Retinoids

Author: Prof. Dr. med. Peter Altmeyer

Last updated on: 29.10.2020

Synonym(s)

Retinoid

Definition
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Retinoids are chemical substances related to vitamin A. This group of substances is used in dermatology both for local (cream/ointment/gel) and systemic therapy.

Retinoids are most frequently used in the treatment of severe acne or various forms of psoriasis. Retinoids are also used in the treatment or prevention of certain tumour diseases of the skin. The therapy of advanced stages of cutaneous T-cell lymphoma is the main focus here.

Pharmacodynamics (Effect)
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The exact mechanism of action of retinoids is not yet fully understood. The activation of selective retinoid X-receptors (RXRs) or RAR (retiniod-acid receptor), which are important in cell metabolism (vitamin D3, thyroid hormone receptor, proliferation-activating receptor in peroxysomes), is being discussed. The retinoid-activated retinoid receptors form homo- or heterodimers which bind to specific DNA sequences and act as transcription factors for genes. RAR regulates cell growth and differentiation, RXR regulates apoptosis.

Retinoids act on:
cell division (antiproliferative)
Stability of the lysosomal membranes
Integrity of cell membranes
Arachidonic acid metabolism
RNA Synthesis
Protein Synthesis
Glycosidation of proteins.

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Indication
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The indications for systemic retinoids vary depending on the preparation, see Table 1, and the indication "cutaneous T-cell lymphomas" for the preparation Bexaroten.

Approved active ingredients are:

Undesirable effects
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See Table 2.

Interactions
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See Table 3.

Contraindication
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Pregnancy, lactation, blood donation, liver dysfunction, pre-existing lipometabolic disorders, contact lens wearers, manifest diabetes mellitus, renal insufficiency, hypersensitivity to the preparation, combination with vitamin A or other retinoids, tetracyclines, methotrexate. S.u. Acitretin, Isotretinoin, Tazarotene, Tretinoin.

Preparations
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acenormin, isoderm, isotrex, isotrexine (combination with erythromycin), neotigason, bexarotene, zorac, isotretinoin, tazarotene

Note(s)
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The risk of PUVA-treated psoriatics to get a spinocellular squamous cell carcinoma is reduced if retinoids are taken at the same time!

Notice! Due to their pronounced teratogenicity, retinoids are not approved for the treatment of women of childbearing age. The consequences under civil and criminal law lie exclusively with the prescribing physician. In principle, women of childbearing age must have a negative pregnancy test before initiating therapy and effective contraception must be carried out 4 weeks before initiating therapy. Regular pregnancy tests must be carried out during therapy. Pregnancy must be ruled out up to 12 weeks after the end of therapy with isotretinoin (e.g. isotretinoin-ratiopharm; acne normin) and 2 years after acitretin

(neotigason). Patients must not donate blood while under retinoid therapy!Cave! Conceptional protection by oral contraceptives is impaired!

Literature
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Boisnic S et al (2002) Topical retinaldehyde treatment in oral lichen planus and leukoplakia. Int J Tissue React 24: 123-30.
Duvic M et al (2003) Analysis of long-term outcomes of combined modality therapy for cutaneous T-cell lymphoma. J Am Acad Dermatol 49: 35-49
Jones PH et al (2003) A phase 1 study of tazarotene in adults with advanced cancer. Br J Cancer 89: 808-815
Nijsten TE, Stern RS (2003) Oral retinoid use reduces cutaneous squamous cell carcinoma risk in patients with psoriasis treated with psoralen-UVA: a nested cohort study. J Am Acad Dermatol 49: 644-650
Xu D et al (2016) Binding characterization, synthesis and biological evaluation of RXRα antagonists targeting the coactivator binding site. Bioorg Med Chem Lett 26:3846-3849.

Tables
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Indications for systemic retinoids

	Indication	Isotretinoin	Acitretin
Keratinization disorders	acne conglobata	++++	++
	acne fulminans	++++	++
	M. Darier	+++	+++
	ichthyosis vulgaris	+	++
	Palmo-Plantar Keratoses	+	+
	Disseminated actinic porokeratosis		++

Inflammatory dermatoses	psoriasis vulgaris	+	++
	pustular psoriasis		+++
	Psoriatic Erythroderma		+++
	Subcorneal pustulose		++
	lichen planus		++

Side effects of retinoids (modified, from Red List)

Organ System	Undesirable side effects (ADR)
Airways	Dryness of the nasal mucosa, nosebleeds, hoarseness, dry throat mucosa

eyes	conjunctivitis, inflammation of the conjunctiva, passagere corneal opacity (rare), opacity of the lens, corneal inflammation
	Increased corneal vulnerability, corneal ulcers (rare)
	visual disorders (reduction of night vision (isotretinoin), temporary reduction of visual acuity, deterioration of light/dark vision, reduced sensitivity to glare)

Blood	thrombocytopenia, anemia, thrombocytosis, neutropenia, BSG ↑, leukopenia
Vessels	Vasculitis, triggering Wegener's granulomatosis

GIT	dryness of the lips or oral mucosa, cheilitis
	Gastrointestinal disorders (abdominal pain, diarrhoea, intestinal bleeding), discontinuation in the event of colitis/ivitis (isotretinoin)
	nausea, vomiting, gastrointestinal ulcers
	Liver dysfunction, hepatitis (individual cases)

Skin	Increased tissue formation (granulation tissue)
	Skin desquamation, skin redness, skin thinning with increased vulnerability
	Skin peeling on palms of hands and soles of feet, rhagade formation
	feeling of "burning" or "sticky" skin, itching, skin irritation on the face, sweating
	Nailwall inflammation, nail dystrophy
	Change of the hair growth rate, pigment shift of skin and hair, hair loss
	Increased light sensitivity of the healing skin, intensification of the signs of disease at the beginning of treatment
	exanthema, eczema, urticaria, purpura, blistering, skin ulcers, Staphylococcus aureus infections

Nervous System	Increase in intracranial pressure, pseudotumour cerebri (rare), headache
Ears	Hearing disorders
Metabolism, Endocrine	Blood lipid values ↑, HDL cholesterol ↓, blood sugar ↑ (connection questionable), diabetes or worsening of diabetes, thirst, freezing, creatine phosphokinase ↑, prolactin and uric acid values ↑, gynecomastia, edema
Support apparatus	muscle and joint pain, bone changes, skeletal hyperostoses, premature closure of the bone growth joints (rare), bone pain, soft tissue calcification, functional movement restrictions
Urogenital tract	Non-specific urethritides and vulvitides, menstrual disorders, hematuria, proteinuria
CNS	Depression, behavioural disorders, seizures

Significant interactions of retinoids

Carbamazepine	Carbamazepine bioavailability ↓
Contraceptives, oral	Contraception ↓
Phenytoin	Phenytoin levels ↑
Tetracyclines	Intracranial pressure increase, combination contraindicated
vitamin A	Vitamin A toxicity ↑, combination contraindicated