Pharmacology-4 PHL 425 Seventh Lecture By Abdelkader Ashour, Ph.D. Phone: 4677212 Email: aeashour@ksu.edu.sa

Anti-Acne Vulgaris Drugs

Acne Vulgaris (Acne), Overview & Pathogenesis Acne is derived from the Greek word “Akme” which means the highest point Acne is the formation of comedones, papules, pustules, nodules, and/or cysts as a result of obstruction and inflammation of pilosebaceous units (hair follicles and their accompanying sebaceous gland)

Acne Vulgaris (Acne), Overview & Pathogenesis Acne is derived from the Greek word “Akme” which means the highest point Acne is the formation of comedones, papules, pustules, nodules, and/or cysts as a result of obstruction and inflammation of pilosebaceous units (hair follicles and their accompanying sebaceous gland)

Sebaceous glands Sebaceous glands secretes sebum which is an oily secretion, its production is stimulated by hormones (androgens) Oil flows into the hair follicle then onto the skin surface Sebum has antibacterial properties and keeps hair and skin soft Normal hair follicle where sebum empties onto skin surface through follicle opening

Pathophysiology of acne 1-Sebaceous glands hyperactivity 2-Pilosebaceous duct obstruction 3-Bacterial colonization and inflammation

Acne, Pathogenesis Acne occurs when pilosebaceous units become obstructed with plugs of sebum and desquamated keratinocytes, then sometimes infected with the normal skin anaerobe Propionibacterium acnes (P. acnes) sebaceous follicle Micro comedo Acne can be inflammatory or noninflammatory, depending on whether P. acnes stimulates inflammation in the follicle or not closed comedo open comedo

Acne, Pathogenesis Noninflammatory acne is characterized by comedones; uninfected sebaceous plugs “a plug of keratin and sebum” impacted within follicles Comedones are termed closed (whiteheads) or open (blackheads) sebaceous follicle Micro comedo A whitehead becomes a blackhead when it enlarges until a dark plug protrudes through the skin surface The color is due to melanin and oxidized lipids, not dirt closed comedo open comedo

Acne, Pathogenesis Inflammatory acne comprises papules, pustules, nodules and cysts Papules appear when lipases from P. acnes metabolize triglycerides into free fatty acids (FFA), which irritate the follicular wall

Acne, Pathogenesis Inflammatory acne comprises papules, pustules, nodules and cysts Pustules occur when active P. acnes infection causes inflammation within the follicle Pustule

Acne, Pathogenesis Inflammatory acne comprises papules, pustules, nodules and cysts Nodules and cysts occur when rupture of follicles due to inflammation, physical manipulation, or harsh scrubbing releases FFAs, bacteria and keratin into tissues, triggering soft-tissue inflammation

This photo shows pustules, papules and comedones on the face of an acne patient

Unpleasant cystic acne in teenager

Acne, Epidemiology & Etiology Acne vulgaris is the most common of all cutaneous disorders and occurs in more than 85% of adolescents. It is more severe in males than in females. Genetic background plays a role in the incidence of this disorder Commonly involved areas are those with the highest concentration of sebaceous glands; the face, neck, chest, shoulders, and upper back The most common trigger is puberty, when surges in androgen stimulate sebum production and hyperproliferation of keratinocytes Other triggers include hormonal changes that occur with pregnancy or throughout the menstrual cycle; occlusive cosmetics, cleansing agents, and clothing; and humidity and sweating Acne may improve in summer months because of sunlight's anti-inflammatory effects

Acne, Epidemiology & Etiology Drugs such as lithium, hydantoin, isoniazid, glucocorticoids, oral contraceptives, androgens (e.g., testosterone), iodides, bromides and danazol are contributory factors Others: Emotional stress can definitely cause exacerbations Occlusion and pressure on the skin, such as by leaning face on hands, very important and often unrecognized exacerbating factor (acne mechanica) Acne is not caused by chocolate or fatty foods or, in fact, by any kind of food

Severity rating for acne Type 1: Comedones only, fewer than 10 lesions on the face, no lesions on the trunk and no scarring Type 2: Papules, 10 to 25 lesions on the face and trunk, mild scarring Type 3: Pustules, more than 25 lesions, moderate scarring Type 4: Nodules or cysts, extensive scarring

Management of Acne: Non- pharmacological Withdrawal of aggravating factors such as cosmetics and drugs is paramount where they appear to be involved in the etiology of acne Trauma, such as picking and vigorously squeezing acne lesions, can aggravate the condition Affected areas should be cleansed daily Extra washing, use of antibacterial soaps, and scrubbing confer no added benefit Changes in diet are also unnecessary and ineffective Cosmetics should be avoided

Pharmacologic Treatment Aims at: 1. Reducing sebum production & comedones formation 2. Reducing keratin production (keratolytic) 3. Killing bacteria and limiting inflammation & infection 4. Reducing scarring Selection of treatment (Topical and Oral)is generally based on severity

Topical medications Topical therapy is preferred over systemic (in mild-moderate acne) Retinoids Keratolytics (comedolytics) Antibiotics

1- Topical Retinoids Synthetic vitamin A analogues Mechanism of action The best topical medication for non-inflammatory acne Clinicians should consider using a topical retinoid as a first-line management for acne treatment They may be combined with topical or oral antibiotics for inflammatory acne Three forms ; cream (dry skin), gel (oily) and lotion Mechanism of action Retinoid enters the cell, interact with nuclear receptors involved in epithelial cell growth and differentiation It reverses thickening of the stratum corneum and the abnormal desquamation of keratinocytes It normalizes follicular keratinization New comedones formation is inhibited Comedones are extruded

Retinoids: Mechanism of action Tretinoin (Retin-A); acid form of vitamin A It has a keratolytic action, helps remove comedones, and converts closed comedones to open comedones Adapalene: 3rd generation Modified retinoid that has a faster onset of action Better tolerated than tretinoin Produces less skin irritation (gel or lotion) Exacerbation of acne often occurs in the first two weeks of therapy because microcomedones and comedones are extruded

Retenoids: Side effects Erythema, scaling and dryness of skin (start with low dose) Photosensitivity (use sunscreen) Cheilitis Teratogenic (oral retinoids)

Retinoids: Patient instructions Wash the skin with mild cleanser Wait 20 min after washing (dry) Should not be applied to wet skin as it increase penetration and irritation Apply very thin layer Sensitive skin  use a sunscreen daily Use moisturizer for irritation Use once at night (to avoid photo sensitivity) Care should be taken to avoid touching with eyes, nose and mouth Should not be used with other keratolytics Optimum results occur in 3 to 4 months

Topical medications Retinoids Keratolytics (comedolytics) Antibiotics

Keratolytics Agents that loosen hard plugs and open pores such as: Benzoyl peroxide Azelaic acid Salicylic acid Tretinoin (Retin-A) Adapalene (Better tolerated than Tretinoin)

Benzoyl peroxide A comedolytic which has peeling and keratolytic effects It is converted in the skin into benzoic acid that has an antibacterial action (specifically against P. acnes) Frequent use inhibits the development of bacterial resistance A common combination includes benzoyl peroxide + clindamycin / erythromycin

Benzoyl peroxide, Side effects Skin dryness & irritation, erythema, so: limit its use to short periods Use water based instead of acetone or alcohol product Use Lotion or cream instead of gel Avoid contact with eyes, mouth, mucous membranes Start treatment with lower strength preparations) Allergic contact dermatitis Bleaching of hair and skin Bleaching of clothing may also occur Other uses: Higher concentrations are used for hair bleach and teeth whitening

Azelaic Acid It is a naturally occurring dicarboxylic acid used for treatment of acne It is also used in treatment of pigmentary disorders because of its inhibition of tyrosinase, the rate-limiting enzyme in the synthesis of melanin Mechanism of action: It has comedolytic and peeling actions It has antibacterial activity against P. acnes It has anti-inflammatory activity Azelaic acid may be synergistic with retinoids Therapeutic uses: Treatment of mild- moderate acne of the face Treatment of skin pigmentation disorders including melasma and post inflammatory hyperpigmentation Side effects: Local irritation, but less than benzoyl peroxide and tretinoin Burning, tingling Local erythema

Salicylic acid Side effects Salicylic acid, a b-hydroxy acid, is keratolytic. It belongs to the same class of drugs as aspirin (salicylates) MOA: It dissolves the intercellular cement (the substance that causes the skin cells to stick together) This makes it easier to shed the skin cells It is a key ingredient in many skin-care products for the treatment of acne, psoriasis and warts Products containing salicylic acid include facial cleansers and antidandruff shampoos Side effects Local irritation even ulceration with the use of high concentrations Systemic absorption with prolonged use causing salicylate poisoning (salicylism; headache, confusion, blurred vision and ringing in the ear) Allergic reactions N. B. It should not be used on the face or on moles, birthmarks or inside the nose or mouth as it may cause severe irritation

Topical Antibiotics They are protein synthesis inhibitors that have inhibitory effect on Propionibacterium acnes They are suitable for mild to moderate inflammatory cases They come in a variety of forms, including lotions, gels, pads and toner-like solutions Possible side effects: Dryness, irritation of the skin  burning sensation Photosensitivity (use sunscreen) Resistance: Monotherapy with topical or systemic antibiotics is discouraged because of development of resistance The concurrent use of topical benzoyl peroxide has been shown to inhibit and decrease resistance

Oral medications Oral Antibiotics Retinoids Oral corticosteroids Anti-androgens

Oral Antibiotics Systemic therapy is prescribed when wide distribution of lesions makes topical therapy impractical and for patients resistant to topical therapy Oral antibiotics are usually administered twice daily for 4- 6 months Tetracycline Erythromycin Clindamycin (oral and topical) Minocycline Trimethoprim-sulfamethoxazole

Inhibitors of bacterial protein synthesis, Overview They are bacteriostatic, protein-synthesis inhibitors that target the ribosome Examples: Tetracyclines, macrolides (e.g., erythromycin 2%), clindamycin (1%)

Tetracycline Side effects: Tetracycline is the most commonly used antibiotic because it is inexpensive, safe and effective Although tetracycline is an antimicrobial agent, its efficacy in acne may be more dependent on its anti-inflammatory activity Side effects: Photosensitization Tooth discoloration Vaginal candidiasis is a common complication that is readily treated with local administration of antifungal drugs It must be taken on an empty stomach Tetracycline should not be given to pregnant women or children under 9 years

Minocycline Side effects: Minocycline is a tetracycline derivative with better GIT absorption than tetracycline and may be less photosensitizing than tetracycline Side effects: Dizziness, N, V Hyperpigmentation of the skin and mucosa It is contraindicated in pregnant or breastfeeding women If used by younger children, it can cause permanent tooth discoloration

Erythromycin It has several advantages It has anti-inflammatory properties It can be taken with food Erythromycin is a better antibiotic option for pregnant or breastfeeding women It also can be used by younger children because, unlike some of the other oral antibiotics, it does not cause tooth discoloration

Oral Retinoids, Isotretinoin Oral vitamin A (Accutane) It is used for treatment of severe acne with cysts and nodules and resistant acne It is indicated only for use in males and females who are not pregnant 4-5 months provides long-term disease control It normalizes keratinization in the sebaceous follicle, decreases sebum synthesis, reduces P. acnes and prevents acne scarring May be used with topical or oral antibiotics

Isotretinoin: Side effects Sever dryness of the skin and mucous membranes Cheilitis and epistaxis  liver enzymes,  blood TG and cholesterol Myalgia and arthralgia are common Regular liver function tests should be performed regularly Use of isotretinoin concomitantly with tetracycline antibiotics may increase the risk of benign intracranial hypertension, BIH: (idiopathic, impaired reabsorption of cerebrospinal fluid) Presented with frequent or unusual headaches; an indication to stop the drug

Contraindications Isotretinoin and pregnancy Pregnancy People with liver disease (it can further impair the liver) Patients with advanced kidney disease Patients with high cholesterol are strongly advised not take this medication Isotretinoin and pregnancy Pregnancy is an absolute contra-indication to the use of isotretinoin If the drug is given within the first 3 weeks of gestation (not dose-related), spontaneous abortion occurs in one-third of patients Teratogenic effects include CNS, cardiac and craniofacial abnormalities

Hormonal Therapy Corticosteroids are used in treatment of severe inflammatory acne mostly in adolescent males (with isotretinoin) Mechanism of action : Corticosteroids suppress inflammation and androgen production Used orally or by direct injection into the cysts Commonly used corticosteroids include prednisone and dexamethasone Side effects of corticosteroids: When taken orally, they can cause truncal obesity and moon face They suppress the immune system Topical corticosteroids (creams or ointments) should not be applied to skin affected by acne, as they may exacerbate the condition Dermatologists sometimes offer steroid injections to make pimples less noticeable. These injections can cause lightening and thinning of the skin

Anti-androgens Acne-prone women tend to have higher levels of androgens Drugs that inhibit androgen production, are used to treat women who are unresponsive to other therapies Cyproterone acetate: It acts by blocking androgen receptors and prevents androgens from binding to them It reduces sebum production It reduces comedones formation

Management of Acne Mild and mild to moderate acne: Single-agent therapy is generally sufficient for comedonal acne (a mainstay of treatment for comedones is daily topical tretinoin in escalating concentrations as tolerated). Azelaic acid has comedolytic and antibacterial properties and may be synergistic with retinoids Papulopustular acne generally requires dual therapy (e.g., the combination of tretinoin with benzoyl peroxide or topical antibiotics) Daily adapalene gel and tazarotene cream or gel are alternatives for patients who cannot tolerate topical tretinoin Treatment should be continued for 6 weeks or until lesions respond. Maintenance treatment may be necessary to maintain control Mild inflammatory acne should be treated with topical benzoyl peroxide, topical antibiotics (e.g., erythromycin, clindamycin) and/or glycolic acid Oral antibiotics (e.g., tetracycline, minocycline, doxycycline, erythromycin) can be used when wide distribution of lesions makes topical therapy impractical

Management of Acne Moderate acne: Moderate acne responds best to oral systemic therapy with antibiotics. Antibiotics effective for acne include tetracycline, minocycline, doxycycline and erythromycin. Full benefit takes ≥ 12 wk Tetracycline is usually a good first choice: 250 or 500 mg bid (between meals and at bedtime) for 4 weeks or until lesions respond, after which it may be reduced to the lowest effective dose Because relapse ordinarily follows short-term treatment, therapy must be continued for months to years, although for maintenance, tetracycline 250 or 500 mg once/day is often sufficient Minocycline 50 or 100 mg bid causes fewer GI adverse effects, is easier to take, is less likely to cause photosensitization Erythromycin and doxycycline are considered 2nd-line agents because both can cause GI adverse effects, and doxycycline is a frequent photosensitizer In women, prolonged antibiotic use can cause candidal vaginitis; if local and systemic therapy does not eradicate this problem, antibiotic therapy for acne must be stopped

Management of Acne, contd. Severe acne: Oral Isotretinoin is nearly always effective. It is also the best treatment for patients with moderate acne in whom antibiotics are unsuccessful and for those with severe inflammatory acne It is limited by adverse effects, including dryness of conjunctiva and genital mucosa, chapped lips, arthralgias, depression, elevated lipids and birth defects. Petrolatum usually alleviates mucosal and cutaneous dryness CBC, liver function, and fasting glucose, triglyceride and cholesterol levels should be determined before treatment. Each should be reassessed at 4 weeks and, unless abnormalities are noted, there is no need to repeat assessments until the end of treatment

Anti-Acne Drugs, Examples The majority of acne patients can be treated with topical medications of three types: benzoyl peroxide products, retinoids and antibiotics. Each has distinct advantages, and concurrent use of these agents may have synergistic effects Topical benzoyl peroxide has both bactericidal and comedolytic activities This agent is particularly useful because of its bactericidal nature, and frequent use inhibits the development of bacterial resistance Irritation evidenced by erythema and scaling is the most significant side effect; skin hypopigmentation and bleaching of clothing may also occur

Anti-Acne Drugs, Examples The topical retinoids (tretinoin, adapalene, tazarotene) normalize keratinocyte differentiation, decreasing the "stickiness" of the epidermal cells lining the follicular lumen. This allows the keratin plug to be expelled, thus preventing formation of comedones All forms should be introduced gradually, to decrease the likelihood of adverse effects such as drying, irritation, or sun sensitivity. Daily therapy can usually be tolerated after several weeks; these agents are generally not used more than once a day Oral isotretinoin is the most effective drug available for the treatment of acne. It directly suppresses sebaceous gland activity leading to significant reduction in sebaceous lipogenesis, normalizes the pattern of keratinization within the sebaceous gland follicle, inhibits inflammation, and – in a secondary manner – reduces growth of P. acnes. It is most active in the treatment of severe recalcitrant nodulocystic acne and in the prevention of acne scarring

Anti-Acne Drugs, Examples Topical antibiotics including 2% erythromycin, 1% clindamycin, or a combination of 3% erythromycin and 5% benzoyl peroxide (Benzamycin) in patients with an inflammatory component These agents decrease colonization of the skin by P. acnes and may also inhibit neutrophil chemotaxis. However, resistant P. acnes has been documented For this reason, monotherapy with topical or systemic antibiotics is discouraged. The concurrent use of topical benzoyl peroxide has been shown to inhibit and decrease resistance Individuals with sensitive skin present a special therapeutic challenge and may benefit from sulfacetamide products or azelaic acid cream, which may also decrease postinflammatory hyperpigmentation Azelaic acid has comedolytic and antibacterial properties and may be synergistic with retinoids