RETINOIDS IN DERMATOLOGY

Presenter: Dr. Meriniya (DVR3)

Moderator: Dr. Debas (Dermatovenereologist)
Outlines
• Introduction and historical perspective
• Vitamin A physiology
• Mechanism of action
• Indication
• Contraindication
• Adverse effect
• Drug interaction
• Monitoring
• References
Introduction
• The term retinoids includes all synthetic and natural compounds that have biologic
activity like that of vitamin A

• Any molecule that, by itself or through metabolic conversion, binds to and

activates the RARs

• Thereby eliciting transcriptional activation of retinoic acid–responsive

genes, resulting in specific biologic responses
History

• The importance of retinoids in cutaneous biology was first appreciated early in

the 20th century by Wolbach

• Isotretinoin(13-cis-retinoic acid ) was first synthesized in 1955, but was tested

years later in clinical trials

• 1970s, Peck and colleagues described the effectiveness of oral isotretinoin in

the treatment of lamellar ichthyosis, disorders of cornification & nodulocystic
acne
Cont'd
• 1962 : therapeutic effectiveness of topical tretinion for disorder of
keratinazation by Von stuttggen
• 1972: Bollag developed two aromatic retinoids: etretinate and its free acid
metabolite, acitretin

• 1998 : etretinate was phased out by Roche (because of its very prolonged
presence in subcutaneous fat) and replaced by its acid metabolite, acitretin
• 1999 : Systemic bexarotene was approved for CTCL
• The approval of a topical formulation of bexarotene followed soon after

• 1999 : Alitretinion approved by FDA for kaposi sarcoma

Vitamin A Physiology
• In mammals, vitamin A exists in interconvertible forms as
• Retinol (vitamin A alcohol) - reproduction

• Retinal (vitamin A aldehyde) - visual function

• Retinoic acid (RA; vitaminA acid) - epithelial differentiation & normal growth
• Retinol and retinal can be converted interchangeably, but retinol is irreversibly
metabolized to RA

• Both retinal and RA play an essential role in epithelial differentiation and

normal growth
Cont'd
• The precursors of vitamin A, such as β-carotene, are classified as carotenoids
• They are synthesized by plants and function as photosensitive structures

• In animals, ingested carotenoids are oxidized to vitamin A

• Every molecule of β-carotene is converted into 2 molecules of retinal in the
intestines before being absorbed

• The primary form of dietary vitamin A in humans is retinyl ester derived from
meat and animal products, such as eggs and milk
 Structure and Nomenclature

• All-trans-retinoic acid (tretinoin) is derived from

sequential oxidation of all-trans-retinol ( vit A) and
all trans retinaldehyde

• It is a 20-carbon molecule that consists of a

cyclohexenyl ring, a side chain with four double
bonds (all arranged in trans-configuration), and a
carboxylic-acid end group

• The terms 9-cis- (alitretinoin) and 13-cis-retinoic acid

(isotretinoin) refer to stereoisomers of all-trans-
retinoic acid
Cont'd

• The 4th carbon atom located in the cyclohexenyl ring of retinoic acid is involved in
hydroxylation reaction to generate 4-hydroxy-retinoic acid
• More polar, making it more amenable to excretion

• Retinyl esters functions as the molecular storage form of retinol

• Formed by esterification of retinol with FA
• Hydrolysis of retinyl esters regenerates retinol
Cont'd

• Retinoids are also classified into

 First-generation retinoids (non-aromatic)
• Tretinoin (all-trans-retinoic acid)
• Isotretinoin (13-cis-retinoic acid )
• Alitretinoin (9-cis-retinoic acid )

 Second-generation retinoids (monoaromatic)

• Formed by replacement of the cyclic end group of vitamin A with various
substituted and nonsubstituted ring systems
• Etretinate
• Acitretin
• Motretinide
Cont'd

 Third-generation retinoids (polyaromatic)

• Formed through cyclization of the polyene side chain
• Adapalene
• Tazarotene
• Bexaroten
Absorption and Distribution
• The oral bioavailability of retinoids is enhanced with food intake
• The effect of fatty meals is especially great with acitretin and bexarotene

• Although it is generally recommended that isotretinoin be consumed with a fatty

meal
• A novel formulation that is encased with lipid agents (isotretinoin-lidose) is
available now

• In serum, natural and synthetic retinoids are transported by plasma proteins

• Similar to vitamin A, synthetic retinoids accumulate in the liver

• But with a lesser affinity than vitamin A for storage in hepatocytes and in Ito
stellate fibroblasts
Cont'd
• When retinoid absorption exceeds liver storage capacity, symptoms of
hypervitaminosis A result

• Because isotretinoin and acitretin are relatively water soluble, there is very little
lipid deposition in adipose tissue
• However, etretinate is approximately 50 times more lipophilic than its metabolite
acitretin
• Resulting in increased storage in adipose tissue, from which it is slowly released, in some
cases, over a period of several years

• The more water-soluble retinoids (isotretinoin, acitretin, and bexarotene) are

undetectable in serum within 1 month after stopping therapy
Cont'd
• Less than 20% of the corresponding serum concentrations of acitretin and its 13-
cis isomer appear in breast milk

• The estimated amount of drug consumed by a suckling infant corresponds to

about 1.5% of the maternal dose
• Should be avoided in breastfeeding women

• The amount of acitretin transferred in semen is equivalent to 1/200,000 of a single

25 mg capsule
Metabolism and Excretion

• Metabolism of retinoids is mainly via oxidation and chain shortening to

biologically inactive, water-soluble products in the liver

• The oxidative metabolism is induced mainly by retinoids themselves

• Possibly also by other agents known to induce hepatic cytochrome P-450
• There are important differences in the terminal elimination half-lives among the
three generations of retinoids

• Acitretin Re-esterification
• Alcohol indirectly enhances the re-esterification of acitretin to etretinate, which is
detectable only after a few days of an acitretin regimen
• Based on these data, the recommended period for contraception after acitretin
therapy has been lengthened from 2 months to 2 years in Europe & 3 years in USA
Cont'd

• Retinoic acid metabolism blocking agents (RAMBA)

• Inhibit catabolism of at-RA by P450 enzymes in the CYP26 family, thereby

raising the intracellular levels of endogenous at-RA in the skin & other
targeted tissues

• Limits systemic exposure and the potential for toxicity, and at-RA levels
return to the physiologic range within 24hrs of DC these medications

• E.g.. Liarazole and talarozole

Mechanism of action

• Retinoids are small-molecule hormones that elicit their biologic effects by

activating nuclear receptors and regulating gene transcription

Transport of Retinoids
• Physiologically, RA is predominantly in the all-trans form (ATRA)
• A small fraction is transported as 13-cis RA
• Serum transport is by albumin
• The intracellular carrier known as cytosolic retinoic acid-binding protein (CRABP)
exists in two isoforms, CRABPI and CRABPII, and transports RA to the cell nucleus
Cont'd

Mechanism At the Nuclear Level

• Retinoids exert their physiologic effects by binding to receptors present in the
nucleus
• There are two families of retinoid receptors
• Retinoic acid receptor (RAR) family
• Retinoid X receptor (RXR) family

• Each having three isoforms (α,β, and γ) encoded by separate genes

• Retinoid receptors belong to the large superfamily of receptors consisting also
of glucocorticosteroid, TH, PPAR and vitamin-D3 receptors
• All of which are DNA-binding proteins and functioning as trans-acting
transcription modulating factors
Cont'd

• RAR are always paired with an RXR

• RXR can exist as a homodimer with

another RXR, or as a heterodimer with
several other families of receptors
Cont'd
• The genes regulated by retinoids contain a retinoic acid response element (RARE),
which is a DNA sequence to which the RAR-RXR heterodimer binds

• Upon binding of a ligand, the RAR-RXR heterodimer acts a transcription factor,

resulting in the expression of a number of proteins involved in growth & regulation

• The retinoid-receptor complex can also act in an indirect fashion by antagonizing

the action of other transcription factors, specifically activating protein 1 (AP-1) &
NF-IL6

• The clinical effects of systemic retinoids in dermatology are related to their ability
to affect pathways involved in inflammation, cellular differentiation, apoptosis, and
sebaceous gland activity
 Retinoids in the Skin

• Vitamin A and its bioactive metabolites play a major role in promoting the
keratinocyte differentiation that occurs from the epidermal basal layer to the SC

• Retinyl esters and retinol are the major retinoids found in the skin, with the former
reaching a concentration of >1000 pmol/g in the epidermis

• Epidermal retinoids can absorb UVB radiation and have ~2–3% of the UVB-filtering
capacity of the melanin in phototype II/III skin
Cont'd

• The UVB absorption process results in dramatic depletion of epidermal retinoids,

which can be prevented by application of topical retinoids

• Nutritional deficiency, aging, and oxidative stress can also lead to lowered
retinoid levels in the skin
Tretinoin
• First retinoid introduced in to clinical use
• MOA
• By reducing microcomedone formation
• Decreasing cohesiveness of follicular corneocytes
• Increasing keratinocyte autolysis
• ATRA is a naturally occurring first-generation retinoid
which is normally present in the skin
• The synthetic form of topical ATRA (tretinoin) has been
approved by the FDA for the treatment of acne and
photoaging
Adapalene
• Photostable, rigid, and highly lipophilic
synthetic retinoid

• While adapalene affects the cellular

differentiation, keratinization, and
inflammatory processes that are abnormal in
acne, it has no sebostatic effect
Cont'd
Tazarotene
• Is a prodrug that is rapidly converted by cutaneous
esterases to its free carboxylic acid (tazarotenic acid),
which is the active metabolite

• Tazarotene appears to modulate the pathogenesis of

psoriasis by regulating expression of retinoid responsive
genes, including those involved

• In cell proliferation, cell differentiation, and inflammation

Cont'd
Acitretin
• Major metabolite and the pharmacologically active form of etretinate

• Etretinate is approximately 50 times more lipophilic than acitretin and binds

strongly to plasma proteins and adipose tissue
• From which it is released slowly, with a long terminal half-life of up to 120 to 160
days

• Acitretin carries a negatively charged group that makes it much less lipophilic
than etretinate
• As a result, acitretin does not accumulate in adipose tissue and is eliminated from
the body more rapidly, with a half-life of 2 days
Cont'd

• Acitretin’s mechanism of action is still not clearly

understood
• Paradoxically, it activates all three RAR subtypes despite
binding poorly to them

• Evidence supports a normalization of differentiation &

proliferation as well as a modification of inflammatory
responses & neutrophil function
 Cont'd
Isotretinoin (13-cis-retinoic acid)
• A naturally occurring retinoid resulting from the metabolism of vitamin A

• There is neither liver nor adipose tissue storage, in contrast to vitamin A

• After discontinuation of isotretinoin, physiologic concentrations of the drug and its

major metabolites are reached within 2 weeks
• 1 month of post-therapy contraception provides an adequate safety margin to avoid
teratogenicity
Cont'd

• Among natural & synthetic retinoids, only oral

isotretinoin and its metabolite significantly
suppress sebum production

• The mechanism of isotretinoin-induced

seboatrophy is thought to involve
• Sebocyte apoptosis
• Inhibition of either sebocyte progenitor
differentiation or the genes encoding sebogenic
enzymes
Cont'd
Bexarotene
• FDA-approved in oral (1999) and topical (2000) forms for
treatment of CTCL
• This compound is about 100-fold more potent at binding
to RXRs than to RARs

• Bexarotene has a clearance profile similar to that of

isotretinoin

• The exact MOA of bexarotene in CTCL is still unknown,

but it probably acts through regulation of cellular
differentiation & proliferation, as well as by induction of
apoptosis
Cont'd

Alitretinoin (9-cis-retinoic acid)

• Naturally occurring pan-agonist retinoid that binds to both RARs and RXRs
• Topical alitretinoin 0.1% gel is indicated for the treatment of cutaneous Kaposi
sarcoma and oral alitretinoin therapy is currently utilized outside the US for
refractory chronic hand eczema

• Concentrations return to normal within 1–3 days after treatment cessation

• The MOA of alitretinoin in chronic hand eczema is unknown

• Alitretinoin has immunomodulatory and anti-inflammatory effects that include
suppressing the expansion of cytokine-activated leukocyte subsets & APC
Indications
Topical Retinoids
• The most important element in topical retinoid therapy is patient education
• Local skin irritation can be expected, and noticeable beneficial effects may take
weeks or months to appear

• Administration of topical retinoids should be titrated depending on cutaneous

irritation, which may mean decreasing the concentration or the frequency of
application or duration (e.g. “short contact” therapy)
• It is wise to begin with a low-strength formulation and then increase the
concentration as tolerance builds

• Another tactic is to start by applying a given concentration every other day

• Daytime moisturizers with sunscreen are important components of any topical
retinoid regimen
Cont'd

Acne
• Topical retinoids, of which tretinoin is the prototype
• Are mainstays in the treatment of comedonal and inflammatory acne vulgaris

• The primary mode of action in acne is thought to be

• The normalization of differentiation & proliferation of the follicular
epithelium
• Leads to the loosening & unseating of microcomedones, thereby preventing
obstruction of the pilosebaceous unit
• In addition, topical retinoids may have anti-inflammatory activity
Cont’d
• The mechanism of action of topical isotretinoin is similar to that of topical
tretinoin because of intraepithelial isomerization of isotretinoin to tretinoin
• In contrast to oral isotretinoin, topical isotretinoin fails to suppress sebum
production
• It is less irritating and probably also somewhat less effective than tretinoin

• Adapalene and tazarotene, have comparable or (for adapalene) improved

tolerability while maintaining efficacy similar to that of topical tretinoin
• Topical retinoids should be applied to the entire face or all acne-prone areas once
a day as tolerated
• With tretinoin applied in the evening to prevent inactivation by UV light
Cont'd

• Applying to dry skin minimizes dermal absorption, which correlates with skin
irritation
• Patients should be advised that beneficial effects do not become evident for 6–8
weeks or longer

• An apparent exacerbation may occur during the first month of therapy, representing
the externalization of deeper-seated acne lesions as the follicular epithelium is
loosening
Cont'd
Psoriasis
• Topical application of tretinoin or isotretinoin has limited efficacy in psoriasis

• Although topical tazarotene was shown to be effective in treating mild to

moderate plaque-type psoriasis affecting ≤20% of the BSA, irritation limits its use
as monotherapy

• A combination of tazarotene and a mid-potency topical corticosteroid can improve

efficacy and reduce the likelihood of both irritation and corticosteroid induced
atrophy
Cont'd

Photoaging
• Tretinoin and tazarotene creams, can improve fine wrinkling & lighten uneven
pigmentation
• Takes 3–6 months of daily applications to see significant clinical improvement

• Cutaneous irritation is usually the limiting factor

• Photoaging is the consequence of UVR-induced damage to the skin, which is
characterized by decreased vitamin A content as well as lower expression of RXR-α
and RAR-γ in the acute setting and then later by upregulation of AP1-driven MMPs

• Promote cellular differentiation & ECM synthesis, including an increase in

hyaluronic acid in addition to decreased MMP production
Cont'd

Other indications

• Other FDA-approved indications for topical retinoids include

• Alitretinoin 0.1% gel for cutaneous Kaposi sarcoma

• Bexarotene 1% gel for CTCL

Systemic retinoids
Psoriasis
• Acitretin is FDA approved and retinoid of choice
• The best results have been obtained in acral or generalized (von Zumbusch)
pustular psoriasis

• The various forms of pustular psoriasis, as well as erythrodermic psoriasis, tend to

clear relatively rapidly with acitretin monotherapy

• Rebound does not usually occur after stopping treatment, and reintroduction
produces a beneficial response
• Plaque-type psoriasis responds variably to these drugs
Cont'd
• An initial worsening with increased erythema and/or extent of involvement of
plaque-type psoriasis may occur within a few days of starting acitretin therapy at a
dosage of 0.5–1 mg/kg per day (~25–70 mg/day in adults)

• Utilization of a lower dose (10 mg/day) initially, followed by a progressive

increase, helps to avoid this complication

• Total clearance of psoriatic plaques usually requires that oral retinoids be

combined with other treatments
• Such as topical corticosteroids, topical vitamin D derivatives, anthralin (dithranol), or
photo(chemo)therapy (narrowband UVB or PUVA)
Cont'd
• The “RePUVA” combination, in which retinoids are given for 14 days before
starting PUVA, can produce an accelerated response rate and resolution of lesions
that would not clear with a retinoid or PUVA alone
• The cumulative UVA exposure required to produce a remission is also significantly
lower with Re-PUVA, reducing the risk of UVA induced carcinogenesis
Cont'd
Acne
• Isotretinoin is still the only treatment that has been shown to induce long-term remissions
and even “cure” acne, because it is the only medication that affects, all the etiologic
factors implicated in acne

• Only isotretinoin has been found to suppress sebum production

• In the early 1980s, oral isotretinoin use was restricted to patients suffering from severe
nodulocystic acne

• With increasing experience, its use has been extended to

• Patients with less severe disease who have responded unsatisfactorily to conventional
therapies such as topical retinoids plus oral antibiotics
• Patients with moderate acne that shows signs of scarring
Cont'd
• Psychosocial consequences of acne range from depression & anxiety to
interpersonal and work-related difficulties
• Isotretinoin treatment significantly improves sociability and self-esteem
• In a dose-comparison study comparing 0.1, 0.5, and 1.0 mg/kg daily for 20 weeks,
clinical improvement was essentially the same for all three groups at the end of 20
weeks,
• with a higher percentage of patients requiring retreatment in the 0.1 mg/kg daily
group.

• Despite the lack of rigorous scientific evidence, an isotretinoin dose in the range
of 0.5 to 1.0 mg/kg daily, until a total cumulative dose of 120 to 150 mg/kg is
reached, seems to be a reasonable therapeutic plan
Cont'd
• A lag period of 1–3 months may occur before the onset of the therapeutic effect

• Approximately one-third of patients with acne require a second course of

isotretinoin therapy, either for persistent disease or for relapse

• A major predictive factor for resistance to isotretinoin treatment is closed

comedonal and microcystic acne

• Because oral isotretinoin is a potent teratogen, prevention of pregnancy in female

patients with childbearing potential is critical
Cont'd
• A flare of disease during the first few weeks of treatment, and subsequent evolution
of acne cysts into lesions resembling pyogenic granulomas, is occasionally observed
with isotretinoin treatment
• The incidence of this side effect may be reduced by using lower doses of isotretinoin
during the first 3–4 weeks of therapy
Cont'd
Cutaneous T-cell lymphoma
• Both oral and topical bexarotene can produce clinical responses in CTCL

• Bexarotene is FDA-approved as oral therapy for CTCL that has been refractory
to at least one systemic agent, and as a topical gel formulation for refractory
early-stage CTCL
• Given the high incidence of side effects, in particular hyperlipidemia, a
commonly recommended starting dose for oral bexarotene is 150 mg/m2/day

• Combination therapies utilizing bexarotene together with PUVA, narrowband

UVB, methotrexate, interferon-α, or denileukin diftitox have also been
evaluated in clinical trials and case series
Cont'd
Chronic hand eczema
• Alitretinoin 10mg or 30mg once daily for 12–24 weeks

• Improvement typically began to develop after ~4 weeks of treatment, and the

median time to relapse was 6 months in the absence of any further therapy

• Oral alitretinoin (currently not available in the US) therefore represents a

therapeutic option for adults with severe, recalcitrant chronic hand eczema, with
the possibility of using intermittent courses to induce intermediate-term
remissions
 Cont'd

Other indications includes

• Rosacea
• PRP
• Darier disease
• Icthyosis
• HS & diseting cellulitus of the
scalp
• Lupus erythematous
• Lichen planus
Contraindications

Topical retinoids
• Should be avoided during pregnancy and nursing, due primarily to medico legal
issues raised by the teratogenicity of oral isotretinoin
• Emotional issue

• Skin resurfacing procedure, use of irritating topical products (e.g. abrasive

cleansers, astringents) should be avoided
 Cont'd
• Relative contraindications
Systemic retinoids • Leukopenia
• Absolute contraindications • Moderate to severe
• Pregnancy or women hypercholesterolemia or
hypertriglyceridemia
contemplating becoming pregnant
• Significant hepatic (especially for
• Non-compliance with bexarotene) or renal dysfunction
contraception • Hypothyroidism (especially for
• Breastfeeding bexarotene and alitretinoin)
• Hypersensitivity to preservatives • Suicidal ideation
present in acitretin capsules • Pseudotumor cerebri

• Patients should be advised not to take vitamin A supplements in excess

Major side effects

• Topical Retinoids

• By far the most common side effect of topical retinoids is skin irritation
• Characterized by erythema and peeling

• “Retinoid dermatitis” typically occurs during the first month of treatment & tends
to recede thereafter
• It usually responds to a temporary reduction in the frequency, amount, or duration of
retinoid application and to the use of moisturizers
Cont’d
• Desquamation and peeling correspond to the hyperproliferative response of the
epidermis to tretinoin mediated by RARs, but the erythema does not seem to be
receptor mediated

• The perioral area of the face is most sensitive to peeling, and retinoid use in this
region can be limited or avoided

• Although no photoallergic or phototoxic reactions have been proven for topical

retinoids, many patients note a decreased tolerance to UVR

• Erythema tends to develop shortly after sun exposure and is often accompanied by
a sensation of heat
Cont'd
• The potential for teratogenicity from use of topical retinoids is very low

• Systemic absorption of topically applied retinoids has been inconsequential in

both animal and human studies, and there is no evidence that topical application
of tretinoin during pregnancy causes congenital disorders

• Temporary worsening of acne may occur within the first weeks of therapy

• Uncommon side effects include transient hypo- or hyperpigmentation,

koebnerization of psoriasis (especially with tazarotene), ACD, and ectropion
Cont’d
Cont'd
Systemic Retinoids

• Teratogenicity is the most concerning adverse effect of oral retinoids

• The side-effect profile of systemic retinoids resembles the toxic effects of vitamin A
or hypervitaminosis A syndrome

• Acute retinoid toxicity can include mucocutaneous (most common) and laboratory
abnormalities, while chronic retinoid toxicity may occasionally produce bony changes
Cont'd
Teratogenicity
• Systemic retinoids are potent teratogens, and fetal deformities are the major
concern in treating fertile women with oral retinoids

• No safe minimal dose during pregnancy has been established

• The defects seen in retinoid embryopathy can include different abnormalities

• These malformations may lead to spontaneous abortion, premature birth, or fetal

death
Cont'd
• The putative mechanism involves toxic effects on neural crest cells, particularly
with exposure during the fourth week of gestation

• No typical retinoid embryopathy malformations have been reported in pregnancies

where only the male partner was taking acitretin or isotretinoin at the time of
conception
• However, it is usually recommended that men who are actively trying to father
children avoid systemic retinoid therapy

• In the US, physicians, both patients (female or, to prevent sharing of medication,
male) and pharmacies must register with a pregnancy risk reduction program
(iPLEDGE™) in order for isotretinoin to be prescribed
Cont'd
Skin and mucous membrane adverse effects
• Dose-dependent mucocutaneous toxicity is the most commonly observed side
effect of oral retinoids
• It reflects decreased production of sebum, reduced stratum corneum thickness, and
altered skin barrier function

• Dry lips or cheilitis is the earliest and the most frequent finding
• Dryness of the mouth (accompanied by thirst), nasal mucosa (associated with
fragility and epistaxis), and eyes are other potential manifestations

• Xerosis of the skin and associated pruritus, peeling (especially of the palms and
soles), and fissuring (particularly of the fingertips) are frequent side effects
• Exacerbations of atopic dermatitis may occur
Cont'd
• Photosensitivity is occasionally observed, in particular with isotretinoin, and
probably reflects a reduction in the thickness of the stratum corneum

• Staphylococcus aureus colonization correlates with isotretinoin-induced reduction

in sebum production and may lead to overt cutaneous infections

• Diffuse hair loss (telogen effluvium) is a relatively common complaint, although

objective alopecia tends to occur only at high dosage levels

• Effects on the nail apparatus can include thinning, fragility, and shedding of the
nail plate as well as paronychia-like changes with periungual granulation tissue
that can resemble pyogenic granulomas
Cont'd
• Mucocutaneous side-effect profiles vary among the systemic retinoids
• Isotretinoin causes more mucosal dryness
• Acitretin has been associated with higher incidences of alopecia and palmoplantar
peeling
• Bexarotene induces milder mucocutaneous and ocular side effects than other oral
retinoids
Drug interactions
References
• Comprehensive Dermatologic drug therapy, 4th edition
• Bolognia, 5th Edition
• Fitzpatrick’s Dermatology, 9th Edition
• Rook’s Textbook of Dermatology,10th Edition
• Up To Date dermatology 2020 Edition
• Journals
• Retinoids: active molecules influencing skin structure formation in cosmetic and
dermatological treatments, 2019
• The growing importance of topical retinoids in clinical dermatology, 2021
THANK YOU