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Systemic and Topical Retinoids in Dermatology
- 1. Systemic and Topical Retinoids Dr. Nishkarsh Chugh PG Resident, Department of Dermatology
- 2. Introduction All synthetic and natural compounds that have either structural (retinol derivative) or functional (Vitamin A activity) similarities are known as retinoids.
- 3. Classification Generation Structure Drugs 1st Nonaromatic Vitamin A Tretinoin Isotretinoin Alitretinoin 2nd Monoaromatic Acitretin Etretinate 3rd Polyaromatic Adapalene Bexarotene Tazarotene
- 4. Classification These retinoids retain the cyclic structure of vitamin A with changes occurring in the polar end group and the polyene side chain These are synthesized by changing the cyclic ring of vitamin A They are polyaromatic retinoid derivatives also known as carotenoids, formed by cyclization of the polyene side chain
- 6. Forms of Retinoids Retinol Retinal Retinoic Acid
- 7. Pharmacokinetics • Oral bioavailability increases with food intake • Especially with fatty meal – acitretin & bexarotene • Accumulates in liver • Etretinate also stored in adipose tissues • If absorption exceeds liver storage capacity, hypervitaminosis A like symptoms appear.
- 8. Drug name Peak levels (hrs) Bioavailability (%) Protein binding (%) Half-life Metabolism Excretion Tretinoin 1–2 - Albumin 99% 40–60 min Hepatic Bile, urine Isotretinoin 3 25 Albumin 99% 10–20 hrs Hepatic (oxidation) Bile, urine Etretinate 4 44 Lipoprotein 99% 80–160 days Hepatic Bile, urine Acitretin 4 60 Albumin 95% 50 hrs Hepatic (isomerizatio n) Bile, urine Bexarotene 2 No data Plasmaproteins 99% 7–9 hrs Hepatic Hepatobiliary Absorption and Distribution
- 9. Retinoid Binds RAR Heterodimerizes with RXR Binds RXR Homodimerizes with RXR or heterodimerizes with RAR, vitamin D3 receptor, or thyroid hormone receptor Dimers act as transcription factors for genes containing RARE Transported to nucleus by CRABP Mechanism of Action
- 11. Effects of Retinoids Keratinization Immunomodul ation and anti- inflammatory Morphogenesis Sebolytic Anti- tumour Wound Healing
- 12. Keratinization Induce differentiation in a number of cell types Epidermis undergoes profound changes - • shows hypergranulosis and hyperplasia • decreased numbers of tonofilaments and desmosomes • widening of intercellular spaces • ↓ corneocyte adhesiveness, impaired permeability barrier, ↑ TEWL • normalises hyperproliferative epidermis: clinical desquamation and peeling The effect on desmosomes - contribute to the keratolytic effect of retinoids in hyperkeratotic disorders
- 13. Immunological and Anti- inflammatory 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
- 14. Sebolytic 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 esterols, cholesterol, ceramides
- 15. Anti tumour effect 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
- 16. Effect on embryonic development and morphogenesis 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
- 17. Effect on intracellular matrix components Physiological concentration: promote wound healing ↑ MPS, collagen, fibronectin & GAG, ↓ collagenase Supraphysiologic concentration: inhibit wound healing ↓ fibroblast proliferation, ↓ collagen 1 & 3, ↓ GAG
- 19. Recommended Methodology • Applied at night • Cleansed and well-dried • Controlled quantity of topical retinoid • First dabbed then gently rubbed to achieve absorption • Avoid nasal folds, periorbital, and perioral areas. • Avoid excessive cleansing and use of astringents. • Begin with short contact :15 minutes and/ or alternate night application • Contact time can be steadily increased to 30 minutes • Thereafter the cream can be left overnight. • Mild cleanser with ph 5.5-7
- 20. Drug Concentration and Formulation FDA Approved Uses Off Label Use Pregn ancy Categ ory Tretinoin • Cream:0.025%, 0.05%, 0.1 • Gel:0.01%, 0.025% • Microsphere gels : 0.04%, 0.08%, 0.1% • Gel(microionized):0.05% • Acne vulgaris grade 1,2 • Photoageing Improvement seen in 8-12 weeks • Actinic keratosis • Hyperpigmentation [melasma, solar lentigenes] • Hyperkeratotic disorders • Early stretch marks • Pretreatment of skin to augment wound healing C Adaplene • 0.1% Gel • 0.3% Cream, Lotion • Acne vulgaris grade 1, 2 Improvement seen in 8-12 weeks • Actinic keratosis • Hyperpigmentation C Isotretinoin • 0.05% Gel Acne vulgaris C
- 21. Drug Concentration and Formulation FDA Approved Uses Off Label Uses Pregn ancy Categ ory Alitretinoin • 0.1% Gel • AIDS related Kaposi Sarcoma • Chronic Hand Eczema Response in 2 weeks • Photoageing D Bexarotene • 1% Gel • CTCL • Lymphomatoid Papulosis • Hand Dermatitis • Psoriasis • Alopecia areata X Tazarotene • 0.1% Cream • 0.05% Gel • Acne Vulgaris • Chronic Plaque Psoriasis (<20% BSA) • Photoageing • CTCL • Hyperpigmentation • Genodermatoses X
- 22. Adverse Effects Retinoid dermatitis • Irritant contact dermatitis • Receptor mediated process rather than the result of direct cytotoxicity • Characterised by erythema, scaling, peeling, dryness, burning and pruritus • Typically occurs within the first 1–2 weeks • Subsides in 1-2 weeks Treatment • Suspending treatment for 3–5 days • Applying moisturizer • Topical calcineurin inhibitor • Low potency topical steroid
- 23. Adverse Effects Other Adverse Effects: • Cheilitis • Peeling • Photosensitivity Contraindications • Hypersensitivity • Pregnancy • Lactation
- 25. Drug Concentration and Formulation Dose FDA Approved Uses Pregn ancy Categ ory Isotretinoin 10, 20, 30, 40mg Capsule 0.5-2mg/kg Total Cumulative Dose: 120- 150mg/kg for 16- 24 weeks • Nodulocystic acne • Recalcitrant acne with tendency for scarring X Alitretinoin 10, 30mg Capsule 10-30mg/day • Chronic Hand Eczema D Acitretin 10, 15, 17.5, 22.5mg Capsule 25-50mg/day Initial Response: 4-6 wks Full Benefit: 3-4 months • Pustular Psoriasis (Localized and von Zumbusch) • Erythrodermic Psoriasis • Severe and recalcitrant psoriasis X
- 26. Drug Concentration and Formulation Dose FDA Approved Uses Pregn ancy Categ ory Bexarotene 75mg 300mg/m2/day • CTCL refractory to at least one prior systemic therapy X
- 27. Off Label Uses Follicular Disorders • Rosacea • Hidradenitis suppurativa • Dissecting cellulitis of scalp Disorders of Keratinization • Pityriasis rubra pilaris • Icythosis • Keratoderma • Dariers disease Inflammatory Dermatoses • Chronic hand eczema • Lupus erythematosus • Lichen planus- oral erosive, palmoplantar • Lichen sclerosus et atrophicus Chemoprevention of Malignancy • Non Melanoma Skin Cancer • Actinic Keratoses • Xeroderma Pigmentosum • Nevoid Basal Cell Carcinoma
- 28. Adverse Effects
- 29. OCULAR • Dry eyes • Blepharoconjunctivits • Photophobia ORAL • Cheilitis • Dry mouth • Sore tongue and mouth NASAL • Nasal mucosa dryness • Decreased mucus secretion • Epistaxis HAIR • Telogen effluvium • Dryness • Abnormal hair texture NAIL • Fragility • Nail softening • Paronychia • Onycholysis
- 30. BONE • Diffuse interstitial skeletal hyperostosis [DISH] • Osteophyte formation • Osteoporotic changes in long bones • Premature epiphyseal closure GASTROINTESTINAL • Nausea • vomiting • Diarrhea • Pancreatitis (due to ↑↑ triglycerides) • Inflammatory bowel disease flare HEPATIC • Transaminase elevations • Toxic hepatitis (rarely) ENDOCRINE • Hypothyroidism ( Bexarotene ) • Diabetes mellitus (controversial) NEUROLOGIC • Pseudotumor cerebri • Headache • Depression MUSCULOSKELETAL • Arthralgia & Myalgia HEMATOLOGIC • Leukopenia • Agranulocytosis • Hypertriglyceridemia
- 31. TERATOGENECITY Retinoid embryopathy • Isotretinoin >> acitretin/etretinate • Spontaneous abortions ADVICE: Contraception • Isotretinoin: 1 month prior & after • Acitretin : 1 month prior & 3 years after 2 forms of contraception necessary • At least one primary method • Primary: tubal ligation, vasectomy, IUDs, OCPs, injectable hormones • Secondary: Condoms, cervical caps with spermicides
- 32. 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 • Craniofacial Abnormalities • Cardiac Abormalities
- 33. Monitoring Guidelines • Clinical Examination • Lab investigations • Serum or sensitive urine pregnancy test • CBC • LFT • Lipid profile • KFT • Special tests • X-ray Wrists, ankles, thoracic spine: • Opthalmology Examination • Bexarotene – Thyroid Profile Before Rx and every 2– 4 weeks for the first 2 months of therapy and then every 3 months
- 34. Contraindications ABSOLUTE RELATIVE • Pregnancy • Breast feeding • Hypersensitivity • Significant hepatic or renal disease • Hypercholesterolemia (moderate to severe) • Suicidal ideation • Pseudotumor cerebri • Hypothyroidism • Leucopenia • Alcoholism
- 35. Drug Interactions Drugs which increases the serum levels (and potential toxicity) of retinoids • Vitamin A • Tetracycline, doxycycline, minocycline • Macrolides, azoles, etc. Reduces the serum levels (via CYP3A4 induction) • Antituberculosis drugs: Rifampin, rifabutin • Anticonvulsants: Phenytoin, phenobarbital, carbamazepine Retinoids may increase the drug levels of: • Cyclosporine Retinoids may reduce the drug levels of: • Progestin only contraceptives Other potentially important drug interactions • Alcohol : Acitretin ‘reverse metabolism’ to etretinate increased with alcohol consumption
- 36. Thank You Dr. Nishkarsh Chugh PG Resident, Department of Dermatology