The therapeutic efficacy of a topical drug relates to both its inherent potency and the ability of that drug to penetrate the skin.1 In fact, many potent agents, such as hydrocortisone and fluocinolone acetonide, are quite poorly absorbed after topical application. Conversely, many well-absorbed agents with weak potency have negligible therapeutic use. Percutaneous absorption necessitates passage through the stratum corneum, epidermis, papillary dermis, and into the bloodstream. (See Chapter 215 for information on the pharmacokinetics of topical therapy.)
In contrast to many orally administered drugs that are nearly completely absorbed within a few hours, topical medicines generally have a poor total absorption and a very slow rate of absorption. For example, less than 2% of a topically applied corticosteroid such as hydrocortisone is absorbed after a single application left on the skin for more than 1 day. Furthermore, peak rates of absorption are reached up to 12–24 hours after application. Fortunately, low absorption does not necessarily translate into low efficacy. Drugs such as topical corticosteroids are effective because of their inherent potency and can exert clinically significant effects in spite of low absorption. In this light, absorption represents only one of many facets of efficacy.
The stratum corneum is the rate-limiting barrier to percutaneous drug delivery. This cornified layer is composed of ceramides, free fatty acids, and cholesterol in a 1:1:1 molar ratio. By weight, the stratum corneum consists of 50% ceramides (acylceramides being the most abundant), 35% cholesterol, and 15% free fatty acids. The stratum corneum thickness and, thus, drug penetration will vary depending on body site.2 Box 214-1 lists varying body sites and their relative resistance to percutaneous absorption.
Box 214-1 Regional Differences in Penetrationa ||Download (.pdf)
Box 214-1 Regional Differences in Penetrationa
Chest and back
Upper arms and legs
Lower arms and legs
Dorsa of hands and feet
Palmar and plantar skin
There are two main routes for permeation through the stratum corneum: (1) the transepidermal and (2) the transappendageal pathways. The transappendageal, or shunt route, involves the flow of molecules through the eccrine glands and hair follicles via the associated sebaceous glands.3 In the transepidermal route, molecules pass between the corneocytes via the intercellular micropathway, or through the cytoplasm of dead keratinocytes and intercellular lipids, defined as the transcellular micropathway.3,4 The intercellular pathway is considered the most important route for cutaneous drug delivery.
An important consideration in topical therapy is that diseased skin may have an altered (increased, decreased, or absent) stratum corneum, thus changing the body site's barrier function. Abraded or eczematized skin presents less of a barrier. Solvents, surfactants, and alcohols can denature the cornified layer and increase penetration; as a result, topical medications with these components may enhance absorption. Importantly, simple hydration of the stratum corneum enhances the absorption of topically applied steroids by four to five times.5
Occlusion via closed, airtight dressings or greasy ointment bases increases the hydration and temperature of the stratum corneum, limits rub-off/wash-off of the drug and, consequently, enhances drug penetration. Occlusion techniques range from application under an airtight dressing such as vinyl gloves, plastic wrap, and hydrocolloid dressings to occlusion with cotton gloves or socks at night for treatment of hands and feet, to application of a medication already impregnated into an airtight dressing, as seen in flurandrenolide tape. To derive the greatest benefit from occlusion, the patient should hydrate the skin by immersion in water for approximately 5 minutes before the application of a cream or ointment. Clinically, this may correspond to application immediately after bathing and before drying completely. With many drugs, occlusion increases drug delivery by 10–100 times the amount of drug delivered when not occluded.6 This approach can lead to more rapid onset times and increased efficacy when compared with topical application alone. On the other hand, occlusion may also lead to a more rapid appearance of the drug's adverse effects, such as the ability of topical corticosteroids to induce local skin atrophy or suppression of the hypothalamus–pituitary–adrenal axis. Occlusion may promote infection, folliculitis, or miliaria. In the case of topical anesthetics such as lidocaine and prilocaine, occlusion hastens absorption into both the skin and the bloodstream, which has led in rare cases to cardiac complications from lidocaine toxicity or methemoglobinemia from prilocaine toxicity.
The frequency of drug application likely has little effect on increasing a topical drug's overall efficacy.6,7 One daily application is enough for most topical glucocorticoids, for example, but the nonspecific emollient or protective effect of creams and ointments are likely enhanced by more frequent applications. Regardless, increasing the contact time for a topical drug augments its total absorption.
The quantity of the drug applied likely has a negligible effect on drug absorption. Obviously enough drug must be dispensed and spread to cover the affected areas. Further, the quantity of drug applied might affect patient adherence to the prescribed regimen. For example, too much applied drug might negatively alter the subjective experience of having a medication on the skin, i.e., the drug may feel “wrong” (greasy, caked, chalky, etc.) or is cosmetically unattractive (shiny, white color). Regardless, the amount prescribed must be adequate to treat the affected body surface area for the necessary length of time. In this regard, patient education is critical to prevent wasteful overuse or ineffective underuse of the medication. The amounts of topical medications to dispense, based on the estimated body surface area, frequency of application, and duration of therapy, are presented in Table 214-1. For topical medications like sunscreens that are used over large areas, underapplication is a problemfor most patients. However, for smaller areas, patients may apply a large amount of an ointment, for example, leading to complaints of greasiness or rubbing off on clothing, which can be minimized by using an appropriate amount.
Table 214-1 Suggested Amounts of Topical Medications to Dispense—Cream or Ointment ||Download (.pdf)
Table 214-1 Suggested Amounts of Topical Medications to Dispense—Cream or Ointment
Estimated% Body Surface Area
Single Application (g)
Twice a Day for 1 Week (g)
Three times a Day for 1 Week (g)
One leg including foot
Topical medication adherence is a critical although often overlooked aspect of medication efficacy. Generally, adherence to a treatment regimen is associated with female gender, employment, being married, and low prescription costs. Lower adherence is seen for patients with extensive disease, and paradoxically, disease on the face.8 One 8-week survey using electronic monitoring showed that adherence to treatment for a twice-daily topical prescription decreased from 84% the first week to 51% during the eighth week, with topical nonadherence being especially notable on weekends.9 Furthermore, adherence is negatively affected by depression, which is common in people with chronic skin conditions and found in up to 20% of patients with psoriasis.10
Defined as the decrease in drug response when used over a prolonged period of time, tachyphylaxis is commonly observed during corticosteroid topical therapy. It is now thought that adherence may be a contributing factor, rather than loss of corticosteroid receptor function.5,11 Increase in adherence may be achieved by asking patients to use it only on weekends (weekend therapy) or specific days of the week (pulse therapy).5
Worsening of preexisting dermatoses can occur in patients who have been using topical potent corticosteroids for prolonged regimens.5 Either tapering down the corticosteroid strength to moderate- or low-potency corticosteroids or increasing the duration of time between applications of the topical drug might prevent the rebound effect.
Vigorous rubbing or massaging of the drug into the skin not only increases the surface area of skin covered, but also increases blood supply to the area locally, augmenting systemic absorption. It may cause a local exfoliative effect that will also enhance penetration. The presence of hair follicles on a particular body site also enhances drug delivery, with the scalp and beard areas presenting less of a barrier when compared with the relatively hairless body sites. Although having a thinner stratum corneum, the skin of older individuals is poorly hydrated, with fewer hair follicles and, therefore, may impede drug delivery.
Reducing the particle size of the active ingredient increases its surface area–volume ratio, allowing for a greater solubility of the drug in its vehicle. This forms the basis for the increased absorption of certain micronized drugs.12
The vehicle is the inactive part of a topical preparation that brings a drug into contact with the skin. Before the mid-1970s pharmaceutical companies performed limited testing of the impact of the vehicle on the potency of a given formulation. The lack of a scientific analysis of the vehicle led to the marketing of topical drugs that, while having different concentrations of the same active ingredient, nevertheless exhibited similar bioavailability and potency. For example, older preparations of triamcinolone acetonide showed no real differences in potency among the 0.025%, 0.1%, and 0.5% concentrations. By contrast, modern drug development attempts to maximize drug bioavailability by optimizing vehicle formulation. Additionally, during the current drug development process, dose-response studies determine the maximal effective concentration within a given vehicle, above which any further increase in concentration serves no therapeutic benefit.
The vehicle of a topical formulation often has beneficial nonspecific effects by possessing cooling, protective, emollient, occlusive, or astringent properties. Rational topical therapy matches an appropriate vehicle that contains an effective concentration of the drug. The vehicle functions optimally when it is stable both chemically and physically and does not inactivate the drug. The vehicle also should be nonirritating, nonallergenic, cosmetically acceptable, and easy to use. Additionally, the vehicle must release the drug into the pharmacologically important compartment of the skin. Finally, the patient must accept using the vehicle or else compliance will be poor. For example, although ointments are often pharmacodynamically more effective than creams, patients generally prefer creams to ointments, and thus, it is no surprise that more prescriptions are written for cream-based formulations. Box 214-2 lists many commonly used ingredients in topical preparations. Many of these compounds may serve more than one function in a particular formulation.
Box 214-2 Vehicle Ingredients Commonly Used in Topical Preparations ||Download (.pdf)
Box 214-2 Vehicle Ingredients Commonly Used in Topical Preparations
- Disodium mono-oleamidosulfosuccinate
- Emulsifying wax
- Polyoxyl 40 stearate
- Sodium laureth sulfate
- Sodium lauryl sulfate
Auxiliary emulsifying agents/emulsion stabilizers
- Benzyl alcohol
- Butylated hydroxyanisole
- Butylated hydroxytoluene
- Citric acid
- Edetate disodium
- Propyl gallate
- Propylene glycol
- Sodium bisulfite
- Sorbic acid/potassium sorbate
- Diisopropyl adipate
- Isopropyl myristate
- Propylene carbonate
- Propylene glycol
- Xanthan gum
Powders absorb moisture and decrease friction. Because they adhere poorly to the skin, their use is mainly limited to cosmetic and hygienic purposes. Generally, powders are used in the intertriginous areas and on the feet. Adverse effects of powders include caking (especially if used on weeping skin), crusting, irritation, and granuloma formation. Further, powders may be inhaled by the user. Most powders contain zinc oxide for its antiseptic and covering properties, talc (primarily composed of magnesium silicate) for its lubricating and drying properties, and a stearate for improved adherence to the skin. Calamine is a popular skin-colored powder composed of 98% zinc oxide and 1% ferric oxide and acts as an astringent to relieve pruritus. Other drugs formulated as powders include some over-the-counter antifungals.12
A poultice, also referred to as a cataplasm, is a wet solid mass of particles, sometimes heated, that is applied to diseased skin. Historically, poultices contained meal, herbs, plants, and seeds. The modern poultice often consists of porous beads of dextranomer. Poultices are used as wound cleansers and absorptive agents in exudative lesions such as decubiti and leg ulcers.12
Ointments are semisolid preparations that spread easily. They are petrolatum-based vehicles, capable of providing occlusion, hydration, and lubrication. Drug potency often is increased by an ointment vehicle due to its ability to enhance permeability.5 Ointment bases used in dermatology can be classified into five categories: (1) hydrocarbon bases, (2) absorption bases, (3) emulsions of water-in-oil, (4) emulsions of oil-in-water, and (5) water-soluble bases. Dermatologists commonly refer to the hydrocarbon bases and absorption bases as ointments and the water-in-oil/oil-in-water emulsion bases as creams. In pharmaceutical terms, all of these preparations are ointments and are specifically indicated for conditions affecting the glabrous skin (palms and soles) and lichenified areas.5
Also called oleaginous bases, hydrocarbon bases are often referred to as emollients because they prevent the evaporation of moisture from the skin and are composed of a mixture of hydrocarbons of varying molecular weights, with petrolatum being the most commonly used (white petrolatum, except for being bleached, is identical to yellow petrolatum). They are greasy and can stain clothing. The silicon ointments are composed of alternating oxygen and silicon atoms bonded to organic groups, such as phenyl or methyl, and are excellent skin protectants. They can be used for diaper rash, incontinence, bedsores, and colostomy sites. Hydrocarbon bases are generally stable and do not contain preservatives. They cannot absorb aqueous solutions, and thus are not used for water-soluble drugs.12
Absorption bases contain hydrophilic substances that allow for the absorption of water-soluble drugs. The hydrophilic (polar) compounds may include lanolin and its derivatives, cholesterol and its derivatives, and the partial esters of polyhydric alcohols such as sorbitan monostearate. These ointments are lubricating and hydrophilic, and they can form emulsions. They function well as emollients and protectants. They are greasy to apply but are easier to remove than the hydrocarbon bases. They do not contain water. Examples include anhydrous lanolin and hydrophilic petrolatum.12
Water‐in-Oil Emulsions (Creams)
Emulsions are two-phase systems involving one or more immiscible liquids dispersed in another, with the assistance of one or more emulsifying agents. A water-in-oil emulsion, by definition, contains less than 25% water, with oil being the dispersion medium. The two phases may separate unless shaken. The emulsifier (or surfactant) is soluble in both phases and surrounds the dispersed drops to prevent their coalescence. Examples of surfactants used include sodium lauryl sulfate, the quaternary ammonium compounds, Spans (sorbitan fatty acid esters), and Tweens (polyoxyethylene sorbitan fatty acid esters). Preservatives are frequently added to increase the emulsion's shelf life. Water-in-oil emulsions are less greasy, spread easily on the skin, and provide a protective film of oil that remains on the skin as an emollient, while the slow evaporation of the water phase provides a cooling effect.8
An oil-in-water emulsion contains greater than 31% water. In fact, the aqueous phase may comprise up to 80% of the formulation. This type of formulation is the one most commonly chosen to deliver a dermatologic drug. Clinically, oil-in-water emulsions spread very easily, are water washable and less greasy, and are easily removed from the skin and clothing. Invariably, they contain preservatives, such as the parabens, to inhibit the growth of molds. Additionally, oil-in-water emulsions contain a humectant (an agent that draws moisture into the skin), such as glycerin, propylene glycol, or polyethylene glycol (PEG), to prevent the cream from drying out. The oil phase may contain either cetyl or stearyl alcohol (paraffin alcohols) to impart a stability and velvety smooth feel upon application to the skin. After application, the aqueous phase evaporates, leaving behind both a small hydrating layer of oil and a concentrated deposit of the drug.12
Water-soluble bases consist either primarily or completely of various PEGs. Depending on their molecular weight, PEGs are either liquid (PEG 400) or solid (PEG 4,000). These formulations are water soluble, will not decompose, and will not support the growth of mold, and therefore require no preservative additives. They are much less occlusive than water-in-oil emulsions, nonstaining, greaseless, and easily washed off of the skin. Without water, this ointment poorly delivers its coformulated drug. Therefore, it will be useful in scenarios where the practitioner desires a high surface concentration and low percutaneous absorption of the drug. For example, topical antifungal drugs and topical antibiotics (e.g., mupirocin) are formulated in this type of base.
Gels are made from water-soluble bases by formulating water, propylene glycol, and/or PEGs with a cellulose derivative or carbopol. A gel consists of organic macromolecules uniformly distributed in a lattice throughout the liquid. After application, the aqueous or alcoholic component evaporates, and the drug is deposited in a concentrated form. This provides a faster release of the drug independent of its water solubility. Gels are popular because of their clarity and ease of both application and removal. They are suitable for facial or hairy areas because after application little residue is left behind.5 Nevertheless, they lack any protective or emollient properties. If they contain high concentrations of alcohol or propylene glycol, they tend to be drying or cause stinging. Gels require preservatives.12 Newer gel formulations may contain the humectant glycerin, the emollient dimethicone, or the viscoelastic polysaccharide hyaluronic acid, which can mitigate some of the associated irritation. Nonaqueous gels, with bases such as glycerol, may be used for poorly solubilized therapeutics such as 5-aminolevulonic acid.13
Microspheres, or microsponges, are formulated in an aqueous gel. Medication, in this case tretinoin, is combined into porous beads 10–25 μm in diameter. The beads are made up of methyl methacrylate and glycol dimethacrylate.
Pastes are simply the incorporation of high concentrations of powders (up to 50%) into an ointment such as a hydrocarbon base or a water-in-oil emulsion. The powder must be insoluble in the ointment. Invariably, they are “stiffer” than the original ointment. The powders commonly used are zinc oxide, starch, calcium carbonate, and talc. Pastes function to localize the effect of a drug that may be staining or irritating (i.e., anthralin). They also function as impermeable barriers that serve as protectants or sunblocks. Pastes are less greasy than ointments, more drying, and less occlusive.12
Liquids can be subdivided into solutions, suspensions, emulsions (discussed in Section “Ointments”), and foams.
A solution involves the dissolution of two or more substances into homogenous clarity. The liquid vehicle may be aqueous, hydroalcoholic, or nonaqueous (alcohol, oils, or propylene glycol). An example of an aqueous solution is aluminum acetate or Burow solution. A hydroalcoholic solution with a concentration of alcohol of approximately 50% is called a tincture. A collodion is a nonaqueous solution of pyroxylin in a mixture with ether and ethanol, and is applied to the skin with a soft brush. Flexible collodions have added castor oil and camphor and are used, for example, to deliver 10% salicylic acid as a keratolytic agent. Liniments are nonaqueous solutions of drugs in oil or alcoholic solutions of soap. The base of oil or soap facilitates application to the skin with rubbing or massage. Liniments can be used as counterirritants, astringents, antipruritics, emollients, and analgesics.12
A suspension, or lotion, is a two-phase system consisting of a finely divided, insoluble drug dispersed into a liquid in a concentration of up to 20%. Nonuniform dosing can result if the suspended particles coalesce and separate out of a homogeneous mixture, therefore shaking of the lotion before application may be required. Examples include calamine lotion, steroid lotions, and emollients containing urea or lactic acid. The applied lotion leaves the skin feeling cooler via evaporation of the aqueous component. Lotions are easier to apply and allow for uniform coating of the affected area, and are often the favorite preparation in treating children. Lotions are more drying than ointments, and preparations with alcohol tend to sting eczematized or abraded skin.12 Lotions are suitable for application to large surface areas due to their ability to spread easily.5
Shake lotions are lotions to which a powder is added to increase the surface area of evaporation. As a result of the increased evaporation, the application of shake lotions effectively dries and cools wet and weeping skin. Generally, shake lotions consist of zinc oxide, talc, calamine, glycerol, alcohol, and water, to which specific drugs and stabilizers may be added. Shake lotions tend to sediment, and derive their name from the need to shake the preparation before each use to obtain a homogeneous suspension. In addition, after water has evaporated from the lotion, the powder component may clump together and become abrasive. Therefore, patients should be instructed to remove the residual particles before the reapplication of shake lotions.12
Foams are triphasic liquids composed of oil, organic solvents and water, which are kept under pressure in aluminum cans. Foams are formulated with a hydrocarbon propellant, either butane or propane.14 The foam lattice is formed when the valve is activated. Once in contact with the skin, the lattice breaks down, the alcohol evaporates within 30 seconds, and leaves minimal residue in the skin. The alcohol component of the foam is thought to act as a penetration enhancer, momentarily altering the barrier properties of the stratum corneum and increasing drug delivery through the intercellular route.14 Previous studies have demonstrated that foam vehicles are highly effective in delivering greater amount of active drug at an increased rate when compared to other vehicles that traditionally depend upon hydration of the intercellular spaces within the stratum corneum.14 Foams have not been associated with an increase in the adverse events and compliance seams to be better with this formulation, especially for localized conditions affecting the scalp.14
Topical aerosols may be used to deliver drugs formulated as solutions, suspensions, emulsions, powders, and semisolids. Aerosols involve formulating the drug in a solution within a pure propellant. Usually, the propellant is a blend of nonpolar hydrocarbons. When applied to abraded or eczematized skin, aerosols lack the irritation of other formulations, especially when the quality of the skin makes direct application painful or difficult. Furthermore, aerosols dispense a drug as a thin layer with minimal waste, and the unused portion cannot be contaminated. Aerosol foams, a relatively new vehicle for drug delivery, are commonly used to deliver corticosteroids such as betamethasone valerate and clobetasol propionate. The foam contains the drug within an emulsion formulated with a foaming agent (a surfactant), a solvent system (such as water and ethanol), and a propellant. On application, a foam lattice forms transiently until it is broken by both the heat of the skin and the heat of rubbing the foam onto the skin. Foams that are alcohol based leave very little residue within seconds of their application. Furthermore, a given corticosteroid formulated in a foam vehicle demonstrates comparable potency when compared with the same corticosteroid in other vehicles.1,15 Although aerosols allow for the ease of application (especially to hair-bearing areas) and high patient satisfaction, they suffer from the disadvantages of being expensive and potentially ecologically damaging.12
A penetration enhancer is a compound that is able to promote drug transport through the skin barrier. Skin hydration and interaction with the polar head group of the lipids are mechanisms for increasing penetration. Water, alcohols (mainly ethanol), sulphoxides (dimethylsulphoxide/DMSO), decylmethylsulphoxide/DCMS, azones (laurocapram), and urea are some of the most commonly used compounds.4 Urea is thought to act as a penetration enhancer due to its keratolytic properties and by increasing the water content in the stratum corneum. Other substances that may also act as enhancers include propylene glycol, surfactants, fatty acids, and esters.
Vesicular systems are widely used in dermatologic and cosmetic fields to enhance drug transport into the skin through the transcellular and follicular pathways. Examples of vesicular systems include liposomes (phospholipid-based vesicles), niosomes (nonionic surfactant vesicles), proliposomes and proniosomes, which, respectively, are converted to liposomes and niosomes upon hydration.16
Physical methods such as the application of a small electric current (iontophoresis), ultrasound energy (phono- or sonophoresis) and the use of microneedles increase cutaneous drug penetration.4 Microdermoabrasion is the application of crystals (generally aluminum oxide) on the skin and the collection of such crystals and skin debris under vacuum suction. This technique enhances drug permeation and facilitates drug absorption by altering the architecture of the stratum corneum.17
Stabilizers are nontherapeutic ingredients and include the preservatives, antioxidants, and chelating agents. Preservatives protect the formulation from microbial growth. The ideal preservative is effective at a low concentration against a broad spectrum of organisms, nonsensitizing, odor free, color free, stable, and inexpensive. Unfortunately, the ideal preservative does not exist. The parabens are the most frequently added preservatives, and are active against molds, fungi, and yeasts, but less effective against bacteria. Alternative agents include the halogenated phenols, benzoic acid, sodium benzoate, formaldehyde, the formaldehyde-releasing agents, and previously, thimerosal. Most commonly used preservatives may act as contact sensitizers.
Antioxidants or preservatives prevent the drug or vehicle from degrading via oxidation. Examples include butylated hydroxyanisole and butylated hydroxytoluene, used in oils and fats. Ascorbic acid, sulfites, and sulfur-containing amino acids are used in water-soluble phases. Chelating agents, such as sodium EDTA and citric acid, work synergistically with antioxidants by complexing heavy metals in aqueous phases.
Thickening agents increase the viscosity of products or suspend ingredients in a formulation. Examples include bees-wax and carbomers. In addition to functioning as an ointment vehicle, petrolatum may be added to an emulsion to increase its viscosity. As in this example, an ingredient may have a therapeutic effect as well as acting as part of a vehicle.
Either the vehicle or its active ingredients may cause local toxicity to the applied site. Local adverse effects are usually minor and reversible. Major cutaneous side effects include irritation, allergenicity, atrophy, comedogenicity, formation of telangiectases, pruritus, stinging, and pain. The mechanism of toxicity may be as simple as the desiccation of the stratum corneum (the removal of sebum and oils by the preparation's emulsifiers, for example), or involve a more complex effect on either the cells of the epidermis or dermis and the structures these cells comprise (i.e., epidermis, adnexae). Local damage may occur either directly at, or within close proximity to, the treated site. Further, irritation and damage may appear even after a drug has been discontinued. Often the therapeutic effects of the active ingredient mask or immediately treat the toxic effects of the formulation so that acutely toxic effects are transient.18 For example, an allergic contact dermatitis to a preservative in a topical steroid may be masked by the effects of the steroid itself.
Irritant Contact Dermatitis
Irritation is driven less by drug penetration and more by drug concentration. Thus, lowering the concentration of an irritating drug may lower the risk of side effects. However, a change in formulation may reduce the preparation's efficacy. Nevertheless, often using a less concentrated preparation over a greater period of time is as therapeutically efficacious while minimizing adverse effects; for example, the use of benzoyl peroxide 2% to 5% preparations in contrast to 10% preparations.18 In some instances, though, skin irritancy might be central to drug efficacy. For example, although not conclusively shown, the power of immunomodulating agents such as imiquimod might rely on an increased innate (inflammatory or irritant) immune response.
Subjective or Sensory Irritant Contact Dermatitis
Patients may detect burning or stinging sensations without any signs of cutaneous irritation after applying a topical medication.19,20 Several compounds may induce sensory irritant contact dermatitis in predisposed individuals, such as tacrolimus,21 sorbic acid, propylene glycol, benzoyl peroxide hydroxy acids, mequinol, ethanol, lactic acid, azelaic acid, benzoic acid, and tretinoin.19,20
Allergic Contact Dermatitis
In contrast to local irritation, contact allergy development depends on local penetration. Allergy, of course, is driven by antigen recognition and presentation, and thus, percutaneous absorption of the drug must be at a level that guarantees interaction with the immune effector cells of the skin. Therefore, the contact allergenicity of a drug relates most significantly to percutaneous absorption. In some instances, cutaneous allergy may be therapeutic, for example, the treatment of patients with cutaneous T-cell lymphoma with topical nitrogen mustard. The shift in malignant T cells from T helper (Th) 2 to Th1-type cytokine expression is believed to lead to apoptosis of the malignant T cells and tumor regression.22
Rarely, topical therapy may result in neoplasia. For example, the risk of secondary malignancies, such as keratoacanthomas, basal and squamous cell carcinomas, lentigo maligna and primary melanoma have been reported with the long-term use of nitrogen mustard.22
The application of topical corticosteroids to the periorbital skin has been reported both to induce cataracts and increase in intraocular pressure.5
One should be aware of the potential systemic toxicities of topical drugs. Although generally safer than the other routes of administration, topical application can result in systemic toxicities ranging from end-organ toxicity (central nervous system, cardiac, renal, etc.), teratogenicity, and carcinogenicity to drug interactions. These outcomes may relate to the drug itself, its metabolites, or even a component of the vehicle.
The kinetics of topically applied drugs differ significantly from those administered by other routes. One important consideration is the lack of hepatic first-pass metabolism of a topical drug. This is especially relevant to drugs such as salicylic acid that are relatively innocuous when given enterally, but may manifest central nervous system toxicity when applied topically. Additionally, acting as a reservoir, the stratum corneum may store large amounts of a topical drug, and a subsequently long diffusion period of many days may ensue, delivering a steady supply of drug to the systemic circulation.
Percutaneous toxicity directly relates to percutaneous absorption. Therefore, factors that modulate absorption also influence toxicity: the concentration of the drug, its vehicle, the use of occlusion, the body site and area treated, frequency of use, the duration of therapy, and the nature of the diseased skin. For example, 6% salicylic acid in Eucerin used for 11 days in the treatment of psoriasis has been associated with epistaxis and deafness, while the same concentration of salicylic acid in hydrophilic cream under occlusion for 4 days for the treatment of dermatitis (involving the same amount of body surface area) may result in hallucination.18 Similar to their effect on systemically administered drugs, renal and hepatic diseases, by influencing drug clearance, also contribute to an increased potential for drug toxicity.
Young children have a greater surface area–volume ratio, and thus are at greater risk of percutaneous toxicity than adults. This phenomenon necessitates alternative drugs, formulations, and dosing schedules for children with widespread cutaneous disease. Patients with acute flares of cutaneous illness (for example, psoriasis or atopic dermatitis) may require the treatment of a larger body surface area in a relatively abbreviated period of time. These patients may also increase their dose and frequency of application during such flares. Coupled with the likely increased percutaneous absorption of the diseased skin, these scenarios exponentially increase the possibility of systemic toxicity, and patient education is vital to prevent adverse outcomes.12 To reduce the risk of toxicity from topical drugs and to increase treatment efficacy, many practitioners will rationally advocate systemic approaches (i.e., methotrexate, cyclosporine, injectable or infusable biologics, or ultraviolet radiotherapy) to patients whose disease involves an extensive body surface area.
Type I Hypersensitivity Reactions
In rare instances, anaphylactic shock can be precipitated by topical drug application. For example, when applied to diseased or abraded skin, bacitracin ointment can induce an immediate-type (type I) hypersensitivity reaction in susceptible individuals. Such reactions might be represented by a local and then subsequently generalized pruritus leading to cardiopulmonary arrest.12 Nonimmunologic acute toxicity results from substances such as pesticides and chemical warfare agents that rapidly diffuse through the skin and reach target organs.
Systemic calcineurin inhibitors have been associated with increased risk of lymphoma and nonmelanoma skin cancer. But the topical use of such drugs does not appear to be related to cancer.23,24 In fact, the risk for lymphoma with the use of topical calcineurin inhibitors was assessed in animal studies that demonstrated an increased risk only when blood levels were 30 times higher than those measured after topical application in human subjects.24 Numerous studies have demonstrated the efficacy and safety of topical calcineurin inhibitors. More than 50 cases of lymphoma have been reported, although the topical calcineurin inhibitor use may be coincidental. Nevertheless, there is a clear need for additional follow-up information to establish the long-term safety profile of this class of drugs. Two long-term trials currently being conducted might help address these concerns.24
Topical corticosteroids can rarely cause hypothalamic–pituitary–adrenal axis suppression, growth retardation, hyperglycemia, iatrogenic Cushing syndrome and femoral head osteonecrosis.5 Factors that enhance drug absorption are directly related to an increase in these side effects; therefore, carefully monitoring must be ensured when prescribing usage in large surfaces areas, prolonged use of potent corticosteroids, usage under occlusion, high potency corticosteroids, or use for the pediatric age group (due to their increased surface to body mass ratio).
Transdermal drug delivery, in contrast to topical drug delivery, uses topical application of therapeutic drug as a delivery system for systemic therapy. Transdermal patches have been approved by the US Food and Drug Administration since 1981 (scopolamine being the first) for the delivery of 13 different medications, with more seeking approval. The most commonly used patches are for nitroglycerin and fentanyl. Advantages of this approach include controlled release, a steady blood-level profile with zero-order kinetics, lack of a plasma peak, and, in some cases, improved patient compliance. These patches remain on the skin for 12 hours to 1 week. A patch consists of a plastic backing, a reservoir of medication, either a rate-controlling membrane or a polymer matrix system for controlled diffusion, followed by an adhesive facing the skin. The most common adhesives used are acrylates, silicones, and polyisobutylenes. These patches have been tested and are approved for use on the thighs, buttocks, lower abdomen, upper arms, and chest; application to other sites can lead to either sub- or supratherapeutic blood levels. Adverse effects of patches include local irritation and allergic contact dermatitis to either an adhesive or to the drug itself and may necessitate discontinuation. Topical therapies are a mainstay of treatment for the dermatologist. An understanding of the interactions between a drug's concentration, penetration, availability, and treatment of diseased skin allows physicians to maximize both efficacy and tolerability of topical therapy. An understanding of local and systemic toxicities allows selection of appropriate, safe therapy for patients and minimizes unwanted effects. Appropriate selection of topical agents and patient education on proper use can optimize therapeutic outcomes.