185: Retinoids Flashcards
What are retinoids and how do they function in the body?
Retinoids are prescription drugs and cosmeceuticals that elicit skin responses by mediating their effects through intranuclear retinoid receptors, acting as transcription factors. They bind to retinoic acid receptors (RARs) and retinoid X receptors (RXRs), activating retinoic acid-responsive genes and resulting in specific biological responses.
What are the structural components of all-trans-retinoic acid (tretinoin)?
All-trans-retinoic acid (tretinoin) is a 20-carbon molecule that consists of: 1. A cyclohexenyl ring 2. A side chain with four double bonds (all arranged in trans-configuration) 3. A carboxylic-acid end group.
How are retinoids classified and what are examples of each generation?
Retinoids are classified into three generations: 1. First: All-trans-retinoic acid (tretinoin), 13-cis-retinoic acid (isotretinoin), 9-cis-retinoic acid (alitretinoin) 2. Second: Etretinate (an ethyl ester), Acitretin (free acid metabolite of etretinate) 3. Third: Adapalene, Tazarotene, Bexarotene.
What is the role of retinoid receptors in gene transcription?
Retinoid receptors have molecular features similar to steroid and thyroid hormone receptors. They bind to regulatory regions in DNA called hormone response elements (target sequences) and activate gene transcription in a ligand-dependent manner.
What are the clinical implications of the structural modifications in retinoids?
Structural modifications in retinoids, such as the addition of a hydroxyl group to the cyclohexenyl ring, can enhance the polarity of the molecule, making it more amenable to excretion and elimination. This can affect the pharmacokinetics and therapeutic efficacy of the retinoid, influencing its clinical use and safety profile.
What are retinoids used for?
As prescription drugs and cosmeceuticals to elicit skin responses.
What do retinoic acid receptors (RARs) and retinoid X receptors (RXRs) do?
They act as transcription factors that mediate the effects of retinoids.
What is the structure of all-trans-retinoic acid (tretinoin)?
It consists of a cyclohexenyl ring, a side chain with four double bonds, and a carboxylic-acid end group.
What is the significance of the 4th carbon atom in retinoic acid?
It is involved in a hydroxylation reaction to generate 4-hydroxy-retinoic acid, making the molecule more polar.
How are retinyl esters formed?
By esterification of retinol with fatty acids, serving as a molecular storage form of retinol.
What distinguishes first-generation retinoids from second and third generations?
First-generation retinoids include all-trans-retinoic acid and its isomers, while second and third generations involve structural modifications and receptor specificity.
What are some examples of third-generation retinoids?
Adapalene, tazarotene, and bexarotene.
What is the physiological ligand for RXR?
9-cis-retinoic acid.
What is the function of cellular retinoic acid binding protein (CRABP) II?
It plays a role in the transport and metabolism of retinoic acid in skin cells.
What are the clinical implications of using all-trans-retinoic acid (tretinoin) in treating skin conditions?
All-trans-retinoic acid (tretinoin) is effective in treating conditions such as acne, psoriasis, and photoaging due to its ability to bind and activate retinoic acid receptors (RARs), leading to transcriptional activation of retinoic acid-responsive genes. This results in improved skin cell turnover, reduced inflammation, and enhanced collagen production.
How do the structural differences between first-generation and second-generation retinoids affect their pharmacological properties?
First-generation retinoids, such as all-trans-retinoic acid and isotretinoin, primarily act through RAR activation. In contrast, second-generation retinoids, like etretinate and acitretin, have modified structures that enhance their receptor specificity and may lead to different pharmacokinetic profiles, potentially resulting in improved efficacy and reduced side effects.
What role do retinoid receptors play in the mechanism of action of retinoids, and how does this influence therapeutic outcomes?
Retinoid receptors, including RARs and RXRs, bind to specific DNA sequences and regulate gene transcription in a ligand-dependent manner. This binding activates retinoic acid-responsive elements (RARE) in gene promoters, influencing cellular processes such as differentiation and proliferation, which are crucial for the therapeutic effects of retinoids in skin conditions.
Discuss the significance of the stereoisomers of all-trans-retinoic acid in clinical applications and their potential effects on treatment outcomes.
The stereoisomers of all-trans-retinoic acid, such as 9-cis-retinoic acid (alitretinoin) and 13-cis-retinoic acid (isotretinoin), exhibit different binding affinities and biological activities at retinoid receptors. This can lead to variations in therapeutic effects, side effects, and overall treatment outcomes, making the choice of stereoisomer important in clinical practice.
What are the potential side effects associated with the use of retinoids, and how can they be managed in clinical practice?
Common side effects of retinoids include skin irritation, dryness, and photosensitivity. Management strategies include gradual dose escalation, using moisturizers, and advising patients on sun protection measures. Monitoring for more severe effects, such as teratogenicity in pregnant patients, is also crucial to ensure safe use of retinoids.
What is the effect of all-trans-retinol or retinaldehyde on retinyl ester levels in the epidermal layer?
Treatment with all-trans-retinol or retinaldehyde increases retinyl ester levels in the epidermal layer by more than 10-fold.
What are the two enzymes that catalyze the esterification and oxidation of retinol?
The two enzymes are: 1. Lecithin/retinol acyltransferase - predominant retinol-esterifying activity in human keratinocytes. 2. Acyl-coenzyme A/retinol acyltransferase.
What are the histologic and molecular alterations that occur after treatment with all-trans-retinoic acid?
The alterations include: - Epidermal hyperplasia - Epidermal spongiosis - Compaction of the stratum corneum - Induction of CRBP, CRABP-II, and CYP26.
How does the bioavailability of oral retinoids change when administered with food?
The oral bioavailability of all retinoids is markedly enhanced when they are administered with food, especially with fatty meals.
What is the major metabolite of isotretinoin and its bioactivity?
The major metabolite of isotretinoin is 4-oxoisotretinoin, which has reduced bioactivity.
What is the pharmacokinetic advantage of acitretin over etretinate?
Acitretin is eliminated more rapidly than etretinate, which has a longer half-life of up to 120 days.
What is the primary use of topical retinoids in acne therapy?
Topical retinoids are extremely effective for acne therapy, especially for comedonal lesions, and they help normalize abnormal follicular epithelial differentiation and desquamation in acne.
What are the approved indications for tazarotene?
Tazarotene is approved for acne, psoriasis, and photoaging.
What is the mechanism of action of alitretinoin gel in treating cutaneous Kaposi sarcoma?
Alitretinoin gel inhibits cellular proliferation and induces apoptosis, and it has an antiviral role against HHV-8.
What are the potential effects of topical retinoids on molluscum contagiosum and warts?
Topical retinoids may improve molluscum contagiosum, warts, and various forms of ichthyosis to a variable degree.
A patient on acitretin therapy for psoriasis consumes alcohol. What are the potential consequences, and what precautions should be taken?
Alcohol consumption during acitretin therapy can lead to the formation of etretinate, which has a longer half-life and extends the time of compulsory contraception to 2 years (3 years in the US). Patients must strictly avoid alcohol during treatment and for 2 months thereafter.
A patient with CTCL is prescribed topical bexarotene. What are its mechanisms of action?
Topical bexarotene inhibits tumor cell growth, encourages terminal differentiation, induces apoptosis, and may play a role in chemoprophylaxis.
What is the primary mechanism of action for all-trans-retinoic acid in human skin?
It increases retinyl ester levels in the epidermal layer by more than 10-fold.
What is the significance of CYP26 in the metabolism of all-trans-retinoic acid?
CYP26 activity is minimally detectable in untreated normal human skin but increases significantly with administration of retinoids.
What is the main difference in the pharmacokinetics of oral retinoids compared to topical retinoids?
Oral retinoids have enhanced bioavailability when administered with food, especially fatty meals.
What is the role of isotretinoin in acne treatment?
It normalizes follicular epithelial differentiation and desquamation, providing protection against the development of new lesions.
What is the recommended duration of contraception after isotretinoin treatment?
One month posttherapy provides an adequate safety margin.
What is the primary use of topical bexarotene?
It is used for the treatment of cutaneous T-cell lymphoma and inhibits tumor cell growth.
What are the indications for alitretinoin gel?
It is approved for cutaneous Kaposi sarcoma caused by human herpes virus 8 (HHV-8).
What is a common side effect of topical retinoids in patients with greater constitutive pigmentation?
Retinoid dermatitis does not usually lead to postinflammatory hyperpigmentation.
What is the effect of topical retinoids on photoaged skin?
They improve fine wrinkles and dyspigmentation, requiring several weeks of treatment for clinical improvement.
What are the metabolic pathways involved in the esterification and oxidation of retinol, and how do they affect skin treatment outcomes?
The metabolic pathways for retinol include: 1. Esterification: All-trans-retinol or retinaldehyde increases retinyl ester levels in the epidermal layer by more than 10-fold. Catalyzed by two enzymes: Lecithin/retinol acyltransferase (predominant in keratinocytes) and Acyl-coenzyme A/retinol acyltransferase. 2. Oxidation: Sequential oxidation of all-trans-retinol forms all-trans-retinoic acid, with all-trans-retinaldehyde as the intermediate metabolite. This oxidation is the rate-limiting step for all-trans-retinoic acid formation. These processes lead to histologic and molecular alterations in the skin, including epidermal hyperplasia and spongiosis, which mimic the effects of all-trans-retinoic acid treatment.
How does the pharmacokinetics of isotretinoin differ from that of acitretin, and what implications does this have for their clinical use?
The pharmacokinetics of isotretinoin and acitretin differ significantly: 1. Metabolism: Isotretinoin undergoes first-pass metabolism in the liver and enterohepatic recycling. Acitretin is a pro-drug of etretinate, undergoing extensive hydrolysis. 2. Half-life: Isotretinoin varies but is generally longer than acitretin (approximately 2 days). 3. Bioactivity: 4-oxoisotretinoin is the major metabolite of isotretinoin with reduced bioactivity, while acitretin is more lipophilic and binds strongly to plasma lipoprotein. 4. Elimination: Isotretinoin is excreted in urine and feces, while acitretin is eliminated more rapidly than etretinate. Clinical implications include the need for a 1-month post-therapy contraception period for isotretinoin due to its longer half-life and potential teratogenic effects, while acitretin requires extended contraception due to the possibility of etretinate formation when taken with alcohol.
What are the indications and contraindications for the use of topical retinoids in acne therapy?
Topical retinoids are indicated for: 1. Acne: Particularly effective for comedonal lesions. 2. Post-inflammatory hyperpigmentation: Especially in black individuals. 3. Actinic dyspigmentation: Notably in Chinese and Japanese individuals. 4. Early stretch marks: Can be beneficial in various age groups, with exceptions for neonates. Contraindications include: Use in pregnancy is discouraged until after delivery due to potential risks to the mother and fetus, and patients with a history of hypersensitivity to retinoids should avoid these treatments.
What is the mechanism of action of alitretinoin gel in the treatment of cutaneous Kaposi sarcoma, and what are its clinical implications?
Alitretinoin gel is approved for the treatment of cutaneous Kaposi sarcoma (KS) caused by human herpes virus 8 (HHV-8). Its mechanism of action includes: 1. Inhibition of cellular proliferation: Alitretinoin inhibits the growth of malignant cells. 2. Induction of apoptosis: It promotes programmed cell death in affected cells. 3. Antiviral activity: It has a role against HHV-8, which is significant in KS. Clinical implications include improvement in skin lesions typically observed after 4 to 8 weeks of treatment, with the most significant response occurring after 14 weeks.
What is the primary use of topical tazarotene?
Topical tazarotene is primarily approved for the treatment of psoriasis and is typically used in combination with topical steroids due to irritation issues.
What are the clinical features improved by isotretinoin in the treatment of acne?
Isotretinoin significantly improves the following clinical features in acne treatment: 1. Sebum production 2. Comedogenesis 3. Colonization with Propionibacterium acnes.
What are the clinical features improved by isotretinoin in the treatment of acne?
Isotretinoin significantly improves the following clinical features in acne treatment:
1. Sebum production
2. Comedogenesis
3. Colonization with Propionibacterium acnes
4. Photoaging
5. Increased collagen
6. Elastic fiber density
What is the recommended dosage of oral bexarotene for CTCL treatment?
The recommended dosage of oral bexarotene for the treatment of CTCL is 300 mg/m² or more per day within the first 2 months.
What is the significance of acitretin in the treatment of psoriasis?
Acitretin is the retinoid of choice for psoriasis, particularly effective in pustular psoriasis of the palmoplantar or generalized type, showing significant improvement in about 50% of treated patients and a decrease in psoriasis area and severity index by approximately 60% to 70% depending on dosage.
What are the expected side effects of topical retinoid therapy?
Expected side effects of topical retinoid therapy include local skin irritation, such as redness and peeling. It is important to educate patients that clinical improvement correlates with the degree of irritation, and that administration should be individualized based on skin reaction.
What is the role of alitretinoin in dermatological treatment?
Alitretinoin is approved in Europe and Canada for the treatment of treatment-resistant chronic hand eczema, requiring between 3 and 6 months of therapy to fully appreciate its effects.
What are the key mechanisms by which isotretinoin treats acne?
Isotretinoin treats acne by reducing sebum production (caused by atrophy of sebaceous glands), inhibiting comedogenesis, and reducing colonization with Propionibacterium acnes.
