Download 7th Lecture 1435

Pharmacology-4 PHL 425
Seventh Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
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 antiinflammatory 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
 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
1. Erythema, scaling and dryness of skin
(start with low dose)
2. Photosensitivity (use sunscreen)
3. Cheilitis
4. 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
1. 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)
2. Allergic contact dermatitis
3.Bleaching of hair and skin
4.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
 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:
1. Dryness, irritation of the skin  burning sensation
2. 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%)
Chloramphenicol
Tetracyclines
Θ
Θ
(P-site)
(A-site)
Θ
Macrolides,
clindamycin
Tetracycline
 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
 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




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