Natural Topical Retinoids with Emphasis on Tretinoin for the Treatment of Acne

D. R. Thomas, MD, FRCPC
Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

Background

Microcomedones are the precursors to all acne lesions. Topical therapies, such as retinoids, have the ability to substantially reduce their number, thereby disrupting the pathways that lead to the development of both inflammatory and noninflammatory acne lesions.

Retinoids naturally occur in the human body and are implicated in the regulation of a variety of physiologic processes. Their mechanism of action can be explained by their interaction with cell receptors. This cellular interactivity, as it relates to acne, involves controlling and slowing the turnover of skin cells, reducing sebum secretion and inhibiting inflammatory responses. Retinoids can access the skin through systemic modes of administration, as well as through metabolism when applied topically. The effects of retinoids on epidermal proliferation, pigment maturation, and collagen production make them important for treating a number of skin conditions, and as such, they are used extensively.

Approved Topical Retinoids

Naturally occurring retinoids

• All-trans retinol (used in over-the-counter cosmeceuticals)
• All-trans retinoic acid (tretinoin)
• Alitretinoin (US FDA approved for AIDS-related Kaposi's sarcoma)*

Synthesized retinoids

• Adapalene
• Tazarotene
• Bexarotene (US FDA approved for cutaneous lymphoma)*

* Not available in Canada

Histological Changes Following Prolonged Use of Topical Retinoids

• Epidermal thickening of atrophic skin
• Elimination of dystrophic keratinocytes, including actinic damaged cells
• Dispersal of melanin granules, such as those seen in sun damaged skin
• New dermal collagen formation
• Angiogenesis, which may be seen as telangiectasias
• Comedolysis, which breaks down comedones

Tretinoin

Tretinoin was introduced as the first topical retinoid in the 1970s. A number of products containing tretinoin have been developed since; each unique formulation incorporates specific bases and delivery systems, and includes claims of enhanced efficacy and reduced irritancy. Topical tretinoin is approved in various jurisdictions for the treatment of acne, well as for photodamage and anti-aging.

Mechanism of Action

• Activates DNA, normalizing gene expression, affecting cell differentiation and keratinization of the follicular epithelium, preventing comedone production, and triggering the lysis of existing comedones.
• Affects cell growth and differentiation, thereby providing the potential for this agent to improve fine lines, wrinkles, mottled pigmentation and skin roughness. Topical tretinoin has been shown to increase procollagen1 production, which plumps up the epidermis in those with depressed scars and wrinkles.
• Inhibition of the toll-like receptor 2 receptors, which are activated by P. acnes, may explain the significant antiinflammatory effects seen in acne.
• Tretinoin, unlike systemic isotretinoin, does not have a direct effect on the sebum production.

Pharmacology

Only 1%-2% is absorbed in normal skin. However, absorption may be 15 times greater if dermatitis is present. There is minimal uptake into the dermis.

• Tretinoin is an active metabolite that does not require conversion.
• It is found normally in plasma.
• It is excreted in the hepatic system, as well as removed by skin desquamation.

Approved Indications for Use

• Acne
• Photoaging

Contraindications

• Nursing
• Pregnancy, at risk Category C, is a relative contraindication. Despite five case reports, there is no clear evidence that topical retinoids are harmful to the fetus. However, it is prudent to avoid, especially in the first trimester.

Precautions

• Exercise care when using with other photosensitizing drugs, e.g., tetracyclines and thiazides.
• Tretinoin can cause photosensitivity. Instruct patients to avoid unnecessary or prolonged exposure to sunlight, and wear sunscreen and protective clothing.
• Tretinoin can also cause skin irritation and hypo- or hyperpigmentation.

Patient Compliance Can Be Influenced by Product Selection

Skin irritation is a significant concern, especially for eczematous patients, whose skin is already hypersensitive from existing topical treatments; and further exacerbation by retinoids is not likely to gain compliance. Minimize irritation by selecting a tretinoin formulation that is combined with a vehicle most suitable for the patient’s skin type. A special microsphere waterbased gel delivery system where the tretinoin is delivered to the epidermis more slowly and evenly can be less irritating. This delivery system also allows more predictable sustained applications to be used in the skin. These new water-based gels must be distinguished from alcohol-based gels.

Other options to improve tolerance for other bases include:

• Using a cream base rather than an alcohol-based gel.
• Initially using a lower concentration of the retinoid.
• For those with oily skin, an aqueous gel might reduce an oily appearance.
• Patients with dry skin, do better by avoiding the traditional alcohol gels.

In the initial phase of treatment, it must be made clear to the patient that the acne can increase or appear to worsen. This perception is common even if there is an actual reduction in acne counts. Visible improvement may be noted after 2 weeks of treatment, but the appearance may be worse for the first few weeks. However, it is important for the sake of compliance to explain that significant improvement may take up to 2–3 months to occur.

Advice to the Patient to Enhance Compliance

Quantity:

Use a moisturizer:

Dry skin:

Time of application:

Contact time:

Frequency of application:

Area of application:

Expectations for rate of response:

How long is treatment required?

Photoprotection:

Benefits

All acne patients can benefit from topical retinoids:

• As a first-line treatment for those with comedonal acne
• Mixed comedonal and inflammatory acne will benefit
• For mild-to-moderate inflammatory acne

Patients with severe acne can be helped by topical tretinoin once the severity of the acne has been diminished by systemic therapy. It can be used to reduce recurrence. Cystic acne needs systemic therapy, but topical retinoids, following the use of oral isotretinoin, may reduce recurrences by preventing the formation of microcomedones, as well as using the collagen enhancing properties to hasten the repair of depressed areas of the skin.

Conclusion

Topical retinoids are the cornerstone of acne therapy and they can be used across the entire spectrum of acne severity. Selecting the most suitable retinoid formulation, as well as dispensing proper advice in terms of drug application, can improve patient compliance. It is also important to establish realistic patient expectations with regard to the rate of improvement in order to ensure compliance and increase the chances of achieving treatment success.

• Natural Topical Retinoids with Emphasis on Tretinoin for the Treatment of Acne
• Topical Antipsoriatic Treatments in 2007
• Dermatological Drug Use in Pregnancy