L-27 Dermatological Pharmacology

• Pharmacology of Dermatological Agents I, Lecture #24
• Presented by Mayur S. Parmar, Ph.D., Assistant Professor of Pharmacology, Department of Foundational Sciences, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Tampa Bay/Clearwater Campus

Learning Objectives

• Identify the mechanism of action, indications, and adverse effects of agents used to treat acne vulgaris.
• Identify the mechanism of action, indications, and adverse effects of agents used to treat psoriasis.
• Identify the mechanism of action, indications, and adverse effects of topical glucocorticoids and antihistamine agents used to treat skin disorders.
• Identify the mechanism of action, indications, and adverse effects of agents used to treat pigmentation disorders.
• Identify the mechanism of action, indications, and adverse effects of trichogenic and antitrichogenic agents.

Psoriasis

• A chronic, immune-mediated inflammatory disorder (IMID) leading to red, itchy, scaly skin patches.

Types of psoriasis:

• Plaque psoriasis: Inflamed skin with scaly, silvery plaques with distinct borders.
• Nail psoriasis: Nail pitting and nail separation occur.
• Guttate psoriasis: Teardrop-shaped bumps appear on the skin.
• Inverse psoriasis: Rash develops in skin folds.
• Pustular psoriasis: Characterized by pus-filled lesions.
• Erythrodermic psoriasis: Severely inflamed skin sheds in large sheets.

Causes of psoriasis:

• Skin trauma
• Infection
• Endocrine disorders
• Stress
• Medicines
• Alcohol abuse

FYI: Psoriasis Info

• IL-12 and IL-23 involved in natural killer cell activation and CD4+ T-cell differentiation/activation.
• IL-12 directs differentiation of naïve T cells into TH1 cells, which secrete IL-2, IFN-γ, and TNF-α.
• IL-23 directs differentiation of naïve T cells into TH17 cells, which secrete IL-17 and IL-22.
• Interleukin-17 (IL-17) is mainly produced by IL-23-induced TH17 cells.
• IL-17 has a central role in inflammation by stimulating production of key inflammatory mediators (IL-6, TNF-a, IL-1ẞ).
• Keratinocytes, fibroblasts, macrophages, and neutrophils respond to IL-17-induced proinflammatory cytokine production.
• IL-17 also stimulates proliferation/survival of neutrophils, T, and B cells.
• TNF-a plays multiple roles in psoriasis including stimulating keratinocyte proliferation, neutrophils, and releasing proinflammatory cytokines.

Psoriasis Treatment

• Treating psoriasis is possible through:
  • Oral medication
  • Topical creams
  • Biologic Agents

Oral Antipsoriatic Agents:

• Acitretin
• Apremilast
• Deucravacitinib

Topical Antipsoriatic Agents:

• Corticosteroids
• Calcipotriene
• Calcitriol
• Roflumilast
• Tapinarof
• Tazarotene

Biologic Antipsoriatic Agents:

• Etanercept
• Infliximab
• Adalimumab
• Certolizumab
• Ustekinumab
• Guselkumab
• Tildrakizumab
• Risankizumab
• Ixekizumab
• Secukinumab
• Brodalumab

Acitretin

• Oral retinoid used to treat psoriasis.

Mechanism of action:

• Binds/activates retinoid X (RXR) and retinoic acid (RAR) receptors.
• Inhibits proinflammatory cytokine expression (IL-6 and interferon-γ).
• Leads to anti-inflammatory and antiproliferative effects.
• Normalizes keratinocyte differentiation in the epithelium.

Therapeutic uses:

• Used for severe plaque psoriasis in adults, especially pustular forms.
• When unresponsive to other therapies.
• Effective for psoriasis with phototherapy.
• Indicated only in men and women of nonreproductive potential.
• Hepatotoxicity and pregnancy (female must sign informed consent before dispending).
• Pregnancy: Acitretin is a teratogen that persists in fat for 2–3 years.
• Women of childbearing age must wait at least 3 years after completing acitretin treatment before considering pregnancy.

Adverse effects:

• Liver problems. Monitor liver enzymes/lipids including abnormal function tests and hepatitis.
• Hematologic and oncologic effects: may cause changes in leukocyturia, hematocrit, hemoglobin levels, neutrophils and WBC count.

Apremilast

• Oral phosphodiesterase-4 (PDE4) inhibitor.

Mechanism of action:

• Inhibits phosphodiesterase-4 (PDE4).
• PDE4 increases pro-inflammatory signals and decreases anti-inflammatory signals.

Therapeutic uses:

• Treatment of mild, moderate, and severe plaque psoriasis and psoriatic arthritis.
• FDA approved for oral ulcers associated with Behcet's Disease.
• Has minimal immunosuppressive effects.

Adverse effects:

• Diarrhea, headache, nausea and vomiting (most common).
• May cause weight loss, depression, and suicidal ideation.

Deucravacitinib

• Selective tyrosine kinase 2 inhibitor.
• It is a once daily dose, approved in 2022.

Mechanism of action:

• Allosteric, selective tyrosine kinase 2 inhibitor.
• Reduces IL-23 pathway and type I IFN pathway-regulated genes.

Therapeutic Uses:

• Treatment of moderate-to-severe plaque psoriasis in adults (over 18 years).
• Do not combine with other potent immunosuppressants.

Warnings:

• May increase risk of infection.
• Screen for latent TB before starting treatment.
• May cause malignancies including lymphomas, and rhabdomyolysis.
• Can cause lab abnormalities such as elevated triglycerides and liver enzymes.

Adverse Effects:

• Can cause upper respiratory infections, elevated CPK, mouth ulcers, and acne.

Key points of biologic agents:

• Useful in treating adult patients with moderate-to-severe plaque psoriasis.
• Interact with cytokines that induce or mediate T-cell function.
• Treats autoimmune diseases such as psoriasis.
• Approved biologics are both injectable and antibody-based proteins produced by recombinant DNA technology.
• Before starting, screen the patient for latent tuberculosis.
• There is a risk of increasing infection (e.g. fungal, upper respiratory infection).
• It is not recommended to use with other immunosuppressant drugs.
• Avoid live vaccines if using TNF-a inhibitors
• You can't use two biologics concurrently.

Biologic antipsoriatic agents:

• Etanercept
• Infliximab
• Adalimumab
• Certolizumab
• Ustekinumab
• Guselkumab
• Tildrakizumab
• Risankizumab
• Ixekizumab
• Secukinumab
• Brodalumab

Etanercept, Infliximab, Adalimumab

• TNF-a inhibitors.

Etanercept:

• Acts as a decoy TNF-a receptor (not a monoclonal antibody).
• Binds to TNF-a to inhibit the TNF-a receptors associated with plaque psoriasis inflammation (SC injection).

Infliximab:

• The antibody is chimeric and partially humanized (mouse) monoclonal.
• Binds to soluble/transmembrane forms of TNF-a and inhibits the TNF-a receptors (IV).

Adalimumab:

• Fully humanized anti-TNF-a IgG1 monoclonal antibody.
• Binds specifically to TNF-α to inhibit receptors (SC injection).

Therapeutic uses:

• Treatment of moderate-to-severe plaque psoriasis and psoriatic arthritis.

Adverse effects:

• Predisposition to infections (sepsis, pneumonia).
• Reactivation of prior infections (e.g., latent TB).
• Drug-induced lupus.

Certolizumab

• TNF-a inhibitor.
• Is a pegylated, humanized antibody Fab' fragment.
• Pegylation allows for delayed elimination and extended half-life.

Mechanism of Action

• Binds and neutralizes human TNF-a activity.
• Does not induce complement activation, antibody-dependent cell-mediated cytotoxicity or apoptosis as lacks Fc region. Therapeutic Uses:
• Treatment of moderate-to-severe plaque psoriasis.
• Treatment of psoriatic arthritis.

Adverse Effects:

• Patients treated with CIMZIA may have an increased risk of severe infections leading to hospitalization or death.

Ustekinumab

• Interleukin-12 and Interleukin-23 (IL-12/IL-23) p40 cytokine inhibitor.
• Human IgG K monoclonal antibody.

Mechanism of Action

• Binds to the p40 protein subunit shared by IL-12 and IL-23 cytokines.
• Inhibits TH1 and TH17 cell-mediated responses, leading to inhibition of proinflammatory cytokines and chemokines release.
• Therapeutic Uses:
  • Treatment of moderate-to-severe plaque psoriasis . Treatment of psoriatic arthritis.

Adverse Effects:

• Causes serious allergic reactions angioedema and anaphylaxis
• Can predispose you to infections

Guselkumab, Tildrakizumab, Risankizumab:

• Interleukin-23 (IL-23) p19 cytokine inhibitors.
  • Guselkumab is a human IgG, lambda monoclonal antibody.
  • Tildrakizumab isa human IgG, kappa monoclonal antibody.

Mechanism of Action:

• Binds to p19 subunit of IL-23 cytokine → inhibit interaction with IL-23 receptor → inhibit release of proinflammatory cytokines and chemokines.

Therapeutic Uses:

• Treatment of moderate-to-severe plaque psoriasis.
• Treat psoriatic arthritis (Guselkumab and Risankizumab only).

Adverse effects:

• Serious allergic reactions (Guselkumab only).
• Cause upper respiratory infections, diarrhea, fungal infection, angioedema, tuberculosis, antibody development...

Secukinumab, Ixekizumab:

• Interleukin-17 (IL-17 or IL-17A) cytokine inhibitors.
  • Secukinumab: Humanized IgG monoclonal antibody
  • Ixekizumab: Humanized IgG4 monoclonal antibody

Mechanism of Action

• Binds with IL-17A cytokine → inhibits interaction with IL-17A receptor → inhibits release of proinflammatory cytokines.

Therapeutic Uses:

• Treatment of moderate-to-severe plaque psoriasis.
• Treatment of active psoriatic arthritis.

Adverse Effects:

• Causes fungal or upper respiratory infections.

Brodalumab

• Anti-IL-17A receptor competitive inhibitor.
• Human IgG2 monoclonal antibody.

Mechanism of Action:

• Inhibits interaction with cytokines IL-17A, IL-17F, and IL-17A/F heterodimer, releasing proinflammatory cytokines and chemokines.
• IL-17 is a pro-inflammatory substance signaling through two receptor subtypes: IL-17RA and IL-17RC.

Therapeutic Uses:

• Treatment of moderate-to-severe plaque psoriasis.
• Treatment of refractory psoriasis.

Black box warnings:

• Suicidal ideation and behavior.
• REMS program is required.

Adverse effects:

• Upper respiratory infections, tinea, and antibody development.

Topical Steroids:

• FDA-approved and used for inflammatory and pruritic dermatologic conditions.
  • Addresses corticosteroid-responsive dermatoses, including plaque psoriasis.
• Use for symptom relief, not prophylactically.
• Do not use them longer than three weeks without consulting doctor.
• Short-term high-potency corticosteroids use only because of side effects.
• Potency choice is based on body site affected:
  • Low potency = face
  • Medium potency = arms, legs, and trunk
  • High potency = hands and feet
• Use low potency agents for children is preferred.
• Avoid around the eyes to prevent cataracts and glaucoma.
• Endocrine & Metabolic adverse effects(long use).

Hydrocortisone:

• Low-potency corticosteroid.

Therapeutic uses:

Addresses corticosteroid-responsive dermatoses, atopic dermatitis, contact dermatitis, vulvar dermatitis, seborrheic dermatitis, plague psoriasis.

• For psoriasis, use on face, groin, and axillae in adults or psoriasis in children (twice a day).

Triamcinolone, Diflorasone, Mometasone:

• Low to medium potency corticosteroid.

Therapeutic uses:

Addresses corticosteroid-responsive dermatoses, and plague psoriasis.

• treat widespread plaques on extremities and trunk BID.

Betamethasone:

• super to high-potency corticosteroid

Therapeutic uses:

• corticosteroid-responsive dermatoses, and plague psoriasis (spray formulation).
• Use on localized, thick plaques on extremities / trunk, BID for 2-4 weeks, alternating with calcipotriene / calcitriol.

Adverse effects

• acne wulgaris, alopecia pruritis

Clobetasol

• high-potency corticosteroid

Therapeutic uses:

• corticosteroid-responsive dermatoses, and plague psoriasis.

• Use on localized, thick plaques on extremities / trunk, BID for 2-4 weeks, alternating with calcipotriene / calcitriol.

Adverse effects

• growth retardation if prolonged use on psoriasis in children (due to systemic toxicity)
• Upper respiratory tract infection, nasopharyngitis, streptococcal pharyngitis

Fluocinolone vs Halobetasol

• Potency: Super to high
• Use: Topical corticosteroid

Fluocinolone

• Treats : corticosteroid-responsive dermatoses, scalp plaque psoriasis (adults/scalp oil)
• Warning: local site reactions

Halobetasol

• Use: Treats (corticosteroid-responsive dermatoses) and Plague psoriasis
• Over 18 years+
• Adverse effect: acne, leukoderma, and secondary infection

Pimecrolimus

• Class: Calcineurin inhibitor
• It Blocks calcineurin.
• Therapeutic Uses: Treats : atopic dermatitis.
• Suppressions on cell-mediated Immune response.

Calcipotriene

• It is a topical and Non-steroidal vitamin D3 analog.

Mechanism of action:

• Binds to vitamin D receptors and inhibits keratinocyte proliferation/enhances keratinocyte differentiation, and inhibits inflammation.

Therapeutic uses:

• Treats plague psoriasis, Use in combination therapy with topical steroids (adults).

Adverse effects

• Causes itching, dryness, burning, irritation/erythema.

Calcitriol

• It is a topical and Non-steroidal - 1,25.

Mechanism of action”

• Has similar to calcipotriene.

Therapeutic uses

• treats plague psoriasis AND use in combination therapy, better tolerated in sensitive areas.

Adverse Effects

• Calcium in the Uline itching.

Roflumilast:

• Non-steroidal and a Once-daily cream.

MECHANISM OF ACTION:

• A phosphodiesterase-4 (PDE4) inhibitor
• ↑ the production of pro-inflammatory signals and ↓ the production of anti-inflammatory signals.

THERAPEUTIC USES:

• Treatment of plaque psoriasis
• Treatment is demonstrated in intertriginous

ADVERSE EFFECTS:

• Diarrhea, headache, insomnia nausea.

Tapinarof:

• Is a Non-steroidal AND Once-daily cream

MECHANIM OF ACTION:

• An aryl hydrocarbon receptor agonist.

THERAPUTIC USES:

• used on plague psoriasis and sensitive locations with skin folds genitals.

SIDE EFFECTS:

• Folliculitis nasopharyngitis.

Antihistamines

Key points:

Sedating antihistamines:

• Sedating antihistamines often used as first-line treatment for pruritus.
• Used for acute and chronic urticaria
• Best at night to reduce scratching, promote rest, and relieve itch-induced stress (sleep).

Non-Sedating antihistamines:

Have limited effect

Cautions:

Elderly population, due to risk of :

• confusion
• urinary retention

Diphenhydramine /Hydroxyzine

• First-generation H₁-antihistamine.

Diphenhydramine

Mechanism

• Antihistamine/blocking H₁-receptor, Therapeutic uses: -pain relief, chronic urticaria, nocturnal itch and drug-related effects: 
  • Drowsiness, xerostomia (enters CNS), confusion, and abrupt withdrawal.

Hydroxyzine:

• Mech- block H₁-receptor
• Uses: managing histamine, allergic conditions and pruritus
• adverse: respiratory depression and abrupt withdrawal

Doxepin

• antihistamine and topical. It block both and H2-receptors Therapeutic, use:. -Moderate pruritus with atopic dermatitis chronicus, Topical (8 days, tops!) adverse: drowsiness, confusion. Interactions: Avoid w/antidepressants and (prolong QT interval/ cardio issues.

Pigmentation & Depigmentation

• Melasma is the darkening parts.
• Chloasma (aka mask of pregnancy) is similar

Hydroquinone:

• Weak hypopigmenting.

Mechanism to follow:

• Enzyme tyrosinase needed for melanin.
• Uses a short-term, temporary method. So treat hyperpigmentation/ unwanted melanin.

Warning

• long term use can create cancerous cells in skin.

Monobenzone:

• Potent demelanizing agent (the monoberzyly hydroquinine Mechanism: -depigmentation and toxic to melanocytes, result: permanent loss use

Therapeutic restricted to patients:

vitiligo

• to reduce contrast or post-inflammatory

Note: Takes 4-6 months, sunscreen: used to protect Sun.

Mequinol

-Combination
    topical, tretinoin Mech.: Mequinol action: Unknown.
    -Treat solar letigies, so use skin care.
    -burning/pruritus/ tingling.
    -not use in pregnancy.

Trichogenic & Antitrichogenic Agents

Minoxidil

• Topical that acts as a vasodilator

Mech:

• hair growth goes back to vasodilation, resting follicles.

Benefits:

• Treats hair , and is halting hair loss in men and -women, may grow some. vertex is better than frontal.

Warnings

• Cessation leads to hair loss in 4-6 after stop it.
• Topical-does NOT effects blood.

Finasteride

• It is an Oral and Reductase enzyme inhibitor .

Mechanisms

• decreases to DTH: DHT causes follicle miniaturization/strophy . so finasteride stops process

Therapeutic

• Treats alopcia and promote prevents, DO NOT take if pregnant or if kid, is first line treatmen.

Warning

• Pregnant/take 3-6 months for hair.

Bimaprost

Mech: increases Eyelash growth increasing + % and duration of time

THERAPUEUTIC USE

Treat Hypootrichos

Caution

application the eyelid margin. adverse effect: Erythema, skin pigmentation and pruritus

Eflornithine

• Topical cream

Mechanism of Action

• Irreversible inhibitor of ornithine decarboxylase.

Therapeuthic Uses:

• Treates women withhirsutism
• Used to shown results for 6 months

Adverse Effects:

• Stinging. Causes burning, and folliculitis

Acne Vulgaris Treatment

• Topical products are recommended:
  • Tretinoin, Adapalene, Tazarotene helps to normalize the shading
  • Azelaic acid reduces inflammation, and hinder P acne reduce
  • Clindamycin, Erythromycin reduce bacteria
• Combination theray

Benzoyl Peroxide:

Mechanisms

• converted benzoic
• releases free radicals or oxidize proteins
• bactericidal

Treatment Use"

• reduce p acnes
• wary: irritation, allergic contact issues

Dapsone

Mech.

• bacteriostatie or anti-flam

  Treatment.

• treats vulgaris in kids + older
• 5thgel apped

Adverse effect

• Met hemoglobin orange staining
• Azelaic Acid: Adverse effects: pregnancy, birth

Mechanism -

• antimicrobial _

• antimicrobial properties, and melanic anti activity.

Treatments

-mild inflammatory acne is

WARNINGS

• hypopigmentation / burning Adverse affect:

Adapalene

is least irritating combined benzoyl works.

• Topical Third-generation retinoid: mechanism bind R beta /y. The topical :Treats Acnes.
• treat the inflammation and acne, works better.

Trifatorene Fourth (2019)Mech limited less irritation treat/ reduce treatment ACNE Vulgasic ( over 3) side effect. advetse:: systemic absorption

Isotretinoin is an oral first-gen retroid(

• -Treats Acnes. What to know/do:
• Ipledge: FDA program and use consent / reg-ister, two forms are needed Adverse effects: hyperlipiremia, *suicidal tho-ughts CONTAINDICATIONS::pregteratagenic,liver desease