Retinoids

Retinoids in Dermatology
Presenter : Dr. Sanjay Singh
Dermatology, AIIMS

 History
 Structure
 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
 Retinoid Teratogenecity
 Newer Retinoids

What are Retinoids?
All synthetic & natural compounds that have biologic activity
similar to Vitamin A.

HISTORY
 First dermatologic use of vitamin A : in 1943 by Staumfjord for Acne
Vulgaris
 In 1962 : Therapeutic effectiveness of Topical Tretinoin : Disorder of
Keratinisation by Stuttgen.
 In 1969 : first topical application of tretinoin for acne vulgaris : by Kligman
& colleagues.
 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
: Acitretin.
 In 1999 : Bexarotene approved : for CTCL.
 In 1999 : Alitretinoin approved by FDA : for Kaposi Sarcoma

STRUCTURE
Cyclohexenyl
Ring
Conjugated
Side Chain
Polar Terminal
Group

 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
side chain.

NATURAL RETINOIDS
 Daily requirement: 0.8-1mg/ 2400-3000IU
 FUNCTIONS :
Retinal(as 11-cis &11-trans isomer) : in Visual function
Retinol : in Reproduction
Retinoic acid : in Epithelial differentiation & normal growth

Retinol
Retinal
Retinoic
acid

CAROTENOIDS
 Organic pigments : Naturally occurring in chlorophyll & chromoplast of
plants .
 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.

RETINOID RECEPTORS
 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
pathways.

Ist GENERATION
 Non-Aromatic Retinoids
Tretinoin (all-trans retinoic acid)
Isotretinoin (13-cis retinoic acid)
Alitretinoin (9-cis retinoic acid)
All-trans Retinoyl B-glucornide
Fenretinide

2nd GENERATION
 Monoaromatic Retinoids
Etretinate
Acitretin
Motretinide

3rd GENERATION
 Polyaromatic Retinoids
Bexarotene
Tazarotene
Tamibarotene (Am-80)
Arotinoid sulfones
Adapalene : Derivative of naphthoic acid with retinoid-like
properties, does not fit precisely into any of three generations.

Newer retinoids
 Seletinoid G
 Arotinoid
 Etretin
 Seletinoid G classified as fourth generation retinoids by some
authors.

Biological
Diversity
Sebolytic
Synthesis of Dermal Matrix
Anti-inflammatory
Epithelial differentiation
Morphogenesis
Angiogenesis
Melanotropism
Immunomodulation

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
increases.
 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

ANTITUMOUR EFFECTS
 Retinoid induced apoptosis :
 Regulation of expression of apoptosis linked gene products: BCL-2,
tissue transglutaminase
 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
transformed cells

Physiological conc : promote wound healing
 ￪MPS, collagen, fibronectin & GAG, ￬collagenase
Supraphysiologic conc: inhibit wound healing
 ￬fibroblast prolif, ￬collagen 1 & 3, ￬GAG

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

INDICATIONS OF RETINOID THERAPY
FDA APPROVED TOPICAL RETINOIDS
Acne Vulgaris Tretinoin, Adapalene, Tazarotene
Photoageing Tretinoin, Tazarotene
Psoriasis Tazarotene
Cutaneous T-cell lymphoma Bexarotene
Kaposi Sarcoma Alitretinoin

FDA-approved Oral Retinoids
Psoriasis
1. Pustular psoriasis (localized and von Zumbusch)
2. Erythrodermic psoriasis
3. Severe and recalcitrant psoriasis
Acitretin
Acne
1. Nodulocystic acne
2. Recalcitrant acne with tendency for scarring
Isotretinoin
Cutaneous T-cell lymphoma Bexarotene

INDICATIONS
 Non FDA approved Off Label Uses
Follicular Disorders
 Acne-related conditions
 Rosacea
 Hidradenitis suppurativa
 Dissecting cellulitis of scalp

Disorders of Keratinization
 Pityriasis rubra pilaris
 Ichthyosis spectrum
 Keratodermas
 Darier’s disease
Inflammatory Dermatoses
 Chronic hand eczema
 Lupus erythematosus
 Lichen planus- oral erosive, palmoplantar
 Lichen sclerosus et atrophicus

Chemoprevention of Malignancies
 Premalignant conditions
 Syndromes with increased risk of cutaneous malignancy
 Transplantation patients
 Frequent BCC or SCC
 Kaposi’s sarcoma

TRETINOIN
All-trans-retinoic acid
 1st retinoid introduced into clinical use – nearly 4 decades ago, for topical Rx of
acne vulgaris
MOA :
 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
tolerated
 Available in 0.1% & 0.04%
 ADVANTAGES :
 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.

ISOTRETINOIN
 13-cis-retinoic acid
 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

Important indications
 Nodulocystic acne
 Inflammatory acne with scarring
 Acne with psychological distress
 Gram-negative follicullitis
 Pyoderma faciale
 Severe rosacea

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
Lower-dose treatment
group (<220 mg/kg)
High-dose group
(>220 mg/kg)
p value
Relapse rate 47.4 % 26.9 % 0.03
Retinoid dermatitis 31.6 % 53.8 % 0.02
Cheilitis and xerosis 100 % 100 %
Other adverse
effects
> 0.05

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.
 80 participants
 Three-year study period
Mean daily
dose
Average time
Duration
Cumulative
dose
Relapse
1.6 mg/kg/day 178 days 290 mg/kg 10 patients
(12.5%)

 No progressive accumulation of drug in skin on chronic administration.
 Absorption enhanced when taken with food.

Acitretin
 Acid metabolite of etretinate
Acitretin 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
Regimens :
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
Erythrodermic Psoriasis
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.
Pustular Psoriasis
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
disease flare
 Low dose retinoid therapy (< 1mg/kg/d) with acceptable remaining disease activity
preferable

BEXAROTENE
 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.

TAZAROTENE
 3rd generation retinoid approved for :
Psoriasis
Acne vulgaris
 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

 ADDITIONAL USE:
 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.

ALITRETINOIN
 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
encoded genes.
 Oral alitretinoin OD approved for : severe chronic hand eczema unresponsive
to t/t with potent topical steroids.
Drugs. 2009; 69(12) :1625-34

Adapalene
 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
tretinoin.
 Has immunoregulating activity : ↓ TLR2, inhibit cytokine prod by P. acne.
 Anti-inflammatory activity : blocks AP1 inflammatory pathway.
 Available as 0.1 % gel/cream

CONTRAINDICATIONS
ABSOLUTE RELATIVE
Pregnancy or woman who is likely to
become pregnant
Leukopenia
Noncompliance with contraception Hypothyroidism (in bexarotene
patients)
Nursing mothers Moderate-to-severe cholesterol or
triglyceride elevation
Significant hepatic/renal dysfunction

Relatively Common Minor Adverse Effects Due to
Systemic Retinoids

Potentially Serious Adverse Effects Due to Systemic Retinoids
 TERATOGENICITY
Retinoic acid embryopathy
Spontaneous abortions
 OCULAR
Reduced night vision
Persistent dry eyes
Staphylococcus aureus infections
 LIPIDS
Hypercholesterolemia
Hypertriglyceridemia

 BONE
Diffuse interstitial skeletal hyperostosis [DISH]
Osteophyte formation
Osteoporotic changes in long bones
Premature epiphyseal closure

 GASTROINTESTINAL
Pancreatitis (due to ↑↑ triglycerides)
Inflammatory bowel disease flare
 HEPATIC
Transaminase elevations
Toxic hepatitis (rarely)

 ENDOCRINE EFFECTS
Hypothyroidism ( Bexarotene )
Diabetes mellitus (controversial)
 HEMATOLOGIC
Leukopenia
Agranulocytosis
 NEUROLOGIC
Pseudotumor cerebri
 Arthralgia & Myalgia

Side effects of acne therapy and their management.
Miller RA. J Cutan Med Surg2(suppl3):14-8 (1998).
Mucocutaneous
Dry Lips 96 %
Facial Dermatitis 55 %
Dry Nose 51 %
Dry skin, Pruritus, Desquamation 20-50 %
Conjuctivitis 19 %
Hair Loss 13%
Impetiginization 7.5 %
Photosensitivity 1-5 %

Arthralgia and Myalgia 15 – 20 %
Headache 5 – 16 %
Impaired Night Vision Unknown

Isotretinoin & Depression : A
controversy

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.
 Case-crossover study
 D : 1984 through 2003.
study.
 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
significant difference.
• Some, in fact, demonstrated a trend toward fewer or less severe depressive symptoms
after isotretinoin therapy.

MONITORING DURING SYSTEMIC RETINOID
THERAPY

ISOTRETINOIN & ACITRETIN
 Clinical Examination
 Lab investigations :
Serum or sensitive urine pregnancy test
CBC Before Rx and 4-6 wks after onset of Rx
LFT Repeat every 3 months
Lipid profile
KFT
Special tests :
X-ray wrists, ankles, thoracic spine
Optha examination
BAD Guidelines 2010
 Follow up : monthly x 3 months, then 3 monthly

BEXAROTENE
 TSH, T4
 Follow up: 2 weekly x 4-8 weeks, then monthly x 3 months, then
3 monthly

TERATOGENECITY
Prescribing Status of systemic Retinoids
in Pregnancy – Category X

Major components Of Retinoid Teratogenecity

Agenesis of
Cerebellar Vermis
Abnormal Cortical
Tracts
CNS
ABNORMALITIES

 CARDIOVASCULAR ABNORMALITIES
VSD
ASD
Hypoplastic or
Interrupted Aortic Arch
Septum

 AUDITORY ABNORMALITIES
Microtia
Absent auditory canals
Conductive hearing loss
Sensorineural hearing loss
Vestibular dysfunction
• OCULAR ABNORMALITIES
Micropthalmia
Optic nerve atrophy

 BONE ABNORMALITIES
Absent clavicle and scapula
Aplasia/hypoplasia of long bones
Short sternum
Sternoumbilical raphe
Absent thumb
 OTHER ABNORMALITIES
Thymic aplasia or hypoplasia
Anal and vaginal atresia

PREGNANCY MONITORING
 GENERAL REQUIREMENTS:
 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
sexual intercourse.

INVESTIGATIONAL RETINOIDS
 MOTRETINIDE
 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
Unstable preparations
• AROTINOID SULPHONES
• Methyl sulphone – sumarotene
• Ethyl sulphone – etarotene
• Do not bind to RARs
• Topical – multiple actinic keratoses

 FENRETINIDE
 Oral, dose: 200 mg/d
 Actinic keratoses, chemoprevention of BCC & oral leukoplakia
 Drug allergy and nyctalopia more frequent
 ALRT 1550
 RAR selective retinoid
 Cervical carcinoma
 CD437
 In the prevention or treatment of cutaneous carcinoma

Summary
• 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
dose reduction.
• Investigational retinoids : less side effects while maintaining efficacy

Retinoids

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