Tretinoin

Usage

Tretinoin, whether topical or oral, is primarily used in dermatology and oncology.

Topical tretinoin is prescribed for:

• Acne vulgaris: It treats comedonal, papular, and pustular acne by increasing skin cell turnover.
• Photoaging: It reduces fine wrinkles, mottled hyperpigmentation, and roughness caused by sun exposure.

Oral tretinoin is indicated for:

• Acute promyelocytic leukemia (APL): It induces differentiation and reduces proliferation of APL cells. It’s often used in combination with arsenic trioxide or chemotherapy.

Pharmacological Classification:

• Topical: Retinoid
• Oral: Antineoplastic, Retinoid

Mechanism of Action (General):

• Tretinoin is a derivative of Vitamin A (retinoic acid) that binds to specific receptors within cells, influencing gene expression related to cell growth and differentiation.

Alternate Names

• All-trans retinoic acid (ATRA)
• Retinoic acid

Brand Names:

• Vesanoid (oral capsules)
• Retin-A (topical cream, gel, liquid)
• Avita (topical cream)
• Renova (topical cream)
• Stieva-A (topical cream, gel)
• Retin-A Micro (topical gel)
• Treclin (topical gel, in combination with clindamycin)

How It Works

Pharmacodynamics:

• Topical: Tretinoin increases the turnover of follicular epithelial cells, reducing comedone formation and treating acne. It also thins the stratum corneum, improving skin texture and reducing wrinkles.
• Oral (APL): Tretinoin induces differentiation of APL cells, halting their uncontrolled proliferation and promoting maturation into normal cells.

Pharmacokinetics:

• Topical: Minimally absorbed systemically.
• Oral: Well-absorbed orally. Metabolized primarily in the liver via CYP enzymes (primarily CYP2C8, CYP3A4, and CYP26). Excreted mainly in bile and feces, with a small portion in urine.

Mode of Action (Cellular/Molecular):

Tretinoin binds to retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which are nuclear receptors that regulate gene transcription related to cell growth, differentiation, and apoptosis.

Elimination Pathways:

• Topical: Primarily through desquamation of skin cells.
• Oral: Primarily hepatic metabolism and biliary excretion, with a small portion renally excreted.

Dosage

Standard Dosage

Adults:

• Topical (Acne/Photoaging): Apply a pea-sized amount to the affected area once daily at bedtime. Start with a lower concentration (0.025% or 0.01%) and increase as tolerated.
• Oral (APL): 45 mg/m²/day orally, divided every 12 hours. Continue until complete remission or up to a maximum of 90 days.

Children:

• Topical: Not recommended for children under 12 years of age for acne. For other uses, consult a physician for specific recommendations.
• Oral (APL): Similar dosing to adults (45 mg/m²/day) can be considered, but a lower dose (25 mg/m²/day) may be used to reduce toxicity.

Special Cases:

• Elderly Patients: Similar to adult dosing.
• Patients with Renal Impairment: No specific dose adjustments typically required for topical use. For oral use, caution is advised, and monitoring is recommended.
• Patients with Hepatic Dysfunction: For oral use, dose reduction and close monitoring are recommended.
• Patients with Comorbid Conditions: Consider individual patient factors and potential drug interactions.

Clinical Use Cases (Oral Tretinoin)

Oral tretinoin is specifically indicated for APL and not typically used in settings like intubation, surgical procedures, mechanical ventilation, ICU use, or general emergency situations.

Dosage Adjustments (Oral Tretinoin)

Dose reduction may be necessary in cases of severe adverse effects, hepatic impairment, or certain drug interactions.

Side Effects

Common Side Effects:

• Topical: Skin dryness, redness, itching, burning, peeling.
• Oral: Headache, fever, fatigue, weakness, dry skin, mucositis, nausea, vomiting, bone pain, increased risk of bleeding.

Rare but Serious Side Effects:

• Topical: Severe skin irritation, allergic reactions.
• Oral: Retinoic acid syndrome (RAS), leukocytosis, severe hypertriglyceridemia, pancreatitis, intracranial hypertension, serious bleeding.

Long-Term Effects:

• Topical: Potential for skin discoloration.
• Oral: Not applicable, as treatment duration is typically limited.

Adverse Drug Reactions (ADR):

• Topical: Severe allergic reactions.
• Oral: RAS, leukocytosis, intracranial hypertension, severe bleeding.

Contraindications

• Topical: Hypersensitivity to tretinoin or any component of the formulation. Caution in pregnancy, especially first trimester.
• Oral: Hypersensitivity to tretinoin or any component of the formulation. Pregnancy (especially first trimester), breastfeeding.

Drug Interactions

• Topical: Concurrent use of other topical acne medications, especially those containing peeling agents (e.g., benzoyl peroxide, salicylic acid), can increase irritation. Concomitant use with photosensitizing drugs can increase sun sensitivity.
• Oral: Numerous drug interactions exist. Consult a comprehensive drug interaction database for detailed information before prescribing. Some examples include:
  • Vitamin A supplements: Can increase the risk of vitamin A toxicity.
  • Tetracycline antibiotics: Can increase photosensitivity.
  • Anticoagulants: Effects may be altered.

Pregnancy and Breastfeeding

• Pregnancy:
  • Topical: Use with caution, especially in the first trimester.
  • Oral: Contraindicated. Effective contraception is essential during and for one month after treatment.
• Breastfeeding:
  • Topical: Generally considered low risk due to minimal systemic absorption. Avoid applying to the nipple area.
  • Oral: Contraindicated.

Drug Profile Summary

• Mechanism of Action: Regulates gene expression related to cell growth and differentiation.
• Side Effects (Topical): Dryness, redness, itching, burning, peeling.
• Side Effects (Oral): Headache, fever, fatigue, mucositis, RAS, leukocytosis, increased bleeding risk.
• Contraindications (Both): Hypersensitivity. Oral: Pregnancy, breastfeeding.
• Drug Interactions (Topical): Other topical acne medications, photosensitizing drugs.
• Drug Interactions (Oral): Numerous, consult a drug interaction database.
• Pregnancy & Breastfeeding: Topical: Use with caution (especially in the first trimester for pregnancy). Oral: Contraindicated.
• Dosage (Topical): Apply pea-sized amount once daily.
• Dosage (Oral APL): 45 mg/m²/day divided every 12 hours.
• Monitoring Parameters (Oral): Complete blood count (CBC) with differential, coagulation studies, liver function tests, lipid panel, signs and symptoms of RAS.

Popular Combinations

• Oral (APL): Tretinoin is frequently used in combination with arsenic trioxide or chemotherapy (e.g., anthracyclines) for APL.
• Topical (Acne): Tretinoin can be used in combination with clindamycin, benzoyl peroxide (with caution due to increased irritation), or other acne medications as prescribed by a doctor.

Precautions

• General Precautions: Hypersensitivity, pre-existing skin conditions.
• Specific Populations: See Pregnancy and Breastfeeding section.
• Lifestyle Considerations: For topical use, sun protection is crucial.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for tretinoin?

A: Dosage depends on the formulation and indication. Topical: Apply pea-sized amount once daily, starting with a lower concentration. Oral (APL): 45 mg/m²/day, divided every 12 hours.

Q2: How does tretinoin work for acne?

A: It increases skin cell turnover, preventing clogged pores and reducing inflammation.

Q3: What are the common side effects of topical tretinoin?

A: Dryness, redness, itching, burning, and peeling are common, especially initially.

Q4: Can pregnant women use tretinoin?

A: Topical use should be discussed with a doctor, especially in the first trimester. Oral tretinoin is contraindicated during pregnancy.

Q5: How long does it take for tretinoin to work?

A: Several weeks to months for both acne and anti-aging effects.

Q6: Can I use tretinoin with other acne medications?

A: Combining with certain medications can increase irritation. Consult with a dermatologist.

Q7: What is retinoic acid syndrome (RAS)?

A: A serious side effect of oral tretinoin characterized by fever, respiratory distress, and other systemic symptoms. Requires immediate medical attention.

Q8: Are there any drug interactions with oral tretinoin?

A: Yes, numerous. Consult a comprehensive drug interaction database before prescribing or dispensing.

Q9: What should I do if I experience severe skin irritation with topical tretinoin?

A: Discontinue use and consult a dermatologist.

Q10: How should topical tretinoin be applied?

A: Apply a pea-sized amount to clean, dry skin once daily at bedtime, avoiding the eyes, mouth, and mucous membranes.