BChD III

FAR 370

Drugs acting on skin and

mucous membranes
Hafiza Parkar
Department of Pharmacology
[email protected]

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 Physiology of the skin
• The skin is largest organ forms part of integument continuous with
mucous membranes
• Consists of 3 layers:
o Epidermis
o Dermis
o Subcutaneous

• Serves several important functions:

o Provides a protective barrier against microbes and soft tissue
trauma
o Secretes waste via sweat glands
o Assists in regulating body temperature
o Stores fat
o Synthesizes vitamin D
o Site for drug absorption
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 Factors influencing drugs applied to the skin
• Pharmacologic response to drugs applied to the skin determined by:
• Regional variation in drug penetration
Some areas are more permeable than others, e.g. face, axilla and scalp

• Concentration gradient
The higher the concentration gradient, the more drug may be transferred across the skin per
unit of time, e.g. resistance to corticosteroids may be overcome by using higher concentrations

• Dosing schedule
The skin acts as a reservoir for many drugs – local half-life may thus be long enough to permit
less frequent application of drugs with a relatively short half-life

• Vehicles and occlusion

o Vehicles should be appropriately chosen as to maximize the ability of the drug to penetrate
the outer layers of the skin

o Occlusion (covering the area to keep the vehicle and drug in close contact with the skin) is
an effective approach to maximize efficacy
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 Dermatological bases
• A drug preparation is applied via a “vehicle” – a carrier base that brings
the drug into direct contact with the skin

• The vehicle may elicit effects of its own due to hydrating, protecting or
cooling properties

• Preparations also contain excipients, e.g. preservatives, colouring agents,

perfumes and penetration enhancers

• Either the vehicle or excipients may lead to adverse reactions

• When mixing preparations, the compatibility of both bases and active

ingredients should be considered as well as the concentration of
preservatives and stabilizers

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 Dermatological bases
• Creams: semi-solid emulsions; well-absorbed, nor particularly occlusive;
contain preservatives
• Ointments: oil/grease continuous phase; occlusive; suitable for chronic,
dry skin lesions
• Lotions: liquid suspensions; suitable for large/hairy areas; suitable for
acute inflammation and weeping dermatoses; contain preservatives
• Shake lotions: contain insoluble powders, e.g. calamine (leaves deposit)
• Pastes: doughy consistency; adhere to skin; suitable for circumscribed
lesions
• Gels: semi-solid aqueous solutions; non-greasy; ideal for intertriginous
and hairy areas; usually contain preservatives
• Dusting powders: fine powders used on intact skin to reduce friction or
moisture
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 Percutaneous absorption

Dermatological preparation Vehicle Drug

Drug diffuses through
stratum corneum
Stratum corneum Drug

Drug partitions into

stratum spinosum
Stratum spinosum Metabolism?
Drug

Drug partitions into

dermis
Basement membrane zone Metabolism?
Drug

Drug partitions into

subcutaneous tissue
Subcutaneous fat Drug

Absorbed into
bloodstream
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 Acne
• Acne vulgaris (common acne) is a skin disorder characterised by:
o Pimples
o Comedones (clogged hair follicles/pores)
 Closed- whiteheads
 Open- blackheads
o Pustules
o Nodules

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 Acne
• Occurs due to alterations in the pilosebaceous units (hair follicles and
sebaceous glands)

• Alterations can occur due to:

o Androgens which stimulate sebaceous glands producing sebum
that leads to follicular keratinization and obstruction
o Propionibacterium acnes (normal skin flora), clogged pore and
multiply, causing redness and inflammation and leading to
papillary, pustulary, and cystic acne

• Treatment for acne aimed at reducing sebum or control P. acnes

o P. acnes is a gram-positive rod associated with

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 Retinoids
• Derivatives of vitamin A that are highly effective in the treatment of acne
• 1st generation:
o Tretinoin (retinoic acid) - topical
o Isotretinoin (Roaccutane)- oral
 Reserved for severe cystic acne resistant to other therapies
• 3rd generation:
o Adapalene- topical
o Tazarotene- topical
o Less irritating and more effective than 1st gen retinoids
o 1st line therapy for comedonal and inflammatory acne

• Side-effects of topical preparations:

o Erythema and dryness in first few weeks of use
o Tumorigenic potential of UV radiation may be increased; wear sunscreen
and avoid exposure

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 Retinoids
• Mechanism of action:
o Retinoids bind directly to and activate retinoic acid receptors eliciting
transcription of retinoic acid‐responsive genes which have the following
effects:
o Increase the proliferation and differentiation of cells
o Normalize abnormal desquamation in acne by increasing follicular
epithelial turnover and accelerating the shedding of corneocytes
o Leading to the expulsion of mature comedones and the suppression of
microcomedone formation

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Retinoids

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 Retinoids
• Isotretinoin (oral)
o Reserved for severe cystic acne resistant to other therapies
o Synthetic oral retinoid
o Well-absorbed, highly protein-bound
o Inhibits sebum production and reduces size of sebaceous glands
o Cystic acne respond to 1-2mg/kg in divided daily doses for four to five
months (60% remission rate)
o Second course may be initiated if acne persists after two months
o Baseline LFT should be performed before initiation of treatment
o Side-effects resemble hypervitaminosis A:
 Dry, itchy skin and mucous membranes; epistaxis; photosensitivity;
mood disorders and suicidal ideations
 Significant risk of teratogenicity – women of childbearing potential
MUST use effective contraception for at least one month prior,
during and at least one menstrual cycle after treatment; pregnancy
must be excluded within 2 weeks
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 Topical antibacterial preparations in acne
o Azelaic acid
 Dicarboxylic acid that is bacteriostatic against P. acnes
 Suitable in mild to moderate acne vulgaris
 Anti-inflammatory actions
 Normalizes keratinization
 Most effective in combination with other agents
 Most common side-effect is mild irritation
 Potential for hypopigmentation – care should be taken in patients with
dark complexions
o Erythromycin and clindamycin (preferred) are available
 These agents may be combined with benzoyl peroxide or the retinoids for
better effectiveness
 Inhibits protein synthesis by binding to the 50S rRNA subunit
 Resistance problematic
 10% systemic absorption of clindamycin; pseudomembranous colitis very
rare
 Acts against Propionibacterium acnes to alleviate acne vulgaris

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 Topical antibacterial preparations in acne
o Benzoyl peroxide:
 Penetrates stratum corneum unchanged; converted to benzoic acid within
epidermis and dermis
 Antimicrobial activity against P acnes; no evidence of resistance
 Oxidant activity, avoid contact with mucous membranes and eyes
 Allergic contact dermatitis and possible post-inflammatory
hyperpigmentation in dark skin
 Most cost-effective option for mild to moderate acne vulgaris when
combined with an antibiotic
o Dapsone
 Synthetic sulfone that Inhibits bacterial synthesis of dihydrofolic acid to
inhibit nucleic acid synthesis
 Anti-inflammatory and immunomodulatory effects by inhibiting oxidant
generation by neutrophils (prevents myeloperoxidase-mediated
conversion of H2O2 to HOCl
 Available as topical gel
o Metronidazole as a topical agent is useful in adult acne, also known as
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rosacea
 Antibacterial agents used for acne
• Systemic antibiotics in acne:
o Aimed at decreasing P. acnes primarily in moderate to severe acne
vulgaris; also reduces dermal free fatty acids
o Resistance to erythromycin common
o Tetracycline antibiotics preferred: doxycyclines and minocycline

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 Dermatitis
• Inflammation of the skin caused by:
o Allergies (food, medication, etc.)
o Irritants
o UV light
• Types of dermatitis
o seborrheic dermatitis
 Skin eruptions on face, scalp and trunk; produces greasy, dry scales and
appears reddish
 Treated with shampoos and creams containing ketoconazole or hydrocortisone;
UV therapy in severe cases
o Contact dermatitis
 Appearance of skin vesicles that ooze, burn, itch, sting or scale
 Treated with soap-free cleansers and creams and lotions containing alpha-
hydroxy-acids, antihistamines and corticosteroids
• Atopic dermatitis
 Lesions on face, neck, knees, elbows, trunk of body
 Emollient creams, oral and topical steroids provide relief 17
 Eczema
• An acute, subacute but usually chronic pruritic inflammation of the
epidermis and the dermis, often occurring in association with a personal
family history of hay fever, asthma, allergic rhinitis or atopic dermatitis.
• Conservative therapy:
o Education (chronicity, prevention and trigger ID)
o Use of astringents and emollients/moisturizers
o OTC products (topical antihistamines, corticosteroids, calamine, etc.)
• Low to mid-potency steroid creams
• High potency steroid creams
• Immunomodulators
o Pimecrolimus (Elidel®) and tacrolimus (Protopic®) – neurokinin
inhibitors that selectively inhibit production and release of pro-
inflammatory cytokines and mediators by T cells and mast cells
• Oral therapy: steroids, cyclosporine, methotrexate
• Coal tar
• PUVA therapy
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 Eczema
Corticosteroid product name Generic name
Group I – Weak

Mylocort®, Dilucort®, Biocort®, Stopitch® hydrocortisone

Group II – Moderately potent

Betnovate® betamethasone valerate

Group III - Potent

Beclate® beclomethasone
Diprosone®, Betnovate®, Lenovate® betamethasone
Nerisone® diflucortolone
Synalar®, Cortoderm® fluocinolone acetonide
Cutivate® fluticasone
Locoid® hydrocortisone butyrate
Advantan® methylprednisolone aceponate
Elocon® momethasone

Group IV – Very potent

Dermovate®, Xenovate® clobetasol

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 Psoriasis
• Chronic, non-contagious autoimmune disease characterized by
raised areas of abnormal skin
• May present anywhere on the body, but most common on the
elbows, knees, scalp and lower back
• Skin typically becomes red and inflamed and may form white, scaly
patches
• May be painful and itchy, crack and bleed

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 Psoriasis

Gan, E.Y.; Chong, W.; Tey, H.L. Therapeutic Strategies in Psoriasis Patients with Psoriatic Arthritis: Focus on New Agents. 2013, BioDrugs 27(4)
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 Antibacterial agents
• Pathogens isolated from most dermatoses are group A β-haemolytic
streptococci and Staphylococcus aureus (surgical wounds infected by
pathogens resident in the environment)
• can cause folliculitis, abscesses, fasciitis, cellulitis, impetigo, and many pus-
forming infections
• Antibiotics and corticosteroids commonly combined in formulations; useful
in diaper dermatitis, otitis externa and impetiginized eczema

• Topical preparations:
o Fusidic acid: protein synthesis inhibitor; inhibits bacterial translation in
Staphylococcus, Streptococcus and Corynebacterium species
o Metronidazole: inhibits nucleic acid synthesis (forms nitroso-radicals to disrupt
DNA); bacterial vaginosis; rosacea (mechanism unknown) anaerobic bacteria and
protozoa
o Mupirocin: mixture of pseudomonic acids; inhibits isoleucine tRNA synthase in
bacteria leading to inhibited protein and RNA synthesis in most gram positive
aerobic bacteria, including MRSA
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 Stomatological preparations
• Aphthous stomatitis
o Recurrent ulceration may be related to inappropriate immunological
responses to stimulation by various oral antigens.
o Local trauma may play a significant role.
o Predisposing factors should be determined and eliminated but if no
correctable cause can be found, treatment relies on symptomatic
relief
• Antibacterial agents prevent secondary infection:
o Chlorhexidine or povidone-iodine: mouthwash may accelerate
healing or recurrent lesions
o Tetracycline: may be beneficial (100mg doxycycline dissolved in 25 mL
water, used to rinse mouth
o Should not be swallowed
o Repeated QID for three days
o Longer courses possible (risk of thrush)
o Contraindicated in children under 8 years)
 Stomatological preparations
• Corticosteroids decrease the duration and severity of lesions:
o Triamcinolone: formulated in sodium carboxymethylcellulose base for
local oral use – base has a mechanical protective effect
o Prednisone: PO in severe ulceration and oral vesculo-bullous
conditions
o Off-label: betamethasone tablets (0,5 mg in 15mL water) and solution
(5mg/mL in 200ml water; 10 mL TDS) as mouthwash;
beclomethasone/budesonide inhaler (50-100 μg BD) used topically
subsequent to systemic treatment for one week

• Topical analgesics relieves pain commonly associated with aphthous

stomatitis:
o Benzydamine: NSAID; has topical analgesic and local anti-
inflammatory effects. Combined with chlorhexidine to effectively
treat erosive, inflammatory and ulcerative conditions
o Local anaesthetics: benzocaine and lidocaine included in several
preparations; should be used sparingly (not under 2 years); avoid
pharynx anaesthesia before meals 24
 Stomatological preparations
• Sore throat
o Most commonly viral; palliative treatment
o If streptococcal infection cannot be excluded, systemic penicillin is indicated

• Thrush
o Local therapy with antifungals
o Nystatin or miconazole until after signs and symptoms have cleared

• Primary herpetic gingivostomatitis

o Often difficult to distinguish from aphthous stomatitis
o Palliative treatment; topical acyclovir for labial lesions; tetracycline
mouthwash may assist to prevent secondary infection

• Necrotizing ulcerating gingivitis

o Metronidazole and analgesics
o Oxygenating mouthwash may be of value; chlorhexidine mouthwash also
beneficial

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 Cutaneous reactions to topical preparations

Reaction type Mechanism Comment

Irritation Non-allergic Most common local reaction
Phototoxicity; usually requires UVA
Photoirritation Non-allergic
exposure
Allergic contact dermatitis Allergic Type IV delayed hypersensitivity
Type IV delayed hypersensitivity; usually
Photoallergic contact dermatitis Allergic
requires UVA exposure
IgE-mediated type I immediate
Immunologic contact urticaria Allergic hypersensitivity; may result in
anaphylaxis
Most common contact urticaria; occurs
Non-immunologic contact urticaria Non-allergic
without prior sensitization

*Refer to adverse drug reaction lecture for more information

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