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`Table 6 Common Afflictions: Brief Outline of Common Dermatological Disorders and Other
`Common Skin Problems
`
`Skin problems
`
`Examples
`
`I. General involvements
`A. Physical damage
`1. Blunt instrument
`2. Sharp instrument
`3. Scraping, rubbing
`4. Heat
`5. Ultraviolet radiation
`6. Insects
`B. Chemical damage
`1. Contact dermatitis
`2. Contact allergy
`3. Solvent extraction
`II. Abnormalities of the epidermis
`A. Stratum comeum
`1. Tardigrade sloughing and thickening
`2. Hyperdryness
`3. Hyperproliferative thickening, abnormal
`structural organization
`B. Viable epidermis
`1. Cell damage and inflammation
`2. Fluid collection
`3. Abnormal cell growth (not division)
`4. Thickening of granular layer
`5. Hyperproliferation, incomplete keratinization
`6. Malignancy
`III. Abnormalities of the dermis and dermal-epidermal
`interface
`A. Melanocyte abnormalities
`1. Hyperfunction
`2. Hypofunction
`3. Abnormal growth
`4. Malignancy
`B. Dermal-epidermal interface
`1. Lifting of the epidermis
`2. Overgrowth of papillary layer
`C. Dermis
`1. Vascular reactions
`2. Abnormal growth of fibrinocyte
`3. Abnormal polymerization
`IV. Abnormalities of the glands (appendages)
`A. Hair follicle
`1. Hyperactivity
`2. Hypoactivity
`B. Sebaceous glands
`1. Hyperactivity
`2. Occlusion
`C. Eccrine sweat gland
`1. Hyperactivity
`2. Occlusion, inflammatio
`V. Infectious diseases
`A. Bacterial
`B. Fungal
`C. Vual
`D. Protozoa!
`
`Source: Refs. 16 and 19.
`
`Contusion, bruise
`Cut, nick, animal bite
`Abrasion, blister
`Bums (1 °, 2°, 3°), blister
`Sunburn
`Mosquito bite, bee sting, ticks, mites
`(chiggers), lice, crab lice
`Poison ivy, poison oak
`Cosmetic dermatitis
`"Dishpan hands''
`
`Ichthyosis
`Chapping, windburn
`Psoriasis
`
`Eczema, general dermatitis
`Blister
`Keratosis
`Lichen planus
`Psoriasis
`Epithelioma
`
`Tanning, chloasma, freckles
`Vitiligo
`Mole
`Melanoma
`
`Dermatitis hypetiformis
`Warts
`
`Urticaria, hives
`Scar, keloid
`Scleroderma, lupus erythematosus
`
`Hirsutism
`Alopecia, baldness
`
`Seborrhea
`Acne, pimples
`
`H yperhidrosis
`
`Athlete's foot, ringworm
`Chickenpox, herpes simplex (cold sores)
`Topical amebiasis
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`Table 7 Pathophysiological Terms: Brief Definitions of Select Pathophysiological Terms
`
`Term
`
`Acne
`
`Alopecia
`Bulla
`Chloasma
`
`Comedo (pl. comedones)
`Dermatitis
`Dermatitis herpetiformis
`
`Eczema
`
`Hirsutism
`lchthyosis
`
`Infiltration
`Keloid
`
`Keratosis
`Lichen planus
`
`Lupus erythematosus
`
`Miliaria
`
`Nodule
`Papilla
`Psoriasis
`
`Pustule
`Scleroderma
`
`Seborrhea
`Urticaria
`
`Vesicle
`Vitiligo
`
`Definition
`
`Inflammatory disease of the sebaceous glands characterized by
`papules, comedones, pustules, or a combination thereof
`Deficiency of hair
`Large blister or vesicle filled with serous fluid
`Cutaneous discoloration occurring in yellow-brown patches and
`spots
`Plug of dried sebum in the sebaceous duct; blackhead
`Inflammation of the skin
`Dermatitis marked by grouped erythematous, papular, vesicular,
`pustular, or bullous lesions occurring in varied combinations
`An inflammatory skin disease with vesiculation, infiltration,
`watery discharge, and the development of scales and crusts
`Abnormal, heavy hairiness
`A disease characterized by dryness. roughness, and scaliness of
`the skin caused by hypertrophy of the stratum corneum
`An accumulation in a tissue of a foreign substance
`Growth of the skin consisting of whitish ridges, nodules, and
`plates of dense tissue
`Any horny growth
`Inflammatory skin disease with wide, flat papules occurring in
`circumscribed patches
`A superficial inflammation of the skin marked by disklike
`patches: with raised reddish edges and depressed centers,
`covered with scales or crusts
`An acute inflammation of the sweat glands, characterized by
`patches of small red papules and vesicles, brought on by
`excessive sweating
`Small node that is solid to the touch
`Small, nipple-shaped elevation
`A skin disease characterized by the formation of scaly red
`patches, particularly on the extensor surfaces of the
`(elbows, knees)
`Small elevation of the skin filled with pus
`A disease of the skin in which thickened, hard, rigid, and
`pigmented patches occur with thickening of the dermal
`connective tissue layer
`A disease of the sebaceous glands marked by excessive discharge
`Condition characterized by the appearance of smooth, slightly
`elevated patches, whiter than the surrounding skin
`Small sac containing fluid; a small blister
`A skin disease characterized by the formation of light-colored
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`serious threat, and physician referral is mandatory. Patients should also be directed to counsel
`with a physician whenever the origins of a skin problem are in question.
`e. Surface Effects
`Of the many possible aforementioned dermatological targets, the skin surface is clearly the
`easiest to access. Surface treatment begins at the fringe of cosmetic practice. Special cosmetics
`are available to hide unsightly blemishes and birthmarks. These lessen self-consciousness and
`are psychologically uplifting. Applying a protective layer over the skin is sometimes desirable.
`For example, zinc oxide pastes are used to create a barrier between an infant and its diaper
`which adsorbs irritants found in urine, ameliorating diaper rash. These same pastes literally
`block out the sun and, at the same time, hold in moisture, protecting the ski enthusiast from
`facial sun and wind burns on the high slopes. Transparent films containing ultraviolet light(cid:173)
`absorbing chemicals are also used as sunscreens. Lip balms and like products lay down occlu(cid:173)
`sive (water-impermeable) films over the skin, preventing dehydration of the underlying stratum
`corneum and, thereby, allaying dry skin and chapping. The actions of calamine lotion and other
`products of the kind are limited to the skin's surface. The suspended matter in these purportedly
`binds urushiol. the hapten (allergen) found in poison ivy and oak. However, these may best
`benefit the patient by drying up secretions, relieving itchiness. In all these instances for which
`the film itself is therapeutic, bioavailability has little meaning.
`Bioavailability does matter with topical antiseptics and antibiotics, even though these also
`act mainly at the skin's surface. These anti-infectives are meant to stifle the growth of surface
`microflora; thus, formulations that penetrate into the cracks and fissures of the skin where the
`microorganisms reside are desirable. The extent to which the surface is sanitized then depends
`on uptake of the anti-infective by the microbes themselves. Slipshod formulation can result in
`a drug being entrapped in its film and inactivated. For instance, little to no activity is to be
`expected when a drug is placed in a vehicle in which it is highly insoluble. Ointment bases
`that contain salts of neomycin, polymyxin, and bacitracin are suspect here, in that hydrocarbon
`vehicles are extremely poor solvents for such drugs. Inunction (rubbing in) may release such
`drugs, but the pharmacist should seek evidence that such formulations are effective before
`recommending them.
`Deodorants are also targeted to the skin surface to keep microbial growth in check. Here
`they slow or prevent rancidification of the secretions of apocrine glands found in and around
`the axillae (armpits) and the anogenital regions. Medicated soaps also belong in thi
`
`C. Stratum Corneum Effects
`
`The stratum corneum is the most easily accessed part of the skin itself, and there are two
`actions targeted to this tissue: namely, emolliency, the softening of the horny tissue, which
`comes about through remoisturizing it; and keratolysis, the chemical digestion and removal of
`thickened or scaly horny tissue. Tissue needing such removal is found in calluses, corns, and
`psoriasis, and as dandruff. Common agents such as salicylic acid and, to a lesser extent, sulfur,
`cause lysis of the sulfhydral linkages holding the keratin of the horny structure together, leading
`to its disintegration and sloughing.
`It has been mentioned that
` and
`on the presence of adequate natural lipids, hygroscopic substances, and moisture [19,20]. Re(cid:173)
`moisturization (emolliency) can be induced by simply occluding the surface and blocking
`insensible perspiration. However, it is best accomplished by lotions, creams, or waxy formu(cid:173)
`lations, or combinations thereof (e.g., lip balms) that replenish lost lipid constituents of the
`stratum corneum. The fatty acids an
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`cracks and crevices in the horny layer, sealing it off, stabilizing its bilayer structures, and
`allowing it to retain moisture. Many emollient products also contain hygroscopic glycols and
`polyols to replenish and augment natural moisturizing factors of this kind, also assisting the
`stratum comeum in retaining moisture.
`The introduction of moisturizing substances into the stratum comeum is ordinarily a straight(cid:173)
`forward process. Deposition of keratolytics, on the other hand, is not as easily achieved, as
`these agents must penetrate into the horny mass itself. Some salicylic acid-containing corn
`removers, therefore, are made up as concentrated nonaqueous solutions in volatile solvents. As
`these volatile solvents evaporate, drug is concentrated in the remaining vehicle and, thereby,
`thermodynamically driven into the tissue. These many examples illustrate that when the ther(cid:173)
`apeutic target is at the skin's surface or is the stratum corneum, the therapeutic rationale behind
`the treatment usually involves enhancing or repairing or otherwise-modulating barrier functions
`(see Table 5).
`
`D. Drug Actions on the Skin's Glands
`
`A few products moderate operation of the skin's appendages. These include antiperspirants (as
`opposed to deodorants), which use the astringency of chemicals such as aluminum chloride to
`reversibly irritate and close the orifice of eccrine glands [21), impeding the flow of sweat.
`Astringents also decimate the population of surface microbes, explaining their presence in
`deodorants. The distinction between antiperspirants and deodorants is legally significant, as
`antiperspirants alter a body function and are regulated as drugs, whereas deodorants are clas(cid:173)
`sified as cosmetics. Thus, measurably reduced sweating has to be scientifically proved before
`it can be claimed for a product. Nevertheless, given the similarities in the compositions of
`deodorants and antiperspirants, they are likely functionally equivalent. Since eccrine glands are
`mediated by cholinergic nerves, sweating also can be shut off by anticholinergic drugs admin(cid:173)
`istered systematically [22) or topically. However, such drugs are too toxic for routine use as
`antiperspirants even when administered topically.
`Acne is a common glandular problem arising from hyperproliferative closure of individual
`glands in the unique set of pilosebaceous glands located in and around the face and across the
`upper back. Irritation of cells lining the ducts of such glands initiates the formation of a lesions.
`Sheets of sloughed, sebum-soaked, keratinized cells that grow out from the walls surrounding
`the sebaceous duct are what clog the duct. Still-forming sebum is then trappe
`obstruction, oftentimes bulging out the skin and giving rise to an observable lesion (papule).
`This may become infected and fill with a purulent exudate (pustule) or, after infection has set
`in, it may internally rupture and thereby begin the processes that lead to ulceration and scarring.
`Alternatively, the buildup of concentric sheets of sloughed cells may widen the glandular
`opening, with melanin in the widening plug darkening to the point of being black (blackhead).
`Soap and water is considered a therapeutic treatment in acne when it is used to unblock the
`pores. Sebum is emulsified, and it and other debris is removed. Alcoholic solvents, often
`packaged as moistened pledgets, are used for the same purpose. With either treatment care
`must be exercised not to dry out and further irritate the skin. Both local and systemic antibiotics
`and antiseptics suppress the
`ulation
`of anerobic microorganisms
`ucts of
`which irritate the lining of the gland, setting off lesion formation. Mild cases of acne improve
`and clear under the influence of astringents, possibly for the same reason. Retinoids, oral and
`topical, reset the processes of epidermal proliferation and differentiation. Through such dra(cid:173)
`matic influences on cell growth p
`w-
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`ever, because of concerns over toxicity, they tend to be used only in the most severe cases of
`acne and thus are prescribed for those patients whose acne lesions progress to cysts.
`Hair is a product of the pilosebaceous apparatus and in this sense is glandular. It often grows
`out visibly in places where such display is unwanted. It may be shaved, but chemical hair
`removers (depilatories) along with other products are also used to remove it. In the main, the
`use of depilatories is cosmetic, rather than therapeutic. However, depilatories may be prescribed
`in hirsutism, when the existence of coarse, dark facial hair is psychologically distressing to the
`female patient for whom shaving is an anathema. Hair, like the stratum corneum is composed
`of layers of dead, keratinized cells. However, its keratin is more susceptible to the action of
`keratolytics because it is structured in ways that make it more chemically pervious. Thiogly(cid:173)
`colate-containing, highly alkaline creams generally dissolve hair in short order, without doing
`great harm to surrounding tissues. Facial skin is delicate, however, and depilatories must be
`used carefully here.
`
`E. Effects in Deep Tissues
`
`Local, Regional, and Systemic Delivery
`When the target of therapy lies beneath the stratum corneum, topical drug delivery is more
`difficult and becomes more uncertain. Therefore, many potentially useful drugs find no place
`in topical therapy owing to their inability to adequately penetrate the skin. Nevertheless, a
`number of pathophysiological states can be controlled through local administration and sub(cid:173)
`sequent percutaneous absorption. For example, most skin conditions are accompanied by in(cid:173)
`flammation of the skin; topical corticosteroids and nonsteroidal anti-inflammatory drugs alike
`are used to provide symptomatic relief in such instances. Corticosteroids are also used in
`psoriasis for which, in addition to suppressing inflammation, they somehow act on the basal
`epidermal layer to slow proliferation and restore the skin's normal tum9ver rhythm [23]. Pain
`originating in the skin can be arrested with locally applied anesthetics. Over-the-counter ben(cid:173)
`zocaine and related prescription drugs are used for this purpose. Hydroquinone is applied to
`the skin to lighten excessively pigmented skin by oxidizing melanin deep within the surface.
`Another treatment that involves percutaneous absorption is the application of fluorouracil (5-
`FU) for the selective eradication of premalignant and basal cell carcinomas of the skin [22].
`In all of these examples, the key to success is the ability we have to get therapeutic amounts
`of the drugs through the stratum corneum and into the viable tissues.
`Systemic actions of some drugs can also be achieved by local application, in w
`their delivery is known as transdermal delivery. The application of warmed, soft masses of
`medicated bread meals and clays over wounds or aching parts of the body dates to antiquity.
`However, few such plasters and poultices (cataplasms) have survived into modern medicine.
`When analytical developments just past the middle of the twentieth century made it possible
`to measure the exceedingly low circulating levels of drugs that build up in the body during
`the course of therapy, research was begun on ways drugs might be delivered to lower their
`risks and extend their durations of action. Novel delivery systems involving nontraditional
`routes of administration were subsequently conceived, constructed, and put to test. Transdermal
`delivery with adhesive patches
`mic
`The possibilities for transd
`toxicities of certain topically contacted chemicals. As long as a century ago it was known _that
`munitions workers who handle nitroglycerine suffered severe headaches and ringing in the ears
`(tinnitus). These same effects are experienced to a degree by those taking nitroglycerin to
`alleviate angina. The association between therapy and the inadvertent percutaneous absorption
`of nitroglycerin was finally made in
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`producing peak blood levels comparable with those attained on sublingual administration of
`traditional tablet triturates, but levels that were also sustained. Since the permeability of human
`skin is highly variable and patient needs themselves vary, patients using nitroglycerin ointments
`were (and are) instructed to gradually lengthen the ribbon of ointment expressed from the tube
`and rubbed into the skin until tinnitus and headache are experienced, and then back off on the
`dosage. The lastingness of the effects of nitroglycerin administered in this fashion freed patients
`from a fear of wakening in the middle of the night with a heart attack (angina). Consequently,
`nitroglycerin ointments became the first commercially successful, therapeutically proved trans(cid:173)
`dermal delivery systems. But ointments are greasy and, as with all semisolids, suffer variability
`in their dosing, even with dose titration, given that different patients apply semisolids more or
`less thinly and, therefore, over more or less area.
`Since about 1980, sophisticated adhesive patches for transdermal delivery of scopolamine
`(motion sickness), nitroglycerin (angina! symptoms), clonidine (regulation of blood pressure),
`13-estradiol (menopausal symptoms), and fentanyl (cancer pain) have been introduced into med(cid:173)
`icine [24-26]. These patches are affixed to an appropriate body location and deliver drug
`continuously for periods ranging from a day (nitroglycerin) to a week (clonidine). To achieve
`such long periods of delivery, the patches contain reservoirs of their respective drugs. In one
`early type of system, nitroglycerin was formulated into a liquid-filled sponge held in direct
`contact with the skin by an adhesive band around the periphery of the patch. In more recent
`patch designs a membrane is placed over the delivery surface of the patch. Adhesive covering
`this membrane anchors the patch to the skin over the entire contact area of the patch. This
`interfacing membrane can be turned into a rate-controlling membrane to regulate delivery and
`prevent dose dumping, should the patch be inadvertently placed over a site of inordinately high
`permeability. Actually, this rate-controlling concept was used in the design of the first patch,
`the scopolamine transdermal system. The development of transdermal patches for yet other
`drugs is an active research area.
`It is obvious from the foregoing that the skin is a formidable barrier, irrespective of whether
`therapy is to be local, regional, or systemic, and the first concern in topical delivery is suffi(cid:173)
`ciency of delivery. With local therapy, the aim is to get enough drug into the living epidermis
`or its surroundings to effect a pharmacological action there without producing a systemically
`significant load of the drug. The latter is actually a rare occurrence, except when massive areas
`of application are involved. Regional therapy involves effects in musculature and joints deep
`beneath the site of application. To be successful, this requires a greater delivery r
`an enormous fraction of the drug that passes through the epidermis is routed syst
`the local vasculature. Indeed, the levels of drug reached in deep local tissues have proved to
`be only a few multiples higher than those obtained after systemic administration of the drug
`[27). Even more drug has to be delivered per unit area to transdermally effectuate a systemic
`action.
`
`Factors Affecting Functioning of the Skin Barrier
`A matter of considerable consequence in topical delivery is variability in skin permeability
`between patients, which may be as much as tenfold. The underlying sources of this high degree
`of variability are thought to be many and diverse. Humans differ in age, gender, race, and
`a full(cid:173)
`health, all of which are alleg
`term baby is born with a ba
`e skin
`remains so through life. There is little convincing evidence that senile skin, which tends to be
`dry, irritable, and poorly vascularized, is actually barrier-compromised [28]. However, pre(cid:173)
`mature neonates have inordinately permeable skins. The incubators used to sustain such infants
`e,
`provide a humidified environmen
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`conditions that not only make the baby comfortable, but that also forestall potentially lethal
`dehydration and hypothermia [29].
`Gender, too, affects the appearance of human skin. Nevertheless, there is little evidence that
`the skins of male and female differ much in permeability. However, there are established
`differences in the barrier properties of skin across the races of man. Although the horny layers
`of whites and blacks are of equal thickness, the latter has more cell layers and is measurably
`denser [30]. As a consequence, black skin tends to be severalfold less permeable [30,31].
`Humidity and temperature also affect permeability. It has long been known that skin
`hydration-however brought about-increases skin permeability. Occlusive wrappings, there(cid:173)
`fore, are placed over applications on occasion to seal off water loss, hydrate the horny layer,
`and increase drug penetration. In the absence of such intervention, the· state of dryness of the
`stratum corneum is determined by the prevailing humidity, explaining why the condition '' dry
`skin'' is exacerbated in the winter mon~hs in northern climates.
`Temperature influences skin permeability in both physical and physiological ways. For in(cid:173)
`stance, activation energies for diffusion of small nonelectrolytes across the stratum corneum
`lie between 8 and 15 kcal/mol [4,32]. Thus thermal activation alone can double the rate of
`skin permeability when there is 10° change in the surface temperature of the skin [33]. Ad(cid:173)
`ditionally, blood perfusion through the skin, in terms of amount and closeness of approach to
`the skin's surface, is regulated by its temperature and also by an individual's need to maintain
`the body's 37°C isothermal state. Since clearance of percutaneously absorbed drug to the
`systemic circulation is sensitive to blood flow, a fluctuation in blood flow might be expected
`to alter the uptake of chemicals. No clear-cut evidence exists that this is so, however, which
`seems to teach us that even the reduced blood flow of chilled skin is adequate to efficiently
`clear compounds from the underside of the epidermis.
`Above all else, the health of the skin establishes its physical and physiological condition,
`and, thus, its permeability. Consequences attributable to an unhealthy condition of skin can be
`subtle or exaggerated. Broken skin represents a high-permeability state, and polar solutes are
`several log orders more permeable when administered over abrasions and cuts. Irritation and
`mild trauma tend to increase the skin's permeability, even when the skin is not broken, but
`such augmentation is far less substantial. Sunburn can be used to illustrate many of the barrier(cid:173)
`altering events that occur in traumatized skin. Vasodilation of the papillary vasculature, with
`marked reddening of the skin, is among the first signs that a solar exposure has been overdone.
`In its inflamed state, the skin becomes warm to the touch. After 1 or 2 days, epider
`begins in earnest, and the tissue is hyperproliferatively rebuilt in its entirety. It d
`thickness, and a new stratum corneum is quickly laid down [34]. Because the newly formed
`stratum corneum's anchorage to existing tissues is faulty, the preexisting horny layer often
`eventually peels. Of more importance, hyperplastic repair leads to a poorly formed horny
`structure of increased permeability to water (as measured by transepidermal water loss) and
`presumably other substances. Given these events surrounding irritation, since many chemicals
`found in the workplace and home are mildly irritating-including the soaps we use to bathe
`and the detergents we use to clean house and clothes-is it really a wonder that the permea(cid:173)
`bility of human skin is so demonstrably variable?
`Some chemicals have prompt, destructive effects on the skin barrier. Saturated aqueous
`phenol, corrosive acids, and st
`roy
`its functionality, even as their
`_ the
`stratum corneum may appear normal following such damage, the skin may be only marginally
`less permeable than denuded tissue [35]. Furthermore, permeability remains high during the
`full duration of wound repair and until a competent stratum comeum is laid down over the
`injured surface. Other chemicals are d
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`of skin and improve drug delivery. For obvious reasons, these are referred to as skin penetration
`enhancers. More will be said of these later.
`Thermal burning produces comparably high states of permeability immediately following
`burning, providing that the surface temperature of the skin is raised above 80°C, a temperature
`on the lower side of temperatures able to denature keratin [36). However, burning temperatures
`below 75°C, although fully capable of deep tissue destruction in seconds, leave the structure
`of the stratum corneum itself relatively unscathed. Burn wounds of this kind remain imper(cid:173)
`meable until tissue repair and restructuring processes get under way and the necrotic tissue
`with its horny capping is sloughed. The differences in permeability state of burned skin im(cid:173)
`mediately following the trauma can be highly consequential in terms of drug delivery. In the
`instance of deep burns obtained at lower than keratin-denaturing temperatures, topical delivery
`of antibiotics and antiseptics into a wound, as may be necessary to control wound sepsis,
`remains difficult for as long as the stratum comeum over the wound stays in place, and ag(cid:173)
`gressive use of antiseptics is warranted. In the other extreme, there is risk of toxic systemic
`accumulation of the antiseptics and antibiotics, particularly in major burns covering 20% or
`more of the body surface area. Conservative treatment is warranted. Since burns are rarely well
`characterized relative to their permeability dimension, attending physicians and pharmacists
`need to monitor antiseptic usages carefully to control wound sepsis without poisoning the
`patient. Finally, if not surgically debrided, the necrotic tissue is eventually walled off, enzy(cid:173)
`matically digested, loosened, and sloughed, producing a denuded, open, granulating surface.
`Small full-thickness wounds are closed and sealed off quickly by reconstruction of the epi(cid:173)
`dermis from the edges of the wound. Large full-thickness injuries take too long to heal by this
`process and require grafting. All such wounds remain highly permeable until covered over
`again with a healthy, fully differentiated epidermis.
`As with burns, physical disruption of the stratum corneum opens the skin in proportion to
`the extent of damage. Cuts and abrasions are associated with high permeability at and around
`such injuries. Eruption of the skin in disease has a similar effect, at least to the extent that the
`stratum corneum's integrity is lost. The skin over eczematous lesions should be considered
`highly permeable. Not all skin diseases raise permeability, however. The states of permeability
`of ichthyosiform, psoriatic, and lichenified skin have not been well characterized, but in all
`likelihood are low for most drugs. It has proved difficult to get potent corticosteroids through
`psoriatic plaque, for instance, and occlusive wrapping is often called for.
`
`Percutaneous Abs01ption: The Process
`The process of percutaneous absorption can be described as follows. When a drug system is
`applied topically, the drug diffuses passively out of its carrier or vehicle and, depending on
`where the molecules are placed down, it partitions into either the stratum corneum or the
`sebum-filled ducts of the pilosebaceous glands. Inward diffusive movement continues from
`these locations to the viable epidermal and dermal points of entry. In this way, a concentration
`gradient is established across the skin up to the outer reaches of the skin's microcirculation,
`where the drug is swept away by the capillary flow and rapidly distributed throughout the
`body. The volume of the epidermis and dermis beneath a 100-cm2 area of application, roughly
`the size of the back of the hand, is approximately 2 cm3
`• The total aqueous volume of a 75-
`ll in
`kg (=165-lb) person is about
`excess of 10,000. Consequent
`ntial.
`Thus, selectively high epidermal concentrations of some drugs can be obtained. However, if
`massive areas of the body (~20% of the body surface) are covered with a topical therapeutic,
`systemic accumulation can be appreciable. For instance, corticosteroids have produced serious
`systemic toxicities on occasion whe
`
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`261
`
`Moreover, as has already been pointed out, if the stratum corneum is not intact, many chemicals
`can gain systemic entrance at alarming rates. Together these factors may place a patient at
`grave risk and should always be taken into account when topical drugs are put in use. The
`pharmacist, therefore, should carefully measure how topicals are to be applied and be on alert
`for untoward systemic responses when body coverages are unavoidably extensive.
`The events governing percutaneous absorption following application of a drug in a thin,
`vehicle film are illustrated in Fig. 2. The important processes of dissolution and diffusion within
`the vehicle are cataloged. These will be discussed later. Two principal absorption routes are
`indicated in the sketch: (a) the transepidermal route, which involves diffusion directly across
`the stratum corneum; and (b) the transfollicular route, for which diffusion is through the fol(cid:173)
`licular pore. Many words have been written concerning the relative importances of these two
`pathways. Claims that one or the other of the routes is the sole absorption pathway are ground-
`
`Dissolution of drug in vehicle
`
`Diffusion of drug through vehicle
`to skin surface
`
`TRANSEPIDERMAL
`ROUTE
`
`TRANS FOLL! CULAR
`ROUTE
`
`Partitioning
`into stratum
`corneum
`
`Partitioning
`into sebum
`
`Diffusion through
`protein-lipid matrix
`of stratum corneum
`
`Diffusion through
`lipids in sebaceous
`pore
`
`Diffusion through cellular
`mass of epidermis
`
`Diffusion through fibrous
`
`Capillary uptake and
`systemic dilution
`
`Fig. 2 Events governing percutaneous a
`
`9
`
`9
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`Flynn
`
`less, since percutaneous absorption is a spontaneous, passive diffusional process that takes the
`path of least resistance. Therefore, depending on the drug in question and the condition of the
`skin, either or both routes can be important. There are also temporal dependencies to the relative
`importances of the routes. Corticosteroids breach the stratum corneum so slowly that clinical
`responses to them, which are prompt, are reasoned to be due to follicular diffusion [ 4].
`One should not lose sight of the fact that the chemical barrier of the skin actually consists
`of all skin tissues between the surface and the systemic entry point. Although it is true that
`the stratum corneum is a source of high diffusional resistance to most compounds and, thus,
`the skin's foremost barrier layer, exceptional situations exist for which it is not the only or
`even the major resistance to be e