Acitretin

Article Author:
Patrick Zito
Article Editor:
Thomas Mazzoni
Updated:
10/11/2019 7:29:49 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.[1][2][3]

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; one must acquire it in the diet through foods 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 converts 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 transplants, acitretin has served 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 a use in Grover disease (transient acantholytic dermatosis), lichen planus, and lupus erythematosus.[4]

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-activated 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.[5][6]

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 converts 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 have its basis in clinical efficacy and tolerability.

In psoriasis treatment with acitretin, improvement is seen approximately at weeks 4 to 6. The 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 two weeks before phototherapy, with a need to decrease the 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.[7]

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 two 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

  • Concomitant administration with methotrexate increases the risk of hepatic adverse effects.
  • Concomitant administration with cyclosporine increases the risk of hypertriglyceridemia.
  • Acitretin can undergo reverse metabolism to etretinate with acitretin if used in combination with alcohol.
  • The 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 prescribed acitretin are 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 genetic defect is high.

Enhancing Healthcare Team Outcomes

Acitretin is frequently used to treat several skin disorders, including acne, psoriasis, lichen planus, and discoid lupus. While the drug is effective, it is crucial for healthcare workers, including pharmacists, nurse practitioners, and the primary care physician to know its potential adverse effects. The drug should never be prescribed to a pregnant female because of the risk of teratogenicity. Also, the FDA has issued several boxed warnings about the risk of hepatitis when combining the agent with alcohol. When prescribing acitretin, the patient must understand the potential adverse effects and the importance of avoiding alcohol.[8][9]

Given the above, it is apparent that an interprofessional team is the best means by which to manage acitretin therapy. Once the prescriber has decided to give the patient the drug, nursing can counsel on the dosing and administration, as well as the teratogenicity if the patient is female. The pharmacist will verify dosing and perform medication reconciliation, alerting the prescriber of any issues. Nursing can also chart the therapeutic progress of the condition treated, so the prescriber can make adjustments to therapy as needed. Through this interprofessional team paradigm, acitretin can deliver maximal benefit with minimal downside, resulting in better patient outcomes. [Level V]


References

[1] Ighani A,Partridge ACR,Shear NH,Lynde C,Gulliver WP,Sibbald C,Fleming P, Comparison of Management Guidelines for Moderate-to-Severe Plaque Psoriasis: A Review of Phototherapy, Systemic Therapies, and Biologic Agents. Journal of cutaneous medicine and surgery. 2018 Nov 21     [PubMed PMID: 30463416]
[2] Skillen LA,Corry A, Combination therapy of sirolimus and acitretin in solid organ transplant recipients: a new cutaneous adverse event. Clinical and experimental dermatology. 2018 Nov 14     [PubMed PMID: 30430627]
[3] Mehrtens SH,de la Hera I,Shankar S, Case of keratoacanthoma centrifugum marginatum treated with acitretin. BMJ case reports. 2018 Nov 1     [PubMed PMID: 30389737]
[4] Kaushik SB,Lebwohl MG, Review of safety and efficacy of approved systemic psoriasis therapies. International journal of dermatology. 2018 Sep 23     [PubMed PMID: 30246393]
[5] Chen W,Zhang X,Zhang W,Peng C,Zhu W,Chen X, Polymorphisms of SLCO1B1 rs4149056 and SLC22A1 rs2282143 are associated with responsiveness to acitretin in psoriasis patients. Scientific reports. 2018 Sep 4     [PubMed PMID: 30181619]
[6] Guenther LC,Kunynetz R,Lynde CW,Sibbald RG,Toole J,Vender R,Zip C, Acitretin Use in Dermatology. Journal of cutaneous medicine and surgery. 2017 Nov/Dec     [PubMed PMID: 28952335]
[7] Chiricozzi A,Panduri S,Dini V,Tonini A,Gualtieri B,Romanelli M, Optimizing acitretin use in patients with plaque psoriasis. Dermatologic therapy. 2017 Mar     [PubMed PMID: 27998019]
[8] Ortiz NE,Nijhawan RI,Weinberg JM, Acitretin. Dermatologic therapy. 2013 Sep-Oct     [PubMed PMID: 24099069]
[9] Dunn LK,Gaar LR,Yentzer BA,O'Neill JL,Feldman SR, Acitretin in dermatology: a review. Journal of drugs in dermatology : JDD. 2011 Jul     [PubMed PMID: 21720660]