3. • CASE STUDY
• A 43-year-old woman presents with a complaint of worsening
rosacea. She initially responded to once-daily
topical metronidazole 0.75% gel with excellent clearing of the
papulopustular component of her acne rosacea. Recently, she has
noted increasing persistent facial erythema. What therapeutic
options are available?
4. • Diseases of the skin offer special opportunities to the clinician.
• In particular, the topical administration route is especially
appropriate for skin diseases, although some dermatologic
diseases respond as well or better to drugs administered
systemically.
5. • The general pharmacokinetic principles governing the use of drugs
applied to the skin are the same as those involved in other routes
of administration
• Although often depicted as a simple three-layered structure,
human skin is a complex series of diffusion barriers
• Quantitation of the flux of drugs and drug vehicles through these
barriers is the basis for pharmacokinetic analysis of dermatologic
therapy, and techniques for making such measurements are
rapidly increasing in number and sensitivity.
6.
7. • Major variables that determine pharmacologic response to drugs
applied to the skin include the following:
i. Regional variation in drug penetration: For example, the
scrotum, face, axilla, and scalp are far more permeable than
the forearm and may require less drug for equivalent effect.
ii. Concentration gradient: Increasing the concentration gradient
increases the mass of drug transferred per unit time, just as in
the case of diffusion across other barriers. Thus, resistance to
topical corticosteroids can sometimes be overcome by use of
higher concentrations of drug.
8. iii. Dosing schedule: Because of its physical properties, 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. For example, once-daily application of
corticosteroids appears to be just as effective as multiple
applications in many conditions.
iv. Vehicles and occlusion: An appropriate vehicle maximizes the
ability of the drug to penetrate the outer layers of the skin. In
addition, through their physical properties, vehicles may themselves
have important therapeutic effects. Occlusion is extremely
effective in maximizing efficacy.
9. REACTIONS TO DERMATOLOGIC
MEDICATIONS
• Skin reacts to many systemic medications with a variety of
symptom-generating responses. In addition, some dermatologic
medications themselves cause skin reactions.
10. DERMATOLOGIC VEHICLES
• Topical medications usually consist of active ingredients incorporated in
a vehicle that facilitates cutaneous application. Important
considerations in vehicle selection include:
solubility of the active agent in the vehicle;
the rate of release of the agent from the vehicle;
the ability of the vehicle to hydrate the stratum corneum, thus
enhancing penetration;
the stability of the therapeutic agent in the vehicle
interactions, chemical and physical, of the vehicle, stratum corneum,
and active agent.
11. cont
• Depending upon the vehicle, dermatologic formulations may be
classified as tinctures, wet dressings, lotions, gels, aerosols,
powders, pastes, creams, foams, and ointments.
• The ability of the vehicle to retard evaporation from the surface
of the skin increases in this series, being least in tinctures and wet
dressings and greatest in ointments.
• In general, acute inflammation with oozing, vesiculation, and
crusting is best treated with drying preparations such as tinctures,
wet dressings, and lotions, whereas chronic inflammation with
xerosis, scaling, and lichenification is best treated with more
lubricating preparations such as creams and ointments.
12. cont
• Tinctures, lotions, gels, foams, and aerosols are convenient for
application to the scalp and hairy areas. Emulsified vanishing-type
creams may be used in intertriginous areas without causing
maceration.
15. INTRO
• Topical antibacterial agents may be useful in preventing infections
in clean wounds, in the early treatment of infected dermatoses
and wounds, in reducing colonization of the nares by
staphylococci, in axillary deodorization, and in the management
of acne vulgaris. Efficacy of antibiotics in these topical
applications is not uniform
16. INTRO
• Some topical anti-infectives contain corticosteroids in addition to
antibiotics. There is no convincing evidence that topical
corticosteroids inhibit the antibacterial effect of antibiotics when
the two are incorporated in the same preparation.
• In the treatment of secondarily infected dermatoses, which are
usually colonized with streptococci, staphylococci, or both,
combination therapy may prove superior to corticosteroid therapy
alone. Antibiotic-corticosteroid combinations may be useful in
treating diaper dermatitis, otitis externa, and impetiginized
eczema.
17. BACITRACIN & GRAMICIDIN
• Bacitracin and gramicidin are peptide antibiotics, active against
gram-positive organisms 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. The use
of bacitracin in the anterior nares may temporarily decrease
colonization by pathogenic staphylococci.
• Bacitracin-induced contact urticaria syndrome, including
anaphylaxis, occurs rarely. Allergic contact dermatitis occurs
frequently, and immunologic allergic contact urticaria rarely.
18. • 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. The
incidence of sensitization following topical application is
exceedingly low in therapeutic concentrations.
19. 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 (see Chapter 50). 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.
20. RETAPAMULIN
• Retapamulin (Altabax) 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. Although
uncommon, allergic contact dermatitis has been reported.
21. 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. Topical preparations may be compounded in
either a solution or ointment base.
• The total daily dose applied to denuded skin or open wounds
should not exceed 200 mg in order to reduce the likelihood of
neurotoxicity and nephrotoxicity. Allergic contact dermatitis to
topically applied polymyxin B sulfate is uncommon.
22. NEOMYCIN & GENTAMICIN
• Neomycin and gentamicin are aminoglycoside antibiotics active
against 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.
23. • 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.
• Neomycin frequently causes allergic contact dermatitis,
particularly if applied to eczematous dermatoses or if
compounded in an ointment vehicle. When sensitization occurs,
cross-sensitivity to streptomycin, kanamycin, paromomycin,
and gentamicin is possible.
25. • Systemic antibiotics traditionally used in the treatment of acne
vulgaris have been shown effective when applied topically.
Currently, two antibiotics are used topically for this
indication: clindamycin phosphate and erythromycin base.
• Effectiveness of topical therapy is less than that achieved by its
oral administration. Therefore, topical therapy is generally
suitable only in mild to moderate cases of inflammatory acne.
26. Clindamycin
• Clindamycin has in vitro activity against Propionibacterium
acnes; this has been postulated as the mechanism of its beneficial
effect in acne therapy. Approximately 10% of an applied dose is
absorbed, and rare cases of bloody diarrhea and
pseudomembranous colitis have been reported following topical
application.
• Allergic contact dermatitis is uncommon. Clindamycin is also
available in fixed-combination topical gels with benzoyl peroxide
(Acanya, BenzaClin, Duac, Onexton) and with tretinoin (Velitin,
Ziana).
27. Erythromycin
• In topical preparations, erythromycin base rather than a salt is used to
facilitate penetration. The mechanism of action of
topical erythromycin in inflammatory acne vulgaris is unknown but is
presumed to be due to its inhibitory effects on P acnes. One
complication of topical therapy is the development of
• Adverse local reactions to erythromycin solution may include a burning
sensation at application time and drying and irritation of the skin. The
topical water-based gel is less drying and may be better tolerated.
• Erythromycin is also available in a fixed combination preparation with
benzoyl peroxide (Benzamycin) for topical treatment of acne vulgaris.
28. Metronidazole
• Topical metronidazole is effective in rosacea treatment. The
mechanism of action may relate to the inhibitory effects
of metronidazole on Demodex brevis; alternatively, the drug may
act as an anti-inflammatory agent by direct effect on neutrophil
cellular function.
• Adverse local effects of the water-based gel formulation
(MetroGel) include dryness, burning, and stinging. Less drying
formulations may be better tolerated.
• Caution should be exercised when applying metronidazole near
the eyes to avoid excessive tearing.
29. Ivermectin
• Topical ivermectin is available as a 1% cream (Soolantra) for the
treatment of inflammatory lesions of rosacea. The mechanism of
action is unknown. Oral ivermectin has antiparasitic activity
against Demodex mites and possibly an anti-inflammatory effect.
Topical application is well tolerated with occasional complaints of
burning and irritation.
30. Sodium Sulfacetamide
• Topical sulfacetamide is available alone as a 10% lotion (Klaron)
and as a 10% wash (Ovace), and in several preparations in
combination with sulfur for the treatment of acne vulgaris and
acne rosacea. The mechanism of action is thought to be inhibition
of P acnes by competitive inhibition of p-aminobenzoic acid
utilization.
• Approximately 4% of topically applied sulfacetamide is absorbed
percutaneously, and its use is therefore contraindicated in
patients having a known hypersensitivity to sulfonamides.
31. Dapsone
• Topical dapsone is available as a 5% and 7.5% gel (Aczone) for the
treatment of acne vulgaris. The mechanism of action is unknown.
Topical use in patients with glucose-6-phosphate dehydrogenase
(G6PD) deficiency has not been shown to cause clinically relevant
hemolysis or anemia, but a slight decrease in hemoglobin
concentration was noted in patients with G6PD deficiency,
suggestive of mild hemolysis.
33. TOPICAL AZOLE DERIVATIVES
• The topical imidazoles, which
include clotrimazole, econazole, ketoconazole, luliconazole, mico
nazole, oxiconazole, sertaconazole, and sulconazole, have a wide
range of activity against dermatophytes
(Epidermophyton, Microsporum, and Trichophyton) and yeasts,
including Candida albicans and Pityrosporum orbiculare
34. Miconazole
• Miconazole (Monistat, Micatin) is available for topical application
as a cream or lotion and as vaginal cream or suppositories for use
in vulvovaginal candidiasis. Clotrimazole (Lotrimin, Mycelex) is
available for topical application to the skin as a cream or lotion
and as vaginal cream and tablets for use in vulvovaginal
candidiasis.
35. • Efinaconazole (Jublia) is available as a 10% solution for the
treatment of onychomycosis of the toenails. Daily application to
affected toenails should be continued for 48 weeks.
• Econazole (Spectazole) is available as a cream for topical
application.
• Oxiconazole (Oxistat) is available as a cream and lotion for topical
use.
• Ketoconazole (Nizoral) is available as a cream for topical
treatment of dermatophytosis and candidiasis and as a shampoo or
foam for the treatment of seborrheic dermatitis.
36. • Luliconazole (Luzu) is available as a cream.
• Sulconazole (Exelderm) is available as a cream or solution.
• Sertaconazole (Ertaczo) is available as a cream. Topical
antifungal-corticosteroid fixed combinations have been introduced
on the basis of providing more rapid symptomatic improvement
than an antifungal agent alone.
• Clotrimazole-betamethasone dipropionate cream (Lotrisone) is
one such combination.
37. CICLOPIROX OLAMINE
• Ciclopirox olamine is a synthetic broad-spectrum antimycotic
agent with inhibitory activity against
dermatophytes, Candida species, and P orbiculare. This agent
inhibits the uptake of precursors of macromolecular synthesis; the
site of action is probably the fungal cell membrane.
• 1–2% of the dose is absorbed when applied as a solution on the
back under an occlusive dressing. Ciclopirox olamine is available
as a 1% cream and lotion (Loprox) for the topical treatment of
dermatomycosis, candidiasis, and tinea versicolor.
• Pruritus and worsening of clinical disease have been reported. The
potential for allergic contact dermatitis is small.
38. TAVABOROLE
• Tavaborole is the first oxaborole antifungal drug approved for the
treatment of toenail onychomycosis. Tavaborole blocks fungal
protein synthesis by inhibiting aminoacyl-transfer ribonucleic acid
synthetase. Tavaborole is available as a 5% solution (Kerydin) that
should be applied to the affected toenails once daily for 48 weeks.
• Complete cure rates in clinical trials are between 6.5% and 9.1%.
39. ALLYLAMINES: NAFTIFINE & TERBINAFINE
• Naftifine hydrochloride and terbinafine (Lamisil) are allylamines
that are highly active against dermatophytes but less active
against yeasts. The antifungal activity derives from selective
inhibition of squalene epoxidase, a key enzyme for the synthesis
of ergosterol (see Figure 48–1).
• They are available as 1% creams and other forms for the topical
treatment of dermatophytosis, to be applied on a twice-daily
dosing schedule for 1–2 weeks. Adverse reactions include local
irritation, burning sensation, and erythema. Contact with mucous
membranes should be avoided.
40. BUTENAFINE
• Butenafine hydrochloride (Mentax) is a benzylamine that is
structurally related to the allylamines. As with the
allylamines, butenafine inhibits the epoxidation of squalene, thus
blocking the synthesis of ergosterol, an essential component of
fungal cell membranes. Butenafine is available as a 1% cream to
be applied once daily for the treatment of superficial
dermatophytosis.
41. TOLNAFTATE
• Tolnaftate is a synthetic antifungal compound effective topically
against dermatophyte infections caused
by Epidermophyton, Microsporum, and Trichophyton. It is also
active against P orbiculare but not against Candida.
• Tolnaftate is available as a cream, solution, powder, or powder
aerosol for application twice daily to infected areas. Recurrences
following cessation of therapy are common, and infections of the
palms, soles, and nails are usually unresponsive
to tolnaftate alone. The powder or powder aerosol may be used
chronically following initial treatment in patients susceptible to
tinea infections.
42. NYSTATIN & AMPHOTERICIN B
• Nystatin and amphotericin B are useful in the topical therapy of C
albicans infections but ineffective against dermatophytes.
• Nystatin is limited to topical treatment of cutaneous and mucosal
candida infections because of its narrow spectrum and negligible
absorption from the gastrointestinal tract following oral
administration.
• Amphotericin B has a broader antifungal spectrum and is used
intravenously in the treatment of many systemic mycoses
45. ACYCLOVIR, VALACYCLOVIR, PENCICLOVIR,
& FAMCICLOVIR
• Acyclovir, valacyclovir, penciclovir, and famciclovir are synthetic
guanine analogs with inhibitory activity against members of the
herpesvirus family, including herpes simplex types 1 and 2.
• Topical acyclovir (Zovirax) is available as a 5% ointment
topical penciclovir (Denavir), as a 1% cream for the treatment of
recurrent orolabial herpes simplex virus infection in
immunocompetent adults. Adverse local reactions
to acyclovir and penciclovir may include pruritus and mild pain
with transient stinging or burning.
46. IMMUNOMODULATORS
• IMIQUIMOD
• Imiquimod is available as 5% cream (Aldara) for the treatment of
external genital and perianal warts in adults, actinic keratoses on the
face and scalp, and biopsy-proven primary superficial basal cell
carcinomas on the trunk, neck, and extremities.
• 2.5% and 3.75% creams are available for the treatment of face and scalp
actinic keratoses.
• The mechanism of its action is thought to be related to imiquimod’s
ability to stimulate peripheral mononuclear cells to release interferon
alpha and to stimulate macrophages to produce interleukins-1, -6, and -
8, and tumor necrosis factor-α (TNF-α).
47. CONT
• Imiquimod should be applied to the wart tissue three times per week
and left on the skin for 6–10 hours prior to washing off with mild soap
and water. Treatment should be continued until eradication of the warts
is accomplished, but not for more than a total of 16 weeks.
• Treatment of superficial basal cell carcinoma consists of five-times-per-
week application of 5% cream to the tumor, including a 1 cm margin of
surrounding skin, for a 6-week course of therapy.
• Percutaneous absorption is minimal, with less than 0.9% absorbed
following a single-dose application. Adverse effects consist of local
inflammatory reactions, including pruritus, erythema, and superficial
erosion.
48. TACROLIMUS & PIMECROLIMUS
• Tacrolimus (Protopic) and pimecrolimus (Elidel) are macrolide
immunosuppressants that have been shown to be of significant
benefit in the treatment of atopic dermatitis. Both agents inhibit
T-lymphocyte activation and prevent the release of inflammatory
cytokines and mediators from mast cells in vitro after stimulation
by antigen-IgE complexes.
49. • Tacrolimus is available as 0.03% and 0.1% ointments,
and pimecrolimus is available as a 1% cream. Both are indicated
for short-term and intermittent long-term therapy for mild to
moderate atopic dermatitis. Tacrolimus 0.03% ointment
and pimecrolimus 1% cream are approved for use in children older
than 2 years of age, although all strengths are approved for adult
use.
