Topical Treatment in skin disorders 皮肤病的外用药治疗

1. Topical Treatment in skin disorders皮肤病的外用药治疗 Professor Zheng Min 郑敏教授

2. Pharmacokinetics and Topical Applications of Drugs in skin disorders therapy • Topical formulations may undergo radical changes in composition and structure. • The effectiveness of the skin barrier often changes with time. • The skin barrier is influenced by the type and progression of a disease.

3. There is regional variation in the barrier properties of the skin. • The viable tissues themselves respond to topical applications in manners that may either enhance or retard percutaneous absorption. • Drugs influence all of these processes in a more or less specific manner.

4. THREE-COMPARTMENT MODEL • Although pharmacokinetic analysis of topical applications may require the description of a relatively large number of compartments, this discussion is confined to the three outlined in • the skin surface, • the stratum corneum • the viable tissue.

5. Diagrammatic representation of three compartments of the skin: • Following surface applications, evaporation and structural/compositional alterations in the applied formulation may play an important role in determining the bioavailability of drugs. • The stratum corneum, the outermost layer, plays the most significant role in determining the diffusion of compounds into the body. • Following absorption, compounds may bind or diffuse withinthe viable tissuesor become resorbed by the cutaneous vasculature.

6. A schematic drawing of the basic organization of the stratum corneum, indicating • the overlapping of the corneocytes • the tortuous path of the intercellular lipid domain (shaded gray). • Though the corneocytes occupy the bulk of the stratum corneum, the only continuous domain is the intercellular lipid, which is followed by compounds undergoing percutaneous absorption.

7. Compartments Encountered by Substances Undergoing Percutaneous Absorption: • General Relevance of Processes to Bioavailability

8. The principal factors determining the pharmacokinetics of a topical application are the physiochemical properties of the bioactive molecule. • Hydrophobicity, molecular weight, and ionic charge determine the feasibility of transdermal delivery for any particular compound. • Formulations influence the pharmacokinetics largely from considerations of the thermodynamic activity of the compound.

9. However, one should not exclude the impact of changes in the formulation that occur following topical application. • Evaporation, and changes in the structure of emulsions, may bring dramatic changes in the thermodynamic activity of the compound at the skin surface. • Under some circumstances, this may lead to the retention of the drug on the skin surface.

10. Topical Therapy 1. topical agents 2. formulation 3. therapy principle

11. The function of topic preparations • The main function of common topic preparation • （1） Cleansing agents • （2） Barrier Preparations • （3） Antipruritics agents • （4） Antibacterial agents • （5） Antifungals agents • （6） Antivirals agents • （7） Antiinflammtory and Anti-allergics agents • （8） Keratoplastics Agents • （9） Keratolytics agents

12. Cleansing agents • Cleansing agents are used to remove debris and to combat infection. • Some are astringents which precipitate protein and in doing as help to seal the moist surface of weeping eczema or a stasis ulcer. • preparations • Physiologic saline； • 1：8000 potassic permanganate； • 2％∽4％boric acid； • Vegetable oil and liquid paraffin;

13. Barrier Preparations • Barrier Preparations are used to protect the skin from irritants • preparations • Talcum powder • Zinc oxide • calamina • Starch • Vegetable oil

14. Antipruritics agents • Preparations that could stop itchness by cooling, local anaesthesia, dimimish inflammation • Preparations： • 0.5%∽2%mint • 2％comphor • 1％∽2％Dyclonine

15. Antibacterial agents • The ideal priparation should have • high antibacterial activity, • low allergenicity, • the durg should not be available for systemic use • This combinaton is hard to find. • Some compromises are given following • Bactroban ointment (mupirocin) • Fucidin ointment,cream or gel (fusidic acid)

16. Antifungals agents • kill or inhibition fungals agents • 5-10%sulphur • 5-30% Glacial Acetic Acid • 6-12% Benzonic acid • 3-10 % Salicylic acid clotrimazole • 1-3% Miconazole • 1% Econazole • 1% Terbinafine

17. Antifungals agents • The first- and second-generation imidazoles include clotrimazole,26 econazole, ketoconazole, miconazole, and sulconazole as topical therapies; they have similar spectrums of efficacy and activity. • They function by blocking synthesis of ergosterol, which plays an integral role in cell membrane structure and function. • The imidazoles delay or inhibit cellular growth at low concentrations and are fungicidal at 5 to 10 times the minimum inhibitory concentration.

18. Antivirals agents • These have little part to play in the management of herpes zoster • However, if used early and frequently, they may help with recurrent herpes simplex infections • Preparations • 2％∽3％ aciclovir cream； • Penciclovir cream • Phthiobuzone cream • Imiqiumod cream；

19. Antiinflammtory and Anti-allergics agents • Antiinflammtory agents • Coal Tar • Anti-allergics agents • Topical Glucocorticoids

20. Antiinflammtory agents • COAL TAR • Coal tar is manufactured as the by-product of processing coke and gas from bituminous coal • Studies suggest that tars depress DNA synthesis and have an antimitotic effect. • Coal tar applied to normal skin produces early suppression of epidermal DNA synthesis followed by a proliferative response.37 • When applications are continued for up to 40 days, there is a cytostatic effect resulting in epidermal thinning.

21. SHALE TAR • Shale tar (ichthammol) originates from shale oil that undergoes chemical degradation with ammonia and sulfuric acid to form a sulfur-rich substance. • It is most often formulated with glycerin and is thought to have both anti-inflammatory and vasoactive properties.

22. WOOD TAR • Wood tars are obtained by distilling wood under controlled conditions. • They can be added to arachis oil (peanut oil) or simple bases as an application to the scalp in seborrheic dermatitis and psoriasis. • Oil of cade is also a major ingredient in the 20-10-5 ointment, which consists of 20% oil of cade, 10% sulfur, and 5% salicylic acid.

23. Anti-allergics agents • Topical Glucocorticoids • Hydrocortisone, the first topically effective glucocorticoid, was introduced by Sulzberger and Witten in 1952.1 • Subsequently, a succession of ever more potent glucocorticoid preparations have been developed. • Currently, topical steroids are the most frequently prescribed of all dermatologic drug products.

24. Steroids can be divided into two classes: • Fluorinated • nonfluorinated. • The term fluorinated steroid is used when referring to the steroids that have been chemically altered to increase their potency. • The strength of a steroid can be increased by halogenation at the 9a position, which allows improved activity within the target cell and decreased breakdown into inactive metabolites.

25. Topical glucocorticoid research has focused on strategies to optimize potency while minimizing side effects. • One strategy is to develop compounds with enhanced anti-inflammatory effects and minimal unwanted atrophogenic and adrenal suppressive effects. • Another strategy is to develop compounds that exert their effects on the epidermis and then are quickly broken down into inactive metabolites. • Research to develop a nonsteroidal compound with the same anti-inflammatory effects of glucocorticoids but without the side effects is currently ongoing.

26. The clinical effectiveness of glucocorticoids • The clinical effectiveness of glucocorticoids is related to four basic properties: • vasoconstriction, • antiproliferative effects, • immunosuppression, • anti-inflammatory effects. • Topical steroids cause capillaries in the superficial dermis to constrict, thus reducing erythema. • The ability of a given glucocorticoid agent to cause vasoconstriction usually correlates with its anti-inflammatory potency • thus vasoconstriction assays are often used to predict the clinical activity of an agent. These assays in combination with

27. Responsiveness of Dermatoses to Topical Application of Corticosteroids

28. ADVERSE EFFECTS • Striae and atrophy • the most commonly observed side effects, occur with prolonged use and are more likely to occur in areas of sweating, occlusion, or high penetration such as the axilla or groin • In general, atrophy does not occur until the agent has been used for 3 to 4 weeks and is usually reversible. .

29. Topical steroids can also cause suppression of the pituitary-adrenal axis • Most topical and systemic side effects are readily reversible if recognized early by the clinician • Patients treated with topical glucocorticoids may develop a contact or irritant dermatitis to the steroid itself or, more commonly, to one of the ingredients used as a preservative.

30. Keratoplastics Agents • Promote normal keratosis • Shrink blood vessel • Reduce effusion and inflammatory infiltration • Preparations • 5-40% pityrol • 2-5％ coal tar • 2-5% resorcinol； • 3％ salicylic acid • 3-5％ sulphur • 0.1-1% anthralin；

31. Keratolytics agents • Make keratinocytes loose and separate and fall off • Preparations • 10-30% Glacial Acetic Acid • 6-15 ％ salicylic acid • 10％sulphur • 15-30％urea • 0.01－0.1％ retinoid acid • 6-15% resorcinol

32. The other functions of topic preparations • antiperapirants • astringent • caustic agents • antineoplastics • sunsreens and sunblocks • depigmenting agents ( or bleaching agents)

33. Principles of topical therapy • (1) classification and clinical application of topical formulations • (2) review of vehicle ingredients commonly used in topical medicaments • (3) appropriate administration and dosage of topical therapy

34. CLASSIFICATION AND CLINICAL APPLICATION OF TOPICAL FORMULATIONS • The term vehicle is used for those substances that bring specific drugs into contact with the skin. • The vehicle itself may have beneficial nonspecific, or “bland,” effects on the skin by possessing cooling, protective, emollient, occlusive, or astringent properties. • For any drug to be effective topically, it must be formulated at the proper concentration and in the proper vehicle.

35. In general, the most important vehicles for topical use may be divided into • Monophasic • Biphasic • Triphasic forms • which can be further classified as shown in the Fig.

36. The derivation of basic forms of topical application. , Monophasic vehicles; biphasic vehicles; triphasic vehicles. (Modified from Polano,7with permission.)

37. Monophasic Vehicles

38. Solutions • Liquids are used as solvents for drugs or are made into gels by the addition of thickening agents. • Clinical applications of liquid preparations include • wet dressings • baths, tinctures • Paints • topical solutions • Aerosols • sprays.

39. Wet dressings are indicated in the treatment of acute inflammatory states characterized by oozing, weeping, and crusting and in bullous disease, erosions, and ulcers. • Solutions of aluminum acetate (Burow's solution; Domeboro) have been used since the nineteenth century for wet dressings.

40. tinctures and spiritus • Tinctures and paintsare organic solvent solutions that evaporate rapidly after application to the skin, leaving a film of active ingredient. • Tinctures were originally alcoholic solutions derived from maceration of herbs. • The term paint refers to staining solutions such as Castellani's paint. • Tinctures and paints are of limited use in modern clinical setting because of their excessive drying and staining properties.

41. powders • In general, powders promote drying. • Since they adhere poorly to the skin, their use is almost completely limited to cosmetic and hygienic purposes. • Most powders used for skin care consist of zinc oxide or titanium oxide for covering properties, talc (hydrous magnesium silicate) for smooth application, and a stearate (usually zinc or magnesium) for improved adherence to the skin. • 注意事项： • 不能用于摩烂处或有渗出处； • 不能用于腔口附近及毛发处；

42. lotions • Lotions and solutions may also be suspended in a propellant to be delivered to the skin in the form of an aerosol or spray. • This form of delivery may be useful when the degree of inflammation, tenderness, or oozing makes direct application difficult or painful.

43. oils • Oils are rarely used alone in topical therapy because they do not adhere to the skin. • The principal use of oils (mineral oil, cottonseed oil, etc.) is the removal of fat-miscible applications from the skin. • Oils added to baths, as mentioned earlier, may function as emollients.

44. gel • Gelsare transparent, colloidal dispersions that liquefy on contact with skin. • They are not greasy and are cosmetically acceptable. • When applied to the skin, gels dry as a nonocclusive film and are appropriate for use on hairy areas.

45. Most gels are solutions of solvents such as water, acetone, alcohol, or propylene glycol thickened with organic polymers such as carbopols. • While having the advantage of being water-washable, nongreasy, and cosmetically elegant, gels have the disadvantages of being easily removed by perspiration and lacking any protective or emollient properties.

46. Biphasic Vehicles

47. SHAKE LOTIONS • These are watery lotions to which powder is added so that the area for evaporation is increased. • Generally, zinc oxide, talcum, calamine, glycerol, alcohol, and water are used, to which specific drugs and stabilizers may be added. • These lotions dry and cool wet, weeping skin.

48. The name shake lotion indicates one of the drawbacks of this formulation: • a tendency to sedimentation requires shaking prior to each use in order to obtain a homogeneous suspension. • In addition, when the water has evaporated from the skin, the powder particles may clump together and become abrasive. • For this reason, patients should be instructed to remove such residues carefully prior to reapplication of shake lotions.

49. emulsion • CREAMS Creams are emulsions of oil-in-water (O/W). • In a cream, the oil droplets are dispersed in a continuous phase of water or a polar liquid. • Emulsifying agents are necessary for such formulations to increase the surface area of the dispersed phase and that of any therapeutic agent in it.

50. Creams may also contain preservatives, which may produce an allergic contact dermatitis. • Creams are used widely for their cooling, moisturizing, and emollient effects.