dermatology1.2 Flashcards
(193 cards)
Penetration of Topical Medication through Stratum Corneum
The outermost layer of the skin, the stratum corneum, acts as the primary barrier to percutaneous absorption of topical medications. The stratum corneum is usually described as a ‘brick and mortar’ structure, where keratinocytes represent the bricks and intercellular lipids acting as the mortar. To be effective, topical medications need to gain entry into the skin and reach the site of action in desired concentrations. Typically, the site of topical medication action is the epidermis or the dermis. Medications gain access to sites of action through three primary mechanisms. First, the medications can move across the stratum corneum by passive diffusion. Second, the agents can be transported through channels or pores within a lacunar system in the stratum corneum. Finally, the medications may be transported via appendageal structures, such as sweat glands or hair follicles.
Factors Influencing Absorption of Topical Medications
Drug formulations for topical medications consist of an active ingredient in a vehicle base. Factors that influence effective percutaneous absorption of topical medications can be categorized into (a) drug factors and (b) patient factors. Drug factors affecting percutaneous absorption include: Active drug concentration, Composition of the vehicle, Molecular size of the drug or prodrug, and Lipophilicity of the drug. Patient factors affecting percutaneous absorption of topical medications include: Presence of barrier disruption, Anatomic location (including thickness of the stratum corneum), Skin hydration, and Occlusion.
Affect of composition of vehicle and active drug concentration on drug absorption
Studies have shown that, given the same vehicle, cutaneous absorption is directly proportional to the concentration of the active ingredient in the medication. However, given the same concentration of the active ingredient, cutaneous absorption can differ when the ingredient is embedded in different vehicles.
Affect of molecular size of the drug on absorption
Molecular size of the drug affects its absorption at the site of action. When absorbed through passive diffusion, molecules need to traverse a tortuous path through the intercellular lipid domains, or the “mortar”. Typically, the diffusion of a compound is inversely proportional to the molecular size of the drug.
Affect of liphophilicity of the drug on drug absorption
Because stratum corneum contains a mixture of lipids that includes ceramides, cholesterol and fatty acids, lipophilic topical agents are more likely to permeate the skin than hydrophilic agents.
Affect of skin hydration on drug absorption
Skin hydration affects percutaneous absorption in important ways, sometimes by several folds. Occlusion of the skin often leads to markedly increased skin hydration. Therefore, active ingredients that are delivered in the form of an ointment, tape, or to the skin folds, reach much higher concentrations because occlusion prevents loss of medication by evaporation, friction, or exfoliation.
Affect of anatomic location on drug absorption
Percutaneous absorption of topical medications is also related to anatomic location. In general absorption is lower in anatomic regions where the stratum corneum is thicker, such as the palms and soles. In contrast, percutaneous absorption is higher in areas where the stratum corneum is thinner, such as the eyelids and scrotum.
Classification of Vehicles
The art of using topical medications often revolves around selecting the appropriate vehicle. Overall, the choice of selecting the appropriate vehicle is as important as selecting the concentration or the active ingredient. Ointments: Water in oil emulsion. Creams: Oil in water emulsion. Gels: Semisolid emulsion in alcohol base. Lotions/Solutions: Powder in water (some oil in water). Foams: pressurized collections of gaseous bubbles in a matrix of liquid film
Ointments
Active ingredients delivered in an ointment vehicle have strong potency. Ointments are hydrating, with very low sensitization risk or irritation risk. Body sites most amenable to ointment use are non-intertreginous sites. It’s best to avoid using ointments on face, hands, and groin. Despite of their many therapeutic advantages, some patients dislike greasiness of ointments. Patient education is necessary as ointments may stain clothing.
Creams
Active ingredients delivered in a cream vehicle have moderate potency. Creams offer some hydration, but they are not as hydrating as ointments. Creams have a significant sensitization risk and a low irritation risk. Virtually all body sites can be amenable to application of cream-based topical agents. Avoid using cream in sites with maceration. There is a high rate of acceptance by patients.
Gels
Active ingredients delivered in a gel vehicle have strong potency. Gels are drying. Gels carry a significant sensitization risk and a relatively high irritation risk. Sites most amenable to gel application are oral mucosal surfaces and the scalp. Avoid applying gels on fissures, erosions, or macerated regions. Patient preference for gels is variable.
Lotions/Solutions
Active ingredients delivered in a lotion or solution vehicle have relatively low potency. Lotions and solutions tend to be variably drying. Lotions and solutions have a significant sensitization risk and moderate irritation risk. Sites most amenable to lotion or solution application are scalp and intertriginous areas. Avoid using lotion or solution on fissures or erosions. There is a relatively high rate of patient acceptance for lotions and solutions.
Foams
Foam vehicles are a relatively newer type of vehicle for topical agents, and I will discuss them relatively more extensively here. The foam matrix is stable at room temperature but readily melts at body temperature. After the foam is applied to the skin, the volatile components (such as alcohol and water) quickly evaporate, leaving behind lipid and polar components containing supersaturated active ingredients to interact with lipids of the stratum corneum. These supersaturated solutions enable maximal delivery of active ingredients into the skin. Interestingly, alcohol, a component of the foam matrix, may play a role in altering the stratum corneum’s barrier properties and lead to improved penetration of the active ingredient. Active ingredients delivered in a foam vehicle have strong potency. Foams are quick- drying, stain-free, and leave almost no residue. Sites most amenable to foam application are hair-bearing areas. Avoid applying gels on fissures or erosions. Patient preference for foam is quite high.
Considerations for Selecting an Appropriate Vehicle
When selecting an appropriate vehicle, three factors are of particular importance: anatomic location, contact allergy/sensitization, and irritancy. As explained in the above text, some vehicles are more appropriate for certain body sites than others. For example, for hair bearing regions, the clinician should consider choosing a solution or foam vehicle over ointment. Various water-based vehicles, such as creams, lotions, and solutions, contain preservatives that may increase the risk of contact allergy and sensitization. These preservatives include known allergens such as parabens and formalin releasers. Irritancy is most notably associated with high concentrations of propylene glycol, other types of alcohols, and certain acidic vehicle ingredients. For example, avoid using formulations containing alcohol or salicylates on extensively fissured, eroded, or macerated areas, which can lead to stinging and burning.
FTU (Fingertip Unit)
1 FTU is the amount of ointment dispensed from a 5 mm diameter nozzle that is applied to the distal third of the index finger, from the crease under the distal interphalangeal joint to the fingertip. 1 FTU=0.5 g
Few other Useful Quantities of Application
1 gram of cream covers approximately 10 cm x 10cm area of skin. 1 gram of ointment spreads 10% further than the same amount of cream. Approximately 20 g are necessary to treat the entire body of an adult man, or roughly 280 g per week if the medication were applied twice daily for 1 week. Quantities of ointment to dispense in children differ according to age due to different body surface areas.
Molecular Mechanism of Action of Glucocorticosteroids
Binding of glucocorticosteroids to their receptors, which are located in the cytoplasm of most cells in the body. Upon binding by glucocorticosteroids, the release of 90 kDa heat shock protein occurs, and subseuqent nuclear localization signals facilitate translocation of the glucocorticoid receptor complex into the nucleus. In the nucleus, the glucocorticoid receptor forms a dimer, which binds to the glucocorticoid response element of the promoter region of steroid-responsive genes. This binding is associated with the following downstream molecular events:
Downstream molecular events from glucocorticosteroids binding to its receptor
Alteration of transcription rate, messenger RNA production, and protein synthesis of associated with various inflammatory pathways. The glucocorticoid receptor interacts with other transcription factors that play a role in the inflammatory response and their coactivator molecules, including cAMP response element binding protein (CREB)-binding protein. Inhibition of nuclear factor-κB pathway, whch leads to reduction in transcription of genes that play a significant role in chronic inflammation, including genes for many cytokines, adhesion molecules, inflammatory enzymes, and growth factors. The glucocorticoid receptor interacts with activating protein 1 (AP-1) (AP-1 is a collective term for the heterodimeric transcription factor composed of c-jun, c-fos and activating transcription factor), which controls transcription of growth factor and cytokine genes. Glucocorticosteroids inhibit TNF-α, granulocyte–macrophage colony-stimulating factor, and several interleukins (e.g. IL-1, IL-2, IL-6, IL-8). Cyclooxygenase and adhesion molecules such as intercellular adhesion molecule- 1 and E-selectin are also inhibited.
General Classification of Topical Steroids
A large numbers of topical glucocorticosteroid medications are available in a wide range of potency. In general, seven classes have been proposed based on potency. The superpotent topical glucocorticosteroids belong to class 1, and the very low-potency topical glucocorticosteroids belong to class 7. These classes were developed based on vasoconstrictor assays. The vehicle can greatly influence the percutaneous absorption and efficacy of the some glucocorticosteroids.
Hydrocortisone 2.5% (cream or ointment)
“The Gentle Touch.” Hydrocortisone 2.5% (cream or ointment) belongs to class 7, the lowest potency class. It is efficacious for mild eczema in children and adults and for treating inflammatory dermatoses involving anatomic regions such as the face, intertriginous areas, or groin, where mid to high-potency topical steroids may be contraindicated.
Triamcinolone Acetonide 0.1% (cream or ointment)
“The Almost All-Purpose Weapon.” Triamcinolone acetonide is affordable and readily available in many different tube sizes (and even in 1 pound jar!). Triamcinolone 0.1% cream or ointment belongs to class 4, or a mid-potency class of topical steroids. Triamcinolone 0.1% is effective against most moderate spongiotic dermatoses (including eczematous dermatitis, atopic dermatitis, allergic contact dermatitis, arthropod bites, id reactions, drug reactions) involving the trunk and extremities. Long-term use of triamcinolone is not recommended for facial, intertriginous, and groin lesions.
Clobetasol Propionate 0.05% (cream or ointment)
“Hercules.” Clobetasol propionate 0.05% cream or ointment belongs to Class 1 of topical steroids, and it is considered one of the most potent topical steroids. Clobetasol is best used in acute eruptions that necessitate relatively rapid amelioration, such as contact dermatitis or acute drug eruptions. Clobetasol should be avoided on the face, intertriginous areas, or the groin, where the skin is relatively thin. Longer-term use of clobetasol requires monitoring of development of adverse effects.
General Considerations for Selecting a Topical Steroid
When selecting an appropriate topical steroid for clinical use, the practitioner should take into account severity of the condition, location of the lesion, and need for hydration or drying effect. Furthermore, the clinician should be aware of the potential for sensitization or irritation of certain types of vehicles. Due to the occlusive nature of an ointment vehicle, the same active glucocorticosteroid ingredient in an ointment vehicle will often be more potent than the same ingredient in a cream, lotion, or solution vehicle. This is because the ointment vehicle enhances hydration of the stratum corneum, which leads to improved penetration of the medication. In general, potent or superpotent topical steroids should be avoided for use on the face, skin folds (axillary and intertriginous folds), and groin areas due to the risk of epidermal atrophy and potential for steroid-induced rosacea/perioral dermatitis on the face.
Adverse Effects of Topical Glucocorticosteroids
The use of topical corticosteroids has been associated with a number of side effects. In general, more potent topical steroids are associated with greater adverse effects. The most common adverse effect is skin atrophy, and this is most commonly associated with long- term use of potent to super-potent topical steroids. Skin atrophy may manifest as shiny, thin skin, telangiectasia, and striae formation. Areas with baseline relatively thin epidermis such as face and intertriginous areas are more susceptible to developing skin atrophy compared to other areas of the body. Extensive and long-term use of potent or super-potent topical steroids have been associated with systemic side effects due to increased systemic absorption of percutaneously delivered active ingredient. Potential systemic side effects include adrenal suppression, Cushing’s syndrome, and growth retardation in children. For example, psoriasis and atopic dermatitis patients may require longer-term use of potent topical steroids to cover larger body surface areas than other dermatologic patient populations. Systemic adverse effects of topical steroids are particularly relevant to these populations. Currently, the AAD guideline for maximum use of class I topical steroids is to not exceed 50 grams per week.
