Dermatologic Pharmacology

Dr. Alia Shatanawi

 Dermatologic Pharmacology
Variables affecting Pharmacologic Response:
• Regional variation in drug penetration
• Concentration gradient:
Increasing the concentration gradient increases the mass of
drug transferred per unit time
• Dosing schedule
• Vehicles and occlusion
Percutaneous Absorption.
 Dermatologic Formulations
• Tinctures
• Wet dressings
• Lotions
• Gels
• Powders
• Pastes
• Creams
• Ointments
Adverse Effects of Dermatologic Preparations

• Burning or stinging sensation

• Drying and irritation
• Pruritus
• Erythema
• Sensitization
• Staining
• Superficial erosion
 Topical Antibacterial Agents
• Bacitracin.
• Gramicidin.
– Gram-positive bacteria.
• Polymyxin B:
• Neomycin.
• Gentamicin.
– Gram-negative bacteria.
 Bacitracin

• Frequently used in combination with other

agents (polymyxin B and neomycin)
• Form: creams, ointments, and aerosol
preparations
• Usually Antiinflammatory agents added
– (Hydrocortisone)

– MOA??
MUPIROCIN
Mupirocin (pseudomonic acid A) is structurally unrelated
to other currently available topical antibacterial agents.
Most gram-positive aerobic bacteria, including
methicillin-resistant S aureus (MRSA), are sensitive to
mupirocin .

It is effective in the treatment of impetigo caused by S

aureus and group A β-hemolytic streptococci.
Intranasal mupirocin ointment for eliminating nasal
carriage of S aureus may be associated with irritation of
mucous membranes caused by the polyethylene glycol
vehicle.
Mupirocin is not appreciably absorbed systemically
after topical application to intact skin.
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RETAPAMULIN
Retapamulin is a semisynthetic pleromutilin derivative effective
in the treatment of uncomplicated superficial skin infection
caused by group A β-hemolytic streptococci and S aureus ,
excluding MRSA.

Topical retapamulin 1% ointment is indicated for use in adult

and pediatric patients, 9 months or older, for the treatment
of impetigo.

Recommended treatment regimen is twice-daily application for

5 days. Retapamulin is well tolerated with only occasional local
irritation of the treatment site..

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POLYMYXIN B SULFATE
Polymyxin B is a peptide antibiotic effective against gram-negative
organisms, including Pseudomonas aeruginosa, Escherichia coli ,
enterobacter, and klebsiella. Most strains of proteus and serratia
are resistant, as are all gram-positive organisms.

NEOMYCIN & GENTAMICIN

Neomycin and gentamicin are aminoglycoside antibiotics active agains
gram-negative organisms, including E coli , proteus, klebsiella,
and enterobacter.
Gentamicin generally shows greater activity against P aeruginosa than
neomycin. Gentamicin is also more active against staphylococci and
group A β-hemolytic streptococci.
Widespread topical use of gentamicin, especially in a hospital
environment, should be avoided to slow the appearance of gentamicin-
resistant organisms.

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 Topical Antibacterials in Acne

• Clindamycin
• Erythromycin
• Metronidazole
• Sodium sulfacetamide
 Clindamycin
• 10% absorbed, so, possibility of Pseudomembranous
colitis
• 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….. well
tolerated and less likely to cause irritation. Allergic
contact dermatitis is uncommon.
• Clindamycin is also available in fixed-combination
topical gels with benzoyl peroxide (Acanya,
BenzaClin, Duac), and with tretinoin (Ziana).
 Metronidazole
• Effective in the treatment of rosacea.
• The mechanism of action is unknown, but it may
relate to the inhibitory effects of metronidazole on
Demodex brevis; This drug may act as an anti-
inflammatory agent by direct effect on neutrophil
cellular function
• Adverse local effects include dryness, burning, and
stinging.
• Less drying formulations may be better tolerated
(MetroCream, MetroLotion, and Noritate cream).
• Caution should be exercised when applying
metronidazole near the eyes to avoid excessive
tearing.
 Metronidazole
• Metronidazole nitroimidazole antibiotic medication used
particularly for anaerobic bacteria and protozoa
• is selectively toxic for amebae and for anaerobic organisms
(including bacteria).
• Mechanism of action
Some anaerobic protozoan parasites (including amebae)
possess ferrodoxin-like electron transport proteins that
participate in metabolic electron removal reactions.

The nitro group of metronidazole is able to serve as an

electron acceptor, forming reduced cytotoxic compounds
that bind to proteins and DNA to result in cell death.
 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 (Benzamycin) for
topical treatment of acne vulgaris.
 Antifungal Chemotherapy

• Fungal infections are termed mycoses and can be

divided into:

(1) Superficial infections: affecting skin, nails, scalp

or mucous membranes
(2) Systemic infections: affecting deeper tissues and
organs.

• Superficial fungal infections can be classified into

the dermatomycoses and candidiasis.

• Dermatomycoses are infections of the skin, hair

and nails, caused by dermatophytes. The
commonest are due to Tinea organisms which
cause various forms of “ringworm”.
 Topical Antifungal Agents
• Azole Derivatives:
– Clotrimazole
– Econazole.
– Ketoconazole.
– Miconazole.
– Oxiconazole.
– Sulconazole.
• Activity against dermatophytes and yeasts, including
Candida albicans.
 Antifungal Chemotherapy

• In superficial candidiasis, the yeast-like organism

infects the mucous membranes of the mouth
(thrush), the vagina (vaginal thrush), or the skin
(penis).

• Systemic diseases (infections) include: systemic

candidiasis, cryptoccocal meningitis or
endocarditis, pulmonary aspergillosis.
 Azole Antifungal Agents

• The azole antifungal agents can be divided

into two broad classes : the Imidazoles and
the Triazoles.

• They share the same antifungal spectrum

and the same mechanism of action.

• They are used topically and systemically,

the Triazoles being less toxic and are thus
the more widely prescribed.
 Azole Antifungal Agents
• Inhibit fungal sterol 14-a-
demethylase

• Impair the biosynthesis of

the ergosterol

• Ergosterol is required for the

fungal cytoplasmic
membrane.

• This leads to cessation of

growth.
The Azole Family
Azole Family

Imidazoles Triazoles

Ketoconazole Fluconazole
Miconazole Itraconazole
Clotrimazole Voriconazole
 Topical Azoles

• Clotrimazole and Miconazole are used topically.

• Indications for the topical azoles include ringworm,

tinea versicolor and mucocutaneous candidiasis.

• Miconazole is a potent inhibitor

of warfarin metabolism
( even topical application)
 Other topical Antifungal Agents
• Ciclopirox Olamine: Tinea versicolor
• Naftifine and Terbinafine: tinea pedis, tinea
cruris, and tinea corporis
• Tolnaftate
• Nystatin and Amphotericin B:
– Only for Candida albicans.
– Available as topical preparations, oral suspension,
or vaginal tablets
 Antifungal Antibiotics

• Amphotericin and Nystatin are polyene macrolide

antibiotics that function by binding to fungal
cytoplasmic membranes.

• Thus, they interfere with membrane permeability

and transport functions.

• One significant outcome is the loss of cellular K+.

• The polyene macrolides are very poorly absorbed

orally and they are reluctant to pass through
mucous membranes.
 Polyene Antifungals:
Amphotericine B & Nystatin
• Mechanism of action: Polyene antifungal drugs bind to
the fungal cell membrane component ergosterol,
leading to increased fungal cell membrane permeability
and the loss of intracellular constituents.

Cell membrane

Yeast cell cytoplasm

 Amphotericin B
• A polyene antifungal drug produced by the actinomycete
Streptomyces.
• Amphotericin has a lesser affinity for the mammalian
cell membrane component cholesterol, but this
interaction does account for most adverse toxic effects
associated with this drug.
• Amphotericin B is most commonly used to treat serious
disseminated yeast and dimorphic fungal infections in
immuno-compromised hospitalized patients.
• Amphoteracin B can be given IV
 Amphotericin B
• Side effects:
– Fever, chills, and tachypnea commonly occur shortly after the
initial intravenous doses of amphotericin B
– Other side effects include anaemia, hypokalaemia, liver
damage, thrombocytopenia and anaphylatic reactions.
– In short, its a very toxic drug.

• Main toxicity of Amphotericin is renal.

• 80% of patients get reduction in kidney function which
generally recovers after treatment.

• Nephrotoxicity is the most common and the most serious long-

term toxicity of amphotericin B administration
 Nystatin

•Nystatin is limited to the topical treatment of

superficial infections caused by C. albicans.

•Infections commonly treated by this drug include

oral candidiasis (thrush), mild esophageal
candidiasis and vaginitis.

•Too toxic for systemic use

 Oral Antifungal Agents
• Azole Derivatives:
– Fluconazole.
– Itraconazole.
– Ketoconazole.
• Affect the permeability of fungal cell membrane
through alteration of sterol synthesis.
• Effective in systemic mycosis, mucocutaneous
candidiasis, and other cutaneous infections.
• Might have systemic side effects: hepatitis and liver
enzyme elevations, and interactions.
 Oral Antifungal Agents
• Azole Derivatives.
• Griseofulvin:
– Effective against epidermophyton, microsporum, and
trichophton.
– Requires prolonged treatment:
• 4-6 weeks for the scalp.
• 6 months for fingernails.
• 8-18 months for toenails.
• Has many side effects.
• Terbinafine:
– Recommended for onchomycosis (ringworm of the nail)
• 6 weeks for fingernails.
• 12 weeks for toenails.
 Topical Antiviral Agents
• Acyclovir.
• Valacyclovir.
• Penciclovir.
• Famciclovir.
– Synthetic guanine analogs with inhibitory activity
against herpes viruses.
– Ointments and creams are useful for recurrent
orolabial herpes simplex infection
 Immunomodulators
• Imiquimod:
– For external genital and perianal warts. (condyloma
acuminatum)
– Actinic keratosis on the face and scalp.
– Primary basal cell carcinoma.
– Stimulates peripheral mononuclear cells to release
interferon- ά and to stimulate macrophages to
produce interleukins-1,-6, and -8 and tumor necrosis
factor-ά.
• Tacrolimus.
• Pimecrolimus.
– Useful for atopic dermatitis.
– Inhibit T-lymphocyte activation and prevent release
of inflammatory cytokines and mast cell mediators
 Ectoparasiticides
• Permethrin:
– Toxic to Pediculus humanus, Pthirus pubis, and Sarcoptes
scabiei
– Pediculosis:cream applied for 10 minutes and then rinsed
off with warm water.
– Scabies: cream applied for the whole body for 8-14 hours.
• Lindane (Hexachlorocyclohexane):
– 10% absorbed and concentrated in fatty tissues.
– Can cause neurotoxicity and hematoxicity
• Crotamiton: drug that is used both as a scabicidal (for
treating scabies) and as a general antipruritic
• Sulfur.
• Malathion.
 Agents affecting Pigmentation
• Hydroquinone: topical application skin whitening to reduce
the color of skin
• Monobenzone
Monobenzone may be toxic to melanocytes resulting in
permanent depigmentation.
• Mequinol
– Topical hydroquinone and mequinol usually result in
temporary lightening.
• Reduce hyperpigmentation of skin by inhibiting the
enzyme tyrosinase which will interfere with
biosynthesis of melanin
 Agents affecting Pigmentation
• Trioxsalen.
• Methoxsalen.
– Are psoralens used for the repigmentation of
depigmented macules of vitiligo.
– Must be photoactivated by long-wave-length
ultraviolet light (320-400nm) to produce a
beneficial effect.
– They intercalate with DNA.
– Can cause cataract and skin cancer.
 Sunscreens and Sunshades
• Sunscreens absorb UV light.
– Examples are para amino benzoic acid
(PABA) and its esters.
• Sunshades are opaque materials that
reflect light, like titanium dioxide.
• Useful in polymorphous light eruption,
lupus erythematosus, and drug –induced
photosensitivity.
 Acne Preparations

• Retinoic Acid and Derivatives:

– Retinoic Acid.
– Adapalene.
– Tazarotene.
 Acne Preparations
• Retinoic Acid and Derivatives:
– Retinoic Acid( Tretinoin): is the acid form of Vitamin A.
Stabilizes lysosomes, increases RNA polymerase activity,
increases PGE2, cAMP, and cGMP levels, and increases the
incorporation of thymidine into DNA.
– Decreases cohesion between epidermal cells and
increases epidermal cell turnover. This will result in
expulsion of open comedones and the transformation of
closed comedones into open ones.
– Also, promotes dermal collagen synthesis, new blood
vessel formation, and thickening of the epidermis, which
helps diminish fine lines and wrinkles.
– Can cause erythema and dryness.
– Tumerogenic in animals
 Acne Preparations
• Isotretinoin( Accutane):
– Restricted for severe cystic acne resistant to
standard treatment.
– Inhibits sebaceous gland size and function.
– Given orally: 1–2 mg/kg, given in two divided doses
daily for 4–5 months
– Toxic: dryness, itching, headache, corneal
opacities, pseudotumor cerebri, inflammatory
bowel disease, anorexia, alopecia, and muscle
and joint pains. Also lipid abnormalities.
– Teratogenicity
 Acne Preparations
• Benzoyl Peroxide:
– Penetrates the stratum corneum or follicular
openings and converted to benzoic acid within
the epidermis and dermis.
– Has antimicrobial activity against P. acnes and
peeling and comedolytic effects.
– Can be combined with erythromycin or
clindamycin.
– Can cause bleaching of hair or colored fabrics.
• Azelaic Acid:
– Has antimicrobial activity.
 Drugs for Psoriasis
• Acitretin:
– Related to isotretinoin.
– Given orally.
– Hepatotoxic and teratogenic.
– Patients should not become pregnant for 3
years after stopping treatment, and also
should not donate blood.
 Drugs for Psoriasis

• Tazarotene:
– Topical.
– Anti-inflammatory and antiproliferative
actions.
– Teratogenic. Also, can cause burning,
stinging, peeling, erythema, and localized
edema of skin.
• Calcipotiene:
– Synthetic vitamin D3 derivative
 Drugs for Psoriasis
• Biologic Agents:
– Alefacept:
• Immunosuppressive dimer fusion protein of
CD2 linked to the Fc portion of human IgG1.
– Efalizumab:
• Recombinant humanized IgG1 monoclonal
antibody.
• Withdrawn :progressive multifocal
leukoencephalopathy (PML),
• Can cause thrombocytopenia.
– Etanercept:
• Dimeric fusion protein of TNF receptor linked
to the Fc portion of human IgG1.
 Anti-inflammatory Agents
• Topical Corticosteroids:
– Hydrocortisone.
– Prednisolone and Methylprednisolone.
– Dexamethasone and Betamethasone.
– Triamcinolone.
– Fluocinonide.
 Anti-inflammatory Agents
• Topical Cortcosteroids:
– Dermatologic disorders very responsive to
steroids:
• Atopic dermatitis.
• Seborrheic dermatitis.
• Lichen simplex chronicus.
• Pruritus ani.
• Allergic contact dermatitis.
• Eczematous dermatitis.
• Psoriasis
 Anti-inflammatory Agents
• Topical Cortcosteroids:
– Adverse Effects:
• Suppression of pituitary-adrenal axis.
• Systemic effects.
• Skin atrophy.
• Erythema.
• Pustules.
• Acne.
• Infections.
• Hypopigmentation.
• Allergic contact dermatitis.
 Anti-inflammatory Agents
• Topical Cortcosteroids.
• Tar compounds:
– Mainly for psoriasis, dermatitis, and lichen
simplex chronicus
– Can cause irritant folliculitis, phototoxicity,
and allergic contact dermatitis.
 Keratolytic and Destructive Agents
• Salicylic acid:
– Solubilizes cell surface proteins resulting in
desquamation of keratotic debris.
– Keratolytic in 3-6% concentration, but
destructive in higher concentrations.
– Locally, can cause urticaria, anaphylactic
and erythema multiforme reactions,
irritation, inflammation, and ulceration.
 Keratolytic and Destructive Agents

• Propylene Glycole:
– Usually used as a vehicle for organic compounds.
– Used alone as a keratolytic agent in
concentrations of 40%- 70%, with plastic
occlusion, or in gel with 6% salicylic acid.
– Minimally absorbed, oxidized in liver to lactic acid
and pyruvic acid.
– Develops an osmotic gradient through the stratum
corneum, thereby increasing hydration of the
outer layers of skin.
 Keratolytic and Destructive Agents

• 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.
– Decreases the unpleasant oily feel of
dermatologic preparations.
– When absorbed, it is excreted in urine.
 Keratolytic and Destructive Agents
• Flurouracil:
– Antimetabolite that resembles uracil and inhibits
thymidylate synthetase, thus interferes with DNA
and may be RNA synthesis.
– Used in multiple actinic keratosis.
 Keratolytic and Destructive Agents
• Nonsteroidal Anti-inflammatory Drugs:
– 3% gel formulation diclofenac.

• Aminolevulinic Acid:
– Used in actinic keratosis.
– After topical application(20%) and exposure to
light, produces a cytotoxic superoxide and
hydroxyl radicals
 Antipruritic Agents
• Doxepine:
– Potent H1 and H2 – receptor antagonist.
– Can cause drowsiness and anticholinergic
effects.
• Pramoxine:
– Is a topical local anesthetic agent.
Trichogenic and Antitrichogenic Agents
• Minoxidil (Rogaine):
– Designed as an antihypertensive agent.
– Effective in reversing the progressive
miniaturization of terminal scalp hairs associated
with androgenic alopecia.
– Vertex balding is more responsive than frontal
balding.
Trichogenic and Antitrichogenic Agents
• Minoxidil.
• Finasteride (Propecia):
– 5ά-reductase inhibitor which blocks the
conversion of testosterone to dihydrotestosterne.
– Oral tablets.
– Can cause decreased libido, ejaculation disorders,
and erectile dysfunction.
Trichogenic and Antitrichogenic Agents
• Minoxidil.
• Finasteride.
• Eflornithine:
– Is an irreversible inhibitor of ornithine
decarboxylase, therefore, inhibits polyamine
synthesis. Polyamines are important in cell
division and hair growth.
– Effective in reducing facial hair growth in 30% of
women when used for 6 months.
 Drugs for Leishmania
Caused by three Leishmania species:
L.tropica causes: Cutaneous leishmaniasis or
oriental sore.
L. brazeliensis causes: Mucocutaneous
leishmaniasis.
L. Donovani causes: Visceral leishmaniasis
 Sodium Stibogluconate
Pentravalent antimonial
Binds to SH groups on proteins.
Typical preparations contain 30% to 34% pentavalent
antimony by weight as well as m-chlorocresol added
as a preservative.
Also, inhibits phosphofructokinase
Local, IM or slow IV, irritant.
Given for 20-28 days.
Drug of choice for all forms of leishmaniasis.
Resistance is increasing, especially in India.
Cough, V, D, myalgia, arthralgia, ECG changes, Rash,
Pruritus.
 Amphotericin
• Antifungal agent, difficult to use, and
toxic.
• Alternative therapy for visceral
leishmaniasis, especially in areas with
high resistance.
 Miltefosine
• For visceral leishmaniasis.
• Given orally, for 28 days.
• Causes V & D, hepatotoxicity,
nephrotoxicity, and it is teratogenic.
 Pentamidine
• Inhibits DNA replication.
• Also, DHF reductase inhibitor

• Given IM or IV injection and Inhalation

• Binds avidly to tissues, not the CNS.
 Pentamidine
Leishmaniasis:
Alternative to Na stibogluconate

Pneumocystis jiroveci:
Treatment and prophylaxis of patients who
cannot tolerate or fail other drugs.

Trypanosomiasis:
For early hemolymphatic stage.
 Pentamidine
• Adverse Effects:
• Rapid Infusion: Hypotension, tachycardia,
dizziness.
• Pain at the injection site.
• Others: Pancreatic, Renal, and Hepatic
toxicity.
 Antilepromatous Drugs
• Dapsone and Sulphones:
– Related to sulphonamides.
– Inhibit folate synthesis.
– Resistance develops.
– Combined with Rifampin and Clofazimine.
– Also used for Pn. Jeroveci in AIDS patients.
– Well absorbed and distributed.
– Retained in the skin, muscle, liver and kidney.
 Antilepromatous Drugs
• Dapsone and Sulphones:
– Hemolysis, particularly in G-6-PD
deficiency.
– GIT intolerance
– Fever, Pruritus, Rashes.
– Erythema Nodosum Leprosum:
suppressed by steroids or
thalidomide.
 Antilepromatous Drugs
• Rifampin:
– Discussed with antituberculous drugs.
• Clofazimine:
– Binds to DNA.
– Stored widely in RES and skin.
– Released slowly from storage sites, t1/2 = 2
months.
– Given for sulphone- resistant or intolerant cases.
– Causes skin discoloration (red-brown to black)
and
GIT intolerance.