Transcript Adverse Local effects of Topical Corticosteroids

In the Name of Allah,
the Beneficent,
the Merciful
Dr. Azam Bakhtiarian
Dept. of Pharmacology,
School of Medicine,
Tehran University of Medical Sciences
 Dermatologic Pharmacology
 The skin offers a number of special opportunities
to the therapist. For example, the topical route of
administration is especially appropriate for
diseases of the skin, though some dermatologic
diseases respond as well or better to drugs
administered systemically.
Major variables that determine
pharmacologic response to drugs
 (1) Regional variation in drug penetration:
Face and scalp are more permeable than the
forearm (require less drug).
 (2) Concentration gradient: Increasing the
conc. gradient increases the mass of drug
transferred per unit time, Thus, resistance to
topical corticosteroids can sometimes be
overcome by use of higher Conc. of drug.
Major variables that determine
pharmacologic response to drugs
 (3) Dosing schedule: The skin acts as a reservoir for
many drugs. As a result, the "local half-life" may be
long enough to permit once-daily application of
drugs with short systemic half-lives. Corticosteroids
 (4) Vehicles and occlusion: An appropriate vehicle
maximizes the ability of the drug to penetrate the
outer layers of the skin.
 Occlusion (application of a plastic wrap to hold the
drug and its vehicle in close contact with the skin) is
extremely effective in maximizing efficacy.
Treatment of Acne
Acne Preparations
 Retinoids: Tretinoin, Adapalene,
Tazarotene, Isotretinoin
 Non- Retinoids: Azelaic acid, Benzoyl
Peroxide,
Antibiotics:
 Topical: Clindamycin, Erythromycin
 Oral: Co-trimoxazole, Erythromycin
Retinoic Acid
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Known as tretinoin
Is the acid form of vitamin A.
Treatment of acne vulgaris.
Decreased cohesion between epidermal
cells and increased epidermal cell turnover.
 Metabolized by the liver
 Excreted in bile and urine.
Retinoic acid
 May induce slight erythema with mild
peeling. (lower Conc. & frequency )
 A timed-release formulation of tretinoin
containing microspheres (Retin-A Micro)
delivers the medication over time.
Retinoic acid
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Prolonged use of tretinoin cream:
Promotes dermal collagen synthesis
New blood vessel formation
Thickening of the epidermis, which helps
diminish fine lines and wrinkles.
Adverse Effects of Retinoic acid
 Erythema and dryness that occur.
 Animal studies : increase the tumorigenic
potential of UV radiation.
 PT should be advised to avoid or minimize
sun exposure and use a sunscreen.
Adapalene (Differin)
 Resembles retinoic acid in structure and
effects.
 Apply 0.1% gel once daily
 less irritating than tretinoin and is most
effective in patients with mild to moderate
acne vulgaris.
Isotretinoin (Accutane)
 Is a synthetic retinoid (oral)
 Restricted to the treatment of severe cystic acne.
 Act by inhibiting sebaceous gland size and
function.
 Well absorbed.
 Bound to plasma albumin.
 T1/2 of 10–20 hours.
Adverse Effects of Isotretinoin
(Accutane)
 resemble hypervitaminosis A
 dryness and itching of the skin and mucous
membranes.
 Less common: headache, corneal opacities,
 IBD, anorexia, alopecia
 muscle and joint pains. ( all reversible)
 Lipid abnormalities (TG)
 Teratogenicity is a significant risk.
Benzoyl Peroxide
 Treatment of acne vulgaris.
 Is converted metabolically to benzoic acid
within the epidermis and dermis.
 Mechanism of action: is related to its
antimicrobial activity against P acnes and to
its peeling.
Benzoyl Peroxide
 Care should be taken to avoid contact with
the eyes and mucous membranes.
 Benzoyl peroxide is an oxidant and may
rarely cause bleaching of the hair or colored
fabrics.
Azelaic acid (Azelex)
 Treatment of acne vulgaris. (cream)
 Its mechanism of action: antimicrobial
activity against P acnes as well as an in vitro
inhibitory effect on the conversion of
testosterone to dihydrotestosterone.
Azelaic acid Side Effects
 Mild irritation with redness and dryness
 Clinical improvement is noted in 6–8 weeks.
Topical Antibiotics in Acne
 Four antibiotics are so utilized:
 clindamycin phosphate, erythromycin,
metronidazole, and sulfacetamide.
 The effectiveness of topical therapy is less
than that achieved by systemic.
 Therefore, topical therapy is generally
suitable in mild to moderate cases of acne.
Clindamycin
 in vitro activity against Propioni bacterium
acnes
 10% of dose is absorbed, and rare cases of
bloody diarrhea and colitis (topical).
 Allergic contact dermatitis is uncommon.
Erythromycin
 Treatment of acne vulgaris due to its
inhibitory effects on P acnes.
 Development of antibiotic-resistant strains of
organisms, including staphylococci.
 If this occurs, topical erythromycin should be
discontinued.
Adverse local reactions
to Erythromycin
 Burning sensation at the time of application
and drying and irritation of the skin.
 The topical water-based gel is less drying
and may be better-tolerated.
Topical metronidazole
 Treatment of acne rosacea.
 Act as an anti-inflammatory agent by direct
effect on neutrophil cellular function.
 Carcinogen in susceptible rodent species.
 Topical use during pregnancy and by
nursing mothers and children is not
recommended.
Adverse local effects of
metronidazole
 The water-based gel formulation (MetroGel)
cause dryness, burning, and stinging.
 Less drying formulations may be bettertolerated (MetroCream, MetroLotion).
Sodium Sulfacetamide
 Treatment of acne vulgaris and rosacea.
 The mechanism of action is thought to be
due to inhibition of P acnes .
 4% of topically applied is absorbed, and its
use is contraindicated in patients having a
known hypersensitivity to sulfonamides.
Treatment of Psoriasis
Treatment of Psoriasis
1)Retinoids: Acitretin, Tazarotene
2)Glucocorticoids: Bethamethazone,
triamcinolone
3)Vitamin D3 derivative: Calcipotriene
4)Monoclonal Antibody: Alefacept,
efalizumab, Etanercept, infliximab
5)Psoralens: Trioxsalen and Methoxsalen
Acitretin (Soriatane)
 a metabolite of the aromatic retinoid
etretinate
 treatment of psoriasis
 It is given orally at a dosage of 25–50 mg/d.
Adverse effects of Acitretin
 Similar to those seen with isotretinoin and
resemble hypervitaminosis A.
 Elevations in cholesterol and triglycerides
 Hepatotoxicity with liver enzyme elevations
 Acitretin is more teratogenic than
isotretinoin.
Acitretin
 Acitretin must not be used by women who
are pregnant .
 Patients must not donate blood during
treatment and for 3 years after acitretin is
stopped.
Tazarotene (Tazorac)
 Is an acetylenic retinoid prodrug. (cream)
 Treatment of psoriasis
 By its anti-inflammatory and antiproliferative
actions.
Tazarotene
 Teratogenic systemic conc. if applied to
more than 20% of total body surface area.
 Treatment of psoriasis should be limited to
once-daily application.
Adverse local effects of Tazarotene
 A burning or stinging sensation
 peeling, erythema, and localized edema of
the skin (irritant dermatitis).
 PTs use sunscreens and protective clothing.
Corticosteroids
 The anti-inflammatory activity
 The antimitotic effects in psoriasis
 Triamcinolone, betamethasone and
flucinolone( ointment)
Adverse Local effects of Topical
Corticosteroids
 Local atrophy
 Shiny, often wrinkled “cigarette paper”
appearing skin
 Erythema
Calcipotriene (Dovonex)
 Is a synthetic vitamin D3 derivative
 Binds vit. D receptor, inhibit prolif.
 The treatment of psoriasis of moderate
severity. (ointment 0.005%).
 Elevation of serum calcium in fewer than 1%
Adverse Effects of Calcipotriene
 burning, itching, and mild irritation,
 with dryness and erythema of the treatment
area.
Alefacept
 Immunosuppressive agent (IV)
 Interferes with lymphocyte activation which
plays a role in the psoriasis
 Reduction in subsets of CD2 , CD4 and
CD8 T lymphocyte counts.
 Treatment of adult patients with moderate
to severe chronic plaque psoriasis.
Alefacept
 Discontinue if the CD4 counts are reduced.
 Should not be administered to patients with
a history of systemic malignancy.
Efalizumab
 is an immunosuppressive
 interferes with lymphocyte activation, which
plays a role in the psoriasis,
 Binds to CD11
 0.7 mg/kg S.C.
 Monitor Platelet counts
TNF Inhibitors: (Etanercept)
 Binds to TNF ( alpha& beta)
 interferes with inflammation Process, which
plays a role in the psoriasis.
 50 mg S.C., twice weekly for 3 months
TNF Inhibitors: (Infliximab)
 Monoclonal antibody
 Binds TNF alpha
 5 mg/kg IV
TNF Inhibitors: (Adalimumab)
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Monoclonal antibody
Binds TNF alpha
Inhibits its binding to TNF alpha receptor
80 mg S.C. followed by 40 mg every other
week.
TNF Inhibitors Side Effects
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Serious life-threatening infections:
Sepsis
Pneumonia
Concurrent use with other
immunosuppressive therapy should be
avoided.
Trioxsalen and Methoxsalen
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are psoralens used for the psoriasis (oral)
Must be photoactivated (UVA)
photo-chemotherapy with oral methoxsalen
inhibit DNA synthesis.
Topical Antiviral Agents
 Acyclovir, valacyclovir, penciclovir, and
famciclovir are synthetic guanine analogs
with inhibitory HSV 1,2.
 interferes with herpesvirus DNA polymerase
and viral DNA replication.
Topical Antiviral Agents
 Acyclovir ointment for application to primary
cutaneous HSV and to limited
mucocutaneous HSV in
immunocompromised patients.
 Topical penciclovir,1% cream for the
treatment of recurrent orolabial.
Immunomodulators
 Imiquimod for the treatment of external genital &
perianal warts.
 Stimulate peripheral mononuclear cells to release
INF & to stimulate macrophages to produce
interleukins-1, -6, -8, and TNF.
 applied to the wart tissue 3 times per week and left
on the skin for 6–10 hours prior to washing off with
mild soap and water.
Adverse side effects of Imiquimod
 Inflammatory reactions
 pruritus
 erythema
Immunosuppressants
 Tacrolimus and pimecrolimus
 Treatment of atopic dermatitis
 Inhibit T lymphocyte activation
 Prevent the release of cytokines
Tacrolimus & pimecrolimus
Side Effect
 Burning sensation in the applied area that
improves with continued use.
 Tacrolimus 0.03% ointment and
pimecrolimus 1% cream are approved for
use in children over 2 years of age, (twice
daily).
 Agents Affecting Pigmentation
Agents Affecting Pigmentation
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Hydroquinone , Monobenzone
To reduce hyperpigmentation of the skin.
Hydroquinone results in lightening of skin.
Monobenzone causes irreversible
depigmentation.
 The mechanism : inhibition of tyrosinase,
thus interfering with the biosynthesis of
melanin.
Hydroquinone and Monobenzone
Side Effects
 Both may cause local irritation.
 Allergic sensitization to these compounds
does occur.
 Combination of hydroquinone, fluocinolone
and retinoic acid (Tri-Luma) is more
effective than hydroquinone alone.
Trioxsalen and Methoxsalen
 are psoralens used for the repigmentation of
vitiligo.
 Psoralens must be photoactivated (UVA)
 Oral Trioxsalen for the vitiligo.
 inhibit DNA synthesis.
Trioxsalen and Methoxsalen Side
Effects
The major long-term risks of
 cataracts
 skin cancer
Sunscreens
 Chemical compounds that absorb UV light, called
sunscreens.
 or opaque materials such as titanium dioxide that reflect
light, sunshades.
 PABA and its esters, the benzophenones &
dibenzoylmethanes.
 Most sunscreen absorb UV B (280 to 320 nm)
 which is the range responsible for most of the erythema
and tanning.
 Chronic exposure to light in this range induces aging of the
skin and photocarcinogenesis.
Sunscreens
 PABA absorbs UVB
 The benzophenones include oxybenzone,
dioxybenzone, and sulisobenzone.
 A broader spectrum of absorption from 250
to 360 nm, but their effectiveness in the
UVB is less.
Dibenzoylmethane
 Parasol and Eusolex absorb UVA, (320- 400
nm), superior photoprotection.
 Use in patients sensitive to UVA:
 Such as cutaneous lupus and drug-induced
photosensitivity.
The protection factor
 The protection factor (PF) of a given sunscreen is
a measure of its effectiveness in absorbing
erythrogenic UV.
 The ratio of the minimal erythema dose with
sunscreen to the minimal erythema dose without
sunscreen is the protection factor.
 Fair skinned who sunburn easily are advised to
use a product with a SPF of 15 or greater.
Keratolytic & Destructive Agents
 Salicylic Acid
 Propylene Glycol
 Urea
Keratolytic & Destructive Agents
Salicylic Acid
 may solubilize cell surface proteins that
keep the stratum corneum
 Keratolytic in conc. of 3–6%.
 greater than 6%, it can be destructive to
tissues.
Salicylism
 Salicylism and death have occurred
following topical application.
 hemodialysis is the treatment of choice.
 The threshold for toxicity is 30–50 mg/dL.
Allergic Reactions to Salicylates
 Urticarial, anaphylactic, and erythema may
occur in patients allergic to salicylates.
 Topical use may cause local irritation, acute
inflammation, and even ulceration.
Propylene Glycol
 keratolytic agent
 oxidized by the liver to lactic acid and
pyruvic acid.
 excreted unchanged in the urine.
 Used with 6% salicylic acid for the treatment
of keratodermas and psoriasis.
Urea
 keratolytic agent
 has a softening and moisturizing effect on
the stratum corneum.
 Increases the water content of the stratum
corneum.
How Alopecia treated?
 Minoxidil
 Finasteride (Propecia)
Minoxidil
 Reversing the miniaturization of terminal
scalp hairs associated with androgenic
alopecia.
 Cessation of treatment will lead to hair loss
in 4–6 months.
 Possible systemic effects on BP
Finasteride (Propecia)
 is a 5a-reductase inhibitor that blocks the
conversion of testosterone to
dihydrotestosterone.
 The androgen responsible for androgenic
alopecia.
 Oral 1 mg/d, promotes hair growth and
prevents further hair loss
Finasteride Side Effects
 Decreased libido
 Ejaculation disorders
 Erectile dysfunction
How hirsutism treated?
 Eflornithine (Vaniqa)
 Mechanical hair removal : Shaving,
plucking, waxing, electrolysis, laser hair
removal
Eflornithine (Vaniqa)
 irreversible inhibitor of ornithine
decarboxylase
 Reducing facial hair growth
 When applied twice daily for 6 months
 Local adverse effects: stinging, burning
PAYAN
Podophyllum Resin & Podofilox
 an alcoholic extract, commonly known as
mandrake root or May apple,
 Treatment of verrucae.
 Active cytotoxic agents with specific affinity
for the microtubule protein of the mitotic
spindle.
Podophyllum Resin & Podofilox
Toxicity
 Nausea, vomiting,
 Muscle weakness, neuropathy with
diminished tendon reflexes, coma, and even
death.
 Contraindicated in pregnancy due to
cytotoxic effects on the fetus.
Fluorouracil
 is a fluorinated pyrimidine antimetabolite
 treatment of multiple actinic keratoses.
 inhibits thymidylate synthetase activity,
interfering with the synthesis of
deoxyribonucleic acid and to a lesser extent
ribonucleic acid.
Local Adverse Reactions of
Fluorouracil
 Pain, pruritus, a burning sensation,
 Hyperpigmentation.
 Contraindicated in patients with known
hypersensitivity.
Antipruritic Agents
Doxepin
 Treatment of pruritus associated with atopic
dermatitis( cream)
 The potent H1 and H2-receptor antagonist
 Drug interactions associated with TCA
 Adverse local effects: burning and stinging
Pramoxine
 A topical anesthetic
 Relief pruritus associated with mild
eczematous dermatoses.
 In combination with hydrocortisone acetate.
 Local adverse effects include transient
burning and stinging.
Non FDA-Approved Drugs in
Treating Hirsutism
 Spironolactone: aldosterone antagonist
and potassium-sparing diuretic competitively
binds DHT receptors, ↓ ovarian androgen
production, and inhibits 5α-reductase.
 Flutamide: Nonsteroidal antiandrogen,
Competitive inhibition at the DHT receptor
(primary) and suppresses adrenal androgen
production.
Non FDA-Approved Drugs in
Treating Hirsutism
 Finasteride: 5α- reductase inhibitor also
used in the treatment male pattern
baldness. Blocks peripheral conversion of
testosterone to DHT.
 Cyproterone: Progestogen derivative of 17OHP used alone or in OCPs. It also inhibits
testosterone and DHT.
 Metformin
Alopecia
1. Androgenic Alopecia
2. Alopecia Areata is a hair loss condition
characterized by the rapid onset of hair
loss in a sharply defined area.
(autoimmune)
 autoimmune factor causing the patient to
develop antibodies to different hair follicle
structures.
Antineoplastic Agents
Alitretinoin (Panretin)
 is a topical formulation of 9-cis-retinoic acid
 treatment of cutaneous lesions in patients
with AIDS-related Kaposi's sarcoma.
 Localized reactions: erythema, edema
Bexarotene (Targretin)
 Member of a subclass of retinoids
 Treatment of cutaneous T cell lymphoma.
 Teratogenicity is a significant risk for both
systemic and topical treatment .
Antiseborrhea Agents
 Treatment of seborrheic dermatitis.
 These are of variable efficacy and may necessitate
concomitant treatment with topical corticosteroids for sever
cases.
 Betamethasone valerate foam (Luxiq)
 Chloroxine shampoo (Capitrol)
 Coal tar shampoo (Ionil-T, Pentrax, Theraplex-T, T-Gel)
 Fluocinolone acetonide shampoo (FS Shampoo)
 Ketoconazole shampoo (Nizoral)
 Selenium sulfide shampoo (Selsun, Exsel)
 Zinc pyrithione shampoo (DHS-Zinc, Theraplex-Z)
Topical Antibacterial Preparations
 Bacitracin and gramicidin are peptide
antibiotics, active G+ such as streptococci,
pneumococci, and staphylococci.
 In addition, most anaerobic cocci,
neisseriae, tetanus bacilli, and diphtheria
bacilli are sensitive.
 Bacitracin is compounded in an ointment
base alone or in combination with neomycin,
polymyxin B, or both.
Bacitracin
 Microbial resistance may develop following
prolonged use.
 Bacitracin-induced contact urticaria
syndrome, including anaphylaxis, occurs
rarely.
 Allergic contact dermatitis occurs frequently.
 Bacitracin is poorly absorbed through the
skin, so systemic toxicity is rare.
Gramicidin
 Gramicidin is available only for topical use,
in combination with other antibiotics such as
neomycin, polymyxin, bacitracin, and
nystatin.
 Systemic toxicity limits this drug to topical
use.
Mupirocin (pseudomonic acid A)
 Most G+ aerobic bacteria, including
methicillin-resistant S aureus
 In the treatment of impetigo caused by S
aureus and group A beta-hemolytic
streptococci.
Polymyxin B
 is a peptide antibiotic against G- :
Pseudomonas aeruginosa, E-coli,
enterobacter, and klebsiella.
 Topical application, daily dose applied to
denuded skin or open wounds should not
exceed 200 mg to reduce neurotoxicity &
nephrotoxicity.
Neomycin & Gentamicin
 Active against G- : E coli, proteus, klebsiella, and
enterobacter.
 Gentamicin shows greater activity against P aeruginosa
than neomycin. Gentamicin is also more active against
staphylococci and group A beta-hemolytic streptococci.
 Neomycin alone and in combination with polymyxin,
bacitracin and as a sterile powder for topical use.
 Gentamicin is available as an ointment or cream.
Neomycin & Gentamicin
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Both drugs are water-soluble and are excreted primarily
in the urine. Renal failure may permit the accumulation of
these antibiotics, with possible nephrotoxicity,
neurotoxicity, and ototoxicity.
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Neomycin frequently causes sensitization, particularly if
applied to eczematous dermatoses .
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When sensitization occurs, cross-sensitivity to
streptomycin, kanamycin, paromomycin, and gentamicin
is possible.
Ectoparasiticides
 Lindane (Hexachlorocyclohexane) an
effective pediculicide and scabicide.
 Percutaneous absorption 10%& excreted in
the urine.
 T1/2 of 24 hours.
 After absorption, It is concentrated in fatty
tissues, including the brain.
 Lindane (Kwell) is available as a shampoo
or lotion.
Lindane
 Single application to the entire body from the neck
down, left on for 8–12 hours, and then washed off.
 Concerns about neurotoxicity and hematotoxicity
have resulted in warnings that lindane should be
used with caution in infants, children, and
pregnant women.
 not be used as a scabicide in premature infants
and in patients with known seizure disorders.
Ectoparasiticides : Crotamiton
 is a scabicide with some antipruritic
properties.
 Cream or lotion.
 for two applications to the entire body from
the chin down at 24-hour intervals.
 alternative to lindane.
Crotamiton Side Effects
 Allergic contact hypersensitivity
 primary irritation
 discontinue the therapy
Ectoparasiticides : Sulfur
 has a long history of use as a scabicide.
 an unpleasant odor, is staining.
 alternative drug for use in infants & pregnant
women.
 The usual formulation is 5% precipitated
sulfur in Vaseline.
Ectoparasiticides : Permethrin
 is neurotoxic to Pediculus humanus, Pthirus
pubis, and Sarcoptes scabiei. Less than 2%
 1% cream for pediculosis .
 For the treatment of scabies, a single
application of 5% cream (Elimite).
Adverse reactions of Permethrin
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Transient burning
Stinging
Pruritus
Cross-sensitization to pyrethrins
Ectoparasiticides : Malathion
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is an organophosphate CHE inhibitor
in treating pediculosis
Malathion is available as a 0.5% lotion
should be applied to the hair when dry and
the hair then combed to remove lice after 4–
6 hours.