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Alopecia: Comprehensive Review for PG Dermatology

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I. DEFINITION AND CLASSIFICATION

Non-Scarring (Non-Cicatricial) Alopecia

• Androgenetic Alopecia (AGA)
• Alopecia Areata (AA)
• Telogen Effluvium (TE)
• Anagen Effluvium
• Traction Alopecia
• Tinea Capitis
• Trichotillomania

Scarring (Cicatricial) Alopecia

• Dermatology 5e (Bolognia), p. 1404

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II. HAIR CYCLE - PHYSIOLOGICAL BASIS

• Anagen (growth): ~90% of scalp hairs; lasts 2-4 years
• Catagen (involution): 0.5-1% of follicles
• Telogen (resting/shedding): ~10% of follicles; lasts ~3 months
• Normal daily shedding: 50-200 hairs
• Total scalp hair follicles: ~100,000

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III. ANDROGENETIC ALOPECIA (AGA)

Pathogenesis

• Polygenic inheritance (polygenic, not simple Mendelian)
• The androgen receptor gene (AR) on the long arm of X chromosome (Xq11-12) is the major determinant in men
• AR-CAG polymorphism: fewer CAG repeats = greater androgen sensitivity = higher AGA risk and better finasteride response
• Men with the G allele of rs6152 have 70% lifetime risk; A allele = low risk
• Other genes: EDA2R (X-linked), WNT10A (bulge expression), APCDD1 (WNT inhibitor), CYP19A1, ESR2 (implicated in female AGA)
• Eunuchs do not develop baldness unless given androgen therapy
• In congenital 5-alpha-reductase type II deficiency, baldness does not occur

• Decrease in anagen/increase in telogen follicles
• Follicular miniaturization and anisotrichosis (variability in shaft diameter) - best seen on transverse sections
• Fibrous tract remnants ("streamers") below miniaturized follicles
• Many mast cells in fibrous tracts; inflammatory cells absent
• Stem cells preserved in bald scalp (progenitor cells are reduced - key finding)
• Fitzpatrick's Dermatology, Ch. 85 | Andrews', p. 872 | Dermatology 5e (Bolognia), p. 3158

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Clinical Patterns

Male Pattern Hair Loss - Hamilton-Norwood Classification

Female Pattern Hair Loss (FPHL) - Ludwig Classification

• Diffuse centroparietal thinning with preservation of the frontal hairline (distinguishes it from male pattern)
• Ludwig scale: 3-point; Sinclair scale: 5-point
• Christmas tree pattern: centroparietal thinning with additional breaching of the frontal hairline
• Role of androgens less certain in women; subset have associated hormonal dysregulation
• Associated genes: CYP19A1 and ESR2 polymorphisms
• Fitzpatrick's Dermatology, p. 1526

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Diagnosis of AGA

• Clinical: history + pattern examination; hair pull test
• Hair pull test (Sabouraud maneuver): Grasp 50-60 hairs; pull firmly. >10% pulled = positive (confirms active shedding). In AGA, positive frontally, negative occipitally.
• Dermoscopy/Trichoscopy: hair diameter variations, loss of trio-hair groups with single terminal hairs, increased vellus hairs, absent follicular ostia (excludes scarring alopecia)
• Biopsy rarely indicated; use if differential diagnosis includes cicatricial alopecia or diffuse AA
• Lab workup in women: ferritin, TSH; if hyperandrogenism signs - full endocrine workup

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Treatment of AGA

First-Line Medical Treatments

• Available as 2% and 5% solutions and 5% foam (both OTC)
• Promotes dermal papilla cell survival, prolongs anagen phase, enlarges shaft diameter
• Best results in: early cases (<10 years), limited extent (bald area <10 cm vertex), pretreatment density >20 hairs/cm²
• Must be used indefinitely to maintain response
• Note: initial telogen effluvium may occur (premature termination of telogen triggering new anagen)
• Low-dose oral minoxidil is also a recognized option (particularly for female AGA)

• Type 2, 5-alpha-reductase inhibitor
• Effective in men aged 18-41 with mild-to-moderate hair loss at vertex, anterior midscalp, and frontal region
• Stops hair loss in up to 90% of men for 5+ years; ~65% demonstrate hair regrowth
• Requires 6+ months for visible response; 12 months to assess failure
• Hair patterning on temples not improved
• Contraindicated in women who may become pregnant
• Long-term use required; regimens combining finasteride + minoxidil more effective than either alone

• Blocks both type 1 and type 2 5-alpha-reductase (broader than finasteride)
• Effective in male-pattern hair loss; also used in FFA

Emerging and Adjunct Treatments

Surgical Treatment

• Hair Transplantation: Follicular units of 1-4 hairs transplanted. Two major methods:
  • FUT (Follicular Unit Transplantation): elliptical donor strip harvesting
  • FUE (Follicular Unit Excision): individual follicle extraction (less invasive)
• Indicated for stable, non-progressive AGA with sufficient donor hair density
• Combination with finasteride 1mg +/- topical minoxidil recommended to reduce postoperative AGA progression
• First hair transplant procedure: 1950s (large punch autografts)
• Andrews', p. 872 | Fitzpatrick's Dermatology, p. 1533-34

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IV. ALOPECIA AREATA (AA)

Pathogenesis

• Loss of immune privilege of the hair follicle: HF normally expresses low MHC Class I/II antigens and produces immunosuppressive cytokines/neuropeptides
• CD8+ NKG2D+ cytotoxic T cells are primary effectors; CD4+ helper T cells promote, Treg cells (CD4+CD25+) suppress disease
• Key cytokines: IFN-gamma, IL-2, IL-15 (CD8+ T cell induction/persistence)
• JAK/STAT pathway is critical - JAK1/2 inhibition is therapeutic
• GWAS-identified associations: CTLA4, ICOS, IL21/IL2, IL2RA, NKG2D ligands, HLA-DR/DQ (dominant susceptibility locus)
• IL-15 neutralization attenuates disease in animal models

• Fitzpatrick's Dermatology, p. 229-230

Clinical Features

• Patchy AA (AAP): well-defined, smooth oval/round patches of hair loss; exclamation-mark hairs at periphery
• Alopecia Totalis (AT): entire scalp hair loss
• Alopecia Universalis (AU): entire scalp + body hair loss
• Nail changes: fine pitting, trachyonychia (20-nail dystrophy)
• Associated: thyroiditis, other autoimmune diseases
• Positive hair pull test at active margins

• Early/active disease ("swarm of bees"): peribulbar mononuclear cell infiltrate (lymphocytes + occasional eosinophils) around terminal anagen/catagen bulbs; exocytosis into bulbar epithelium; trichomalacia; pigment casts
• Chronic/stable disease: majority in catagen/telogen; diffuse miniaturization; numerous "nanogen" (rapidly cycling miniaturized) hairs; mild peribulbar infiltrate
• Dermatology 5e (Bolognia), p. 3052-73

Treatment of Alopecia Areata

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V. TELOGEN EFFLUVIUM (TE)

Types and Pathophysiology

1. Immediate anagen release (premature, sudden termination of anagen)
2. Delayed anagen release (post-pregnancy: prolonged anagen released simultaneously)
3. Short anagen syndrome (shortened anagen phase)
4. Immediate telogen release (prolonged telogen curtailed by systemic trigger)
5. Delayed telogen release (synchronization of telogen leading to massive shedding)

• Surgery, parturition, febrile illness, crash dieting, medications (heparin, retinoids, beta-blockers, carbamazepine, anticoagulants, hormonal contraceptives)
• Hypothyroidism, iron deficiency (low ferritin), zinc deficiency, protein malnutrition
• Lupus erythematosus, inflammatory scalp disorders, significant emotional stress
• SARS-CoV-2 infection (quarter of infected patients developed TE within 2 months)
• Note: Topical minoxidil initiation can cause transient TE (premature termination of telogen to initiate anagen)

• Idiopathic diffuse club hair loss in middle-aged women (4th-6th decade)
• Telogen shedding >6 months; fluctuating course
• Patients typically have denser-than-average hair before onset; marked bitemporal recession
• Positive pull test at both vertex AND occiput (distinguishes from AGA, which is frontal only)

• Normal total number of hairs
• Normal terminal (large) hair number
• Telogen count >20% (>15% is suggestive); rarely >50%; >80% inconsistent with TE
• No inflammation, no scarring

Diagnosis

• Hair pull test: >4-6 club hairs (with visible depigmented club-shaped bulb, no sheath)
• Trichogram (50 hairs plucked with Kelly clamp): anagen:telogen ratio
• Lab: CBC, ferritin, TFTs, zinc, ANA
• Normal 100-150 hairs shed daily; TE: 150-400+ hairs/day

Treatment

• Identify and treat the underlying cause
• Reassurance (most acute TE resolves within 6 months)
• Nutritional supplementation if deficient (iron, zinc, biotin)
• Topical minoxidil if prolonged/chronic
• Treat concurrent scalp conditions (seborrheic dermatitis)

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VI. CICATRICIAL (SCARRING) ALOPECIAS - Key Entities

Lichen Planopilaris (LPP)

• Pathophysiology: Lymphocytic infiltrate targeting the infundibulo-isthmic (bulge) region - irreversible follicle destruction
• Demographics: Predominantly White women, 40-60 years
• Clinical: Progressive scalp pruritus/burning, perifollicular erythema and perifollicular scaling, small patches coalescing to larger areas of cicatricial alopecia; NO hair follicle openings
• Trichoscopy: Perifollicular scaling, absence of follicular openings
• Histology: Lymphocytic infiltrate at isthmus and infundibulum; fibrosis
• Treatment: Hydroxychloroquine (first-line systemic), intralesional/topical corticosteroids, cyclosporine, mycophenolate mofetil, pioglitazone (PPARgamma agonist)

Frontal Fibrosing Alopecia (FFA)

• Band-like frontotemporal recession with loss of eyebrows, perifollicular erythema and hyperkeratosis
• May have "lonely hairs" at the hairline margin, glabellar red follicular dots, facial papules
• May coexist with classic lichen planus or lichen planus pigmentosus
• Treatment: Similar to LPP; oral finasteride or dutasteride may be beneficial (reduces vellus hair follicle proportion, the primary target in FFA)

Graham Little-Piccardi-Lasseur Syndrome

Central Centrifugal Cicatricial Alopecia (CCCA)

• Demographics: Most commonly Black women; some patients have PADI3 mutations
• Slowly progressive, symmetric cicatricial alopecia centered on mid-scalp/vertex
• Treatment: Topical/intralesional corticosteroids, oral tetracyclines, adjuvant immunosuppressives

Folliculitis Decalvans (Neutrophilic)

• Recurrent pustules around follicles, progressive scarring; Staphylococcus aureus implicated
• Treatment: prolonged rifampicin + clindamycin combination; doxycycline

Dissecting Cellulitis of the Scalp (Neutrophilic)

• Deep follicular and perifollicular abscesses, sinuses, scarring alopecia; mainly Black men
• Part of follicular occlusion tetrad
• Treatment: isotretinoin; biologics (adalimumab) for refractory disease

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VII. TRACTION ALOPECIA

• Caused by chronic mechanical tension on the hair shaft (tight braiding, extensions, tight hairstyles)
• Initially reversible, becomes permanent if tension continues
• Marginal pattern (fronto-temporal) in braiding-related traction
• Treatment: Cease offending hairstyle; topical minoxidil in early stages

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VIII. CLINICAL APPROACH TO ALOPECIA

Key Historical Points

• Shedding (telogen effluvium) vs. reduced density only (miniaturization/AGA) vs. breakage
• Rate of onset, duration, pattern distribution
• Scalp symptoms: pruritus, burning, pain (active cicatricial)
• Precipitating events (surgery, fever, delivery, stress, medication changes)
• Family history; medications; nutritional status
• Signs of hyperandrogenism in women (acne, hirsutism, irregular menses)

Diagnostic Algorithm

Alopecia
├── Scarring (no follicular openings, fibrosis)
│   ├── Lymphocytic → LPP, FFA, DLE, CCCA
│   ├── Neutrophilic → Folliculitis decalvans, Dissecting cellulitis
│   └── Mixed → Acne keloidalis
└── Non-Scarring
    ├── Diffuse
    │   ├── With precipitant → Telogen Effluvium
    │   ├── Patterned → AGA
    │   └── Diffuse, no precipitant → Chronic TE / Diffuse AA
    └── Patchy
        ├── Smooth patches + exclamation hairs → Alopecia Areata
        ├── Broken hairs of varying length → Trichotillomania
        └── Scaling + inflammation → Tinea Capitis

Biopsy Guidelines

• 4mm punch biopsy at hair-bearing margin (guided by trichoscopy), extending into subcutaneous fat
• Two biopsies recommended: one for vertical sectioning, one for horizontal sectioning
• Do NOT biopsy the central scarred zone (only end-stage fibrosis will be seen)

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IX. SUMMARY TABLE: KEY DIFFERENTIALS

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• Lesion configurations (annular, targetoid, herpetiform, Koebner, sporotrichoid, Blaschkolinear, etc.)
• Surface topography terms (lichenoid, umbilicated, verrucous, pedunculated)
• Color significance guide
• 10 key clinical signs (Nikolsky, Auspitz, Darier's, Asboe-Hansen, etc.)
• Quick-reference summary table of all lesions

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Visual Dermatology Lesion Gallery

With Textbook Clinical Photographs

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PRIMARY LESIONS

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1. MACULE

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Diagnosis clue: Blue-gray color = dermal melanin location. Unilateral periorbital + scleral involvement = Nevus of Ota (oculodermal melanocytosis). Risk of glaucoma and melanoma.

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Diagnosis clue: Multiple discrete brown macules on sun-exposed face. Voriconazole (antifungal) causes photocarcinogenesis and lentigines - ask about azole use in transplant patients.

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Diagnosis clue: Axillary/inguinal freckling (Crowe's sign) = pathognomonic for NF1. Along with ≥6 café-au-lait macules (>5mm prepubertal, >15mm postpubertal) and Lisch nodules (iris hamartomas). NF1 diagnostic criteria require 2/7 features.

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2. PATCH

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Diagnosis clue: Chalk-white depigmented (not hypopigmented) patches with well-defined borders. Autoimmune destruction of melanocytes. Wood's lamp: chalk-white fluorescence. Associated with thyroiditis, DM, Addison's. Treatment: tacrolimus, NB-UVB, JAK inhibitors (ruxolitinib cream FDA approved).

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Diagnosis clue: Hypopigmented (NOT white) patch, present since birth, stable, irregular "moth-eaten" borders. Melanocytes present but functionally reduced. Wood's lamp: does NOT fluoresce chalk-white (unlike vitiligo). Does NOT repigment.

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3. PAPULE

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Diagnosis clue: Yellow papules with erythematous halo on extensor surfaces, buttocks. Sudden-onset = very high triglycerides (>1000 mg/dL). Associated with: diabetes, hypothyroidism, pancreatitis risk. Treat: triglyceride reduction (fibrates, dietary). Yellow skin color: xanthoma, jaundice, carotenemia.

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4. PLAQUE

Classic plaque examples on the ward:

• Psoriasis: Silver-white micaceous scale on erythematous plaques; Auspitz sign; extensor surfaces, scalp, nails
• Lichen simplex chronicus: Lichenified plaques from chronic rubbing; posterior neck, legs
• Mycosis fungoides: Indurated erythematous plaques (cutaneous T-cell lymphoma); "patch → plaque → tumour" progression
• Morphea: Indurated sclerotic plaque; palpable but not visibly elevated (lilac ring at active margin)
• Discoid LE: Follicular plugging, central atrophy, scarring with peripheral hyperpigmentation

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5. NODULE

Key nodule diagnoses:

• Erythema nodosum: Tender nodules on anterior shins = septal panniculitis; not ulcerating; causes: Strep, TB, sarcoid, IBD, OCP
• Lipoma: Soft, lobulated, compressible subcutaneous nodule; "slip sign" - slides under fingers
• Dermatofibroma: Firm, indurated nodule; "dimple sign" (Fitzpatrick sign) on lateral pressure; lower leg, women
• Epidermoid cyst: Firm nodule, central punctum, cheesy malodorous contents
• Prurigo nodularis: Hyperkeratotic, crusted nodules from chronic picking; chronic pruritus

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6. VESICLE

Key vesicle diagnoses on the ward:

• Herpes zoster: Dermatomal grouped vesicles on erythematous base; unilateral; "zosteriform" distribution
• Herpes simplex: Grouped vesicles, recurrent at same site; fever, lymphadenopathy
• Varicella: "Dew drop on a rose petal" - vesicle on erythematous base, different stages simultaneously, centripetal
• Dyshidrotic eczema (pompholyx): Deep vesicles on palms/soles/lateral fingers; intensely pruritic; summer flare
• Dermatitis herpetiformis: Intensely pruritic vesicles on elbows/knees/buttocks; associated with celiac disease; anti-tTG IgA; granular IgA on DIF

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7. BULLA

Bulla identification flowchart:

Tense bulla (dome-shaped, difficult to break) → Subepidermal → Bullous pemphigoid

Flaccid bulla (collapses, breaks easily) → Intraepidermal → Pemphigus vulgaris

Feature	Bullous Pemphigoid	Pemphigus Vulgaris
Blister	Tense	Flaccid
Nikolsky	Negative	Positive
Mucosa	Rare	Early, prominent
Age	Elderly (>60)	Middle age
Level	Subepidermal	Intraepidermal (suprabasal)
Antigen	BP180, BP230	Desmoglein 3 (mucosal), Dsg1+3 (mucocutaneous)
DIF	Linear IgG+C3 at BMZ	Intercellular "chicken-wire" IgG

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8. PUSTULE

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This shows the maculopapular (morbilliform) variant. Note the generalized distribution, blanchable erythema, and confluent pattern. This is the most common drug eruption pattern (aminopenicillins, anticonvulsants, allopurinol).

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Pustule diagnoses:

• Follicular pustules: Acne vulgaris (comedones + inflammatory papules/pustules/nodules); folliculitis (Staphylococcus aureus - round pustules around follicle)
• Non-follicular sterile pustules: Pustular psoriasis (GPP - "lakes of pus" on erythematous skin + systemic toxicity; PPP - palmar/plantar); AGEP (acute onset, drug-induced, miliary pustules, fever, rapid resolution)
• Subcorneal pustular dermatosis (Sneddon-Wilkinson): Sterile pustules with hypopyon arrangement; trunk/flexures; older women
• IgA pemphigus: Flaccid pustules, annular configuration; IIF/DIF: intercellular IgA

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9. WHEAL

Wheal diagnoses:

• Acute urticaria: Duration <6 weeks; triggers: food (nuts, shellfish), drugs (NSAIDs, penicillin), infection (Strep); IgE-mediated
• Chronic spontaneous urticaria: Duration >6 weeks; no identifiable trigger in >50%; autoimmune (anti-FcεRI, anti-IgE) in ~40%; cyclosporine + omalizumab (anti-IgE) if antihistamines fail
• Dermographism: Linear wheals from stroking; "skin writing"; most common physical urticaria
• Cholinergic urticaria: Small (1-3mm) wheals triggered by heat/exercise/sweating; distinguish from exercise-induced anaphylaxis

REMEMBER: If individual lesion lasts >24h, it may be urticarial vasculitis - order C3/C4, ANA, biopsy (leukocytoclastic infiltrate).

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10. CYST

Cyst diagnoses:

• Epidermoid cyst: Most common; central punctum; cheesy malodorous keratin; face/neck/trunk; may rupture → foreign body granuloma
• Pilar (trichilemmal) cyst: Scalp, familial, may calcify; smoother wall, no granular layer on histology
• Milia: 1-2mm white keratin cysts; face; secondary = healed blisters (EB, PCT - dorsal hands + milia = classic PCT sign)
• Steatocystoma multiplex: Multiple cysts + oily contents; KRT17 mutation; overlaps with pachyonychia congenita

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SECONDARY LESIONS

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11. SCALE

Scale type → Diagnosis (high-yield for exams):

Scale character	Disease
Silver/micaceous	Psoriasis
Powdery/furfuraceous	Pityriasis (tinea) versicolor
Leading scale (outer edge)	Tinea corporis
Trailing scale (inner edge)	Erythema annulare centrifugum
Gritty	Actinic keratosis
Collarette (peripheral)	Pityriasis rosea (secondary lesions)
Greasy yellow	Seborrheic dermatitis
Fish-scale (adherent, limb flexors)	X-linked ichthyosis (steroid sulfatase deficiency)
Fine, white, generalized	Ichthyosis vulgaris (filaggrin mutation)
Oyster-shell/rupia crust	Crusted (Norwegian) scabies; tertiary syphilis

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12. CRUST

Crust color → Diagnosis:

Crust color	Contents	Disease
Honey-yellow	Serous + bacteria	Impetigo (Staph/Strep) - pathognomonic
Hemorrhagic	Blood	Herpes zoster/simplex resolving; vasculitis
Yellow-green	Pus	Secondary infected eczema
Oyster-shell (rupia)	Layered serous + hemorrhagic	Crusted scabies, tertiary syphilis
Meliceric	Honey-like	Bullous impetigo resolving
Black eschar	Necrotic	Anthrax, ecthyma gangrenosum, calciphylaxis

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13. EROSION

Key erosion diagnoses:

• Pemphigus vulgaris (oral erosions appear first; flaccid bullae break → painful erosions)
• Herpes simplex/zoster (vesicles rupture → erosions)
• Any blistering disease post-rupture
• Impetigo (primary = vesicle/bulla → erosion → honey crust)

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14. ULCER

Ulcer borders (clinical diagnosis):

Border	Disease
Violaceous, undermined, "ragged"	Pyoderma gangrenosum (pathergy +ve; IBD/RA association)
Punched-out, painless	Syphilitic chancre (primary syphilis, indurated, clean base)
Raised, rolled, pearly	BCC (rodent ulcer)
Raised, everted, necrotic	SCC
Sloping, irregular, shallow	Venous ulcer (gaiter area, lipodermatosclerosis)
Punched-out, exquisitely painful	Arterial ulcer (no pulses, pale, pulseless)
Painless, callus surrounding	Neuropathic ulcer (diabetes, leprosy)
Necrotic, rapid onset	Ecthyma gangrenosum (Pseudomonas, immunocompromised)

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15. LICHENIFICATION

• Lichen simplex chronicus: isolated; neck, lower leg, anogenital
• Atopic dermatitis: flexural lichenification (antecubital/popliteal fossae)
• Any chronic pruritic condition

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16. ATROPHY

• Striae distensae: Linear atrophic bands; early = violaceous (striae rubra); late = white (striae alba)
• Anetoderma: Focal dermal atrophy → skin "bulges outward" when pushed; macular atrophy
• Lichen sclerosus: Ivory-white atrophic plaques, anogenital; squamous cell carcinoma risk (~5%)
• Steroid atrophy: Thinning, telangiectasias, striae from prolonged topical steroid use

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SPECIAL LESIONS WITH CLINICAL IMAGES

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17. CONFIGURATION EXAMPLES

Lichen planus diagnosis: 4 P's = Pruritic, Polygonal, Purple (violaceous), Papules. On mucosa: reticular white striae (Wickham striae). Koebner phenomenon +ve. Nail involvement: pterygium (dorsal). Histology: "sawtooth" rete ridges, band-like lymphocytic infiltrate, colloid (Civatte) bodies, hypergranulosis.

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• Herpes zoster: Unilateral, dermatomal vesicles on erythematous base → "zosteriform"
• Dermatitis herpetiformis: Bilateral, extensor surfaces (elbows/knees/buttocks) → "herpetiform" grouping. Both have vesicles but completely different etiology and treatment.

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COMPLETE LESION QUICK-REFERENCE WITH DIAGNOSIS

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Posting tip: When you see a new lesion on the ward, immediately ask yourself: (1) Is it flat or raised? → Macule/Patch vs Papule/Plaque/Nodule. (2) Does it have fluid? → Clear fluid = vesicle/bulla; Pus = pustule; Edema = wheal. (3) Is there surface change? → Scale, crust, erosion, lichenification. (4) What is the configuration and distribution? This systematic approach narrows the differential rapidly.

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Antifungal Agents - Comprehensive Guide

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OVERVIEW: WHY ANTIFUNGALS ARE CHALLENGING

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CLASSIFICATION BY MECHANISM OF ACTION

ANTIFUNGAL DRUGS
│
├── CELL MEMBRANE (ergosterol binding)
│   └── Polyenes: Amphotericin B, Nystatin
│
├── ERGOSTEROL SYNTHESIS (inhibitors)
│   ├── Azoles (CYP51/14α-demethylase inhibitor)
│   │   ├── Imidazoles: Ketoconazole, Clotrimazole, Miconazole,
│   │   │              Econazole, Oxiconazole, Sertaconazole
│   │   └── Triazoles: Fluconazole, Itraconazole, Voriconazole,
│   │                  Posaconazole, Isavuconazole, Otesoconazole
│   ├── Allylamines (squalene epoxidase inhibitor)
│   │   └── Terbinafine, Naftifine, Butenafine
│   └── Others: Amorolfine (morpholine)
│
├── CELL WALL (β-glucan synthesis)
│   └── Echinocandins: Caspofungin, Micafungin, Anidulafungin
│
├── DNA/RNA SYNTHESIS
│   └── Pyrimidine analog: Flucytosine (5-FC)
│
└── MITOSIS (microtubule disruption)
    └── Griseofulvin

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CLASS 1: POLYENES

Amphotericin B

• Candidiasis, Cryptococcosis, Aspergillosis
• Histoplasmosis, Blastomycosis, Coccidioidomycosis
• Mucormycosis (Zygomycetes), Sporotrichosis

• Nephrotoxicity - most important and dose-limiting (renal tubular acidosis, hypokalemia, hypomagnesemia)
• Infusion-related reactions: fever, chills, rigors, headache, hypotension (premedicate with paracetamol, diphenhydramine, hydrocortisone)
• Anemia (reduced erythropoietin)
• Thrombophlebitis at infusion site
• Hypokalemia, hypomagnesemia (electrolyte monitoring essential)

• Empiric therapy in febrile neutropenia when unresponsive to antibacterials
• Severe/life-threatening invasive mycoses (when azoles not suitable)
• Mucormycosis (echinocandins NOT active)
• Cryptococcal meningitis induction (L-AmB + flucytosine × 2 weeks)

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Nystatin

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CLASS 2: AZOLES

Mechanism (All Azoles)

• Cyclosporine, tacrolimus, sirolimus → increased levels → toxicity
• Warfarin → increased anticoagulation
• Statins (simvastatin, lovastatin) → increased levels → myopathy
• Phenytoin, rifampicin → decreased azole levels
• Antacids, H2 blockers, PPIs → decreased ketoconazole/itraconazole absorption

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IMIDAZOLES (2 nitrogens in ring)

Ketoconazole

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Topical Imidazoles (all available OTC or Rx)

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TRIAZOLES (3 nitrogens in ring)

Fluconazole

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Itraconazole

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Voriconazole

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Posaconazole

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Isavuconazole (Isavuconazonium sulfate = prodrug)

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Otesoconazole (newest)

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CLASS 3: ALLYLAMINES

Terbinafine

• Onychomycosis toenail: 250 mg/day × 12 weeks
• Onychomycosis fingernail: 250 mg/day × 6 weeks
• Tinea capitis: 250 mg/day × 2-6 weeks (for Trichophyton spp.; less effective for Microsporum)
• Superficial tinea: 250 mg/day × 2 weeks (or topical 1-2 weeks)

Naftifine & Butenafine

• Topical allylamines
• Used for tinea pedis, tinea cruris, tinea corporis
• Naftifine: 1% cream/gel; Butenafine: 1% cream (classified as benzylamine - similar MOA)

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CLASS 4: ECHINOCANDINS

Caspofungin, Micafungin, Anidulafungin

• Preferred over fluconazole in critically ill/septic patients with candidiasis
• Activity in azole-resistant Candida (C. glabrata, C. krusei)
• Can be combined with voriconazole or L-AmB for refractory infections

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CLASS 5: PYRIMIDINE ANALOGUE

Flucytosine (5-FC, 5-Fluorocytosine)

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CLASS 6: GRISEOFULVIN

• Children: 10-20 mg/kg/day (microsize) or 5-10 mg/kg/day (ultramicrosize)
• Adults: 500 mg/day (microsize) or 330-375 mg/day (ultramicrosize)
• Tinea capitis: 6-12 weeks
• Tinea unguium (nails): 6-12 months (fingernails) or 12-18 months (toenails)

Key exam point: Griseofulvin remains drug of choice for tinea capitis caused by Microsporum spp. in children (terbinafine is preferred for Trichophyton spp. tinea capitis and is FDA approved from age 4).

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TOPICAL ANTIFUNGALS: ADDITIONAL AGENTS

Ciclopirox Olamine

• Unique mechanism: Chelates polyvalent metal cations (Fe3+, Al3+) → inhibits metal-dependent enzymes → disrupts multiple fungal pathways (cell membrane, mitochondria, DNA repair)
• Spectrum: Broad - dermatophytes, Candida, Malassezia; also anti-inflammatory and antibacterial
• Use: Tinea pedis/corporis/cruris/versicolor, onychomycosis (8% nail lacquer × 48 weeks), seborrheic dermatitis (1% shampoo)
• Nail lacquer: Apply daily × 1 week, clean with alcohol; repeat cycle × 48 weeks

Tolnaftate

• Mechanism: Inhibits squalene epoxidase (like allylamines)
• Use: Dermatophytes, Malassezia; NOT active against Candida
• OTC available; less effective than azoles or allylamines

Undecylenic Acid

• Antifungal fatty acid; OTC; mainly for athlete's foot

Amorolfine (morpholine)

• Topical nail lacquer; inhibits sterol synthesis at two sites (different from azoles)
• Used for onychomycosis; available in Europe/Asia

Tavaborole

• Boron-containing antifungal (inhibits leucyl-tRNA synthetase)
• Topical 5% solution for onychomycosis; applied daily × 48 weeks
• Advantage: smaller molecule → better nail penetration

Efinaconazole

• Triazole nail lacquer (10% solution)
• Applied daily × 48 weeks for onychomycosis
• Good nail plate penetration; low protein binding in nail

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DRUG RESISTANCE MECHANISMS

• C. krusei → inherently resistant to fluconazole
• C. glabrata → frequently acquired resistance to fluconazole
• C. auris → often multidrug resistant (fluconazole, amphotericin B)
• A. terreus → inherently resistant to amphotericin B
• Mucorales → resistant to echinocandins and voriconazole

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ANTIFUNGAL SELECTION BY INFECTION TYPE

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SUMMARY COMPARISON TABLE

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Hereditary Angioedema (HAE) - PG Dermatology Guide

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1. Overview and Historical Note

• NO urticaria or pruritus
• NO response to antihistamines, epinephrine, or corticosteroids
• Frequent GI involvement (can mimic surgical emergency)
• Laryngeal edema risk (main cause of mortality)
• Duration: 48-72 hours per attack, often followed by a refractory period

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2. Classification of HAE - Three Types

Type III is now further subdivided into HAE3-HAE8 based on the mutated gene - HAE3 (F12 mutation), HAE4 (PLG/plasminogen), HAE5 (ANGPT1/angiopoietin-1), HAE6 (KNG1/kininogen-1), HAE7 (MYOF/myoferlin), HAE8 (HS3ST6); a 7th subgroup with unknown mutation also exists.

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3. Genetics and Molecular Basis

• Expected level with one non-functional allele = 50% of normal
• Actual measured level = only 5-30% of normal (type I)
• Reason: trans-inhibition of the normal allele OR increased catabolism of C1-INH
• Rare homozygous autosomal recessive severe HAE also reported

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4. Biochemistry - The Kallikrein-Kinin System

4a. Normal Kinin Pathway

• Kallikreins - serine proteases existing in two forms:
  • Plasma kallikrein - activated by FXIIa (Hageman factor); cleaves HMW kininogen → bradykinin (9 amino acids)
  • Tissue kallikrein - cleaves LMW kininogen → kallidin (Lys-bradykinin, 10 amino acids)
• Kininogens - precursor proteins, synthesized in liver:
  • HMW kininogen - confined to bloodstream, substrate for plasma kallikrein
  • LMW kininogen - crosses capillary walls, substrate for tissue kallikrein
• Kinins - potent vasoactive peptides (half-life <15 seconds):
  • Bradykinin = predominant plasma kinin
  • Kallidin = major urinary form; can be converted to bradykinin by aminopeptidase
• Kinin degradation (kininases):
  • Kininase I (carboxypeptidase N) - removes C-terminal arginine from bradykinin
  • Kininase II = ACE (angiotensin-converting enzyme) - the same enzyme! Converts angiotensin I → angiotensin II AND inactivates bradykinin

Exam pearl: This is why ACE inhibitors cause bradykinin-mediated angioedema - they block kininase II, preventing bradykinin degradation.

4b. Bradykinin Receptor Pharmacology

4c. C1-INH and Its Substrates

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5. Pathophysiology of HAE - The Central Biochemical Loop

Trigger (trauma/surgery/estrogen/emotional stress)
         ↓
Factor XII (FXII) activation → FXIIa
         ↓
FXIIa activates Plasma prekallikrein → Plasma KALLIKREIN
         ↓
Kallikrein cleaves HMW kininogen → BRADYKININ ↑↑↑
                                                    ↓
               (C1-INH absent/dysfunctional - no brake!)
                                                    ↓
                           BRADYKININ → B2 receptor on endothelium
                                                    ↓
                                    NO + PGI2 + substance P
                                                    ↓
                          ↑↑ Vascular permeability → ANGIOEDEMA

Plasmin activates C1 → C1r, C1s active → C4 and C2 cleaved/consumed
         ↓
C4 perpetually LOW (even between attacks) ← DIAGNOSTIC HALLMARK
         ↓
C2 kinin also generated (contributes to swelling)

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6. Complement Profile - Diagnostic Biochemistry

Key diagnostic tip: In Type I/II HAE, C1q is NORMAL. In Acquired C1-INH deficiency, C1q is LOW (because anti-C1q antibodies or malignancy consumes C1q along with the whole C1 complex). This C1q level is what differentiates acquired from hereditary.

• Urinary histamine elevated
• Serum C1 levels elevated
• CH50, C4, C2 all decrease further

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7. Triggers of HAE Attacks

• Physical trauma (minor cuts, dental procedures)
• Surgery/intubation (major risk period)
• Emotional stress
• Estrogens - oral contraceptives, pregnancy (upregulate F12 transcription and bradykinin sensitivity)
• ACE inhibitors (compound the defect by reducing kininase II activity)
• Infections
• Sudden temperature changes
• Prodromal sign: some families develop a transient erythema marginatum-like rash before an attack (NOT urticaria)

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8. Clinical Features

• Onset usually before age 20 (2nd decade most common)
• Attacks last 48-72 hours (range: 2-5 days)
• Frequency: as often as every 2 weeks
• Between attacks: C4 always low, but patient is asymptomatic
• ABSENT: urticaria, pruritus, flushing, bronchospasm

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9. Diagnosis - Algorithm

Recurrent angioedema WITHOUT urticaria/pruritus
              ↓
Check C4 level
    ↓ LOW → Check C1-INH antigen + C1-INH function
              ↓
    C1-INH antigen LOW + function LOW → Type I HAE
    C1-INH antigen normal/HIGH + function LOW → Type II HAE
    C1q also LOW? → Acquired C1-INH deficiency
    ↓ NORMAL C4 → Check FXII mutation, PLG, KNG1, ANGPT1
              → Type III HAE (nC1-INH-HAE)

• Family history (AD pattern - 50% offspring affected)
• Age of onset (HAE typically <20 years; acquired typically >40 years)
• Response to treatment (HAE doesn't respond to antihistamines/steroids)
• SERPING1 genetic sequencing for confirmation
• In acquired form: look for lymphoproliferative disease, monoclonal gammopathy, SLE

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10. Treatment - Comprehensive Pharmacology

10a. Acute Attack Treatment

Epinephrine, antihistamines, corticosteroids - NOT effective (do NOT delay definitive treatment by using these)

10b. Short-term Prophylaxis (Before procedures: dental, endoscopy, surgery, intubation)

• C1-INH concentrate (most preferred, fastest acting)
• Danazol (attenuated androgen) - 2.5 mg/kg/day beginning 5-10 days before
• Tranexamic acid - antifibrinolytic; inhibits plasminogen → reduces C1 activation (see biochemistry diagram)

10c. Long-term Prophylaxis (Prevention of recurrent attacks)

Type III HAE does NOT respond to C1-INH replacement but may respond to danazol (which increases functional C1-INH) or progestin-only contraceptives (avoid combined OCP as estrogen worsens it).

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11. Drug Target Map - Tying Biochemistry to Pharmacology

C1-INH ← Replaced by: C1-INH concentrate (plasma-derived or recombinant)
       ← Upregulated by: Danazol, Stanozolol (attenuated androgens)

FXIIa ← Blocked by: Anti-FXIIa monoclonal antibodies (in development: garadacimab)
       ← Reduced substrate: Tranexamic acid (↓ plasmin → ↓ C1 activation → ↓ FXIIa)

Plasma Kallikrein ← Inhibited by:
                   - Ecallantide (recombinant kallikrein inhibitor, acute)
                   - Lanadelumab (anti-kallikrein MAb, prophylaxis)
                   - Berotralstat (oral kallikrein inhibitor, prophylaxis)

Bradykinin B2 receptor ← Blocked by:
                        - Icatibant (decapeptide B2 antagonist, acute)

Kininase II (= ACE) ← Inhibited by ACE inhibitors → ↑bradykinin [AVOID in HAE!]

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12. Acquired C1-INH Deficiency (Acquired Angioedema, AAE)

• Onset after 4th decade (no family history)
• Clinically identical to HAE
• No pruritus/urticaria

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13. ACE Inhibitor-Induced Angioedema (Bradykinin-mediated)

• ACE = Kininase II - normally degrades bradykinin
• ACE inhibitors block kininase II → bradykinin accumulates → B2 receptor activation → angioedema
• Incidence: ~0.1-0.7% of ACE inhibitor users; higher in Black patients and the elderly
• Usually orofacial - tongue and lip swelling predominant
• Can be life-threatening (laryngeal edema)
• Occurs anytime during treatment, even after years of tolerating the drug

• Stop ACE inhibitor immediately
• Icatibant or C1-INH concentrate (evidence is mixed but used in severe cases)
• Switch to ARB (angiotensin receptor blocker) if antihypertensive needed - ARBs do NOT affect bradykinin metabolism

Exam pearl: C4 is NORMAL in ACE inhibitor-induced angioedema (unlike HAE where C4 is always low)

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14. Summary Comparison - Angioedema Types

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• Dermatology 2-Volume Set 5e (Boliviana), Ch. 18 - p.376, Figs. 18.6
• Andrews' Diseases of the Skin, Ch. on HAE
• Harrison's Principles of Internal Medicine 22e (2025), Ch. 363
• Katzung's Basic and Clinical Pharmacology 16e, Ch. 17 (Kallikrein-Kinin system)
• Fitzpatrick's Dermatology 9e, Ch. 41
• Quick Compendium of Clinical Pathology 5e, §6.3.8.1
• Janeway's Immunobiology 10e