This document provides an overview of retinoids, including: - Retinoids are derivatives of vitamin A or compounds with similar structure or function to vitamin A. - They have a long history of medical use dating back to ancient Egypt. - Retinoids act through nuclear retinoid receptors and influence gene expression and cell differentiation. - They have various applications in dermatology for conditions like acne and psoriasis, ophthalmology for preventing blindness, and oncology for treating cancers like cutaneous T-cell lymphoma. - Both topical and oral retinoids are used depending on the condition, and they can have beneficial effects as well as potential adverse side effects that require monitoring.

1. Retinoids in
Therapy
Something in
Everything
Presenter: Dr Panini Patankar
Guide: Dr Shirish Joshi

2. Flow of Seminar
 Definition & classification
 History
 Physiology of retinoids
 Retinoids in dermatology
 Retinoids in ophthalmology
 Retinoids in oncology
 Miscellaneous uses of retinoids
 Adverse effects of retinoids

3. What Are
Retinoids
Chemical compounds
which are derivatives of
Vitamin A or compounds
sharing structural or
functional similarity with
Vitamin A
Khalil S, Bardawil T, Stephan C, Darwiche N, Abbas O, Kibbi A et al. Retinoids: a journey from the molecular structures and
mechanisms of action to clinical uses in dermatology and adverse effects. Journal of Dermatological Treatment.
2017;28(8):684-696.

4. Vitamin A & Metabolites
O'Byrne S, Blaner W. Retinol and retinyl esters: biochemistry and physiology. Journal of Lipid Research.
2013;54(7):1731-1743.

5. Classification
First Generation: Non-aromatic
naturally occurring retinoids: retinol,
retinal, isotretinoin & alitretinoin
Second generation: Monoaromatic
lipophilic compounds: Etretinate,
Acitretin, Motretinate
Third generation: Cyclised polyene
side chain compounds: Adapalene,
Tazarotene & Bexarotene
Goodman L, Gilman A, Brunton L, Hilal-Dandan R, Knollmann B.
Goodman & Gilman's the pharmacological basis of therapeutics. 13th
ed. New York [etc.]: McGraw Hill Education; 2018.

6. History
Egyptians using liver
juices to treat night
blindness
1500 BC
McCollum et al, first
to identify Vitamin A
1913
Wolbach et al
studied Vitamin A
deprivation in mice
1925
P. Karrer et al
determined chemical
structure of retinol
1931
First dermatological
use of Vitamin A by
Staumfjord for Acne
vulgaris
1943
Wolf G. A history of vitamin A and retinoids. The FASEB Journal. 1996;10(9):1102-1107.

7. History
Isler & W.
Huber
synthesised
this vitamin
1947
First topical
application of
Tretinoin for
acne vulgaris
by Kligman et
al
1969
Etretinate &
Acitretin
discovered
by Bollag et
al
1972
Isotreitinoin
approved by
FDA for
nodulocystic
acne
1982
Etretinate
approved
by FDA for
Psoriasis
1987
Bexarotene
approved by
FDA for CTCL
1999
Research for
many new
indications
2000s

8. Retinoid Physiology
Retinol, Retinal & Retinoic acid are interconvertible
Absorption through proximal small intestine in association with
chylomicron
Retinol: Main circulation form
Retinoic Acid: Main storage form
Retinol binding proteins (RBPs) include RBP-4 in plasma & cellular RBPs
(CRBPs)
Khalil S, Bardawil T, Stephan C, Darwiche N, Abbas O, Kibbi A et al. Retinoids: a journey from the molecular structures
and mechanisms of action to clinical uses in dermatology and adverse effects. Journal of Dermatological Treatment.
2017;28(8):684-696.

11. Retinoid
Receptors
Two types of receptors: RARs & RXRs
Exist in α, β & γ subtypes
Upregulate gene expression by binding to
Retinoid Acid Response Elements (RARE)
Downregulate expression of transcription
factors like AP1
O'Byrne S, Blaner W. Retinol and retinyl esters: biochemistry and
physiology. Journal of Lipid Research. 2013;54(7):1731-1743.

12. Retinoids in Dermatology

14. Effects of Retinoids on skin
Effects on Keratinization: normalises hyper-proliferative
epidermis & thus keratinization
Immunologic & anti-inflammatory effects: Inhibits pro-
inflammatory cytokines & enzymes of phagocytosis
Effect on sebaceous gland activity: Decreases
gland size by decreased proliferation of basal sebocytes &
maximum effect seen with Isotretinoin
Cong T, Hao D, Wen X, Li X, He G, Jiang X. From pathogenesis of acne vulgaris to anti-acne
agents. Archives of Dermatological Research. 2019;311(5):337-349.

15. FDA Approved Indications
Condition Retinoid Route
Acne vulgaris Tretinoin, Adapalene,
Tazarotene
Topical
Photoaging Tretinoin, Tazarotene Topical
Psoriasis Tazarotene Topical
Nodulocystic &
recalcitrant acne
Isotretinoin Parenteral
Pustular Psoriasis
Erythrodermic Psoriasis
Recalcitrant Psoriasis
Acitretin Parenteral

16. Retinoids
in Acne
Vulgaris
Acne vulgaris: Disorder of
pilosebaceous unit affecting
85% population between 12-
25 years age
Management depends upon
severity of acne

17. Severity of Acne
vulgaris

18. Zaenglein A. Acne Vulgaris. New England Journal of Medicine. 2018;379(14):1343-1352.

19. Topical Retinoids in Acne
 Topical retinoids are first choice in acne
but under prescribed
 Good efficacy but poor compliance
 All topical retinoids photosensitive &
concurrent sunscreen use essential
 Difficult to rank topical retinoids due to
limited comparative trials
Lee YH, Liu G, Thiboutot DM, Leslie DL, Kirby JS. A retrospective analysis of the duration
of oral antibiotic therapy for the treatment of acne among adolescents: investigating
practice gaps and potential cost-savings. J Am Acad Dermatol 2014; 71: 70-6.

20. Tretinoin
 First retinoid
introduced into
clinical use
 Availability: 0.01%-
0.1% as cream or gel
 New microsphere
preparation is 4
times potent &
better tolerance
Sumita J, Leonardi G, Bagatin E. Tretinoin peel: a critical view. Anais Brasileiros de
Dermatologia. 2017;92(3):363-366.

21. Adapalene
 Derivative of naphthoic acid
 Chemical & sunlight stability
with high lipophilicity
 Lack of effect on CRAB 1 &
CRAB 2 & thus better
tolerability
 Anti-proliferative action >
Tretinoin
 Availability: 0.1% gel/cream

22. Kolli S, Pecone D, Pona A, Cline A, Feldman S. Topical Retinoids in Acne Vulgaris: A Systematic
Review. American Journal of Clinical Dermatology. 2019;20(3):345-365.

23. Kolli S, Pecone D, Pona A, Cline A, Feldman S. Topical Retinoids in Acne Vulgaris: A Systematic
Review. American Journal of Clinical Dermatology. 2019;20(3):345-365.

24. Systemic
Retinoids
in Acne
 Isotretinoin: Only FDA
approved retinoid to treat
recalcitrant nodulocystic
acne
 Decreases sebum & has
comedolytic effects
 Potent teratogen
 Common A/E: Dryness of
mouth & increased serum
triglycerides
 Dosing range: 0.5-2
mg/kg/day
Greywal T, Zaenglein A, Baldwin H, et al. Evidence based
recommendations for the management of acne fulminans and
its variants. J Am Acad Dermatol 2017;77(1):109–17

25. Retinoids in
Psoriasis
 Psoriasis: Chronic
inflammatory disease of skin;
silvery plaques & may involve
joints
 Chronic Plaque Psoriasis:
Most common
 FDA approved retinoid:
Topical Tazarotene &
parenteral Acitretin for
pustular psoriasis &
erythrodermic Psoriasis
Heath M, Sahni D, Curry Z, Feldman S. Pharmacokinetics of tazarotene and acitretin in psoriasis.
Expert Opinion on Drug Metabolism & Toxicology. 2018;14(9):919-927.

26. Pathophysiology of Psoriasis
Dysregulated interactions between immune
system & cutaneous cells
Pro-inflammatory & proliferative cytokines
produced throughout the body
Increased expression of adhesion molecules
& keratinocyte proliferation
Inflammatory cascade triggers endothelial
cell induction & epidermal hyperplasia

27. Tazarotene
 First topical retinoid approved by
FDA to treat Psoriasis
 Tazarotenic Acid: Active form &
has high affinity for RAR γ isomers
 Mechanism of Action: Modulates
keratinocyte differentiation &
proliferation & decreases expression of
IL-6
 Availability: 0.05% & 0.1% cream

28. Acitretin
 Acid metabolite of etretinate
 Less lipophilic & 98% eliminated in 2
months & small amount converted to
etretinate
 Period of contraception lengthened from
2 months to 3 years by FDA
 MOA: Similar to Tazarotene
 Initial response: 4-6 weeks & full benefit
by 3-4months
Sarkar R, Chugh S, Garg V. Acitretin in dermatology. Indian Journal of Dermatology, Venereology,
and Leprology. 2013;79(6):759.

29. Regimens of Acitretin

30. Off-label Uses of Oral Isotretinoin
Nickle SB, Peterson N, Peterson M. Updated Physician's Guide to the Off-
label Uses of Oral Isotretinoin. J Clin Aesthet Dermatol. 2014;7(4):22–34.

31. Off label
Uses of
Topical
Retinoids
Sarkar R, Chugh S, Garg V. Acitretin in dermatology. Indian
Journal of Dermatology, Venereology, and Leprology.
2013;79(6):759.

32. Retinoids in
Ophthalmology

33. National
Vitamin A
Prophylaxis
Programme
Five year trial by NIN: Massive dose of Vit A
(200000 IU) administered per 6 months between 1
& 3 years reduces corneal xerophthalmia by 80%
1970: National Prophylaxis Programme Against
Nutritional Blindness
2006: Age group broadened; 6 months-5 years
Dose: 100000 IU at 9 months followed by 200000
IU, 6 monthly up to 5 years
National Vitamin A prophylaxis program | National Health Portal Of India
[Internet]. Nhp.gov.in. 2019 [cited 6 June 2019]. Available from:
https://www.nhp.gov.in/national-vitamin-a-prophylaxis-program_pg

34. Retinoids in
Degenerative
Retinal Diseases
Age related Macular Degeneration (AMD), Retinitis
Pigmentosa, Leber’s congenital amaurosis & Stargardt
macular dystrophy (SMD)
Treatment: 9-cis-retinyl and 9-cis-β-carotene may help restoring 11-cis-retinal levels
Insufficient Phase III data
Oral Isotretinoin: Good efficacy for SMD in murine models but human evidence is lacking
Vitamin A Palmitate: Berson et al, long term doses of 15000 IU/day slows photoreceptor functional damage
Hussain R, Gregori N, Ciulla T, Lam B. Pharmacotherapy of retinal disease with
visual cycle modulators. Expert Opinion on Pharmacotherapy. 2018;19(5):471-
481.

35. Ongoing Studies for Degenerative
Retinal Diseases

36. Retinoids in
Oncology

37. FDA Approved Retinoids
Bexarotene: Topical
oral for Cutaneous T-
cell Lymphoma (CTCL)
Alitretinoin: Topical
Application in
Kaposi’s sarcoma

38. Cutaneous T-Cell
Lymphoma
 Heterogenous subset of extra-
nodal Non Hodgkin’s
lymphoma of skin homing T
cells mainly localised to skin
 Most common: Mycosis
fungoides
 Treatment: Early disease
topical followed by systemic

39. Bexarotene
 Rexinoid: Selectively binds to RXRs
 Metabolism: CYP3A4 & more drug interactions
 FDA Approval: 1999
 MOA: Induces tumour cell apoptosis by activating p53
pathway by activation of ATM protein
 Dosage: 200-300 mg/m2 & should be started with low
dose of 150 mg/m2 daily
 A/E: Most common: Hypertriglyceridemia (82%)
 Use with caution in hepatic insufficiency
Lowe M, Plosker G. Bexarotene. American Journal of Clinical Dermatology. 2000;1(4):245- 250.

40. Alitretinoin
 FDA Approval: 1999 for treatment of
localised Kaposi’s sarcoma
 MOA: Binds to all classes of RARs & RXRs;
anti-inflammatory, anti-proliferative,
immunomodulatory & apoptotic effects
 Availability: 0.1% gel
 Dosage: Sufficient twice daily application
followed by 4 applications per day
 Response Duration: 2 weeks
Bubna A. Alitretinoin in dermatology-An update. Indian Journal of Dermatology.
2015;60(5):520.

41. Off-label Uses: Oral Isotretinoin
Nickle SB, Peterson N, Peterson M. Updated Physician's Guide to the Off-label Uses of Oral
Isotretinoin. J Clin Aesthet Dermatol. 2014;7(4):22–34.

42. Off-label Uses: Oral Acitretin
Li W, Liu Y, Luo Q, Li X, Zhang X. Off-label uses of retinoids in dermatology. Our Dermatology Online.
2012;3(Suppl.1):259-279.

43. Miscellaneous
Uses of
Retinoids

44. Retinoid
Antibiotics
 Two synthetic
retinoids: CD437 &
CD1530 have shown
to kill both growing
& persister MRSA by
lipid bilayer
destruction
 Show synergism with
gentamycin & hold
promise as antibiotic
Kim W, Zhu W, Hendricks G, Van Tyne D, Steele A, Keohane C et al. A new class of synthetic
retinoid antibiotics effective against bacterial persisters. Nature. 2018;556(7699):103-107.

45. Other
Disorders:
Conflicting
Reports
Diabetes Mellitus
Prophylaxis of Cardiovascular events
Treatment of neuroblastoma
Treatment of colonic cancer
Memory enhancer
Antioxidant

46. Adverse Effects: Topical Retinoids
 Retinoid Reaction: Dryness,
peeling erythema & pruritus
 Photosensitivity: Decreased
tolerance to sunlight
 Prophylaxis:
a) Start with lowest dose &
frequency & then gradually
increase
b) Use of sunscreens &
moisturisers
Khalil S, Bardawil T, Stephan C, Darwiche N, Abbas O, Kibbi A et al. Retinoids: a journey from the molecular structures and
mechanisms of action to clinical uses in dermatology and adverse effects. Journal of Dermatological Treatment.
2017;28(8):684-696.

47. Systemic Retinoids: Minor Adverse Effect
 Dose dependent &
mucocutaneous effects
common
 Cheilitis: Most common &
earliest adverse effect
 Xerophthalmia: Retinoid
induced meibomian gland
dysfunction
 Xerosis & fingertip
fissuring

48. Systemic
Retinoids:
Major
Adverse
Effects
 Musculoskeletal: Myalgia, arthralgias
& bony pain
 Bone: Increased osteoclastic activity
& inhibition of cortical bone
formation
 Neurological: Headaches,
pseudotumor ceribri
 Ocular: Nyctalopia by inhibition of
11-cis retinol dehydrogenase
 Gastrointestinal: Nausea & increased
risk of pancreatitis
 Lipid profile: Increase triglycerides,
total cholesterol & decrease in high
density lipoproteins
 Liver enzymes: Increase for couple of
weeks & then normalise in a month

49. Systemic Retinoids:
Teratogenicity
 As per US FDA, oral retinoids are
category X
 Retinoid Acid Embryopathy: Neural
crest defects
 Studies failed to show significant
increase in plasma concentration
post topical use & hence safe
 iPLEDGE: US program to prevent use
of isotretinoin in pregnancy

50. Retinoids & Mood Changes
 Still debatable
 Many case reports indicate direct association between
isotretinoin & depression
 Most large scale studies however refute the claim
 Warning present on drug label
Oliveira J, Sobreira G, Velosa J, Telles Correia D, Filipe P. Association of Isotretinoin With Depression and
Suicide: A Review of Current Literature. Journal of Cutaneous Medicine and Surgery. 2017;22(1):58-64.

51. Summary
 Compounds related structurally or functionally to Vitamin A are called
Retinoids
 Retinoids act through two types of receptors: RARs & RXRs
 Currently retinoids are most commonly used in dermatology followed by
oncology
 Topical retinoids is the first line of pharmacotherapy in treatment of acne
vulgaris
 Acitretin is drug of choice for systemic therapy of psoriasis
 Retinoids have many promising off-label uses in both dermatology & other
fields
 Systemic retinoids are highly teratogenic & should be avoided in
pregnancy