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Miscellaneous Topical Agents


Questions

  • Q57.1 What is the function of endogenous vitamin C, and by what mechanisms does topical vitamin C reportedly reduce clinical findings of photoaging? (Pg. 625)

  • Q57.2 What are the clinical advantages of aluminum chloride used for hemostasis, compared with Monsel’s solution and electrocautery? (Pg. 627x2)

  • Q57.3 How are aluminum chloride products typically used for treatment of hyperhidrosis? (Pg. 627)

  • Q57.4 What are the most likely mechanisms by which topical minoxidil induces hair growth? (Pg. 627)

  • Q57.5 Which products discussed in this chapter have literature reports to support off-label use for selected cases of alopecia areata? (Pg. 628)

  • Q57.6 What is the proposed mechanism of action for anthralin? (Pg. 629x2)

  • Q57.7 What are the rationale and therapeutic guidelines for short-contact anthralin therapy (SCAT) (Pg. 629x3)

  • Q57.8 What is the most common adverse effect for topical brimonidine gel? (Pg. 629)

  • Q57.9 What serious adverse effect has been reported for topical brimonidine gel for achieving hemostasis in the peri-operative setting? (Pg. 629)

  • Q57.10 What other α-adrenergic receptor agonist has been shown to improve the persistent facial erythema from rosacea with once daily application? (Pg. 630)

Abbreviations used in this chapter

ATP

Adenosine triphosphate

CEFer

Vitamin C, Vitamin E, ferulic acid

OTC

Over the counter

PDL

Pulsed-dye laser

SCAT

Short-contact anthralin therapy

UVA

Ultraviolet A

UVB

Ultraviolet B

VEGF

Vascular endothelial growth factor

Introduction

This chapter on miscellaneous topical agents is divided into three sections: (1) topical antioxidants, (2) topical agents for hemostasis and hyperhidrosis, and (3) other topical agents ( Box 57.1 ). Many of the topical therapeutics discussed in this chapter are available in over-the-counter (OTC) preparations; only a few of these medications require a prescription, namely bimatoprost, brimonidine, and anthralin. Oxymetazoline 1% cream is available by prescription, although the 0.05% nasal solution is available over the counter. Eskata is intended for in-office use only.

Box 57.1
Drugs Discussed in This Chapter

Topical Antioxidants

  • Ascorbic acid (vitamin C)

  • Vitamin E

  • Selenium

  • Zinc

  • (Plant antioxidants— Table 57.2 )

Topical Agents for Hemostasis and Hyperhidrosis

  • Aluminum chloride

  • Ferric subsulfate

  • (Silver nitrate— Table 57.3 )

Other Topical Agents

  • Phytonadione (vitamin K 1 )

  • Minoxidil

  • Bimatoprost

  • Capsaicin

  • Anthralin

  • Aloe vera

Brimonidine

Oxymetazoline

Hydrogen peroxide

Topical Antioxidants

The incorporation of antioxidants into topical formulations is a response to overwhelming demand from the lay public, which is amplified by the media. Unfortunately, data concerning the clinical use of these topically applied agents in human subjects are scarce. The most recent supporting evidence, with theoretical clinical correlations, is discussed. The physiologic antioxidants are reviewed in greater detail below and in table form ( Table 57.1 ), with plant antioxidants listed in table form only ( Table 57.2 ).

Table 57.1
Physiologic Antioxidants
Antioxidant Chemical Name Mechanism of Action Possible Uses
Vitamin C L -ascorbic acid Aqueous reductant, free radical scavenger UVA/UVB protection, photoaging
Vitamin E Tocopherol a Prevents lipid peroxidation UVA/UVB protection, psoriasis
Selenium L -selenomethionine Cofactor for glutathione peroxidase and thioredoxin reductase Photoprotection
Zinc Zinc Not well understood—may compete with harmful free-radical-producing Fe 2+ and Cu + in cellular reactions, and/or meteallothionin b Photoprotection
UVA, Ultraviolet A; UVB, ultraviolet B.

a Most active form is α-tocopherol.

b Theoretical mechanism.

Table 57.2
Plant Antioxidants
Antioxidant Source Mechanism of Action Possible Uses
Silymarin Extract of milk thistle plant ( Silybum marianum ) Prevents lipid peroxidation, inhibits lipoprotein oxidation, scavenges reactive oxygen species UVB photoprotection, anticarcinogenic
Genistein Soybeans (soy isoflavones) Inhibitor of tyrosine kinase, prevents lipid peroxidation, scavenges peroxyl radicals UVA/UVB photoprotection, anti-carcinogenic
Green tea polyphenols Camellia sinensis (tea) Reduces lipid peroxidation, quenches free oxygen radicals UVA/UVB photoprotection, antiangiogenic, anticarcinogenic
UVA, Ultraviolet A; UVB, ultraviolet B.

The topical antioxidants discussed in this section include ascorbic acid (vitamin C), vitamin E, selenium, and zinc. The greatest emphasis will be given to ascorbic acid and vitamin E.

Ascorbic Acid (Vitamin C)

Pharmacology

A variety of commercially available preparations of topical vitamin C are available over the counter in varying concentrations, including products by Skinceuticals, Cellex-C International, and Revision, among others.

Mechanism of Action

Q57.1 Ascorbic acid is a necessary cofactor for the enzymes prolyl hydroxylase and lysyl hydroxylase. These enzymes are used in the formation of a stable collagen molecule and the cross-linking of collagen, respectively.

L-ascorbic acid is the predominant cutaneous antioxidant. It is theorized that topical ascorbic acid scavenges free oxygen radicals in the aqueous compartments, and in addition stimulates collagen synthesis. Alone, ascorbic acid does not absorb ultraviolet A (UVA) or ultraviolet B (UVB), but L-ascorbic acid in combination with α-tocopherol (vitamin E) has recently been shown to provide the skin with significant UVA and UVB protection. Vitamin C protects vitamin E from oxidation. Topical 15% L -ascorbic acid and 1% α-tocopherol provide a marked increase in photoprotectivity.

Another issue is the bioavailability of topically applied vitamin C. The addition of tyrosine and zinc to vitamin C has been shown to provide more than 20 times the amount of ascorbic acid found in normal skin. The Cellex-C Advanced-C Serum contains resveratrol (a free radical scavenger extracted from mulberries and grapes) and L -ergothioneine (also a natural antioxidant) to further stabilize vitamin C.

Clinical Use

Dermatologic Uses

Photoaging

Topical ascorbic acid is commonly used in the treatment of photoaged skin. Although few randomized controlled trials in humans have been carried out, limited data suggest it may improve the appearance of photodamaged skin. One randomized, double-blind, vehicle-controlled study showed improvement in fine wrinkling, tactile roughness, coarse rhytides, skin laxity, and yellowing. The greatest clinical improvement was noted for tactile roughness/texture and skin hydration. In another small, randomized, split-face trial in 10 patients, a mixture of water- and lipid-soluble forms of vitamin C were found to significantly improve the appearance of photoaged skin. This included demonstrating increased collagen production on punch biopsy specimens. In a placebo-controlled trial, 3% vitamin C cream was found to improve the appearance of photoaging of the forearm skin of 33 women, which was correlated with microscopic findings of increased density of dermal papillae. Vitamin C has also been shown to inhibit melanogenesis induced by UVA, and has been used with some success both in topical and mesotherapy (injected) forms to improve periorbital dark circles, as well as in combination with other treatments for melasma.

Photoprotection

Lin and associates elucidated the advantage of a combination of vitamin C and vitamin E for absorbing UVA and UVB radiation, over either topically applied vitamin alone. The study was performed on porcine models. These results and others are now reflected in the addition of both vitamin C and vitamin E in sunscreens, daily moisturizers, and other nonprescription skin care products. Investigation of vitamins C and E combined with ferulic acid (a plant-derived antioxidant) has further demonstrated both improved chemical stability and a doubled photoprotective ability. In another study of the above combination (abbreviated CEFer), UVB-exposed skin of treated patients demonstrated significant protection from induction of erythema, sunburn cells, and thymine dimer formation.

Adverse Effects

Topical ascorbic acid adverse events (AE) are mild and typically resolve in the first 2 months of continuous therapy. These minor AE included stinging (55%), erythema (24%), and dry skin (1%).

Therapeutic Guidelines

After cleansing areas that will be exposed to sunlight, vitamin C-containing compound (or combination product with vitamins C and E) is applied evenly over the skin surface. Sunscreens may be applied subsequently, ideally allowing 30 minutes or more between products to avoid significant dilution.

Pregnancy Prescribing Status

Oral ascorbic acid (vitamin C) is pregnancy prescribing class C. There are no pregnancy guidelines for the topically applied formulations.

Vitamin E

Pharmacology

There are eight molecular forms of vitamin E—four tocopherols and four tocotrienols. Of these eight molecular forms, α-tocopherol is the most physiologically active isomer, owing to the presence of a specific α-tocopherol transfer protein. The transfer protein selectively transfers α-tocopherol into lipoproteins.

Mechanism of Action

Vitamin E is a free radical scavenger that prevents lipid peroxidation. It is the major lipid phase antioxidant in humans. Vitamin E is the main lipid-soluble antioxidant for the protection of cell membranes.

Clinical Use

Dermatologic Uses

Photoprotection

Topical vitamin E has been effective in reducing UV-induced erythema and edema in murine models. It has also been shown to reduce skin photoaging effects, skin cancer, and UV radiation-induced immunosuppression in animals. More specifically, α-tocopherol inhibits cyclopyrimidine dimer formation via the epidermal p53 tumor suppressor gene.

The photoprotective combination of topically applied vitamin E with vitamin C was discussed in an earlier section.

Adverse Effects

Overall, AE from vitamin E are quite uncommon. Vitamin E may inhibit clotting, and therefore it may be unwise to apply these products on an open, healing wound.

There are no published data concerning the use of these products in pregnancy.

Selenium

Selenium is an essential cofactor for glutathione peroxidase and thioredoxin reductase. The aforementioned enzymes are very important in cellular defense against oxidative stress.

Topical L -selenomethionine has been shown to increase the minimal erythema dose of UV radiation in human subjects. Further studies on murine models illustrated protection against UV-induced erythema and skin cancer. The L -selenomethionine compound studied in the aforementioned trial is not yet commercially available. Several related products (without published data concerning their use) with L -selenomethionine include Vitastic Soothing Shave Gel and Perfect Day Vitamin and Mineral Formula.

Zinc

The protective properties of topically applied zinc compounds are not yet fully understood. One possible mechanism is that zinc replaces harmful redox-active entities, including Fe 2+ and Cu + . A second theory suggests that zinc induces the synthesis of metallothionein, a free radical scavenger which plays a role in heavy-metal detoxification. An experimental model in hamsters demonstrated an increase in metallothionein protein in skin treated with a topical erythromycin and zinc preparation (Zineryt).

The topical application of zinc salts to murine models was shown to reduce UV-induced sunburn cell formation. In vitro studies with cultured human fibroblasts also demonstrate the protective effect of zinc on UVA induced DNA damage. In a small study of Iraqi patients with melasma, a 10% zinc sulfate lotion applied twice daily was found to produce a significant improvement in the condition. The authors attributed the efficacy to the photoprotective and antioxidant effects of zinc.

Topical Agents for Hemostasis and Hyperhidrosis

This section of the chapter includes discussion of two drugs: (1) aluminum chloride, and (2) ferric subsulfate (Monsel’s solution). The products are discussed in some detail because of the widespread use of these agents in dermatology. Silver nitrate, which is less commonly used in dermatology, is mentioned briefly in table format only ( Table 57.3 ). Brimonidine gel is discussed later in this chapter with other topical agents, given its primary use for rosacea; it has also been used for perioperative hemostasis.

Table 57.3
Topical Hemostatic Agents
Common Name Chemical Name Chemical Formula Clinical Uses
Monsel’s solution Ferric sulfate/ferric subsulfate Fe 2 (SO 4 ) 3 Hemostasis
Aluminum chloride Aluminum chloride AlCl 3 Hemostasis, hyperhidrosis
Silver nitrate Silver nitrate AgNO 3 Hemostasis, antimicrobial

Aluminum Chloride

Pharmacology

Aluminum chloride has the chemical formula AlCl 3 . This drug is available as a 20% solution in anhydrous ethyl alcohol (Drysol) and a 12% solution (Certain Dri pads and roll-on bottle).

Mechanism of Action

Aluminum chloride reversibly inhibits eccrine gland secretion by obstructing the eccrine pores and inducing transient secretory cell atrophy. Aluminum creates a low-grade generation of thrombin, which is followed by activation of the platelet-dependent clotting factor XI to XIa.

Clinical Use

Dermatologic Uses

Hemostasis During Surgical Procedures

Aluminum chloride 20% is most often used for hemostasis after minor procedures such as shave biopsies or curettage. Q57.2 The advantage of aluminum chloride over Monsel’s solution is that it does not leave an iron residue that can persist in the dermis, essentially creating a tattoo. The advantage of aluminum chloride over electrocautery for hemostasis is that aluminum chloride does not cause as much scarring. In contrast, more pronounced bleeding during a procedure will typically require electrocautery for hemostasis.

Hyperhidrosis

Aluminum chloride is useful for the treatment of palmar, plantar, and axillary hyperhidrosis. Aluminum chloride has also been reported to be useful in facial and scalp hyperhidrosis. Prevention of foot blisters caused by walking long distances in the heat, such as in hikers and military recruits, is an additional use for aluminum chloride.

Adverse Effects

Uncommon minor reactions include irritant contact dermatitis, burning, or a prickling sensation. Significant caution should be given for use near the eye. Clinicians should be aware that aluminum chloride may be flammable if not allowed to dry completely before electrocautery (alternatively, rinse well with water).

Therapeutic Guidelines for Treatment of Hyperhidrosis

Q57.3 Recommendations regarding the frequency of applications for hyperhidrosis vary in the literature, ranging from daily to once weekly. Generally, it is believed that the lower-concentration solutions can be applied daily. Initially, the 20% solution can be used daily, and then tapered to thrice weekly or even once weekly as needed. The solution should be applied to completely dry skin.

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