat, targeting specific pathways in inflammation, cellular proliferation, differentiation, and microbial pathogenesis.

Topical Corticosteroids

Topical corticosteroids exert their anti-inflammatory, immunosuppressive, antiproliferative, and vasoconstrictive effects primarily through genomic mechanisms. Lipophilic molecules diffuse across the cell membrane and bind with high affinity to cytosolic glucocorticoid receptors. The ligand-receptor complex translocates to the nucleus, where it modulates gene transcription by binding to glucocorticoid response elements (GREs) or by interacting with other transcription factors such as nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1). This interaction leads to the transactivation of anti-inflammatory genes (e.g., encoding lipocortin-1, which inhibits phospholipase A2) and the transrepression of pro-inflammatory genes (e.g., those for cytokines like IL-1, IL-2, IL-6, TNF-α, and chemokines). The vasoconstrictive effect, which correlates with clinical potency, is thought to involve inhibition of nitric oxide synthase and reduced expression of vasodilatory mediators.

Topical Calcineurin Inhibitors

Tacrolimus and pimecrolimus are macrolide lactones that inhibit calcineurin, a calcium/calmodulin-dependent serine/threonine phosphatase. In T-lymphocytes, calcineurin activation dephosphorylates the nuclear factor of activated T-cells (NFAT), enabling its translocation to the nucleus and subsequent transcription of genes for pro-inflammatory cytokines such as IL-2, IL-4, and TNF-α. By binding to the immunophilin FKBP-12 and forming a complex that inhibits calcineurin, these drugs prevent NFAT activation and cytokine production. This mechanism provides a steroid-sparing, non-atrophogenic alternative for conditions like atopic dermatitis.

Retinoids

Retinoids exert their effects by binding to and activating specific nuclear receptors: retinoic acid receptors (RARs α, β, γ) and retinoid X receptors (RXRs α, β, γ). These receptors function as ligand-activated transcription factors. Topical retinoids (tretinoin, adapalene, tazarotene) normalize keratinocyte differentiation, reduce hyperkeratinization and microcomedone formation, and possess anti-inflammatory properties. Adapalene also exhibits some modulation of cellular differentiation and inflammation via interaction with specific RARs. Systemic isotretinoin is a prodrug for all-trans retinoic acid and induces profound changes in sebaceous gland function, reducing sebum production by approximately 90% through sebocyte apoptosis and reduced proliferation. It also normalizes follicular keratinization and exhibits anti-inflammatory effects.

Vitamin D Analogues

Calcipotriene and calcitriol are analogues of 1,25-dihydroxyvitamin D3 (calcitriol). They bind to the intracellular vitamin D receptor (VDR), which heterodimerizes with the RXR. This complex binds to vitamin D response elements in the promoter regions of target genes, regulating transcription. In psoriasis, these agents inhibit keratinocyte proliferation, induce keratinocyte differentiation, and exert immunomodulatory effects by inhibiting T-cell activation and modulating cytokine profiles.

Biologic Response Modifiers

Biologics are engineered proteins that target specific components of the immune system implicated in inflammatory skin diseases.

• TNF-α Inhibitors: Monoclonal antibodies (adalimumab, infliximab) or a receptor fusion protein (etanercept) that bind to and neutralize soluble and membrane-bound TNF-α, a pivotal pro-inflammatory cytokine in diseases like psoriasis and hidradenitis suppurativa.
• IL-12/23 Inhibitor: Ustekinumab is a monoclonal antibody that targets the shared p40 subunit of interleukin-12 and interleukin-23, cytokines critical for the differentiation and maintenance of Th1 and Th17 lymphocyte subsets, respectively.
• IL-17 Inhibitors: Secukinumab and ixekizumab directly neutralize IL-17A, a cytokine produced by Th17 cells that drives keratinocyte activation and production of antimicrobial peptides and other inflammatory mediators in psoriasis.
• IL-4/13 Inhibitor: Dupilumab is a monoclonal antibody that binds to the shared IL-4Rα subunit, blocking signaling of both IL-4 and IL-13, key cytokines in the Th2 pathway central to atopic dermatitis pathogenesis.

Antimicrobial Agents

Mechanisms vary by class. Topical antibiotics like clindamycin inhibit bacterial protein synthesis. Mupirocin inhibits bacterial isoleucyl-tRNA synthetase. Benzoyl peroxide exerts bactericidal activity against Cutibacterium acnes through the release of free oxygen radicals and is also comedolytic. Azelaic acid has antimicrobial, anti-inflammatory, and comedolytic properties, and may inhibit mitochondrial enzymes and DNA synthesis in hyperactive melanocytes. Topical antifungal azoles inhibit fungal cytochrome P450-dependent 14α-demethylase, disrupting ergosterol synthesis in the fungal cell membrane.

4. Pharmacokinetics

The pharmacokinetics of dermatological agents are profoundly influenced by the route of administration. For topical agents, percutaneous absorption is the critical determinant of systemic exposure and efficacy.

Principles of Topical Drug Absorption

Percutaneous absorption occurs via passive diffusion through the stratum corneum, the primary barrier, followed by passage through the viable epidermis and dermis into the systemic circulation. The process is governed by Fick’s law of diffusion: J = K_p × ΔC, where J is the flux, K_p is the permeability coefficient, and ΔC is the concentration gradient. Key factors influencing absorption include:

• Drug Properties: Lipophilicity (optimal log P ~2-3), molecular weight (<500 Da preferred), and concentration in the vehicle.
• Vehicle/Formulation: Ointments generally enhance absorption compared to creams, lotions, or gels. Penetration enhancers (e.g., propylene glycol) may be included.
• Skin Condition: Absorption is increased in diseased skin (e.g., inflamed, eroded), in areas with a thin stratum corneum (face, intertriginous areas), and when the skin barrier is compromised (occlusion, wounds).
• Anatomical Site: Permeability varies significantly (scalp > forehead > postauricular > arm > palm).

Absorption, Distribution, Metabolism, and Excretion

Topical Corticosteroids

Absorption varies by potency, formulation, and site. Occlusion can increase absorption up to tenfold. Once absorbed, they bind to plasma proteins (transcortin and albumin) and are distributed widely. Hepatic metabolism via cytochrome P450 enzymes (primarily CYP3A4) converts active drugs to inactive metabolites, which are then renally excreted. The systemic half-life is short for most topical steroids, but prolonged use on large body surface areas or under occlusion can lead to hypothalamic-pituitary-adrenal (HPA) axis suppression.

Topical Calcineurin Inhibitors

Systemic absorption is minimal on intact skin (<1% of applied dose), but may be increased with application to diseased skin or under occlusion. Tacrolimus is extensively metabolized in the liver by CYP3A4 and excreted primarily in feces. Pimecrolimus undergoes similar metabolism. Detectable blood levels are rare with appropriate use.

Systemic Retinoids (Isotretinoin)

Oral isotretinoin is absorbed with a high-fat meal, which increases bioavailability approximately 1.5-2 fold compared to fasting. It is highly protein-bound (>99.9%), primarily to albumin. Isotretinoin undergoes extensive hepatic metabolism via CYP enzymes, including CYP2C8, CYP2C9, and CYP3A4, to multiple metabolites, including its active form, 4-oxo-isotretinoin. The terminal elimination half-life of isotretinoin is approximately 21 hours, while that of its major metabolite is longer. Excretion occurs via both the biliary and renal routes.

Biologic Agents

Administered via subcutaneous injection or intravenous infusion, these large protein molecules are not absorbed through the skin or gastrointestinal tract. Distribution is generally limited to the plasma and extracellular fluid. They are metabolized via proteolytic degradation throughout the body, similar to endogenous immunoglobulins, and do not rely on hepatic cytochrome P450 systems. Elimination occurs through target-mediated disposition and proteolytic catabolism, resulting in long and variable terminal half-lives (e.g., approximately 2 weeks for adalimumab, 3-4 weeks for ustekinumab).

Dosing Considerations

Topical dosing is typically described in terms of application frequency (e.g., once or twice daily) and quantity. The “fingertip unit” (FTU), the amount of ointment expressed from a tube to cover the distal phalanx of an adult index finger (approximately 0.5 g), is a practical measure to standardize application and avoid overuse. Systemic agents require precise weight-based or fixed dosing schedules with consideration for therapeutic drug monitoring where applicable (e.g., methotrexate, cyclosporine).

5. Therapeutic Uses/Clinical Applications

Dermatological agents are employed across a vast spectrum of cutaneous diseases. Their use is guided by disease severity, affected body surface area, patient age, and comorbidities.

Inflammatory Dermatoses

• Atopic Dermatitis/Eczema: First-line therapy involves emollients and topical corticosteroids of appropriate potency. Topical calcineurin inhibitors (tacrolimus, pimecrolimus) and crisaborole are used for sensitive areas (face, neck) and for proactive maintenance therapy. For moderate-to-severe disease, systemic immunomodulators (cyclosporine, methotrexate, mycophenolate mofetil) or biologics (dupilumab, tralokinumab) are indicated.
• Psoriasis: Treatment is stratified by disease type and severity. Topical therapies include corticosteroids, vitamin D analogues, retinoids (tazarotene), and calcineurin inhibitors. Phototherapy is a common second-line option. Systemic therapies include conventional agents (methotrexate, cyclosporine, acitretin) and biologics targeting TNF-α, IL-17, IL-12/23, or IL-23 alone. Small molecule JAK inhibitors (e.g., tofacitinib, deucravacitinib) are also available.
• Contact Dermatitis: Primarily managed with avoidance of the allergen/irritant and short-term use of topical corticosteroids.

Acne Vulgaris

Treatment is based on lesion type (comedonal, inflammatory, mixed) and severity.

• Mild Acne: Topical retinoids (tretinoin, adapalene), benzoyl peroxide, and/or topical antibiotics (clindamycin, often combined with benzoyl peroxide to reduce resistance).
• Moderate Acne: Combination therapy with topical agents plus oral antibiotics (tetracyclines like doxycycline or minocycline, macrolides). Hormonal therapies (combined oral contraceptives, spironolactone) are effective in females.
• Severe Nodulocystic Acne or Acne Resistant to Other Therapies: Oral isotretinoin is the treatment of choice.

Infections and Infestations

• Bacterial (Impetigo, Folliculitis): Topical mupirocin or retapamulin; oral antibiotics for extensive disease.
• Fungal (Dermatophytosis, Candidiasis): Topical azoles, allylamines, or ciclopirox. Oral terbinafine or itraconazole for extensive tinea, onychomycosis, or recalcitrant infections.
• Viral (Herpes Simplex): Topical acyclovir or penciclovir for mild recurrences; oral valacyclovir or famciclovir for treatment or suppression.
• Parasitic (Scabies, Lice): Topical permethrin, ivermectin (oral or topical).

Precancerous and Malignant Conditions

• Actinic Keratosis: Field-directed therapies include topical 5-fluorouracil, imiquimod, ingenol mebutate, diclofenac gel, and photodynamic therapy.
• Basal Cell Carcinoma (superficial): Topical imiquimod or 5-fluorouracil may be used in selected cases.
• Cutaneous T-cell Lymphoma (early stage): Topical therapies include corticosteroids, nitrogen mustard, carmustine, and bexarotene gel.

Other Common Applications

• Rosacea: Topical metronidazole, azelaic acid, ivermectin, brimonidine; oral doxycycline (sub-antimicrobial dose).
• Vitiligo: Topical corticosteroids, topical calcineurin inhibitors, phototherapy.
• Pruritus: Topical corticosteroids, calcineurin inhibitors, doxepin, capsaicin; systemic antihistamines, gabapentinoids.

6. Adverse Effects

Adverse effects range from local cutaneous reactions to significant systemic toxicity, often related to the degree of percutaneous or systemic absorption.

Topical Corticosteroids

• Local Cutaneous Effects: Skin atrophy (thinning, striae, telangiectasias), purpura, steroid-induced acne or rosacea, perioral dermatitis, hypertrichosis, hypopigmentation, delayed wound healing. These are more common with higher potency steroids, prolonged use, occlusion, and application to thin-skinned areas.
• Systemic Effects: With significant absorption: HPA axis suppression, Cushing’s syndrome, hyperglycemia, glaucoma (with periocular use), and growth retardation in children. The risk is highest with high-potency steroids used on large body surface areas, under occlusion, or in infants.

Topical Calcineurin Inhibitors

The most common adverse effect is a transient burning or pruritus at the application site. There is a theoretical risk of increased cutaneous infections (e.g., herpes simplex, molluscum contagiosum) and a long-debated potential risk of malignancy (skin cancer, lymphoma) due to systemic immunosuppression, leading to a black box warning. Epidemiological studies have not established a causal link, but their use is generally avoided in patients with known immunosuppression or extensive, continuous long-term use.

Systemic Retinoids (Isotretinoin)

Isotretinoin is associated with a wide array of adverse effects, necessitating careful monitoring.

• Teratogenicity: It carries an absolute black box warning for teratogenicity. Major fetal abnormalities (craniofacial, cardiac, central nervous system) can occur with any dose or duration of exposure during pregnancy. Strict pregnancy prevention programs (iPledge in the United States) are mandatory.
• Mucocutaneous: Nearly universal cheilitis, xerosis, conjunctivitis, epistaxis, and skin fragility.
• Musculoskeletal: Myalgias, arthralgias, hyperostosis (especially with long-term use), and premature epiphyseal closure in children.
• Ophthalmic: Dry eyes, night blindness (rare, due to altered dark adaptation).
• Psychiatric: A controversial association with depression, suicidal ideation, and psychosis; a causal link is not definitively proven but requires vigilance.
• Laboratory Abnormalities: Reversible elevation of serum triglycerides, cholesterol, and transaminases.

Biologic Agents

Adverse effects are primarily related to immunosuppression and immunogenicity.

• Infections: Increased risk of bacterial, viral (including reactivation of latent tuberculosis and hepatitis B), and fungal infections. Screening for latent TB is mandatory prior to initiation.
• Infusion/Injection Reactions: Local injection site reactions are common. Infusion reactions (fever, chills, urticaria) can occur with intravenous agents.
• Malignancy: A potential increased risk of lymphoma and non-melanoma skin cancer, particularly with TNF-α inhibitors.
• Autoimmunity: Induction of autoantibodies (ANA, dsDNA) and, rarely, lupus-like syndromes or demyelinating disorders.
• Class-Specific Effects: TNF-α inhibitors may worsen congestive heart failure. IL-17 inhibitors can exacerbate or trigger inflammatory bowel disease and candidiasis.

Other Notable Adverse Effects

• Topical Retinoids: Local irritation, erythema, scaling, and photosensitivity (“retinoid dermatitis”).
• Benzoyl Peroxide: Skin irritation, bleaching of hair and fabrics.
• Hydroquinone: Local irritation, exogenous ochronosis (blue-black discoloration) with prolonged use.
• Methotrexate: Hepatotoxicity (fibrosis, cirrhosis), myelosuppression, pulmonary toxicity, mucositis. Requires folic acid supplementation and periodic liver biopsy or non-invasive monitoring in some protocols.
• Cyclosporine: Nephrotoxicity, hypertension, hyperlipidemia, gingival hyperplasia, hypertrichosis, increased risk of malignancy.

7. Drug Interactions

Significant drug interactions occur with both systemic and, less commonly, topical dermatological agents.

Systemic Retinoids

• Vitamin A Supplements: Concomitant use with isotretinoin or acitretin can lead to additive hypervitaminosis A toxicity.
• Tetracyclines: Combined use with isotretinoin may increase the risk of benign intracranial hypertension (pseudotumor cerebri).
• Alcohol: Consumption during acitretin therapy can enhance its conversion to etretinate, a metabolite with a much longer half-life (up to 120 days), prolonging the teratogenic risk period. Patients must avoid alcohol during and for 2 months after acitretin therapy.
• Hepatotoxic Drugs: Concurrent use of other hepatotoxic agents (e.g., methotrexate, azathioprine, high-dose acetaminophen) may increase the risk of liver injury.

Immunosuppressants

• Cyclosporine: Metabolism is mediated by CYP3A4 and P-glycoprotein. Strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, grapefruit juice) can markedly increase cyclosporine levels and toxicity. Inducers (e.g., rifampin, phenytoin, St. John’s wort) can decrease levels, risking therapeutic failure. Additive nephrotoxicity can occur with NSAIDs, aminoglycosides, and amphotericin B.
• Methotrexate: NSAIDs, salicylates, probenecid, and trimethoprim-sulfamethoxazole can reduce renal clearance of methotrexate, leading to severe myelosuppression and mucositis. Hepatotoxic drugs have additive risks.
• Biologics: Concurrent use with other immunosuppressive agents may increase the risk of serious infections. Live vaccines are contraindicated. The combination of multiple TNF-α inhibitors or a TNF-α inhibitor with anakinra (IL-1 receptor antagonist) is not recommended due to increased infectious risks without added benefit.

Topical Agents

Significant systemic interactions are rare but possible with extensive application. For instance, topical salicylic acid in high concentrations over large areas (as in psoriasis) can lead to systemic salicylism, potentially interacting with anticoagulants or other drugs affected by salicylate displacement from plasma proteins.

Contraindications

• Absolute: Pregnancy for isotretinoin, acitretin, and mycophenolate mofetil. Active, untreated tuberculosis or severe active infection for biologic agents. Hypersensitivity to the drug or any component of its formulation.
• Relative: Severe hepatic impairment for methotrexate, acitretin, and isotretinoin. Severe renal impairment for methotrexate. Uncontrolled hypertension or renal dysfunction for cyclosporine. History of malignancy (especially lymphoma) for biologic agents and cyclosporine. History of inflammatory bowel disease for IL-17 inhibitors.

8. Special Considerations

Pregnancy and Lactation

The use of dermatological agents in pregnancy and lactation requires meticulous risk-benefit analysis.

• Category X (Absolute Contraindication): Isotretinoin, acitretin, mycophenolate mofetil. Topical tazarotene is also contraindicated in pregnancy.
• Generally Considered Safe with Caution: Topical corticosteroids (low-to-mid potency, minimal use), topical calcineurin inhibitors (limited systemic absorption), and many topical antimicrobials. Systemic prednisone may be used for severe conditions but carries risks of cleft palate (first trimester) and adrenal suppression in the neonate.
• Biologics: Data are limited but growing. TNF-α inhibitors (adalimumab, etanercept, infliximab) are often considered compatible in the first two trimesters as they do not cross the placenta in significant amounts until the late second/third trimester. Use in the third trimester may lead to detectable levels in the infant, complicating live vaccine administration. Decisions are individualized.
• Lactation: Most topical agents are considered compatible due to minimal systemic absorption. Systemic agents like methotrexate and cyclosporine are generally contraindicated due to secretion into breast milk. Biologics, being large proteins, are unlikely to be excreted in significant amounts in breast milk or absorbed by the infant’s gut.

Pediatric Population

Children have a higher body surface area to weight ratio, thinner stratum corneum, and potentially immature metabolic and excretory pathways, increasing the risk of systemic toxicity from topical agents.

• Low- to mid-potency topical corticosteroids are preferred; high-potency steroids should be used with extreme caution, for short durations, and on limited areas to avoid HPA axis suppression and growth retardation.
• Topical calcineurin inhibitors are approved for children ≥2 years (tacrolimus) and ≥3 months (pimecrolimus).
• Systemic isotretinoin is used for severe acne but requires careful monitoring of skeletal growth and psychiatric status.
• Dosing of systemic immunosuppressants like methotrexate and cyclosporine is weight-based.

Geriatric Population

Aged skin is thinner, drier, and more fragile, altering the pharmacokinetics and increasing susceptibility to adverse effects of topical agents.

• Increased risk of skin atrophy, purpura, and delayed healing with topical corticosteroids; lower potencies are often sufficient.
• Polypharmacy is common, elevating the risk of drug interactions with systemic agents like methotrexate and cyclosporine.
• Comorbid conditions (renal impairment, hypertension, heart failure) may contraindicate or necessitate dose adjustments for systemic therapies.
• Increased risk of malignancy may influence the choice of immunosuppressive therapies.

Hepatic and Renal Impairment

Hepatic Impairment: Many dermatological drugs are metabolized hepatically. Isotretinoin, acitretin, and methotrexate are contraindicated in severe hepatic impairment and require monitoring in mild-to-moderate disease. Dose reduction or avoidance may be necessary for cyclosporine and azathioprine. Biologic agents, which are not hepatically metabolized, may be preferred in some cases.

Renal Impairment: Methotrexate is primarily renally excreted and is contraindicated in significant renal impairment due to risk of severe toxicity. Cyclosporine can cause nephrotoxicity, and its use requires caution with pre-existing renal disease. Dose adjustments for other renally excreted drugs (e.g., acyclovir, antibiotics) must be considered when used for dermatological indications.

9. Summary/Key Points

• Dermatological pharmacology integrates principles of topical drug delivery with systemic pharmacotherapy to treat a wide range of cutaneous diseases.
• The stratum corneum is the major barrier to topical drug absorption; factors such as drug lipophilicity, vehicle, skin integrity, and anatomical site critically influence percutaneous penetration and systemic exposure.
• Topical corticosteroids remain a cornerstone of anti-inflammatory therapy but carry risks of local atrophy and, with overuse, systemic HPA axis suppression. Their potency should be matched to disease severity and site.
• Systemic retinoids, particularly isotretinoin, are highly effective for severe acne but are potent teratogens requiring rigorous pregnancy prevention programs and monitoring for mucocutaneous, musculoskeletal, and laboratory adverse effects.
• Biologic response modifiers have revolutionized the treatment of moderate-to-severe psoriasis and atopic dermatitis by targeting specific cytokine pathways (e.g., TNF-α, IL-17, IL-4/13). Their use requires screening for latent infections and monitoring for immunosuppression-related risks.
• Topical calcineurin inhibitors provide a steroid-sparing option for inflammatory conditions like atopic dermatitis, especially on sensitive skin, though a black box warning regarding a theoretical malignancy risk remains.
• Significant drug interactions are common with systemic dermatological agents, especially those metabolized via CYP450 enzymes (e.g., cyclosporine, retinoids) or affecting immune function.
• Special population considerations are paramount: the risk of teratogenicity dictates contraceptive use; pediatric patients are more susceptible to systemic effects from topical drugs; and geriatric patients or those with hepatic/renal impairment often require dose adjustments or alternative agents.

Clinical Pearls

• Use the lowest potency topical corticosteroid that controls the disease, and limit duration of use on the face and intertriginous areas to minimize atrophy.
• When prescribing isotretinoin, ensure enrollment in a validated pregnancy prevention program (e.g., iPledge), obtain baseline lipids and LFTs, and counsel patients thoroughly on teratogenicity and common mucocutaneous side effects.
• Prior to initiating a biologic agent, screen for latent tuberculosis (with an interferon-gamma release assay or tuberculin skin test) and hepatitis B, and ensure vaccinations are up-to-date (avoiding live vaccines during therapy).
• For patients applying topical agents to large body surface areas, educate on the use of fingertip units to avoid over-application and potential systemic toxicity.
• In patients with renal or hepatic impairment, carefully select and dose systemic agents, favoring those with safer profiles (e.g., biologics over methotrexate in renal failure) when appropriate.

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