Retinoidsin Skin Disease and Care

  • Class of natural and synthetic compounds chemically related to vitamin A
  • Vitamin A exists in three interconvertible forms: retinol (vitamin A alcohol), retinal (aldehyde), retinoic acid (acid)
  • Function
    • Normalizes keratinization (allowing for decrease in follicular occlusion): inhibits ornithine decarboxylase, inhibits collagenase, downregulates proliferative keratins (K6 and K16), increases filaggrin production/keratin filaments/ KHGs, antagonizes function of AP-1 and IL-6, downregulates TLR2
  • Binds two types of nuclear receptors: retinoic acid receptors (RARs) and retinoid X receptors (RXRs)
    • RARs: all-trans RA ligand, RARγ is the most ubiquitous RAR in human skin and likely main mediator of retinoid effects on keratinocytes, nuclear receptors activated and gene transcription affected
    • RXRs: cis RA ligand, receptors activated in bexarotene
  • Retinoids classified into three generations (see Table 7-7)
  • Isotretinoin
    • 13-cis retinoic acid; increased absorption with fatty meal; half-life 18–20 h; goal cumulative dose 120–150 mg/kg (0.5–2 mg/kg/day for 16–20 weeks); start with lower dose in markedly inflammatory acne
    • Results in atrophy of sebaceous glands, reduction in sebum (up to 90%) so P. acnes unable to thrive, normalization of follicular keratinization
    • Treatment for nodulocystic acne, recalcitrant inflammatory acne, pyoderma faciale, acne fulminans, and gramnegative folliculitis
    • Females must avoid pregnancy for at least 1 month after discontinuing drug
    • Side effects: cheilitis, xerosis, alopecia, skin fragility, eczematous dermatitis, photophobia, keratitis, myalgias (associated with ↑ creatine phosphokinase levels), headache, pseudotumor cerebri (with concomitant TCN use), skeletal hyperostosis, premature closure of epiphyseal plates, teratogenicity, elevated triglycerides (25–45%, most common lab abnormality), elevated liver transaminases, reduced night vision, pyogenic granulomas, staph colonization
    • Retinoid teratogenicity: craniofacial, cardiac, thymic, and CNS malformations
  • Acitretin:
    • Metabolite of etretinate; half-life 2 days
    • Females must avoid pregnancy for at least 3 years after discontinuing acitretin (since drug can re-esterify to etretrinate, which is highly lipophilic with 120 day half-life)
    • Side effects: teratogenicity, hyperlipidemia, alopecia, arthralgias, abnormal liver function tests, reduced night vision, bone and joint pain, pseudotumor cerebri, xerosis of mucous membranes
  •    
     Gemfibrozil may increase plasma
    level of bexarotene
     
       
    Bexarotene:
    • RXR-specific retinoid; approved for treatment of cutaneous T-cell lymphoma (CTCL); half-life 7–9 h; metabolized by cytochrome p450 enzymes and elimination via hepatobiliary system
    • SE: similar to other retinoids with addition of
      drug-induced hypothyroidism

   
 
Table 7-7 Retinoids
 Generation of RetinoidNameHalf-life
 
First generation
Tretinoin (all-trans RA)
Isotretinoin (13-cis RA)
Half-life: 48 min
Half-life: 20 h
 
Second generation
Etretinate
Acitretin
Half-life: 120 days (highly lipophilic)
Half-life: 50 h
 
Third generation
Tazarotene, Adapalene
Bexarotene
Half-life: 7 h