Topical medications usually consist of active ingredients incorporated in a vehicle that facilitates cutaneous application. Important considerations in vehicle selection include the solubility of the active agent in the vehicle; the rate of release of the agent from the vehicle; the ability of the vehicle to hydrate the stratum corneum, thus enhancing penetration; the stability of the therapeutic agent in the vehicle; and interactions, chemical and physical, of the vehicle, stratum corneum, and active agent.
Depending upon the vehicle, dermatologic formulations may be classified as tinctures, wet dressings, lotions, gels, aerosols, powders, pastes, creams, foams, and ointments. The ability of the vehicle to retard evaporation from the surface of the skin increases in this series, being least in tinctures and wet dressings and greatest in ointments. In general, acute inflammation with oozing, vesiculation, and crusting is best treated with drying preparations such as tinctures, wet dressings, and lotions, whereas chronic inflammation with xerosis, scaling, and lichenification is best treated with more lubricating preparations such as creams and ointments. Tinctures, lotions, gels, foams, and aerosols are convenient for application to the scalp and hairy areas. Emulsified vanishing-type creams may be used in intertriginous areas without causing maceration.
Emulsifying agents provide homogeneous, stable preparations when mixtures of immiscible liquids such as oil-in-water creams are compounded. Some patients develop irritation from these agents. Substituting a preparation that does not contain them or using one containing a lower concentration may resolve the problem.
Topical Antibacterial Preparations
Topical antibacterial agents may be useful in preventing infections in clean wounds, in the early treatment of infected dermatoses and wounds, in reducing colonization of the nares by staphylococci, in axillary deodorization, and in the management of acnevulgaris. The efficacy of antibiotics in these topical applications is not uniform. The general pharmacology of the antimicrobial drugs is discussed in Chapters 43, 44, 45, 46, 47, 48, 49, 50, and 51.
Some topical anti-infectives contain corticosteroids in addition to antibiotics. There is no convincing evidence that topical corticosteroids inhibit the antibacterial effect of antibiotics when the two are incorporated in the same preparation. In the treatment of secondarily infected dermatoses, which are usually colonized with streptococci, staphylococci, or both, combination therapy may prove superior to corticosteroid therapy alone. Antibiotic-corticosteroid combinations may be useful in treating diaper dermatitis, otitis externa, and impetiginized eczema.
The selection of a particular antibiotic depends upon the diagnosis and, when appropriate, in vitro culture and sensitivity studies of clinical samples. The pathogens isolated from most infected dermatoses are group hemolytic streptococci, Staphylococcus aureus, or both. The pathogens present in surgical wounds will be those resident in the environment. Information about regional patterns of drug resistance is therefore important in selecting a therapeutic agent. Prepackaged topical antibacterial preparations that contain multiple antibiotics are available in fixed dosages well above the therapeutic threshold. These formulations offer the advantages of efficacy in mixed infections, broader coverage for infections due to undetermined pathogens, and delayed microbial resistance to any single component antibiotic.
Bacitracin & Gramicidin
Bacitracin and gramicidin are peptide antibiotics, active against gram-positive organisms such as streptococci, pneumococci, and staphylococci. In addition, most anaerobic cocci, neisseriae, tetanus bacilli, and diphtheria bacilli are sensitive. Bacitracin is compounded in an ointment base alone or in combination with neomycin, polymyxin B, or both. The use of bacitracin in the anterior nares may temporarily decrease colonization by pathogenic staphylococci. Microbial resistance may develop following prolonged use. Bacitracin-induced contact urticaria syndrome, including anaphylaxis, occurs rarely. Allergic contact dermatitis occurs frequently, and immunologic contact urticaria rarely. Bacitracin is poorly absorbed through the skin, so systemic toxicity is rare.
Gramicidin is available only for topical use, in combination with other antibiotics such as neomycin, polymyxin, bacitracin, and nystatin. Systemic toxicity limits this drug to topical use. The incidence of sensitization following topical application is exceedingly low in therapeutic concentrations.
Mupirocin (pseudomonic acid A) is structurally unrelated to other currently available topical antibacterial agents. Most gram-positive aerobic bacteria, including methicillin-resistant S aureus (MRSA), are sensitive to mupirocin (see Chapter 50). It is effective in the treatment of impetigo caused by S aureus and group A -hemolytic streptococci.
Intranasal mupirocin in Bactroban Nasal ointment for eliminating nasal carriage of S aureus may be associated with irritation of mucous membranes caused by the polyethylene glycol vehicle. Mupirocin is not appreciably absorbed systemically after topical application to intact skin.
Retapamulin is a semisynthetic pleromutilin derivative effective in the treatment of uncomplicated superficial skin infection caused by group A http://www.accessmedicine.com/images/special/betalowerhemolytic streptococci and S aureus, excluding MRSA. Topical retapamulin 1% ointment is indicated for use in adult and pediatric patients, 9 months or older, for the treatment of impetigo. Recommended treatment regimen is twice-daily application for 5 days. Retapamulin is well tolerated with only occasional local irritation of the treatment site.
Polymyxin B Sulfate
Polymyxin B is a peptide antibiotic effective against gram-negative organisms, including Pseudomonas aeruginosa, Escherichia coli, enterobacter, and klebsiella. Most strains of proteus and serratia are resistant, as are all gram-positive organisms. Topical preparations may be compounded in either a solution or ointment base. Numerous prepackaged antibiotic combinations containing polymyxin B are available. Detectable serum concentrations are difficult to achieve from topical application, but the total daily dose applied to denuded skin or open wounds should not exceed 200 mg in order to reduce the likelihood of neurotoxicity and nephrotoxicity. Hypersensitivity to topically applied polymyxin B sulfate is uncommon.
Neomycin & Gentamicin
Neomycin and gentamicin are aminoglycoside antibiotics active against gram-negative organisms, including E coli, proteus, klebsiella, and enterobacter. Gentamicin generally shows greater activity against P aeruginosa than neomycin. Gentamicin is also more active against staphylococci and group A http://www.accessmedicine.com/images/special/betalower-hemolytic streptococci. Widespread topical use of gentamicin, especially in a hospital environment, should be avoided to slow the appearance of gentamicin-resistant organisms.
Neomycin is available in numerous topical formulations, both alone and in combination with polymyxin, bacitracin, and other antibiotics. It is also available as a sterile powder for topical use. Gentamicin is available as an ointment or cream.
Topical application of neomycin rarely results in detectable serum concentrations. However, in the case of gentamicin, serum concentrations of 1-18 mcg/mL are possible if the drug is applied in a water-miscible preparation to large areas of denuded skin, as in burned patients. Both drugs are water-soluble and are excreted primarily in the urine. Renal failure may permit the accumulation of these antibiotics, with possible nephrotoxicity, neurotoxicity, and ototoxicity.
Neomycin frequently causes sensitization, particularly if applied to eczematous dermatoses or if compounded in an ointment vehicle. When sensitization occurs, cross-sensitivity to streptomycin, kanamycin, paromomycin, and gentamicin is possible.
Topical Antibiotics in Acne
Several systemic antibiotics that have traditionally been used in the treatment of acnevulgaris have been shown to be effective when applied topically. Currently, four antibiotics are so utilized: clindamycin phosphate, erythromycin base, metronidazole, and sulfacetamide. The effectiveness of topical therapy is less than that achieved by systemic administration of the same antibiotic. Therefore, topical therapy is generally suitable only in mild to moderate cases of inflammatory acne.
Clindamycin has in vitro activity against Propionibacterium acnes; this has been postulated as the mechanism of its beneficial effect in acne therapy. Approximately 10% of an applied dose is absorbed, and rare cases of bloody diarrhea and pseudomembranous colitis have been reported following topical application. The hydroalcoholic vehicle and foam formulation (Evoclin) may cause drying and irritation of the skin, with complaints of burning and stinging. The water-based gel and lotion formulations are well tolerated and less likely to cause irritation. Allergic contact dermatitis is uncommon. Clindamycin is also available in fixed-combination topical gels with benzoyl peroxide (BenzaClin, Duac), and with tretinoin (Ziana).
In topical preparations, erythromycin base rather than a salt is used to facilitate penetration. The mechanism of action of topical erythromycin in inflammatory acnevulgaris is unknown but is presumed to be due to its inhibitory effects on P acnes. One of the possible complications of topical therapy is the development of antibiotic-resistant strains of organisms, including staphylococci. If this occurs in association with a clinical infection, topical erythromycin should be discontinued and appropriate systemic antibiotic therapy started. Adverse local reactions to erythromycin solution may include a burning sensation at the time of application and drying and irritation of the skin. The topical water-based gel is less drying and may be better tolerated. Allergic hypersensitivity appears to be uncommon. Erythromycin is also available in a fixed combination preparation with benzoyl peroxide (Benzamycin) for topical treatment of acne vulgaris.
Topical metronidazole is effective in the treatment of rosacea. The mechanism of action is unknown, but it may relate to the inhibitory effects of metronidazole on Demodex brevis; alternately, the drug may act as an anti-inflammatory agent by direct effect on neutrophil cellular function. Oral metronidazole has been shown to be a carcinogen in susceptible rodent species, and topical use during pregnancy and by nursing mothers and children is therefore not recommended.
Adverse local effects of the water-based gel formulation (MetroGel) include dryness, burning, and stinging. Less drying formulations may be better tolerated (MetroCream, MetroLotion, and Noritate cream). Caution should be exercised when applying metronidazole near the eyes to avoid excessive tearing.
Topical sulfacetamide is available alone as a 10% lotion (Klaron) and as a 10% wash (Ovace), and in several preparations in combination with sulfur for the treatment of acnevulgaris and acne rosacea. The mechanism of action is thought to be inhibition of P acnes by competitive inhibition of p-aminobenzoic acid utilization. Approximately 4% of topically applied sulfacetamide is absorbed percutaneously, and its use is therefore contraindicated in patients having a known hypersensitivity to sulfonamides.
The treatment of superficial fungal infections caused by dermatophytic fungi may be accomplished (1) with topical antifungal agents, eg, clotrimazole, miconazole, econazole, ketoconazole, oxiconazole, sulconazole, sertaconazole, ciclopirox olamine, naftifine, terbinafine, butenafine, and tolnaftate; or (2) with orally administered agents, ie, griseofulvin, terbinafine, ketoconazole, fluconazole, and itraconazole. Superficial infections caused by candida species may be treated with topical applications of clotrimazole, miconazole, econazole, ketoconazole, oxiconazole, ciclopirox olamine, nystatin, or amphotericin B. Chronic generalized mucocutaneous candidiasis is responsive to long-term therapy with oral ketoconazole.
Topical Antifungal Preparations
Topical Azole Derivatives
The topical imidazoles, which currently include clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sulconazole, and sertaconazole, have a wide range of activity against dermatophytes (epidermophyton, microsporum, and trichophyton) and yeasts, including Candida albicans and Pityrosporum orbiculare (see Chapter 48).
Miconazole (Monistat, Micatin) is available for topical application as a cream or lotion and as vaginal cream or suppositories for use in vulvovaginal candidiasis. Clotrimazole (Lotrimin, Mycelex) is available for topical application to the skin as a cream or lotion and as vaginal cream and tablets for use in vulvovaginal candidiasis. Econazole (Spectazole) is available as a cream for topical application. Oxiconazole (Oxistat) is available as a cream and lotion for topical use. Ketoconazole (Nizoral) is available as a cream for topical treatment of dermatophytosis and candidiasis and as a shampoo for the treatment of seborrheic dermatitis. Sulconazole (Exelderm) is available as a cream or solution. Sertaconazole (Ertaczo) is available as a cream. Topical antifungal-corticosteroid fixed combinations have been introduced on the basis of providing more rapid symptomatic improvement than an antifungal agent alone. Clotrimazole-betamethasone dipropionate cream (Lotrisone) is one such combination.
Once- or twice-daily application to the affected area will generally result in clearing of superficial dermatophyte infections in 2-3 weeks, although the medication should be continued until eradication of the organism is confirmed. Paronychial and intertriginous candidiasis can be treated effectively by any of these agents when applied three or four times daily. Seborrheic dermatitis should be treated with twice-daily applications of ketoconazole until clinical clearing is obtained.
Adverse local reactions to the imidazoles may include stinging, pruritus, erythema, and local irritation. Allergic contact dermatitis appears to be uncommon.
Ciclopirox olamine is a synthetic broad-spectrum antimycotic agent with inhibitory activity against dermatophytes, candida species, and P orbiculare. This agent appears to inhibit the uptake of precursors of macromolecular synthesis; the site of action is probably the fungal cell membrane.
Pharmacokinetic studies indicate that 1-2% of the dose is absorbed when applied as a solution on the back under an occlusive dressing. Ciclopirox olamine is available as a 1% cream and lotion (Loprox) for the topical treatment of dermatomycosis, candidiasis, and tinea versicolor. The incidence of adverse reactions has been low. Pruritus and worsening of clinical disease have been reported. The potential for delayed allergic contact hypersensitivity appears small.
Topical 8% ciclopirox olamine (Penlac nail lacquer) has been approved for the treatment of mild to moderate onychomycosis of fingernails and toenails. Although well tolerated with minimal side effects, the overall cure rates in clinical trials are less than 12%.
Allylamines: Naftifine & Terbinafine
Naftifine hydrochloride and terbinafine (Lamisil) are allylamines that are highly active against dermatophytes but less active against yeasts. The antifungal activity derives from selective inhibition of squalene epoxidase, a key enzyme for the synthesis of ergosterol (see Figure 48-1).
They are available as 1% creams and other forms for the topical treatment of dermatophytosis, to be applied on a twice-daily dosing schedule. Adverse reactions include local irritation, burning sensation, and erythema. Contact with mucous membranes should be avoided.
Butenafine hydrochloride (Mentax) is a benzylamine that is structurally related to the allylamines. As with the allylamines, butenafine inhibits the epoxidation of squalene, thus blocking the synthesis of ergosterol, an essential component of fungal cell membranes. Butenafine is available as a 1% cream to be applied once daily for the treatment of superficial dermatophytosis.
Tolnaftate is a synthetic antifungal compound that is effective topically against dermatophyte infections caused by epidermophyton, microsporum, and trichophyton. It is also active against P orbiculare but not against candida.
Tolnaftate (Aftate, Tinactin) is available as a cream, solution, powder, or powder aerosol for application twice daily to infected areas. Recurrences following cessation of therapy are common, and infections of the palms, soles, and nails are usually unresponsive to tolnaftate alone. The powder or powder aerosol may be used chronically following initial treatment in patients susceptible to tinea infections. Tolnaftate is generally well tolerated and rarely causes irritation or allergic contact sensitization.
Nystatin & Amphotericin B
Nystatin and amphotericin B are useful in the topical therapy of C albicans infections but ineffective against dermatophytes. Nystatin is limited to topical treatment of cutaneous and mucosal candida infections because of its narrow spectrum and negligible absorption from the gastrointestinal tract following oral administration. Amphotericin B has a broader antifungal spectrum and is used intravenously in the treatment of many systemic mycoses (see Chapter 48) and to a lesser extent in the treatment of cutaneous candida infections.
The recommended dosage for topical preparations of nystatin in treating paronychial and intertriginous candidiasis is application two or three times a day. Oral candidiasis (thrush) is treated by holding 5 mL (infants, 2 mL) of nystatin oral suspension in the mouth for several minutes four times daily before swallowing. An alternative therapy for thrush is to retain a vaginal tablet in the mouth until dissolved four times daily. Recurrent or recalcitrant perianal, vaginal, vulvar, and diaper area candidiasis may respond to oral nystatin, 0.5-1 million units in adults (100,000 units in children) four times daily in addition to local therapy. Vulvovaginal candidiasis may be treated by insertion of 1 vaginal tablet twice daily for 14 days, then nightly for an additional 14-21 days.
Amphotericin B (Fungizone) is available for topical use in cream and lotion form. The recommended dosage in the treatment of paronychial and intertriginous candidiasis is application two to four times daily to the affected area.
Adverse effects associated with oral administration of nystatin include mild nausea, diarrhea, and occasional vomiting. Topical application is nonirritating, and allergic contact hypersensitivity is exceedingly uncommon. Topical amphotericin B is well tolerated and only occasionally locally irritating. Hypersensitivity is rare. The drug may cause a temporary yellow staining of the skin, especially when the cream vehicle is used.
Oral Antifungal Agents
Oral Azole Derivatives
Azole derivatives currently available for oral treatment of systemic mycosis include fluconazole (Diflucan), itraconazole (Sporanox), ketoconazole (Nizoral), and others. As discussed in Chapter 48, imidazole derivatives act by affecting the permeability of the cell membrane of sensitive cells through alterations of the biosynthesis of lipids, especially sterols, in the fungal cell.
Patients with chronic mucocutaneous candidiasis respond well to a once-daily dose of 200 mg of ketoconazole, with a median clearing time of 16 weeks. Most patients require long-term maintenance therapy. Variable results have been reported in treatment of chromomycosis.
Ketoconazole is effective in the therapy of cutaneous infections caused by epidermophyton, microsporum, and trichophyton species. Infections of the glabrous skin often respond within 2-3 weeks to a once-daily oral dose of 200 mg. Palmar-plantar skin is slower to respond, often taking 4-6 weeks at a dosage of 200 mg twice daily. Infections of the hair and nails may take even longer before resolving, with low cure rates noted for tinea capitis. Tinea versicolor is responsive to short courses of a once-daily dose of 200 mg.
Nausea or pruritus occurs in approximately 3% of patients taking ketoconazole. More significant adverse effects include gynecomastia, elevations of hepatic enzyme levels, and hepatitis. Caution is advised when using ketoconazole in patients with a history of hepatitis. Routine evaluation of hepatic function is advisable for patients on prolonged therapy.
Fluconazole is well absorbed following oral administration, with a plasma half-life of 30 hours. In view of this long half-life, daily doses of 100 mg are sufficient to treat mucocutaneous candidiasis; alternate-day doses are sufficient for dermatophyte infections. The plasma half-life of itraconazole is similar to that of fluconazole, and detectable therapeutic concentrations remain in the stratum corneum for up to 28 days following termination of therapy. Itraconazole is effective for the treatment of onychomycosis in a dosage of 200 mg daily taken with food to ensure maximum absorption for 3 consecutive months. Recent reports of heart failure in patients receiving itraconazole for onychomycosis have resulted in recommendations that it not be given for treatment of onychomycosis in patients with ventricular dysfunction. Additionally, routine evaluation of hepatic function is recommended for patients receiving itraconazole for onychomycosis.
Administration of oral azoles with midazolam or triazolam has resulted in elevated plasma concentrations and may potentiate and prolong hypnotic and sedative effects of these agents. Administration with HMG-CoA reductase inhibitors has been shown to cause a significant risk of rhabdomyolysis. Therefore, administration of the oral azoles with midazolam, triazolam, or HMG-CoA inhibitors is contraindicated.
Griseofulvin is effective orally against dermatophyte infections caused by epidermophyton, microsporum, and trichophyton. It is ineffective against candida and P orbiculare. Griseofulvin's mechanism of antifungal action is not fully understood, but it is active only against growing cells.
Following the oral administration of 1 g of micronized griseofulvin, drug can be detected in the stratum corneum 4-8 hours later. Reducing the particle size of the medication greatly increases absorption of the drug. Formulations that contain the smallest particle size are labeled "ultramicronized." Ultramicronized griseofulvin achieves bioequivalent plasma levels with half the dose of micronized drug. In addition, solubilizing griseofulvin in polyethylene glycol enhances absorption even further. Micronized griseofulvin is available as 250 mg and 500 mg tablets, and ultramicronized drug is available as 125 mg, 165 mg, 250 mg, and 330 mg tablets and as 250 mg capsules.
The usual adult dosage of the micronized ("microsize") form of the drug is 500 mg daily in single or divided doses with meals; occasionally, 1 g/d is indicated in the treatment of recalcitrant infections. The pediatric dosage is 10 mg/kg of body weight daily in single or divided doses with meals. An oral suspension is available for use in children.
Griseofulvin is most effective in treating tinea infections of the scalp and glabrous (nonhairy) skin. In general, infections of the scalp respond to treatment in 4-6 weeks, and infections of glabrous skin will respond in 3-4 weeks. Dermatophyte infections of the nails respond only to prolonged administration of griseofulvin. Fingernails may respond to 6 months of therapy, whereas toenails are quite recalcitrant to treatment and may require 8-18 months of therapy; relapse almost invariably occurs.
Adverse effects seen with griseofulvin therapy include headaches, nausea, vomiting, diarrhea, photosensitivity, peripheral neuritis, and occasionally mental confusion. Griseofulvin is derived from a penicillium mold, and cross-sensitivity with penicillin may occur. It is contraindicated in patients with porphyria or hepatic failure or those who have had hypersensitivity reactions to it in the past. Its safety in pregnant patients has not been established. Leukopenia and proteinuria have occasionally been reported. Therefore, in patients undergoing prolonged therapy, routine evaluation of the hepatic, renal, and hematopoietic systems is advisable. Coumarin anticoagulant activity may be altered by griseofulvin, and anticoagulant dosage may require adjustment.
Terbinafine (described above) is quite effective given orally for the treatment of onychomycosis. Recommended oral dosage is 250 mg daily for 6 weeks for fingernail infections and 12 weeks for toenail infections. Patients receiving terbinafine for onychomycosis should be monitored closely with periodic laboratory evaluations for possible hepatic dysfunction.
Topical Antiviral Agents
Acyclovir, Valacyclovir, Penciclovir, & Famciclovir
Acyclovir, valacyclovir, penciclovir, and famciclovir are synthetic guanine analogs with inhibitory activity against members of the herpesvirus family, including herpes simplex types 1 and 2. Their mechanism of action, indications, and usage in the treatment of cutaneous infections are discussed in Chapter 49.
Topical acyclovir (Zovirax) is available as a 5% ointment; topical penciclovir (Denavir), as a 1% cream for the treatment of recurrent orolabial herpes simplex virus infection in immunocompetent adults. Adverse local reactions to acyclovir and penciclovir may include pruritus and mild pain with transient stinging or burning.
Imiquimod (Aldara) is an immunomodulator approved for the treatment of external genital and perianal warts in adults, actinic keratoses on the face and scalp, and biopsy-proven primary basal cell carcinomas on the trunk, neck, and extremities. The mechanism of its action is thought to be related to imiquimod's ability to stimulate peripheral mononuclear cells to release interferon
Imiquimod should be applied to the wart tissue three times per week and left on the skin for 6-10 hours prior to washing off with mild soap and water. Treatment should be continued until eradication of the warts is accomplished, but not for more than a total of 16 weeks. Recommended treatment of actinic keratoses consists of twice-weekly applications on the contiguous area of involvement. The cream is removed after approximately 8 hours with mild soap and water. Treatment of superficial basal cell carcinoma consists of five-times-per-week application to the tumor, including a 1-cm margin of surrounding skin, for a 6-week course of therapy.
Percutaneous absorption is minimal, with less than 0.9% absorbed following a single-dose application. Adverse side effects consist of local inflammatory reactions, including pruritus, erythema, and superficial erosion.
Tacrolimus & Pimecrolimus
Tacrolimus (Protopic) and pimecrolimus (Elidel) are macrolide immunosuppressants that have been shown to be of significant benefit in the treatment of atopic dermatitis. Both agents inhibit T-lymphocyte activation and prevent the release of inflammatory cytokines and mediators from mast cells in vitro after stimulation by antigen-IgE complexes. Tacrolimus is available as 0.03% and 0.1% ointments, and pimecrolimus is available as a 1% cream. Both are indicated for short-term and intermittent long-term therapy for mild to moderate atopic dermatitis. Tacrolimus 0.03% ointment and pimecrolimus 1% cream are approved for use in children older than 2 years of age, although all strengths are approved for adult use. Recommended dosing of both agents is twice-daily application to affected skin until clearing is noted. Neither medication should be used with occlusive dressings. The most common side effect of both drugs is a burning sensation in the applied area that improves with continued use. The FDA has added a black box warning regarding the long-term safety of topical tacrolimus and pimecrolimus because of animal tumorigenicity data.
Permethrin is toxic to Pediculus humanus, Pthirus pubis, and Sarcoptes scabiei. Less than 2% of an applied dose is absorbed percutaneously. Residual drug persists up to 10 days following application.
It is recommended that permethrin 1% cream rinse (Nix) be applied undiluted to affected areas of pediculosis for 10 minutes and then rinsed off with warm water. For the treatment of scabies, a single application of 5% cream (Elimite) is applied to the body from the neck down, left on for 8-14 hours, and then washed off. Adverse reactions to permethrin include transient burning, stinging, and pruritus. Cross-sensitization to pyrethrins or chrysanthemums has been alleged but inadequately documented.
The gamma isomer of hexachlorocyclohexane was commonly called gamma benzene hexachloride, a misnomer, since no benzene ring is present in this compound. Percutaneous absorption studies using a solution of lindane in acetone have shown that almost 10% of a dose applied to the forearm is absorbed, to be subsequently excreted in the urine over a 5-day period. After absorption, lindane is concentrated in fatty tissues, including the brain.
Lindane (Kwell, etc) is available as a shampoo or lotion. For pediculosis capitis or pubis, 30 mL of shampoo is applied to dry hair on the scalp or genital area for 4 minutes and then rinsed off. No additional application is indicated unless living lice are present 1week after treatment. Then reapplication may be required.
Recent concerns about the toxicity of lindane have altered treatment guidelines for its use in scabies; the current recommendation calls for a single application to the entire body from the neck down, left on for 8-12 hours, and then washed off. Patients should be retreated only if active mites can be demonstrated, and never within 1 week of initial treatment.
Concerns about neurotoxicity and hematotoxicity have resulted in warnings that lindane should be used with caution in infants, children, and pregnant women. The current USA package insert recommends that it not be used as a scabicide in premature infants and in patients with known seizure disorders. California has prohibited the medical use of lindane following evaluation of its toxicologic profile. The risk of adverse systemic reactions to lindane appears to be minimal when it is used properly and according to directions in adult patients. However, local irritation may occur, and contact with the eyes and mucous membranes should be avoided.
Crotamiton, N-ethyl-o-crotonotoluidide, is a scabicide with some antipruritic properties. Its mechanism of action is not known. Studies on percutaneous absorption have revealed detectable levels of crotamiton in the urine following a single application on the forearm.
Crotamiton (Eurax) is available as a cream or lotion. Suggested guidelines for scabies treatment call for two applications to the entire body from the chin down at 24-hour intervals, with a cleansing bath 48 hours after the last application. Crotamiton is an effective agent that can be used as an alternative to lindane. Allergic contact hypersensitivity and primary irritation may occur, necessitating discontinuance of therapy. Application to acutely inflamed skin or to the eyes or mucous membranes should be avoided.
Sulfur has a long history of use as a scabicide. Although it is nonirritating, it has an unpleasant odor, is staining, and is thus disagreeable to use. It has been replaced by more aesthetic and effective scabicides in recent years, but it remains a possible alternative drug for use in infants and pregnant women. The usual formulation is 5% precipitated sulfur in petrolatum.
Malathion is an organophosphate cholinesterase inhibitor that is hydrolyzed and inactivated by plasma carboxylesterases much faster in humans than in insects, thereby providing a therapeutic advantage in treating pediculosis (see Chapter 7). Malathion is available as a 0.5% lotion (Ovide) that should be applied to the hair when dry; 4-6 hours later, the hair is combed to remove nits and lice.
Agents Affecting Pigmentation
Hydroquinone, Monobenzone, & Mequinol
Hydroquinone, monobenzone (Benoquin, the monobenzyl ether of hydroquinone), and mequinol (the monomethyl ether of hydroquinone) are used to reduce hyperpigmentation of the skin. Topical hydroquinone and mequinol usually result in temporary lightening, whereas monobenzone causes irreversible depigmentation.
The mechanism of action of these compounds appears to involve inhibition of the enzyme tyrosinase, thus interfering with the biosynthesis of melanin. In addition, monobenzone may be toxic to melanocytes, resulting in permanent loss of these cells. Some percutaneous absorption of these compounds takes place, because monobenzone may cause hypopigmentation at sites distant from the area of application. Both hydroquinone and monobenzone may cause local irritation. Allergic sensitization to these compounds can occur. Prescription combinations of hydroquinone, fluocinolone acetonide, and retinoic acid (Tri-Luma) and mequinol and retinoic acid (Solagé) are more effective than their individual components.
Trioxsalen & Methoxsalen
Trioxsalen and methoxsalen are psoralens used for the repigmentation of depigmented macules of vitiligo. With the recent development of high-intensity long-wave ultraviolet fluorescent lamps, photochemotherapy with oral methoxsalen for psoriasis and with oral trioxsalen for vitiligo has been under intensive investigation.
Psoralens must be photoactivated by long-wavelength ultraviolet light in the range of 320-400 nm (ultraviolet A [UVA]) to produce a beneficial effect. Psoralens intercalate with DNA and, with subsequent UVA irradiation, cyclobutane adducts are formed with pyrimidine bases. Both monofunctional and bifunctional adducts may be formed, the latter causing interstrand cross-links. These DNA photoproducts may inhibit DNA synthesis. The major long-term risks of psoralen photochemotherapy are cataracts and skin cancer.
Topical medications useful in protecting against sunlight contain either chemical compounds that absorb ultraviolet light, called sunscreens, or opaque materials such as titanium dioxide that reflect light, called sunshades. The three classes of chemical compounds most commonly used in sunscreens are p-aminobenzoic acid (PABA) and its esters, the benzophenones, and the dibenzoylmethanes.
Most sunscreen preparations are designed to absorb ultraviolet light in the ultraviolet B (UVB) wavelength range from 280 to 320 nm, which is the range responsible for most of the erythema and tanning associated with sun exposure. Chronic exposure to light in this range induces aging of the skin and photocarcinogenesis. Para-aminobenzoic acid and its esters are the most effective available absorbers in the B region.
The benzophenones include oxybenzone, dioxybenzone, and sulisobenzone. These compounds provide a broader spectrum of absorption from 250 to 360 nm, but their effectiveness in the UVB erythema range is less than that of PABA. The dibenzoylmethanes include Parasol and Eusolex. These compounds absorb wavelengths throughout the longer UVA range, 320 to 400 nm, with maximum absorption at 360 nm. Patients particularly sensitive to UVA wavelengths include individuals with polymorphous light eruption, cutaneous lupus erythematosus, and drug-induced photosensitivity. In these patients, dibenzoylmethane-containing sunscreen may provide improved photoprotection. Terephthalylidene dicamphorsulfuric acid (Mexoryl) appears to provide greater UVA protection than the dibenzoylmethanes and is less prone to photodegradation.
The sun protection factor (SPF) of a given sunscreen is a measure of its effectiveness in absorbing erythrogenic ultraviolet light. It is determined by measuring the minimal erythema dose with and without the sunscreen in a group of normal people. The ratio of the minimal erythema dose with sunscreen to the minimal erythema dose without sunscreen is the SPF. Fair-skinned individuals who sunburn easily are advised to use a product with an SPF of 15 or greater.
Retinoic Acid & Derivatives
Retinoic acid, also known as tretinoin or all-trans-retinoic acid, is the acid form of vitamin A. It is an effective topical treatment for acnevulgaris. Several analogs of vitamin A, eg, 13-cis-retinoic acid (isotretinoin), have been shown to be effective in various dermatologic diseases when given orally. Vitamin A alcohol is the physiologic form of vitamin A. The topical therapeutic agent, retinoic acid, is formed by the oxidation of the alcohol group, with all four double bonds in the side chain in the trans configuration as shown.
Retinoic acid is insoluble in water but soluble in many organic solvents. Topically applied retinoic acid remains chiefly in the epidermis, with less than 10% absorption into the circulation. The small quantities of retinoic acid absorbed following topical application are metabolized by the liver and excreted in bile and urine.
Retinoic acid has several effects on epithelial tissues. It stabilizes lysosomes, increases ribonucleic acid polymerase activity, increases prostaglandin E2, cAMP, and cGMP levels, and increases the incorporation of thymidine into DNA. Its action in acne has been attributed to decreased cohesion between epidermal cells and increased epidermal cell turnover. This is thought to result in the expulsion of open comedones and the transformation of closed comedones into open ones.
Topical retinoic acid is applied initially in a concentration sufficient to induce slight erythema with mild peeling. The concentration or frequency of application may be decreased if too much irritation occurs. Topical retinoic acid should be applied to dry skin only, and care should be taken to avoid contact with the corners of the nose, eyes, mouth, and mucous membranes. During the first 4-6 weeks of therapy, comedones not previously evident may appear and give the impression that the acne has been aggravated by the retinoic acid. However, with continued therapy, the lesions will clear, and in 8-12 weeks optimal clinical improvement should occur. A timed-release formulation of tretinoin containing microspheres (Retin-A Micro) delivers the medication over time and may be less irritating for sensitive patients.
The effects of tretinoin on keratinization and desquamation offer benefits for patients with photo damaged skin. Prolonged use of tretinoin promotes dermal collagen synthesis, new blood vessel formation, and thickening of the epidermis, which helps diminish fine lines and wrinkles. A specially formulated moisturizing 0.05% cream (Renova) is marketed for this purpose.
The most common adverse effects of topical retinoic acid are erythema and dryness that occur in the first few weeks of use, but these can be expected to resolve with continued therapy. Animal studies suggest that this drug may increase the tumorigenic potential of ultraviolet radiation. In light of this, patients using retinoic acid should be advised to avoid or minimize sun exposure and use a protective sunscreen. Allergic contact dermatitis to topical retinoic acid is rare.
Adapalene (Differin) is a derivative of naphthoic acid that resembles retinoic acid in structure and effects. It is applied as a 0.1% gel once daily. Unlike tretinoin, adapalene is photochemically stable and shows little decrease in efficacy when used in combination with benzoyl peroxide. Adapalene is less irritating than tretinoin and is most effective in patients with mild to moderate acnevulgaris.
Tazarotene (Tazorac) is an acetylenic retinoid that is available as a 0.1% gel and cream for the treatment of mild to moderately severe facial acne. Topical tazarotene should be used by women of childbearing age only after contraceptive counseling. It is recommended that tazarotene should not be used by pregnant women.
Isotretinoin (Accutane) is a synthetic retinoid currently restricted to the oral treatment of severe cystic acne that is recalcitrant to standard therapies. The precise mechanism of action of isotretinoin in cystic acne is not known, although it appears to act by inhibiting sebaceous gland size and function. The drug is well absorbed, extensively bound to plasma albumin, and has an elimination half-life of 10-20 hours.
Most patients with cystic acne respond to 1-2 mg/kg, given in two divided doses daily for 4-5 months. If severe cystic acne persists following this initial treatment, after a period of 2 months, a second course of therapy may be initiated. Common adverse effects resemble hypervitaminosis A and include dryness and itching of the skin and mucous membranes. Less common side effects are headache, corneal opacities, pseudotumor cerebri, inflammatory bowel disease, anorexia, alopecia, and muscle and joint pains. These effects are all reversible on discontinuance of therapy. Skeletal hyperostosis has been observed in patients receiving isotretinoin with premature closure of epiphyses noted in children treated with this medication. Lipid abnormalities (triglycerides, high-density lipoproteins) are frequent; their clinical relevance is unknown at present.
Teratogenicity is a significant risk in patients taking isotretinoin; therefore, women of childbearing potential must use an effective form of contraception for at least 1 month before, throughout isotretinoin therapy, and for one or more menstrual cycles following discontinuance of treatment. A negative serum pregnancy test must be obtained within 2 weeks before starting therapy in these patients, and therapy should be initiated only on the second or third day of the next normal menstrual period. In the USA, health care professionals, pharmacists, and patients must utilize a mandatory registration and follow-up system.
Benzoyl peroxide is an effective topical agent in the treatment of acnevulgaris. It penetrates the stratum corneum or follicular openings unchanged and is converted metabolically to benzoic acid within the epidermis and dermis. Less than 5% of an applied dose is absorbed from the skin in an 8-hour period. It has been postulated that the mechanism of action of benzoyl peroxide in acne is related to its antimicrobial activity against P acnes and to its peeling and comedolytic effects.
To decrease the likelihood of irritation, application should be limited to a low concentration (2.5%) once daily for the first week of therapy and increased in frequency and strength if the preparation is well tolerated. Fixed-combination formulations of 5% benzoyl peroxide with 3% erythromycin base (Benzamycin) or 1% clindamycin (BenzaClin) appear to be more effective than individual agents alone.
Benzoyl peroxide is a potent contact sensitizer in experimental studies, and this adverse effect may occur in up to 1% of acne patients. Care should be taken to avoid contact with the eyes and mucous membranes. Benzoyl peroxide is an oxidant and may rarely cause bleaching of the hair or colored fabrics.
Azelaic acid is a straight-chain saturated dicarboxylic acid that is effective in the treatment of acnevulgaris (in the form of Azelex) and acne rosacea (Finacea). Its mechanism of action has not been fully determined, but preliminary studies demonstrate antimicrobial activity against P acnes as well as in vitro inhibitory effects on the conversion of testosterone to dihydrotestosterone. Initial therapy is begun with once-daily applications of the 20% cream or 15% gel to the affected areas for 1 week and twice-daily applications thereafter. Most patients experience mild irritation with redness and dryness of the skin during the first week of treatment. Clinical improvement is noted in 6-8 weeks of continuous therapy.
Drugs for Psoriasis
Acitretin (Soriatane), a metabolite of the aromatic retinoid etretinate, is quite effective in the treatment of psoriasis, especially pustular forms. It is given orally at a dosage of 25-50 mg/d. Adverse effects attributable to acitretin therapy are similar to those seen with isotretinoin and resemble hypervitaminosis A. Elevations in cholesterol and triglycerides may be noted with acitretin, and hepatotoxicity with liver enzyme elevations has been reported. Acitretin is more teratogenic than isotretinoin in the animal species studied to date, which is of special concern in view of the drug's prolonged elimination time (more than 3 months) after chronic administration. In cases where etretinate is formed by concomitant administration of acitretin and ethanol, etretinate may be found in plasma and subcutaneous fat for many years.
Acitretin must not be used by women who are pregnant or may become pregnant while undergoing treatment or at any time for at least 3 years after treatment is discontinued. Ethanol must be strictly avoided during treatment with acitretin and for 2 months after discontinuing therapy. Patients must not donate blood during treatment and for 3 years after acitretin is stopped.
Tazarotene (Tazorac) is a topical acetylenic retinoid prodrug that is hydrolyzed to its active form by an esterase. The active metabolite, tazarotenic acid, binds to retinoic acid receptors, resulting in modified gene expression. The precise mechanism of action in psoriasis is unknown but may relate to both anti-inflammatory and antiproliferative actions. Tazarotene is absorbed percutaneously, and teratogenic systemic concentrations may be achieved if applied to more than 20% of total body surface area. Women of childbearing potential must therefore be advised of the risk prior to initiating therapy, and adequate birth control measures must be utilized while on therapy.
Treatment of psoriasis should be limited to once-daily application not to exceed 20% of total body surface area. Adverse local effects include a burning or stinging sensation (sensory irritation) and peeling, erythema, and localized edema of the skin (irritant dermatitis). Potentiation of photosensitizing medication may occur, and patients should be cautioned to minimize sunlight exposure and to use sunscreens and protective clothing.
Calcipotriene (Dovonex) is a synthetic vitaminD3 derivative that is effective in the treatment of plaque-type psoriasis vulgaris of moderate severity. Approximately 6% of the topically applied 0.005% ointment is absorbed through psoriatic plaques, resulting in a transient elevation of serum calcium in fewer than 1% of subjects treated in clinical trials. Improvement of psoriasis was generally noted following 2 weeks of therapy, with continued improvement for up to 8 weeks of treatment. However, fewer than 10% of patients demonstrate total clearing while on calcipotriene as single-agent therapy. Adverse effects include burning, itching, and mild irritation, with dryness and erythema of the treatment area. Care should be taken to avoid facial contact, which may cause ocular irritation. Recently, a once-daily two-compound ointment containing calcipotriene and betamethasone dipropionate (Taclonex) has become available. This combination is more effective than its individual ingredients and is well tolerated, with a safety profile similar to betamethasone dipropionate.