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

41. Efalizumab 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) 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) TNF Inhibitors: (Infliximab)  Monoclonal antibody  Binds TNF alpha  5 mg/kg IV

44. TNF Inhibitors: (Adalimumab) 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 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. Adverse local reactions to acyclovir & penciclovir  pruritus  mild pain with  transient stinging or burning.

50. 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.

51. Adverse side effects of Imiquimod  Inflammatory reactions  pruritus  erythema

52. Immunosuppressants  Tacrolimus and pimecrolimus  Treatment of atopic dermatitis  Inhibit T lymphocyte activation  Prevent the release of cytokines

53. Tacrolimus & pimecrolimus Side Effect  Burning sensation in the applied area that improves with continued use.  Tacrolimus 0.03% ointment and pimecrolimus 1% cream are approved for use in children over 2 years of age, (twice daily).

54.  Agents Affecting Pigmentation

55. Agents Affecting Pigmentation  Hydroquinone, Monobenzone  To reduce hyperpigmentation of the skin.  Hydroquinone results in lightening of skin.  Monobenzone causes irreversible depigmentation.  The mechanism : inhibition of tyrosinase, thus interfering with the biosynthesis of melanin.

56. Hydroquinone and Monobenzone Side Effects  Both may cause local irritation.  Allergic sensitization to these compounds does occur.  Combination of hydroquinone, fluocinolone and retinoic acid (Tri-Luma) is more effective than hydroquinone alone.

57. Trioxsalen and Methoxsalen  are psoralens used for the repigmentation of vitiligo.  Psoralens must be photoactivated (UVA)  Oral Trioxsalen for the vitiligo.  inhibit DNA synthesis.

58. Trioxsalen and Methoxsalen Side Effects The major long-term risks of  cataracts  skin cancer

59. Sunscreens  Chemical compounds that absorb UV light, called sunscreens.  or opaque materials such as titanium dioxide that reflect light, sunshades.  PABA and its esters, the benzophenones & dibenzoylmethanes.  Most sunscreen absorb UV B (280 to 320 nm)  which is the range responsible for most of the erythema and tanning.  Chronic exposure to light in this range induces aging of the skin and photocarcinogenesis.

60. Sunscreens  PABA absorbs UVB  The benzophenones include oxybenzone, dioxybenzone, and sulisobenzone.  A broader spectrum of absorption from 250 to 360 nm, but their effectiveness in the UVB is less.

61. Dibenzoylmethane  Parasol and Eusolex absorb UVA, (320- 400 nm), superior photoprotection.  Use in patients sensitive to UVA:  Such as cutaneous lupus and drug-induced photosensitivity.

62. The protection factor  The protection factor (PF) of a given sunscreen is a measure of its effectiveness in absorbing erythrogenic UV.  The ratio of the minimal erythema dose with sunscreen to the minimal erythema dose without sunscreen is the protection factor.  Fair skinned who sunburn easily are advised to use a product with a SPF of 15 or greater.

63. Keratolytic & Destructive Agents  Salicylic Acid  Propylene Glycol  Urea

64. Keratolytic & Destructive Agents Salicylic Acid  may solubilize cell surface proteins that keep the stratum corneum  Keratolytic in conc. of 3–6%.  greater than 6%, it can be destructive to tissues.

65. Salicylism  Salicylism and death have occurred following topical application.  hemodialysis is the treatment of choice.  The threshold for toxicity is 30–50 mg/dL.

66. Allergic Reactions to Salicylates  Urticarial, anaphylactic, and erythema may occur in patients allergic to salicylates.  Topical use may cause local irritation, acute inflammation, and even ulceration.

67. Propylene Glycol  keratolytic agent  oxidized by the liver to lactic acid and pyruvic acid.  excreted unchanged in the urine.  Used with 6% salicylic acid for the treatment of keratodermas and psoriasis.

68. Urea  keratolytic agent  has a softening and moisturizing effect on the stratum corneum.  Increases the water content of the stratum corneum.

69. How Alopecia treated?  Minoxidil  Finasteride (Propecia)

70. Minoxidil  Reversing the miniaturization of terminal scalp hairs associated with androgenic alopecia.  Cessation of treatment will lead to hair loss in 4–6 months.  Possible systemic effects on BP

71. Finasteride (Propecia)  is a 5  -reductase inhibitor that blocks the conversion of testosterone to dihydrotestosterone. dihydrotestosterone.  The androgen responsible for androgenic alopecia.  Oral 1 mg/d, promotes hair growth and prevents further hair loss

72. Finasteride Side Effects  Decreased libido  Ejaculation disorders  Erectile dysfunction

73. How hirsutism treated?  Eflornithine (Vaniqa)  Mechanical hair removal : Shaving, plucking, waxing, electrolysis, laser hair removal

74. Eflornithine (Vaniqa)  irreversible inhibitor of ornithine decarboxylase  Reducing facial hair growth  When applied twice daily for 6 months  Local adverse effects: stinging, burning

75. PAYAN

76. Podophyllum Resin & Podofilox  an alcoholic extract, commonly known as mandrake root or May apple,  Treatment of verrucae.  Active cytotoxic agents with specific affinity for the microtubule protein of the mitotic spindle.

77. Podophyllum Resin & Podofilox Toxicity  Nausea, vomiting,  Muscle weakness, neuropathy with diminished tendon reflexes, coma, and even death.  Contraindicated in pregnancy due to cytotoxic effects on the fetus.

78. Fluorouracil  is a fluorinated pyrimidine antimetabolite  treatment of multiple actinic keratoses.  inhibits thymidylate synthetase activity, interfering with the synthesis of deoxyribonucleic acid and to a lesser extent ribonucleic acid.

79. Local Adverse Reactions of Fluorouracil  Pain, pruritus, a burning sensation,  Hyperpigmentation.  Contraindicated in patients with known hypersensitivity.

80. Antipruritic Agents Doxepin  Treatment of pruritus associated with atopic dermatitis( cream)  The potent H1 and H2-receptor antagonist  Drug interactions associated with TCA  Adverse local effects: burning and stinging

81. Pramoxine  A topical anesthetic  Relief pruritus associated with mild eczematous dermatoses.  In combination with hydrocortisone acetate.  Local adverse effects include transient burning and stinging.

82. Non FDA-Approved Drugs in Treating Hirsutism  Spironolactone: aldosterone antagonist and potassium-sparing diuretic competitively binds DHT receptors, ↓ ovarian androgen production, and inhibits 5α-reductase.  Flutamide: Nonsteroidal antiandrogen, Competitive inhibition at the DHT receptor (primary) and suppresses adrenal androgen production.

83. Non FDA-Approved Drugs in Treating Hirsutism  Finasteride: 5α- reductase inhibitor also used in the treatment male pattern baldness. Blocks peripheral conversion of testosterone to DHT.  Cyproterone: Progestogen derivative of 17- OHP used alone or in OCPs. It also inhibits testosterone and DHT.  Metformin

84. Alopecia 1.Androgenic Alopecia 2.Alopecia Areata is a hair loss condition characterized by the rapid onset of hair loss in a sharply defined area. (autoimmune)  autoimmune factor causing the patient to develop antibodies to different hair follicle structures.

85. Antineoplastic Agents Alitretinoin (Panretin)  is a topical formulation of 9-cis-retinoic acid  treatment of cutaneous lesions in patients with AIDS-related Kaposi's sarcoma.  Localized reactions: erythema, edema

86. Bexarotene (Targretin)  Member of a subclass of retinoids  Treatment of cutaneous T cell lymphoma.  Teratogenicity is a significant risk for both systemic and topical treatment.

87. Antiseborrhea Agents  Treatment of seborrheic dermatitis.  These are of variable efficacy and may necessitate concomitant treatment with topical corticosteroids for sever cases.  Betamethasone valerate foam (Luxiq)  Chloroxine shampoo (Capitrol)  Coal tar shampoo (Ionil-T, Pentrax, Theraplex-T, T-Gel)  Fluocinolone acetonide shampoo (FS Shampoo)  Ketoconazole shampoo (Nizoral)  Selenium sulfide shampoo (Selsun, Exsel)  Zinc pyrithione shampoo (DHS-Zinc, Theraplex-Z)

88. Topical Antibacterial Preparations  Bacitracin and gramicidin are peptide antibiotics, active G+ such as streptococci, pneumococci, and staphylococci.  In addition, most anaerobic cocci, neisseriae, tetanus bacilli, and diphtheria bacilli are sensitive.  Bacitracin is compounded in an ointment base alone or in combination with neomycin, polymyxin B, or both.

89. Bacitracin  Microbial resistance may develop following prolonged use.  Bacitracin-induced contact urticaria syndrome, including anaphylaxis, occurs rarely.  Allergic contact dermatitis occurs frequently.  Bacitracin is poorly absorbed through the skin, so systemic toxicity is rare.

90. Gramicidin  Gramicidin is available only for topical use, in combination with other antibiotics such as neomycin, polymyxin, bacitracin, and nystatin.  Systemic toxicity limits this drug to topical use.

91. Mupirocin (pseudomonic acid A)  Most G+ aerobic bacteria, including methicillin-resistant S aureus  In the treatment of impetigo caused by S aureus and group A beta-hemolytic streptococci.

92. Polymyxin B  is a peptide antibiotic against G- : Pseudomonas aeruginosa, E-coli, enterobacter, and klebsiella.  Topical application, daily dose applied to denuded skin or open wounds should not exceed 200 mg to reduce neurotoxicity & nephrotoxicity.

93. Neomycin & Gentamicin  Active against G- : E coli, proteus, klebsiella, and enterobacter.  Gentamicin shows greater activity against P aeruginosa than neomycin. Gentamicin is also more active against staphylococci and group A beta-hemolytic streptococci.  Neomycin alone and in combination with polymyxin, bacitracin and as a sterile powder for topical use.  Gentamicin is available as an ointment or cream.

94. Neomycin & Gentamicin  Both drugs are water-soluble and are excreted primarily in the urine. Renal failure may permit the accumulation of these antibiotics, with possible nephrotoxicity, neurotoxicity, and ototoxicity.  Neomycin frequently causes sensitization, particularly if applied to eczematous dermatoses.  When sensitization occurs, cross-sensitivity to streptomycin, kanamycin, paromomycin, and gentamicin is possible.

95. Ectoparasiticides  Lindane (Hexachlorocyclohexane) an effective pediculicide and scabicide.  Percutaneous absorption 10%& excreted in the urine.  T1/2 of 24 hours.  After absorption, It is concentrated in fatty tissues, including the brain.  Lindane (Kwell) is available as a shampoo or lotion.

96. Lindane  Single application to the entire body from the neck down, left on for 8–12 hours, and then washed off.  Concerns about neurotoxicity and hematotoxicity have resulted in warnings that lindane should be used with caution in infants, children, and pregnant women.  not be used as a scabicide in premature infants and in patients with known seizure disorders.

97. Ectoparasiticides : Crotamiton  is a scabicide with some antipruritic properties.  Cream or lotion.  for two applications to the entire body from the chin down at 24-hour intervals.  alternative to lindane.

98. Crotamiton Side Effects  Allergic contact hypersensitivity  primary irritation  discontinue the therapy

99. Ectoparasiticides : Sulfur  has a long history of use as a scabicide.  an unpleasant odor, is staining.  alternative drug for use in infants & pregnant women.  The usual formulation is 5% precipitated sulfur in Vaseline.

100. Ectoparasiticides : Permethrin  is neurotoxic to Pediculus humanus, Pthirus pubis, and Sarcoptes scabiei. Less than 2%  1% cream for pediculosis.  For the treatment of scabies, a single application of 5% cream (Elimite).

101. Adverse reactions of Permethrin  Transient burning  Stinging  Pruritus  Cross-sensitization to pyrethrins

102. Ectoparasiticides : Malathion  is an organophosphate CHE inhibitor  in treating pediculosis  Malathion is available as a 0.5% lotion  should be applied to the hair when dry and the hair then combed to remove lice after 4– 6 hours.