Retinoids Flashcards
What are retinoids?
Vitamin A and related natural and synthetic compounds are known as retinoids
What are the 3 interconvertible forms of retinoids?
Retinol (alcohol), Retinal (aldehyde), and retinoic acid (acid)
What are some natural sources of vitamin A/retinoids?
Diary, fish, meat, eggs, leafy greens, and orange/yellow vegetables (carotenoids like beta-carotene are precursors of vitamin A
Where is retinol stored and how is it mobilized to the plasma?
Stored in the liver, and it is mobilized/transported in the plasma by bindings to a complex of retinol-binding protein and transthyretin
Where are the receptors that retinoids act on located within the cell?
Binds cytosolic binding protein and is then transported to the nucleus where it binds intracellular nuclear receptors
What are the two sub-types of retinoid receptor and what are the subsets of these receptors?
Retinoid acid receptors (RAR) and Retinoid X receptors (RXR). Within each of these, there are 3 isotypes (alpha, beta, and gamma)
What are the most common retinoid receptors in keratinocytes?
RXR-alpha and RAR-gamma (RAR-gamma is most common in the skin)
What effect does photoaging have on retinoic acid receptors?
Decreases both RAR-gamma and and RXR-alpha
What effects do retinoids have on the skin structure?
Increase stratum corneum thickness, epidermal hyperplasia, dermal collagen I, papillary dermal elastic fibers, hyaluronic acid. Decreases matrix metalloproteinases, and angiogenesis and helps with correction of atypia, and dispersion of melanin granules
Retinoids’ effects on what proteins are important in the proliferation and inflammatory response modulation?
Inhibits AP1 and NF-IL-6 (both important in the proliferation and inflammatory responses)
What toll-like receptor is affected by retinoids?
TLR2, which is important in inflammation
What keratins are downregulated by the antikeratinization effect of retinoids?
K6 and K16 were downregulated
How do retinoids affect the Th1 vs Th2 pathways?
Retinoids increase Th1 cytokines and decrease the Th2 cytokines (helpful in CTCL)
How long is contraception recommended after acitretin therapy in the US?
3 years
Why is strict avoidance of EtOH required during treatment with acitretin?
Metabolism of acitretin w/ consumption of EtOH leads to re-esterification of acitretin to etretinate. This is substantially more lipophilic and can re-distribute to the fat and lead to elevated plasma levels of etretinate for months.
What is the only retinoid that binds to ALL RAR and RXR receptors?
alitretinoin (topical)
What is Alitretinoin used for?
Kaposi’s sarcoma
What receptors are RAR’s always paired with?
RXR’s –> these are always a heterodimer of RAR + RXR
What receptors are RXR’s paired with?
These can be paired with RXR’s, (homodimer), or as heterodimers with other types of receptors like vitamin-D3 receptors, thyroid hormone receptors and peroxisome proliferator-activated receptors
What cellular effects do retinoids have?
Many, but some highlights
- Inhibits AP1 and NF-IL-6 (inflammation/proliferation)
- Inhibits TLR2 (inflammation)
- Decreases tumorigenesis and induces apoptosis
- Antikeratinization (downregulates K16/K6)
- Inhibits ornithine decarboxylase
- Increases Th1 cytokines and decreases Th2 cytokines (useful in CTCL)
What is the earliest and most common side effect of systemic retinoids?
Cheilitis (dry lips)
What are the mucocutaneous side effects seen with systemic retinoids?
Cheilitis, thirst, epistaxis, xerosis, xerophthalmia, palmoplantar peeling, photosensitivity, exacerbation of eczema, staph aureus colonization in isotretinoin patients (75-90%) as a results of dryness of the nasal mucosa, telogen effluvium, nail fragility, pyogenic granuloma-like lesions, and sticky sensation on the palms and soles
What are some systemic side effects of systemic retinoids that we should be aware of?
Myalgias, arthralgias, anorexia, nausea, diarrhea, abdominal pain, Headache, pseudotumor cerebri (especially if used with tetracyclines, avoid these!), fatigue, reduced night vision, hepatitis, pancreatitis secondary to hypertriglyceridemia, rare bone toxicity (diffuse idiopathic skeletal hyperostosis; more common with acitretin), calcification of tendons and ligaments and premature epiphyseal closure
What is the most common lab abnormality seen with the systemic retinoids and which medication has the highest risk?
Elevated triglycerides, bexarotene is the highest risk for it
When should systemic retinoids be decreases in regards to triglyceride levels and why?
If >800 due to risk of pancreatitis
Where are LFT abnormalities most commonly seen and what is the clinical progression of these elevations?
Most often seen within the first 2-8 weeks of starting the medication. These usually normalize after another 2-4 weeks of treatment
At what level of LFT elevation should systemic retinoids be discontinued?
3x the upper limit of normal
Which retinoid most commonly has elevations in LFTs?
Acitretin
What is an important side effect for bexarotene and how often does it occur?
Hypothyroidism, occurs in 80% of patients on this medication
What medication should be started with bexarotene?
Levothyroxine should be started in all patients getting bexarotene
Prognosis of hypothyroidism in patients taking bexarotene?
Reversible should go back after tx
What pattern of lab abnormality is seen in bexarotene induced hypothyroidism and why?
You see reduced TSH and T4. This is because the medication stimulates the production of peripheral thyroid hormones leading to central suppression
There is also some evidence to suggest that there is increased metabolism of thyroid hormones peripherally such that TSH levels may be normal but T4 levels may be decreased significantly
What CBC abnormality might be seen with bexarotene?
Leukopenia
This is much more common in bexarotene than any of the other systemic retinoids
What percentage of pregnancies with isotretinoin exposure appear normal at birth and what is the long-term concern?
50-60% appear normal looking at birth. However, decreased mental function becomes apparent in the majority over time. 30% will have gross mental retardation and 60% will have mild-moderate mental deficits
In what percent of retinoid exposed pregnancies is spontaneous abortion seen?
20%
What are the most common retinoid embryopathies seen?
Seen in 18-28% of retinoid exposed pregnancies
Craniofacial: microtia, cleft palate, microphthalmia, hypertelorism, dysmorphic facies, and ear abnormalities
CNS: microcephaly, hydrocephalus, CN7 palsy, and cortical and cerebellar defects
Thymic: thymic aplasia/ectopia
Is there risk of retinoid embryopathy from male partners taking retinoids?
No, IPledge requires male registration because there have been pregnancies where women have borrowed their partner’s medications
Contraindications for systemic retinoids?
Absolute: Pregnancy, women contemplating pregnancy, non-compliance with birth control, hypersensitivity to parabens (some capsules amy contain parabens)
Relative: leukopenia, moderate to severe hypercholesterolemia or hypertriglyceridemia, hepatic or renal dysfunction, hypothyroidism (bexarotene)
Is it best to take retinoids with a meal? What type of meal?
Yes, and a fatty meal increases bioavailability
What medication is contraindicated in bexarotene therapy?
Gemfibrozil, this inhibits P450 3A4 which increases levels of bexarotene –>severe hypertriglyceridemia
If you see elevated LDL in someone taking a retinoid what statin should be avoided?
Simvastatin, interacts with P450 3A4
What should be used to treat hypertriglyceridemia in patients on a retinoid?
Fenofibrate and or omega 3 fatty acids
How long does it take to see improvement with use of tretinoin (topical)?
8-12 weeks
Why should tretinoin be put on at night?
It is inactivated by UV light
What other topical medication should not be mixed with tretinoin?
Benzoyl peroxide, oxidizes tretinoin
Is adapalene susceptible to UV breakdown like tretinoin?
No, it is light stable
How long does topical bexarotene take to work on things like CTCL, LyP, etc?
20 weeks
What stages of CTCL should topical bexarotene be used for?
Stage 1A and 1B
What is the only systemic retinoid to be approved by the FDA for psoriasis?
Acitretin
How long after stopping acitretin should women of childbearing age wait to consume EtOH?
2 months
What types of psoriasis is acitretin best used for?
Pustular, erythrodermic, severe and recalcitrant plaque
What is systemic tretinoin (all-trans retinoic acid) used for?
Acute promyelocytic leukemia
What is the usually daily dosing for isotretinoin and what is the goal cumulative dose?
0.5-2mg/kg/day
Goal cumulative dose is 120-150 mg/kg
What should patients be counseled regarding their complexion initially?
Patients should be counseled that their complexion may worsen for the first 4-6 weeks
What will a patient’s acne be like if it recurs after a regimen of isotretinoin (responsiveness to therapy)?
Will tend to be more responsive to traditional therapies
What therapy can acitretin be combined with for better efficacy in psoriasis?
Combined with PUVA it is better. Acitretin is given 10-14 days prior to starting PUVA
