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PharmModule5.pptxGeneral Principles: Drug Absorption Through the Skin
General Principles
Drugs can be applied to skin for two purposes
To directly treat disorders of the skin
Many skin diseases can be treated with topical pharmacological agents
Examples
Corticosteroids (e.g., atopic dermatitis, psoriasis)
Antibiotics (e.g., impetigo, acne vulgaris, acne rosacea)
Retinoids (e.g., acne vulgaris, psoriasis, cutaneous T-cell lymphoma)
Fluorouracil (e.g., actinic keratosis, superficial basal cell carcinoma)
To deliver drugs systemically
Many systemic diseases can be treated with active pharmacological agents topically
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Examples of Drugs Used Topically for Systemic Effects
| Drug | Indications | Examples (Product Name) |
| Clonidine | Hypertension | Catapress-TTS® |
| Estradiol | Menopausal symptoms | Estraderm® |
| Estradiol/levonorgestrel | Menopausal symptoms | Climara Pro® |
| Estradiol/norethidrone | Menopausal symptoms | Combipatch® |
| Ethinyl estradiol/norelgestromin | Contraception | Ortho Evra® |
| Fentanyl | Chronic pain | Duragesic, Ionsys® |
| Methylphenidate | ADHD | Daytrana® |
| Nicotine | Smoking cessation | Nicoderm®, Habitrol®, Prostep® |
| Nitroglycerin | Angina pectoris | Transderm-Nitro® |
| Oxybutinyl | Overactive bladder | Oxytrol® |
| Rivastigmine | Dementia | Exelon® |
| Rotigotine | Parkinson’s disease | Neupro® |
| Scopolamine | Motion Sickness | Transderm-Scop® |
| Selegiline | Major depressive disorder | Emsam® |
| Testosterone | Testosterone deficiency | Testoderm® |
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General Principles
Understanding basic principles of percutaneous drug absorption and metabolism are essential for their effective use
Selection of an appropriate agent requires consideration of the…
Areas of the body affected
State of the diseased skin
Concentration of the drug
Type of vehicle (e.g., ointment, cream, lotion)
Method of application, and
Duration of use that both maximizes efficacy and minimizes adverse side effects
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Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e. http://www.accessmedicine.com.
Percutaneous Drug Absorption
Occurs through the stratum corneum
Stratum Corneum
Comprised of "dead" (enucleated) epidermal cells
Consists of 50% ceramides, 35% cholesterol, and 15% free fatty acids
Dermis
Stratum Bassale
Stratum Granulosum
Stratum Spinosum
Stratum Corneum
Stratum Lucidum
Structure of the Epidermis
Living keratinocytes
Dead Keratinocytes those on the surface flake off
Dendritic cell
Melanocyte
Dividing keratinocyte (stem cell)
Tactile cell
Sensory nerve ending
YOUNG
OLD
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Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e. http://www.accessmedicine.com.
Percutaneous Drug Absorption
Occurs through the stratum corneum
Stratum Corneum
Major barrier to percutaneous drug absorption
Possesses multiple proteins and lipids that may reversibly or irreversibly bind drugs
Described as a brick wall-like structure, in which the corneocytes represent the “bricks”, embedding in a “mortar” of the intercellular lipids, interlinked by desmosomes that anchor the corneocytes together.
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Percutaneous Drug Absorption
The formulation* itself forms a reservoir from which the compound must be released
After application, formulations do not remain homogeneous over time
Evaporation
May mix with skin-surface lipids
May undergo changes in composition as excipients, drugs undergo absorption
Source: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. Fitzpatrick's Dermatology in General Medicine, 9; 2019.
*Formulation = dosage form in which the product is provided (cream, ointment, gel, solution, etc.)
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Percutaneous Drug Absorption
After release from the formulation, the drug then must
Penetrate the stratum corneum
Diffuse into/through the viable epidermis into the dermis (permeation)
Gain access to the systemic circulation through the vascular system (resorption)
The drug may also diffuse through the dermal and hypodermal layers to reach underlying tissues
Source: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. Fitzpatrick's Dermatology in General Medicine, 9; 2019.
*Formulation = dosage form in which the product is provided (cream, ointment, gel, solution, etc.)
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Percutaneous Drug Absorption
Source: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. Fitzpatrick's Dermatology in General Medicine, 9; 2019.
*Formulation = dosage form in which the product is provided (cream, ointment, gel, solution, etc.)
Within each compartment, the drug may
Diffuse along its concentration gradient
Bind to specific components, or
Be metabolized
The changes in composition may impact bioavailability of the active ingredients
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Percutaneous Drug Absorption
Source: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. Fitzpatrick's Dermatology in General Medicine, 9; 2019.
*Formulation = dosage form in which the product is provided (cream, ointment, gel, solution, etc.)
The stratum corneum can function as a reservoir* for drugs that will diffuse into the rest of skin even after topical application is discontinued
E.g. Duragesic® (transdermal fentanyl)
*Reservoir amount of an active ingredient that adheres to the skin surface and resides in the upper layers of the stratum corneum.
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Three Penetration Pathways Through the Stratum Corneum
Transappendageal route – through sweat ducts, hair follicles, associated sebaceous glands
Transepidermal routes – across the continuous stratum corneum
The intercellular lipid route
between the corneocytes (most
important route, in general)
The transcellular route through
the corneocytes and lipids
From: Vitorino C et al. Current Pharmaceut Design. 2015; 21:2698-2712.
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Drug Characteristics to Consider
Other Important Considerations When a Drug Is Applied to the Skin
How does the chemistry of the drug affect the penetration?
How does the vehicle affect the penetration?
How much of the drug penetrates the skin?
What are the intended pharmacological targets?
What host and genetic factors influence drug function in the skin?
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Attributes of the Drug
Physical / chemical
Molecular size
Molecular charge
Lipid solubility
Too hydrophilic
Unable to partition from the vehicle into the stratum corneum
Too lipophilic
Will be retained in intercellular stratum corneum lipids and will not partition to the more aqueous viable epidermis, thus limiting their skin permeation rate
Vitorino C et al. Overcoming the Skin Permeation Barrier: Challenges and Opportunities. Curr Pharmaceut Design. 2015; 21:2698-2712.
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Attributes of the Drug
Other*
High therapeutic potency
Deliverable dose ideally below 20 mg/day
Poor oral bioavailability
Short biological half-live
Not an irritant to the skin
Does not stimulate an immune reaction in the skin
Vitorino C et al. Overcoming the Skin Permeation Barrier: Challenges and Opportunities. Curr Pharmaceut Design. 2015; 21:2698-2712.
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The Vehicle
Vehicle – the “inactive” part of a topical preparation that brings a drug into contact with the skin; the “carrier”
The vehicle determines the rate at which the active ingredient is absorbed through the skin
Products are formulated to maximize drug bioavailability
Formulation can affect potency of product
Often has nonspecific, beneficial effects by possessing cooling, protective, emollient, occlusive, or astringent properties
Components of some bases may cause irritation or allergy
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Formulation Affects Potency Example: Topical Corticosteroids
| Drug | Brand Name | Strength | Potency Group |
| Desonide | DesOwen cream | 0.05 | Group VI |
| Desonide | DesOwen lotion | 0.05 | Group VI |
| Desonide | DesOwen ointment | 0.05 | Group V |
| Triamcinolone acetonide | Kenalog lotion | 0.1 | Group V |
| Triamcinolone acetonide | Kenalog cream | 0.1 | Group V |
| Triamcinolone acetonide | Kenalog ointment | 0.1 | Group IV |
Potency Groups: Group I > Group II> Group III > Group IV > Group V > Group VI > Group VII
Adapted from: Habif T. Topical therapy and topical corticosteroids. In: Clinical Dermatology. Sixth Ed. Elsevier Inc. 2016.
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| Physical Composition | Advantages | Disadvantages | |
| Solution | Two or more substances into homogenous clarity | Drying effect beneficial for acute phase (weeping) rashes | Can cause irritation |
| Gel | Water-soluble bases with water, propylene glycol, and/or PEGs | Drying effect beneficial for acute phase (weeping) rashes; can be applied to hairy areas | Can cause irritation |
| Cream | Oil-in-water emulsion (greater than 31% water.; the aqueous phase may comprise up to 80% of the formulation) | Provides lubrication, hydration; less greasy, spread easily on the skin, and provides a protective film of oil that remains on the skin as an emollient, while the slow evaporation of the water phase provides a cooling effect | |
| Lotion | A two-phase system consisting of a finely divided, insoluble drug dispersed into a liquid in a concentration of up to 20% | Provides lubrication, hydration; can be applied to hairy areas; easier to apply than creams/ointments; allows for uniform coating of affected area; useful for application to large surface areas | |
| Ointment | Semisolid; hydrocarbon-based, silicone-based, lanolin, water-in-oil emulsion; contains less than 25% water | Provides lubrication, hydration; most occlusive dosage form | Can cause irritation; Too occlusive for acute phase rashes; not for use in intertriginous areas |
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Variables That Determine Pharmacologic Response
Efficacy of a topically applied drug depends on its inherent potency
E.g., topical corticosteroids are effective because they are inherently potent and can exert clinically significant effects in spite of low absorption
Topical medicines generally have a poor total absorption and very slow rates of absorption
E.g., < 2% of a topically applied hydrocortisone is absorbed after a single application left on the skin for more than 1 day
Peak rates of absorption are reached up to 12–24 hours after application
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Variables That Determine Pharmacologic Response
Efficacy of a topically applied drug depends on its inherent potency
Low absorption does not necessarily translate into low efficacy
Efficacy of a topically applied drug also depends on its ability to penetrate skin
Factors affecting penetration include
Concentration of the medication
Absorption is by passive diffusion (driven by concentration gradient)
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Variables That Determine Pharmacologic Response
Factors affecting penetration include
Dosing schedule/frequency of application
Skin acts as a reservoir for many drugs
The “local half-life” may be long enough to permit once-daily application of drugs with short systemic half-lives
Frequency of application has little effect on increasing a topical drug's overall efficacy
Example: Once-daily application of corticosteroids appears to be just as effective as multiple applications in many conditions
Occlusion, including occlusiveness of the vehicle
Thickness and integrity of the stratum corneum
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Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e. http://www.accessmedicine.com.
Stratum Corneum Thickness: Regional Differences in Penetration
The stratum corneum thickness varies by site; thus, drug penetration will vary depending on body site
| Scrotum – 5 μm Eyelids Face Chest and back Upper arms and legs Lower arms and legs Dorsa of hands and feet Palmar and plantar skin– 400-600 μm Nails |
Key: Greatest penetration with number 1; less penetration with increasing numbers
INCREASING THICKNESS
INCREASING PENETRATION
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Regional Variation in the Percutaneous Penetration of Hydrocortisone
Hengge et al. J Am Acad Derm. 2006; 54:1-15.
%
300-fold
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Integrity of the Stratum Corneum
Any insult that removes water, lipids, or protein from the epidermis alters the integrity of this barrier and compromises its function
A hydrated stratum corneum allows more percutaneous absorption
Skin hydration is important
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Integrity of the Stratum Corneum
When the integrity of the stratum corneum is compromised (dermatological disease, injury, etc.), percutaneous absorption may be increased, which can cause systemic toxicity
Penetration is increased several-fold in the inflamed skin of atopic dermatitis
In severe exfoliative diseases (e.g., erythrodermic psoriasis), there appears to be little barrier to drug penetration
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Toxicity of Topically Applied Drugs
Local Effects
Irritation
Allergic reactions
Atrophy
Comedogenicity
Telangiectases
Pruritus
Stinging and pain
Uncommon
Cataracts
Increased intraocular pressure
Neoplasms
Ulcers
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Toxicity of Topically Applied Drugs
Systemic effects
End-organ toxicity (central nervous system, cardiac, renal, etc.)
Electrolyte abnormalities
Endocrine dysfunction
Teratogenicity
Carcinogenicity
Drug interactions
Anaphylactic shock
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Skin Metabolism
Skin contains a wide range of enzymatic activities, including phase I and phase II reactions, and a full complement of drug-metabolizing enzymes
Metabolic activity is found in
Skin-surface microorganisms
Appendages
Stratum corneum
Viable epidermis
Dermis
Skin Cell
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Skin Enzymes and Transporters
Many enzymes have genetically determined variants that may affect drug activity
Transporter proteins that influence influx (OATP) or efflux (MDR, P-glycoprotein) of certain drugs are also present in human keratinocytes
May influence bioavailability of topically administered drugs
Skin metabolism plays a role in determining the fate of a topically applied prodrugs and drugs
Extent of metabolism is normally modest, i.e., 2%–5% of the absorbed compounds
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Drug Targets in the Skin
Drugs may target enzymes or cells of any of the skin compartments (more precisely, structures/systems within those cells), including inflammatory cells not normally in present that compartment
In the clinical setting, the exact amount of drug entering or leaving the skin is not usually measured
The clinical endpoint (e.g., reduction in inflammation) usually is the desired effect
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Topical Corticosteroids
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Glucocorticoid Receptor
Glucocorticoid binding to its receptor relieves an inhibitory constraint on the transcription-stimulating activity of the protein
In the absence of hormone, the receptor is bound to hsp90, a protein that prevents normal folding into the active conformation of the receptor
From: Katzung BG, Trevor AJ. Basic & Clinical Pharmacology, 13th ed. www.accesspharmacy.com.
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Glucocorticoid Receptor
Glucocorticoid binding to its receptor relieves an inhibitory constraint on the transcription-stimulating activity of the protein
Binding of hormone triggers release of hsp90
This allows a change to functionally active conformations
The activated receptor initiates transcription of target genes
From: Katzung BG, Trevor AJ. Basic & Clinical Pharmacology, 13th ed. www.accesspharmacy.com.
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Topical Glucocorticoids
Anti-inflammatory effects
Inhibit the arachidonic acid cascade
Inhibit transcription factors involved in the activation of proinflammatory genes
Decrease the release of proinflammatory cytokines (e.g. IL-1α) from keratinocytes
Stabilization of lysosomal membranes of phagocytizing cells
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Topical Glucocorticoids
Immunosuppressive effects
Cause lymphocyte and monocyte apoptosis
Inhibit leukocyte migration to sites of inflammation
Inhibit phagocytosis
Interfere with the function of endothelial cells, granulocytes, mast cells, fibroblasts, and macrophages and other antigen-presenting cells
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Other Relevant Dermatological Effects
Vasoconstriction when applied directly to the skin
Inhibit natural vasodilators (histamine, bradykinins and prostaglandins); inhibit mast cell degranulation
Decreased capillary permeability
Reduce the amount of histamine released by basophils and mast cells
Decreased epidermal cell mitosis
Antimitotic effects may contribute to their efficacy in psoriasis and other dermatologic diseases associated with increased epidermal cell turnover
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Classifying Topical Corticosteroids*
Grouped into 7 classes (in order of decreasing potency)
| Group | Description |
| Group 1 | Super (Ultra) Potency; Megapotent |
| Group 2 | Upper High Potency |
| Group 3 | Lower High Potency |
| Group 4 | Moderate/Medium Potency |
| Group 5 | Lower Moderate/Medium Potency |
| Group 6 | Low Potency |
| Group 7 | Lowest Potency |
*For listing of products by group, see Table in Habif T, Clinical Dermatology, Sixth Edition. 2016, Elsevier Inc. Available online , Taubman Medical Library. https://www.clinicalkey.com/#!/content/book/3-s2.0-B9780323261838000370.
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Suggested Strength of Topical Steroids to Initiate Treatment*
* Stop treatment, change to less potent agent, or use intermittent treatment once inflammation is controlled.; †Use on the face may be justified.; ^Brief course to control inflammation.
| Groups I-II | Groups III-V | Groups VI-VII |
| Psoriasis | Atopic dermatitis | Mild dermatitis (face) |
| Lichen planus | Nummular eczema | Mild anal inflammation |
| Discoid lupus† | Stasis dermatitis | Mild intertrigo |
| Severe hand eczema | Seborrheic dermatitis | Dermatitis (eyelids; diaper area) |
| Hyperkeratotic eczema | Tinea^ | |
| Chapped feet | Scabies (after scabicide) | |
| Nummular eczema (severe) | Intertrigo^ | |
| Poison ivy (severe) | Severe dermatitis (face) | |
| Atopic dermatitis (resistant adult cases) | Anal inflammation (severe cases) |
Adapted from Habif T. Clinical Dermatology. Sixth Ed. 2016, Elsevier Inc.
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Topical Steroids: General Guidelines for Safe and Effective Use
Choose the lowest potency agent that will clear an eruption in the shortest period of time
High potency fluorinated corticosteroids are usually not indicated for children, elderly
The more potent the steroid, the shorter the duration of treatment should be
Group 1: 2-3 weeks (QD to BID), then 1 week of rest
Groups 2-7: Limit use to 2-6 weeks (BID). If adequate control is not achieved, stop treatment for 4-7 days, then begin another treatment course
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Topical Steroids: General Guidelines for Safe and Effective Use
For most dermatoses, a moderate potency agent used once or twice daily for 3 to 10 days is effective
Often used in 3-5 day bursts to gain control
Usually used for 2-4 weeks in moderate-to-severe AD
Following initial improvement
Decrease to one daily application of the steroid
Substitute bland moisturizer into the regimen once or twice daily
After stabilization, consider “proactive secondary prevention”
Applied TCS to previously active sites for 2 consecutive days/week
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Topical Steroids: General Guidelines for Safe and Effective Use: Occlusion
Increases hydration and temperature of the stratum corneum
Use of an impermeable film such as plastic wrap is an effective method of enhancing penetration, yielding a 10 to 100-fold increase in absorption
Best results obtained if the dressing remains in place for at least 2 hours
May promote infection, folliculitis, or miliaria
May lead to a more rapid appearance of the drug's adverse effects
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Topical Steroids: General Guidelines for Safe and Effective Use
High potency agents and some moderate potency agents may cause tachyphylaxis
Tachyphylaxis – a rapidly decreasing response to a drug or physiologically active agent after administration of a few doses
Does it frequently occur with topical steroids?
Side effects can occur and may be severe
Use only low potency agents on the face, genitalia and other intertriginous areas
Widespread dermatoses with minimal symptoms should be treated with low potency preparations
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Topical Steroid Side Effects
Atrophy of skin
May present as depressed, shiny, often wrinkled-appearing skin; increased transparency; appearance of striae; hypopigmentation
Often permanent, although degree of atrophy may improve if topical corticosteroids are discontinued as soon as cutaneous changes are noticed
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Topical Steroid Side Effects
Habif TP. Clinical Dermatology, 6th ed. St. Louis, MO. Mosby-Year Book, Inc. 2016.
2) Hengge UR, Ruzicka T, Schwarts RA, Cork MJ. J Am Acad Dermatol 2006;54:1-15.
Daily application of group II topical steroid to eyelids resulted in almost complete atrophy of the dermis. The lids bled spontaneously when touched. There was marked improvement in the atrophy 8 weeks after stopping the topical steroid.
Daily application for months of a group II topical steroid to the skin on the abdomen produced severe atrophy with telangiectasia.
Steroid atrophy under the foreskin. Application of the group V topical steroid under the foreskin each day for 8 weeks produced severe atrophy and prominent telangiectasia of the shaft of the penis. The foreskin acted like an occlusive dressing to greatly enhance penetration of the steroid. Bleeding occurred with the slightest trauma. There was marked improvement 3 weeks after the medication was stopped.
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Topical Steroid Side Effects
Telangectasias
Habif TP. Clinical Dermatology, 6th ed. St. Louis, MO. Mosby-Year Book, Inc. 2016.
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Topical Steroid Side Effects
Striae are permanent and irreversible
http://library.med.utah.edu/kw/derm/pages/detr_8.htm;Habif TP. Clinical Dermatology, 5th ed. St. Louis, MO. Mosby-Year Book, Inc. 2009; Habif TP. Clinical Dermatology, 6th ed. St. Louis, MO. Mosby-Year Book, Inc. 2016.
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Topical Steroid Side Effects
.
Steroid Acne
Steroid rosacea and perioral dermatitis
Purpura
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Topical Steroid Side Effects
Long-term use
*Use of hydrocortisone valerate 0.2% cream for 20 years
Red Skin Syndrome (Topical Steroid Withdrawal)*
Atrophic skin and white scarring, long with telangiectases after uncontrolled use of high potency steroids for 9 months.
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Topical Steroid Side Effects
Other Topical Effects
Rebound worsening of underlying dermatitis
Delayed wound healing
Masking infection or infestation
Dermatophyte
Bacterial infection
Scabies
Contact dermatitis
Impetiginized eczema with satellite pustules after treatment of exudative, infected eczema with a group V topical steroid.
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Topical Steroid Side Effects
Systemic Effects
Cataracts, glaucoma (periorbital use)
Hypertension
Cushing’s syndrome
Hyperglycemia
Other
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Topical Steroid Side Effects
HPA axis suppression
May cause acquired adrenal insufficiency
Corticosteroid-related Addison crises have caused death
HPA axis suppression often occurs with iatrogenic Cushing’s syndrome, especially in children
Recent case report and review of the literature* documented 43 cases exogenous Cushing’s syndrome
50% were children; most (86%) were infants with diaper dermatitis treated with super-potent agents (clobetasol or betamethasone).
Average time to recovery from HPA axis suppression– 3.5 months
2 infants died from severe disseminated cytomegalovirus infection
*Tempark T, et al. Endocrine 2010; 38:328–334.
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Eczematous Dermatitis: Basic Pathophysiology
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What is …
Dermatitis?
Inflammation of the skin
Eczema?
A type of inflammatory reaction of the skin
Final common expression of various disorders
Atopic dermatitis
Contact dermatitis
Seborrheic dermatitis
Chronic vesicular hand dermatitis (dyshidrotic eczema)
Nummular dermatitis
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Three Stages of Eczema
| Eczematous Inflammation | |||
| Stage | Primary and Secondary Lesions | Symptoms | Examples of Etiologies and Clinical Presentation |
| Acute | Papules, vesicles, bullae, intense erythema | Intense pruritus | Contact allergy (poison ivy), severe irritation, fungal infections |
| Subacute | Erythema, scale, fissuring, dry appearance, scalded appearance | Mild to moderate pruritus, pain, stinging, burning | Contact allergy, irritation, atopic dermatitis, fungal infections |
| Chronic | Thickened skin, skin lines accentuated (lichenified skin), excoriations, fissuring | Moderate to intense pruritus | Atopic dermatitis, habitual scratching |
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Complications of Eczema
Bacterial Infection
Staphylococcus aureus
Group A -hemolytic streptococci
Types of infections
Impetigo
Pyoderma
Osteomyelitis
Viral Infection
Herpes simplex
Antiviral therapy
Molluscum contagiosum
Psychological distress
Physical limitation
Pain, discomfort
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Eczematous Disorders
What is Atopic Dermatitis?
“A chronic, relapsing, noncontagious, pruritic inflammatory skin disease that occurs more commonly in children, but also affects many adults and has an age-specific typical morphology and distribution. It is often associated with elevated serum IgE levels and a personal or family history of allergic conditions such as allergic rhinoconjunctivitis, asthma, or food allergies.”*
*Boguniewicz M, et al. J Allergy Clin Immunol Pract. 2017; 65:1519-31.
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Atopic Dermatitis
Incidence: 7-24 individuals per 1000, > 2% of the population
Most common in children, affecting 20-30% of children 3-11 years of age
90% of AD patients develop first symptoms by age 5
Prevalence in adults, 7%-10%
Increasingly being recognized as a systemic disease
Signs of systemic inflammation, including systemic T-cell activation
Nonlesional skin shows extensive immune and barrier abnormalities
*Boguniewicz M, et al. J Allergy Clin Immunol Pract. 2017; 65:1519-31.
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The Pathogenesis of Atopic Dermatitis
Pathogenesis is multifactorial, arising from complex interplay between
Genetic factors
Environmental influences
Alterations in the cutaneous microbiota
Changes in both innate and adaptive immunity
Eyerich K, et al. Trends in Immunology. 2015; 36(12): 788-801.
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The Pathogenesis of Atopic Dermatitis
Hallmarks of AD are type 2 immunity and epidermal barrier impairment
“Inside to out” versus “outside to inside” hypotheses
Chronic eczema additionally shows a mixed immune response and epithelial remodeling (e.g., lichenification)
Eyerich K, et al. Trends in Immunology. 2015; 36(12): 788-801.
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The Microbiome and AD
Abnormalities in cutaneous microbial colonization plays an integral role in AD pathogenesis
Normal skin is colonized with diverse commensal bacteria
Augment skin defenses against infectious agents by producing antimicrobial peptides (defensins and cathelicidins) that modulate immunity against microbial pathogens directly and through immunostimulatory effects
Deficiencies in these antimicrobial peptides in AD patients are extensively documented
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The Microbiome and AD
Loss of cutaneous microbial diversity of commensal skin bacteria occurs during AD exacerbations
Lack of commensal skin bacteria contributes to abnormal proliferation of S. aureus
S. aureus colonization promotes development of AD in numerous ways, including disruption of barrier function and stimulating Th2-mediated immune responses
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Immune-mediated Abnormalities and AD
Excessive macrophage (Langerhans cells) function
Abnormal Th2 lymphocyte activation in skin
Imbalance of cytokines (e.g., IL-4, IL-13)
Excessive production of IgE
Excessive Eosinophilia
Mechanical injury
Lesions NOT due to antibody-antigen interaction, but to scratching and rubbing
“itch-scratch-itch” cycle
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Clinical Presentation
Onset: > 12 years
Involves flexor folds, face, neck, dorsum of hands and feet, upper arms, back
Thick, dry lesions; confluent papules; may have weeping, crusting
Adult
(> 12 years)
Onset: 4-10 years
Greater tendency toward chronicity, lichenification
Involves wrists, ankles, antecubital and popliteal fossae
Sometimes associated with asthma or allergic rhinitis
Onset: 2-6 months
Usually involves cheeks, forehead, scalp, then trunk and extremities
Pruritus, erythema, vesicles, papules, oozing and crusting are characteristic
Resolves in 50% by 2-3 years
Childhood
(2-12 Years)
Infantile
(Birth-2 Years)
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What is Contact Dermatitis?
An eczematous reaction that results from contact with an
Irritant (soaps/detergents, sunscreens, cosmetics, solvents, acids, etc)
Mechanism: irritants damage skin barrier function to cause a nonimmunologic eczematous response
Allergen (poison ivy, nickel, sunscreens, cosmetics, latex, etc)
Mechanism: delayed hypersensitivity reaction
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Clinical Presentation
Characteristic signs and symptoms
Hands commonly involved, but other areas can be affected (back, thighs, axilla, face, etc.)
Asymmetric lesions; sharply demarcated
Itching
Acute CD: erythema, local edema, vesicles; ulceration and necrosis can occur
Chronic CD: dry, thickened, fissured skin
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Drug Therapy of Eczematous Dermatis
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Assessing the Extent of the Rash
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Treatment Goals
Protect the affected area (acute stage)
Eliminate inflammation and other symptoms
Prevent or treat infection
For poison ivy/oak/sumac
Prevent accumulation of debris and complications of oozing/crusting
Restore integrity of stratum corneum
Stop self-inflicted damage during itching
Promote healing
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General Treatment Approaches
| Stage of Inflammation | Treatment |
| Acute | Cold wet compresses; topical, oral or intramuscular steroids; antihistamines (?); antibiotics |
| Subacute | Hydration/lubrication, topical steroids (with or without occlusion); antihistamines (?); antibiotics |
| Chronic | Hydration/lubrication, topical steroids (with or without occlusion); intralesional steroids; antihistamines (?); antibiotics |
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Stepwise Management of AD
Systemic Therapy
(e.g., CSA, Mycophenolate or UV therapy)
Mid Potency TCS or TCI*
Basic Treatment
Mid Potency TCS or TCI*
Basic Treatment
Low-Mid Potency TCS or TCI*
Basic Treatment
Basic Treatment
Skin hydration, emollients, avoidance of irritants, identification and addressing of specific trigger factors
Step 1
Step 2
Step 3
Step 4
INTENSITY OF DISEASE
Recalcitrant, severe AD
Moderate to severe AD
Mild to moderate AD
Dry skin only
*TCS = Topical Corticosteroids; TCI = Topical Calcineurin Inhibitor.
Adapted from Adkis CA, et al. J Allerg Clin Immunol. 2006; 118:152-69.
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Moisturizers and Emollients
Aquaphor Ointment
Vanicream
CeraVe Cream
Eucerin Cream
Crisco, Vegetable Shortening
Ceramide-rich Moisturizers
CeraVe
Ceratopic
TriCeram
EpiCream
Nonsteroidal Creams
FDA-approved as medical devices
Atopiclair, Pruclair
Mimyx, Prumyx
Glycyrrhetinic acid: antiinflammatory, antipruritic)
Vitis vinifera: antioxidant, antiprotease activity; protects against epidermial breakdown
Telmestine: antiprotease; inhibits other skin enzymes
Replenishes deficient fatty acids, restores barrier function to skin
71
Bacterial Colonization
Patients with AD tend to be colonized with S. aureus which can
Exacerbate or contribute to persistent skin inflammation
Increase risk for infection
Should antibiotics be used to eradicate colonization?
No clear evidence of benefit
Patients treated with antibiotics quickly recolonize
Treatment with TCS and TCIs reduces S. aureus colonization
Proactive therapy
For patients whose AD tends to relapse in the same location
After stabilization, TCS or TCI is applied to previously involved, but normal-appearing skin rather than waiting for another flare
72
Determining Response to Treatment
No validated biomarkers to monitor treatment response
No standard definition of treatment failure in AD
Types of treatment failure*
Inadequate clinical improvement
Failure to achieve stable long-term disease control
Failure to relieve impairment
Unacceptable adverse events
Treatment resistance - lack of response to therapeutic agents despite complete compliance to the prescribed regimen
*Boguniewicz M, et al. J Allergy Clin Immunol Pract. 2017; 65:1519-31.
73
Determining Response to Treatment
When to consider treatment failure
No specific time after initiation to demonstrate the efficacy of TCSs, given the range of potency and dosage forms.
Recent guidelines recommend* using TCSs for up to 4 weeks for active treatment and 2 to 3 times weekly for preventative treatment.
Acute treatment with potent TCSs reduces disease burden in as early as 3 days, with continual improvement over 3 weeks for moderate-to-severe AD
However, the need for consecutive daily TCS use for more than 4 weeks may not be a reasonable definition of treatment failure in many patients with AD, particularly those with severe disease who may need to apply TCSs daily to different lesions as long as necessary to maintain disease control
*Boguniewicz M, et al. J Allergy Clin Immunol Pract. 2017; 65:1519-31.
74
Choosing the Right Topical Steroid
Habif TP. Clinical Dermatology, 6th ed. St. Louis, MO. Mosby-Year Book, Inc. 2016.
Atopic Dermatitis Children
Atopic Dermatitis Adults
Eyelid Dermatitis, Diaper Dermatitis
I
Superpotent (Clobetasol)
II & III
(Diflorasone)
(Desoximetasone)
IV & V
Medium
(Triamcinolone)
(Hydrocortisone Valerate)
VI & VII
(Desonide)
(Hydrocortisone)
Revaluate if disease does not respond in 28 days
Avoid long-term continuous treatment in any area
Not for face, axillae, groin, or under breasts
Limit use to about 14 days
Psoriasis Hand Eczema
Warning Limitations
Diagnosis
Determine Potency
Not for face, axillae, groin, or under breasts
Limit use to about 21 days
Limit use in children to 7 - 21 days
Limit use in intertriginous areas
75
Choosing the Right Topical Steroid
Habif TP. Clinical Dermatology, 6th ed. St. Louis, MO. Mosby-Year Book, Inc. 2016.
Atopic Dermatitis Children
Eyelid Dermatitis, Diaper Dermatitis
IV & V
Medium
(Triamcinolone)
(Hydrocortisone Valerate)
Limit use in children to 7 – 12 days
Limit use in intertriginous areas
VI & VII
(Desonide)
(Hydrocortisone)
Revaluate if disease does not respond in 28 days
Avoid long-term continuous treatment in any area
76
Other Topical Treatment Alternatives for Atopic Dermatitis
Topical Calcineurin Inhibitors
Pimecrolimus - Elidel 1% Cream
Equivalent in effectiveness to low potency topical steroids (Groups VI, VII); less effective than moderately potent (Group III, IV) topical steroids
Useful for long-term maintenance to prevent flares in mild AD
May have benefit for treatment of face, intertriginous areas
77
Other Topical Treatment Alternatives for Atopic Dermatitis
Topical Calcineurin Inhibitors
Tacrolimus - Protopic 0.03%, 0.1% Ointment
More effective that low potency topical steroids (Groups VI, VII); equivalent to moderately potent topical steroids (Group V)
Useful for moderate-to-severe cases of AD
Both have steroid sparing effects when used at first appearance of erythema and/or pruritus
78
How Topical Calcineurin Inhibitors Work
TCIs bind to the macrophilin-12 receptor (MP-12) within the T-cell
This inhibits calcineurin (CaN), a calcium-dependent phosphatase required for T cells activation
Thus, these agents block the
inflammatory cascade produced
by pathologic T cells in the skin,
preventing synthesis of
proinflammatory cytokines and
T-cell proliferation
Am J Clin Dermatol. 2008; 9:233-234.
79
FDA Label Warnings
Potential cancer risk - based on information from animal studies, small series of case reports and knowledge of pharmacology
Topical Tacrolimus
Topical Pimecrolimus
http://druginserts.com/lib/rx/meds/protopic-2/page/2/; http://druginserts.com/lib/rx/meds/elidel-2/
80
Risks with TCIs?
A case-control study of 293,253 patients with AD found no increased risk of lymphoma with the use of TCIs.2
Short- and long-term studies including over 4000 infants <2 yr old3
Showed pimecrolimus effectively treats AD in infants, with sustained improvement with long-term intermittent use
Provided no evidence for systemic immunosuppression and did not support potential safety concerns
1) Fonacier L, Spergel J, Charlesworth EN, et al. J Allergy Clin Immunol. 2005;115:1249-1253. 2) Arellano FM, Wentworth CE, Arana A, et al. J Invest Dermatol. 2007; 127:808-816, 2007. 3) Luger T, et al. Pediatr Allergy Immunol. 2015;26:306-315.
81
Risks with TCIs?
A Joint Task Force of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology reviewed available data and concluded 1
“The risk/benefit ratios of tacrolimus ointment and pimecrolimus cream are similar to those of most conventional therapies for the treatment of chronic relapsing eczema”
1) Fonacier L, Spergel J, Charlesworth EN, et al. J Allergy Clin Immunol. 2005;115:1249-1253. 2) Arellano FM, Wentworth CE, Arana A, et al. J Invest Dermatol. 2007; 127:808-816, 2007. 3) Luger T, et al. Pediatr Allergy Immunol. 2015;26:306-315.
82
FDA Recommendations for Use of Calcineurin Inhibitors
Use only as second-line agents for short-term and intermittent treatment of atopic dermatitis in patients unresponsive to, or intolerant of other treatments
Avoid use in children < than 2 years of age
The effect on the developing immune system in infants and children is not known
Use only for short periods of time, not continuously
The long-term safety of these drugs is unknown
83
FDA Recommendations for Use of Calcineurin Inhibitors
Patients with a weakened or compromised immune system should not use topical pimecrolimus or tacrolimus
Use the minimum amount of pimecrolimus or tacrolimus needed to control the patient’s symptoms
84
Crisaborole (Eucrisa®)
Topical phosphodiesterase (PDE4) inhibitor
Phosphodiesterase - intracellular enzyme that degrades cAMP
Eczematous inflammation is characterized by elevated phosphodiesterase (specifically, PDE4) activity
AD: Atopic dermatitis; ATP: Adenosine triphosphate; cAMP: cyclic adenosine monophosphate; IFN-γ: Interferon gamma; IL: Interleukin; NFAT: Nuclear factor of activated T cells; NF-κB: Nuclear factor κB; PDE4: Phosphodiesterase 4; PKA-c/r: cAMP-dependent protein kinase catalytic subunits c and r; TNF-α: Tumor necrosis factor alpha. Zane LT, et al. Immunotherapy (2016) 8(8), 853–866.
85
Crisaborole (Eucrisa®)
Topical phosphodiesterase (PDE4) inhibitor
Increased PDE4 results in
’d cAMP metabolism (’d cAMP levels)
’d concentrations of inflammatory mediators
’d concentrations of ANTI-inflammatory mediators
An imbalance of T-cell activity characterized by excessive T-helper (Th-2) cells
AD: Atopic dermatitis; ATP: Adenosine triphosphate; cAMP: cyclic adenosine monophosphate; IFN-γ: Interferon gamma; IL: Interleukin; NFAT: Nuclear factor of activated T cells; NF-κB: Nuclear factor κB; PDE4: Phosphodiesterase 4; PKA-c/r: cAMP-dependent protein kinase catalytic subunits c and r; TNF-α: Tumor necrosis factor alpha. Zane LT, et al. Immunotherapy (2016) 8(8), 853–866.
86
Crisaborole (Eucrisa®)
Inhibition of PDE4 increases intracellular cAMP, which then activates protein kinase A (PKA)
Activation of PKA leads to improved regulatory control of cytokine production
’d cAMP metabolism (’d cAMP levels)
’d concentrations of ANTI-inflammatory mediators
’d concentrations of inflammatory mediators
’d inflammation
AD: Atopic dermatitis; ATP: Adenosine triphosphate; cAMP: cyclic adenosine monophosphate; IFN-γ: Interferon gamma; IL: Interleukin; NFAT: Nuclear factor of activated T cells; NF-κB: Nuclear factor κB; PDE4: Phosphodiesterase 4; PKA-c/r: cAMP-dependent protein kinase catalytic subunits c and r; TNF-α: Tumor necrosis factor alpha. Zane LT, et al. Immunotherapy (2016) 8(8), 853–866.
Crisaborole (Eucrisa®)
Approved for mild to moderate AD in mild to moderate atopic dermatitis in adult and pediatric patients 3 months of age and older
Dose: Apply twice daily to affected areas
Available as a topical ointment containing 2% crisaborole
Adverse Effects
Well-tolerated; just over 4% of study patients experienced application site burning or stinging
Hypersensitivity reactions, including contact urticaria, have occurred in < 1% of patients
*Paller AS, et al. J Am Acad Dermatol. 2016;75(3):494–503.
Ghandi N, et al. Nature Reviews Drug Discovery 15, 35–50.
Dupilumab (Dupixent)
A human monoclonal IgG4 antibody that blocks interleukin-4 (IL-4) and interleukin-13 (IL-13), cytokines known to play key roles in TH-2 helper cell inflammation that characterizes AD
89
Ghandi N, et al. Nature Reviews Drug Discovery 15, 35–50.
Dupilumab (Dupixent)
IL-4Rα forms two distinct receptor complexes to mediate the biological functions of IL-4 and IL-13
Type I receptors bind IL-4
Type II receptors are the primary receptors for IL-13 but also bind IL-4
90
Ghandi N, et al. Nature Reviews Drug Discovery 15, 35–50.
Dupilumab (Dupixent)
Dupilumab inhibits IL-4 and IL-13 cytokine-induced responses by binding to the IL-4Rα subunit of the receptor complexes
Inhibits release of proinflammatory cytokines, chemokines and IgE
91
Dupilumab (Dupixent)
Indication
For treatment of patients aged 6 years and older with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable
Can be used with or without TCS or TCIs
Continuing with or stopping concomitant topical treatments is at prescriber’s discretion based on patient’s condition
TCS should not be discontinued abruptly upon initiation with dupilumab , but gradually and under medical supervision, to avoid systemic withdrawal symptoms and/or unmasking of conditions previously suppressed by systemic effects of corticosteroids
Dupilumab (Dupixent)
Therapeutic Response
In clinical trials, itch reduction was rapid, occurring as early as Week 2 of treatment
Dosing
Adults
Initial dose: 600 mg (two 300 mg SC injections)
Maintenance dose: 300 mg given every other week
Children
| Body Weight | Initial Dose | Maintenance Dose |
| 5 to < 30 kg | 600 mg | 300 mg every 4 weeks |
| 30 to < 60 kg | 400 mg | 200 mg every other week |
| > 60 kg | 600 mg | 300 mg every other week |
Dupilumab (Dupixent)
Use in Pregnancy
Available data have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes
Human IgG antibodies are known to cross the placental barrier; therefore, dupilumab may be transmitted from the mother to the developing fetus
Lactation
No data on the presence of dupilumab in human milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk
The effects of local gastrointestinal exposure and limited systemic exposure to dupilumab on the breastfed infant are unknown
When to Refer – Atopic Dermatitis
Patients should be referred to a specialist under the following conditions
Diagnostic uncertainty
Poor compliance or over- or under-usage of topical steroid
Parental concern
Treatment failure with appropriate topical therapy regimen
Need to use potent topical steroid every day or every other day
Involvement of sites that are difficult to treat, e.g. face
Frequent infections
Poor sleep or excessive scratching
Psychological disturbance or marked deleterious effects of the disease on the child or family
95
Treatment of Contact Dermatitis
Similar to treatment of atopic dermatitis
Avoid further allergen exposure
Self-care: for mild cases
Alleviate pruritus: Calamine, counter-irritant lotions; hydrocortisone cream; sodium bicarbonate compresses or baths; Burow’s compresses, oatmeal baths, systemic antihistamines, topical corticosteroids
Avoid topical anesthetics, antihistamines, antibiotics
Moderate to severe
Medical evaluation; draining of bullae
Systemic corticosteroids
96
Non-Corticosteroid Therapies for Eczematous Dermatitis
Other Topical Treatment Alternatives for Atopic Dermatitis
Topical Calcineurin Inhibitors
Pimecrolimus - Elidel 1% Cream
Equivalent in effectiveness to low potency topical steroids (Groups VI, VII); less effective than moderately potent (Group III, IV) topical steroids
Useful for long-term maintenance to prevent flares in mild AD
May have benefit for treatment of face, intertriginous areas
98
Other Topical Treatment Alternatives for Atopic Dermatitis
Topical Calcineurin Inhibitors
Tacrolimus - Protopic 0.03%, 0.1% Ointment
More effective that low potency topical steroids (Groups VI, VII); equivalent to moderately potent topical steroids (Group V)
Useful for moderate-to-severe cases of AD
Both have steroid sparing effects when used at first appearance of erythema and/or pruritus
99
How Topical Calcineurin Inhibitors Work
TCIs bind to the macrophilin-12 receptor (MP-12) within the T-cell
This inhibits calcineurin (CaN), a calcium-dependent phosphatase required for T cells activation
Thus, these agents block the
inflammatory cascade produced
by pathologic T cells in the skin,
preventing synthesis of
proinflammatory cytokines and
T-cell proliferation
Am J Clin Dermatol. 2008; 9:233-234.
100
FDA Label Warnings
Potential cancer risk - based on information from animal studies, small series of case reports and knowledge of pharmacology
Topical Tacrolimus
Topical Pimecrolimus
http://druginserts.com/lib/rx/meds/protopic-2/page/2/; http://druginserts.com/lib/rx/meds/elidel-2/
101
Risks with TCIs?
A case-control study of 293,253 patients with AD found no increased risk of lymphoma with the use of TCIs.2
Short- and long-term studies including over 4000 infants <2 yr old3
Showed pimecrolimus effectively treats AD in infants, with sustained improvement with long-term intermittent use
Provided no evidence for systemic immunosuppression and did not support potential safety concerns
1) Fonacier L, Spergel J, Charlesworth EN, et al. J Allergy Clin Immunol. 2005;115:1249-1253. 2) Arellano FM, Wentworth CE, Arana A, et al. J Invest Dermatol. 2007; 127:808-816, 2007. 3) Luger T, et al. Pediatr Allergy Immunol. 2015;26:306-315.
102
Risks with TCIs?
A Joint Task Force of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology reviewed available data and concluded 1
“The risk/benefit ratios of tacrolimus ointment and pimecrolimus cream are similar to those of most conventional therapies for the treatment of chronic relapsing eczema”
1) Fonacier L, Spergel J, Charlesworth EN, et al. J Allergy Clin Immunol. 2005;115:1249-1253. 2) Arellano FM, Wentworth CE, Arana A, et al. J Invest Dermatol. 2007; 127:808-816, 2007. 3) Luger T, et al. Pediatr Allergy Immunol. 2015;26:306-315.
103
FDA Recommendations for Use of Calcineurin Inhibitors
Use only as second-line agents for short-term and intermittent treatment of atopic dermatitis in patients unresponsive to, or intolerant of other treatments
Avoid use in children < than 2 years of age
The effect on the developing immune system in infants and children is not known
Use only for short periods of time, not continuously
The long-term safety of these drugs is unknown
104
FDA Recommendations for Use of Calcineurin Inhibitors
Patients with a weakened or compromised immune system should not use topical pimecrolimus or tacrolimus
Use the minimum amount of pimecrolimus or tacrolimus needed to control the patient’s symptoms
105
Crisaborole (Eucrisa®)
Topical phosphodiesterase (PDE4) inhibitor
Phosphodiesterase - intracellular enzyme that degrades cAMP
Eczematous inflammation is characterized by elevated phosphodiesterase (specifically, PDE4) activity
AD: Atopic dermatitis; ATP: Adenosine triphosphate; cAMP: cyclic adenosine monophosphate; IFN-γ: Interferon gamma; IL: Interleukin; NFAT: Nuclear factor of activated T cells; NF-κB: Nuclear factor κB; PDE4: Phosphodiesterase 4; PKA-c/r: cAMP-dependent protein kinase catalytic subunits c and r; TNF-α: Tumor necrosis factor alpha. Zane LT, et al. Immunotherapy (2016) 8(8), 853–866.
106
Crisaborole (Eucrisa®)
Topical phosphodiesterase (PDE4) inhibitor
Increased PDE4 results in
’d cAMP metabolism (’d cAMP levels)
’d concentrations of inflammatory mediators
’d concentrations of ANTI-inflammatory mediators
An imbalance of T-cell activity characterized by excessive T-helper (Th-2) cells
AD: Atopic dermatitis; ATP: Adenosine triphosphate; cAMP: cyclic adenosine monophosphate; IFN-γ: Interferon gamma; IL: Interleukin; NFAT: Nuclear factor of activated T cells; NF-κB: Nuclear factor κB; PDE4: Phosphodiesterase 4; PKA-c/r: cAMP-dependent protein kinase catalytic subunits c and r; TNF-α: Tumor necrosis factor alpha. Zane LT, et al. Immunotherapy (2016) 8(8), 853–866.
107
Crisaborole (Eucrisa®)
Inhibition of PDE4 increases intracellular cAMP, which then activates protein kinase A (PKA)
Activation of PKA leads to improved regulatory control of cytokine production
’d cAMP metabolism (’d cAMP levels)
’d concentrations of ANTI-inflammatory mediators
’d concentrations of inflammatory mediators
’d inflammation
AD: Atopic dermatitis; ATP: Adenosine triphosphate; cAMP: cyclic adenosine monophosphate; IFN-γ: Interferon gamma; IL: Interleukin; NFAT: Nuclear factor of activated T cells; NF-κB: Nuclear factor κB; PDE4: Phosphodiesterase 4; PKA-c/r: cAMP-dependent protein kinase catalytic subunits c and r; TNF-α: Tumor necrosis factor alpha. Zane LT, et al. Immunotherapy (2016) 8(8), 853–866.
Crisaborole (Eucrisa®)
Approved for mild to moderate AD in mild to moderate atopic dermatitis in adult and pediatric patients 3 months of age and older
Dose: Apply twice daily to affected areas
Available as a topical ointment containing 2% crisaborole
Adverse Effects
Well-tolerated; just over 4% of study patients experienced application site burning or stinging
Hypersensitivity reactions, including contact urticaria, have occurred in < 1% of patients
*Paller AS, et al. J Am Acad Dermatol. 2016;75(3):494–503.
Ghandi N, et al. Nature Reviews Drug Discovery 15, 35–50.
Dupilumab (Dupixent)
A human monoclonal IgG4 antibody that blocks interleukin-4 (IL-4) and interleukin-13 (IL-13), cytokines known to play key roles in TH-2 helper cell inflammation that characterizes AD
110
Ghandi N, et al. Nature Reviews Drug Discovery 15, 35–50.
Dupilumab (Dupixent)
IL-4Rα forms two distinct receptor complexes to mediate the biological functions of IL-4 and IL-13
Type I receptors bind IL-4
Type II receptors are the primary receptors for IL-13 but also bind IL-4
111
Ghandi N, et al. Nature Reviews Drug Discovery 15, 35–50.
Dupilumab (Dupixent)
Dupilumab inhibits IL-4 and IL-13 cytokine-induced responses by binding to the IL-4Rα subunit of the receptor complexes
Inhibits release of proinflammatory cytokines, chemokines and IgE
112
Dupilumab (Dupixent)
Indication
For treatment of patients aged 6 years and older with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable
Can be used with or without TCS or TCIs
Continuing with or stopping concomitant topical treatments is at prescriber’s discretion based on patient’s condition
TCS should not be discontinued abruptly upon initiation with dupilumab , but gradually and under medical supervision, to avoid systemic withdrawal symptoms and/or unmasking of conditions previously suppressed by systemic effects of corticosteroids
Dupilumab (Dupixent)
Therapeutic Response
In clinical trials, itch reduction was rapid, occurring as early as Week 2 of treatment
Dosing
Adults
Initial dose: 600 mg (two 300 mg SC injections)
Maintenance dose: 300 mg given every other week
Children
| Body Weight | Initial Dose | Maintenance Dose |
| 5 to < 30 kg | 600 mg | 300 mg every 4 weeks |
| 30 to < 60 kg | 400 mg | 200 mg every other week |
| > 60 kg | 600 mg | 300 mg every other week |
Dupilumab (Dupixent)
Use in Pregnancy
Available data have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes
Human IgG antibodies are known to cross the placental barrier; therefore, dupilumab may be transmitted from the mother to the developing fetus
Lactation
No data on the presence of dupilumab in human milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk
The effects of local gastrointestinal exposure and limited systemic exposure to dupilumab on the breastfed infant are unknown
When to Refer – Atopic Dermatitis
Patients should be referred to a specialist under the following conditions
Diagnostic uncertainty
Poor compliance or over- or under-usage of topical steroid
Parental concern
Treatment failure with appropriate topical therapy regimen
Need to use potent topical steroid every day or every other day
Involvement of sites that are difficult to treat, e.g. face
Frequent infections
Poor sleep or excessive scratching
Psychological disturbance or marked deleterious effects of the disease on the child or family
116
Treatment of Contact Dermatitis
Similar to treatment of atopic dermatitis
Avoid further allergen exposure
Self-care: for mild cases
Alleviate pruritus: Calamine, counter-irritant lotions; hydrocortisone cream; sodium bicarbonate compresses or baths; Burow’s compresses, oatmeal baths, systemic antihistamines, topical corticosteroids
Avoid topical anesthetics, antihistamines, antibiotics
Moderate to severe
Medical evaluation; draining of bullae
Systemic corticosteroids
117
Drug Therapy for Minor Skin Infections – Topical Antibiotics
118
Causes of Minor Bacterial Skin Infections
| Primary Pyodermas* | Etiologic Agents |
| Impetigo | Staphylococcus aureus Group A -hemolytic streptococcus (S. pyogenes) |
| Folliculitis | S. Aureus Group A -hemolytic streptococcus Pseudomonas aeruginosa Candida, Pityrosporum ovale |
| Furuncles, carbuncles | S. aureus |
*pyoderma – any purulent skin infection
119
Topical Antibiotics
Used to
Treat superficial infections (pyodermas)
Prevent infections
Reduce nasal colonization
Management of acne vulgaris, acne rosacea, and other noninfectious disorders
Selection of a particular antibiotic depends on diagnosis and, when appropriate, culture and sensitivity results
120
Topical Antibiotics
Most infected dermatoses due to S. aureus or Group A beta hemolytic streptococcus
Pathogens causing surgical infections may be those resident in the environment
Local resistance patterns are important
121
Impetigo - Clinical Presentation
impetigo
Small vesicles
Blisters
Crusting
From: http://home.teleport.com/~bobh/impetigo.htm and http://www.vh.org/Providers/Lectures/PietteDermatology/BlackTray/24Impetigo.html.
122
Nonbullous Impetigo
123
Bullous Impetigo
124
Treatment Options
Topical Antibiotics
Advantages
Limited systemic exposure
High concentration of drug infection site
Fewer ADEs
Greater patient adherence
Indicated for
Uncomplicated superficial skin infection
Limited localized lesions*
< 10 lesions over < 100 cm2, or
< 2% BSA as a “rule of thumb”
*Parameters used in clinical studies
125
Treatment Options
Systemic Antibiotics
Indicated if
Topical therapy is inadequate, for example
Multiple sites of infection or Lack of adequate response to topical therapy
Impetigo is widespread
Systemic signs or symptoms of infection are present
126
Bacitracin
Active against gram positive organisms
Used mainly for prophylaxis
MOA
Inhibits cell-wall synthesis by preventing the incorporation of amino acids and nucleotides into the cell wall
Used alone or in combination with neomycin, polymixin B
Not absorbed from intact or denuded skin, wounds, or mucous membranes
Can cause allergic contact dermatitis, anaphylactoid reactions (rarely)
127
Gramicidin
Active against gram positive organisms
Used mainly for prophylaxis
MOA
Binds to/inserts into cell bacterial membranes disrupting their permeability and function
Used only in combination with other antimicrobial agents (neomycin, bacitracin, polymixin B, nystatin, etc.)
Not significantly absorbed
128
Mupirocin
Active against gram positive aerobic bacteria, including MRSA
MOA: Inhibits RNA synthetase, which inhibits protein synthesis
Indications
Impetigo and superficial skin infections in patients > 2 months
To eliminate nasal colonization of S. aureus
Not appreciably absorbed systemically after topical application
Adverse effects
Local irritation; rarely, systemic effects (nausea, dizziness, abdominal pain)
129
Retapamulin
Active against S. aureus (methicillin-susceptible strains only) and Group A beta hemolytic streptococcus
MOA
Inhibits protein synthesis by binding to the 50S subunit of bacterial ribosome
Indications
Impetigo in patients > 9 months
Systemic bioavailability is low following application to intact or abraded skin
Adverse effects
Local irritation, headache, nausea, diarrhea
130
Aminoglycosides
Active against gram negative organisms, including E. coli, proteus spp., klebsiella spp., and enterobacter spp.
Neomycin
Indications: Prevent or treat minor skin infections
Not appreciably absorbed topically
Frequently causes allergic contact dermatitis
Gentamicin
Indication: Minor skin infections
Can produce serum levels of 1–18 mcg/mL if applied in a water-miscible preparation to large areas of denuded skin (e.g., burn patient)
Can cause nephrotoxicity, ototoxicity
131
Polymixin B
Active against gram negative organisms, including E. coli, proteus spp., klebsiella spp., and enterobacter spp.
MOA
Interacts with the lipopolysaccharide of the cytoplasmic membrane to alter membrane permeability and causing cell death
Indications: Used only in combination with other antimicrobials to treat or prevent minor skin infections
Poorly absorbed topically
However, total daily dose applied to denuded skin or open wounds should not exceed 200 mg to reduce likelihood of neurotoxicity, nephrotoxicity
132
Drug Therapy for Minor Skin Infections –Topical Antifungals
133
Causes of Minor Fungal Skin Infections
Dermatophytes
Common organisms
Microsporum spp.
Trichophyton spp.
Epidermophyton spp.
Infect stratum corneum
Pityrosporum orbiculare
Pityrosporum ovale
Candida (usually albicans)
134
| Tinea Infections and Their Causative Organisms | ||
| Disease | Site of Infection | Causative Organism |
| Tinea capitis | Scalp | Trichophyton tonsurans, Microsporum audouinii, Microsporum canis, Trichophytan verrucosum, Midrosporum gypseum |
| Tinea corporis | Arms, legs, torso | Trichophyton rubrum, Microsporum canis, Trichophyton mentagrophytes, Epidermophyton floccosum |
| Tinea cruris | Genitocrural folds | |
| Tinea pedis | Feet | |
| Tinea versicolor | Skin | Pityrosporum obiculare or P. ovale |
| Cutaneous | Skin, mucous | Candida spp. |
135
Treatment Goals
Provide symptomatic relief
Eradicate existing infection
Prevent complications
Prevent future infection
136
Medical Evaluation/Treatment Needed
Self-care is contraindicated in the following conditions
Involvement of oral mucosa, face, scalp or nails
Diabetes, systemic infection or immune deficiency
No improvement after 1-2 weeks of self-care with OTC antifungal treatment
Severe symptoms
Excessive or continuous exudation
Signs of secondary infection
Fever, malaise, or both
Infection secondary to underlying dermatologic condition
137
Topical Antifungal Treatments
Azoles
Clotrimazole
(Lotrimin AF)*
Econazole
Miconazole*
Ketoconazole
Oxiconazole
Sulconazole
Sertaconazole
Source: Antifungal Agents, Basic & Clinical Pharmacology. In: Katzung BG, Trevor AJ. Basic & Clinical Pharmacology, 13e; 2015
*Available OTC. ^This class of produces higher cure rates and more rapid responses in dermatophyte infections than do older agents, such as clotrimazole, and a higher cure rate and lower relapse rate than antifungal/corticosteroid combination therapy.
138
Topical Antifungal Treatments
Allylamines/
Benzylamines^
Butenafine
(Lotrimin Ultra)*
Naftifine
(Naftin)
Terbinafine
(Lamisil)*
Source: Antifungal Agents, Basic & Clinical Pharmacology. In: Katzung BG, Trevor AJ. Basic & Clinical Pharmacology, 13e; 2015
*Available OTC. ^This class of produces higher cure rates and more rapid responses in dermatophyte infections than do older agents, such as clotrimazole, and a higher cure rate and lower relapse rate than antifungal/corticosteroid combination therapy.
139
Topical Antifungals and Spectrum of Coverage
Adapted from: Habif TP. Clinical Dermatology, 6th ed. St. Louis, MO. Mosby-Year Book, Inc. 2016.