1. Pharmacology-4 PHL 425
Seventh Lecture By Abdelkader Ashour, Ph.D. Phone:

2. Anti-Acne Vulgaris Drugs

3. 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)

4. 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)

5. 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

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

7. 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

8. 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

10. 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

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

12. 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

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

14. Unpleasant cystic acne in teenager

16. 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

17. 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

18. 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

19. 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

20. 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

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

22. 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

23. 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

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

25. 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

26. Topical medications
Retinoids
Keratolytics (comedolytics)
Antibiotics

27. 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)

28. 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

29. 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

30. 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

31. 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

32. 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

33. Oral medications Oral Antibiotics Retinoids Oral corticosteroids
Anti-androgens

34. 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

35. 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%)

36. 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

37. 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

38. 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

39. 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

40. 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

41. 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

42. 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

43. 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

44. 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

45. 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

46. 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

47. 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

48. 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

49. 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