PHYSIOLOGY OF THE SKIN

Skin protects the body against the environment and preventsexcessive loss of protein, electrolytes, water, and heat. It is oneof the largest organs, with a surface area of approximately1.8 m2, and accounts for 16% of body weight. It is composedof epidermis, dermis, and subcutis (Fig. 23.1).

PATHOPHYSIOLOGY AND DISEASES OFTHE SKIN

The treatment of skin damage produced by trauma or diseaseis aimed at:• Healing or eliminating the disease.• Replacing or amplifying normal skin function.Skin treatment preparations therefore include:• Preparations aimed at the specific disease state.• Preparations that increase protection from the environment

and prevent loss of protein, electrolytes, water, and heat.Although skin disease can be disfiguring and affect the quality of life, it is rarely life threatening.The risk–benefit ratioof any treatment must be considered when deciding on therapy.There are a number of skin disorders for which there is no safeand effective treatment, but under such circumstances theimportance of camouflage creams and wigs must not beoverlooked.

■ Drugs used to treat skin disease are ideally not absorbedbeyond the skinTreatment applied to the skin may be designed for use in skindisease or the skin may act as a transdermal delivery system(see Chapter 5). Cutaneously applied drugs are delivered by a variety of vehicles, including ointments, creams, pastes,powders, aerosols, gels, lotions, and tinctures (Fig. 23.2).Thechoice of vehicle depends on:• The solubility of the active drug.• The ability of the vehicle to hydrate the stratum corneum

and therefore enhance penetration.• The stability of the drug in the vehicle.• The ability of the vehicle to retard evaporation from the

surface of the skin.This is greatest for ointments, and leastfor tinctures.

However, absorption of the drug depends on:• Body site (e.g. drug absorption is low from the palms and

soles, higher from the scalp and face, and very high fromthe scrotum and vulva).

• Skin hydration (e.g. oil-in-water emulsions and occlusivedressings).

• Skin condition (e.g. damage due to inflammation or burnsincreases absorption).

Increasing the concentration gradient across the skin increasesthe mass of drug transferred per unit time. The ability of theskin to act as a reservoir for drugs must be considered when

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Chapter 23

hair shaft

sebaceous gland

epidermis

dermis

subcutis

sweat glandhair follicle

Fig. 23.1 Skin is composed of three layers. The most superficiallayer of the skin is the epidermis, which varies in thickness from site tosite. Beneath this lies the dermis, composed of collagen and someelastic fibers. The subcutis is the deepest layer of the skin and consistsmainly of adipose tissue intersected by fibrocollagenous septa.

determining dosing schedules, as drugs with a short systemichalf-life may have a longer local half-life in the skin.

Although topical treatment is attractive for treating skindisease in terms of the risk–benefit ratio, many conditionsrequire systemic therapy. The retinoids were specifically de-signed to treat skin diseases, but many other systemic agentsused in the treatment of skin disease were originally developedfor other conditions.

SKIN DISEASES

Skin disease accounts for 10–20% of all consultations in generalpractice.The most common skin complaints are dermatitis andeczema (5% of population), acne (1%), urticaria (1%),

psoriasis (0.5%), viral warts (>1%), and skin cancer approxi-mately 0.1% per year.

ECZEMA AND DERMATITIS

Eczema and dermatitis are interchangeable terms and describea pattern of inflammation in the skin characterized by thepresence of intercellular edema (spongiosis) in the epidermisrather than a single disease (Fig. 23.3).Although the unqualifiedterm is often used to denote atopic eczema, eczema can alsoarise as the result of contact with irritants, e.g. strong acids, orcontact allergens, e.g. nickel; hypersensitivity to Pityrosporumyeast (seborrheic dermatitis); local factors such as venous stasis(varicose eczema); or hypersensitivity reactions to drugs.

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Vehicle Physical and chemical properties Use Commercial examples

Ointments Thicker than creams

Water-soluble Mixtures of polyethylene glycols to form Lubricants; burn dressings; to improve the Macrogels and macrogels; consistency can be varied; penetration of active drugs (e.g. polyethylene glycol easily washed off hydrocortisone) into the skin mixtures

Emulsifying Allow evaporation; mix with water and skin Emulsifying exudate ointment

Nonemulsifying Do not mix with water; act as occlusive Chronic dry skin conditions, but are difficult Paraffin ointmentdressings, therefore enhancing hydration to remove except with oil or detergents, Simple ointmentand drug penetration, and softening crusts, and are rather messy and inconvenientbut preventing evaporation and heat loss

Creams Emulsion of oil in water or water in oil

Oil in water Vanish easily; washable; mix with serous Cosmetically acceptable; a vehicle for Aqueous cream, discharge. Some contain a surface tension water-soluble substances cetomacroglycolreducing agent

Water in oil Act like oils (i.e. do not mix with serous More cosmetically acceptable than Oily cream, zinc discharge and aid skin hydration) ointments because they vanish easily, and cream

are easy to apply; can be used on hairy areas; a vehicle for fat-soluble substances

Pastes Thick, semi-occlusive ointment containing Zinc compound insoluble powders; very adhesive and can pasteabsorb some discharge

Powders Absorbent, but can cause crusting if A vehicle for antifungal powders Zinc starch, talcapplied to exudates; reduce friction between skin surfaces and have a cooling effect by increasing the effective surface area of the skin

Gels Semi-solid colloidal solutions or suspensions

Lotions Main component is water; evaporation of Can be used in hairy areas and in the the water cools the skin and the subsequent presence of exudationvasoconstriction reduces inflammation

Shake lotions A means of applying powder to the skin, Should not be used if there is much Calamine lotionwith additional cooling due to evaporation exudate

Vehicles used for topically applied skin preparations

Fig. 23.2 Vehicles used for topically applied skin preparations.

Rational treatment of eczema includes attempts to remove orminimize the above triggers as well as drugs aimed at reduc-ing inflammation (corticosteroids, cyclosporine, azathioprine).The damage of the skin caused by the inflammation results inincreased transepidermal water loss which can be partiallycorrected by the use of topical and bath emollients. Soapsubstitutes are used to minimize irritation of the damaged skinand antihistamines are used to reduce itching and hence furtherdestruction of the skin surface by scratching.

Glucocorticosteroids (see also page 515)Topical glucocorticosteroids are the mainstay of treatment ofatopic eczema.They are anti-inflammatory and vasoconstricting,and reduce keratinocyte cell division. They are classified intofour groups (Fig. 23.4), according to their vasoconstrictingpotency, which correlates remarkably well with their clinicalefficacy.

Note that the different salts of hydrocortisone have verydifferent potencies. Dermatologists therefore avoid nonspecificprescribing of glucocorticosteroids. The fluorinated gluco-corticosteroids are particularly potent and are absorbedsystemically. It is claimed that the newer glucocorticosteroidsfluticasone propionate and mometasone fumarate are potenttopical glucocorticosteroids with less systemic absorption.

Systemic steroids are rarely necessary in the treatment of atopic eczema, even in adults. They show relative lack ofefficiency, tachyphylaxis and rebound and can interfere withgrowth particularly during the adolescent growth spurt.Glucocorticoids are discussed in detail in Chapter 16.

CyclosporineThe efficacy of cyclosporine in atopic eczema was discoveredby chance in patients undergoing organ transplantation whohad coexistent eczema. Clinical trials in both adults andchildren have shown efficacy which is often rapid in onset butthe condition relapses within weeks of stopping therapy. It is

currently recommended in adults for short-term treatment ofsevere atopic eczema which has failed to respond to con-ventional therapy.

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spongiosis

emollientsparakeratosis

inflammationglucocorticosteroids

secondary infectionlymphocyte

eosinophil

acanthosis

antibioticsantiseptics

ba

Fig. 23.3 Eczema. (a) Eczema is characterized histologically by epidermal spongiosis, permeated by an inflammatory infiltrate, predominantly ofmonocytes. (Courtesy of Dr P. McKee.) (b) Sites of drug action in eczema: emollients help to reduce transepidermal water loss, which is increasedas a result of spongiosis; glucocorticosteroids are anti-inflammatory and vasoconstricting, and reduce keratinocyte cell division.

Mild potency Hydrocortisone 0.1, 0.5, 1, 2.5%Hydrocortisone acetate 1%Fluocinolone acetonide 0.0025%Methylprednisolone acetate 0.25%

Moderate Hydrocortisone with ureapotency Alclometasone dipropionate 0.05%

Betamethasone valerate 0.025%Clobetasone butyrate* 0.05%Deoxymethasone 0.05%Fluocinolone acetonide 0.00625% Fluocortolone hexanoate 0.1% , 0.25% Fluocortolone pivalate 0.1%, 0.25%Flurandrenolide 0.0125%

Potent Hydocortisone butyrate 0.1%Beclomethasone dipropionate 0.025%, 0.05%Betamethasone valerate 0.1%Budesonide 0.025%Deoxymethasole 0.25%Diflucortolone valerate 0.1%Flucloronide 0.025%Fluocinolone acetonide 0.025%Fluocinonide 0.05%Fluticasone propionate 0.05%Mometasone furoate 0.1%Triamcinolone acetonide 0.1%

Very potent Clobetasol propionate 0.05%Diflucortolone valerate 0.3%Halcinonide 0.1%

Glucocorticosteroids and their vasoconstrictingpotencies

Fig. 23.4 Glucocorticosteroids and their vasoconstrictingpotencies.

Cyclosporine acts mainly on T lymphocytes, but may alsohave a direct effect on DNA synthesis and proliferation inkeratinocytes. Cyclosporine is discussed in detail in Chapter 15.

Patients need careful evaluation prior to starting cyclo-sporine, particularly with regard to renal function. Cyclo-sporine blood levels are not routinely measured in patients withskin diseases as the doses used (maximum 5 mg/kg) are wellbelow those typically used in organ transplantation. Patientstaking cyclosporine are advised to avoid excess sun exposure,UVB or PUVA therapy (because of the well established excessof skin cancers in patients who have had transplants which mayin part be attributable to immunosuppressive therapy).

Cyclosporine is used for psoriasis more widely than foratopic eczema. It is indicated for severe psoriasis where con-ventional therapy is ineffective or inappropriate. Cyclosporineis beneficial in psoriatic arthropathy (see Chapters 16 and 20)and can be used in conjunction with methotrexate to minimizethe toxicity and cumulative dose of each agent.

The value of cyclosporine in a variety of rare and severedermatoses, such as pyoderma gangrenosum, is being evaluated.

AzathioprineAzathioprine is a cytotoxic immunosuppressant which is usedin unresponsive atopic eczema both as a steroid sparing agentand alone. (See Chapters 12 and 16 for more information aboutazathioprine.)

EmollientsCreams and ointments that improve skin hydration are calledemollients. Ointments are generally greasy preparations whichare insoluble in water and anhydrous, and are more occlusivethan creams. Some newer ointments have both a hydrophilicand lipophilic component while others are water solubleointments. Emollients reduce the excess transepidermal waterloss, a feature of eczema, as evidenced by surface electricalcapacitance, measurement of transepidermal water loss, andmoulding of skin surface replicas.Thus they help restore barrierfunction but do not have an anti-inflammatory effect.They cansoothe itching by their cooling effect but this is a transientbenefit. There is some evidence that they reduce the suscep-tibility of eczematous skin to irritants.

Emollients form the mainstay of treatment of ichthyosis.Preparations containing urea and propylene glycol, whichimprove penetration, have been shown to be superior to otheremollients in lamellar ichthyosis. Emollients are also useful inthe treatment of other dry scaly skin conditions such aspsoriasis.

There is a wide selection of commercially available emol-lients, containing a variety of ointments and creams (see Fig.23.2), some of which are very greasy and can be too occlusive,while others are more water soluble and creamy, but lesshydrating and need more frequent application. A mixture ofsoft white paraffin and liquid paraffin in equal parts is a thickemollient, whereas many of the cream formulations are thinemollients. Patient preference is an important considerationsince these agents need to be used regularly and persistently.In practice this is influenced by stinging on application, ease

of application, appearance on the skin (is it obviously greasy?),smell, duration of action, effect on clothing, and ease ofremoval.

Bath emollients are similar to emollients in action and aredesigned for addition to the bath water to prevent skin dryingwhile bathing.

Soap substitutesCreamy cleansers are preferred to soaps in patients with atopiceczema, as the detergent in soaps can be both irritant anddrying.

AntihistaminesH1 antagonists are widely used in the treatment of atopicdermatitis in an effort to alleviate the itch (see Chapter 16).Although many clinical trials have suggested that the beneficialeffect of antihistamines is due to their sedative effect (inhibitingscratching) some of the newer antihistamines, e.g. cetirizine,may have anti-inflammatory properties which may be relevantto their action in atopic dermatitis.

Antihistamines are the mainstay of treatment of urticariaand are also useful in the management of acute anaphylaxis andangioedema. In the treatment of urticaria, the choice of agentdepends on the need for sedation, which is often desirable inacute urticaria but not in the chronic form.

For prolonged treatment, patients prefer longer-acting drugs. Astemizole is the longest-acting H1 antagonist, but liketerfenadine interacts with drugs commonly used in primarycare (e.g. erythromycin) to produce prolongation of the QTinterval, and this must be considered when using these agents.Loratadine is a long-acting antihistamine that appears not toproduce these interactions.

Histamine H2 antagonists have sometimes been advocatedin urticaria but the evidence regarding their efficacy isconflicting.They have more recently been used at high dosageto treat viral warts but the results of clinical trials to date havebeen variable.

Approaches to the treatment of eczema are summarized inFig. 23.3.

Acne■ Acne is a disease of the pilosebaceous unitAcne is characterized by comedones (keratin plugs in thesebaceous duct opening), inflammatory papules, pustules,nodules, cysts, and scars.The rash occurs where there is a highdensity of pilosebaceous glands (e.g. on the face, back, andchest). Androgenic stimulation of the sebaceous glands atpuberty accounts for the high prevalence of acne at puberty,and the active pilosebaceous follicles are heavily colonized byPropionibacterium acnes.The mechanism for keratin plug formationis poorly understood, but is thought to be pivotal. Continuedgland secretion then results in swelling of the glands and ducts,with nodule and cyst formation and the induction of aninflammatory response, which produces inflammatory papulesand pustules. Approaches to the treatment of acne are shownin Fig. 23.5.

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KeratolyticsTopical keratolytics (e.g. salicylic acid, sulfur) are used in acneto reduce pore occlusion which is characteristic of acne.

SULFUR although of proven efficacy is rarely used because ofits smell.

SALICYLIC ACID is soluble in alcohol but only slightly solublein water. It is thought to act by solubilizing the cell surface

proteins that keep the stratum corneum intact, resulting indesquamation. It is keratolytic at a concentration of 3–6%.Higher concentrations can destroy tissues.

Salicylic acid is absorbed percutaneously, and 1 g of 6%salicylic acid results in plasma concentrations of approximately0.5 mg/dl (0.04 mmol/liter). Salicylism and death have beenrecorded after topical application but the threshold for toxicityis 30–50 mg/dl (2.17–3.62 mmol/liter). Such concentrationsare unlikely to be achieved with keratolytic concentrations(3–6%) but should be borne in mind with higher, destructiveconcentrations, especially in children.

Adverse effects include urticarial and anaphylactic reactionsin patients who are sensitive to salicylates.

Clinical uses other than acne include destruction of viralwarts in concentrations of 16–40%, use in conjunction withtopical steroids to increase skin penetration (concentrations of approx 10%), and in conjunction with benzoic acid inWhitfield’s ointment which is fungicidal.

AZELAIC ACID is a saturated nine-carbon-atom dicarboxylicacid. It was originally obtained by the oxidation of oleic acidby nitric acid but it can also be obtained by fermentation by avariety of micro-organisms.

The observations that the Pityrosporum fungus can oxidizeoleic acid to azelaic acid in culture, and that azelaic acid is acompetitive inhibitor of tyrosinase, led to studies to test thehypothesis that this acid was responsible for the hypo-pigmentation which characterizes pityriasis versicolor andtherefore might have a role in hyperpigmentation disorders.

In subsequent studies azelaic acid was shown to have abeneficial effect in melanosis due to hyperfunction of pro-liferative melanocytes but to lack a de-pigmenting effect onnormal skin. In patients being treated for melasma those withco-incident acne noticed improvement. Subsequent researchhas demonstrated that azelaic acid has:• Anti-enzymatic and antimitochondrial activity: it is a

reversible inhibitor of cytochrome P-450 reductase and 5α-reductase and can reversibly inhibit some enzymes of therespiratory chain as well as being a competitive inhibitor oftyrosinase. It also has an inhibitory effect on anaerobicglycolysis.

• Antimicrobial and antiviral effect: in culture azelaic acidinhibits both aerobic and anaerobic micro-organismsincluding P. acnes, and an inhibitory effect on vaccinia virusreplication has been shown.

• Effect on tumoral cells in culture: a dose-dependent effecton proliferation and viability of melanoma cells, lymphomaand leukemia derived cell lines while not affecting normalcells in culture.

In acne, inhibition of aerobic respiration and anaerobicglycolysis are thought to be important in its effects on micro-organisms, and the reduction of cellular energy formation in keratinocytes may be relevant. Azelaic acid is keratolytic and comedolytic and in part normalizes the disturbed terminal differentiation of keratinocytes in the follicleinfundibulum. It is available as a topical cream for the treatmentof acne.

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b poral occlusion keratolytics

tretinoinisotretinoinazelaic acid

glandular hyperplasiaisotretinoinoral contraceptive pill

rancid sebumantibiotics

niacinamide

rudimentary hair

a

Fig. 23.5 Acne. (a) Histologically, acne is characterized by keratinplugs (comedones) which block the sebaceous follicle, so that sebumcannot escape. The sebaceous glands are often hyperplastic, andthere can be an intense neutrophil influx. (Courtesy of Dr P. McKee.)(b) Sites of drug action in acne.

Furthermore, anaerobic glycolysis is thought to be import-ant in sebaceous glands, so that there may be an additionaldirect effect on sebaceous gland activity.

Azelaic acid is well tolerated. Benefit is often not seen forup to 4 weeks and treatment should be continued for severalmonths.

In pigmentary disorders the primary effect of azelaic acid isthought to be the reduction of cellular energy formation. It hasbeen shown to be as effective as hydroquinone 4% in thisregard.

BENZOYL PEROXIDE penetrates the stratum corneum andfollicular openings unchanged, but is converted to benzoic acidin the epidermis and dermis. It has several actions:• Germicidal—having an effect on the reduction in facial

microbial flora equal to that of systemic tetracycline.• Keratolytic.• Comedolytic.• Anti-inflammatory.• Sebostatic? (subject of some controversy).Adverse effects of benzoyl peroxide include irritation withincreasing concentrations, and sensitizing properties: up to 1%of patients develop a contact allergic dermatitis. Bleaching ofhair, skin and clothing can be unacceptable.

In addition to its use in acne, benzoyl peroxide has beenused in combination with miconazole, where it is said toincrease efficacy, and a 20% lotion has been used to promoterapid re-epithelialization of wounds.

Mild keratolytics are also used to enhance the emollienteffect of a cream or vehicle (e.g. urea). Stronger keratolytictherapy is used for conditions such as viral warts.

NiacinamideNiacinamide is the amide of vitamin B3. Physiologically, it isconverted to nicotinamide adenine dinucleotide (NAD) or thedinucleotide phosphate (NADP), both of which function ascoenzymes (see Chapter 27). Niacinamide is thought to act by electron scavenging, inhibition of phosphodiesterase,and/or increased tryptophan conversion to serotonin. It alsohas direct effects on inflammatory cells, inhibiting neutrophils,suppressing lymphocyte transformation, and inhibiting mastcell histamine release. Niacinamide may be a useful treatmentfor acne. Clinical trials to date suggest that topical niacinamidegel is as effective as topical clindamycin for mild to moderateacne, and represents a nonantibiotic treatment that appears tobe well tolerated. In acne its main effect seems to be inhibitionof cyclic AMP phosphodiesterase and lymphocyte trans-formation, which may inhibit epithelial proliferation in thepilosebaceous unit.

Antibiotics (see Chapter 9)TOPICAL ANTIBIOTICS Topical administration of antibiotics foracne (Fig. 23.6) has been shown to be equi-effective to benzoylperoxide or tretinoin, but their long-term use risks the emerg-ence of resistant organisms.

SYSTEMIC ANTIBIOTICS Oral antibiotics (Fig. 23.7) are moreeffective than topical antibiotics in the treatment of acne.Treatment should be continued for a minimum of 6 monthsbut some improvement should be evident at 3 months. If thereis no improvement consider changing antibiotic as resistantstrains of P. acnes are increasingly common, particularly to

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Antibiotic Efficacy Other issues affecting choice

Clindamycin 1% clindamycin phosphate = oral minocycline and tetracyline = 5% benzoyl peroxide gel

• topical tetracycline

• < topical niacinamide

Erythromycin Only lipid soluble formulations—propionate or Erythromycin resistance commonstearate—are effective2% erythromycin gel = 1% clindamycin phosphate1.5% erythromycin solution = 1% clindamycin phosphate solution

Erythromycin with zinc castor May delay emergence of resistanceoil in oily cream 1:9

Erythromycin with benzoyl peroxide May delay emergence of resistance

Tetracyclines Effective and considered cosmetically acceptable Tetracycline resistance commonby 90% patients Stain clothing and skin

Topical antibiotics—acne

Fig. 23.6 Topical antibiotics—acne.

erythromycin, tetracycline, and doxycycline. Some of the thera-peutic effect of these antibiotics is due to nonbacterial effectswhich include:• Enzyme inhibition, e.g. Corynebacterium acnes lipase.• Modulation of chemotaxis.• Modulation of lymphocyte function.• Modulation of cytokines, especially IL-1α expression.

Retinoids (Fig. 23.8)Retinoids include vitamin A and its derivatives, and have potenteffects on:• Cell differentiation, which they induce.• Cell growth, inducing hyperplasia, hypergranulosis, and

decreased numbers of tonofilaments and desmosomes in theepidermis. The latter effect is thought to account for thekeratolytic effect.

• The immune response, stimulating cell-mediated cytotox-icity and acting as an adjuvant to stimulate antibody pro-duction to antigens that were not previously immunogenic.

They also reduce neutrophil migration, although the mech-anism for this is not known.

Intracellularly, retinoids stabilize lysosomes, increaseribonucleic acid polymerase activity, increase incorporation ofthymidine into DNA, and increase prostaglandin (PG) E2, cAMPand cGMP concentrations.The action of retinoids is mediatedby retinoic acid receptors (RARs) which are members of thethyroid/steroid superfamily of receptors. The RARs bindretinoids and DNA, and function as transcription factorsinitiating transcription (see Chapter 27).

TOPICAL RETINOIDS (Fig. 23.9) Tretinoin is the acid form ofvitamin A (i.e. retinoic acid). It is formed by oxidation of thealcohol group in vitamin A alcohol, with all four double bondsin the side chain in the transconfiguration. It is insoluble inwater, but soluble in many organic solvents. It is availabletopically for use in acne, where its efficacy is attributed todecreased cohesion between epidermal cells and increasedepidermal cell turnover. It is thought that this helps removecomedones, and convert closed comedones to open comedones.

The main adverse effect is skin irritation, but patients alsoshould be warned to avoid exposure to ultraviolet light whileusing tretinoin as it appears to increase the tumorigenicpotential of ultraviolet light in animal studies.

A regular application of 0.05% tretinoin cream for aminimum of 4 months improves the appearance of photo-

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Antibiotic Advantages Disadvantages

Tetracyclines Antibiotic of choice. Bacteriostatic at high doses; Not recommended under the age of 12 because of at low doses affect bacterial function discoloration of teeth. Avoid in pregnancy and

breastfeeding

• Oxytetracycline Chelates with calcium-containing food, so needs to be taken with water half an hour before food otherwise there is reduced absorption

• Minocycline Compliance improved by once-daily dosage, as Can cause hyperpigmentation due to deposition of better absorbed drug in skin

• Doxycycline Compliance improved by once-daily dosage, as Photosensitivity dose-relatedbetter absorbed

Erythromycin BacteriostaticCan be used in patients who may become pregnant or breastfeeding

Trimethoprim Equi-effective to tetracyclineReserved for third-line treatment

Clindamycin Useful because of lipid solubility Not to be used routinely because of risk of pseudomembranous colitis

Systemic antibiotics—acne

Fig. 23.7 Systemic antibiotics—acne.

Drug Disease

1st Generation Retinol AcneTretinoinIsotretinoin

2nd Generation Etretinate Psoriasis (and other Acitretin papulosquamous diseases)

Retinoids

Fig. 23.8 Retinoids.

damaged skin, and is licensed for the treatment of mottledhyperpigmentation and fine wrinkling caused by chronic sunexposure.

ORAL RETINOIDS Isotretinoin is a synthetic retinoid that is nowavailable for systemic and topical use. Its main effect seems tobe to reduce the size and function of the sebaceous glands, anda 4–6-month course is highly effective in the treatment of acnein the majority of patients.

Isotretinoin is well absorbed, extensively bound to plasmaproteins, and eliminated. It is given at a dose of 0.5–1 mg/kg.

The adverse effects of isotretinoin resemble the effects ofhypervitaminosis A, producing dry skin and mucous mem-branes, and epidermal fragility. Rarely, visual disturbances, hairthinning, myalgia and arthralgia, and raised liver enzymes have been reported. Cutaneous complications include photo-sensitivity, allergic vasculitis, granulomatous lesions, and acne

fulminans. Isotretinoin can cause benign intracranialhypertension (BIH), so frequent or unusual headaches are anindication to stop treatment and investigate as appropriate. Astetracyclines can also cause BIH, the two drugs should not begiven together. Triglyceride concentrations increase duringtreatment, but with normal initial concentrations this increaseis rarely sufficient to stop therapy and is reversible on stoppingtreatment.

■ Isotretinoin is teratogenic and should be given to womenof child-bearing age only after appropriate counseling andwith adequate contraception

PsoriasisPsoriasis is a genetically determined hyperproliferative disorderthat can be triggered by infection, trauma, drugs, ultravioletlight, and stress, and rarely by hypocalcemia. Psoriatic skinturns over in seven days rather than the normal 56 days. It ischaracterized by:• Thickened skin plaques with superficial scales.• Capillary dilation in the papillary dermis.• An inflammatory infiltrate, predominantly of lymphocytes,

in the dermis.• A neutrophil infiltrate in the epidermis.The capillary dilation may be an initiating event or an attemptto nourish the hyperproliferating skin.The precise contributionof the inflammatory cells to the clinical disease is not clear.

Approaches to the treatment of psoriasis are shown in Fig.23.10.

Treatment for patients with psoriasis must be individualized.For localized disease, topical therapy is often sufficient.VitaminD analogs are rapidly becoming first-line treatment not leastbecause they are clean, nonstaining, nonsmelling preparationswhich afford a cosmetic advantage over tar and anthralinpreparations. However, these preparations need to be appliedaccurately to affected sites and if the percentage of body areaaffected is large, the potential to disturb systemic calciumhomeostasis needs to be considered. Anthralin (see below) isstill the least toxic agent and offers the potential benefit ofinducing remission. However, it is very messy to use andirritation can be a problem particularly in the fair skinned. Most

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Drug name Advantages Mode of action

Tretinoin Binds to cytosolic Retinoic acid retinoid acid-binding 0.01–0.05 in protein (RAR) with high cream or gel affinity. Binds all

nuclear receptors

Isotretinoin = Benzoyl peroxide 0.05% and topical tretinoin

Adapalene More effective with Does not bind cytosolic less irritation than retinoid RAR and binds tretinoin. Only RAR β and α selectively topical retinoid in nucleuswith significant anti-inflammatory effect

Topical retinoids

Fig. 23.9 Topical retinoids.

Adverse effects of isotretinoin

• Teratogenicity

• Dry skin and mucous membranes

• Epidermal fragility

• Rarely, visual disturbances, hair thinning, myalgia andarthralgia, and raised liver enzymes

• Allergic vasculitis

• Granulomatous lesions

• Acne fulminans

• Benign intracranial hypertension

• Increased triglyceride concentrations

• Keratolytics should be used as first-line therapy

• If a systemic antibiotic is needed, tetracyclines areindicated in children over 12 years of age, but should notbe given to children under 12 because of their effects onmaturing teeth

• Oxytetracycline should be given before minocyclinebecause of the rare reaction to minocycline involvingliver, joints, and fever

• In children under 12 years of age erythromycin is thesystemic drug of choice

• In adults, tetracyclines should be given in preference toerythromycin as erythromycin is used for life-threateninginfections such as Mycoplasma pneumoniae

• Antibiotic resistance to Propionibacterium acnes is as highas 40% in patients with acne referred to hospital

Treatment of acne

patients requiring anthralin are treated in daycare centers or asinpatients, so that a time commitment is required from thepatients to be worthwhile.Tar preparations often offer the bestcompromise between efficacy, ease of application, and tolerablemess and smell.

In patients with more widespread disease, combinationtherapy—in particular with light therapy—is often instigated.Again to be effective phototherapy demands committedpatients, as treatment regimes involve visits to the hospital twicea week for 6–8 weeks.

In patients with associated psoriatic arthropathy, and inpatients where the extent of the disease is causing greatdisability, systemic therapy may be contemplated. All systemicagents used for psoriasis—methotrexate, hydroxyurea,cyclosporine, and acitretin—have potentially serious adverseeffects and the decision to embark on such treatment needs tobe reached after careful discussion with patients, and with welldefined clinical justification.

Vitamin D■ The naturally occurring active metabolite of vitamin D3,1α 25 dihydroxyvitamin D3 (calcitriol), and two syntheticanalogs—calcipotriol and tacalcitol—are effective whenapplied topically in psoriasisVitamin D analogs inhibit epidermal proliferation, induceterminal keratinocyte differentiation, and have anti-inflam-matory properties in vitro and in vivo.

Vitamin D receptors (VDRs) are found in keratinocytes,melanocytes, Langerhans’ cells, dermal fibroblasts, monocytes,and T lymphocytes in normal skin. They belong to the largefamily of structurally related ligand-inducible transcriptionfactors, which includes the retinoid receptors and thyroidhormone receptors (see Chapters 15 and 27).

In psoriasis, there is increased expression of VDRs in thebasal and suprabasal layers of the epidermis, as well as a marked

increase in the density of VDR positivity in intra-epidermal andperivascular T cells and macrophages.

The effects of vitamin D analogs include:• Inhibition of T cell proliferation by blocking the transition

of T cells from the early to the late G1 phase of the cell cycle.• Inhibition of the release of various cytokines, including

interleukin (IL)-2, IL-6, IL-8, interferon (IFN)-γ, tumornecrosis factor (TNF)-β, and granulocyte–macrophagecolony stimulating factor (GM-CSF).

• A reduction in the capacity of monocytes to stimulate T cellproliferation and lymphokine release from T cells.

• Reduced neutrophil accumulation in psoriatic skin.The mechanism of action of these analogs is not yet elucidated.The goal is to develop analogs that induce the expression ofthe vitamin D-responding genes governing Ca2+ homeostasisand analogs that induce expression of the vitamin D-responding genes influencing the keratinocyte cell cycle.

Clearly, for the treatment of skin disease, such analogs shouldoptimally affect the cell cycle and have a minimal effect onsystemic Ca2+ homeostasis.

CALCIPOTRIENE is a vitamin D3 analog (a side-chain modifi-cation of 1α 25-dihydroxyvitamin D3). It is available for thetopical treatment of psoriasis as a cream, ointment, and scalpsolution. It is effective alone, and has been shown to have asparing effect when used with ultraviolet light treatment,cyclosporine, methotrexate, and retinoids. Calcium metabolismis not affected at doses of less than 100 g/week.

Calcipotriene has become the drug of choice for mild to moderate psoriasis. Its non-staining formulation greatlyimproves patient compliance compared with that for coal tarand anthralin preparations. It causes facial irritation in somepatients. Calcipotriene has also been reported to be of benefitin the treatment of other dyskeratotic states and pityriasis rubrapilaris.

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parakeratosishyperkeratosis

keratolytics

emollients

hyperproliferationof keratinocytes

topicalcoal tar

anthralinvitamin D

analogs

systemicmethotrexatehydroxyurea

inflammatory cellinfiltrationcyclosporine

ba

Fig. 23.10 Psoriasis. (a) Psoriasis is characterized by epidermal acanthosis, with clubbed papillae, suprapapillary thinning with dilation of thecapillaries, and hyper- and parakeratosis. Lymphocytes predominate in the dermis, whereas neutrophils may form microabscesses in theepidermis. (Courtesy of Dr P. McKee.) (b) Sites of drug action in psoriasis.

TACALCITOL (1α 24-dihydroxyvitamin D3) has recently be-come available in the UK for the topical treatment of psoriasis.It is applied once daily, and in clinical trials was tolerated onthe face and in the flexures.

AnthralinThe anti-psoriatic component of goa powder was identified as chrysarobin, an easily oxidizable reduction product ofchrysophanic acid, in 1878. The synthetic chrysarobin sub-stitute, anthralin, was introduced in 1915.

One of the challenges of anthralin formulation has beenachieving a compound which is stable in the reduced activeform over long periods while permitting it to oxidize rapidlywithin the tissue. This has traditionally been achieved usingzinc and salicylic acid paste, although newer cream formu-lations and liposomal formulations have been developed.

One of the limitations of anthralin compounds is that theycause irritation and staining.Anthralin is unique because it canlead to remission of psoriasis.

Anthralin is available as a cream (0.1–2%) and ointment(0.1–2%) for home use. The treatment is usually applied for30–60 minutes (short-contact anthralin therapy) and thenremoved.Anthralin paste is largely confined to hospital use andcan be applied for 24 hours or for shorter time periods.Anthralin must be applied to a test area first before treating thewhole body, as patient tolerance varies.The strength of anthralinis gradually increased (e.g. doubling concentrations every3–5 days). Therapy is discontinued when the plaques haveflattened.Anthralin inevitably stains the skin and this stain canbe removed with a keratolytic agent. It also stains clothing.Anthralin can be used in combination with light therapy, andcoal tar baths (Ingram regimen).

No systemic toxicity has been reported with anthralin.However, it is irritant to normal skin and therefore must beapplied accurately to the plaques of psoriasis.

Tar preparationsTherapeutic tars are products of the destructive distillation ofwood, coal, or bitumen.They are highly complex mixtures withsome 10,000 constituents. Petroleum tars have no therapeuticimportance.

WOOD TARS (OIL OF CADE, BEE, BIRCH, AND PINE) are availableas ointments, pastes, and alcohol paints. They may sensitize,but do not photosensitize.

BITUMINOUS TARS were originally obtained from the distil-lation of shale deposits containing fossilized fish. Some have ahigh sulfur content. They are less effective than coal tars anddo not photosensitize.

COAL TAR is a black fluid with a characteristic smell. Differentmethods of distilling heated coal have been used to try toremove its color and odor. Coal tar modifies keratinization butits mechanism of action is poorly understood. The highboiling-point tar acids (phenolics) may be responsible for itstherapeutic effect, possibly by releasing lysosomes in the

granular layer. Coal tars are also antipruritic (and are thereforeused for eczema as well as psoriasis), mildly antiseptic, andphotosensitizing. Refined tars are less phototoxic, but photo-toxicity is directly related to therapeutic efficacy in psoriasis.

The carcinogenicity of pitch and heavy tar fractions is wellestablished, but malignant tumors are extremely rare in relationto tar therapy.A few cases of genital cancer have been reported,but a recent study with a 25-year follow up has shown that theincidence of skin tumors in patients using coal tar is notincreased.

The photosensitizing potential of coal tars is exploited inthe Goeckerman regimen (i.e. combination therapy withultraviolet light B) for psoriasis, which reduces epidermal DNAsynthesis, possibly by forming cross-links between oppositestrands on the DNA double helix.

The most common adverse effect is an irritant folliculitis.Phototoxicity and contact allergic dermatitis can also occur.

AcitretinAcitretin is the main active metabolite of etretinate; etretinateis an aromatic retinoid with a slow terminal elimination phaseof several months.

Acitretin was developed in the hope that its decreasedlipophilicity and reduced elimination half-life (50 hours ratherthan 80 days for etretinate) would be an advantage particularlyin women of child-bearing potential as the retinoids are highlyteratogenic. However, in some patients reversed metabolism ofacitretin to etretinate has been demonstrated, so that pregnancymust be avoided for at least 2 years after the ingestion ofacitretin, like its predecessor, etretinate.

Acitretin is used in the treatment of psoriasis, particularlyerythrodermic and generalized pustular psoriasis, at doses of0.5–1 mg/kg. Higher doses are needed for chronic plaquepsoriasis, but its use in combination therapy with psoralen plusultraviolet light A (PUVA) or ultraviolet light B is increasingbecause it has an ultraviolet light-sparing effect.

Acitretin has a narrow therapeutic window and at doses of1 mg/kg adverse effects are common. Dryness of the lips, eyes,and mucous membranes are frequent as is desquamation ofpalms and soles and skin burning sensations. Hair loss, nosebleeds and paronychia are often a nuisance and may limit thedose. More serious adverse effects include musculoskeletaleffects resembling diffuse idiopathic skeletal hyperostosis. Priorand periodic radiographic screening is therefore advised forlong-term use. As with isotretinoin, liver function and lipidsneed regular monitoring.

In patients who cannot tolerate doses of acitretin which aresufficient to control their disease, combination therapy can beconsidered. Acitretin has been used in combination with tar,dithranol, UVB and PUVA. Combination with methotrexate hasbeen reported in difficult cases but these drugs pose potentialinteractions with increased blood levels of methotrexate andcombined effects on liver toxicity. However, it is sometimesnecessary to continue acitretin in a patient until the therapeuticeffects of methotrexate are established as this takes 6 to 8 weeks.

It has been claimed that tumors, including solar keratoses,kerato-acanthoma, epidermodysplasia verruciformis, basal cell

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epithelioma (BCE) and leukoplakia, sometimes clear followingtreatment with isotretinoin or etretinate. The use of retinoidsin preventing skin tumors in high-risk patients, such as thosewith xeroderma pigmentosum and transplant patients, iscurrently being investigated in ongoing trials.

MethotrexateMethotrexate exerts a strong antimitotic effect on keratinocytesby inhibiting DNA synthesis by competitive inhibition ofdihydrofolate reductase (see Chapter 16).At doses used in thetreatment of psoriasis, methotrexate also inhibits neutrophilchemotaxis. It is administered once a week for the treatmentof psoriasis. Patients taking methotrexate must refrain totallyfrom alcohol. Renal, hepatic, and bone marrow function mustbe assessed prior to, and during, methotrexate treatment, andnote should be taken of potential drug interactions (seeChapters 17 and 28).

CYCLOSPORINE (see Eczema above)

Photo(chemo)therapyUVB therapy is effective in many patients with psoriasis. Otherpatients require stronger, PUVA photochemotherapy (psoralens+ UVA). Psoralens are photoctivated chemicals that intercalatewith DNA, forming cyclobutane adducts with pyrimidine inbases on subsequent exposure to ultraviolet light A.This formsthe basis of PUVA photochemotherapy. This is an establishedtreatment for psoriasis and mycosis fungoides, and clinical trialsare being conducted to investigate its use in vitiligo.

Drugs acting on hairFINASTERIDE at 1 mg/ml has recently been launched for thetreatment of male androgenic alopecia (see Chapter 22 fordescription of finasteride).

TOPICAL MINOXIDIL reverses androgenic alopecia in somepatients. Its mechanism of action is unknown and its effect onandrogenic alopecia is not permanent, with hair loss occurringwithin 4–6 months when it is stopped.

CYPROTERONE ACETATE in conjunction with ethinyl estradiolis used to prevent the progression of androgenic alopecia infemales.

Cyproterone acetate is the treatment of choice for femalehirsutism. It is an anti-androgen and:• Decreases adrenal androgen secretion.• Competes with both testosterone and dihydrotestosterone

for the androgen receptor.• Inhibits the 5α-reductase enzyme.• Inhibits luteinizing hormone secretion by its progestational

effects.A dose of 2 mg daily is sufficient, and it is usually given incombination with an estrogen to ensure regular menstrualbleeding.An improvement may not be evident for 6–12 months.A male fetus will probably be feminized if a pregnancy occurswhen cyproterone acetate is used alone.

LUTEINIZING HORMONE RELEASING HORMONE ANALOGS mayimprove hirsutism in patients with high androgen levels ofovarian origin.

DRUGS THAT MODIFY INFLAMMATORYRESPONSES IN THE SKIN

GlucocorticosteroidsThe efficacy of glucocorticosteroid required depends on:• The skin disease (e.g. very potent for lichen planus).• The site to be treated (e.g. mild to moderate only for facial

application).• The age of the patient (e.g. the indications for a potent

glucocorticosteroid in a child are limited).In general, very potent glucocorticosteroids should be givento adults only under specialist supervision and should not beprescribed for children without consultation with a specialist.

Glucocorticosteroid penetration varies with:• Body site. It is higher when applied to the genitals, face, and

scalp than when applied to the trunk and limbs.• State of the skin. It is enhanced by erythema or erosion.• Occlusion, which increases penetration at least tenfold.• The vehicle used. Ointments produce higher penetration

than creams.• Concentration of drug. A high concentration produces

higher penetration than a low concentration, but penetrationis not proportional to the concentration difference (e.g.increasing the concentration of hydrocortisone tenfoldresults in a fourfold increase in penetration).

■ Intralesional glucocorticosteroids are used for keloid andhypertrophic scars, chondrodermatitis nodularis helicis, andacne cystsLocal injection is also sometimes helpful in alopecia areata andhypertrophic lichen planus that has not responded to topicalglucocorticosteroids.

Intralesional administration of glucocorticosteroids over-comes the limited penetration of topical glucocorticosteroidsand is used to provide a high local concentration of gluco-corticosteroid. Relatively insoluble glucocorticosteroids (e.g.triamcinolone acetonide, triamcinolone diacetate, triamcinolonehexacetonide, betamethasone acetate–phosphate) are used to achieve high local doses, which are gradually released for3–4 weeks.The injections must be limited to 1 mg per site toavoid local skin atrophy.

■ Topical glucocorticosteroids are indicated in thetreatment of inflammatory skin disorders and are a vitalpart of the acute treatment of most forms of dermatitis(eczema)The potency of topical glucocorticosteroid used must betitrated to the disease severity and the minimum effectivestrength determined for each patient. In seborrheic dermatitis,a combination of glucocorticosteroids and antipityrosporalagents is useful to calm the eczema, but antipityrosporal agentsused early in relapse should be sufficient.

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Topical glucocorticosteroids are useful in the treatment offlexural psoriasis, but should not be used as a first-line treat-ment elsewhere as a rebound exacerbation of the disease occurson withdrawal. It is not uncommon for patients to requireincreasing doses of glucocorticosteroids to control the disease.If very potent glucocorticosteroids are then withdrawn,generalized pustular psoriasis can ensue, which is a medicalemergency and often requires systemic treatment with agentssuch as methotrexate (see page 177).

Potent topical glucocorticosteroids are used short-term inthe treatment of vitiligo and alopecia areata, but should not becontinued for more than 4 weeks.

A trial of topical glucocorticosteroids is worthwhile forsarcoidosis, discoid lupus erythematosus, and pemphigus,although systemic treatments are often necessary.

■ Systemic glucocorticosteroids are used for severe acutedermatoses, pemphigus, pemphigoid, and lichen planusSystemic glucocorticosteroids are used only for severe dermato-logic diseases because the treatment benefits must outweighthe risks of long-term use (see Chapter 12).They are indicatedfor:• Severe acute dermatoses such as anaphylaxis, acute contact

allergic dermatitis, acute autoimmune connective tissuediseases and generalized vasculitis, and generalized drugeruptions.

• Chronic disabling disorders such as pemphigus andpemphigoid.

• Severe lichen planus.• Pyoderma gangrenosum.• Sarcoidosis.• Various other unusual dermatoses.

■ All the adverse effects of systemic glucocorticosteroidscan be observed if there is significant systemic absorption oftopical glucocorticosteroidsLocal adverse reactions include worsening and spread of anyinfection (viral, bacterial, and fungal). Skin atrophy, striae,hirsutism, acne, and depigmentation may occur with long-termuse, and the application of potent glucocorticosteroids on theface induces a ‘perioral dermatitis.’

Antimalarial drugsHydroxychloroquine, chloroquine, and mepacrine have abeneficial effect on discoid and systemic lupus erythematosus,polymorphic light eruption, and solar urticaria, and there is some evidence of a therapeutic response in cutaneoussarcoidosis and porphyria cutanea tarda.Their mechanism ofaction in these disorders is unknown, but they have beenshown to:• Inhibit prostaglandin synthesis, chemotaxis, and hydrolytic

enzymes.• Stabilize membranes.• Bind to DNA.

Sulfa drugsDapsone is the drug of choice for leprosy, and is also used inthe treatment of dermatitis herpetiformis, immunobullousdisorders, and numerous other rare dermatoses (see Chapter9). Its mechanism of action is unclear, although neutrophilsand immune complexes seem to play a part in the diseasesinfluenced by the drug. Patients taking dapsone must bemonitored for signs of hemolysis and methemoglobinemiabecause hemolytic anemia is a common adverse reaction and,although rare, methemoglobinemia can be a rapidly fatalcomplication.

Other sulfa drugs having some of the useful effects ofdapsone are sulfapyridine and sulfamethoxypyridazine.

Other drugs modifying the immuneresponseCOLCHICINE is an alkaloid derived from the autumn crocusthat:• Inhibits neutrophil and monocyte chemotaxis, collagen

synthesis, and mast cell histamine release.• Increases collagenolysis.• Arrests mitosis in metaphase and is therefore antimitotic.Colchicine has been used in the treatment of a variety ofdermatologic diseases characterized by leukocyte infiltrationof the skin, including Behçet’s syndrome, psoriasis, palmo-plantar pustulosis, dermatitis herpetiformis, Sweet’s syndrome,necrotizing vasculitis, childhood dermatomyositis, and systemicsclerosis.

Adverse effects include gastrointestinal disturbances, whichare very frequent in patients taking relatively large doses ofcolchicine.

THALIDOMIDE is an immunomodulatory drug whose activitiesare not well characterized but may involve decreasing concen-trations of TNF-α. It is used for the treatment of recalcitrantaphthous ulceration, especially in patients with HIV, and hasbeen beneficial in the treatment of pyoderma gangrenosumand Behçet’s syndrome. It is efficacious in erythema nodosumleprosum.

Adverse effects include teratogenicity which may be pro-found: the drug is contraindicated in any woman who mightbecome pregnant. Patients need to be closely monitored inorder to detect neuropathy at an early stage, ideally while theproblem is subclinical.

The kinetics of thalidomide are not well characterized; it hasa half-life of 3–5 hours.

ORAL CONTRACEPTIVES Combination contraceptive pills con-taining cyproterone acetate, ethinyl estradiol, and desogestrolare ‘acne-friendly,’ unlike most other contraceptive pills whichtend to aggravate acne.

ALKYLATING AGENTS AND ANTIMETABOLITES Drugs such asalkylating agents and antimetabolites (see Chapter 28) are usedin dermatology only if the disease is sufficiently disabling tojustify the risks of their use (Fig. 23.11).

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DRUGS THAT PROTECT THE SKIN FROMENVIRONMENTAL DAMAGE

SunscreensThe growing incidence of melanoma and non-melanoma skincancers and skin ageing has been associated with exposure toultraviolet light. Sunburn before 10 years of age is a major riskfactor for malignant melanoma. Photosensitivity can be amanifestation of some diseases and the use of certain drugs.These conditions are best prevented by sun avoidance or usingphysical barriers to solar penetration, such as clothing. Ifexposure is unavoidable chemical sunscreens can be used tominimize exposure.The topical use of sunscreens reduces therisk of sunburn and probably prevents squamous cell carcinomaof the skin when used mainly during unintentional sunexposure. However, the use of sunscreens to extend the dur-ation of intentional sun exposure may negate any beneficialeffect on preventing melanoma skin cancer.

Sunscreens are classified as either absorbent or reflectant:• Absorbent sunscreens are photo-absorbing chemicals and

can be categorized according to their predominant activewavelength (Fig. 23.12).

• Reflectant sunscreens are inert minerals such as titaniumdioxide, zinc oxide, red petroleum, and calamine, which arecosmetically less attractive because they are greasy and stickyand do not vanish on the skin.

Commercial preparations contain these ingredients in variousproportions.

■ In practice, the sun protection of a sunscreen is abouthalf that suggested by the skin protection factor (SPF)The efficacy of a sunscreen is expressed as the skin protectionfactor (SPF), which is the ratio of the time required to produceminimal erythema with a sunscreen to the time required toproduce minimal erythema without a sunscreen. However, the

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Drug Uses

Cyclophosphamide Pemphigus, pemphigoidWegener’s granulomatosisLupus erythematosusPolymyositisMycosis fungoidesHistiocytosis X

Chlorambucil Mycosis fungoidesBehçet’s diseaseLupus erythematosusWegener's granulomatosisGlucocorticosteroid-resistant sarcoidosisSézary syndrome

Mustine injection Mycosis fungoides

Dacarbazine injection Metastatic malignant melanoma

Methotrexate (given Psoriasisweekly; caution in Reiter’s syndromethe elderly and in Pityriasis rubra pilarisrenal impairment) Ichthyosiform erythroderma

SarcoidosisPemphigus/pemphigoidGlucocorticosteroid-resistant dermatomyositis

Hydroxyurea Psoriasis(less effective than methotrexate)

Azathioprine Pemphigus/pemphigoid(glucocorticosteroid- Lupus erythematosus sparing agent) Dermatomyositis

Wegener’s granulomatosis Actinic reticuloid Pityriasis rubra pilarisIntractable eczema in adults

Bleomycin Squamous cell carcinomaMycosis fungoides and other lymphomasViral warts (intralesional)

Melphalan Scleromyxedema

Cyclosporine PsoriasisAtopic dermatitis Pemphigus/pemphigoidMycosis fungoides/

Sézary syndrome

5-Fluorouracil Solar keratoses (topical)Keratoacanthoma (intralesional)

Alkylating agents and antimetabolites and theirdermatologic disease indications

Fig. 23.11 Alkylating agents and antimetabolites and theirdermatologic disease indications. Their use is justified only if thedisease is sufficiently disabling.

Cinnamates UVB

para-Aminobenzoic acid UVB

Salicylates UVB

Benzophenones UVA

Camphor UVA

Dibenzoylmethane UVA

Aminobenzoates (padimate O) UVB

Anthralin UVA

Absorbent sunscreens and the predominantwavelength screened

Fig. 23.12 Absorbent sunscreens and the predominantwavelength screened. (Ultraviolet [UV] A, 320–360 nm; UVB,290–320 nm)

amount of drug applied in the laboratory to determine suchprotection is much greater per unit area than the same amountapplied in practice and it is difficult to make allowances for lossof the sunscreen with sweating and swimming so that the sunprotection of a sunscreen is about half that suggested by theSPF in practice.Therefore:• If the SPF is less than 10, the sunscreen is only mildly

protective.• If the SPF is 10–15, the sunscreen is moderately protective.• If the SPF is higher than 15, the sunscreen will provide

appreciable protection.• If the SPF is higher than 25, the sunscreen will provide

almost full protection, as required by patients withphotosensitivity.

Sunscreen preparations have been refined to increase cosmeticacceptability, water resistance, durability, and effectiveness.However, the active ingredients, the base, the fragrances, andthe stabilizers can all cause irritant, allergic, phototoxic, orphotoallergic adverse reactions.

Antiviral agents (see also Chapter 8)Acyclovir cream can be used for primary or recurrent labialherpes simplex (cold sores) and for genital herpes simplexinfections.

Penciclovir cream is a newer topical antiviral preparationwhich is licenced for labial herpes simplex infection. Bothagents need to be used as early as possible in the outbreak andone study showed shortening of an attack by a mean of only0.7 days using acyclovir cream.

Systemic therapy is recommended for vaginal or buccalinfections and for herpes zoster. In addition to reducing viralshedding and aiding healing, there is good evidence that earlyantiviral treatment lessens the incidence of postherpeticneuralgia which can be very disabling. Acyclovir is variablyabsorbed when orally administered. Consequently, in severedisease and in eczema herpeticum, parenteral administrationis recommended. Prior to the development of antiviral agents,eczema herpeticum carried a significant mortality, and long-term eye damage caused considerable morbidity.

■ In adults, valacyclovir, a pro-drug which ensures muchbetter bioavailability of acyclovir, has largely supersededacyclovirAntiviral therapy can be life-saving for both chickenpox/shingles and herpes simplex infections in immunocom-promised patients, and is sometimes used in this populationfor prophylaxis. It is generally inappropriate to treat immuno-competent patients with chickenpox in whom the disease ismilder.

Systemic acyclovir, valacyclovir, and famciclovir decreasehealing time and sometimes abort attacks of genital herpes.They are also useful for the treatment of varicella zosterinfections (i.e. chickenpox, shingles). In shingles, admin-istration of antiviral therapy within 72 hours of onset of therash, shortens the duration of pain as well as of the rash, andreduces the incidence, severity, and duration of chronic pain(postherpetic neuralgia). The risk of visual complications

of zoster affecting the ophthalmic branch of the Vth cranialnerve is also reduced by prompt treatment. Prophylacticacyclovir is indicated for immunocompromised patients, andpatients who develop recurrent erythema multiforme afterherpes infections.

Antibacterial agentsTopical antibiotics (Fig. 23.13 and see Chapter 9)Topical antibiotics are used in the treatment of acne (seeabove).

Fusidic acid is active against Staphylococcus aureus on the skinand can be used to treat early superficial skin infections suchas impetigo and folliculitis although systemic antibiotics areoften necessary in these conditions. Fusidic acid resistancedevelops relatively rapidly, but a pause from the use of the drugleads to re-colonization with fusidic acid-sensitive species.Mupirocin is also active against S. aureus including MRSA but forthis reason should probably be reserved for the treatment ofMRSA.

Nasal carriage of S. aureus, which can be the source of re-current skin staphylococcal infection, can be treated with neo-mycin and chlorhexidine. Nasal mupirocin can be used forresistant organisms. Silver sulfadiazine is often used in theprevention and treatment of infection in burn wounds.This isa sulfonamide and some absorption occurs if extensive areasare treated (monitor for pancytopenia). Argyria has also beenreported after prolonged use.

Topical metronidazole is used in the treatment of rosacea.

Systemic antibioticsThe large majority of patients with cellulitis give the typicalhistory of severe flu-like symptoms preceding by 12–36 hoursany symptoms in the affected part, which then becomes red,warm and swollen, characteristic of streptococcal infection.Thedrug of choice is systemic penicillin. Rarely, staphylococcalinfection causes cellulitis in debilitated, immunodeficient ordiabetic patients; in these cases anti-staphylococcal antibioticsshould accompany the penicillin. Erythromycin should be usedfor patients who are penicillin allergic. Despite adequate anti-biotic therapy, the signs may take several weeks to resolve.Thetemptation to change antibiotic therapy if the cellulitis is notspreading should be resisted.The time to resolution is least inpatients who are treated adequately as soon as symptomsdevelop. Patients who have had one episode of cellulitis shouldbe warned that they are at increased risk of a second attack andthat antibiotic therapy should be sought immediately. Consider-ation should be given to continuing penicillin V longer term,e.g. 250 mg b.d. for 3–6 months, as second, and indeed,sequential attacks of streptococcal cellulitis are so common.

Antifungal agentsThere are many topical and systemic antifungal agents for thetreatment of skin, hair, and nail infections with fungi and yeasts(see Chapter 10).

Antiseptic agents (Fig. 23.14)These may obviate the need for antibiotics.

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Antiparasite preparations (Fig. 23.15)Aqueous preparations of these drugs are preferred in thetreatment of scabies as the alcoholic lotions are irritant.A singleapplication is usually sufficient, but an application on two orthree consecutive days is needed for hyperkeratotic scabies.Allmembers of the household must be treated at the same time.

Applications are usually applied from the neck down, buttreatment of the scalp, face, and neck is recommended forchildren under 2 years of age, elderly patients, immuno-compromised patients, and those for whom a previous treat-ment has failed. Benzyl benzoate may require up to threeapplications on consecutive days.

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Drug Activity spectrum Uses Complications

Bacitracin Gram-positive organisms, anaerobic Nasal Resistance with long-term use cocci, Neisseria, tetanus bacilli, staphylococcal Contact allergic dermatitis diphtheria bacilli carriers Rarely contact urticaria

Gramicidin As for bacitracin Rarely contact allergic dermatitis(available only in combination with neomycin, polymyxin, bacitracin, and nystatin)

Mupirocin Most Gram-positive aerobic bacteria Impetigo, nasal May cause irritation of nasal mucosa including methicillin-resistant staphylococcal (contains propylene glycol)Staphylococcus aureus (MRSA) carriage

Polymyxin B sulfate Gram-negative organisms including Used in Neurotoxic and nephrotoxic if systemically Pseudomonas, Escherichia coli, compound absorbed, therefore to be avoided in Enterobacter, and Klebsiella antibiotic open wounds or denuded skin

preparations Contact dermatitis uncommon

Neomycin Gram-negative organisms including Serum concentrations rarely detectable E. coli, Proteus, Klebsiella, and Contact dermatitis common with cross-Enterobacter sensitivity to streptomycin, kanamycin,

paromomycin, gentamicin

Gentamicin As for neomycin, but more effective Use of topical gentamicin should be against Pseudomonas, and active limited because of concerns about the against staphylococci and group A emergence of resistancehemolytic streptococci Neurotoxic, nephrotoxic, and ototoxic if

absorbedDetected in plasma if applied to a large skin area, especially if denuded skin

Clindamycin Propionibacterium acnes Acne 10% absorptionRarely pseudomembranous colitis Skin irritation with alcohol vehicle, less with gel

Erythromycin P. acnes Acne Resistance increasing

Erythromycin in combination Combinations are claimed to reduce

with benzoyl peroxideemergence of resistant strains

Erythromycin in combination with zinc acetate

Metronidazole Rosacea Drying, burning, stinging

Tetracyclines P. acnes Acne Temporary yellow staining of skin (tetracycline, meclocycline) Photosensitivity has not been a problem,

but phototoxic Contraindicated in pregnancy, and in renal and hepatic disease

Activities and uses of topical antibacterial drugs used in dermatology and their complications

Fig. 23.13 Activities and uses of topical antibacterial drugs used in dermatology and their complications.

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Drug Disease Mechanism Adverse effects

Lindane Scabies (head lice resistance high Avoid in pregnancy, breast feeding mothers, so no longer recommended) patients with low body weight, young Crab lice children, and those with a history of epilepsy

Malathion Scabies: kills both adult lice and Organophosphate ova in vitro cholinesterase inhibitorHead lice Crab lice

Permethrin Scabies NeurotoxicLice (but resistance increasing)

Benzyl benzoate Irritant, avoid in children

5% precipitate of Rarely used because of odor and stainingsulfur in petrolatum It is a possible alternative for treating

pregnant women and infants

Carbaril Head lice

Antiparasite preparations

Fig. 23.15 Antiparasite preparations.

Drug name Uses Comments

Chlorhexidine Antiseptic skin cleanser Alcoholic solutions not suitable before diathermy

Benzalkonium chloride Antiseptic skin cleanser

Triclosan Antiseptic skin cleanser

Potassium permanganate Antiseptic skin cleanser, 1:10,000 solution astringent

Cetrimide Disinfectant and detergent Occasional sensitizerproperties

Hydrogen peroxide Disinfectant used for deep wounds and ulcers

Streptokinase–streptodornase Aid ulcer desloughing, which and dextranomer preparations helps eradicate local infection

Povidone iodine Disinfectant, less irritant Caution in pregnancy, breast feeding and renal impairment. Application to large wounds or severe burns may produce systemic effects such as metabolic acidosis, hypernatremia and renal impairment. Avoid regular use in patients with thyroid disease or those receiving lithium therapy. Rarely sensitivity

Hexachlorophene Irritant Avoid in neonates and large raw surfacesAvoid in pregnancyCan cause sensitivity and, rarely, photosensitivity

Chlorinated solutions, e.g. No longer recommended because of irritancy, bleaches dilute hypochlorite solution clothing

Antiseptic agents

Fig. 23.14 Antiseptic agents.

Patients should be told that the itch of scabies can persist forseveral weeks and that itching does not necessarily indicatetreatment failure.

For head lice, both malathion and carbaril should be usedas lotions rather than shampoos, and left in contact with thescalp for 12 hours. Aqueous formulations are preferred forasthmatic patients and small children to avoid alcoholic fumes.The treatment should be repeated after 7 days to kill liceemerging from any eggs that might have survived the firstapplication.

For crab lice, treatment should be applied to the whole bodyfor 12 hours, and repeated 7 days later.

Insect repellentsThese agents repel insects primarily by vaporization of theactive ingredients diethyltoluamide and dimethyl phthalate.The duration of action is limited by the rate of vaporizationand washing and rubbing off. Few preparations currently avail-able are effective for more than a few hours. Allergic reactionscan develop, especially with prolonged use.

Barrier preparationsBarrier creams have been developed to protect the skin fromirritants (e.g. in industry, for patients with dermatitis). Theyrely on:• Water-repellent substances (e.g. silicones).• Soaps.• Impermeable deposits such as titanium, zinc, and calamine.Their efficacy is limited because they must be removable bywashing and cannot be so occlusive that they block pores andfollicles. They have a role in protecting skin from dischargesand secretions and are used for diaper rash and colostomies.

Bandages and dressingsA variety of bandages and dressings are prescribable and playan important role in the management of skin problems. Medi-cated bandages impregnated with zinc paste, with or withoutcoal tar/ichthammol are useful in the management of eczema,acting as an emollient, antipruritic, and barrier to scratching.Bandages containing calamine and clioquinol and fabricdressings impregnated with povidone-iodine, chlorhexidine,framycetin, sodium fusidate, and paraffin are also available.

Silicone gel sheets are clear, soft, and semi-occlusive, andconform well to awkward contours of the body. They have arole in the treatment of hypertrophic scars. Their mechanismof action is not fully understood: pressure, temperature of thescar, and oxygen tension within the scar are not involved, andit is currently believed that the gel may work by promoting scarhydration.

DRUGS ACTING ON SKIN CONSTITUENTS

Drugs acting on keratinocytesUREA makes creams and lotions feel less greasy, increases thehydration of the stratum corneum (concentration, 2–20%),and is a keratolytic (20%). A concentration of 30–50% urea

with occlusion can be used to soften the nail plate before nailavulsion.

Urea appears to act by modifying prekeratin and keratin,leading to increased solubilization. It may also cleave thehydrogen bonds that keep the stratum corneum intact. It isabsorbed percutaneously, but is a natural product of metab-olism, and is excreted in the urine without systemic toxicity.

Adverse effects include irritation and stinging, especiallywith occlusion and in the perineal area.

SALICYLIC ACID Low concentrations (up to 2%) of salicylicacid are used in the treatment of acne (see above). Higherconcentrations (up to 50%) can be used to eradicate warts andcalluses, but are contraindicated in patients with diabetesmellitus or peripheral vascular disease because they can induceulceration. Salicylic acid is absorbed percutaneously, and 1 g of6% salicylic acid results in plasma concentrations of approxi-mately 0.5 mg/dl (0.04 mmol/liter).

PROPYLENE GLYCOL is keratolytic at a concentration of40–70% and is useful in the treatment of hyperkeratoticconditions such as palmoplantar keratoderma, psoriasis,pityriasis rubra pilaris, and hypertrophic lichen planus.Propylene glycol also increases the water content of the stratumcorneum. This hygroscopic characteristic encourages thedevelopment of an osmotic gradient through the stratumcorneum, increasing the hydration of the outermost layers anddrawing water out of the inner layers of the skin. Propyleneglycol can be used alone or in a gel with 6% salicylic acid. Ithas the advantage of minimal absorption, and what is absorbedis oxidized in the liver to lactic acid and pyruvic acid, whichare then used in general metabolism. Its major adverse effectis irritancy, and it can cause contact allergic dermatitis.

PODOPHYLLUM RESIN is an alcoholic extract of Podophyllumpeltatum, and is used in the treatment of condyloma acuminatumand plantar warts. Podophyllotoxin and its derivatives arecytotoxic agents that act on the microtubule proteins of themitotic spindle, preventing normal assembly of the spindle andarresting epidermal mitoses in metaphase.The tincture needsto be applied accurately to the wart tissue to prevent severeerosion of the surrounding normal skin, and allowed a contacttime of 2–3 hours (possibly increasing to 6–8 hours if tole-rated) for 3–5 applications only. If this is not successful,alternative treatment modalities should be considered as theresin is absorbed and distributed in lipids, including those inthe central nervous system. If extensive areas need treatmentthey should be treated in sections to minimize absorption,particularly from intertriginous areas and large moist warts.

Adverse effects include nausea, vomiting, muscle weakness,neuropathy, and even coma and death. Local irritation iscommon. Podophyllum resin is contraindicated during preg-nancy because of its possible cytotoxic effects on the fetus.

Drugs acting on glandsSee Isotretinoin and Niacinamide.

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Drugs acting on nerves■ Topical nonsteroidal anti-inflammatory drugs andcapsaicin can relieve painLocal pain can be transiently relieved by topical nonsteroidalanti-inflammatory drugs (NSAIDs) (see Chapter 7), whilecapsaicin (0.075%) cream is licensed for the treatment of post-herpetic neuralgia. Capsaicin is a naturally occurring alkaloidfound in fruits and capsicum. Crude extracts of capsicum orcapsicum oleo-resin contain small amounts of capsaicin and anumber of co-capsaicinoids, which are thought to cause thecounter-irritant erythematous reaction that accompanies theapplication of these extracts. Capsaicin itself acts by depletingsensory C fibers of neuropeptides, particularly substance P. Itis not a traditional counter-irritant and does not inducevasodilation.

Recently, capsaicin has also been reported to activatevanilloid receptors on sensory nerves and it is possible that thisactivation renders the vanilloid densensitized to endogenousactivators which include low pH, heat and certain lipidmediators generated during the inflammatory process.

■ Topical applications relieve itch, partly by a cooling effectPhenol, menthol, and camphor are often added to topicalapplications to relieve itch and probably act as weak localanesthetics. Calamine, astringents such as aluminum acetateand tannic acid, and coal tar also have some topical antipruriticeffect.

■ Itch may be relieved systemically by histamine H1antagonists (see eczema)Hypnotics, chlorpromazine, trimeprazine, and sedative anti-depressants are sometimes helpful in the treatment of pruritus,possibly because they alter the perception of itch.

CAMOUFLAGE CREAMS

Camouflage creams contain titanium dioxide in an ointmentbase with a variety of color shades that can be matched to thesite and skin color of the patient.The best results are achievedby camouflage consultants.

FURTHER READINGDutz JP, Ho VC. Immunosuppressive agents in dermatology. An update.Dermatol Clin 1998; 16: 235–251. [Review.]

Leppard L, Ashton R. Treatment in Dermatology. Oxford: Radcliffe MedicalPress; 1993. [Aimed at undergraduates and nonspecialists, explaining therationale for treatment of skin diseases.]

Shelley W, Shelley ED. Advanced Dermatologic Therapy, 2nd edn.Philadelphia: WB Saunders; 2001. [Detailed review of treatment of skindiseases.]

Williams LC, Nesbitt LT Jr. Update on systemic glucocorticosteroids indermatology. Dermatol Clin 2001; 19: 63–77. [Review.]

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