This is probably achieved by competition between RARs and other transcription factors for commonly shared coactivator and corepressor proteins
Oral synthetic retinoidsinc skin fragility,high risk for abnormal healing,excessive granulation tissueavoid dermaabrasin,laser resurfacing co1 laser,waxing,epilation process and tattooing.
Pilots n drivers should avoid
Mc-cheilitis.prevented by topical emolient or low potent steroid.indicates compliance.lubrication of ant nares needed dry nasal mucosa and bleeding.50% xerosis more in atopics.sticking of palms more with acitretin.atrophy n skin fragilityavoid dermaabrasion 6 months after completion of rx
LFT>3 fold discontinuation,<3 folddec the dose.
Retinoids in dermatology seminar
MODERATOR-DR .JAYASHREE NAYAK
RETINOIDS IN DERMATOLOGY
• NATURAL RETINOIDS AND CAROTENOIDS
• MECHANISM OF ACTION
• EFFECT OF RETINOIDS ON HUMAN BODY
• INDIVIDUAL DRUGS
• SIDE EFFECTS,DRUG INTERACTION
• NEWER RETINOIDS
• All synthetic and natural compounds that have
biological activity similar to Vitamin A.
• First dermatological use 1943 by Straumford for
• 1962Stuttgen –Therapeutic effectiveness of topical
tretinoin for keratinisation disorders.
• 1969Kligman and colleguestopical tretinoin for
• 1955Isotretinoin first synthesised in Europefirst
used for disorder of keratinisationacne vulgaris.
• 1982FDA approved isotretinoin for severe
• 1972Bollag discovered etretinate and Acitretin
• 1986 Etretinate used for PSORIASIS
• 1988Etretinate phased out ,replaced by
• 1999Bexarotene approved for CTCL
• 1999Alitretinoin approved for KAPOSI SARCOMA
All classes of Retinoids : basic sructure of Vit A with
1st gen. Retinoids 2nd gen. Retinoids 3rd gen
Change of Polar end
group & polyene
Replacing cyclic end group of
Vit A with subsituted & non
subsituted ring systems.
polyene side chain.
Daily requirement: 0.8-1mg/ 2400-3000IU
Retinal(as 11-cis &11-trans isomer) : in Visual
Retinol : in Reproduction
Retinoic acid : in Epithelial differentiation &
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,
ABSORBTION AND DISTRIBUTION
• BA fatty foodmax Acitretin and Bexarotene
• Serum transporter albumin .
• Storge ito cells hepatocytes
• Cytosolic transporter CRABP1Modulates level of
RA in tissues.
• CRABP 2 Human epidermisepidermal
• RA predominantly all trans RA (ATRA)
ISOTRTINOIN and ACITRETIN water soluble,less deposition
Belongs to Steroid thyroid hormone receptor
Exists as α, β, γ types
Human skin mainly contains RXRγ & RARα
BASIC PRINCIPLES: RETINOID
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.
• POLYAROMATIC RETINOIDS
Adapalene:- naphtoic acid derivative have properties of
retinoids,not in 3 generations
• Seletinoid –G :-4th generation
The effects of a novel synthetic retinoid, seletinoid G, on the
expression of extracellular matrix proteins in aged human skin
EFFECTS ON EPIDERMAL GROWTH AND
• Modulate the growth and differentiation.
• Have actions on cultured keratinocytes and invivo
• Promote cell proliferation in normal epidermis
• Normalisation of hyperkeratotic skin.
• TGF –α,EGF,c AMP mediated cell growth,TGF-β2
mediated cell growth.
• Reduction of tonofilaments, corneocyte
cohesiveness,impaired function of the permeability
NORMALISE HYPERPROLIFERATIVE EPIDERMIS,DESQUAMATION AND
EFFECTS ON SEBACEOUS GLANDS
• Reduce gland size by 90% decr proliferation of
sebocytes and suppressing sebum production.
• Oral isodecr TAG , free sterols and ceramide in
• 80% in local DHT pdn and 2x androgen binding
• Mechanism unknown-not receptor mediated.
IMMUNOMODULATORY AND ANTI INFLAMMATORY
• Inhibits Proinflammatory cytokines and enzymes of
• ￪ 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
ANTI PSORIATIC ACTION
• Reduce the proliferation rate by downregulating the
no of cycling cells
• Promote terminal differentiation and filaggrin
• Regulate desquamation of corneocytenormalise
• Modulation of lymphocyte functions and inhibition
of neutrophilic migration.
• Effects seen over 6-12 weeks
ANTI TUMOR EFFECTS
• Retinoid induced apoptosis :
• Regulation of expression of apoptosis linked gene
products: BCL-2, tissue transglutaminase
• Activation of tumour suppressor genes, viz. p21,
• ￪ Caspase proteolytic activity
• Inhibition of AP-1
• SPHINGOMYELINcontrol proli n differentiation
• intracellular ceramideinhibit
proliferation,induction of differentiation and
EFFECTS ON EMBRYONIC DEVELOPMENT
• 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
• Retinoids not binding to RAR/RXR – likely non
CLINICAL USES –TOPICAL
FDA APPROVED TOPICAL RETINOIDS
ALL TRANS RETINOIC ACIDAcne vulgaris,fine
rytids,mottled pigmentation,tactile roughness of facial skin
TAZOROTENEAcne vulgaris,Psoriasis (<20%)
ALITRETINOINAIDS related kaposi sarcoma
BEXAROTENECTCL (Stage 1A & 1B)
• ALL TRANS RETINOIC ACID
• 1st retinoid introduced in clinical use.
• MOA:-Gene transcription affects growth and
differentiation of cells
• Decreasing cohesiveness of follicular corneocyte.
• Effects :-Comedolysis
• Palliative effects on fine wrinkling,Mottled
• Available topically as 0.01% to 0.1% cream,gel,solutn
• New microsphere formation in 0.1% and 0.04%
• 4*more potent,less irritation,better tolerated
• Enhance efficacy by target delivery system
• Preg C
1. Inhibit abn proli of keratinocyte
2. Decr infl lesions
3. Improve differentiation
4. Inhibit TLR-2anti infl
5. No direct role on sebum /P.acne
Aerobic environmentnon compatable to P.acne
First line non-infl acne
Not used in severe nodular acne vulgaris
• Inc Basal and granular layer thickness
• melanocytic activity, dispersion of melanin
• glycosaminoglycan secretion into intracellular space.
• synthesis of collagen and elastin
1. Smoothness of skin(4-6
2. Lightening of
3. Diminished fine
• 13-cis-retinoic acid
• No affinity for RAR/RXR
• First retinoid for systemic use
• Initially evaluated for ichthyotic disorder,later 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
1. Nodulocystic acne
2. Inflammatory acne with scarring
3. Acne with psychological distress
4. Gram negative folliculitis
5. Pyoderma faciale
6. Severe rosacea
7. Hidradenitis suppurativa and dissecting cellulitis of
8. Darier’s disease
• 1mg/kg/day for 4-5 months.
• Start with 0.5mg/kg/day gradually to 1mg/kg for 4-5
• Total cumulative dose120mg-150mg/kg
• Acne fulminans0.5-1mg/kg/day with prednisolone.
telengiectasia,erythema,papules and pustules
• Hidradenitis suppurativa1-2mg/kg/day
• DSOSIso+rifamp more effective
• Lichen planuswidespread,hypertrophic or oral
erosive LPIso+low dose CS
High dose Isotretinoin in acne vulgaris:Improved
treatment outcomes and quality of life
Three year study period
Isotretinoin therapy for acne: Results of a multicentre dose response
John S,Ronald P JAAD 10:490-496,1984
• 150 patients nodulocystic acne
• Double blinded study with 0.1,0.5,1mg/kg/day
• Comparing clinical response,s/e,lab abnormalities and
duration of induced remission.
• Results no significant difference in the clinical response
• 42% patients with 0.1mg/kg/dayrelapse.
• 10% relapsed in 1mg/kg/day
• Minor effects in s/e and lab abnormalities
• CONCLUSIONHIGHER DOSES ARE INDICATED
To compare the efficacy and tolerability
Daily,alternate,pulse,low dose regime
30 group each
mg A/D 16 weeks and follow up 8 weeks.
Conventional dose for 8 weeks and maintain
with low dose-nodulocystic acne
• Max sebosuppression
• Alter VEGF incidence of pyogenic granuloma
• Failure on microcystic acne and closed comedones
• Total cumulative dose 120mg/kg150mg/kg with no
• Acid metabolite of etretinate.
• Retinoids as monotherapy in psoriasis
• Effects thickness,scaling,itching
• Initial effects4-6 weeks
• Full effects3-4 months
• Maintenance dose z needed
• Re –esterification
• Contraception 2 years in Europe and 3 years in USA
CHRONIC PLAQUE POSORIASIS 0.3-1 mg/kg/day for 4-12 weeks
25mg stat 2 weeks prior to the therapy.
0.3-0.5mg/kg/day for 6 weeks.
If pt on stable dose of UV,reduce by 30-70%
7days after acitretin therapy
Erythrodermic psoriasis Start with 0.3mg/kg/day ,inc to 0.5-
0.6mg/kg/day for 3 months.maintenance to
Pustular psoriasis Start with 1mg/kg/day,dec to 0.5-
0.6mg/kg/day for 3-6 months,maintenance
to 6-12 months
• Not combined with MTX/Ciclosporin
• Sequential therapy z preferred
• Combination therapytopical/PUVA/NBUVB
PRECAUTIONS ON ACITRETIN
• NOT donate blood for 1 year after stoppage
• Not recommed in childrenbone changes
• Effects of UV radiation enhanced,avoid excessive
exposure to sunlight
• Refrain from waxingskin fragility
• Greater insulin sensitivityinduce hypoglycaemia on
OHA.Serum BS should check
• Avoid excess intake of vit A
• Lamellar ichthyosisgood
• Rapid response,long term treatment
• Low dose in BCIE,Darier’s prevent relapses
• <1mg/kg/day preferrable
OthersPRP,chemoprevention of non-melanoma skin
cancer in solid organ transplant receipients
• Modulation of RXR receptors
• apoptosis through redn of anti-apoptotic
protein,activates capsase 3
• effects;induces tumor regression by PPAR
Incre cellular differentiation and decreased cellular
• Inhibit G1,G2,M phase of cell cycle
• 99%plasma bound,mets by CYP450.
• Central hypothyroidism
• Sun protection ,preg X
• FDAEarly stage I A&I B persistant or refractory
• Application A/D
• Response early as 4 week
• Relapse rate 28%
• Effective in lymphamatoid papulosis,chronic severe
• S/Esite reaction,rash,pruritis,icd,pain
• fre of appl /+steroid.
• Unlike other retinoids, very little renal elimination –
extreme caution in liver insuff.
• Prodrugtazorotenic acid
• High affinity RAR gammaregulate cell pro n diff
• inflammation and proliferation throu AP-1 in
• Highest cutaneous conc,rapidly metabolised
• T1/2 <20 min
• Preg X
• USES1st topical approved in C/C Psoriasis
• Photo damaged skinclinical and histological
• USES1st topical approved in C/C Psoriasis
as mono/combination therapy1st line.
• Photo damaged skinclinical and histological
• Early stage of CTCL
• Genodermatosis (LI,EKV)
• Doses 0.05% and 0.1%
• Naturally occuring
• Binds to all retinoid receptor
• Down regulate IL-6,alter the expression of oncogen
• Dose0.1% gel.
• FDAAIDS related kaposi sarcoma
• Other usesnon AIDS Kaposi
• Preg D
• Expensive,long term Rx
• Derivative of napthoic acid
• Affinity to RAR
• More stable,less photoliable,more lipophilic
• Not binding to CRABP I and II
• Less systemic exposure
• Anti inflammatory action LT,PG,Anti AP-1 action
• Immunomodulatory action TLR-2,Cytokine
• Comedolysis, microcomedone formation
• Not carcinogenic,mutagenic
• Not teratogenic,genotoxic
• More photostable
• Used for acne,hyperpigmentation,AK,Photoaging
• S/Eerythema, scaling
• Available in 0.1%gel,cream
• BONE ABNORMALITIES
Absent clavicle and scapula
Aplasia/hypoplasia of long bones
• OTHER ABNORMALITIES
Thymic aplasia or hypoplasia
Anal and vaginal atresia
Concomitant administration of vitamen E does not change the
side effects of isotretinoin as used in acne vulgaris: a random-
Strauss JS, Gottlieb AB, Jones T et al
J Am Acad Dermatol 2000;43:777-84
• Strauss et al, however, found that vitamin E at
dose 800 IU/d provided no significant improvement
when used in acne patients on isotretinoin.
Jacobs DG, Deutsch NL, Brewer M. Suicide, depression and
isotretinoin is there a causal link?
J Am Acad Dermatol 2001;45:S168-75.
• Systematic review article 19 articles
• found no biologic basis for depression and
• further stated that no evidence for a causal
connection existed between isotretinoin and
depression or suicide.
• the authors do recommend the physician monitor for
signs of these symptoms.
Jick SS, Kremers HM, Vasilakis-Scaramozza C. Isotretinoin use and
risk of depression, psychotic symptoms, suicide, and attempted
suicide. Arch Dermatol 2000;136:1231-6
• Cohort study
• found no significant difference in depression or
suicide rates between patients that took oral
antibiotics and patients that took isotretinoin for
An analysis of reports of depression and suicide in patients treated with isotretinoin.
Wysowski DK, Pitts M, Beitz J. J Am Acad Dermatol 2001;45:515-9
• found in an analysis of depression,suicide or suicidal
thoughts a temporal association between depression
by positive de-challenges (improvement upon
medication stoppage), and positive re-challenges
(recurrence of symptoms on re-starting) with
• The study called for further research to establish a
causal relationship and to elucidate a possible
synergistic interaction between individuals
predisposed to depression and isotretinoin usage.
Isotretinointreatment for acne and risk of depression: A systematic reviewandmeta-
Yu-Chen Huang, MD, Ying-Chih Cheng, MD,J Am Acad Dermatol july 2017,volume
• A systematic review and meta-analysis of the literature
published from inception to September 30, 2016, was
• change in depression scores from baseline was not
significantly different between patients receiving
isotretinoin treatment and those receiving an alternative
treatment (95% confidence interval [CI] −0.680 to 0.011).
• The prevalence of depression after isotretinoin
treatment significantly declined (relative risk [RR] 0.588,
95% CI 0.382–0.904).
• The mean depression scores significantly decreased from
baseline (SMD −0.335, 95% CI −0.498 to −0.172).
Isotretinoin treatment for acne does not appear to be
associated with an increased risk for depression.
The treatment of acne appears to ameliorate depressive
BAD GUIDELINES 2010 FOR ISO & ACITRETIN
Before the treatment and every
2-4 weeks for 2 months,then
BAD GUIDELINES 2010 FOR ISO & ACITRETIN
• Special tests
X-ray of wrist,ankles,thoracic spine(long term
All symptomatic joint should be evaluated
• Free T3,T4 and TSH and FLP
• Highest TAGStatin or fenofibrate prior Rx.
• >300-500mg/dllife style n diet
• >500-800mg/dl dose/add a LLA,freq monitoring
• >800-1000mgdldrug discontinue(pancreatitis)
• Follow up
• Every 2 weeks*1-2 months
• Monthly *next 3 months
• Every 2-3 months
GUIDELINESS FOR PREGNANCY
• 2 Urine/serum preg test
• One 2 weeks before of initiation of isotretinoin
• 2nd during first 5 days of the menstruation/11 days
after the last act of unprotected sexual intercourse.
• Each month –ve UPT
• Therapy start on 2nd or 3rd day of next cycle
• 2 forms of contraception for atleast 1 month
prior,during and 3 years after discontinuation.
• Written consent
Increase the level(toxicity)
Decrease the retinoid
EFFECTS OF MINI
RXR panagonist,in clinical trial
Topical antipsoriatic agent
Induction of apoptosiscutaneous carcinoma
Used in chemotherapy
Augment activity of Doxorubicin,5FU,IL
• AROTINOID SULPHONES
• Used in AK
• Do not bind RAR.
LESS SIDE EFFECTS ,MORE EFFICACY
TAKE HOME MESSAGE
• Retinoids are biologically and structurally related to
• TretinoinMultifunctional from acne to
pigmentation to photodamaging.
• Adapalenesimilar efficacy with less side effects
• Isotretinoinhighly effective in nodulocystic acne
;max sebosuppression.long term for severe and
• Acitretinbest in keratinisation disorder.
long term use
recurrence after discontinuation
contraception from 2-3 years.
• Etretinate best for psoriasis
• phased out due to side effects.
• Bexaroteneeffective for early stages of CTCL.
Max s/ecareful monitoring
• Investigational retinoidslesser side effects