This is probably achieved by competition between RARs and other transcription factors for commonly shared coactivator and corepressor proteins
80% ￬ of local DHT producn + 2x ￬ of androgen receptor binding capacity
Telogen Effluvium, Abnormal hair texture, dryness Fragility with nail softening Paronychia Onycholysis, pyogenic granuloma
Retinoids in Dermatology
Presenter : Dr. Sanjay Singh
Natural Retinoids and carotenoids
Mechanism of Retinoids
Classification of synthetic Retinoids
Effects of Retinoids on Human Skin
Brief description of Individual Drugs and side effects
What are Retinoids?
All synthetic & natural compounds that have biologic activity
similar to Vitamin A.
First dermatologic use of vitamin A : in 1943 by Staumfjord for Acne
In 1962 : Therapeutic effectiveness of Topical Tretinoin : Disorder of
Keratinisation by Stuttgen.
In 1969 : first topical application of tretinoin for acne vulgaris : by Kligman
In 1972 : Bollag discovered : Etretinate & Acitretin.
IN 1982 : Isotretinoin first approved by FDA : severe nodulocystic acne.
IN 1987 : Etretinate approved by FDA : for Psoriasis.
In 1998 : Etretinate phased out by Roche & replaced by its acid metabolite
In 1999 : Bexarotene approved : for CTCL.
In 1999 : Alitretinoin approved by FDA : for Kaposi Sarcoma
All classes of Retinoids : basic sructure of Vit A with modifications
1st gen. Retinoids 2nd gen. Retinoids 3rd gen Retinoids
Change of Polar end group
& polyene side chain
Replacing cyclic end group of Vit A with
subsituted & non subsituted ring systems.
Cyclization of polyene
Daily requirement: 0.8-1mg/ 2400-3000IU
Retinal(as 11-cis &11-trans isomer) : in Visual function
Retinol : in Reproduction
Retinoic acid : in Epithelial differentiation & normal growth
Organic pigments : Naturally occurring in chlorophyll & chromoplast of
They are not biologically active until converted to one of the retinoids in
the body .
1 mol. Of β carotenes = 2 mol. of retinal.
Found in vegetables and fruits.
Ex : Carotene α, Carotene β, Lutein, Lycopene, Zeaxanthin
Mechanism of Action
RA is predominantly in ATRA form.
Serum transport by Albumin.
Intracellular transport to nucleus is by : CRABP.
CRABP 1 : modulates level of RA in various tissues.
CRABP 2 : main form in human epidermis.
Belongs to Steroid thyroid hormone receptor superfamily
Exists as α, β, γ types
Human skin mainly contains RXRγ & RARα
BASIC PRINCIPLES: RETINOID RECEPTORS
RARs and RXRs are ligand-dependent transcription factors that regulate gene
expression in two ways:
Upregulate expression of genes by binding to RARE located in the
promoter region of target genes
Downregulate expression of transcription factors such as AP1.
The RARs and RXRs always exist as dimers in vivo.
The RARs always exist as heterodimers complexed with RXRs.
RXRs can exist as homodimers or as heterodimers with RARs or a
variety of other nuclear receptors (VDRs and T3Rs).
Provide a mechanism for cross - talk between hormone signalling
Adapalene : Derivative of naphthoic acid with retinoid-like
properties, does not fit precisely into any of three generations.
Seletinoid G classified as fourth generation retinoids by some
EFFECTS on KERATINIZATION
Different keratin profile on cultured keratinocytes and in vivo human skin
In Vivo level of Keratin 1, 2, 10 decreases and Keratin 4,6,13,16,17,19
Induces heparin binding (HB)-EGF, TGF α and amphiregulin
Reduction of tonofilaments, ￬corneocyte adhesiveness, impaired
permeability barrier, ￪TEWL
Normalise hyper-proliferative epidermis
Clinical desquamation and peeling
IMMUNOLOGIC & ANTIINFLAMMATORY EFFECTS
Inhibits Proinflammatory cytokines and enzymes of Phagocytosis
￪cell surface antigens of T cells and NK cells
Inhibition of Transcription factor AP-1
￬Neutrophil migration, leukotriene B4 mediated chemotaxis, NO, TNFα levels
• Psoriasis : ￪IL6, IL8, ICAM1
EFFECT ON SEBACEOUS GLAND ACTIVITY
Isotretinoin >> tretinoin > acitretin >> other retinoids
90% ￬in sebaceous gland size by ￬ing proliferation of basal sebocytes
70-90% ￬in sebum production
Altered sebum composition :
￬TGs, wax/steryl esters, FFA
Squalene normal or mildly ￬
￪free sterols, cholesterol, ceramides
Retinoid induced apoptosis :
Regulation of expression of apoptosis linked gene products: BCL-2,
Activation of tumour suppressor genes, viz. p21, p38, p53
￪Caspase proteolytic activity
Restoration of RAR β activity in premalignant oral lesions
Suppress production of COX 2 and PGE2 , whose activity is upregulated in
Vit A & retinoids needed for formation of face, heart, eye, limb,
& nervous system
All RAR agonists – strong teratogens
All RXR agonists – low to absent teratogenic response
Retinoids not binding to RAR/RXR – likely non teratogenic
Chemoprevention of Malignancies
Syndromes with increased risk of cutaneous malignancy
Frequent BCC or SCC
1st retinoid introduced into clinical use – nearly 4 decades ago, for topical Rx of
By reducing microcomedone formation
Decreasing cohesiveness of follicular corneocytes
Increasing keratinocyte autolysis
Availiable topically as : .01% to 0.1% as cream, gel, solution forms
New microsphere preparation: 4x potent, faster response, better
Available in 0.1% & 0.04%
Decrease irritation by slowing release of drug.
Enhance efficacy by targeting delivery to sebaceous follicle
Photodamaged skin :
￪Basal & granular layer thickness.
￬Melanocytic activity, even distribution of melanin.
￪glycosaaminoglycan secretion into intercellular space.
￪synthesis of collagen and elastin
Improvement in skin smoothness and tightening of skin in 2 to 4 weeks
Decreased fine wrinkles and mottled hyperpigmentation at 2 to 4 months
Coarse wrinkles require at least 6 months of therapy.
No affinity for RAR/RXR
First retinoid for systemic use
Initially evaluated for icthyotic disorders in the 1970’s, found to be
very effective in nodulocystic acne
Best agent for acne vulgaris : targets all pathogenic factors of acne
Rapid and early improvement in the inflammatory lesions (pustules)
Closed comedonal acne & microcystic acne are less responsive
Inflammatory acne with scarring
Acne with psychological distress
Standard dosing recommendations
1 mg/kg/d for 4 to 5 months
Start at 0.5 mg/kg/d and increase gradually to 1 mg/kg for 4 to 5 months.
Acne fulminans - Prednisolone 0.5–1 mg/kg/d
Acne flare - Prednisolone 0.5–1 mg/kg/d
Gram-negative folliculitis - 0.5–1 mg/kg/d
Acne rosacea/rosacea - 10 mg/d for 4 months
High-dose isotretinoin treatment and the rate of retrial,
relapse, and adverse effects in patients with acne vulgaris.
Blasiak RC, Stamey CR, Burkhart CN et al. JAMA Dermatol. 2013 ;149(12):1392-8.
• Prospective, observational, intervention study
• 116 participants, 12-month follow-up survey
group (<220 mg/kg)
Relapse rate 47.4 % 26.9 % 0.03
Retinoid dermatitis 31.6 % 53.8 % 0.02
Cheilitis and xerosis 100 % 100 %
High-dose isotretinoin in acne vulgaris: improved treatment
outcomes and quality of life.
Cyrulnik AA, Viola KV, Gewirtzman AJ et al. Int J Dermatol. 2012 ;51(9):1123-30.
Three-year study period
1.6 mg/kg/day 178 days 290 mg/kg 10 patients
No progressive accumulation of drug in skin on chronic administration.
Absorption enhanced when taken with food.
Acid metabolite of etretinate
Less lipophilic Highly lipophilic
Elimination half life 2 to 4 days ≥ 120 days
> 98 % eliminated 2 months > 98 % eliminated 2 or more years
Small amounts converts converts to Etretinate,
Metabolized to Acitretin
accelerated in presence of Ethanol
• Hence recommended period of contraception lengthened from 2mnths to 2 yrs in Europe
& 3 yrs in USA
Effectiveness : Higher doses [50 & 75mg] > Low doses [10 & 25mg]
Initial response : 4-6 weeks
Full benefit : 3-4 month
Acitretin and Psoriasis
Plaque Psoriasis 0.3 – 1.0 mg/kg/d for 4–12 wks
Combination with PUVA or UVB 0.3 - 0.5mg/kg for 6 wks
Start at 0.3 mg/kg/d and ↑ to 0.5–0.6 mg/kg/d for 3 month.
Maintainance required for upto 6 months.
Start at 1 mg/kg/d ↓ to 0.5–0.6 mg/kg/d over 3 to 6 month.
Maintainance required for upto 6-12 months
Better efficacy in combination Rx : UVB, PUVA, topical Rx
(steroids, anthralin, vit D)
Comb with MTX not recommended
Benefit on psoriatic arthritis not established unlike etretinate
Disorders of Keratinization
Good to excellent efficacy
Rapid response, long term Rx req
Best results: lamellar icthyoses
Lower doses in bullous icthyosiform erythroderma, darier’s disease: prevents
Low dose retinoid therapy (< 1mg/kg/d) with acceptable remaining disease activity
It selectively binds RXRs.
Metabolised by CYP3A4, so chances of drug interactions more.
Used in CTCL refractory to atleast one prior systemic therapy.
Dose : 300mg/m2 daily
Tablets : 10mg & 75mg
Single daily dose with meal
Initial dose : 300 mg/m2, ￪to 400 mg/m2
Response seen within 4 weeks
Response better in early stage disease (54% vs 45%)
Remission gen durable, relapse rate: 28%
Therapy may be cont. indefinitely based on clinical response
Unlike other retinoids, very little renal elimination – extreme caution in liver insuff.
3rd generation retinoid approved for :
It is the first topical retinoid approved by FDA for tt of psoriasis.
Its active metabolite tazarotenic acid
Availiable as : 0.o5 & 0.1% cream
In treatment of Photodamaged skin.
Good evidence of improvement in both clinical & histological
signs of photodamaged skin.
A review of tazarotene in the treatment of photodamaged skin
Ogden S, Samuel M, Griffiths CE. Clin Interv Aging. 2008;3(1):71-6.
Binds to all types of retinoid receptors.
Approved only for treatment of the skin manifestations of Kaposi Sarcoma.
￬IL-6, growth factor for Kaposi sarcoma cells & altering expressions of virally
Oral alitretinoin OD approved for : severe chronic hand eczema unresponsive
to t/t with potent topical steroids.
Drugs. 2009; 69(12) :1625-34
Derivative of napthoic acid
Achieved by replacing the unstable double bonds of tretinoin with napthoic
acid aromatic rings
Chemical and sunlight stability and high lipophilicity
Inspired by a need to ￬S/E of tretinoin
Lack of effect on CRABP I & II accounts for its better tolerability
Marked anti-proliferative action : Comedolytic & anticomedogenic ≥ than
Has immunoregulating activity : ↓ TLR2, inhibit cytokine prod by P. acne.
Anti-inflammatory activity : blocks AP1 inflammatory pathway.
Available as 0.1 % gel/cream
Pregnancy or woman who is likely to
Noncompliance with contraception Hypothyroidism (in bexarotene
Nursing mothers Moderate-to-severe cholesterol or
Significant hepatic/renal dysfunction
Isotretinoin and the risk of depression in patients with acne vulgaris: a case-crossover
Azoulay L, Blais L, Koren G, LeLorier et al. J Clin Psychiatry. 2008;69(4):526-32.
D : 1984 through 2003.
30,496 subjects in the initial cohort, 126 (0.4%) cases met inclusion criteria.
Relative risk for those exposed to isotretinoin was 2.68.
Association of suicide attempts with acne and treatment with
isotretinoin: retrospective Swedish cohort study.
Sundström A, Alfredsson L, Sjölin-Forsberg G et al. BMJ. 2010 Nov 11;341
Retrospective cohort study
5,756 patients ranging in age from 15 to 49 years
Slight ↑ depression/suicide attempts during during and up to one year after treatment
Trend towards improvement after 1 year
H/o attempted suicide may not need to be a contraindication when considering
treatment with isotretinoin
Depression and suicidal behavior in acne patients treated
with isotretinoin : a systematic review.
Marqueling AL, Zane LT. Semin Cutan Med Surg. 2005 Jun;24(2):92-102.
Nine studies met the qualifying criteria
• Studies comparing depression before and after treatment did not show statistically
• Some, in fact, demonstrated a trend toward fewer or less severe depressive symptoms
after isotretinoin therapy.
ISOTRETINOIN & ACITRETIN
Lab investigations :
Serum or sensitive urine pregnancy test
CBC Before Rx and 4-6 wks after onset of Rx
LFT Repeat every 3 months
Special tests :
X-ray wrists, ankles, thoracic spine
BAD Guidelines 2010
Follow up : monthly x 3 months, then 3 monthly
Follow up: 2 weekly x 4-8 weeks, then monthly x 3 months, then
Prescribing Status of systemic Retinoids
in Pregnancy – Category X
Absent clavicle and scapula
Aplasia/hypoplasia of long bones
Thymic aplasia or hypoplasia
Anal and vaginal atresia
2 negative UPT or serum pregnancy tests
Each month of therapy, patient must have negative urine or serum pregnancy test.
Must commit 2 forms of contraception 1 mnth before & after Isotretinoin therapy.
For patients with amenorrhoea , 2nd test should be atleast 11 days after last act of
Dev in Europe as topical med
Less irritating & efficacious than tretinoin
TEMAROTENE (Ro 15-0778)
Some immunosuppressive activity like cyclosporine
No sebosuppr, antikeratinizing property
AROTINOID ETHYL ESTER
Analogous to etretinate, oral agent
Highly effective in Rx etretinate resistant DOK
S/E profile similar to etretinate
• GLUCURONIDE ANALOGS
Topical agents, less Mucocutaneous S/E
• AROTINOID SULPHONES
• Methyl sulphone – sumarotene
• Ethyl sulphone – etarotene
• Do not bind to RARs
• Topical – multiple actinic keratoses
Oral, dose: 200 mg/d
Actinic keratoses, chemoprevention of BCC & oral leukoplakia
Drug allergy and nyctalopia more frequent
RAR selective retinoid
In the prevention or treatment of cutaneous carcinoma
• Retinoids : synthetic & natural compounds with biological activity of Vit. A.
• Vit. A & Carotenoids are needed for various biological functions.
• Various generation of synthetic retinoids have been developed by changing str. of Vit. A
• Tretinoin : very effective in mild to moderate grade acne.
• Adapalene : similar efficacy with less local adverse effects.
• Isotretinoin : highly effective in nodulocystic acne due to its significant sebosupp. effects
: Higher doses for longer duration in resistant & severe acne.
• Acitretin : very effective in disorders of keratinization, major drawback is recurrence
after stoppage of therapy.
• Bexarotene : response in all stages of CTCL.
: More side effects than other retinoids, managed with monitoring and
• Investigational retinoids : less side effects while maintaining efficacy