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Therapeutic Shampoos
Questions
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Q51.1 What are the major scalp conditions commonly treated with therapeutic shampoos? (Pg. 576)
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Q51.2 What is the evidence for the role of Pityrosporum yeast in the pathogenesis of seborrheic dermatitis, and which shampoo ingredients reduce its growth? (Pg. 578)
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Q51.3 What are the primary mechanisms of action by which therapeutic shampoos treat scalp conditions? (Pg. 578)
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Q51.4 Which factors play the most important role in the percutaneous absorption of topical agents, and which therapeutic shampoo ingredients have a clinically significant risk related to systemic absorption?? (Pg. 579)
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Q51.5 Which ingredients in therapeutic shampoos produce either irritant or allergic contact dermatitis? (Pg. 581)
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Q51.6 Which therapeutic shampoos should be avoided or used with caution in (1) pregnancy or (2) in young children? (Pg. 582x2)
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Q51.7 (1) Which combination regimens are considered to be first-line for the treatment and management of seborrheic dermatitis, and (2) which agents have demonstrated comparable clinical efficacy? (Pg. 583)
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Q51.8 Which combination regimen is used for the treatment and maintenance of psoriasis scalp involvement? (Pg. 583)
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Q51.9 Which therapeutic shampoos are recommended for the adjunctive treatment of tinea capitis infections? (Pg. 583)
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Q51.10 Which therapeutic shampoos are currently available by prescription only? (Pg. 584, Box 51.1 )
Abbreviations used in this chapter
ACD
Allergic contact dermatitis
BSA
Body surface area
CS
Corticosteroid(s)
EGCG
Epigallocatechin gallate
FDA
US Food and Drug Administration
HPA
Hypothalamic–pituitary–adrenal (axis)
LCD
Liquor carbonis detergens
LSC
Lichen simplex chronicus
MCI/MI
Methylchloroisothiazolinone/methylisothiazolinone
OTC
Over-the-counter
PABA
Para-amino benzoic acid
PAH
Polycyclic aromatic hydrocarbon
PLA 2
Phospholipase A 2
PUVA
Psoralen plus UVA
SJS
Stevens–Johnson syndrome
SAE
Systemic adverse effect
TCS
Topical corticosteroid(s)
UVA
Ultraviolet A
Introduction
Therapeutic shampoos are commonly used to treat inflammatory dermatoses of the scalp. These products are convenient because they cleanse the scalp while simultaneously delivering effective treatment in an efficient manner. Compliance is further improved when effective products are simple to use and cosmetically elegant. Therapeutic shampoos are available as both over-the-counter (OTC) and prescription products, and these agents can be categorized on the basis of their primary mechanism of action and active ingredient(s) ( Table 51.1 ).
Table 51.1
Therapeutic Shampoos Used in Dermatology
| Shampoo formulations | Mechanism(s) of action | |||||
|---|---|---|---|---|---|---|
| Active ingredient(s) | Strength (%) | Common Trade Name | Keratolytic | Antiproliferative cytostatic | Antimicrobial | Anti-inflammatory |
| Antifungal Agents | ||||||
| Ketoconazole | 1 | Nizoral A-D | +++ | ++ | ||
| 2 | Nizoral a | |||||
| Ciclopirox olamine | 1 | Loprox a | +++ | ++ | ||
| Selenium sulfide | 1 | Selsun Blue | + | ++ | +++ | |
| Head & Shoulders Intensive Treatment |
||||||
| 2.5 | Selsun a | |||||
| 2.25 | Selseb | |||||
| 2.3 | SelRx (not by prescription) | |||||
| Zinc pyrithione | 1 | Head & Shoulders | + | ++ | ++ | |
| Zincon | ||||||
| T-Gel Daily Control | ||||||
| 2 | DHS Zinc | |||||
| Topical Corticosteroids | ||||||
| Clobetasol propionate | 0.05 | Clobex a | +++ | +++ | ||
| Fluocinolone acetonide | 0.01 | Capex a | +++ | +++ | ||
| Agents for Hyperkeratosis | ||||||
| Coal tar preparations | + | +++ | + | ++ | ||
| Coal tar solution | 0.5 | DHS Tar | ||||
| 2 | Ionil T | |||||
| Solubilized CTE | 0.5 | T-Gel | ||||
| 4 | T-Gel XS | |||||
| Salicylic acid | 2 | Baker’s P&S | +++ | ++ | ||
| Ionil Plus | ||||||
| 3 | T-Sal | |||||
| 6 | Salex | +++ | ++ | |||
| Combination Products | ||||||
| Coal tar + salicylic acid | 2–2 | Ionil T Plus | +++ | +++ | + | ++ |
| Salicylic acid + sulfur | 3–5 | MG 217 Tar-Free |
+++ | ++ | ++ | |
| 2–2 | Sebulex | |||||
| Other Antimicrobial Agents | ||||||
| Sodium sulfacetamide | 10 | OVACE Plus | +++ | + | ||
| Povidone–iodine | 7.5 | Betadine | +++ | |||
| Hypoallergenic Shampoos | ||||||
| Vanicream Free & Clear | ||||||
CTE, Coal tar extract.
Dermatoses Involving the Scalp
The scalp is a common site of predilection for a number of skin conditions. Although representing only around 5% of the total body surface area (BSA), scalp involvement can be severe and distressing to the patient, resulting in significantly decreased quality of life. Scalp eruptions are usually characterized clinically by a variable degree of erythema, scaling, and pruritus, regardless of the underlying etiology. As such, dermatoses of the scalp can be difficult to differentiate, and careful attention must be paid for accurate diagnosis because identification of the underlying etiology may be necessary before selecting the appropriate therapy. Several dermatoses discussed in this chapter may present with additional characteristic cutaneous (or extracutaneous) manifestations that can aid in diagnosis, underscoring the importance of a thorough examination, even in patients presenting with isolated scalp complaints.
Q51.1 Clinically, the primary conditions for which therapeutic shampoos are indicated generally fall into one of the following categories: (1) seborrheic dermatitis (including infantile ‘cradle cap’ and dry ‘dandruff’ variants), (2) psoriasis, (3) eczematous dermatitis (including atopic dermatitis and contact dermatitis), and (4) superficial mycoses (including tinea [pityriasis] versicolor, Pityrosporum [ Malassezia ] folliculitis, the piedras, and tinea capitis), which may affect other sites besides the scalp. Additionally, lichen simplex chronicus (LSC) and pityriasis (tinea) amiantacea are two important secondary clinical manifestations that can complicate long-standing scalp disease and require special consideration. Rarely, chronic drug eruptions, connective tissue diseases (particularly dermatomyositis and cutaneous lupus erythematosus), scarring alopecias, erythrodermas, or lymphoproliferative disorders can present as diagnostically or therapeutically challenging scalp conditions.
Q51.2 Importantly, an etiologic role for Pityrosporum yeast has been confirmed in tinea versicolor and strongly implicated in seborrheic dermatitis and Pityrosporum folliculitis. It has been more recently linked to psoriasis, including the ‘sebopsoriasis’ phenotype, as well as the ‘head and neck’ clinical subtype of atopic dermatitis.
Historical Perspective
The use of topical medications to treat scaling scalp conditions dates to 1876, when Duhring wrote: ‘Among external remedies which are of the greatest service and should be employed in all cases, baths of various kinds, simple or medicated, the preparations of tar, the mercurial ointments, sulphur, sapo viridis, and solutions of caustic potassa will be found most useful.’ A number of scalp medicaments have been commercially available for many years, although many of these have not been rigorously tested in modern clinical trials.
Pharmacology
Mechanism of Action
General Properties of Shampoos
Shampoos are complex, multifunctional cleansers specifically designed for the scalp and hair They are composed of a variety of surface-acting agents, or ‘surfactants,’ which are bipolar molecules composed of both hydrophobic and hydrophilic ends that act to decrease surface tension between interfaces. The primary surfactants used in shampoos function as detergents and ‘wetting’ agents. Detergents remove sebum and other soils (including epithelial debris or ‘scale’, hair products, and other environmental particulates) through emulsification, which enhances wetting of the scalp and dispersion of active ingredients, as well as eliminates irritation associated with retention of these substances. Interestingly, although seborrhea is not a pathologic feature of scalp dermatoses, abnormal sebum composition has been associated with increased production of inflammatory mediators by Pityrosporum, which has been implicated in seborrheic dermatitis as well as multiple other inflammatory scalp and skin conditions.
Therapeutic Properties of Shampoos
Q51.3 The mechanisms by which the active agents in therapeutic shampoos function in inflammatory scalp dermatoses can be broadly classified into the following categories: (1) antifungal activity, (2) anti-inflammatory activity, (3) antiproliferative/cytostatic activity, and (4) keratolytic activity. The active agents in therapeutic shampoos generally have multiple and overlapping mechanisms, many of which are incompletely understood. Most of these agents are discussed in detail elsewhere ( Chapters 41, Chapters 42, Chapters 45, Chapters 55 ), but they will be briefly reviewed here.
Ketoconazole is a synthetic azole derivative with antifungal anti-inflammatory properties. It is fungistatic against Pityrosporum via inhibition of lanosterol 14-α-demethylase, preventing conversion of lanosterol to ergosterol, an important component of the fungal cell wall. Anti-inflammatory activity involves inhibition of polymorphonuclear (PMN) cell chemotaxis and leukotriene synthesis. Other azole agents that have been developed into shampoo formulations include climbazole, miconazole, fluconazole, and bifonazole, but these products are not commercially available in the United States.
Ciclopirox olamine is a hydroxypyridone antimicrobial agent with antifungal, antibacterial, and anti-inflammatory activity. Fungicidal against Pityrosporum , ciclopirox chelates polyvalent cations that are essential for enzymatic activity and membrane transport of precursor molecules. Its anti-inflammatory activity is mediated through inhibition of eicosanoid biosynthesis pathways. A related agent, piroctone (ethan)olamine, also demonstrates antifungal and antioxidant properties, and is commonly used in OTC antidandruff shampoos, particularly outside of the United States.
Selenium sulfide demonstrates both antifungal and antiproliferative activity, as well as mild keratolytic activity. It is fungicidal against Pityrosporum through a poorly understood mechanism, and it exerts a cytostatic effect on keratinocytes, likely through the inhibition of key proliferative enzymes.
Zinc pyrithione is a broad-spectrum antimicrobial agent that also demonstrates antiproliferative and keratolytic activities. It is a zinc ionophore that inhibits fungal growth via transmembrane intracellular copper transportation, which interferes with essential mitochondrial iron-sulfur proteins. The mechanisms for its antiproliferative and keratolytic activity are incompletely characterized.
Topical corticosteroids exhibit potent anti-inflammatory and antipruritic activity through complex mechanisms. They are thought to induce production of phospholipase A 2 (PLA 2 ) inhibitory proteins (lipocortins), which prevent PLA 2 -mediated release of arachidonic acid from membrane phospholipids, resulting in decreased production of inflammatory eicosanoids. Corticosteroids (CS) also decrease production of proinflammatory cytokines and have broad inhibitory and antiproliferative effects on inflammatory cells.
Keratolytic agents are a heterogeneous group of compounds that function to reduce hyperkeratosis. The primary agents of interest include coal tar, salicylic acid (SA), and sulfur, and they are commonly formulated as combination products. Tar is a heterogeneous organic compound distilled from various sources, with coal tar being the most widely used form in dermatology. Coal tar has a complex mechanism, including antiproliferative activity via suppression of deoxyribonucleic acid (DNA) synthesis, as well as immunosuppressive, antimicrobial, and keratolytic properties. Salicylic acid has both keratolytic and anti-inflammatory activity through multiple partially characterized mechanisms. It reduces corneocyte adhesion via disruption of intracellular lipids, corneodesmosomes, and transmembrane glycoproteins. It exerts anti-inflammatory activity through inhibition of prostaglandin synthesis. Sulfur demonstrates keratolytic and antimicrobial properties, and its mechanism is thought to be mediated by specific interactions with other sulfur-containing compounds, including cysteine in keratinocytes (keratolytic), formation of pentathionic acid (antifungal), and inactivation of sulfhydryl groups on bacterial enzymes (antibacterial).
Sodium sulfacetamide is a broad-spectrum antibiotic that inhibits bacterial folate synthesis by competitive inhibition of para-amino benzoic acid (PABA). It also reportedly demonstrates nonspecific anti-inflammatory activity by an unknown mechanism.
Botanical and Herbal Agents
Natural ingredients have long been recognized for their therapeutic properties, and several compounds have been incorporated into therapeutic shampoos and evaluated in clinical studies, primarily for the treatment of seborrheic dermatitis and dandruff. Tea tree oil has been well-recognized for its anti-inflammatory and antifungal properties, and it has demonstrated efficacy in inflammatory scalp dermatoses. Glycyrrhetinic acid, derived from licorice root extract, is structurally similar to cortisol, and has been shown to inhibit 11-β-hydroxysteroid hydroxylase and potentiate the effect of hydrocortisone. It also has antioxidant and antimicrobial properties. It has been incorporated into piroctone olamine-based OTC antidandruff shampoos (Sebclair/Promiseb) with other active botanical compounds, including lactoferrin, telmesteine, and grapevine (vitis vinifera) extract. It has also been combined with ciclopirox and zinc pyrithione (Kelual DS) as an investigational product for the treatment of chronic seborrheic dermatitis. A shampoo containing rose petal ( Rosa centifolia ) extract and epigallocatechin gallate (EGCG), incorporated with climbazole and zinc pyrithione, has been developed utilizing the antioxidant, anti-inflammatory, and keratolytic properties of these two botanical compounds.
Systemic Absorption
Q51.4 The risk for systemic absorption from the use of topical agents is highly dependent on a number of key factors, including the biochemical properties of the active ingredient, vehicle formulation, presence of permeability enhancers, application parameters, and epidermal barrier characteristics. Although shampoo formulations are generally applied to a small surface area for a short duration, systemic absorption with these agents has been described and warrants discussion.
Systemic absorption from topical corticosteroids (TCS) is a well-recognized concern, owing to the potential risk of iatrogenic hypercortisolism and hypothalamic–pituitary–adrenal (HPA) axis suppression. Percutaneous absorption is highly variable, but super-potent formulations confer the greatest risk. A recent review evaluating the incidence of HPA-axis suppression with use of super-potent TCS in adults found the risk to be substantially lower than previously assumed, with only a handful of cases reported worldwide. Despite the relatively short contact time and small surface area, use of clobetasol shampoo can still lead to systemic absorption, particularly in pediatric patients. However, it has consistently demonstrated an excellent safety profile for adults with both short-term and long-term use, and no cases of HPA-axis suppression have been reported with shampoo use in adults to date. Although fluocinolone also carries a theoretical risk for HPA-axis suppression, this has not been reported in the literature.
Significant absorption of tar occurs even when shampoo is used on an intact scalp. The mutagenic and carcinogenic effects of crude coal tar has been well documented—primarily with occupational exposure—from absorption of polycyclic aromatic hydrocarbon (PAH) components. Despite observed levels similar to those seen with occupational exposure, the use of tar products in shampoos for decades has not been implicated in localized or systemic tumor formation. This has been validated by a large cohort study of long-term use of coal tar in both psoriasis and eczema patients, with no increased risk of cancer identified. Acute systemic toxicity (characterized by fever, hypotension, renal failure, and hepatotoxicity) is mediated by absorption of phenol compounds found primarily in wood tar preparations, which are uncommonly used therapeutically.
Systemic absorption from topical SA ranges from 9% to 25% on intact skin, generally with no systemic adverse effects (SAE) observed when used in lower concentrations over limited areas. Percutaneous absorption in general is maximized when applied under occlusion or to sites of barrier disruption, resulting in rapid and measurable systemic absorption. Salicylate toxicity (‘salicylism’) is a rare but potentially fatal complication that develops with plasma concentrations reaching approximately 35 mg/dL. Although toxicity is generally seen with treatments applied to 40% to 50% of the body with SA ointment concentrations of 10% or more, toxicity with 6% concentrations has been reported. Neonatal toxicity has been reported with SA concentrations as low as 1% to 2%. Notably, systemic absorption has not been reported from currently available SA shampoos.
Systemic absorption of sodium sulfacetamide applied to intact skin is approximately 4%. Absorption is substantially elevated when applied over large or damaged areas, and severe hypersensitivity reactions may develop similar to those seen with systemic sulfonamides, including Stevens–Johnson syndrome (SJS).
Selenium sulfide demonstrates minimal systemic absorption when used on intact skin. Previous studies have failed to demonstrate detectable blood or urine levels after full body application for treatment of tinea versicolor. Interestingly, an isolated case of selenium toxicity was reported in the 1960s from the use of selenium sulfide shampoo two to three times weekly for 8 months in a patient with damaged scalp skin, but no additional cases of toxicity have since been reported.
Minimal or no systemic absorption has been detected with ketoconazole, zinc pyrithione, or ciclopirox shampoos, and no SAE have been reported with the use of these agents. Several studies evaluating the safety and systemic absorption of topical ketoconazole have been unable to detect measurable plasma levels, even with chronic or extensive use. Additionally, application of ketoconazole to the scalp of infants with ‘cradle cap’ over a 10-day period did not reveal measurable quantities in plasma. In clinical trials for ciclopirox shampoo, trace plasma levels (∼10–13 ng/mL) were detected in one-third (6 of 18) of patients, but this was clinically inconsequential. Zinc pyrithione is primarily retained on the surface of the scalp and superficial follicular infundibulum, and demonstrates poor affinity for percutaneous absorption.
Clinical Use
Indications
The shampoos discussed in this chapter are useful in the treatment of inflammatory scalp dermatoses, as both primary treatment and in conjunction with other therapies. In general, they are used to control symptoms, rather than to cure scalp conditions. Multiple systematic reviews have been published reviewing the efficacy and superiority of these agents, but evidence is generally considered to be of low or moderate quality. As such, art must be combined with science to develop treatment regimens tailored for individual patients. Because many of these agents are available as OTC formulations, they are not subjected to the same regulatory and compliance standards as prescription products, and therefore often lack ‘official’ US Food and Drug Administration (FDA) indications. Additionally, because many of the active components of therapeutic shampoos are also formulated into other topical vehicles (such as creams, ointments, or foams), their efficacy may be extrapolated from indications of different preparations, without formal FDA approval of the shampoo formulation. Specific FDA-approved and off-label indications are listed in Box 51.1 .
Box 51.1
Indications and Availability of Therapeutic Shampoos
US Food and Drug Administration-Approved Indications
Scaling Scalp and Dandruff
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Selenium sulfide 1% and 2.5% a
Available by prescription only.
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Zinc pyrithione 1% and 2%
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Ketoconazole 1%
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Coal tar
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Salicylic acid
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Sulfur
Seborrheic Dermatitis
Psoriasis
Tinea Versicolor
Off-Label Dermatologic Uses
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