the layer of skin beneath the epidermis, which provides structural support to the skin and is composed of blood vessels, nerves, and appendages.


the outermost layer of the skin composed of five layers.


third layer of skin composed of adipose (fat) tissue.

Integumentary system

the skin and its appendages (hair, glands, nails).


drug effect at site of application.


cells located in the epidermis responsible for skin color.

Stratum corneum

outermost layer of the epidermis composed of nonliving keratinocytes.


applied to a surface of the body, such as the skin.


drug transport across or through the skin into the bloodstream.


After completing this chapter, you should be able to

  1. Describe the skin as an organ system:

    1. List the three functionally distinct regions of the skin and describe their function.

    2. Describe the roles of keratinocytes, melanocytes, and Langerhans cells as components of the epidermis.

    3. Define mast cell.

    4. Identify the skin appendages located in the dermis.

    5. Define adipose tissue.

  2. Explain how changes in skin thickness, integrity, hydration, and age can alter topical drug absorption.

  3. Describe how the vehicle in a topical formulation can influence the absorption of the active drug.

  4. Name and describe two types of transdermal preparations.

The skin is the largest organ in the body. Together the skin and its appendages (glands, hair, and nails) are known as the integumentary system. The main function of the skin is to work as a barrier to separate internal body components from the outside environment. This barrier is very important to protect the internal body organs from injury and water loss (dehydration) and to prevent infectious organisms or toxic substances from entering the bloodstream. The following chapter will discuss the structure and function of the skin and how different types of drug therapies work when applied topically.

Skin Structure and Function

The skin is divided into three main layers known as the epidermis, dermis, and hypodermis (Figure 32-1). The epidermis is the outermost layer of the skin and is composed of several layers (strata) of cells. The majority of the cells in the epidermis are known as keratinocytes. Keratinocytes are responsible for the production of keratin, the structural protein of the skin, hair, and nails. Structural changes occur to the keratinocytes as they move from the bottommost layer of the epidermis, the stratum germinativum, to the outermost layer of the epidermis, the stratum corneum. As they move toward the stratum corneum, keratinocytes dry out, die, and are eventually sloughed off. Another major cell type in the epidermis is the melanocyte, found in the stratum germinativum. Melanocytes are responsible for skin color. The third major cell type of the epidermis are the Langerhans cells. These cells are found in the stratum spinosum, the layer above the stratum germinativum. Langerhans cells function to produce an immune response and are involved in the development of allergic reactions on the skin.

FIGURE 32-1.

The dermis is the second main layer of the skin and is located directly below the epidermis. The dermis is the largest component of the skin structure and is composed of two major cell types: mast cells and fibroblasts. Mast cells are involved in the pathogenesis of allergic skin disorders. Fibroblasts are responsible for the synthesis of elastic fibers and collagen, the structural support components of the skin. Unlike the epidermis, the dermis contains blood vessels, nerves, and appendages. The nerves in the dermis provide the sensation of touch, pain, temperature, and pressure. Appendages located in the dermis are sweat glands, sebaceous glands, and hair follicles. Sebaceous glands secrete sebum, a waxy substance that helps keep the skin moist, and sweat glands secrete toxins and fluids to help maintain body temperature.

The hypodermis is the third main layer of the skin and is located below the dermis. The hypodermis is composed mainly of adipose tissue (fat cells), collagen, and larger blood vessels. The main functions of the hypodermis are to provide cushioning to protect the body from injury and regulation of body temperature.

Topical Administration


Mrs. Williams is a 65-year-old woman with seasonal allergies, asthma, psoriasis, and high blood pressure. Her physician is adding a clonidine patch (Catapres-TTS) to her drug regimen to lower her blood pressure. Other topical therapies she is currently using include an ointment and a cream for the management of her psoriasis.

The primary goal of most topical drug preparations is to provide local action on one or more layers of the skin. For example, sunscreen, calamine lotion, keratolytic agents, and topical anti-itch agents are designed to exert their effects on the skin surface to prevent and treat skin disorders. The effects at the site where the preparation is administered are considered local actions. Although some of the active drug in these topical products intended for local uses may reach systemic circulation, typically the amount is subtherapeutic and not of great concern. Systemic agents, on the other hand, such as tablets, capsules, and intravenous (IV) medications, are absorbed or administered directly into the bloodstream and can affect the entire body. Some transdermal products are formulated for systemic absorption, such as fentanyl patches, which provide pain relief throughout the body and not at the site of application. Regardless of the desired site of action, monitoring the absorption of topical drugs is very important, especially in certain patient populations who may be at risk for serious adverse effects.


Is the action of Mrs. William’s clonidine patch considered to be local or systemic? How does this action differ from the cream and ointment prescribed for her psoriasis?

Skin Conditions That Affect Drug Absorption

Drugs are absorbed into the skin by a process known as passive diffusion. There are many factors that affect the rate of drug absorption through the skin and into the bloodstream. The first factor is the thickness of the skin. Thick skin will decrease the rate of absorption of drugs, while thin skin will increase the rate of absorption of drugs. This is because the depth of the stratum corneum layer of the epidermis is the rate-limiting barrier to drug absorption. Thick skin, like that on the bottom of the feet, has a very deep stratum corneum layer and thin skin, like that of the scalp, has a very shallow stratum corneum layer. Once the drug moves past the stratum corneum barrier, its molecules easily pass through the dermis and systemic absorption can occur. Therefore, drug absorption will occur more quickly in areas where the skin is thin.

Other factors that affect drug absorption are skin integrity, temperature, and hydration. As mentioned above, the skin is a protective barrier. When a cut or abrasion occurs on the skin, the protective barrier is broken, allowing foreign material to enter the bloodstream. If a drug is placed on an area of broken or inflamed skin, it can bypass the stratum corneum, allowing for quick absorption. In addition to skin integrity, skin temperature and skin hydration also affect drug absorption. Warm, moist skin provides the highest potential for drug absorption. Hydration (addition of moisture) of the stratum corneum increases the space between the skin cells, allowing an open pathway for drugs to move through this skin barrier. Also, moist skin will help to dissolve the drug, allowing for easier passage. Placing bandages or wraps over the skin also prevents water loss, increasing hydration and temperature and allowing for faster drug absorption. Since the goal of topical drug administration is to provide a local action, it is important to recognize what skin conditions increase systemic absorption of these preparations in order to maximize topical effectiveness and avoid adverse effects.


Why should Mrs. Williams avoid placing a heating pad over the application site of her patch (or any topical agent)?

Drug Absorption in Special Patient Populations

Systemic absorption of topical preparations should be monitored closely in pediatric and geriatric patients. These populations are at higher risk for systemic toxicity of topically applied drugs for various reasons.


Some over-the-counter (OTC) topical preparations, including rubbing alcohol, antiseptics, and pain relief products have been shown to cause toxicity in newborns. Package instructions limiting use in children below a certain age should be closely observed.

Infants and children have a higher ratio of total body surface area to body mass, which places them at risk for increased exposure to topical agents and high systemic concentrations of drugs. Additionally, infants may not be able to metabolize absorbed drugs effectively due to the immaturity of their organ systems. Along with monitoring infants and children closely, it is also important to monitor pregnant or nursing mothers because topically absorbed drugs may affect the unborn fetus or the nursing infant.

Geriatric patients may also have altered absorption of topical drug preparations. Many changes to the skin occur with increasing age. For example, skin becomes wrinkled, dry, and thinner with age. Thin skin, which has a smaller amount of subcutaneous fat, may increase drug absorption. Also, these normal skin changes place older adults at increased risk of skin injuries. It is important to avoid applying topical drug products to broken or damaged skin.


Just because a topical product is not being ingested or injected into the body does not mean it is safe to use it in ways other than directed by the prescriber or package. Overdoses can still occur and are more likely if products are used in quantities greater than the usual dose or for patients in an age group for which it is not recommended. Consumers purchasing OTC topical products should be reminded to read and follow all package instructions. Patients with prescriptions for medications to be placed on the skin should be reminded that the pharmacist can discuss proper application with them.

Many skin conditions predispose patients to increased topical drug absorption. Examples of these include sunburn (especially after skin peeling), eczema, psoriasis, thermal burns, and chemical peels.

Vehicles for Topical Drug Administration

There are many formulations available for topical drug administration, such as liquids, creams, gels, ointments, pastes, and powders, as well as some solid dosage forms. Drugs may be applied topically to the skin, mucous membranes, eyes, nose, rectum, and vagina. Often, a drug may be available in several topical dosage forms. Understanding the differences between available vehicles can aid in proper product selection and improve patient adherence.

Ointments are considered semisolid preparations and may be formulated with a variety of bases. Ointments are known for their occlusive (protecting and sealing against water loss) properties and may stay in place better than creams or gels. The emollient property (softening or soothing the skin) of ointments aids in skin hydration and absorption, and the oleaginous (fatty) base improves drug penetration. Ointments are preferred for patients with dry, chapped skin or in disease states such as psoriasis, where the emollient property can help soften the plaques and improve drug delivery. Due to their thicker, oily bases, ointments may discolor clothing and may be more difficult to apply to hairy areas of the skin.

Creams, like ointments, are semisolid dosage forms with emollient effects. However, creams may be more cosmetically pleasing to patients due to their water washable property. Creams are less occlusive than ointments and may be easier to apply. Creams may be used to administer drugs via the vaginal route.

Topical solutions are liquid preparations that contain a drug dissolved in a solvent. Drug particles in a solution disperse very evenly, which allows for uniform dosage when applied. Solutions are less stable than other semisolid dosage forms and should be kept away from light and extreme heat. Solutions or suspensions that are applied topically are often referred to as lotions.

Gels may be preferred by patients for their quick-drying, transparent properties. Gels do not leave a residue on the skin and can be washed off with water. Compared with ointments and creams, gels generally provide faster drug release. Due to their water-soluble bases, gels may be the preferred vehicle for hydrophilic (water-soluble) drugs to optimize their delivery.

The term “paste” refers to an ointment that has a large amount of solid integrated. Pastes are generally stiff and dry and can be applied to areas of skin where oozing or weeping is occurring, as they will absorb secretions. Although pastes are not very occlusive, they remain in place and can protect lesions by serving as a physical barrier.

Powders are finely divided, dry solid dosage forms. Powders intended for topical use should be applied to intact skin for a local effect. Powders are also available for systemic use by mixing in suspensions or solutions for drinking, sprinkling on food, or for compounding into tablets or capsules. Proper dosing and application may be more difficult with powders.


Patients and caregivers applying topical powders should be careful to avoid inhalation of powders, as they can irritate the lungs.


Why might patients with thick plaque psoriasis, like Mrs. Williams, prefer topical agents formulated as ointments rather than creams or gel and patients with itching due to an insect bite prefer a cream or gel rather than ointment?

Transdermal Preparations


Mrs. Smith 53 years old and has begun to experience severe hot flashes and night sweats, along with longer and varying intervals between her menstrual periods. Due to her difficulty in managing these perimenopausal symptoms, her physician has prescribed an estradiol/norethindrone (CombiPatch) transdermal patch.


Many topical preparations are formulated for application to a specific part of the body and are inappropriate for use elsewhere. For example, ointments for application to the skin may have active ingredients identical to those for the eye, but must not be used ophthalmically because ophthalmic preparations must be sterile and may require adjustments in pH or other characteristics of the ointment base to make them suitable for the more delicate tissues of the eye.

The primary goal of transdermal drug administration, unlike topical drug administration, is to achieve and maintain adequate systemic drug concentrations. Transdermal preparations do not target diseases of the skin; rather, they are designed to use the skin as a means for drug absorption. Transdermal patches provide several advantages over oral dosage forms, particularly in those patients who have difficulty swallowing or taking tablets or capsules. Additionally, transdermal semisolids such as nitroglycerin ointment and testosterone gel are available by prescription. Transdermal products are often dosed less frequently than oral forms, which can aid in compliance and may improve disease state control. Transdermal products deliver drugs at a consistent, steady rate, which can avoid side effects that may be due to peaks (high concentrations). First pass metabolism, the breakdown of drugs by the liver, can be avoided with transdermal products because the absorbed drug will not travel to the liver prior to distribution through the body (as oral preparations do). Although the goal of transdermal products is systemic absorption, some products like diclofenac gel are applied to the affected joints of patients with osteoarthritis for pain relief at the site of application. The drug is absorbed through the skin and concentrates in the joint space, rather than the bloodstream.

Although there are several good reasons for choosing a transdermal drug product, there are also several disadvantages. Refer to Table 32-1 for a list of advantages and disadvantages of transdermal drug delivery. The most common adverse effect with transdermal administration is irritation at the site of application. Patients may experience redness, itching, and swelling, which may be caused by the drug, adhesive, or other components of a patch or vehicle. Drug delivery via the transdermal route of administration is limited by certain drug properties, particularly lipophilicity (fat solubility), molecule size, and potency. Lipophilic drugs can more easily move through the skin compared to hydrophilic drugs. Even though lipophilic drugs can move more easily through the stratum corneum, achieving high systemic concentrations can be difficult using transdermal delivery methods. There are several formulations of drug patches designed to maximize drug delivery and minimize local irritation.

TABLE 32-1.

Advantages and Disadvantages of Transdermal Delivery



  • Steady absorption of drug across skin for consistent serum drug levels

  • Lack of peak drug concentrations may decrease side effects

  • Less invasive than intravenous route

  • Patch is easily removed if toxicity develops

  • Less frequent administration increases compliance

  • Alternate route if oral formulation is not tolerated (nausea, stomach upset, unconscious)

  • Alternate route for drugs that undergo degradation by stomach contents or extensive first pass metabolism

  • Local irritation at site of application from drug, adhesive, or other excipients (redness, itching, swelling)

  • Low permeability of skin limits the number of drugs suitable for this route

  • Substantial amount of drug left in patch after use leads to potential for exposure to children and pets

  • Damaged or cut patches may lead to dose dumping


What may be the advantage of a twice-weekly patch (CombiPatch) compared to daily oral hormone replacement therapy for Mrs. Smith?

Transdermal Patch Formulations

There are two types of drug patches: matrix or reservoir. See Figures 32-2 and 32-3 for a comparison of the matrix delivery system and the reservoir delivery system. The matrix delivery system contains a polymer matrix in which the drug is embedded. The matrix is designed to release drug at a steady rate. These patches tend to be smaller and thinner than reservoir patches. In the reservoir system a membrane is placed between the reservoir, which contains the drug, and the adhesive. The purpose of the membrane is to control the release of drug so constant blood levels can be achieved. As noted in Figures 32-2 and 32-3, both of these delivery systems contain a release liner that protects the patch before use and is removed prior to application.

FIGURE 32-2.
FIGURE 32-2.

Matrix delivery system.

FIGURE 32-3.
FIGURE 32-3.

Reservoir delivery system.

Transdermal patches may utilize one of several adhesives. Newer pressure-sensitive adhesives, the most commonly used, provide strong adhesion once in contact with the skin, can be removed easily, and tend to produce less skin irritation. Other substances may be incorporated into transdermal patches, such as chemicals that may enhance drug penetration. Compounds that improve hydration, prevent water loss, or remove lipids from the skin may aid in drug delivery (see Medication Table 32-1, located at the end of the chapter).

Patients should be reminded to follow closely the printed instructions for product placement and removal. Some patches may be applied for several hours, while others are intended for week-long use. All patches, regardless of type, should be placed at the recommended application site on clean, dry skin. Periodically changing application sites can minimize skin irritation. Patients should always store patches in the original packaging until use. Cutting or tearing a patch may destroy the polymer matrix or reservoir and may lead to increased drug absorption and adverse effects. The patient should always remove the used patch before placing a new patch on the skin. Active drug will still be present in the used patch and overdosing could occur. Some patches may be discarded in the trash, while others should be flushed down the toilet to prevent accidental exposure or abuse.


Many transdermal products are intended for uninterrupted use; however, patients using nitroglycerin patches should have a 10- to 12-hour patch-free interval each day. Prescribing directions frequently instruct patients to apply one patch in the morning and remove it before bedtime.


Patients should be reminded not to cut or tear patches as this may lead to increased absorption and possible toxicity.


Application to the skin provides a convenient method for topical and systemic drug administration. Understanding the skin’s structure, drug properties, and available product formulations can aid in the selection of the most appropriate product to maximize drug absorption and minimize potential adverse effects. Transdermal patches offer a unique dosage form for the administration of systemic agents by providing consistent drug levels in the blood, less frequent dosing intervals, and avoiding the need for oral administration. Currently available transdermal patches utilize the matrix or reservoir systems of drug delivery and the patient should always be advised to follow the manufacturer’s recommendations for use and disposal.


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  • Elder DL, eds. A Practical Guide to Contemporary Pharmacy Practice and Compounding. 4th ed. Philadelphia, PA: Wolters Kluwer; 2018.

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  • Saleem MD, Maibach HI, Feldman SR. Principles of topical therapy. In: Kang S, Amagai M, Bruckner AL, et al., eds. Fitzpatrick’s Dermatology in General Medicine. 9th ed. New York, NY: McGraw-Hill; 2019. Accessed January 11, 2020.

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  • Sewell MJ, Burkhart CN, Morrell DS. Dermatological pharmacology. In: Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 13th ed. New York, NY: McGraw-Hill; 2018. Accessed January 11, 2020.

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  • Wilkosz MF, Bogner RH. Transdermal drug delivery. Part 1: Current status. US Pharmacist. 2003;28(4).


  1. Describe the three functionally distinct layers of the skin.

  2. Name four factors that affect drug absorption, and describe how they affect drug absorption.

  3. The manufacturers of IcyHot (7.6% menthol) cream for arthritis recommend not to apply the medication immediately before or after exercise and not to bandage or wrap the area after application. Based on what you have learned about factors of drug absorption, why does the manufacturer make these recommendations?

  4. Name two advantages and two disadvantages of transdermal drug administration.

  5. Describe the differences between matrix and reservoir delivery systems.

  6. How should a patient dispose of a fentanyl patch?



Representative Transdermal Patches*

Generic Name


Brand Name

Type of Patch




Fentanyl (FEN ta nil)

Reservoir (brand and some generic formulations), matrix (generic formulations)

Replace patch and rotate sites every 72 hours; apply to chest, back, flank, or upper arm

Some patients report differences in efficacy when switching between reservoir and matrix formulations; avoid direct exposure to heat as this may increase fentanyl absorption and potential toxicity; dispose of removed patches by folding sticky sides of the patch together and flush down toilet; remove patch prior to undergoing an MRI

Buprenorphine (byoo pre NOR feen)



Replace patch and rotate sites every 7 days; apply to upper arm, upper back, upper chest, or side of the chest; do not put a new patch on the same skin area as an old patch for at least 21 days

Dispose used or unused patches using the Patch-Disposal Unit provided in packaging; alternatively, can fold sticky sides of used patches together and flush down the toilet

Lidocaine (LYE doe kane)

Lidoderm, ZTlido


Apply 1 to 3 patches to painful area for up to 12 hours in a 24-hour period (12 hours with patch on, 12 hours with patch off)

Available over the counter; may cut patch to fit the exact area of pain; remove patch prior to undergoing an MRI; patch should not get wet

Diclofenac (dye KLOE fen ak)



Apply 1 patch to the most painful area twice a day

Remove patch prior to undergoing an MRI; do not wear when bathing or showering

Attention Deficit Hyperactivity Disorder

Methylphenidate (meth il FEN i date)



Apply to area 2 hours before effect is needed; may wear patch up to 9 hours; apply patch to hip area, alternating sides daily

Dispose of removed patches by folding sticky sides of the patch together and flush down toilet or dispose of in a lidded container.

Smoking Cessation

Nicotine (NIK oh teen)

Nicoderm CQ, Nicoderm CQ Clear, Habitrol

Reservoir (Nicoderm CQ), matrix (Habitrol)

Replace patch and rotate sites every 16–24 hours; apply to nonhairy skin of upper body

Remove Nicoderm CQ patch prior to undergoing an MRI

Blood Pressure/Angina

Clonidine (KLOE ni deen)



Replace patch and rotate sites once a week; apply to upper arm or outer chest

Remove patch prior to undergoing an MRI

Nitroglycerin (nye troe GLI ser in)



Apply patch once a day for 12–14 hours (remove patch for the remaining 10–12 hours of each day); apply patch to a nonhairy area and rotate site daily

Remove patch for 10–12 hours in the evening to avoid nitrate tolerance; remove patch prior to undergoing an MRI


Estradiol (es tra DYE ole)

Alora, Climara, Menostar, Minivelle, Vivelle-Dot


Climara and Menostar: replace patch and rotate sites once a week; apply to abdomen or buttocks; do not apply to breasts

Alora, Minivelle, Vivelle-Dot: replace patch and rotate sites twice a week; apply to abdomen or buttocks; do not apply to breasts

Estradiol/norethindrone (es tra DYE ole) (nor ETH in drone)



Replace patch and rotate sites twice a week; apply to lower abdomen; do not apply to breasts

Store refrigerated prior to dispensing; after dispensing, patient may keep at room temperature for up to 6 months

Estradiol/levonorgestrel (es tra DYE ole) (lee voe nor JES trel)

Climara Pro


Replace patch and rotate sites once a week; apply to lower abdomen; do not apply to breasts

Ethinyl estradiol/norelgestromin (ETH in il) (es tra DYE ole) (nor el JES troe min)



Replace patch and rotate sites once a week for 3 weeks; do not wear a patch on week 4; buttock, abdomen, upper arm, or back; do not apply to breasts

Testosterone (tes TOS ter one)



Replace patch and rotate sites once a day; apply patch at night to back, abdomen, upper arms, and thighs; do not apply to scrotum; do not apply a new patch to the same site for 7 days

Avoid bathing or swimming for at least 3 hours after applying patch

Overactive Bladder

Oxybutynin (ox i BYOO ti nin)



Replace patch and rotate sites twice a week; apply to abdomen, hips, or buttocks; do not apply a new patch to the same site for 7 days

Available over the counter

Alzheimer’s Disease

Rivastigmine (ri va STIG meen)



Replace patch and rotate sites daily; apply to upper or lower back, upper arm, or chest; do not apply a new patch to the same site for 14 days

Parkinson’s Disease

Rotigotine (roe TIG oh teen)


Replace patch and rotate sites daily; apply to abdomen, thigh, hip, flank, shoulder, or upper arm; do not apply a new patch to the same site for 14 days

Major Depressive Disorder

Selegiline (se LE ji leen)



Replace patch and rotate sites daily; apply to upper chest, back, abdomen, upper thigh, or outer upper arm

Motion Sickness

Scopolamine (skoe POL a meen)

Transderm Scop


Apply 4 hours before needed and replace patch and rotate sites after 3 days; apply to hairless area behind one ear

Remove patch prior to undergoing an MRI; limit contact with water

MRI = magnetic resonance imaging.

* National Library of Medicine, DailyMed. Bethesda, MD: U.S. National Library of Medicine, National Institutes of Health, Health & Human Services; 2021. Accessed July 12, 2021

** Pronunciations have been adapted with permission from USP Dictionary of USAN and International Drug Names (USP Dictionary) © 2022.