In the Name of Allah, the Beneficent, the Merciful

1. In the Name of Allah, the Beneficent, the Merciful

2. Dr. Azam Bakhtiarian Dept. of Pharmacology, School of Medicine, Tehran University of Medical Sciences

3. Dermatologic Pharmacology

4. The skin offers a number of special opportunities to the therapist. For example, the topical route of administration is especially appropriate for diseases of the skin, though some dermatologic diseases respond as well or better to drugs administered systemically.

5. Major variables that determine pharmacologic response to drugs • (1) Regional variation in drug penetration: Face and scalp are more permeable than the forearm (require less drug). • (2) Concentration gradient: Increasing the conc. gradient increases the mass of drug transferred per unit time, Thus, resistance to topical corticosteroids can sometimes be overcome by use of higher Conc. of drug.

6. Major variables that determine pharmacologic response to drugs • (3) Dosing schedule: The skin acts as a reservoir for many drugs. As a result, the "local half-life" may be long enough to permit once-daily application of drugs with short systemic half-lives. Corticosteroids • (4) Vehicles and occlusion: An appropriate vehicle maximizes the ability of the drug to penetrate the outer layers of the skin. • Occlusion (application of a plastic wrap to hold the drug and its vehicle in close contact with the skin) is extremely effective in maximizing efficacy.

7. Treatment of Acne

8. Acne Preparations • Retinoids: Tretinoin, Adapalene, Tazarotene, Isotretinoin • Non- Retinoids: Azelaic acid, Benzoyl Peroxide, Antibiotics: • Topical: Clindamycin, Erythromycin • Oral: Co-trimoxazole, Erythromycin

9. Retinoic Acid • Known as tretinoin • Is the acid form of vitamin A. • Treatment of acne vulgaris. • Decreased cohesion between epidermal cells and increased epidermal cell turnover. • Metabolized by the liver • Excreted in bile and urine.

10. Retinoic acid • May induce slight erythema with mild peeling. (lower Conc. & frequency ) • A timed-release formulation of tretinoin containing microspheres (Retin-A Micro) delivers the medication over time.

11. Retinoic acid • Prolonged use of tretinoin cream: • Promotes dermal collagen synthesis • New blood vessel formation • Thickening of the epidermis, which helps diminish fine lines and wrinkles.

12. Adverse Effects of Retinoic acid • Erythema and dryness that occur. • Animal studies : increase the tumorigenic potential of UV radiation. • PT should be advised to avoid or minimize sun exposure and use a sunscreen.

13. Adapalene (Differin) • Resembles retinoic acid in structure and effects. • Apply 0.1% gel once daily • less irritating than tretinoin and is most effective in patients with mild to moderate acne vulgaris.

14. Isotretinoin (Accutane) • Is a synthetic retinoid (oral) • Restricted to the treatment of severe cystic acne. • Act by inhibiting sebaceous gland size and function. • Well absorbed. • Bound to plasma albumin. • T1/2 of 10–20 hours.

15. Adverse Effects of Isotretinoin (Accutane) • resemble hypervitaminosis A • dryness and itching of the skin and mucous membranes. • Less common: headache, corneal opacities, • IBD, anorexia, alopecia • muscle and joint pains. ( all reversible) • Lipid abnormalities (TG) • Teratogenicity is a significant risk.

16. Benzoyl Peroxide • Treatment of acne vulgaris. • Is converted metabolically to benzoic acid within the epidermis and dermis. • Mechanism of action: is related to its antimicrobial activity against P acnes and to its peeling.

17. Benzoyl Peroxide • Care should be taken to avoid contact with the eyes and mucous membranes. • Benzoyl peroxide is an oxidant and may rarely cause bleaching of the hair or colored fabrics.

18. Azelaic acid (Azelex) • Treatment of acne vulgaris. (cream) • Its mechanism of action: antimicrobial activity against P acnes as well as an in vitro inhibitory effect on the conversion of testosterone to dihydrotestosterone.

19. Azelaic acid Side Effects • Mild irritation with redness and dryness • Clinical improvement is noted in 6–8 weeks.

20. Topical Antibiotics in Acne • Four antibiotics are so utilized: • clindamycin phosphate, erythromycin, metronidazole, and sulfacetamide. • The effectiveness of topical therapy is less than that achieved by systemic. • Therefore, topical therapy is generally suitable in mild to moderate cases of acne.

21. Clindamycin • in vitro activity against Propioni bacterium acnes • 10% of dose is absorbed, and rare cases of bloody diarrhea and colitis (topical). • Allergic contact dermatitis is uncommon.

22. Erythromycin • Treatment of acne vulgaris due to its inhibitory effects on P acnes. • Development of antibiotic-resistant strains of organisms, including staphylococci. • If this occurs, topical erythromycin should be discontinued.

23. Adverse local reactionsto Erythromycin • Burning sensation at the time of application and drying and irritation of the skin. • The topical water-based gel is less drying and may be better-tolerated.

24. Topical metronidazole • Treatment of acne rosacea. • Act as an anti-inflammatory agent by direct effect on neutrophil cellular function. • Carcinogen in susceptible rodent species. • Topical use during pregnancy and by nursing mothers and children is not recommended.

25. Adverse local effects of metronidazole • The water-based gel formulation (MetroGel) cause dryness, burning, and stinging. • Less drying formulations may be better-tolerated (MetroCream, MetroLotion).

26. Sodium Sulfacetamide • Treatment of acne vulgaris and rosacea. • The mechanism of action is thought to be due to inhibition of P acnes . • 4% of topically applied is absorbed, and its use is contraindicated in patients having a known hypersensitivity to sulfonamides.

27. Treatment of Psoriasis

28. Treatment of Psoriasis 1)Retinoids: Acitretin, Tazarotene 2)Glucocorticoids: Bethamethazone, triamcinolone 3)Vitamin D3 derivative: Calcipotriene 4)Monoclonal Antibody: Alefacept, efalizumab, Etanercept, infliximab 5)Psoralens: Trioxsalen and Methoxsalen

29. Acitretin (Soriatane) • a metabolite of the aromatic retinoid etretinate • treatment of psoriasis • It is given orally at a dosage of 25–50 mg/d.

30. Adverse effects of Acitretin • Similar to those seen with isotretinoin and resemble hypervitaminosis A. • Elevations in cholesterol and triglycerides • Hepatotoxicity with liver enzyme elevations • Acitretin is more teratogenic than isotretinoin.

31. Acitretin • Acitretin must not be used by women who are pregnant . • Patients must not donate blood during treatment and for 3 years after acitretin is stopped.

32. Tazarotene (Tazorac) • Is an acetylenic retinoid prodrug. (cream) • Treatment of psoriasis • By its anti-inflammatory and antiproliferative actions.

33. Tazarotene • Teratogenic systemic conc. if applied to more than 20% of total body surface area. • Treatment of psoriasis should be limited to once-daily application.

34. Adverse local effects of Tazarotene • A burning or stinging sensation • peeling, erythema, and localized edema of the skin (irritant dermatitis). • PTs use sunscreens and protective clothing.

35. Corticosteroids • The anti-inflammatory activity • The antimitotic effects in psoriasis • Triamcinolone, betamethasone and flucinolone( ointment)

36. Adverse Local effects of Topical Corticosteroids • Local atrophy • Shiny, often wrinkled “cigarette paper” appearing skin • Erythema

37. Calcipotriene (Dovonex) • Is a synthetic vitamin D3 derivative • Binds vit. D receptor, inhibit prolif. • The treatment of psoriasis of moderate severity. (ointment 0.005%). • Elevation of serum calcium in fewer than 1%

38. Adverse Effects of Calcipotriene • burning, itching, and mild irritation, • with dryness and erythema of the treatment area.

39. Alefacept • Immunosuppressive agent (IV) • Interferes with lymphocyte activation which plays a role in the psoriasis • Reduction in subsets of CD2 , CD4 and CD8 T lymphocyte counts. • Treatment of adult patients with moderate to severe chronic plaque psoriasis.

40. Alefacept • Discontinue if the CD4 counts are reduced. • Should not be administered to patients with a history of systemic malignancy.

41. Efalizumab • is an immunosuppressive • interferes with lymphocyte activation, which plays a role in the psoriasis, • Binds to CD11 • 0.7 mg/kg S.C. • Monitor Platelet counts

42. TNF Inhibitors: (Etanercept) • Binds to TNF ( alpha& beta) • interferes with inflammation Process, which plays a role in the psoriasis. • 50 mg S.C., twice weekly for 3 months

43. TNF Inhibitors: (Infliximab) • Monoclonal antibody • Binds TNF alpha • 5 mg/kg IV

44. TNF Inhibitors: (Adalimumab) • Monoclonal antibody • Binds TNF alpha • Inhibits its binding to TNF alpha receptor • 80 mg S.C. followed by 40 mg every other week.

45. TNF Inhibitors Side Effects • Serious life-threatening infections: • Sepsis • Pneumonia • Concurrent use with other immunosuppressive therapy should be avoided.

46. Trioxsalen and Methoxsalen • are psoralens used for the psoriasis (oral) • Must be photoactivated (UVA) • photo-chemotherapy with oral methoxsalen • inhibit DNA synthesis.

47. Topical Antiviral Agents • Acyclovir, valacyclovir, penciclovir, and famciclovir are synthetic guanine analogs with inhibitory HSV 1,2. • interferes with herpesvirus DNA polymerase and viral DNA replication.

48. Topical Antiviral Agents • Acyclovir ointment for application to primary cutaneous HSV and to limited mucocutaneous HSV in immunocompromised patients. • Topical penciclovir,1% cream for the treatment of recurrent orolabial.

49. Immunomodulators • Imiquimod for the treatment of external genital & perianal warts. • Stimulate peripheral mononuclear cells to release INF & to stimulate macrophages to produce interleukins-1, -6, -8, and TNF. • applied to the wart tissue 3 times per week and left on the skin for 6–10 hours prior to washing off with mild soap and water.

50. Adverse side effects of Imiquimod • Inflammatory reactions • pruritus • erythema