Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Retinoids

6,598 views

Published on

Retinoids in dermatology, isotretinoin, tretinoin, Acitretin, retinoids teratogenecity

Published in: Education
  • How To Get Rid Of Acne, The amazing clear skin secret Of top models and celebrities ◆◆◆ https://bit.ly/2SaU9sk
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here
  • Discover How to Cure Acne At Any Age, Even If You�ve Tried Everything And Nothing Has Ever Worked For You Before Click Here ◆◆◆ https://tinyurl.com/ybbtmvh8
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here

Retinoids

  1. 1. Retinoids in Dermatology Presenter : Dr. Sanjay Singh Dermatology, AIIMS
  2. 2.  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
  3. 3. What are Retinoids? All synthetic & natural compounds that have biologic activity similar to Vitamin A.
  4. 4. 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.
  5. 5.  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
  6. 6. STRUCTURE Cyclohexenyl Ring Conjugated Side Chain Polar Terminal Group
  7. 7.  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.
  8. 8. 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
  9. 9. Retinol Retinal Retinoic acid
  10. 10. 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
  11. 11. 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.
  12. 12. Retinol
  13. 13. RETINOID RECEPTORS  Belongs to Steroid thyroid hormone receptor superfamily  Exists as α, β, γ types  Human skin mainly contains RXRγ & RARα
  14. 14. 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.
  15. 15.  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.
  16. 16. CLASSIFICATION OF RETINOIDS
  17. 17. 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
  18. 18. 2nd GENERATION  Monoaromatic Retinoids Etretinate Acitretin Motretinide
  19. 19. 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.
  20. 20. Newer retinoids  Seletinoid G  Arotinoid  Etretin  Seletinoid G classified as fourth generation retinoids by some authors.
  21. 21. Biological Diversity Sebolytic Synthesis of Dermal Matrix Anti-inflammatory Epithelial differentiation Morphogenesis Angiogenesis Melanotropism Immunomodulation
  22. 22. 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
  23. 23.  Reduction of tonofilaments, ↓corneocyte adhesiveness, impaired permeability barrier, ↑TEWL Normalise hyper-proliferative epidermis Clinical desquamation and peeling
  24. 24. 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
  25. 25. 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
  26. 26. 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
  27. 27. Physiological conc : promote wound healing  ↑MPS, collagen, fibronectin & GAG, ↓collagenase Supraphysiologic conc: inhibit wound healing  ↓fibroblast prolif, ↓collagen 1 & 3, ↓GAG
  28. 28. 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
  29. 29. 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
  30. 30. 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
  31. 31. INDICATIONS  Non FDA approved Off Label Uses Follicular Disorders  Acne-related conditions  Rosacea  Hidradenitis suppurativa  Dissecting cellulitis of scalp
  32. 32. 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
  33. 33. Chemoprevention of Malignancies  Premalignant conditions  Syndromes with increased risk of cutaneous malignancy  Transplantation patients  Frequent BCC or SCC  Kaposi’s sarcoma
  34. 34. 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
  35. 35.  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
  36. 36. 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.
  37. 37. Sunscreen use is necessary
  38. 38. 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
  39. 39.  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
  40. 40. Important indications  Nodulocystic acne  Inflammatory acne with scarring  Acne with psychological distress  Gram-negative follicullitis  Pyoderma faciale  Severe rosacea
  41. 41. 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
  42. 42. 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
  43. 43. 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%)
  44. 44.  No progressive accumulation of drug in skin on chronic administration.  Absorption enhanced when taken with food.
  45. 45. 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
  46. 46. 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
  47. 47.  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
  48. 48. 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
  49. 49. 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
  50. 50.  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.
  51. 51. 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
  52. 52.  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.
  53. 53. 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
  54. 54. 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
  55. 55.  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
  56. 56. 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
  57. 57. SIDE EFFECT PROFILE
  58. 58. Relatively Common Minor Adverse Effects Due to Systemic Retinoids
  59. 59.  HAIRS & NAILS
  60. 60. 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
  61. 61.  BONE Diffuse interstitial skeletal hyperostosis [DISH] Osteophyte formation Osteoporotic changes in long bones Premature epiphyseal closure
  62. 62.  GASTROINTESTINAL Pancreatitis (due to ↑↑ triglycerides) Inflammatory bowel disease flare  HEPATIC Transaminase elevations Toxic hepatitis (rarely)
  63. 63.  ENDOCRINE EFFECTS Hypothyroidism ( Bexarotene ) Diabetes mellitus (controversial)  HEMATOLOGIC Leukopenia Agranulocytosis  NEUROLOGIC Pseudotumor cerebri  Arthralgia & Myalgia
  64. 64. 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 %
  65. 65. Arthralgia and Myalgia 15 – 20 % Headache 5 – 16 % Impaired Night Vision Unknown
  66. 66. Isotretinoin & Depression : A controversy
  67. 67. 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.
  68. 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
  69. 69. 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.
  70. 70. MONITORING DURING SYSTEMIC RETINOID THERAPY
  71. 71. 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
  72. 72. BEXAROTENE  TSH, T4  Follow up: 2 weekly x 4-8 weeks, then monthly x 3 months, then 3 monthly
  73. 73. TERATOGENECITY Prescribing Status of systemic Retinoids in Pregnancy – Category X
  74. 74. Major components Of Retinoid Teratogenecity
  75. 75. CRANIOFACIAL ABNORMALITIES
  76. 76. Agenesis of Cerebellar Vermis Abnormal Cortical Tracts CNS ABNORMALITIES
  77. 77.  CARDIOVASCULAR ABNORMALITIES VSD ASD Hypoplastic or Interrupted Aortic Arch Septum
  78. 78.  AUDITORY ABNORMALITIES Microtia Absent auditory canals Conductive hearing loss Sensorineural hearing loss Vestibular dysfunction • OCULAR ABNORMALITIES Micropthalmia Optic nerve atrophy
  79. 79.  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
  80. 80. 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.
  81. 81. 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
  82. 82. • 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
  83. 83.  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
  84. 84. 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.
  85. 85. • 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

×