NCLEX: Drugs for Dermatologic Disorders

The skin is the largest organ system of the body. It has many essential functions including serving as a protective barrier, helping to regulate temperature, offering defense against infections and toxic chemicals, serving as a source of vitamin D, and providing sensation to touch, temperature, sexual pleasure, and pain. Skin disorders, such as acne and dermatitis, are among the top reasons that patients seek medical attention. Pharmacological approaches to correct skin abnormalities, including infections, can be administered topically or systemically, depending on the nature and extent of the disorder. This chapter discusses drugs that are used for the treatment of common skin disorders including acne, bacterial infections, ectoparasitic infections, psoriasis, and others.

Drugs for Dermatologic Disorders

Drugs for Dermatologic Disorders: TOPICAL PREPARATIONS

Focus topic: Drugs for Dermatologic Disorders

The skin is composed of two main layers, the epidermis and the dermis. The epidermis itself is composed of many layers and serves as a defense against pathogens. The outermost layer of the epidermis, the stratum corneum, consists of a lipophilic keratinous layer of skin. The dermis is located between the epidermis and the subcutaneous tissue, and it is composed of connective tissue. It also contains specialized structures such as sweat glands, sebaceous glands, hair follicles, and blood vessels.

Use of topical agents for treatment of dermatologic disorders is not only convenient but also minimizes systemic adverse effects. Topical agents may be formulated as sprays, powders, lotions, creams, pastes, packed dressings, ointments, and aerated foams. The bioavailability of these agents and the ability to retain therapeutic effect on the skin involve factors such as the vehicle (water or oil based) and the physical methods used to localize them, such as the use of a patch formulation. The therapeutic efficacy of topical agents is dependent on the thickness of the stratum corneum, the drug concentration and permeability, frequency of dosing, and other factors such as age and health of the skin. Lipophilic agents are more readily absorbed than those that are hydrophilic.

Drugs for Dermatologic Disorders

Drugs for Dermatologic Disorders: AGENTS FOR ACNE

Focus topic: Drugs for Dermatologic Disorders

Acne vulgaris (common acne) is a common skin disorder that is characterized by pimples, comedones, pustules, and sometimes nodules and scarring. Comedones are clogged hair follicles (pores) in the skin, which can be open (blackhead) or closed (whitehead). Acne occurs due to alterations in pilosebaceous units—skin structures that contain a hair follicle and a sebaceous (oil) gland. Androgens stimulate sebaceous glands, thereby producing sebum that leads to follicular keratinization and obstruction. Propionibacterium acnes, part of the normal skin flora, can enter the clogged pore and multiply, causing redness and inflammation and leading to papillary, pustulary, and cystic acne. Treatments for acne help to reduce sebum production or control P. acnes. [Note: Use of oral contraceptives may help decrease circulating levels of free androgen and reduce symptoms of acne.

Drugs for Dermatologic Disorders

A. Retinoids

Retinoids are derivatives of vitamin A that are highly effective in the treatment of acne, as well as other skin conditions such as psoriasis and photoaging. Tretinoin [TRET-in-oin] and isotretinoin [eye-so-TRET-i-noyn] are first-generation retinoids that are used for the management of acne. Third-generation retinoids include adapalene [a-DAP-a-leen] and tazarotene [ta-ZAR-oh-teen]. Third-generation agents are less irritating and more effective than first-generation retinoids and are considered first-line therapy for comedonal and inflammatory acne. These agents are applied topically, with the exception of isotretinoin, which is an oral drug. Due to the adverse effect profile, use of isotretinoin should be reserved for severe cystic acne.

  • Mechanism of action: Retinoids influence a wide variety of biological activities, including cellular proliferation and differentiation, immune function, inflammation, and sebum production. Unlike the first-generation agents, the third-generation agents do not influence sebum production. They are comedolytic and anti-inflammatory. The molecular actions of retinoids are mediated through nucleic retinoic acid receptors. Once bound to the receptors, retinoids function as transcription factors that enhance initiation of transcription.
  • Adverse effects: Irritation, dryness, and skin peeling are all complications with the use of retinoids. Photosensitivity is also an adverse effect, and patients should be cautioned to wear sunscreen. Other adverse effects include dry mucous membranes and dry eyes. Suicide or suicide attempts have been associated with the use of oral isotretinoin. There is a very high risk of birth defects if pregnancy occurs while taking isotretinoin, and this drug as well as other retinoids are contraindicated in pregnancy.

Drugs for Dermatologic Disorders

B. Benzoyl peroxide

Benzoyl peroxide [BEN-zoyl per-OX-ide] is considered the first-line agent for mild to moderate acne with no inflammation. The mechanism of action includes antiseptic effects against P. acnes as well as opening of the pores. Benzoyl peroxide is a topical agent that is available in many over-the-counter acne treatment products, as well as some prescription products. Dry skin, peeling, and irritation are local adverse effects.

C. Salicylic acid

Topical salicylic [sal-i-SIL-ik] acid, a β-hydroxy acid, penetrates the pilosebaceous unit and works as an exfoliant to clear comedones. Its comedolytic effects are not as pronounced as those of the retinoids. The drug has mild anti-inflammatory activity and is keratolytic at higher concentrations. Salicylic acid is used as a treatment for mild acne and is available in many over-the-counter facial washes and medicated treatment pads. Mild skin peeling, dryness, and local irritation are adverse effects.

D. Azelaic acid

Azelaic [aze-eh-LAY-ik] acid, a dicarboxylic acid, has antibacterial activity against P. acnes as well as anti-inflammatory actions. Azelaic acid normalizes keratinization and is anticomedogenic. It is available as a topical preparation for the treatment of mild to moderate inflammatory acne. It is generally well tolerated, with mild skin irritation as the most common adverse effect.

E. Antibiotics

As noted above, P. acnes is a gram-positive rod that is associated with inflammatory lesions in acne. For moderate to severe acne with inflammatory lesions, use of topical or oral antibiotics is useful for inhibition of P. acnes. Topical formulations of erythromycin and clindamycin (preferred) are available. These agents may be combined with benzoyl peroxide or the retinoids for better effectiveness. Dapsone, a synthetic sulfone, is available as a topical gel that treats acne. Its mechanism of action in the treatment of acne is unknown. [Note: Metronidazole as a topical agent is useful in adult acne, also known as rosacea.] Oral antibiotics commonly used for the management of moderate to severe acne include minocycline, doxycycline, and erythromycin. Erythromycin is used infrequently due to gastrointestinal adverse effects. Each of these agents is covered in more detail in the chapters on anti-infective therapy.

Drugs for Dermatologic Disorders: TOPICAL ANTIBACTERIAL AGENTS

Focus topic: Drugs for Dermatologic Disorders

Organisms such as staphylococci and streptococci can cause folliculitis, abscesses, fasciitis, cellulitis, impetigo, and many pus-forming infections. Several gram-positive and gram-negative bacteria cause infections that are not limited to the skin and may cause serious diseases, since they can spread and become systemic infections.

A. Gram-positive infections

Bacitracin [bas-i-TRAY-sin] is a peptide antibiotic active against many gram-positive organisms. It is used mainly in topical formulations; if used systemically, it is toxic. Bacitracin is mostly used for the prevention of skin infections after burns or minor scrapes. It is frequently found in combination products with neomycin and/or polymyxin (see below). Mupirocin [mue-PIR-oh-sin] is a protein synthesis inhibitor that is useful in treating impetigo (a contagious skin infection caused by streptococci or staphylococci; Retapamulin [RE-te-PAM-ue-lin] is a newer protein synthesis inhibitor that treats impetigo. Adverse effects are minimal with these agents and usually consist of mild local skin reactions.

Drugs for Dermatologic Disorders

B. Gram-negative infections

Polymyxin [paw-lee-MIX-in] B is a cyclic hydrophobic peptide that disrupts the bacterial cell membrane of gram-negative organisms. As noted above, it is commonly combined with neomycin and bacitracin (“triple antibiotic”) in topical products used for the prevention of skin infections after minor skin trauma. Neomycin [nee-oh-MY-sin] in combination with other agents and also gentamicin can be used to treat skin infections caused by gram-negative organisms such as Pseudomonas, E. coli, and Klebsiella sp. Topical use of these agents rarely causes systemic side effects. Rare adverse reactions such as allergic dermatitis and other sensitivities occur with neomycin.

Drugs for Dermatologic Disorders: AGENTS USED IN ECTOPARASITIC INFECTIONS

Focus topic: Drugs for Dermatologic Disorders

Ectoparasites are parasites that live on the skin of animals from which they derive nutrition. Pediculosis (infestation with lice) and scabies (caused by Sarcoptes scabiei, human mite; Lice infestations may be caused by Pediculus capitis (head louse), Pediculus corporis (body louse), or Pthirus pubis (pubic or crab louse). Lindane [LIN-dane] is a cyclohexane derivative that is available as a cream or shampoo. Lindane is toxic when absorbed by the parasite and is an effective pediculicide (kills lice) and scabicide. Permethrin [per-METH-rin] is a synthetic pyrethroid that is neurotoxic to lice (1% nonprescription) and is effective in 5% concentration by prescription to treat scabies. Permethrin is preferred over lindane for the treatment of lice and scabies, since lindane can cause neurotoxicity. [Note: Oral ivermectin (see Chapter 44) is an alternative treatment for lice and scabies]. Synergized pyrethrins (pyrethrins [pye-REE-thrins] with piperonyl butoxide [pye-PER-oh-nil bue-TOX-ide]) is a nonprescription product approved to treat head and pubic lice. Pyrethrins are pesticides and piperonyl butoxide prevents the lice from metabolizing the pyrethrins, thereby enhancing their effect. Due to a low risk of toxicity, this agent is considered a first-line treatment for pediculosis. Crotamiton [crow-TAmi- ton] is a scabicide and has antipruritic functions. Its mechanism of action is unknown.

Drugs for Dermatologic Disorders

Drugs for Dermatologic Disorders: AGENTS FOR PIGMENTATION DISORDERS

Focus topic: Drugs for Dermatologic Disorders

Agents for pigmentation disorders include hydroquinone and methoxsalen, which are used for the treatment of hyperpigmented skin conditions and vitiligo, respectively.

A. Hydroquinone

Hydroquinone [HYE-droe-KWIN-one] is a topical skin whitening agent that reduces hyperpigmentation associated with freckles and melasma. It is often used in combination with topical retinoids to treat the signs of photo-aging. The mechanism of action of hydroquinone is inhibition of the tyrosinase enzyme required for melanin synthesis. Hydroquinone lightens the skin temporarily and is commonly used as a 4% preparation. It should not be used in higher concentrations, or in excessive quantities for an extended duration, as it is associated with possible carcinogenicity. Local skin irritation is the most common adverse effect. Monobenzone [mon-oh-BEN-zone], the benzyl ether of hydroquinone, is sometimes used to even out the skin discoloration associated with vitiligo (depigmentation disorder of the skin; The drug may cause permanent depigmentation and is no longer available in many markets.

Drugs for Dermatologic Disorders

B. Methoxsalen

Methoxsalen [meth-OX-ah-len] is a photoactive substance (psoralen) that stimulates melanocytes and is used as a repigmentation agent for patients with vitiligo. It must be photoactivated by UV radiation to form a DNA adduct inhibiting DNA replication by a method called PUVA (psoralen plus UVA radiation). Methoxsalen inhibits cell proliferation and promotes cell differentiation of epithelial cells. Topical methoxsalen may be used for small patches of vitiligo, and oral therapy is used for more widespread disease. Because of the possibilities for aging of the skin and possible carcinogenicity, it is used with caution.

Drugs for Dermatologic Disorders: DRUGS FOR PSORIASIS

Focus topic: Drugs for Dermatologic Disorders

Psoriasis is a skin disease that presents with erythematous scaling plaques. It manifests with increased epidermal cell proliferation. Psoriasis appears to have both genetic factors and T-cell–mediated immune components. The majority of patients have mild to moderate psoriasis, and this can be managed with topical treatments including retinoids, vitamin D analogues, keratolytic agents and corticosteroids. More severe cases require systemic therapy with phototherapy (methoxsalen followed by UVA or UVB alone), methotrexate, cyclosporine, or biologic response modifiers (for example, etanercept, adalimumab;

Drugs for Dermatologic Disorders

A. Retinoids

Tazarotene is a topical retinoid used for the treatment of plaque psoriasis. Adverse effects are similar to other retinoids. Acitretin [a-si-TRE-tin] is a second-generation retinoid used orally in the treatment of pustular forms of psoriasis. It is a metabolite of etretinate (no longer available), which has a half-life of 120 days. Since ingestion of ethanol can increase transesterification of acitretin to etretinate, ethanol is contraindicated with this agent. Like other retinoids, acitretin is teratogenic and women must avoid pregnancy for at least 3 years after the use of this drug (due to the long duration of teratogenic potential). Cheilitis, pruritus, peeling skin, and hyperlipidemia are common adverse effects.

B. Vitamin D analogues

Calcipotriene [cal-sih-poh-TRY-een] and calcitriol [kal-si-TRYE-ol] are synthetic vitamin D3 derivatives used topically to treat plaque psoriasis. They inhibit keratinocyte proliferation and increase keratinocyte differentiation. Their therapeutic effectiveness does not appear to decrease upon continued use. Transient elevations in calcium levels have been reported in some patients. Adverse effects include itching, dryness, burning irritation, and erythema.

C. Keratolytic agents

Keratolytic agents such as coal tar and salicylic acid are effective in localized psoriasis, especially on the scalp. They improve corticosteroid penetration. Coal tar inhibits excessive skin cell proliferation and may also have anti-inflammatory effects. Because it is cosmetically unappealing, coal tar may have a low acceptance rate among patients and, consequently, its use has been largely supplanted by the newer topical agents.

Drugs for Dermatologic Disorders: TOPICAL CORTICOSTEROIDS

Focus topic: Drugs for Dermatologic Disorders

Corticosteroids (glucocorticoids) have immunosuppressive and antiinflammatory properties. Topical corticosteroids are used for the treatment of psoriasis, eczema, contact dermatitis, and other skin conditions manifested by itching and inflammation. They are administered locally and via topical and intralesional routes. Corticosteroids work via intracellular receptors and initiate several transcriptions and translations leading to their multiple effects. The actions include inhibitory effects on the arachidonic acid cascade, depression of production of many cytokines, and effects on inflammatory cells. In psoriasis, they inhibit epidermal cell mitosis. Numerous topical corticosteroids are available, with varying potencies and multiple vehicles of delivery. Tachyphylaxis (decrease in response after repetitive use, tolerance) can occur with continuous use. Substitution of a different corticosteroid or less frequent use can minimize tolerance. Adverse effects include skin atrophy (thinning of the skin), striae, purpura, acneiform eruptions, dermatitis, local infections, and hypopigmentation. In children, potent agents applied to a large surface area can cause systemic toxicity, including depression of the hypothalamic–pituitary–adrenal axis and growth retardation.

Drugs for Dermatologic Disorders

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Drugs for Dermatologic Disorders: TRICHOGENIC AGENTS

Focus topic: Drugs for Dermatologic Disorders

Minoxidil [min-OX-i-dil] and finasteride [fih-NAH-steh-ride] are trichogenic agents that are indicated for the treatment of androgenic alopecia (“male pattern baldness”). Minoxidil, originally used as a systemic antihypertensive, was noted to have the adverse effect of increased hair growth. This adverse effect was turned into a therapeutic application in the treatment of alopecia. For hair loss, the drug is available as a nonprescription topical foam or solution. As a topical therapy, it does not cause systemic hypotension. Minoxidil is effective at halting hair loss in both men and women and may produce hair growth in some patients. Although the mechanism of action is not fully known, it is believed to act, at least in part, by shortening the rest phase of the hair cycle. The drug must be used continuously to maintain effects on hair growth.

Finasteride is an oral 5-α reductase inhibitor that blocks conversion of testosterone to the potent androgen 5-α dihydrotestosterone (DHT). High levels of DHT can cause the hair follicle to miniaturize and atrophy. Finasteride decreases scalp and serum DHT concentrations, thus inhibiting a key factor in the etiology of androgenic alopecia. [Note: Finasteride is used in higher doses for the treatment of benign prostatic hyperplasia.] Adverse effects include decreased libido, decreased ejaculation, and erectile dysfunction. The drug should not be used or handled in pregnancy, as it can cause hypospadias in a male fetus. Like minoxidil, use must be continued to maintain therapeutic benefits.

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