Isotretinoin is available in oral dosage form and preserved for very sever acne cases because it is very very toxic drug

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1 **This sheet include all the sildes' material in bold sand what dr said in light.. We will continue our taking about acne We said that acne is one of the most common skin diseases which actually a lot of people suffer from In general we said that the is No cure but in realty there are severe cases that need treatment Some patient found that oral preparation is effective but it is still questionable (wither these drugs is really effective or the lesions resolve by them selves ).. However we will take about what we need to know about the treatment.. Drugs in acne Retinoic acid and derivatives: Retinoic acid (Tretinoin, Retin-A ) dapalene Tazarotene Isotretinoin Oral Available in cream, gel and ointment dosage forms Isotretinoin is available in oral dosage form and preserved for very sever acne cases because it is very very toxic drug

2 The most side effects that 1 st three drugs have is local irritation and sensitivity But still the most sever side effect is for isotertioin.. Lets discus every one of them separately Tretinoin (Retin A), Adapalene, Tazarotene Excellent choice for comedomal acne Excellent choice for comedomal acne Comedome means white &black vacuoles which get with time smaller in size So comodeletic effect drugs that dissolve such comedome lead to disappearance of such vacuoles Improves follicular desquamation and dyschromia dyschromia with hyper or hypo pigmentation inflammatory action (Adapalene best) Adapalene has the best anti-inflammatory effect among all retinoic acid derivatives Use at night over entire face, exposure to the sun increases irritation

3 It is preferd to use at night because it is photosensitive and it might be degraded by sun Results in six to eight weeks. May increase concentration over time May increase the dose if there is no response to applied dose Degraded by prolonged exposure to the sun and when used with benzoyl peroxide (Adapalene most photostable) So Adapalene Is the most photo stable, most antiinflammatory, less irritation (but we still advice to use at night ) Side effects to Retinoids Could lead to irritation (Tazarotene most irritating, Adapalene least) Sun sensitivity Pustular eruption after Potential risk of weeks of use Potential risk of hyper/ hypopigmentation Contraindicated in pregnancy (tumerogenic in animals)

4 We can generalized that all anti-acne preparation have teratogenic activity so they are contraindicated in pregnancy Isotretinoin It is orally given in capsule dosage form and this drug is preserve for severe acne cases (even if your patient improved after use it, we still say don't use it except in severe cases because of its huge side effects) Systemic retinoid used for nodulo-- cystic acne (caps.) Most effective treatment with remission in 60 % after single course ( weeks) Requires long course treatment some times up to six months Reduces sebum production Normalizes follicular keratinization (dr said it inhibits keratinization ) Decreases inflammation Extremely toxic: Teratogenic (can occur with single exposure during gestation), myalgias/arthralgias, photosensitivity, lipid abnormalities, pancreatitis, leucopenia,

5 elevated platelets and ESR, proteinuria, hematuria Benzoyl Peroxide Has bactericidal effect on P.acnes No evidence of resistance If combined with a topical antibiotic (erythromycin or clindamycin) may help in decreasing the emergence of resistant of P.acnes species As you know the problem in bacteria in general is the resistance to anti-biotic and chemotherapeutic agents, and we can come over this problem by combining drugs to gather for example( benzyl peroxide with erythro or clindamycin) Has mild comedolytic action(it dissolve comodome) reduces inflammations,and decreases free fatty acids Free fatty acids is aby product due to the effect of lipase enzyme (which produced by bacteria)

6 Such free fatty acids leads to irritation ( so you must be careful with irritation, don't touch the acne because it will leads to disfigurement which is the major problem with acne and this happen because most people try to remove it (Remember that the acne is not abases (if it is bacterial abases yes you open and drain it then you take an anti-biotic) Available in cleansing liquid or bar, lotion, cream, and gel Adverse effects include: Irritation, bleaches clothing and hair, allergic contact dermatitis Irritation which is common and shared with all acne preparations Common question in exam Which of the followings is common side effect between most topically anti acne preparations?? The answer is Irritation Even not just to acne, any skin preparation which is locally applied will lead to Irritation

7 But when we say proteinuria, hematuria, these side effects is just for isotretinon (not common to all others) Azelaic Acid Has antimicrobial activity and inhibits conversion of testosterone to dihydrotetosterone testosterone is synthesized in males (testes) and in small quantities in females (ovaries) testosterone which is the major androgen male sex hormone is converted to more potent product known as dihydrotetosterone which interacts with androgen receptors So Azelaic Acid has anti-androgenic effect by inhibit this conversion It is a dicarboxylic acid that is bacteriostatic against P.acnes and normalizes keratinization ( decrease keratinization ) Most effective when used with other agents

8 Comes as a gel and a cream Side effects uncommon Use in caution in teens with dark complexions (dark skin) due to potential risk of hypopigmentation Topical antibacterials in Acne Clindamycin Erythromycin Metronidazole Sodium sulfacetamide In addition to oral or systemic antibiotics used against problems that related to bacterial acne Erythromycin, Clindamycin (locally applied) Decrease P.acnes Slow to act and percentage of free fatty acids Resistance often develops over time Best used in combination with topical retinoids/benzoyl peroxide Combination therapy

9 5 % Benzoyl Peroxide and 3% Erythromycin 5 %Benzoyl Peroxide and 1% Clindamycin Topical antibiotics and Azelaic acid or Tretinion Erythromycin In topical preparations, erythromycin base rather than a salt is used to facilitate penetration One of the possible complications of topical therapy is the development of antibiotic resistant strains of organisms, including staphylococci Adverse local reactions to erythromycin solution may include a burning sensation at the time of application and drying and irritation of the skin Erythromycin is also available in a fixed combination preparation with benzoyl peroxide for topical treatment of acne vulgaris Clindamycin (locally applied)

10 10% absorbed, so, possibility of Pseudomembranous colitis ( which is the most dangerous side effect related to this drug (also called antibiotic associated colitis), in this case we will stop this drug and give the drug of choice which is Vancomyocin ) The hydroalcoholic vehicle and foam formulation (Evoclin) may cause drying and irritation of the skin, with complaints of burning and stinging The water-based gel and lotion formulations are well tolerated and less likely to cause irritation. Allergic contact dermatitis is uncommon Clindamycin is also available in fixedcombination topical gels with benzoyl peroxide, and with tretinoin Metronidazole - It is antibiotic and anti-parasitic medication that is highly effective against microorganism

11 - It is widely used in dentistry because in oral cavity there are many anaerobic bacteria - In addition it has anti-acne effect Effective in the treatment of rosacea Rosacea داء الوردية : redness swollen face, this condition has a genetic background also it has a role in certain mites that normally present in skin, one of these mites called ( Demodex brevis) which cause this condition ( there is a role of bacteria also ). The mechanism of action is unknown, but it may relate to the inhibitory effects of neutrophil metronidazole on Demodex brevis It has an anti inflammatory effect by direct effect on cellular function Adverse local effects of the water-based gel formulation include dryness, burning, and stinging. Less drying formulations may be better tolerated Caution should be exercised when applying Metronidazole near the eyes to avoid excessive tearing

12 Systemic antibiotics in acne Primarily used for moderate to severe inflammatory acne Decrease P.acnes Reduces amount of free fatty acids Cases with high rates of resistance to Erythromycin Preferred agents include Tetracycline, Doxycycline, Minocycline (those drugs belong to tetracyclin group which differ in pharmacokinetics parameters particularly مش واضحة بالريكورد in Hormonal control of acne - We in general don't like to use hormonal therapy especially with people normal endocrine function - Such pills or tablets (oral contraceptive pills) consist of combination of estrogen and progesterone (female sex hormones) - So if you give this drug to females (or even males (this could lead to irreversible damage to the reproductive axis in the body (this axis us responsible for reproduction, pregnancy and sex)

13 - The severe side effect of this drug is due to estrogenic component (progesterone as compered to estrogen has few side effects ), so what they do nowadays is to reduce as much as possible the percentage of estrogen in order to reduce side effect (which damage the reproductive axis and lead to infertile in men and women) - Oral contraceptive pills are available with different estrogen to progesterone ratios Oral contraceptive pills in females Increase production of sex hormone binding globulin leading to a decrease of circulating androgens Decrease ovarian androgen production Ortho tri cyclen (ethinyl estradiol and norgestimate), Estrostep (ethinyl estradiol and norethindrone acetate) FDA approved for the treatment of acne

14 Norethindrone is progesterone medication used in combination with ethinyl estradiol Oral antiandrogens (spironolactone) can be useful Spironolactone is an aldosterone antagonist, it is found that is highly effective in certain cases of acne and in case of female hirsutism ( dense abnormal growth of hair on a person's face and body, especially on a woman.) This drug absorb Na+ & water and increase serum K+ level ( prevents your body from absorbing too much salt and keeps your potassium levels from getting too low.) it can cause hyperkalemia Oral corticosteroids, short course for patients with severe inflammatory disease ( for sever cases and last choice) Summary Mild acne: Topical therapy with retinoid for comedomes, add Benzoyl

15 Peroxide or topical antibiotic if mild inflammation present Moderate acne: Topical therapy plus oral antibiotics for inflammatory lesions, add Benzoyl Peroxide to reduce antibiotic resistance. Consider OCPs Severe acne: Isotretinoin if topical therapy and oral antibiotics fail Advices to patients with acne Avoid applying medication right after washing face Always remember that local application of different dosage form is better on dry skin Avoid over use of medication Always start with applying a test dose because there is a probability of having severe irritation or sensitiveness on some patients. Apply on all acne prone areas If face gets dry apply oil free moisturizer Always apply test dose Start at low concentrations

16 Apply retinoids at night Avoid use of at night Benzoyl Peroxide )الصدفية( Drugs in psoriasis Autoimmune disease (the immune system is directed against normal tissues) o A chronic skin condition, immune mediated dermal inflammation consists of painful reddened papules that form plaques with distinct borders. Other patches appear as silvery yellow white scales o Usually located in elbows, scalp, knees, feet and genitalia (but any parts of this skin could be affected also by this condition) Drugs in psoriasis Topical Coaltarointment Calcipotriene Tazarotene

17 Systemicc PUVAA Citretin Alefacept Coal tar ointment Relieves itching, irritation, redness, dryness, scaling caused by psoriasis, seborrhea, or eczemait is a keratolytic works by slowing bacterial growth and loosening and softening scales Calcipotriene Derivative of vitamin D, acts by slowing down the growth of skin cellsused topically (cream; solution) in the treatment of psoriasis Safe for longterm application Tazarotene (cream, gel, or foam) It is a retinoid prodrug which is converted to its active form, the cognate carboxylic acid of tazarotene Binds to all three members of the retinoic acid receptor (RAR) (Retinoic

18 acid receptors) family: RARα, RARβ, and RARγ but shows relative selectivity for β, and γ and may modify ( alteration and amplification) gene expression in stem cells Has anti-- inflammatory and anti proliferative actions Teratogenic and can cause burning, stinging, peeling, erythema, and localized edema of skin UV light )using UV light for persons which called phototherapy) Patients with psoriasis noticed an improvement in their skin after exposure to sunshine Of the many different UV rays emitted by the sun, only UVA and UVB are helpful to people with psoriasis (Not all wave lengths used in phototherapy like UVC which is cause skin cancer but dose not enter to atmosphere because our planet is preserved by ozone layer )

19 Ultraviolet light reduces inflammation in the skin, that s why it can be effective for psoriasis and other inflammatory skin conditions PUVA (Psoralens + UVA) Psoralens include psoralen; methoxsalen & Trioxsalen, which are furocoumarins, can be used both topically and systemically ( Furocoumarins are class of organic chemical compounds produced by variety of plants ) Psoralens increase sensitivity to solar radiation (given first and followed by UV) Methoxsalen has the best oral bioavailability, undergoes less first pass effect and most effective Effective in psoriasis, eczema, vitiligo (which is decrease of pigmentation of certain area of the skin), mycosis fungoides and cutaneous T-cell lymphoma

20 PUVA MOA involves : (Mechanism of action) inhibit DNA replication Decrease in DNA-dependent proliferation Alteration of the immune system, suppress T lymphocytes and epidermal Langerhans cells Inhibit mast cell release of inflammatory mediators Photo activation stimulates melanocytes and induce their proliferation promotion of melanogenesis Puva side effects include: Nausea, blistering, painful erythema, squamous cell carcinoma, malignant melanoma (extensive PUVA therapy > 15 years) = ( with chronic use (more than 10 years)), cataract (patient should use UVA absorbing eye glasses)

21 Acitretin Related to isotretinoin Given orally for severe pustular psoriasis, good effect Normalizes desregulated keratinocytes and has anti-inflammatory action. Does not suppress sebum Accumulates in fat prolonged elimination t months after chronic use) Hepatotoxic and teratogenic ½ (> 3 Adverse effects to Acitretin are similar to other retinoids More teratogenic than other retinoids Should not be used in pregnant ladies or those who might get pregnant while on the drug or any time after at least 3 years of discontinuation of therapy and also should not donate blood

22 Alefacept Immunosuppressant, stops the activity of T lymphocytes Given IM, major adverse effect infection Severe cases of psoriasis could be managed with a high potency corticosteroids or methotrexate Keratolytic agents Drugs that remove warts تواليل and other lesions in which the epidermis produces excess skin Salicylic acid o Solubilizes cell surface proteins resulting in desquamation of keratotic debris o Keratolytic in 36 % concentration, but destructive in higher concentrations When you apply Keratolytic agents you should not exceed such percentages,otherwise it will burn your skin o Can result in salicylism due to systemic absorption

23 o Locally, can cause urticaria, erythema multiforme, irritation, inflammation, and ulceration *It is applies to the warts and remove it but many dermatologic prefer to use laser therapy *warts may have viral involvement **Don't forget that salicylic acid could be absorbed to the circulation leading to salicylism (toxicity) which is the main side effects to aspirin ( which is acetylsalicylic acid) Propylene Glycole o Usually used as a vehicle for organic compounds o Develops an osmotic gradient through the stratum corneum, thereby increasing hydration of the outer layers of skin o %70 Used alone as a keratolytic agent in concentrations of 40 %, with plastic occlusion, or in gel with salicylic acid o 6 % It is also an effective humectant and increases the water content )مرطب ) of the stratum corneum

24 Urea Has a humectant activity, i.e. softening and moisturizing effect on the stratum corneum Increases water content as a result of its hygroscopic characteristics Urea is also keratolytic by altering prekeratin and keratin, leading to increased solubilization Urea is available in a compatible cream vehicle or ointment It decreases the unpleasant oily feel of dermatologic preparations (makes skin preparations feel less greasy) Podophyllum Resin & Podophyllotoxin An alcoholic extract of Mandrake root or Podophyllum Mayapple ) peltatum ( Used in the treatment of other verrucae( this is another term for warts (paploma virus infection leads to warts) ) Cytotoxic condyloma acuminatum activity with specific affinity for

25 the microtubule protein of the mitotic spindle. and Normal assembly of the spindle is prevented, and epidermal mitoses are arrested Application should be restricted to wart tissue only A 25 % concentration of tincture of benzoin podophyllum is used for resin in compound condyloma acuminatum Podophyllum Resin & Podophyllotoxin... The patient should wash off the preparation hours after the initial application 23 Use during pregnancy is contraindicated in view of possible cytotoxic effects Pure 0.5 % podophyllotoxin (podofilox) is used for genital condylomas Can cause N, V, (means nausea and vomiting) muscle weakness, neuropathy, coma, and even death

26 Flurouracil: Antimetabolite that resembles uracil and inhibits thymidylate synthetase, thus interferes with DNA and may be RNA synthesis Used in multiple actinic keratosis Aminolevulinic Acid: Used in actinic keratosis ( keratinization due to sun exposure which happen with people who have sensitivity to sun light) After topical application( 20 %) and exposure to light, produces a cytotoxic superoxide and hydroxyl radicals