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54 Cards in this Set

  • Front
  • Back
HPV Pathophys
a. Human papillomaviruses (HPV) are very widespread-to-ubiquitous in humans. They cause a variety of cutaneous and mucosal infections.
b. Three clinical manifestations of cutaneous HPV infections include common warts (Verruca vulgaris), plantar warts (Verruca plantaris), and flat warts (Verruca plana).
c. The most common presentation of mucosal HPV infection is condyloma
acuminatum (genital wart), a sexually transmitted disease
Molluscum contagiosum virus (MCV) Pathophys
a. Molluscum contagiosum is a self-limited epidermal viral infection, characterized by skin-colored papules occurring in children and sexually active adults.
b. Molluscum contagiosum virus (MCV) is poxvirus (30% homology with smallpox virus)
Actinic keratoses Pathophys
1. Presentation
a. Single or multiple, discrete, dry, rough, adherent scaly lesions
b. Occurring on the habitually sun-exposed skin of adults
2. Pathogenesis--Prolonged and repeated solar exposure leads to cumulative damage to keratinocytes by the action of ultraviolet radiation, mostly UVB.
3. Actinic keratoses can develop into SCC
5-Fluorouracil--Mechanism
Classified as an antimetabolite. It is cell cycle specific for the S phase of the
cell cycle.
Formation of FdUMP
Check notes, too extensive
5-Fluorouracil--Clinical Uses
Topical formulations are used in multiple actinic keratoses
5-Fluorouracil---Adverse Effects
Treated areas may become severely inflamed during treatment, but the inflammation subsides after the drug is stopped.
Imiquimod
1. Mechanism of action
Exerts immunomodulatory effects by acting as a ligand at toll-like receptors in the innate immune system and inducing the cytokines interferon-α (IFN-α),
tumor necrosis factor-α (TNF-α), and others.
Imiquimod--Adverse Effects
Irritant reactions including edema, vesicles, erosions, or ulcers
Imiquimod--Clinical Uses
a. Genital warts
b. Actinic keratoses
c. Molluscum contagiosum
Podofilox
1. Mechanism of action
a. Podophyllin is a mixture of chemicals from the plant Podophyllum peltatum (mandrake or May apple). The major constituent of the resin is podophyllotoxin (podofilox).
b. It binds to microtubules and causes mitotic arrest in metaphase
Podofilox--Adverse Effects
Irritation and ulcerative local reactions
Podofilox--Clinical Uses
Genital Warts
Actinic Keratoses--Typical Treatment
Actinic keratoses are usually treated surgically (e.g., cryosurgery or excision). Topical chemotherapy with 5-fluorouracil and imiquimod is an alternative to surgery. They require considerable time to work and side effects to use, especially with 5-FU
represent a treatment challenge.
The mechanism of drugs used in treating psoriasis include one or more targets:
1. Reduction of pathogenic T cells
2. Inhibition of T-cell activation
3. Interference with T-cell trafficking to the skin
4. Induction of immune deviation (from a TH1 to a TH2 immune response)
5. Blockade of the activity of inflammatory cytokines
6. Correct abnormal cell differentiation
Calcipotriene
1. Mechanism of action
Topical Drug--psoriasis
a. A vitamin D analog
b. Vitamin D and its analogs inhibit keratinocyte differentiation and proliferation, provide anti-inflammatory benefits by inducing a shift towards Th2 cytokine expression. In addition, it induces inhibition of nuclear factor-κB protein in lymphocytes, leading to a reduced transcription of IL-2.
Calcipotriene--Admin and Elim
a. Cream, ointment or solution for topical application
b. The drug is rapidly metabolized to inactive products in the skin. (Vitamin D typically causes hypercalcemia but calcipotriene is 100 times less active on systemic calcium metabolism because of its rapid local metabolism.)
Calcipotriene--Adverse Effects
Lesional and perilesional irritation consisting of mild burning and stinging
Glucocorticoids--Mech of Action
Topical Drug for Psoriasis
Topical corticosteroids inhibit indirectly phospholipase A2 thus reducing the levels of arachidonic acid, prostaglandins, and leukotrienes in skin. In addition, activation of steroid receptors in the skin DNA inhibits synthesis
and mitosis in epidermal cells thereby decreasing epidermal proliferation.
Gluccocorticoids --Admin
a. Topical corticosteroids are available in ointments, creams, lotions, gels, sprays, shampoos, and mousses.
b. An ointment is considered the most clinically effective dosage form in psoriasis treatment because it consists of an oily phase that is occlusive
and conveys a hydrating effect.
Gluccocorticoids--Adverse Rxns
a. Tissue atrophy, epidermal and dermal degeneration, and striae are manifestations of corticosteroid effect on collagen synthesis and fibroblast growth.
b. Thinning of the epidermis may result in visibly distended capillaries (telangiectasias) and purpura.
c. Acneiform eruptions
d. Masking of symptoms of bacterial or fungal skin infections
e. Systemic consequences of topical corticosteroid use include risk of suppression of the hypothalamic-pituitary-adrenal axis, hyperglycemia,
and development of cushingoid features.
Gluccocorticoid--Clinical Use (topical/highpotency)
Topical corticosteroids are the most widely used agents in the treatment of psoriasis in the United States. The super-high potency steroids such as clobetasol are used primarily as alternatives to systemic therapy when local therapy is feasible (e.g., thick, chronic psoriatic plaques). They should be used for finite periods of time (as short as possible) and on
relatively small body surface areas.
Gluccocorticoid--Clinical Use (low potency)
The low potency steroids (e.g., hydrocortisone 1%) have a weak antiinflammatory effect and are safest for long-term application. They are the safest for use on the face and intertriginous areas, in infants and young children, and with occlusion when necessary and appropriate.
Gluccocorticoid--Clinical Use (medium potency)
Medium-potency products (e.g., desonide) are used in moderate inflammatory dermatoses. Medium potency preparations may be used on
the face and intertriginous areas for limited periods of time.
Tazarotene
1. Mechanism of action
a. Retinoids exhibit vitamin A activity and have many important functions throughout the body, including roles in vision, regulation of cell proliferation and differentiation and bone growth, immune defense, and tumor suppression.
b. Retinoic acid (RA) exerts its effects on gene expression by activating two
families of receptors—retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Human skin contains mainly RARα and RARβ. Retinoids (ligands) bind transcription factors (nuclear receptors), and the ligand-receptor complex then binds to the promoter regions of target genes to regulate their expression. The gene products formed contribute to the pharmacological effects and their side effects.
c. In the skin, the retinoids may act in the keratinocyte nucleus to correct abnormal cell differentiation. Tazarotene suppresses markers of
epidermal inflammation and inhibits cornification of the keratinocyte.
Tazarotene--admin
Tazarotene gel--Topical
Tazarotene--Adverse effects
a. Burning, itching, and skin irritation
b. Teratogenic
i. Women should not be pregnant when initiating therapy
ii. Birth control should be used during treatment
Alefacept--class
Systemic Drugs--Psoriasis
A. Biological agents
1. T cell activation inhibitors
Alefacept--Mechanism
Consists of a recombinant human fusion protein composed of the binding site of the leukocyte function-associated antigen 3 (LFA-3) protein and a human IgG1 Fc domain.
i. The LFA-3 portion of the alefacept molecule binds to CD2 on the surface of T cells, thus blocking costimulation of T-cells; naive T cells are unaffected since CD2 is expressed on memory-effector T cells
ii. In addition, the IgG1 portion of the molecule simultaneously binds to
immunoglobulin receptors on cytotoxic cells inducing apoptosis of memory-effector T cells
Alefacept--Admin
Intramuscular injection (1/week for 12 weeks; additional 12-week course can be initiated, if required)
Alefacept--Adverse Effects
Reduction in CD4+ lymphocyte counts
i. A baseline T-lymphocyte count should be performed before initiating therapy with alefacept
ii. Weekly monitoring of T cells during therapy is required
Adalimumab, Ifliximab, Etanercept--Class
III. Systemic Drugs--Psoriasis
A. Biological agents
TNF-α inhibitors
Adalimumab--Mechanism
Adalimumab is a human IgG antibody to TNF-α. Binds to TNF-α such that it cannot bind to its receptor. (Does not bind to TNF-β)
Infliximab
Infliximab is a chimeric monoclonal antibody combining portions of mouse and human IgG directed against TNF-α. Binds to TNF-α such that it cannot bind to its receptor. (Does not bind to TNF-β)
Etanercept--Mechanism
Etanercept is a fusion protein containing the ligand-binding portion of the p75 TNF receptor linked to the Fc portion of human IgG. Binds to TNF-α (and β) forming inactive complexes and preventing it from interacting with cell-surface TNF receptors and thereby activating cells.
Adalimumab, Ifliximab, Etanercept--Adverse Effects
i. Increased risk of infection
There is an increased risk of infection. Those who develop infections should discontinue until the infection is cured. Latent tuberculosis can become active. Tuberculin skin testing is recommended before treatment with these drugs.
Etanercept and Adalimumab---Injection Rxns
Etanercept and adalimumab are injected subcutaneously and can cause erythema, pain, and pruritus at the injection site
Infliximab--injection rxn
Infliximab is administered intravenously and can cause an
infusion reaction manifested as fever and chills
TNF-a inhibitor--Contraindications
i. Patients with an active infection, history of recurring infections, or medical conditions predisposing them to infection
ii. Patients with severe heart failure-these drugs increase mortality
Cyclosporine
a. Mechanism of action
Immunosuppressant/cytotoxic agent for systemis psoriatic treatment

Cyclosporine crosses the plasma membrane and binds to the cytoplasmic immunophilin cyclophilin (right side of figure--check it out). The cyclosporine-cyclophilin complex binds to calcineurin, preventing the activation of calcineurin phosphatase activity by Ca2+/calmodulin.
This suppresses IL-2 production and T cell proliferation.
Cyclosporine--Admin and Elim
(a) Orally administered (capsules and solution)
(b) Extensively metabolized in the liver
Cyclosporin--Adverse Effects
(a) Hypertension (monitor BP)
(b) Renal dysfunction (monitor serum creatinine)
(c) Increased risk of cutaneous, solid organ, and lymphoproliferative malignancies
Methotrexate
a. Mechanism of action
i. A folic acid analog that competitively inhibits dihydrofolate reductase
ii. Targets rapidly proliferating epithelial cells in the skin
iii. Can also inhibit replication and function of T cells and suppress secretion of cytokines (due to release of adenosine)
Methotrexate--Adverse Effects
i. Thrombocytopenia
ii. Hepatotoxicity
iii. Teratogenic
Adverse effects can be managed with leucovorin, if necessary.
Methotrexate--Contraindications
i. Pregnancy (The drug is teratogenic and should not be given to women who are or may become pregnant.)
ii. Patients with liver disease (the drug can cause hepatotoxicity)
Acitretin--Class and
1. Mechanism of action
Retinoid
a. See tazarotene.
b. In the skin, the retinoids may act in the keratinocyte nucleus to correct abnormal cell differentiation.
Acitretin--Admin and elim
Orally administered metabolized in the liver
Acitretin--Adverse Effects
a. Retinoids cause dry skin and mucous membranes, xerophthalmia, and hair thinning
b. Oral retinoids are potent teratogens and cause severe fetal malformations. Because of this, systemic retinoids should be used with great caution in females of childbearing potential.
Acitretin--Drug Interaxns
In the presence of ethanol, acitretin is esterified to produce etretinate which has a very long half-life. Alcohol should not be ingested by female patients during treatment and for 2 months following treatment.
Acitretin--Contraindications
Acitretin is a potent teratogen and should not be used by females who intend to become pregnant during therapy or at any time for at least 3 years following discontinuation of therapy.
Choice of drug therapy for Psoriasis
A. Mild to moderate psoriasis is generally treated with topical corticosteroids; calcipotriene or tazarotene are topical alternatives.
B. Systemic drugs are usually reserved for moderate to severe disease
1. The first-line drugs include the biological agents
a. T cell activation inhibitors (Alefacept)
b. TNFα inhibitors (Adalimumab, Etanercept, Infliximab)
2. Acitretin, cyclosporine and methotrexate are considered second line drugs
Efalizumab-- Mechanism of action
monoclonal antibody against CD11a molecule of LFA1. Systemic Biological agent for psoriasis

Binds to CD11a on T cells to prevent binding of LFA1 to intracellular adhesion molecule 1 or ICAM 1 on the surface of APCs, vascular endothelial cells, and cells in the epidermis and dermis. This interferes with T cell activation and migration and cytotoxic T cell function.
Efalizumab---Admin
subcutaneously once a week for 12-24 weeks.
Efalizumab---Adverse Effects
rebound of the disease after therapy and thrombocytopenia (requires periodic evaluation of platelet levels)