Topical corticosteroids are a mainstay of therapy in dermatology, and the choices of available agents are plentiful. There is a wide array of options among these agents with variables including chemical structures, halogenation and vehicles. Clinical efficacy, local tolerability and safety also relate to varying pharmacologic properties of topical corticosteroids.
This article updates current understanding of the mechanisms of action, pharmacologic properties, pharmacodynamic effects, vehicle considerations, impact of halogenation and safety considerations related to topical corticosteroids. Clinical implications are also discussed.
Altering Corticosteroids
In 1952, the properties in topically applied “compound F”, a corticosteroid compound, were first described.1 Since that time, research scientists have examined numerous modifications of the basic cyclopentanophenanthrene corticosteroid nucleus through “molecular roulette”, ultimately determining alterations at specific locations in the ring structure or at side chains. These alterations affect properties such as potency, pharmacodynamic activity and potential adverse reaction risks.2-4
As a result, several new topical corticosteroid compounds with potencies ranging from mild to super-potent have been developed over the past five decades, with subsequent approval for use by the FDA. When used appropriately, topical corticosteroids are effective and safe, and remain widely prescribed for a variety of dermatoses. These drugs are used either as monotherapy or in combination with other topical agents, such as calcipotriene (Dovonex), tazarotene (Tazorac), tacrolimus (Protopic) and pimecrolimus (Elidel).5-8
The following discusses structure-activity relationships of corticosteroids, clinical impact and effects of halogenation and specific implications, including hypothalamic-pituitary-adrenal (HPA) axis suppression.
Structure-Activity Relationships
Basic Structural Considerations. The basic structure of adrenal steroids, including corticosteroids and their synthetic derivatives, is the cyclopentanophenanthrene nucleus, which is comprised of three 6-carbon rings (A, B, C) and a single 5-carbon ring (D).3 The chemical structure of the corticosteroid skeleton is depicted in Figure 1.3,4 Certain location-specific structural moieties are necessary for production of and/or accentuation of glucocorticosteroid/anti-inflammatory activity by individual corticosteroid molecules.3 These include the following:
• A ketone group at the third carbon (C-3) of ring A
• A double-bond between C-4 and C-5 on ring A
• Beta-hydroxyl group at C-11
• Ketone group at C-20 (side chain carbon).
In addition, maintaining 3-D spatial and stearic conformations of specific structural groups relates to pharmacologic function.3 Alpha isomers project below and beta isomers above the configuration plane.
The potency of topical corticosteroids is significantly increased by the following structural modifications.4
• C-6a fluorination
• C-9a fluorination
• Halogenation at the C-21 position
• Esterification at the C-17 hydroxyl position
• Esterification at the C-21 hydroxyl position
• Double bond between C-1 and C-2 on ring A.
Specific combinations of the above modifications may further increase topical corticosteroid potency, with higher potency agents, including super-potent compounds (eg. clobetasol, halobetasol) produced in some cases.
Dihalogenation, depending on the site and type of modification, may or may not have a major impact on topical
corticosteroid potency. For example, the addition of a C-6 fluorine to a C-9 fluorinated corticosteroid (eg. halobetasol) does not increase potency as compared to C-9 fluorination alone (eg. clobetasol).4
Significance of Halogenation
Topical corticosteroid potency is most often assessed by vasoconstrictor assay, which appears to correlate with clinical effect.2,9 Results from clinical trials and “real-world” experience also put topical corticosteroids to the test in treating dermatoses, with clinical results either supporting or refuting potency categorizations that have been determined by vasoconstrictor assay for specific formulations.
Halogenation of topical corticosteroids has been equated with production of higher potency and greater potential for adverse reactions, especially application site effects such as atrophy, striae and telangiectasia. This generalization is true in part. However, it may be misleading in terms of differentiating among both halogenated and non-halogenated topical corticosteroid compounds as related to their relative potency and adverse reaction risk. In fact, augmented potency correlates specifically with halogenation at specific structural sites and also with the type of halogen atom used (eg. fluorine, chlorine).3,4
Location-Dependency. As stated above, the degree of impact on topical corticosteroid potency correlates directly with the structural position of halogenation and type of halogen atom that is used.3,4 Maximal augmentation of potency occurs through replacement of hydrogen at C-9 with fluorine (fluorination), with lesser potentiation through fluorination at C-6.4,10 Another modification noted to increase topical corticosteroid potency is additional halogenation at the C-21 position.
Halogen-Type Dependency. The importance of the type of halogen atom used during the halogenation process is supported by the observation that replacement of the C-9 hydrogen with fluorine (fluorination) as opposed to chlorine (chlorination) produces a significantly greater increase in potency.4,10
Misconceptions Regarding Halogen-ation. It is important to recognize that the correlation between halogenation, marked augmentation in potency, and increased risk of adverse reactions, especially local side effects, is dependent on the location and nature of halogenation.
In addition to halogenation, other types of structural modification may lead to varying increases in topical corticosteroid potency.3,4 These include esterification at the C-17 hydroxyl and C-21 hydroxyl positions. The side chain structure used in the esterification process may impact significantly upon topical corticosteroid potency, even in the presence of C-9 and C-6 fluorination. For example, halobetasol propionate and fluticasone propionate exhibit identical chemical structures excepting for their C-17 ester side chains.4 Halobetasol propionate 0.05%, a super-potent topical corticosteroid, is a C-17 chloromethylcarbonyl ester and fluticasone propionate 0.05%, a mid-potency agent, is a C-17 fluorothiomethylcarbonyl ester. Therefore, differences in the esterification side chain at C-17 alone may significantly alter topical corticosteroid potency.
Clocortolone pivalate 0.1% cream, a mid-potency topical corticosteroid, is a dihalogenated agent. The combination of C-9 chlorination and C-6 fluorination modulates potency augmentation to the mid-potency level.11
As described above, the term halogenation alone does not indicate anything specific about corticosteroid potency without knowing additional details. In addition, non-halogenated topical corticosteroids (eg. hydrocortisone butyrate) may exhibit similar potency to halogenated corticosteroids (eg. clocortolone pivalate, mometasone furoate) based on vasoconstrictor assay and may be associated with an equivalent or higher risk for adverse effects.4
Lipophilicity
Overall, lipophilicity of topical corticosteroids has been shown to correlate with steroid receptor affinity using chromatographic techniques and competition assays.12 The exceptions are corticosteroids esterified at C-21, which are classified as prodrugs.
Correlations with HPA Axis Suppression
A concern with prolonged and widespread topical corticosteroid use, especially in infants and small children because of increased skin surface-to-body mass ratio, is HPA axis suppression.5 The safety of judicious use of low- and mid-potency topical corticosteroids has been demonstrated in the pediatric population over a period of 3 to 4 weeks in multiple HPA axis suppression studies.5,13,14 Nevertheless, caution is recommended, especially with use in children, as therapy may become unexpectedly prolonged. This is most likely to occur with treatment of chronic-recurrent disorders such as atopic dermatitis and psoriasis vulgaris.
Laboratory evidence of HPA axis suppression may be associated with use of either halogenated or non-halogenated topical corticosteroids. Clinical significance is not always apparent, especially with limited courses of therapy. Table 1 on page 88 depicts results of HPA axis suppression studies inclusive of both halogenated and non-halogenated topical corticosteroids.4
Impact of Vehicle on Topical Corticosteroid Potency
The impact of vehicle formulation on topical corticosteroid potency based on vasoconstrictor assay testing is well established. Vehicles may differ in terms of drug release characteristics and percutaneous penetration.15 A given corticosteroid compound in the same concentration may be of higher potency when formulated in one vehicle as compared to another.16 For example, the cream and lotion formulations of betamethasone dipropionate 0.05% are rated as high-potency and mid-potency, respectively.
Summary of Variables
• Specific structural modifications impact on the pharmacologic behavior and potency of topical corticosteroids.
• The structural position of halogenation and type of halogen atom that is used correlate with impact on topical corticosteroid potency.
Dihalogenation may or may not significantly alter topical corticosteroid potency depending on the nature and location of halogenation. Several other modifications other than halogenation increase topical corticosteroid potency, such as double-bond placements and esterification at specific positions.
• The lower- and mid-potency topical corticosteroid category includes both halogenated and non-halogenated compounds. Potency and side effect risk are not exclusively dependent on presence of halogenation, as evidenced by studies evaluating laboratory evidence of adrenal suppression.
HPA AXIS STUDY COMPARISONS WITH SELECTED TOPICAL CORTICOSTEROIDS
Study Description: 12 healthy male volunteers underwent therapy with one of either of the following therapies. Study participants either received therapy with:
1. hydrocortisone butyrate 0.1% cream, a non-halogenated mid-potency agent
2. mometasone furoate 0.1% cream, a halogenated mid-potency agent.
During the study, 16 g of the drug was topically applied under occlusion for
11 hours on five separate days (days 3,4,5,6,7). A total of 80 g of either agent
was applied. Mean serum cortisol levels were determined through assays from
days 1, 8 and 15.
Results. Both the non-halogenated (hydrocortisone butyrate 0.1%) and the
halogenated (mometasone furoate 0.1%) topical corticosteroid creams produced
laboratory evidence of adrenal suppression at day 8 with recovery by day 15
(8 days after last application).
Study Description: 10 healthy male volunteers underwent therapy with 60 g of
clocortolone pivalate 0.1% cream applied under occlusion for 12 hours each day over a duration of 21 days. Total cumulative amount of drug applied was 1260 grams. Mean serum cortisol levels were determined through assays completed
on days 1, 12 through 16 and 21.
Results. A dihalogenated (clocortolone pivalate 0.1%) topical corticosteroid
cream exhibited no evidence of adrenal suppression at all tested points
throughout the study.
Commentary. The above studies indicate that laboratory evidence of adrenal
suppression may or may not occur independent of halogenation and cannot be
compared between agents based solely on the amount of drug applied daily or
over time. Several factors may influence potential for HPA axis suppression
among different topical corticosteroid compounds and vehicle formulations.
Topical corticosteroids are a mainstay of therapy in dermatology, and the choices of available agents are plentiful. There is a wide array of options among these agents with variables including chemical structures, halogenation and vehicles. Clinical efficacy, local tolerability and safety also relate to varying pharmacologic properties of topical corticosteroids.
This article updates current understanding of the mechanisms of action, pharmacologic properties, pharmacodynamic effects, vehicle considerations, impact of halogenation and safety considerations related to topical corticosteroids. Clinical implications are also discussed.
Altering Corticosteroids
In 1952, the properties in topically applied “compound F”, a corticosteroid compound, were first described.1 Since that time, research scientists have examined numerous modifications of the basic cyclopentanophenanthrene corticosteroid nucleus through “molecular roulette”, ultimately determining alterations at specific locations in the ring structure or at side chains. These alterations affect properties such as potency, pharmacodynamic activity and potential adverse reaction risks.2-4
As a result, several new topical corticosteroid compounds with potencies ranging from mild to super-potent have been developed over the past five decades, with subsequent approval for use by the FDA. When used appropriately, topical corticosteroids are effective and safe, and remain widely prescribed for a variety of dermatoses. These drugs are used either as monotherapy or in combination with other topical agents, such as calcipotriene (Dovonex), tazarotene (Tazorac), tacrolimus (Protopic) and pimecrolimus (Elidel).5-8
The following discusses structure-activity relationships of corticosteroids, clinical impact and effects of halogenation and specific implications, including hypothalamic-pituitary-adrenal (HPA) axis suppression.
Structure-Activity Relationships
Basic Structural Considerations. The basic structure of adrenal steroids, including corticosteroids and their synthetic derivatives, is the cyclopentanophenanthrene nucleus, which is comprised of three 6-carbon rings (A, B, C) and a single 5-carbon ring (D).3 The chemical structure of the corticosteroid skeleton is depicted in Figure 1.3,4 Certain location-specific structural moieties are necessary for production of and/or accentuation of glucocorticosteroid/anti-inflammatory activity by individual corticosteroid molecules.3 These include the following:
• A ketone group at the third carbon (C-3) of ring A
• A double-bond between C-4 and C-5 on ring A
• Beta-hydroxyl group at C-11
• Ketone group at C-20 (side chain carbon).
In addition, maintaining 3-D spatial and stearic conformations of specific structural groups relates to pharmacologic function.3 Alpha isomers project below and beta isomers above the configuration plane.
The potency of topical corticosteroids is significantly increased by the following structural modifications.4
• C-6a fluorination
• C-9a fluorination
• Halogenation at the C-21 position
• Esterification at the C-17 hydroxyl position
• Esterification at the C-21 hydroxyl position
• Double bond between C-1 and C-2 on ring A.
Specific combinations of the above modifications may further increase topical corticosteroid potency, with higher potency agents, including super-potent compounds (eg. clobetasol, halobetasol) produced in some cases.
Dihalogenation, depending on the site and type of modification, may or may not have a major impact on topical
corticosteroid potency. For example, the addition of a C-6 fluorine to a C-9 fluorinated corticosteroid (eg. halobetasol) does not increase potency as compared to C-9 fluorination alone (eg. clobetasol).4
Significance of Halogenation
Topical corticosteroid potency is most often assessed by vasoconstrictor assay, which appears to correlate with clinical effect.2,9 Results from clinical trials and “real-world” experience also put topical corticosteroids to the test in treating dermatoses, with clinical results either supporting or refuting potency categorizations that have been determined by vasoconstrictor assay for specific formulations.
Halogenation of topical corticosteroids has been equated with production of higher potency and greater potential for adverse reactions, especially application site effects such as atrophy, striae and telangiectasia. This generalization is true in part. However, it may be misleading in terms of differentiating among both halogenated and non-halogenated topical corticosteroid compounds as related to their relative potency and adverse reaction risk. In fact, augmented potency correlates specifically with halogenation at specific structural sites and also with the type of halogen atom used (eg. fluorine, chlorine).3,4
Location-Dependency. As stated above, the degree of impact on topical corticosteroid potency correlates directly with the structural position of halogenation and type of halogen atom that is used.3,4 Maximal augmentation of potency occurs through replacement of hydrogen at C-9 with fluorine (fluorination), with lesser potentiation through fluorination at C-6.4,10 Another modification noted to increase topical corticosteroid potency is additional halogenation at the C-21 position.
Halogen-Type Dependency. The importance of the type of halogen atom used during the halogenation process is supported by the observation that replacement of the C-9 hydrogen with fluorine (fluorination) as opposed to chlorine (chlorination) produces a significantly greater increase in potency.4,10
Misconceptions Regarding Halogen-ation. It is important to recognize that the correlation between halogenation, marked augmentation in potency, and increased risk of adverse reactions, especially local side effects, is dependent on the location and nature of halogenation.
In addition to halogenation, other types of structural modification may lead to varying increases in topical corticosteroid potency.3,4 These include esterification at the C-17 hydroxyl and C-21 hydroxyl positions. The side chain structure used in the esterification process may impact significantly upon topical corticosteroid potency, even in the presence of C-9 and C-6 fluorination. For example, halobetasol propionate and fluticasone propionate exhibit identical chemical structures excepting for their C-17 ester side chains.4 Halobetasol propionate 0.05%, a super-potent topical corticosteroid, is a C-17 chloromethylcarbonyl ester and fluticasone propionate 0.05%, a mid-potency agent, is a C-17 fluorothiomethylcarbonyl ester. Therefore, differences in the esterification side chain at C-17 alone may significantly alter topical corticosteroid potency.
Clocortolone pivalate 0.1% cream, a mid-potency topical corticosteroid, is a dihalogenated agent. The combination of C-9 chlorination and C-6 fluorination modulates potency augmentation to the mid-potency level.11
As described above, the term halogenation alone does not indicate anything specific about corticosteroid potency without knowing additional details. In addition, non-halogenated topical corticosteroids (eg. hydrocortisone butyrate) may exhibit similar potency to halogenated corticosteroids (eg. clocortolone pivalate, mometasone furoate) based on vasoconstrictor assay and may be associated with an equivalent or higher risk for adverse effects.4
Lipophilicity
Overall, lipophilicity of topical corticosteroids has been shown to correlate with steroid receptor affinity using chromatographic techniques and competition assays.12 The exceptions are corticosteroids esterified at C-21, which are classified as prodrugs.
Correlations with HPA Axis Suppression
A concern with prolonged and widespread topical corticosteroid use, especially in infants and small children because of increased skin surface-to-body mass ratio, is HPA axis suppression.5 The safety of judicious use of low- and mid-potency topical corticosteroids has been demonstrated in the pediatric population over a period of 3 to 4 weeks in multiple HPA axis suppression studies.5,13,14 Nevertheless, caution is recommended, especially with use in children, as therapy may become unexpectedly prolonged. This is most likely to occur with treatment of chronic-recurrent disorders such as atopic dermatitis and psoriasis vulgaris.
Laboratory evidence of HPA axis suppression may be associated with use of either halogenated or non-halogenated topical corticosteroids. Clinical significance is not always apparent, especially with limited courses of therapy. Table 1 on page 88 depicts results of HPA axis suppression studies inclusive of both halogenated and non-halogenated topical corticosteroids.4
Impact of Vehicle on Topical Corticosteroid Potency
The impact of vehicle formulation on topical corticosteroid potency based on vasoconstrictor assay testing is well established. Vehicles may differ in terms of drug release characteristics and percutaneous penetration.15 A given corticosteroid compound in the same concentration may be of higher potency when formulated in one vehicle as compared to another.16 For example, the cream and lotion formulations of betamethasone dipropionate 0.05% are rated as high-potency and mid-potency, respectively.
Summary of Variables
• Specific structural modifications impact on the pharmacologic behavior and potency of topical corticosteroids.
• The structural position of halogenation and type of halogen atom that is used correlate with impact on topical corticosteroid potency.
Dihalogenation may or may not significantly alter topical corticosteroid potency depending on the nature and location of halogenation. Several other modifications other than halogenation increase topical corticosteroid potency, such as double-bond placements and esterification at specific positions.
• The lower- and mid-potency topical corticosteroid category includes both halogenated and non-halogenated compounds. Potency and side effect risk are not exclusively dependent on presence of halogenation, as evidenced by studies evaluating laboratory evidence of adrenal suppression.
HPA AXIS STUDY COMPARISONS WITH SELECTED TOPICAL CORTICOSTEROIDS
Study Description: 12 healthy male volunteers underwent therapy with one of either of the following therapies. Study participants either received therapy with:
1. hydrocortisone butyrate 0.1% cream, a non-halogenated mid-potency agent
2. mometasone furoate 0.1% cream, a halogenated mid-potency agent.
During the study, 16 g of the drug was topically applied under occlusion for
11 hours on five separate days (days 3,4,5,6,7). A total of 80 g of either agent
was applied. Mean serum cortisol levels were determined through assays from
days 1, 8 and 15.
Results. Both the non-halogenated (hydrocortisone butyrate 0.1%) and the
halogenated (mometasone furoate 0.1%) topical corticosteroid creams produced
laboratory evidence of adrenal suppression at day 8 with recovery by day 15
(8 days after last application).
Study Description: 10 healthy male volunteers underwent therapy with 60 g of
clocortolone pivalate 0.1% cream applied under occlusion for 12 hours each day over a duration of 21 days. Total cumulative amount of drug applied was 1260 grams. Mean serum cortisol levels were determined through assays completed
on days 1, 12 through 16 and 21.
Results. A dihalogenated (clocortolone pivalate 0.1%) topical corticosteroid
cream exhibited no evidence of adrenal suppression at all tested points
throughout the study.
Commentary. The above studies indicate that laboratory evidence of adrenal
suppression may or may not occur independent of halogenation and cannot be
compared between agents based solely on the amount of drug applied daily or
over time. Several factors may influence potential for HPA axis suppression
among different topical corticosteroid compounds and vehicle formulations.
Topical corticosteroids are a mainstay of therapy in dermatology, and the choices of available agents are plentiful. There is a wide array of options among these agents with variables including chemical structures, halogenation and vehicles. Clinical efficacy, local tolerability and safety also relate to varying pharmacologic properties of topical corticosteroids.
This article updates current understanding of the mechanisms of action, pharmacologic properties, pharmacodynamic effects, vehicle considerations, impact of halogenation and safety considerations related to topical corticosteroids. Clinical implications are also discussed.
Altering Corticosteroids
In 1952, the properties in topically applied “compound F”, a corticosteroid compound, were first described.1 Since that time, research scientists have examined numerous modifications of the basic cyclopentanophenanthrene corticosteroid nucleus through “molecular roulette”, ultimately determining alterations at specific locations in the ring structure or at side chains. These alterations affect properties such as potency, pharmacodynamic activity and potential adverse reaction risks.2-4
As a result, several new topical corticosteroid compounds with potencies ranging from mild to super-potent have been developed over the past five decades, with subsequent approval for use by the FDA. When used appropriately, topical corticosteroids are effective and safe, and remain widely prescribed for a variety of dermatoses. These drugs are used either as monotherapy or in combination with other topical agents, such as calcipotriene (Dovonex), tazarotene (Tazorac), tacrolimus (Protopic) and pimecrolimus (Elidel).5-8
The following discusses structure-activity relationships of corticosteroids, clinical impact and effects of halogenation and specific implications, including hypothalamic-pituitary-adrenal (HPA) axis suppression.
Structure-Activity Relationships
Basic Structural Considerations. The basic structure of adrenal steroids, including corticosteroids and their synthetic derivatives, is the cyclopentanophenanthrene nucleus, which is comprised of three 6-carbon rings (A, B, C) and a single 5-carbon ring (D).3 The chemical structure of the corticosteroid skeleton is depicted in Figure 1.3,4 Certain location-specific structural moieties are necessary for production of and/or accentuation of glucocorticosteroid/anti-inflammatory activity by individual corticosteroid molecules.3 These include the following:
• A ketone group at the third carbon (C-3) of ring A
• A double-bond between C-4 and C-5 on ring A
• Beta-hydroxyl group at C-11
• Ketone group at C-20 (side chain carbon).
In addition, maintaining 3-D spatial and stearic conformations of specific structural groups relates to pharmacologic function.3 Alpha isomers project below and beta isomers above the configuration plane.
The potency of topical corticosteroids is significantly increased by the following structural modifications.4
• C-6a fluorination
• C-9a fluorination
• Halogenation at the C-21 position
• Esterification at the C-17 hydroxyl position
• Esterification at the C-21 hydroxyl position
• Double bond between C-1 and C-2 on ring A.
Specific combinations of the above modifications may further increase topical corticosteroid potency, with higher potency agents, including super-potent compounds (eg. clobetasol, halobetasol) produced in some cases.
Dihalogenation, depending on the site and type of modification, may or may not have a major impact on topical
corticosteroid potency. For example, the addition of a C-6 fluorine to a C-9 fluorinated corticosteroid (eg. halobetasol) does not increase potency as compared to C-9 fluorination alone (eg. clobetasol).4
Significance of Halogenation
Topical corticosteroid potency is most often assessed by vasoconstrictor assay, which appears to correlate with clinical effect.2,9 Results from clinical trials and “real-world” experience also put topical corticosteroids to the test in treating dermatoses, with clinical results either supporting or refuting potency categorizations that have been determined by vasoconstrictor assay for specific formulations.
Halogenation of topical corticosteroids has been equated with production of higher potency and greater potential for adverse reactions, especially application site effects such as atrophy, striae and telangiectasia. This generalization is true in part. However, it may be misleading in terms of differentiating among both halogenated and non-halogenated topical corticosteroid compounds as related to their relative potency and adverse reaction risk. In fact, augmented potency correlates specifically with halogenation at specific structural sites and also with the type of halogen atom used (eg. fluorine, chlorine).3,4
Location-Dependency. As stated above, the degree of impact on topical corticosteroid potency correlates directly with the structural position of halogenation and type of halogen atom that is used.3,4 Maximal augmentation of potency occurs through replacement of hydrogen at C-9 with fluorine (fluorination), with lesser potentiation through fluorination at C-6.4,10 Another modification noted to increase topical corticosteroid potency is additional halogenation at the C-21 position.
Halogen-Type Dependency. The importance of the type of halogen atom used during the halogenation process is supported by the observation that replacement of the C-9 hydrogen with fluorine (fluorination) as opposed to chlorine (chlorination) produces a significantly greater increase in potency.4,10
Misconceptions Regarding Halogen-ation. It is important to recognize that the correlation between halogenation, marked augmentation in potency, and increased risk of adverse reactions, especially local side effects, is dependent on the location and nature of halogenation.
In addition to halogenation, other types of structural modification may lead to varying increases in topical corticosteroid potency.3,4 These include esterification at the C-17 hydroxyl and C-21 hydroxyl positions. The side chain structure used in the esterification process may impact significantly upon topical corticosteroid potency, even in the presence of C-9 and C-6 fluorination. For example, halobetasol propionate and fluticasone propionate exhibit identical chemical structures excepting for their C-17 ester side chains.4 Halobetasol propionate 0.05%, a super-potent topical corticosteroid, is a C-17 chloromethylcarbonyl ester and fluticasone propionate 0.05%, a mid-potency agent, is a C-17 fluorothiomethylcarbonyl ester. Therefore, differences in the esterification side chain at C-17 alone may significantly alter topical corticosteroid potency.
Clocortolone pivalate 0.1% cream, a mid-potency topical corticosteroid, is a dihalogenated agent. The combination of C-9 chlorination and C-6 fluorination modulates potency augmentation to the mid-potency level.11
As described above, the term halogenation alone does not indicate anything specific about corticosteroid potency without knowing additional details. In addition, non-halogenated topical corticosteroids (eg. hydrocortisone butyrate) may exhibit similar potency to halogenated corticosteroids (eg. clocortolone pivalate, mometasone furoate) based on vasoconstrictor assay and may be associated with an equivalent or higher risk for adverse effects.4
Lipophilicity
Overall, lipophilicity of topical corticosteroids has been shown to correlate with steroid receptor affinity using chromatographic techniques and competition assays.12 The exceptions are corticosteroids esterified at C-21, which are classified as prodrugs.
Correlations with HPA Axis Suppression
A concern with prolonged and widespread topical corticosteroid use, especially in infants and small children because of increased skin surface-to-body mass ratio, is HPA axis suppression.5 The safety of judicious use of low- and mid-potency topical corticosteroids has been demonstrated in the pediatric population over a period of 3 to 4 weeks in multiple HPA axis suppression studies.5,13,14 Nevertheless, caution is recommended, especially with use in children, as therapy may become unexpectedly prolonged. This is most likely to occur with treatment of chronic-recurrent disorders such as atopic dermatitis and psoriasis vulgaris.
Laboratory evidence of HPA axis suppression may be associated with use of either halogenated or non-halogenated topical corticosteroids. Clinical significance is not always apparent, especially with limited courses of therapy. Table 1 on page 88 depicts results of HPA axis suppression studies inclusive of both halogenated and non-halogenated topical corticosteroids.4
Impact of Vehicle on Topical Corticosteroid Potency
The impact of vehicle formulation on topical corticosteroid potency based on vasoconstrictor assay testing is well established. Vehicles may differ in terms of drug release characteristics and percutaneous penetration.15 A given corticosteroid compound in the same concentration may be of higher potency when formulated in one vehicle as compared to another.16 For example, the cream and lotion formulations of betamethasone dipropionate 0.05% are rated as high-potency and mid-potency, respectively.
Summary of Variables
• Specific structural modifications impact on the pharmacologic behavior and potency of topical corticosteroids.
• The structural position of halogenation and type of halogen atom that is used correlate with impact on topical corticosteroid potency.
Dihalogenation may or may not significantly alter topical corticosteroid potency depending on the nature and location of halogenation. Several other modifications other than halogenation increase topical corticosteroid potency, such as double-bond placements and esterification at specific positions.
• The lower- and mid-potency topical corticosteroid category includes both halogenated and non-halogenated compounds. Potency and side effect risk are not exclusively dependent on presence of halogenation, as evidenced by studies evaluating laboratory evidence of adrenal suppression.
HPA AXIS STUDY COMPARISONS WITH SELECTED TOPICAL CORTICOSTEROIDS
Study Description: 12 healthy male volunteers underwent therapy with one of either of the following therapies. Study participants either received therapy with:
1. hydrocortisone butyrate 0.1% cream, a non-halogenated mid-potency agent
2. mometasone furoate 0.1% cream, a halogenated mid-potency agent.
During the study, 16 g of the drug was topically applied under occlusion for
11 hours on five separate days (days 3,4,5,6,7). A total of 80 g of either agent
was applied. Mean serum cortisol levels were determined through assays from
days 1, 8 and 15.
Results. Both the non-halogenated (hydrocortisone butyrate 0.1%) and the
halogenated (mometasone furoate 0.1%) topical corticosteroid creams produced
laboratory evidence of adrenal suppression at day 8 with recovery by day 15
(8 days after last application).
Study Description: 10 healthy male volunteers underwent therapy with 60 g of
clocortolone pivalate 0.1% cream applied under occlusion for 12 hours each day over a duration of 21 days. Total cumulative amount of drug applied was 1260 grams. Mean serum cortisol levels were determined through assays completed
on days 1, 12 through 16 and 21.
Results. A dihalogenated (clocortolone pivalate 0.1%) topical corticosteroid
cream exhibited no evidence of adrenal suppression at all tested points
throughout the study.
Commentary. The above studies indicate that laboratory evidence of adrenal
suppression may or may not occur independent of halogenation and cannot be
compared between agents based solely on the amount of drug applied daily or
over time. Several factors may influence potential for HPA axis suppression
among different topical corticosteroid compounds and vehicle formulations.
