---

TOPICAL DRUG THERAPY IN DERMATOLOGY

Comprehensive Resident's Study Note

---

PART 1: PRINCIPLES OF TOPICAL THERAPY

1.1 Why Topical Therapy Matters

---

1.2 Drug Concentration Conventions

Key point: Efficacy is NOT always proportionate to concentration - site, skin thickness, occlusion, and disease state all modulate absorption.

---

1.3 Vehicles

Types of Vehicles and Their Properties

Rule: Wet lesions - wet treatment; dry lesions - ointment. Hairy areas - lotion/gel/foam.

---

1.4 Quantity to Be Applied

Fingertip Unit (FTU)

• Quantity extruded from a 5 mm nozzle from the distal crease to the tip of the index finger
• Weight: ~0.49 g (males), ~0.43 g (females)
• Covers ~300 cm²

FTU Guide (Adults)

Weekly Requirements for Twice-Daily Whole Body Application

Rule of Hand: An area coverable by 4 adult hands = 1 g of ointment = 2 FTUs.

---

1.5 Regional Absorption Differences

Clinical Pearl: The scrotum absorbs 42x more than the forearm - NEVER use potent/super-potent steroids on genital skin.

---

1.6 Penetration Enhancers

• Propylene glycol
• Dimethyl sulfoxide (DMSO)
• Urea
• Azone (laurocapram)
• Salicylic acid (enhances steroid penetration in psoriasis but not in normal skin)
• Occlusion (polythene film increases penetration markedly)

---

1.7 Hazards of Topical Therapy

• Irritant contact dermatitis (most common with retinoids, BPO)
• Allergic contact dermatitis (to active drug, preservatives, vehicle constituents, fragrances)
• Sensitisers: neomycin, bacitracin, corticosteroids, topical anaesthetics, cetearyl alcohol, lanolin, colophonium, parabens, isothiazolinones

• Salicylism: 6% salicylic acid, twice daily, to 40% BSA can cause toxicity; at least 4 deaths reported
• Steroid suppression: significant absorption especially in children, flexures, occluded sites, diseased skin

---

---

PART 2: TOPICAL CORTICOSTEROIDS (TCS)

2.1 Historical Note

---

2.2 Mechanism of Action

• Suppression of inflammatory cytokines
• Inhibition of T-cell activation (via NFκB, AP-1, NFAT inhibition)
• Vasoconstriction (basis of potency assay)
• Inhibition of phospholipase A2 via lipocortin induction → reduced arachidonic acid → less prostaglandins + leukotrienes
• Antiproliferative effect on keratinocytes

---

2.3 Potency Classification

USA Classification (ASHP, Class 1-7)

UK Classification (BNF, 4 Groups)

Memory Trick: "Come Back For Mometasone" = Clobetasol > Betamethasone > Fluocinolone > Mometasone (descending potency for common agents)

---

2.4 Structural Modifications That Increase Potency

• Fluticasone propionate: fluoride thioester carbothioate at C21 - rapidly inactivated on hepatic first pass
• Methylprednisolone aceponate, mometasone furoate: similar rapid hepatic metabolism
• Prednicarbate: metabolised within the skin itself

---

2.5 Potency Measurement: Vasoconstrictor Assay

• Also called the McKenzie-Stoughton assay
• Measures skin blanching (pallor) caused by vasoconstriction
• Peak pallor at 9-12 hours post-application, then falls
• Correlates with clinical potency AND atrophy risk
• Basis of all major international potency scales

---

2.6 Indications with Evidence Grades

---

2.7 Side Effects

Local Side Effects

• Cutaneous atrophy (epidermal + dermal)
• Striae (inner arms, inner thighs - most vulnerable)
• Telangiectasia and purpura (loss of connective tissue support)
• Perioral/periorbital/periorificial dermatitis
• Acneiform/rosaceiform eruptions (face, upper trunk)
• Tachyphylaxis (controversial; not demonstrated in RCTs)
• Rebound on withdrawal (especially generalised pustular psoriasis after potent TCS withdrawal)
• Hypertrichosis
• Hypopigmentation (especially under occlusion or intralesional)
• Promotion of infections: tinea incognita, herpes simplex, Candida
• Impaired wound healing
• Contact allergy to steroid molecule (0.2-5% of patch-tested patients); key markers: tixocortol pivalate (Group 1) and budesonide (Group 2)

Systemic Side Effects (Rare)

• HPA axis suppression: >50 g/week of super-potent or >100 g/week of potent
• 8/40 subjects developed reversible adrenal suppression after 98 g of super-potent over 2 weeks
• Cushingoid features in children and infants
• Hypertension, hyperglycaemia
• Low birth weight with super-potent TCS in pregnancy (no congenital abnormality/preterm delivery association)
• Cataract, glaucoma (periorbital use)

---

2.8 Cross-Sensitisation Groups

Two patterns: cross-reactivity within Group 1 only, OR reactivity to all groups.

---

2.9 Practical Prescribing Principles

• Face/flexures: Use mild-moderate (Class 5-7) only; short courses
• Body/limbs (adults): Moderate to potent acceptable; limit duration
• Scalp: Use lotion, gel, foam, shampoo
• Palms/soles/lichenified plaques: Potent to super-potent acceptable
• Genitalia: Mild-moderate maximum (scrotum absorbs 42x more)
• Children: Go one class lower than for adults for same indication
• Frequency: Once daily is often as effective as twice daily for most agents
• Proactive maintenance: Twice-weekly potent TCS to previous sites reduces AD relapse (RCTs show no atrophy at 40 weeks)
• Occlusion: Greatly increases penetration; use for hyperkeratotic plaques; increases risk of side effects

---

---

PART 3: TOPICAL CALCINEURIN INHIBITORS (TCIs)

3.1 Mechanism of Action

Key advantage: Unlike corticosteroids, TCIs do NOT cause cutaneous atrophy, even with long-term use - safe for face, eyelids, flexures, genitalia.

---

3.2 Tacrolimus (Protopic)

• Macrolide lactam from Streptomyces tsukubaensis; MW 822 Da
• Licensed concentrations: 0.03% (children ≥2 years) and 0.1% (adults) ointment
• 0.03% nearly as effective as 0.1% in children; NOT equal in adults
• Efficacy comparable to mid-potency TCS in AD (multiple RCTs)
• Main side effect: Burning sensation (minutes after application) - substance P release + TRPV1 phosphorylation; resolves within days
• Systemic bioavailability: ~0.5% of IV route
• Effective for: AD, facial/flexural/intertriginous psoriasis, seborrhoeic dermatitis (Level A), oral lichen planus (Level A), vitiligo (Level B), chronic actinic dermatitis (Level B), and many off-label uses (see Table 18.8)

Netherton Syndrome Warning

---

3.3 Pimecrolimus (Elidel)

• Macrolactam, more lipophilic but less potent than tacrolimus
• Concentration: 1% cream
• Approved from 3 months of age in some countries
• Less effective than betamethasone valerate 0.1% but reduces steroid requirement
• Reduces AD flares in long-term studies
• Systemic exposure: usually undetectable
• Side effects: transient burning (less than tacrolimus), rare paradoxical rosacea
• No increase in infections or neoplasia after 2+ decades of clinical use

---

3.4 Black Box Warning and Safety

---

---

PART 4: TOPICAL RETINOIDS

4.1 Classification and Receptors

---

4.2 Mechanism of Action

---

4.3 Individual Agents

Tretinoin (All-Trans Retinoic Acid)

• First topical retinoid (>30 years of use)
• Concentrations: 0.01-0.1% (cream, gel, lotion, microsphere gel)
• Indications: Acne vulgaris (especially comedonal), photoageing (fine/coarse wrinkling, dyspigmentation), actinic keratoses (alone or + 5-FU), hyperpigmentation
• Application: Nighttime; alternate nights initially to build tolerance
• Key Study: 0.025% and 0.1% equally efficacious for acne but the former less irritating - irritation does NOT correlate with efficacy
• Side effects: erythema, peeling, photosensitivity, initial acne flare
• Contraindicated in pregnancy (despite low systemic absorption - precautionary)

Isotretinoin (13-cis Retinoic Acid) - Topical

• Less irritating than tretinoin but probably less effective
• Topical isotretinoin mainly inhibits comedogenesis; penetrates sebaceous glands
• Available as 0.05% gel; also as combination with erythromycin
• Does NOT suppress sebum production topically (unlike oral form)

Adapalene

• 3rd generation; selective RAR-β and RAR-γ agonist
• Highly lipophilic - enhanced follicular penetration
• Anti-inflammatory properties (unlike tretinoin)
• Less irritating than tretinoin 0.025% or isotretinoin 0.05% - best tolerability profile
• Available: 0.1% and 0.3% gel, 0.1% cream/lotion
• Combination with BPO 2.5% (Epiduo): more effective than either alone; faster onset; adapalene resists oxidation by BPO (unlike tretinoin - this is unique to adapalene)
• 0.3% adapalene + BPO 2.5%: helps prevent/reduce atrophic acne scars

Tazarotene

• Prodrug rapidly hydrolysed to tazarotenic acid
• Selective for RAR-α, β, γ; does NOT bind RXR; more stable (no isomerisation)
• Available: 0.05% and 0.1% gel/cream (Tazorac)
• Indications: Psoriasis, acne vulgaris, photoageing
• Most irritating of topical retinoids; lotion < cream for irritation
• For psoriasis (0.1% gel): 65% of patients show ≥50% improvement at 12 weeks
• Rare side effects: severe genital ulceration, pyogenic granuloma

Bexarotene (Targretin)

• Rexinoid - selective RXR agonist
• 1% gel approved by FDA for early (plaque-stage) mycosis fungoides
• Complete + partial response in 21% + 42% respectively

Trifarotene

• 4th generation; selective RAR-γ agonist
• Rapidly metabolised in hepatic microsomes (safer systemic profile)
• Developed for truncal acne
• Less burning, redness, peeling than earlier retinoids

---

---

PART 5: VITAMIN D ANALOGUES (DELTANOIDS/SECOSTEROIDS)

5.1 Mechanism

• Reduces keratinocyte proliferation
• Promotes normal keratinocyte differentiation (increases K1, K10, involucrin, transglutaminase, loricrin, filaggrin)
• Reduces IL-22-driven S100A7 upregulation in psoriatic skin
• Regulates barrier lipid (glycosylceramide) synthesis
• Modulates cutaneous immune balance
• Induces apoptosis

---

5.2 Individual Agents

Calcipotriol Safety Limits

• Maximum: 100 g/week (adults), equivalent to avoiding systemic hypercalcaemia risk
• Children from age 2 years: demonstrated safety
• Circumlesional scaling: pathognomonic marker of compliance (Figure 18.11 in Rook's) - a ring of scaling around treated psoriasis plaques

Combined Calcipotriol + Betamethasone Dipropionate (Daivobet/Taclonex)

• More effective than either alone for psoriasis
• Widely prescribed globally; however, long-term use associated with atrophy, rebound, tachyphylaxis

---

---

PART 6: EMOLLIENTS AND MOISTURISERS

Key Principles

• Fundamental component in any dry skin condition (atopic eczema, ichthyoses, psoriasis)
• Efficacy is NOT related to cost; IS related to compliance
• White soft paraffin (petrolatum) = most effective emollient; least cosmetically acceptable
• Aqueous cream BP: fallen out of favour as leave-on product due to irritant reactions (increases TEWL in experimental studies)
• Emollient-soaked clothing is a fire hazard (especially paraffin-based) - MHRA alert 2016

Types

• Ointments (most occlusive): best for very dry skin
• Creams: balance of cosmetic acceptability and efficacy
• Gels: excellent compliance for daytime use
• Bath oils: liquid paraffin base; reduce drying effect of bathing
• Soap substitutes: most emollients can be used this way; preferable to soap in atopic eczema

---

---

PART 7: TOPICAL ANTIBIOTICS

7.1 Summary Table

Key principle: Prefer antiseptics over topical antibiotics where possible to reduce resistance pressure. Avoid topical use of antibiotics important for systemic therapy (gentamicin, neomycin).

---

---

PART 8: TOPICAL ANTIFUNGALS

8.1 Classification and Mechanism

Other Antifungals

• Whitfield's ointment (6% benzoic acid + 3% salicylic acid in petrolatum): effective for tinea - fungistatic (benzoic acid) + keratolytic (salicylic acid); used in resource-limited settings
• Selenium sulphide 2.5%: effective for pityriasis versicolor (10 min daily for 7 days)
• Zinc pyrithione 1%: pityriasis versicolor (5 min daily for 14 days)
• Griseofulvin 1% spray: tinea pedis (OTC)
• Azelaic acid: antifungal + depigmenting properties

Steroid + antifungal combinations: controversial - may impair antifungal response; risk of masking infection; reserve for clearly infected, inflamed skin.

---

---

PART 9: TOPICAL ANTIVIRAL AGENTS

---

---

PART 10: TOPICAL ANTIPARASITICS (SCABICIDES/PEDICULICIDES)

---

---

PART 11: ASTRINGENTS AND ANTISEPTICS

Astringents

Antiseptics

---

---

PART 12: OTHER MAJOR TOPICAL AGENTS

12.1 Tars

• Coal tar: antipruritic, anti-inflammatory, antiproliferative
• Suppresses DNA synthesis in keratinocytes
• Available as shampoos, creams, bath additives, paste bandages
• Used for: psoriasis, atopic eczema, seborrhoeic dermatitis
• Caution: potentially carcinogenic (occupational exposure); not in pregnancy

12.2 Dithranol (Anthralin)

• Prepared in Lassar's paste: zinc oxide 24%, salicylic acid 2%, starch 24%, white soft paraffin 50%
• Inhibits keratinocyte proliferation; anti-inflammatory
• Used for: chronic plaque psoriasis
• Short-contact therapy: high concentration (1-3%) applied for 20-30 min; less staining
• Stains skin, fabrics, bathroom surfaces (brown)
• Pastes allow precise localisation, avoiding normal skin

12.3 Sunscreens

• Chemical (organic): absorb UV radiation (benzophenones, cinnamates, salicylates)
• Physical (inorganic): reflect/scatter UV (zinc oxide, titanium dioxide)
• SPF: measures protection against UVB
• PPD/PA system: measures protection against UVA
• Broad-spectrum = protection against both UVA and UVB
• SPF should be ≥30 for adequate protection; reapply every 2 hours

12.4 Depigmenting Agents

12.5 Cytotoxic/Antineoplastic Topical Agents

---

---

PART 13: NOVEL/NEWER TOPICAL AGENTS

---

---

PART 14: CLINICAL PEARLS

1. Scrotum absorbs 42x more than forearm - never use potent/superpotent TCS on genital skin; use mild-moderate only. (Feldmann & Maibach 1967, Rook's)
2. Tinea incognita: When a fungal infection is treated with a potent TCS, pruritus improves but infection spreads. The border becomes raised and papulopustular. Always exclude tinea before prescribing TCS. (Rook's Ch. 18)
3. Steroid phobia is as dangerous as steroid overuse: 21-83.7% of AD patients/carers have "steroid phobia" (systematic review) - leads to under-treatment and disease persistence. Address fears specifically. (Rook's Ch. 18; Dermatology 2-Volume Set 5e)
4. FTU is practical but variable: Nozzle size varies between manufacturers. Always clarify expected quantity. (Rook's Ch. 18, Long & Finlay 1991)
5. Fingertip rule for atrophy: 0.1% betamethasone valerate under occlusion for 3 weeks causes ~15% reduction in dermal thickness. Collagen synthesis is suppressed within 3 days and this inhibition persists for 2 weeks after stopping - even mild hydrocortisone suppresses collagen synthesis. (Rook's Ch. 18)
6. Twice-weekly proactive maintenance with mid-potency TCS to previously affected skin in AD markedly reduces relapse - no evidence of atrophy at 40 weeks in RCTs. (Dermatology 2-Volume Set 5e - Bologna)
7. Adapalene + BPO is the only stable retinoid + BPO combination: Adapalene's rigid structure resists oxidation by BPO (unlike tretinoin). (Fitzpatrick's Dermatology Table 185-2)
8. Circumlesional scaling around psoriasis plaques treated with vitamin D analogues is a reliable marker of compliance - almost as reliable as the staining from dithranol. (Rook's Ch. 18)
9. KMnO4 staining protection: Apply petroleum jelly to nails before soaking in potassium permanganate to prevent brown staining of nails. (Rook's Ch. 18)
10. Calcitriol 3 µg/g ointment is the vitamin D analogue with the least potential for irritation and is the one that can be safely used on the face for facial psoriasis. (Rook's Ch. 18)
11. Tacrolimus in Netherton syndrome: Despite being generally safe, tacrolimus can produce significant systemic absorption in Netherton syndrome due to severely compromised barrier. Use with caution. (Rook's Ch. 18)
12. Mupirocin covers MRSA but not Pseudomonas - Pseudomonas can actually overgrow when mupirocin is used. For Pseudomonas infections, use gentamicin, polymyxin B, or proflavine (especially for otitis externa). (Rook's Ch. 18)
13. Tachyphylaxis: real or myth? Clinically reported but not demonstrated in RCTs of AD or psoriasis. Intermittent disease activity is more likely to blame. However, biochemical evidence of decreasing vasoconstrictor response with repeated TCS application does exist. (Rook's Ch. 18)
14. Super-potent TCS limit: No more than 50 g/week (super-potent) or 100 g/week (potent) to avoid HPA axis suppression. (Rook's Ch. 18)
15. Pimecrolimus approved from 3 months - the youngest age for any calcineurin inhibitor. Tacrolimus 0.03% is approved for ≥2 years. (Rook's Ch. 18)
16. Aqueous cream BP as a leave-on emollient is now discouraged - it increases TEWL in experimental models and causes irritant reactions, especially in children with AD. Use it only as a soap substitute if at all. (Rook's Ch. 18)
17. Allergy to corticosteroids is often missed - the anti-inflammatory effect of the TCS mutes the delayed hypersensitivity response. Screen with tixocortol pivalate (Group 1) and budesonide (Group 2). (Rook's Ch. 18)
18. Dapsone 7.5% gel: particularly effective in female patients with mild-moderate acne. Excessive use (widespread truncal acne) risks methemoglobinaemia. (Rook's Ch. 18)
19. Salicylism risk: 6% salicylic acid applied twice daily to 40% BSA can cause systemic toxicity; at least 4 deaths reported. Risk even higher in infants with thinner skin and higher BSA:weight ratio. (Rook's Ch. 18)
20. Emollients can be a fire hazard: Paraffin-based emollients soaked into clothing or dressings + naked flame = fire. MHRA UK alert 2016. Counsel patients explicitly. (Rook's Ch. 18)

---

---

PART 15: VIVA QUESTIONS AND ANSWERS

---

---

PART 16: QUIZ - QUESTIONS AND ANSWERS

---

---

SOURCES

1. Rook's Textbook of Dermatology, 10th Edition (2024) - Chapter 18: Principles of Topical Therapy (Buckley DA) - Primary source. All major sections of this note.
2. Fitzpatrick's Dermatology, 9th Edition - Volumes 1 & 2 (9780071837781) - Topical corticosteroids (block 14), Topical retinoids (block 29), Topical calcineurin inhibitors (block 4)
3. Dermatology 2-Volume Set, 5th Edition (Bologna et al.) (9780702082252) - Topical corticosteroids (block 3), Topical retinoids (block 8), Vehicle/drug potency/bioavailability (block 27), Topical antifungals (block 28)
4. Andrews' Diseases of the Skin: Clinical Dermatology, 13th Ed. (9780323547536) - Topical calcineurin inhibitors (block 1), Topical corticosteroids in lichen sclerosus (block 3)
5. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 13th Ed. (9781264258079) - Glucocorticoid mechanisms, topical steroid use (block 20)
6. Lippincott Illustrated Reviews: Pharmacology (9781975170561) - Topical corticosteroids classification (block 5)
7. Feldmann RJ, Maibach HI (1967) - Regional variation in percutaneous penetration of 14C cortisol in man. Arch Dermatol 95:152-154. (Cited in Rook's Ch. 18, Table 18.4)
8. Long CC, Finlay AY (1991) - The finger-tip unit - a new practical measure. Clin Exp Dermatol 16(6):444-7. (Cited in Rook's Ch. 18)
9. Baeck M, Goossens A (2012) - Corticosteroid cross-sensitisation groups. (Cited in Rook's Ch. 18, Box 18.2)
10. Sidiropoulou P et al. (2024) - Topical calcineurin and mTOR inhibitors in inflammatory dermatoses: Current challenges and nanotechnology-based prospects. Int J Mol Med. [PMID: 39129316]
11. Ahuja K, An M, Lio P (2024) - A Brief Review of Vehicles for Topical Therapies. Skin Pharmacol Physiol. [PMID: 39265546]