CHAPTER 25
PRINCIPLES OF DERMATOLOGY TREATMENT:
PHARMACOLOGIC AGENTS AND PHOTOTHERAPY IN DERMATITIS, ACNE AND OTHER COMMON SKIN DISEASES
I. Dermatopharmacology and Phototherapy
A. Corticosteroids（コルチコステロイド）
B. Antihistamines（抗ヒスタミン剤）
C. Retinoids（レチノイド）
D. Phototherapy（光線療法）
E. Antimicrobial Agents（抗生剤）
F. Antifungal Agents（抗真菌剤）
G. Others: Dapsone and Immuran, etc.
II. Dermatitis and Types of Topical Medications
A. Dermatitis
1. Allergic Contact Dermatitis (ACD)（アレルギー性接触皮膚炎）
a. Definition and pathogenesis -
antigen-specific, type IV, delayed-type hypersensitivity to environmental agents following direct contact with skin, e.g., poison ivy dermatitis. On initial contact requires 7-10 days, whereas re-exposure causes an inflammatory response within 48-72 hours.
b. Clinical features - itch is the cardinal symptom
acute contact - erythema, papules, vesicles or bullae
chronic contact - lichenification, scaling, fissuring
Note - the distribution and arrangement of the eruption are important clues to the diagnosis and identification of the offending allergen.
c. Common allergens
1) plants, poison ivy, poison oak
2) nickel - earrings, finger rings, metal clasps (e.g., at waist on pants), coins
3) dyes - e.g., para-phenylenediamine in hair dyes
4) rubber accelerators, e.g., in shoes, elasticized undergarments, bras, condoms, rubber gloves
5) potassium dichromate, e.g., in tanning of shoe leather, in cement
6) topical creams, cosmetics and toothpaste, e.g.,
a) vehicles: lanolin
b) preservatives: quaternium 15
c) fragrances: Balsam of Peru
d) flavoring: cinnamates, cloves
7) formaldehyde - paper products, rugs, shampoos, bleached clothing, new clothing
8) "caine" family of topical anesthetics, e.g., benzocaine
9) neomycin - topical antibiotic
10) adhesives, e.g., p-ter-butylphenol formaldehyde resin in shoes
d. Diagnosis - contact patch test
e. Therapy - avoidance, systemic and topical corticosteroids, antihistamines
2. Nummular Dermatitis（貨幣状皮膚炎）
Coin-shaped lesions usually less than 10 cm in diameter which occur on legs, arms, dorsum of hands and trunk, in order of decreasing frequency. The peak age is between 55 and 65 years. Edema and exudation characterize acute lesions, whereas scale and lichenification indicate chronicity. Itch is the dominant symptom. Pathogenesis is unknown, although dryness, irritants, frequent bathing and excessive sweating have been implicated.
3. ID Reaction (also called autosensitization dermatitis)（自家感作性皮膚炎）
ID reaction refers to a phenomenon whereby an acute eczematous dermatitis develops at cutaneous sites distant from an inflammatory focus. The ID reaction consists of very itchy, symmetrical, scattered, erythematous, maculopapular or papulovesicular patches/plaques.
4. Examples of Inciting Conditions:
a. stasis dermatitis（鬱滞性皮膚炎）
b. dermatophyte infections（皮膚糸状菌感染）, e.g., tinea pedis
c. bacterial infections - especially in skin folds, interdigital webs
d. bites, e.g., spider
The diagnosis is one of exclusion and therapy addresses symptomatic treatment of the ID reaction (systemic/topical corticosteroids, antihistamines) and correction of the inciting condition.
B. Types of Topical Medications
Principle of Topical Medication
In general, acute inflammation is treated with aqueous drying preparations and chronic inflammation is treated with greasier, more lubricating compounds, as noted in the following:
1. Open Wet Dressings
a. Cool and dry through evaporation
b. Cause vasoconstriction, decreasing the augmented local blood flow present in inflammation
c. Cleanses the skin of exudate, crusts, and debris, and helps maintain drainage of infected areas
d. Indicated in the therapy of acute inflammatory conditions, erosions, and ulcers.
2. Powders（粉末剤）
a. Promotes drying by increasing the effective skin surface area
b. Used primarily in intertriginous areas to reduce moisture, maceration and friction
3. Liquids（液体）
a. Lotions consisting of suspensions of a powder in water
b. Tinctures consisting of alcoholic or hydroalcoholic solutions
c. Sprays and aerosols leaving a uniform film of powder on the skin
4. Gels（ジェル）
a. Creams
Semisolid emulsions of oil in water (O/W)
b. Gels
A transparent and colorless semisolid emulsion that liquifies on contact with the skin, drying as a thin, greaseless, non-occlusive, nonstaining film
5. Ointments（軟膏）
a. Suspended in the continuous phase of oil (W/O) or of inert bases such as petrolatum
b. Three types: those soluble in water, those that will emulsify with water, and those completely insoluble in water
6. Lubricants（滑剤）, Bases （基剤）and Protective Coverings（被覆保膜剤）
a. Oil-in-Water Emulsion
Water-washable ("vanishing cream"), cosmetically pleasing
b. Water-in-Oil Emulsions
Better lubricants than oil-in-water creams, retain heat, impede water loss, increase hydration, and may thereby encourage percutaneous absorption. Not used in oozing or infected areas.
c. Lotions, Sprays and O/W Emulsions
Applied to hirsute areas and scalp
III. Acne and Topical Antimicrobial Agents
A. Acne（ざ瘡）
1. Definition of Acne
a. A polyetiological disease of the skin areas rich in sebaceous follicles.
b. Characterized by seborrhea, disturbed keratinization in the follicles with the formation of comedones and subsequent inflammatory reactions, i.e., papules, pustules, and nodular abscesses and scars.
2. Pathogenesis of Acne
Possible pathogenic factors of acne:
a. Inheritance; autosomal dominant inheritance assumed.
b. Sebaceous glands and sebum of acne; the quantity and quality of the sebum (e.g., free fatty acids) secreted by the sebaceous glands is the most important factor of acne. Free fatty acids act as comedogenic compounds, that are responsible for hyperkeratosis required for the comedone production and toxic substances, favouring the conversion of comedones to papules and pustules by rupture of comedo epithelium.
c. Bacteria, fungi and mites of acne; Propionibacterium acnes (formally Corynebacterium acnes; type I), Propinobacterium granulosum (type II) and Propionibacetium pavum (type III) produce lipases, protease and hyaluronidase primarily responsible for the quality of lipids (e.g., free fatty acid formation), and chemotactic factors primarily for neutrophils.
d. Hormones; androgens, gonadotropins, corticosteroids and ACTH influence the sebum production.
e. Immunology; No primary abnormal immune reactions, but in severe acne patients, e.g., acne conglobata, reduced cellular immune response of the delayed type to various recall antigens.
3. Pathophysiology of Acne
Four major processes participate, including:
a. Sebum production (quantity and quality) in the lower portion of the infundibulum
b. Propionifacterium acnes
c. Altered keratinization of infundibular epidermis
d. Inflammation
4. Acne Lesions
a. Primary Non-Inflammatory Acne Lesions
1) Closed comedo（面ぽう） (whitehead): The continuous accumulation of corneocytes in the infundibulum forming spherical, milium-like comedo.
2) Open comedo (blackhead): Arise from closed comedo. The comedo plug consists of a very densely-packed set of closely adhering corneocytes, together with sebum and numerous propionibacterium acnes as well as staphylococci.
b. Secondary Inflammatory Acne Lesions
1) Papules and pustules
2) Indurated nodules
3) Nodular abscesses
4) Draining sinus
c. Post-Inflammatory Residual Scarring
1) Fistulated comedones
2) Cysts
3) Scars
5. Acne Varieties
a. Acne Comedonica（集簇性ざ瘡）
1) Acne grade I
2) Open and closed comedones
b. Acne Papulopustulosa（丘疹性膿胞性ざ瘡）
1) Acne grade II
2) Inflamed comedones are converted into papules and pustules
c. Acne Conglobata（集簇性ざ瘡）
1) Acne grade III
2) The most severe form
3) Affect males more often than females
4) Comedones, papules, pustules and hemorrhagic crusts
B. Topical Antimicrobial Agents
1. Erythromycin
a. Mechanism of Action
1) Bacteriostatic macroide antibiotic produced from Streptomyces erythreusl
2) Binds to the 50S ribosomal unit, inhibiting protein synthesis
3) Gram-positive organisms
b. Indications
1) Acne vulgaris: most effective grade II and III acne
2) Other infections: superficial pyogenic infections
c. Contraindications and Precautions
1) None to the mucous membranes
2) Cumulative irritant effect
3) Overgrowth of fungi and nonsusceptible organisms
d. Regimens
1) Available in 1.5% or 2% concentrations
2) Combination with benzoyl peroxide
e. Side effects
1) Ocular irritation and scaling
2) Allergic contact dermatitis (rare)
2. Clindamycin Phosphate
a. Mechanism of Action
1) Lincosamide that binds the 50S subunit of bacterial ribosomes
2) Effective against anaerobic and aerobic gram-positive organisms
b. Indications
1) Acne vulgaris: most effective to inflammatory acne
2) Superficial skin infections; perioral dermatitis, acne rosacea, folliculitis, etc.
c. Contraindications and Precautions
1) Contraindicated in patients with a history of regional enteritis, ulcerative colitis or antibiotic-associated colitis
2) None to the mucous membranes
3) Cautiously used in atopic dermatitis patients with thinned skin
4) Overgrowth of fungi and nonsusceptible organisms
d. Regimen
Available in 1% solution, lotion and gel forms
e. Side Effects
1) Skin dryness: the most common adverse reaction
2) Gram-negative folliculitis
3) Diarrhea, bloody diarrhea, and pseudomembraneous colitis
3. Gentamycin
a. Mechanism of Action
1) A bactericidal aminoglycoside that binds to the bacterial 30S ribosomal unit
2) Gram-positive organisms and some gram-negative organisms
b. Indications
1) Minor bacterial infections: folliculitis, furunculitis, ecthyma, impetigo, etc.
2) Secondary infected skin lesions: stasis ulcers, eczematous dermatitis
c. Contraindications and Precautions
1) Nephrotoxicity and ototoxicity
2) Emergence of resistant bacteria and fungi
3) Hypersensitivity reaction
4) Avoid using over large area
d. Regimen
Available in 0.1% cream or ointment (Garamycin)
e. Side Effects
1) Itching, redness, and swelling
2) Allergic contact dermatitis
IV. Antifungal Agents
A. Topical Antifungal Agents（外用抗真菌剤）
A topical antifungal, topical creams and lotions are often adequate therapy for fungal infections involving the skin. Infection of the hair or nails usually require systemic treatment.
1. Imidazoles
a. Mechanism of Action
Imidazoles are highly effective broad spectrum, fungistatic agents
b. Indications
1) Tinea corporis
2) Tinea pedis
3) Tinea manuum
4) Tinea cruris
5) Candidal infection
6) Tinea versicolor
c. Contraindications and Precautions
Only individuals known to be hypersensitive to any of the ingredients
d. Regimen
1) Miconazole nitrate 2% (Monistat-Derm cream and lotion, Micatin cream)
2) Clotrimazole 1% (Lotrimin cream and lotion, Mycelex cream and lotion)
3) Econazole nitrate 1% (Spectazol cream)
4) Ketoconazole 2% (Nizoral cream)
e. Side Effects
1) Burning and stinging
2) Contact dermatitis
B. Systemic Antifungal Agents（内服抗真菌剤）
1. Griseofulvin
a. Mechanism of Action
1) Derived from several species of Penicillin, including Pgiseofulvum
2) Fungistatic - not fungicidal - effect
3) The fungi are removed by the natural outward growth (effluvial current) of the stratum corneum, hair and nails
b. Indications
All dermatophyte infections
c. Contraindications and Precautions
1) Porphyria of all types and hepatocellular failure
2) Diminishes the anticoagulant effect of the warfarin-type anticoagulants
3) Not in pregnant women
4) Periodic monitoring of the complete blood count and blood chemistries, potential for causing hepatic and bone marrow toxicity
d. Regimen
1) Griseofulvin microsize (Fulvicin U/F, Grifulvin V, Grisactin)
2) Griseofulvin ultramicrosize (Fulvicin P/G, Gris-PEG, Grisactin Ultra)
3) Griseofulvin microsize suspension
e. Side Effects
1) Indigestion and headache
2) Leukopenia, drug eruptions, and photosensitivity
3) Alcohol ingestion causes tachycardia and flushing
4) Lupus erythematosus-like syndrome or exacerbation of lupus erythematosus
2. Ketoconazole
a. Mechanism of Action
1) Broad-spectrum oral antifungal agent with fungistatic action against candidal infections
2) Impairs the synthesis and functioning of fungal cell membranes
3) The fungi are removed by the natural outward growth (effluvial current) of the stratum corneum, hair and nails
b. Indications
1) Chronic mucocutaneous candidiasis
2) Deep fungal infections
3) Highly effective for tinea versicolor
4) Severe recalcitrant dermatophyte infections that have not responded to topical therapy or oral griseofulvin or when griseofulvin is not tolerated
c. Contraindications and Precautions
1) Individual who are hypersensitive to it
2) Use with caution in patients with hepatic disease and those taking multiple drugs
3) In pregnancy - unknown
d. Regimen
1) Adults: One 200 mg tablet daily
2) Children over 2 years of age: 3.3 mg/kg/QD
3) Children under 2 years of age: Safety and efficacy not established
e. Side Effects
1) Nausea, vomiting and gastrointestinal symptoms and pruritus
2) Hepatic toxicity
3) Headache, anaphylaxis, gynecomastia, impotence, chills and fever, photophobia, thrombocytopenia
V. Topical Corticosteroids（外用ステロイド剤）
A. Mechanism of Action
1. Anti-inflammatory and hepatic gluconeogenic effects
2. Antimitotic effect on epidermal cells
B. Indications
1. Acute and chronic inflammatory dermatosis (e.g., allergic contact dermatitis, atopic dermatitis)
2. Hyperproliferative disorders (e.g., psoriasis)
3. Infiltrative disorders (e.g., cutaneous sarcoidosis)
C. Contraindications and Precautions
1. Should be used with caution on areas of the body susceptible to local side effects (e.g., the face, eyelids or skin around the eyes, genitalia, and intertriginous skin folds)
2. Caution in any situation in which absorption of topical agents may be increased, leading to systemic side effects
D. Regimen
1. Schedule of application: "More" is not necessarily "better" with topical corticosteroids
2. Choice of vehicle for application
3. Choice of pharmacologic agent:
a. Low-, medium-, high-, and ultrahigh-potency agents are available
b. The more potent the agent, the greater the degree of vasoconstriction it will induce (see Table)
E. Side Effects
1. Local Side Effects（局所性副作用）
a. Atrophy
b. Striae, stellate pseudoscars
c. Telangiectasia, purpura, erythema
d. Hypopigmentation
e. Impaired wound healing
f. Exacerbation of cutaneous infections (e.g., scabies, pediculosis) and infestations (e.g., bacterial, dermatophyte)
g. Candida superinfection
h. Miliaria
i. Periorofacial dermatitis
j. Rosacea-like eruption
k. Acneiform eruption
2. Systemic Side Effects（全身性副作用）
May occur when systemic absorption is increased. Identical to those associated with systemic corticosteroid therapy:
a. Cardiovascular effects, Hypertension
b. Central nervous system effects: mood alterations, psychosis, pseudotumor cerebri
c. Endocrine effects: hypothalamic-pituitary-adrenal axis suppression: hirsutism, menstrual irregularities, truncal obesity, moon facies, buffalo hump
d. Gastrointestinal effects: peptic ulcer, pancreatitis
e. Hepatic effects: diabetes mellitus
f. Hematologic effects: lymphopenia, monocytopenia, neutrophilia
g. Immunologic effects: Opportunistic infections
h. Musculoskeletal effects: Osteoporosis, aseptic necrosis of femoral or humeral heads, myopathy
i. Ophthalmic effects: Glaucoma, cataracts (posterior subcapsular)
Renal effects: Sodium and fluid retention, hypokalemic alkalosis
VI. Systemic Retinoids
A. Mechanism of Action
1. Derivatives of retinol (vitamin A)
2. Only isotretinoin [13-cis-retinoic acid (Accutane)] and etretinate (Tegison) are available in the USA and Canada
3. Retinoids have a profound effect on epithelial differentiation, normally epidermal cell maturation, affect glycoprotein synthesis and have anti-inflammatory actions
4. Have the peculiar property of causing profound sebaceous gland atrophy
B. Indications
1. Isotretinoin: severe nodulocystic acne vulgaris
2. Etretinate: profound effects on psoriasis, especially the severe forms of exfoliative and pustular psoriasis, but little effect on acne vulgaris
3. Retinoids in combination with phototherapy: very effective in psoriasis
C. Contraindications and Precautions
1. Teratogenic effects
2. Lipid metabolism: they commonly cause elevation of serum triglyceride levels and less frequently increase serum cholesterol levels
D. Regimen
1. Acne vulgaris: Isotretinoin (Accutane): 1 mg/kg taken over 4-6 months to obtain remission (Not available in Japan)
2. Severe exfoliative or pustular psoriasis: etretinate 0.5 - 1 mg/kg/QD
E. Side Effects
1. Hepatotoxicity
2. Lipid abnormalities
3. Teratogenicity
4. Cheilitis
5. Dry skin
6. Dry eyes
7. Musculoskeletal problems; aches and pains around the joints
8. Headaches
VII. Phototherapy（光線療法）
A. UV-B Phototherapy
1. Mechanism of Action
a. Wavelengths 290-320 nm
b. In psoriasis, phototherapy corrects the accelerated rate of epidermal cell turnover by causing impaired cell division secondary to damage of DNA
c. Immunosuppressive effects
2. Indications
a. Acne vulgaris
b. Atopic dermatitis
c. Metabolic pruritus
d. Pityriasis rosea
e. Kyrle's disease
f. Reactive perforating collagenosis
g. Parapsoriasis
h. T-cell lymphoma
3. Contraindications and Precautions
a. Dosage should be continuously monitored (see Table)
b. Any history of photosensitivity
c. Medications that produce photosensitivity
d. Physical and mental stresses
e. Topical corticosteroids should be minimized
Initial Phototherapy Regimens for Various Skin Types
|
Skin Type |
UVB Dosage |
PUVA Dosage |
|
(Always burns, vitiligo) |
10 mJ |
0.5 J |
|
(Slight tanning) |
15 mJ |
1.0 J |
|
(Tans easily, dark complexion) |
20 mJ |
2.0 J |
|
(Light black skin) |
30 mJ |
2.5 J |
|
(Dark Black skin) |
50 mJ |
3.0 J |
4. Regimen
a. Pretreatment Assessment and Procedures
1) Skin type
2) Distribution of lesions: mammary glands, genitalia necessitates careful dosimetry, face should be shielded
b. Adjunctive Therapies
1) Topical agents; coal tar (Goeckerman regimen)
2) Systemic agents:
a) Methotrexate
b) Retinoids: highly effective in the therapy of psoriasis when combined with UVB
5. Side Effects and Drug Interactions
a. Acute side effects: phototoxicity (sunburn) and photoallergy
b. Chronic side effects: cutaneous carcinomas and accelerated skin aging
B. PUVA
1. Mechanism of Action
a. Psoralens plus ultraviolet A (320-400 nm)
b. 8-Methoxypsoralen intercalates between opposite pyrimidine bases and cross-links the strands of DNA when exposed to UVA light, preventing cell division
2. Indications
a. Psoriasis
b. Vitiligo
c. Atopic dermatitis
d. Lichen planus
e. Parapsoriasis
f. Mycosis fungoides
g. Graft-versus-host disease (GVH disease)
h. Mastocytosis
i. Scleromyxedema
j. Pruritus
k. Polymorphous light eruption
3. Contraindications and Precautions
a. Hepatotoxicity
b. Ocular toxicity: aphakia leads to increased penetration of the retina by UVA, cataracts
c. Autoimmune disorders: induce and increase antinuclear antibody production. Patients with a FANA titre of 1:160 or more should not be treated
d. Photosensitivity
4. Regimen
a. General considerations: doses are usually determined on an individual and directed by an experienced phototherapist
b. PUVA with oral psoralen
1) Indications
a) severe generalized psoriasis
b) vitiligo
c) severe widespread eczema
d) cutaneous T-cell eruption
e) polymorphous light eruption
f) actinic reticuloid
g) persistent light reactivity
2) Method
Oral 8-methoxypsoralen (Oxsoralen-Ultra) 0.6 mg/kg
3) PUVA with topical psoralen
a) Indications
i) localized vitiligo
ii) localized PUVA-sensitive dermatoses
b) Method: begin with 0.1% concentration
5. Side Effects
a. Nausea
b. Pruritus
c. Headache
d. Phototoxic reactions
e. Hyperpigmentation