P621 Exam 2 - Dermatological Disorders Pharmacotherapy

Dupilumab (Dupixent) -Indications -Ages it's ok for -Used with or without TCS or TCI?

-Moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable -6 years or older -Can be used with or without TCSs or TCIs. Up to provider discretion. HOWEVER, you should not abruptly withdrawal steroids (wean, basically, because you don't know what could be suppressed by the systemic effects of TCSs)

The microbiome and atopic dermatitis

-Patients with AD often are deficient in producing antimicrobial peptides in their skin -Lack of commensal skin bacteria contributes to the proliferation of staph aureus ○S. aureus colonization promotes development of AD in numerous ways, including disruption of barrier function and stimulating Th2-mediated immune responses

In general, when do peak rates of absorption occur with topically applied drugs?

12-24 hours after administration/application to the skin

Solution -pro/cons

2+ substances mixed into homogenous clarity Pro and con: Drying effect (can cause irritation but can also be beneficial with acute phase weeping rashes)

Lotion -pro/cons

A two-phase system consisting of a finely divided, insoluble drug dispersed into a liquid in a concentration of up to 20% PROS: 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 CONS: None

Is skin more acidic or basic and what does this mean for absorption of drugs?

Acidic (usually 4 to 5) This means that absorption will be favorable in more acidic drugs (think pKa more acidic)

Guidelines for duration of treatment for: -acute treatment -preventative treatment

Acute treatment: Use TCSs for up to 4 weeks Preventative treatment: Use 2-3 times weekly

Dosing of Dupilumab (Dupixent) -Adults -Children

Adults: -Initial dose is 600mg, which is 2 - 300mg injections -Maintenance is 300mg every 2 weeks Children: -Weight based -Initial 400-600mg -Maintenance 200-300mg (every other or every 4 weeks)

Age-related changes to Stratum corneum/skin absorption

Aged skin characteristics: -dryer with less surface lipids -thinner, more friable Paradoxically: skin permeability increases with age. Increased drug absorption -absorption of more lipophilic substances is reduced -absorption of more hydrophilic substances is not reduced

Skin hydration differs with age

At birth: skin is dryer than older children, increases in first 3-4 months ----The SC in infants is significantly more hydrated during 3-12 months compared to adult skin ----Increased risk for toxicity Newborn BSA:BW ratio more than twice that of adults ---- Topical doses (even adjusted for weight) will still cover more BSA than in adults

What conditions are level 3 to 5 steroids indicated for when initiating treatment?

Atopic dermatitis Nummular eczema Stasis dermatitis Seborrheic dermatitis Tinea^ Scabies (after scabicide) Intertrigo^ Severe dermatitis (face) Anal inflammation (severe cases)

Epidermis anatomy/physiology

Avascular, arises from stratum basale which produces the keratinocytes, etc. Other information in the video

Step 1 in therapy of AD (dry skin)

Basic treatment: Skin hydration Emollients Avoidance of irritants Identification and addressing of specific trigger factors

How do glucocorticoids work (think receptor activity)

Binds to the glucocorticoid receptor Causes the release off hsp90 (protein that inhibits folding into the active conformation of the receptor) Activated receptor initiates the transcription of target genes

Treatment during the acute phase of Eczematous Dermatis

Cold wet compresses; topical, oral or intramuscular steroids; antihistamines (?); antibiotics

Stratum corneum role in drug absorption

Comprised of "dead" (enucleated) epidermal cells Consists of 50% ceramides, 35% cholesterol, and 15% free fatty acids ○Major barrier to percutaneous drug absorption ○Possesses multiple proteins and lipids that may reversibly or irreversibly bind drugs

What factors affect penetration of drug into the skin?

Concentration of the medication (This is because absorption is by passive diffusion, so you need a strong gradient) Occlusion (including occlusiveness of the vehicle) Thickness and integrity of the stratum corneum Drug schedule/frequency - no effect Little/no effect of drug frequency/schedule of application with steroids

Risk with TCIs - the evidence on cancer and immunosuppression risk

HUGE case control study showed no increased risk of lymphoma in patients who used it for AD Study of infants <2yo showed: pimecrolimus is effective for long term intermittent use for AD and no evidence of systemic immunosuppression ○"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"

Viral infections as a complication of eczema

Herpes simplex Antiviral therapy Molluscum contagiosum

Do you want high or low therapeutic potency for a drug going through the skin?

High. Goal is for dose of <20mg/day

Treatment during the subacute phase of Eczematous Dermatis

Hydration/lubrication, topical steroids (with or without occlusion); antihistamines (?); antibiotics

Treatment during the chronic phase of Eczematous Dermatis

Hydration/lubrication, topical steroids (with or without occlusion); intralesional steroids; antihistamines (?); antibiotics

Dupilumab (Dupixent) - what it is/MOA

IgG4 antibody that blocks IL4, IL13 (cytokines that play a role in TH-2 cell activation which is a key cause of inflammation in AD) Blocks the binding of IL4 and IL13 to receptor IL4Ra. This stops the further release of proinflammatory cytokines, chemokines, and IgE

Anti-inflammatory effects of glucocorticoids -MOA

Inhibits the arachidonic acid cascade Inhibit transcription factors involving proinflammatory genes, Decrease release of proinflammatory cytokines from keratinocytes, Stabilization of membranes of phagocytizing cells

When is the therapeutic response to Dupilumab (Dupixent)?

Itch reduction is rapid, occurring as early as week 2

Appropriate treatment option for psoriasis and hand eczema

Level 1 TCS - Superpotent such as Clobetasol Do NOT use on face, axillae, groin, or under breast (as these areas of skin are very thin, toxicity) Limit use to about 14 days (2 weeks)

Appropriate treatment option for atopic dermatitis (AD) in adults

Level 2 and 3 TCS - Diflorasone and Desoximetasone Do NOT use on face, axillae, groin, or under breast (as these areas of skin are very thin, toxicity) Limit use to no more than 21 days (3 weeks)

Appropriate treatment option for atopic dermatitis (AD) in children

Level 4 and 5 (medium potency) TCS - Triamcinolone, Hydrocortisone Valerate Limit use in children to 7 - 21 days Limit use in intertriginous areas

Appropriate treatment option for eyelid and diaper dermatitis

Level 6 and 7 (least potent) TCS - Desonide and hydrocortisone Revaluate if disease does not respond in 28 days Avoid long-term continuous treatment in any area

When is pimecrolimus usually indicated?

Long term maintenance to prevent flares of mild AD Can be useful on the face and intertrigous areas

Step 2 in therapy of AD (mild to mod)

Low to mid potency topical corticosteroid (TCS) or TCI (topical calcineurin inhibitors) and basic treatment (from step 1)

Step 3 in therapy of AD (moderate to severe)

Mid potency TCS or TCI and basic treatment (from step 1)

What conditions are level 6 to 7 steroids indicated for when initiating treatment?

Mild dermatitis (face) Mild anal inflammation Mild intertrigo Dermatitis (eyelids; diaper area)

What is Crisaborole (Eucrisa) approved for? Ages it's ok for? Dosing?

Mild to moderate AD -ok for 3 months and older Apply twice daily to affected areas, available as a 2% concentration

When is tacrolimus usually indicated?

Moderate to severe cases of AD

How are corticosteroids grouped?

Order of potency in 7 groups. Group 1 is most potent, group 7 is least potent

How long on TCS treatment for AD without improvement/resolution is considered treatment failure?

Over 4 weeks. ■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

Crisaborole (Eucrisa) - pharmacologic class and MOA

PDE4 inhibitor (topical phosphodiesterase inhibitor) -Phosphodiesterase is responsible for breaking down cAMP -Eczema is characterized by high PDE4 levels (which leads to increase cAMP, increase inflammatory mediators) HOWEVER, with INCREASED cAMP from this drug, you get: -Activates protein kinase A (PKA) -This improves regulatory control of cytokine production -Increases anti-inflammatory mediators, decreases proinflammatory ones

Bacterial colonization of patients with AD

Patients with AD tend to be colonized with s. aureus, which can exacerbate or contribute to persistent skin inflammation and increase the risk for infection

Transdermal vs percutaneous absorption

Percutaneous - absorption through the skin, regardless of skin condition Transdermal absorption - absorption through unbroken skin

Skin absorption in preterm infants, newborns, and children

Permeability barrier function of the skin is not yet intact -The acid mantle (slightly acidic film on surface of human skin) develops in the first 4 weeks after birth Newborn skin has higher permeability to topical agents Pediatric skin is thinner, potentially increased rates/extent of absorption

Topical Calcineurin Inhibitors (TCIs) - names of the two and MOA

Pimecrolimus and tacrolimus Bind to MP-12 within the T cell, which inhibits calcineurin (this is required for t cell activation) Blocks the inflammatory cascade produced by pathologic t cells in the skin Prevents the synthesis of proinflammatory cytokines and t cell proliferation

FDA label warning with TCIs (tacrolimus and pimecrolimus)

Potential cancer risk - based on information from animal studies, small series of case reports and knowledge of pharmacology Safety of long term use not established

What conditions are level 1-2 steroids indicated for when initiating treatment?

Psoriasis Lichen planus Discoid lupus† Severe hand eczema Hyperkeratotic eczema Chapped feet Nummular eczema (severe) Poison ivy (severe) Atopic dermatitis (resistant adult cases)

Thickness of stratum corneum at different sites - KNOW THE CONTINUUM FOR THE EXAM

Scrotum/eyelids - thinnest (more risk for systemic absorption) Face Chest and back Upper arms and legs Lower arms and legs Dorsa of hands and feet Palmar and plantar skin Nails are the thickest

Ointment -pro/cons

Semisolid; hydrocarbon-based, silicone-based, lanolin, water-in-oil emulsion; contains less than 25% water PROS: Provides lubrication, hydration; most occlusive dosage form CONS: Can cause irritation; Too occlusive for acute phase rashes; not for use in intertriginous areas (hair). Feel greasy, less cosmetic acceptance

Do you want a long or short half life for drugs being absorbed through the skin?

Short

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

Stratum corneum as a Reservoir

Some drugs may be sequestered in the stratum corneum and form a reservoir of the drug that is slowly diffuse into the other layers over time even after the formulation/vehicle has been removed.

After how long does treatment with potent TCSs relieve disease burden?

Start to relieve disease burden (AD) in about 3 days. Continued improvement over 3 weeks for moderate to severe AD

Stepwise management of atopic dermatitis -Just list the four steps and which severity of disease they apply to (will go into further detail in the next few flashcards)

Step 1 - Dry skin only Step 2 - Mild to moderate AD Step 3 - Moderate to severe AD Step 4 - Recalcitrant, severe AD

Step 4 in therapy of AD (recalcitrant, severe AD)

Systemic Therapy (e.g., CSA, Mycophenolate or UV therapy) Mid potency TCS or TCI and basic therapy (from step 1)

Which is stronger: primecrolimus or tacrolimus?

Tacrolimus is stronger (more effective than low potency TCS 6-7, same effectiveness as moderate potency TCS level 5. Primecrolimus is as potent as low potency TCS levels 6-7. less effective than moderate potency 3-4

Length of treatment depending on steroid potency - depending on which group/level

The more potent the steroid, the shorter the duration of treatment should be Level 1: 2-3 weeks (QD to BID), then 1 week of rest Level 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

Lipophilicity of drugs and absorption percutaneously

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 Need a balance between both characteristics!

Topical vs percutaneous absorption

Topical - delivery of a drug into the skin to treat a dermal disorder. Skin is the target tissue Percutaneous - delivery of a drug through the skin for a systemic effect. Drug gets into the blood stream. AKA transdermal absorption

Transepidermal routes (2)

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. Though this one is the shortest distance, it takes longest b/c it requires crossing of lipophilic membranes, etc. Few drugs are able to go this way. Preferential route for hydrophilic drugs

FDA Recommendations for the use of TCIs

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 in children under 2 years (effect on developing immune system unknown, long term safety unknown. Only for short term if needed) DO NOT use in patients with a weakened or compromised immune system Use the minimum amount needed to control symptoms

KEY TOPIC: The vehicle for percutaneous drug delivery

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

Gel -pro/cons

Water-soluble bases with... -water -polyethylene glycol -and/or PEGs CON: Drying effect can irritate (tend to have high alcohol content) PRO: Can be applied to hairy areas, drying effect good for acute phase weeping rashes good for wet lesions like in poison ivy rash

Adverse effects of Crisaborole (Eucrisa)

Well tolerated 4% application site burning/stinging Hypersensitivity reactions, including contact urticaria, have occurred in < 1% of patients

Does the vehicle effect the rate/extent of drug release from a formulation? How?

Yes -Modulating the vehicle/SC (stratum corneum) partition -Altering the skin barrier properties by modifying the SC -Promoting increased drug solubility in the SC Effects of the vehicle on the SC include interaction with intrinsic elements of the SC (lipid and protein components, promoting SC hydration by an occlusive effect)

Do TCIs (topical calcineurin inhibitors) reduce the amount of steroid needed in the treatment of AD?

Yes, when applied at the first appearance of erythema/pruritis, there is a steroid sparing effect

High potency fluorinated corticosteroids are not usually indicated for _____ and _____.

children and the elderly

Red skin syndrome

corticosteroid withdrawal syndrome Nitric oxide (vasodilator) secretion is inhibited by cortisol (corticosteroids) and so rebound after LONG TERM use can cause red skin syndrome

Efficacy of a topically applied drug depends on its _________________ and ___________________

inherent potency and ability to penetrate the skin If a drug has a high potency, it will be more efficacious. This is because there is so little of the drug that will actually get absorbed through the skin (usually <2% with hydrocortisone after 1 day, for example)

Toxicity of topically applied drugs - local effects

oIrritation oAllergic reactions oAtrophy oComedogenicity oTelangiectases oPruritus oStinging and pain Uncommon (Cataracts, Increased IOP, neoplasms, Ulcers) Usually reducing concentration and using over a greater period of time will help reduce local effects

Cream -pro/cons

oil-in-water emulsion for external use Aqueous phase may be up to 80% of formulation PRO: lubrication, hydration. Less greasy. Protective film of oil left behind. Slow evaporation of water phase = cooling effect CON: Less potent than ointments (because provides less hydration due to less occlusive effects)

pH effect on percutaneous absorption

pH of a site will effect how much of the drug is ionized (charged) at any time. Charged molecules are not able to cross natural barriers (of which the stratum corneum is one)

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 oSkin metabolism plays a role in determining the fate of a topically applied prodrugs and drugs oExtent of metabolism is normally modest, i.e., 2%-5% of the absorbed compounds

What bacteria causes impetigo?

•Staphylococcus aureus •Group A b-hemolytic streptococcus (S. pyogenes)

Nonsteroidal creams

■Atopiclair, Pruclair ■Mimyx, Prumyx FDA approved as medical devices •Replenishes deficient fatty acids, restores barrier function to skin

Is Dupilumab (Dupixent) safe during 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

Immunosuppressive effects of glucocorticoids -MOA

○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

Following initial improvement with a steroid you should...

○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

When to refer with atopic dermatitis

○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

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

Should antibiotics be used to eradicate bacterial colonization in patients with AD?

○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

Is Dupilumab (Dupixent) safe during 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

Bacterial infections as a complication of eczema

○Staphylococcus aureus ○Group A b-hemolytic streptococci ○Types of infections ■Impetigo ■Pyoderma ■Osteomyelitis

What changes the integrity of the stratum corneum? What increases the SC's ability to absorb?

●Any insult that removes water, lipids, or protein from the epidermis alters the integrity of this barrier and compromises its function ---This increases the risk for systemic toxicity ○A hydrated stratum corneum allows more percutaneous absorption

Systemic side effects of topical corticosteroid use

●Cataracts, glaucoma (periorbital use) ●Hypertension ●Cushing's syndrome ●Hyperglycemia ●Other

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

What level corticosteroid should be used for more dermatoses and for how long/how often?

●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

Pathophysiology 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)

Tachyphylaxis with topical steroids

●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? YES

Occlusion when using topical steroids

●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 oBest 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

Hypothalamic pituitary axis suppression with topical corticosteroids

●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

Atrophy of skin with topical corticosteroids

●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

Overview of 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

Transappendageal route

●Transappendageal route - through sweat ducts, hair follicles, associated sebaceous glands This is a method by which it penetrates the stratum corneum Very minor route as these structures are a small SA of the skin

Effects of topical glucocorticoids (other than anti-inflammatory and immunosuppresion) - 3 effects and their MOAs

●Vasoconstriction - 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

Glycyrrhetinic acid

antiinflammatory, antipruritic

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

Vitis vinifera

antioxidant, antiprotease activity; protects against epidermial breakdown

Telmestine

antiprotease; inhibits other skin enzymes

Why do formulations not remain homogenous once applied to the skin?

Evaporation Mixing with skin surface lipids Undergo changes in composition -excipients and drugs that undergo absorption

Example of how vehicle type/formulation effects drug potency through the skin

For desonide, ointment is more potent than lotion/cream For triamcinolone, ointment is LESS potent than lotion/cream Group I = most potent Group VII = least potent

Steps of percutaneous absorption

Formulation applied (reservoir/vehicle that carries the drug) Formulation can change over time once applied to the skin (factors effecting this on next flashcard) Once released from formulation the drug may: ●penetrates stratum corneum (going through this layer) ●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

Abnormal stratum corneum pH

Found in many conditions Basic stratum corneum Basic drugs will be more unionized and therefore better absorbed