Dermatological pharmacology

DERMATOLOGICAL PHARMACOLOGY GLUCOCORTICOIDS Glucocorticoids are used topically for a large variety of dermatologicacl conditions. They benefit by virtue of their antiinflammatory, immunosuppressive, vasoconstrictor and antiproliferative (for scaling lesions) actions. They are administered locally, through topical and intralesional routes, and systemically, through intramuscular, intravenous, and oral routes. Mechanisms of glucocorticoid include apoptosis of lymphocytes, inhibitory effects on the arachidonic acid cascade, depression of production of many cytokines, and myriad effects on inflammatory cells. Topical glucocorticoids have been grouped into seven classes in order of decreasing potency; many of the more potent drugs have a fluorinated hydrocortisone backbone. USES Many inflammatory skin diseases respond to topical or intralesional administration of glucocorticoids. Absorption varies among body areas; the steroid is selected on the basis of its potency, the site of involvement, and the severity of the skin disease. Often, a more potent steroid is used initially, followed by a less potent agent. Most practitioners become familiar with one glucocorticoid in each class so as to select the appropriate strength of drug. Twice-daily application is sufficient, and more frequent application does not improve response. In general, only nonfluorinated glucocorticoids should be used on the face or in occluded areas such as the axillae or groin. Local adverse effects of topical steroids: Thinning of epidermis, dermal changes-atrophy, telangiectasia, striae, easy bruising, hypopigmentation, delayed wound healing, fungal and bacterial infections, purpura and acneiform eruptions Systemic adverse effects of topical steroids Adrenal pituitary suppression can occur if large amounts are applied repeatedly. Infants and children are particularly susceptible. Rarely, Cushing's syndrome has been reported. With proper use, the systemic risks are minimal. Table-Potency of selected topical glucocorticoids CLASS OF DRUG 1 GENERIC NAME, FORMULATION Betamethasone dipropionate cream, ointment 0.05% Clobetasol propionate cream, ointment 0.05% Diflorasone diacetate ointment 0.05% Halobetasol propionate ointment 0.05% 2 Amcinonide ointment 0.1% Betamethasone dipropionate ointment 0.05% Desoximetasone cream, ointment 0.25%, gel 0.05% Diflorasone diacetate ointment 0.05% Fluocinonide cream, ointment, gel 0.05% 3 Betamethasone dipropionate cream 0.05% Betamethasone valerate ointment 0.1% Diflorasone diacetate cream 0.05% Triamcinolone acetonide ointment 0.1%, cream 0.5%
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Dermatological pharmacology

Amcinonide cream 0.1% Fluocinolone acetonide cream 0.2% Hydrocortisone valerate ointment 0.2% Triamcinolone acetonide ointment 0.1%

Betamethasone dipropionate lotion 0.05% Betamethasone valerate cream, lotion 0.1% Fluocinolone acetonide cream 0.025% Hydrocortisone butyrate cream 0.1%

Aclometasone dipropionate cream, ointment 0.05% Desonide cream 0.05% Fluocinolone acetonide cream, solution 0.01%

Dexamethasone sodium phosphate cream 0.1%

Hydrocortisone cream, ointment, lotion 0.5%, 1.0%, 2.5% Class 1 is most potent; class 7 is least potent. Systemic Glucocorticoids Uses Systemic glucocorticoid therapy is used for severe dermatological illnesses. In general, it is best to reserve this method for allergic contact dermatitis to plants (e.g., poison ivy) and for lifethreatening vesiculobullous dermatoses such as pemphigus vulgaris and bullous pemphigoid. Chronic administration of oral glucocorticoids is problematic, given the side effects associated with their long-term use. Daily morning dosing with prednisone generally is preferred, although divided doses are used occasionally to enhance efficacy. Fewer side effects are seen with alternate-day dosing, and if required for chronic therapy, prednisone is tapered to every other day as soon as it is practical. Pulse therapy using large intravenous doses of methylprednisolone sodium succinate is an option for severe resistant pyoderma gangrenosum, pemphigus vulgaris, systemic lupus erythematosus with multisystem disease, and dermatomyositiss. The dose usually is 0.5 g to 1 g given over 2 to 3 hours. More rapid infusion has been associated with increased rates of hypotension, electrolyte shifts, and cardiac arrhythmias. Side effects Oral glucocorticoids have numerous systemic effects. Most side effects are dose-dependent. Long-term use is associated with a number of complications, including psychiatric problems, cataracts, myopathy, osteoporosis, avascular bone necrosis, glucose intolerance or overt diabetes mellitus, and hypertension. In addition, psoriatic patients treated with parenteral or topical glucocorticoids may have a pustular flare, particularly if the steroid is tapered rapidly. RETINOIDS Retinoids include natural compounds and synthetic derivatives of retinol that exhibit vitamin A activity. Retinoids have many important functions throughout the body, including roles in vision, regulation of cell proliferation and differentiation, bone growth, immune defense, and tumor suppression. Because vitamin A affects normal epithelial differentiation, it was investigated as a treatment for cutaneous disorders but was abandoned initially because of unfavorable side effects. Molecular modifications yielded compounds with vastly improved margins of safety.
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Dermatological pharmacology

First-generation retinoids include retinol, tretinoin (all-trans-retinoic acid), isotretinoin (13-cisretinoic acid), and alitretinoin (9-cis-retinoic acid). Second-generation retinoids, also known as aromatic retinoids, were created by alteration of the cyclic end group and include acitretin. Third-generation retinoids contain further modifications and are called arotinoids. Members of this generation include tazarotene and bexarotene. Adapalene, a derivative of naphthoic acid with retinoid-like properties, does not fit precisely into any of the three generations. Retinoic acid (RA) exerts its effects on gene expression by activating two families of receptorsretinoic acid receptors (RARs) and the retinoid X receptors (RXRs)-that are members of the thyroid/steroid hormone receptor superfamily. Retinoids (ligands) bind transcription factors (nuclear receptors), and the ligandreceptor complex then binds to the promoter regions of target genes to regulate their expression. The gene products formed contribute to the desirable pharmacological effects of these drugs and their unwanted side effects. Additional complexity arises because each receptor has three isoforms (, , and ) that form homo- and heterodimers. Retinoid-responsive tissues express one or more RAR and RXR subtypes in various combinations that determine activity locally. Human skin contains mainly RAR and RXR. First- and second-generation retinoids can bind to several retinoid receptors because of the flexibility imparted by their alternating single and double bonds. This relative lack of receptor specificity may lead to greater side effects. The structures of third-generation retinoids are much less flexible than those of earlier-generation retinoids and therefore interact with fewer retinoid receptors. Acute retinoid toxicity is similar to vitamin A intoxication. Side effects of retinoids include dry skin, nosebleeds from dry mucous membranes, conjunctivitis, and hair loss. Less frequently, musculoskeletal pain, pseudotumor cerebri, and mood alterations occur. Oral retinoids are potent teratogens and cause severe fetal malformations. Because of this, systemic retinoids should be used with great caution in females of childbearing potential. USES Retinoids are used in the treatment of diverse diseases and are effective in the treatment of inflammatory skin disorders, skin malignancies, hyperproliferative disorders, photoaging, and many other disorders. 1. Acne 2. Disorder of keratinization 3. Skin cancer 4. Precancerous conditions 5. Psoriasis 6. Cutaneous aging 7. Miscellaneous: Discoid lupus erythematous, subcornial pustular dermatosis, lichen planus, sarcoidosis, porokeratosis. PHOTOCHEMOTHERAPY Electromagnetic radiation is defined by its wavelength and frequency; for convenience, it can be classified into different regions based on its photon energy. For therapeutic purposes, dermatologists are most concerned with the ultraviolet (UV) B (290 to 320 nm), A-I (320 to 340 nm), and A-II (340 to 400 nm) and visible (400 to 800 nm) portions of the solar spectrum. UVC (100 to 290 nm) is absorbed by stratospheric ozone, does not reach earth's surface, and is no longer used therapeutically. UVB is the most erythrogenic and melanogenic type of radiation. It is the major action spectrum for sunburn, tanning, skin cancer, and photoaging. The longer wavelengths of UVA are a thousand times less erythrogenic than UVB; however, they penetrate more deeply into the skin and contribute substantially to photoaging and photosensitivity
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Dermatological pharmacology

diseases. They also enhance UVB-induced erythema and increase the risk of skin carcinogenesis. Visible radiation may augment the severity of some photosensitive eruptions. Electromagnetic radiation has proven to be highly efficacious in the treatment of numerous dermatologic diseases. Phototherapy and photochemotherapy are treatment methods in which ultraviolet or visible radiation is used to induce a therapeutic response either alone or in the presence of a photosensitizing drug. Phototherapy using broad-band (290 to 320 nm) or narrow-band (311 to 313 nm) UVB or high-dose UVA-I is efficacious in selected dermatological diseases. To be effective, the incident radiation must be absorbed by a target or chromophore in the skin-which in phototherapy is endogenous and in photochemotherapy must be administered exogenously. Patients treated with these modalities should be monitored for concomitant use of other potential photosensitizing medications before initiation of therapy. Such drugs include phenothiazines, thiazides, sulfonamides, nonsteroidal antiinflammatory agents, sulfonylureas, tetracyclines, and benzodiazepines. PUVA: Psoralens and UVA Photochemotherapy with psoralen-containing plant extracts was employed for the treatment of vitiligo in Egypt and India as early as 1500 B.C. Orally administered 8-methoxypsoralen followed by UVA (PUVA) is FDA approved for the treatment of vitiligo, psoriasis, and cutaneous T cell lymphoma. Psoralens belong to the furocoumarin class of compounds, which are derived from the fusion of a furan with a coumarin. They occur naturally in many plants. Two psoralens, 8methoxypsoralen and 4, 5, 8-trimethylpsoralen are available in the United States. Pharmacokinetics The psoralens are absorbed rapidly after oral administration. Photosensitivity typically is maximal 1 to 2 hours after ingestion of methoxsalen. There is significant but saturable first-pass elimination in the liver, which may account for variations in plasma levels among individuals after a standard dose. Methoxsalen has a serum half-life of approximately 1 hour, but the skin remains sensitive to light for 8 to 12 hours. Despite widespread drug distribution throughout the body, it is photoactivated only in the skin where the UVA penetrates. Mechanism of Action The mechanism by which PUVA induces photosensitivity is not known. The action spectrum for oral PUVA is between 320 and 400 nm. Two distinct photoreactions take place. Type I reactions involve the oxygen-independent formation of mono- and bifunctional adducts in DNA. Type II reactions are oxygen-dependent and involve sensitized transfer of energy to molecular oxygen. The therapeutic effects of PUVA in psoriasis may result from a decrease in DNA-dependent proliferation after adduct formation. Perhaps more important, PUVA can alter cytokine profiles and cause immunocyte apoptosis, thereby interrupting immunopathologic processes. PUVA promotes melanogenesis in normal skin. Increased pigmentation results from augmented transfer of melanosomes from melanocytes to keratinocytes; however, there is no change in the size of melanosomes or in their distribution pattern. Uses Methoxsalen is supplied in soft gelatin capsules (OXSORALEN-ULTRA) and hard gelatin capsules (8-MOP). The dose is 0.4 mg/kg for the soft capsule and 0.6 mg/kg for the hard capsule taken 1.5 to 2 hours before UVA exposure. A lotion containing 1% methoxsalen (OXSORALEN) also is available for topical application. It can be diluted for use in bath water to minimize systemic absorption. The risk of phototoxicity is increased with topical PUVA therapy. In U.S. and European multicenter cooperative studies of PUVA for the treatment of psoriasis, initial clearance rates approaching 90% were achieved. Relapse occurs within 6 months of
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cessation of treatment in many patients, which has prompted efforts to design maintenance protocols. PUVA also is used to repigment the leukoderma of vitiligo. Success rates are highest in young individuals with recent onset of disease involving nonacral areas. Localized vitiligo can be treated with topical PUVA and more extensive disease with systemic administration. PUVA also is employed in the treatment of cutaneous T cell lymphoma, atopic dermatitis, alopecia areata, lichen planus, urticaria pigmentosa, and as a preventive modality in some forms of photosensitivity. Adverse effects: The major acute side effects of PUVA include nausea, blistering, and painful erythema. PUVAinduced redness and blistering generally peak within 48 to 72 hours. Chronic PUVA therapy accelerates photoaging and the development of actinic keratoses, nonmelanoma skin cancer, and melanoma. Squamous cell carcinomas occur at 10 times the expected frequency. In patients receiving 250 or more treatments, there is an increased risk of melanoma. Careful monitoring of patients for cutaneous carcinoma therefore is essential. ANTIMICROBIAL AGENTS These drugs are used commonly to treat superficial cutaneous infections (pyoderma) and noninfectious diseases. Topical agents are very effective for the treatment of superficial bacterial infections and acne vulgaris. Systemic antibiotics also are prescribed commonly for acne and for deeper bacterial infections. Numerous topical anti-infectives contain corticosteroids in addition to antibiotics. There is no convincing evidence that topical corticosteroids inhibit the antibacterial effect of antibiotics when the two are incorporated in the same preparation. In the treatment of secondarily infected dermatoses, which are usually colonized with streptococci, staphylococci, or both, combination therapy may prove superior to corticosteroid therapy alone. Antibiotic-corticosteroid combinations may be useful in treating diaper dermatitis, otitis externa, and impetiginized eczema. The selection of a particular antibiotic depends of course upon the diagnosis and, when appropriate, in vitro culture and sensitivity studies of clinical samples. Gram-positive organisms, including Staphylococcus aureus and Streptococcus pyogenes, are the most common cause of pyoderma. Skin infections with gram-negative bacilli are rare, although they can occur in diabetics and patients who are immunosuppressed; appropriate parenteral antibiotic therapy is required for their treatment. Information about regional patterns of drug resistance is therefore important in selecting a therapeutic agent. Prepackaged topical antibacterial preparations that contain multiple antibiotics are available in fixed dosages well above the therapeutic threshold. These formulations offer the advantages of efficacy in mixed infections, broader coverage for infections due to undetermined pathogens, and delayed microbial resistance to any single component antibiotic. Bacitracin & Gramicidin- Bacitracin and gramicidin are active against gram-positive organisms such as streptococci, pneumococci, and staphylococci. Mupirocin-Most gram-positive aerobic bacteria, including methicillin-resistant S aureus, are sensitive to mupirocin. It is effective in the treatment of impetigo caused by S aureus and group A b-hemolytic streptococci. Polymyxin B Sulfate- Polymyxin B is effective against gram-negative organisms, including Pseudomonas aeruginosa, Escherichia coli, enterobacter, and klebsiella. Numerous prepackaged antibiotic combinations containing polymyxin B are available. Neomycin & Gentamicin-Neomycin and gentamicin are active against gram-negative organisms, including E coli, proteus, klebsiella, and enterobacter. Gentamicin generally shows greater activity against P aeruginosa than neomycin. Gentamicin is also more active against
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Dermatological pharmacology

staphylococci and group A b-hemolytic streptococci. Neomycin is available in numerous topical formulations, both alone and in combination with polymyxin, bacitracin, and other antibiotics. It is also available as a sterile powder for topical use. Gentamicin is available as an ointment or cream. Topical antibiotics in Acne Several systemic antibiotics that have traditionally been used in the treatment of acne vulgaris have been shown to be effective when applied topically. Currently, four antibiotics are so utilized: clindamycin phosphate, erythromycin base, metronidazole, and sulfacetamide. The effectiveness of topical therapy is less than that achieved by systemic administration of the same antibiotic. Therefore, topical therapy is generally suitable in mild to moderate cases of inflammatory acne. ANTIFUNGAL AGENTS Fungal infections are among the most common causes of skin disease in the United States, and numerous effective topical and oral antifungal agents have been developed.The treatment of superficial fungal infections caused by dermatophytic fungi may be accomplished (1) with topical antifungal agents, eg, clotrimazole, miconazole, econazole, ketoconazole, oxiconazole, sulconazole, ciclopirox olamine, naftifine, terbinafine, butenafine, and tolnaftate; or (2) with orally administered agents, ie, griseofulvin, terbinafine, ketoconazole, fluconazole, and itraconazole. Superficial infections caused by candida species may be treated with topical applications of clotrimazole, miconazole, econazole, ketoconazole, oxiconazole, ciclopirox olamine, nystatin, or amphotericin B. Chronic generalized mucocutaneous candidiasis is responsive to long-term therapy with oral ketoconazole. CLASSIFICATION 1. Antibiotics A. Polyenes : AmphotericinB (AMB), Nystatin, Hamycin, Natamycin (Pimaricin) B. Heterocyclic benzofuran: Griseofulvin 2. Antimetabolite: Flucytosine(5-FC) 3 Azoles A. Imidazoles (topical): Clotrimazole, Econazole, Miconazole, Oxiconazole (systemic): Ketoconazole B. Triazoles (systemic): Fluconazole, Itraconazole, Voriconazole 4. Allylamine: Terbinafine 5. Other topical agents: Tolnaftate, Undecylenic acid, Benzoic acid, Quiniodochlor, Ciclopirox olamine, Butenafine, Sod. thiosulfate. The azoles miconazole and econazole and the allylamines naftifine and terbinafine are effective topical agents for the treatment of localized tinea corporis and uncomplicated tinea pedis. Topical therapy with the azoles is preferred for localized cutaneous candidiasis and tinea versicolor. Systemic therapy is necessary for the treatment of tinea capitis. Oral griseofulvin has been the traditional medication for treatment of tinea capitis. Oral terbinafine is a safe and effective alternative to griseofulvin in treating tinea capitis in children. Topical Azole Derivatives The topical imidazoles, which currently include clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, and sulconazole, have a wide range of activity against dermatophytes (epidermophyton, microsporum, and trichophyton) and yeasts, including Candida albicans. Miconazole is available for topical application as a cream or lotion and as vaginal cream or
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Dermatological pharmacology

suppositories for use in vulvovaginal candidiasis. Clotrimazole is available for topical application to the skin as a cream or lotion and as vaginal cream and tablets for use in vulvovaginal candidiasis. Econazole is available as a cream for topical application. Oxiconazole is available as a cream and lotion for topical use. Ketoconazole is available as a cream for topical treatment of dermatophytosis and candidiasis and as a shampoo for the treatment of seborrheic dermatitis. Sulconazole is available as a cream or solution. Topical antifungal-corticosteroid fixed combinations have recently been introduced on the basis of providing more rapid symptomatic improvement than an antifungal agent alone. Clotrimazole-betamethasone dipropionate cream is one such combination. Oral Azole Derivatives Azole derivatives currently available for oral treatment of systemic mycosis include fluconazole, itraconazole, ketoconazole, and others. Imidazole derivatives act by affecting the permeability of the cell membrane of sensitive cells through alterations of the biosynthesis of lipids, especially sterols, in the fungal cell. KETOCONAZOLE Ketoconazole was the first orally active azole available for the treatment of systemic mycoses Mechanism of action: Azoles are predominantly fungistatic. They inhibit C-14 -demethylase (a cytochrome P450 enzyme), thus blocking the demethylation of lanosterol to ergosterol, the principal sterol of fungal membranes. This inhibition disrupts membrane structure and function and, thereby, inhibits fungal cell growth. Antifungal spectrum: Ketoconazole is active against many fungi, including Histoplasma, Blastomyces, Candida, and Coccidioides, but not aspergillus species. Although itraconazole has largely replaced ketoconazole in the treatment of most mycoses because of its broader spectrum, greater potency, and fewer adverse effects, ketoconazole, as a second-line drug, is a less expensive alternative for the treatment of mucocutaneous candidiasis. Pharmacokinetics: Ketoconazole is only administered orally. It requires gastric acid for dissolution and is absorbed through the gastric mucosa. Drugs that raise gastric pH, such as antacids, or that interfere with gastric acid secretion, such as H2-histamine receptor blockers and proton-pump inhibitors, impair absorption. Administering acidifying agents, such as cola drinks, before taking the drug can improve absorption in patients with achlorhydria. Ketoconazole is extensively bound to plasma proteins. Although penetration into tissues is limited, it is effective in the treatment of histoplasmosis in lung, bone, skin, and soft tissues. The drug does not enter the CSF. Extensive metabolism occurs in the liver, and excretion is primarily through the bile. Levels of parent drug in the urine are too low to be effective against mycotic infections of the urinary tract. Adverse effects: In addition to allergies, dose-dependent gastrointestinal disturbances, including nausea, anorexia, and vomiting, are the most common adverse effects of ketoconazole treatment. Endocrine effects, such as gynecomastia, decreased libido, impotence, and menstrual irregularities, result from the blocking of androgen and adrenal steroid synthesis by ketoconazole. Transient increases in serum transaminases are found in from 2 to 10 percent of patients. Frank hepatitis occurs rarely but requires immediate cessation of treatment. Contraindications: ketoconazole is teratogenic in animals, and it should not be given during pregnancy.

Dermatological pharmacology

telangiectasis = small dark red spots on the skin, formed by swollen capillaries striae = (stretchmarks) pale line on skin which is stretched (as in obese people) striae gravidarum = stretchmarks, lines on the skin of the abdomen of a pregnant woman or of a woman who has recently given birth purpura = purple colouring on the skin, similar to a bruise, caused by blood disease and not by trauma Cushing's disease or Cushing's syndrome = condition where the adrenal cortex produces too many corticosteroids lichen planus = skin disease where itchy purple spots appear on the arms and thighs melanoma = tumour formed of dark pigmented cells malignant melanoma = dark tumour which develops on the skin from a mole, caused by exposure to strong sunlight impetigo = irritating and very contagious skin disease caused by staphylococci