Presenter : Dr. Sanjay Singh

Dermatology, AIIMS

Retinoids in Dermatology

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

CyclohexenylRing

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

RetinalRetinoic

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.

Retinol

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.

CLASSIFICATION OF

RETINOIDS

Non-Aromatic Retinoids

Tretinoin (all-trans retinoic acid)

Isotretinoin (13-cis retinoic acid)

Alitretinoin (9-cis retinoic acid)

All-trans Retinoyl B-glucornide

Fenretinide

Ist GENERATION

Monoaromatic Retinoids

Etretinate

Acitretin

Motretinide

2nd 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.

3rd GENERATION

Seletinoid G

Arotinoid

Etretin

Seletinoid G classified as fourth generation retinoids by some

authors.

Newer retinoids

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

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

IMMUNOLOGIC & ANTIINFLAMMATORY EFFECTS

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 acne2. 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.

Sunscreen use is necessary

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

• Prospective, observational, intervention study

• 116 participants, 12-month follow-up survey

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.

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

80 participants

Three-year study period

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.

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

• 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

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, accelerated in presence of Ethanol

Metabolized to Acitretin

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 PsoriasisStart 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 PsoriasisStart 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 t\t 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

Derivative of napthoic acid

Achieved by replacing the unstable double bonds of tretinoin with napthoicacid 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

Adapalene

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 bexarotenepatients)

Nursing mothers Moderate-to-severe cholesterol or triglyceride elevation

Significant hepatic/renal dysfunction

SIDE EFFECT PROFILE

Relatively Common Minor Adverse Effects Due to Systemic Retinoids

HAIRS & NAILS

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

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 %

Side effects of acne therapy and their management. Miller RA. J Cutan Med Surg2(suppl3):14-8 (1998).

Arthralgia and Myalgia 15 – 20 %

Headache 5 – 16 %

Impaired Night Vision Unknown

Isotretinoin & Depression : A controversy

Case-crossover study

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.

Isotretinoin and the risk of depression in patients with acne vulgaris: a case-

crossover study.

Azoulay L, Blais L, Koren G, LeLorier et al. J Clin Psychiatry. 2008;69(4):526-32.

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

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

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.

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.

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

Follow up : monthly x 3 months, then 3 monthly

BAD Guidelines 2010

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

CRANIOFACIAL ABNORMALITIES

Agenesis of Cerebellar Vermis

Abnormal Cortical Tracts

CNS

ABNORMALITIES

CARDIOVASCULAR ABNORMALITIES

ASD

VSD

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