Acitretin

Article Author:
Patrick Zito
Article Editor:
Thomas Mazzoni
Updated:
10/27/2018 12:31:20 PM
PubMed Link:
Acitretin

Indications

Acitretin belongs to a group of drugs known as retinoids. Retinoids include natural and synthetic compounds that have similar activity to vitamin A. Vitamin A helps regulate the immune system; impacts cellular growth, differentiation, proliferation; and plays a role in embryonic development. Other effects of retinoids include immunologic anti-inflammatory effects, induction of apoptosis, and inhibition of tumor promotion.

Vitamin A exists as retinol (vitamin A alcohol), retinal (vitamin A aldehyde), and retinoic acid (RA, vitamin A acid). The body cannot synthesize Vitamin A; therefore; it is acquired through diets such as eggs and milk. Carotenoids are precursors of vitamin A that are synthesized by plants. In the intestines, beta-carotene is converted to retinal then absorbed. Each molecule of beta-carotene is converted into two molecules of retinal. Animals with vitamin A deficiency have been observed to have epidermal hyperkeratosis, squamous metaplasia of mucous membranes and precancerous lesions. 

Currently, three generations of synthetic retinoids exist. First generation retinoids include tretinoin (all-trans RA), isotretinoin (13-cis-retinoic acid), and alitretinoin (9-cis RA). Second generation retinoids include etretinate and acitretin. Third generation retinoids include adapalene, tazarotene, and bexarotene. In 1972, Bolag developed two aromatic retinoids: etretinate and acitretin. Acitretin is the retinoic acid metabolite of etretinate. Acitretin is relatively water soluble in comparison and has a little deposition in adipose tissue. 

Acitretin is FDA-approved for psoriasis (severe plaque-type psoriasis, pustular psoriasis generalized, pustular psoriasis localized, combination therapy with ultraviolet B (UVB) or psoralen ultraviolet A (PUVA), combination therapy with cyclosporine, combination therapy with biologic therapies. Acitretin is the only systemic retinoid that is FDA-approved for psoriasis and effective as monotherapy. 

Acitretin has been used off-label in dermatology for other uses.  In those with solid organ transplant, acitretin has been used as a chemoprevention measure for nonmelanoma skin cancers. Acitretin has also been used for Darier disease, pityriasis rubra pilaris (PRP), and ichthyoses such as lamellar ichthyosis. Additionally, acitretin has been used in Grover disease (transient acantholytic dermatosis), lichen planus, and lupus erythematosus.

Mechanism of Action

Retinoids bind cytosolic retinoic acid binding protein (CRABP) that acts as the intracellular carrier transporting it to the nucleus. In the nucleus, retinoids impact transcription by binding of two families of nuclear receptors: retinoic acid receptors (RAR) and retinoid X receptors (RXR). RAR and RXR families contain three receptor subtypes: alpha, beta, and gamma that are encoded by different genes. RAR can bind with RXR forming a heterodimer. RXR can bind with itself forming a homodimer or bind with other nuclear receptors such as thyroid hormone receptor, vitamin D3 receptor, and peripheral peroxidase activating receptor (PPAR). Dimers of RAR/RXR or RXR/RXR bind to DNA regulatory sequences in the promoter region, retinoid acid response elements (RAREs). Once the ligand binds, it undergoes a conformational change to release co-repressors and recruit co-activators. The retinoid-receptor complex may antagonize the action of other transcription factors thus working indirectly. Acitretin competes with RA for CRABP. Acitretin activates but does not bind to multiple RAR.

Acitretin has anti-inflammatory and anti-proliferative effects. It normalizes keratinocyte differentiation in the epithelium. It also hinders the expression of the proinflammatory cytokines like interleukin-6 (IL-6), migration inhibitory factor-related protein-8 (MRP-8), and interferon-gamma. The agent acts by binding and activating all nuclear subtypes of retinoid X-receptors and retinoic acid receptors.

Metabolism

The initial metabolism of acitretin involves isomerization. This differs from isotretinoin where initial metabolism is oxidation. Acitretin is converted to isoacitretin. Acitretin is ultimately eliminated in the bile as beta-glucuronide derivatives or through the kidneys as soluble metabolites.

Acitretin can undergo reverse metabolism to etretinate with acitretin is used in combination with alcohol.

Administration

Initial: Administer 25 to 50 mg orally daily as a single dose with the main meal.

Maintenance: Administer 25 to 50 mg orally daily after initial response to treatment. The maintenance dose should be based on clinical efficacy and tolerability.

In psoriasis treatment with acitretin, improvement is seen approximately at weeks 4 to 6. Maximum benefit may take between 3 to 4 months. Treatment dosing is initiated at 25 mg orally once daily. When the disease is stable, dosing is often reduced to 10 mg orally once daily or 25 mg orally every other day as a maintenance protocol. Treatment with acitretin leads to decreased plaque thickness, scaling, and pruritis. However, there is not much reduction in body surface area (BSA).

In combination with phototherapy, dosing is recommended at 25 mg orally once daily for 2 weeks prior to phototherapy with a need to decrease initial dose of ultraviolet (UV) light. If a patient is already on a stable dose of UV light and is starting acitretin, reduce the dose by 30% to 50% approximately 7 days after initiation of acitretin.

Adverse Effects

Capillary leak syndrome, exfoliative dermatitis, hypercholesterolemia, increased liver enzymes, increased creatinine phosphokinase, hepatotoxicity, hyperesthesia, paresthesia, rigors, cheilitis, alopecia, exfoliation of skin, xeroderma, nail disease, pruritus, erythematous rash, paronychia, hypertriglyceridemia, hyperglycemia, hypoglycemia, reticulocytosis, xerophthalmia, rhinitis, pseudotumor cerebri, tinnitus, and epistaxis.

United States Boxed Warning

Hepatitis

Contraindications

Absolute Contraindications

  • Pregnancy or woman who is likely to become pregnant
  • Non-compliance with contraception
  • Nursing mothers

Hypersensitivity to drug or components, pregnancy, intent to become pregnant within 3 years after treatment discontinuation, severe hepatic or renal dysfunction, chronic abnormally elevated blood lipid levels, or concomitant use with methotrexate or tetracyclines.

It is vital that clinicians who prescribe acitretin to women of childbearing age ensure that the female does not get pregnant for at least 3 years after discontinuing the medication. 

United States Boxed Warning

Female patients should abstain from ethanol during therapy and for at least 2 months after discontinuing therapy.

Monitoring

  • Lipid profile
  • Liver function tests
  • Complete blood count (CBC)
  • Blood glucose in patients with diabetes
  • Evaluation of bone abnormalities
  • Serum pregnancy testing

Toxicity

Caution

  • Combination with methotrexate increases the risk of hepatic adverse effects.
  • Combination with cyclosporine increases the risk of hypertriglyceridemia.
  • Acitretin can undergo reverse metabolism to etretinate with acitretin if used in combination with alcohol.
  • Use of other vitamin A compounds can lead to hypervitaminosis A-like toxicities.
  • Combination of tetracyclines and retinoids can lead to pseudotumor cerebri and should be avoided.

Individuals who are prescribed acitretin are also advised against giving blood donations for at least 3 years. The drug is known to remain in the blood for a long time, and the risk of a birth defect is high.