madman
Super Moderator
Abstract
Retinoids are defined as molecules that bind to and activate retinoic acid receptors to influence the proliferation and differentiation of cells. Topical retinoids have evolved over the past several decades, being used in multiple dermatological conditions. This review aims to differentiate between synthetic and natural retinoids, discuss the pharmacology behind topical retinoids, highlight clinical applications, and categorize all the commercially available agents, including combination products. Understanding retinoid affinities for unique receptor subtypes can impact clinical decisions, resulting in optimizing treatment and enhancing patient adherence.
Introduction
Topical retinoids have evolved over the past several decades, being used in an array of dermatological conditions. Some of these approved indications include acne vulgaris, psoriasis, photoaging/rhytides, cutaneous T-cell lymphoma, and Kaposi’s sarcoma. They are also used off-label in conditions such as keratosis pilaris and hyperpigmentation.1 In general, retinoids are divided into 4 generations based on their molecular structure and receptor selectivity. Topical retinoids are divided into 6 classes. The 6 classes of topical retinoids include Tretinoin (alltrans retinoic acid), adapalene, tazarotene, trifarotene, alitretinoin, and bexarotene. The last 2 classes, alitretinoin, and bexarotene are topical and oral retinoids used in Kaposi’s sarcoma and cutaneous T-cell lymphoma, although infrequently. The availability of alitretinoin and bexarotene topically are limited and are usually required to be compounded. Alitretinoin and bexarotene will not be discussed further in this review. This review aims to differentiate between synthetic and natural topical retinoids, discuss the pharmacology behind topical retinoids, highlight clinical applications, and categorize all the commercially available agents and their combination products.
*The Link Between Vitamin A, Retinoic Acid, and the Body
*Topical Retinoids Mechanism of Action
*Pharmacology of Retinoids and Their Receptors
Nuclear Receptors of Retinoids and Their Roles in Treatment
*Retinoids and Pregnancy
*Clinical Application of Retinoids
First Generation Retinoids
Tretinoin (All-trans retinoic acid) is the first topical retinoid to be developed. Tretinoin is indicated in the treatment of acne vulgaris and photoaging/rhytides. It is also used off-label to treat keratosis pilaris, actinic keratosis, and hyperpigmentation (melasma, solar lentigines).1 Tretinoin comes in different formulations, including cream and gel. Tretinoin is one of the more cost-effective retinoids; however, it is slightly irritating and is more photolabile than others.36 The development of microsphere technology, seen in tretinoin formulations (Retin-A Micro 0.04%, 0.1%), has helped improve photostability and mitigate some of the adverse effects seen using these agents.37 Microspheres help facilitate the delivery of potentially irritating drugs, minimizing irritation, resulting in better patient adherence.37
Tretinoin has also been formulated as a combination product with clindamycin for the treatment of acne vulgaris.
Second Generation Retinoids
There are no topically available second-generation formulations of retinoids.
Third Generation Retinoids
Tazarotene is a topical retinoid indicated in acne vulgaris and the only retinoid indicated in the use of plaque psoriasis. As a mono-therapy, it is available as a cream and gel formulation (0.05% and 0.1%) and is one of the most potent of the retinoids.38 It has also been combined in a lotion, with the high potency topical corticosteroid halobetasol, as a topical agent for plaque psoriasis.
Adapalene is a topical retinoid indicated in acne vulgaris. Off-label is also used in the treatment of hyperpigmentation and actinic keratosis, and due to its tolerability, it is often used off-label for photoaging/rhytides.1 It is available in 2 different concentrations, like cream and gel in 0.1% and gel in 0.3%, and is available over the counter (OTC) in the United States. Adapalene is the least irritating and least prone to photodegradation,36 allowing for daytime application. Adapalene has also been formulated in conjunction with benzoyl peroxide for use in acne vulgaris. It should be noted that both retinoids and benzoyl peroxide can be irritating and drying to the skin; therefore, their use in a combination product can amplify this side effect. Slow titration of combination products used in this class may result in better tolerance over time.
Fourth Generation Retinoids
Trifarotene is a fourth-generation topical retinoid with selectivity towards the RAR receptor located in the epidermis. Trifarotene is indicated for acne vulgaris of the face and trunk; this agent is available as a cream formulation. It is presumed that the trunk and face indications of this agent are based upon data demonstrating a lower risk of systemic absorption associated with its use. Studies using laboratory testing to assess systemic absorption of trifarotene demonstrated unquantifiable levels within their target populations, those aged (≥18 years) and pediatric patients (9‐17 years) with moderate to severe acne.39
*Differentiating Cosmetic Retinols and Prescription Retinoids
*Future Developments in Topical Retinoids
Conclusion
Topical retinoids have evolved over the decades from first-generation tretinoin, which is still a commonly used treatment approach for many dermatologists. The continued investigation of these agents led to the discovery of third and fourth-generation retinoids, which have advantages in potency, tolerability, photostability, and other indications. Research into receptor binding sites of retinoids has also led to discovering a fourth-generation retinoid, trifarotene, which has selectivity towards RAR. Ongoing research will undoubtedly lead to further developments and understanding of topical retinoids and their uses.
Retinoids are defined as molecules that bind to and activate retinoic acid receptors to influence the proliferation and differentiation of cells. Topical retinoids have evolved over the past several decades, being used in multiple dermatological conditions. This review aims to differentiate between synthetic and natural retinoids, discuss the pharmacology behind topical retinoids, highlight clinical applications, and categorize all the commercially available agents, including combination products. Understanding retinoid affinities for unique receptor subtypes can impact clinical decisions, resulting in optimizing treatment and enhancing patient adherence.
Introduction
Topical retinoids have evolved over the past several decades, being used in an array of dermatological conditions. Some of these approved indications include acne vulgaris, psoriasis, photoaging/rhytides, cutaneous T-cell lymphoma, and Kaposi’s sarcoma. They are also used off-label in conditions such as keratosis pilaris and hyperpigmentation.1 In general, retinoids are divided into 4 generations based on their molecular structure and receptor selectivity. Topical retinoids are divided into 6 classes. The 6 classes of topical retinoids include Tretinoin (alltrans retinoic acid), adapalene, tazarotene, trifarotene, alitretinoin, and bexarotene. The last 2 classes, alitretinoin, and bexarotene are topical and oral retinoids used in Kaposi’s sarcoma and cutaneous T-cell lymphoma, although infrequently. The availability of alitretinoin and bexarotene topically are limited and are usually required to be compounded. Alitretinoin and bexarotene will not be discussed further in this review. This review aims to differentiate between synthetic and natural topical retinoids, discuss the pharmacology behind topical retinoids, highlight clinical applications, and categorize all the commercially available agents and their combination products.
*The Link Between Vitamin A, Retinoic Acid, and the Body
*Topical Retinoids Mechanism of Action
*Pharmacology of Retinoids and Their Receptors
Nuclear Receptors of Retinoids and Their Roles in Treatment
*Retinoids and Pregnancy
*Clinical Application of Retinoids
First Generation Retinoids
Tretinoin (All-trans retinoic acid) is the first topical retinoid to be developed. Tretinoin is indicated in the treatment of acne vulgaris and photoaging/rhytides. It is also used off-label to treat keratosis pilaris, actinic keratosis, and hyperpigmentation (melasma, solar lentigines).1 Tretinoin comes in different formulations, including cream and gel. Tretinoin is one of the more cost-effective retinoids; however, it is slightly irritating and is more photolabile than others.36 The development of microsphere technology, seen in tretinoin formulations (Retin-A Micro 0.04%, 0.1%), has helped improve photostability and mitigate some of the adverse effects seen using these agents.37 Microspheres help facilitate the delivery of potentially irritating drugs, minimizing irritation, resulting in better patient adherence.37
Tretinoin has also been formulated as a combination product with clindamycin for the treatment of acne vulgaris.
Second Generation Retinoids
There are no topically available second-generation formulations of retinoids.
Third Generation Retinoids
Tazarotene is a topical retinoid indicated in acne vulgaris and the only retinoid indicated in the use of plaque psoriasis. As a mono-therapy, it is available as a cream and gel formulation (0.05% and 0.1%) and is one of the most potent of the retinoids.38 It has also been combined in a lotion, with the high potency topical corticosteroid halobetasol, as a topical agent for plaque psoriasis.
Adapalene is a topical retinoid indicated in acne vulgaris. Off-label is also used in the treatment of hyperpigmentation and actinic keratosis, and due to its tolerability, it is often used off-label for photoaging/rhytides.1 It is available in 2 different concentrations, like cream and gel in 0.1% and gel in 0.3%, and is available over the counter (OTC) in the United States. Adapalene is the least irritating and least prone to photodegradation,36 allowing for daytime application. Adapalene has also been formulated in conjunction with benzoyl peroxide for use in acne vulgaris. It should be noted that both retinoids and benzoyl peroxide can be irritating and drying to the skin; therefore, their use in a combination product can amplify this side effect. Slow titration of combination products used in this class may result in better tolerance over time.
Fourth Generation Retinoids
Trifarotene is a fourth-generation topical retinoid with selectivity towards the RAR receptor located in the epidermis. Trifarotene is indicated for acne vulgaris of the face and trunk; this agent is available as a cream formulation. It is presumed that the trunk and face indications of this agent are based upon data demonstrating a lower risk of systemic absorption associated with its use. Studies using laboratory testing to assess systemic absorption of trifarotene demonstrated unquantifiable levels within their target populations, those aged (≥18 years) and pediatric patients (9‐17 years) with moderate to severe acne.39
*Differentiating Cosmetic Retinols and Prescription Retinoids
*Future Developments in Topical Retinoids
Conclusion
Topical retinoids have evolved over the decades from first-generation tretinoin, which is still a commonly used treatment approach for many dermatologists. The continued investigation of these agents led to the discovery of third and fourth-generation retinoids, which have advantages in potency, tolerability, photostability, and other indications. Research into receptor binding sites of retinoids has also led to discovering a fourth-generation retinoid, trifarotene, which has selectivity towards RAR. Ongoing research will undoubtedly lead to further developments and understanding of topical retinoids and their uses.
