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In 1998 : Etretinate phased out by Roche & replaced by its acid metabolite
: Acitretin.
Polar Terminal
Conjugated Group
Side Chain
Cyclohexenyl
Ring
All classes of Retinoids : basic sructure of Vit A with modifications
Change of Polar end group Replacing cyclic end group of Vit A with Cyclization of polyene
& polyene side chain subsituted & non subsituted ring systems. 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
Retinal
acid
CAROTENOIDS
They are not biologically active until converted to one of the retinoids in
the body .
Exists as α, β, γ types
RARs and RXRs are ligand-dependent transcription factors that regulate gene
expression in two ways:
Non-Aromatic Retinoids
Tretinoin (all-trans retinoic acid)
Fenretinide
2nd GENERATION
Monoaromatic Retinoids
Etretinate
Acitretin
Motretinide
3rd GENERATION
Polyaromatic Retinoids
Bexarotene
Tazarotene
Tamibarotene (Am-80)
Arotinoid sulfones
Arotinoid
Etretin
Seletinoid G classified as fourth generation retinoids by some
authors.
Epithelial differentiation
Morphogenesis Sebolytic
Melanotropism Biological
Synthesis of Dermal Matrix
Diversity
Immunomodulation Anti-inflammatory
Angiogenesis
EFFECTS on KERATINIZATION
Psoriasis Tazarotene
Psoriasis
Acitretin
1. Pustular psoriasis (localized and von Zumbusch)
2. Erythrodermic psoriasis
3. Severe and recalcitrant psoriasis
Acne
Isotretinoin
1. Nodulocystic acne
2. Recalcitrant acne with tendency for scarring
Follicular Disorders
Acne-related conditions
Rosacea
Hidradenitis suppurativa
Premalignant conditions
Transplantation patients
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
13-cis-retinoic acid
Nodulocystic acne
Gram-negative follicullitis
Pyoderma faciale
Severe rosacea
Standard dosing recommendations
1 mg/kg/d for 4 to 5 months
80 participants
Three-year study period
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
Low dose retinoid therapy (< 1mg/kg/d) with acceptable remaining disease activity
preferable
BEXAROTENE
It selectively binds RXRs.
Unlike other retinoids, very little renal elimination – extreme caution in liver insuff.
TAZAROTENE
↓ IL-6, growth factor for Kaposi sarcoma cells & altering expressions of virally
encoded genes.
ABSOLUTE RELATIVE
Pregnancy or woman who is likely to Leukopenia
become pregnant
Noncompliance with contraception Hypothyroidism (in bexarotene
patients)
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
Mucocutaneous
Dry Lips 96 %
Facial Dermatitis 55 %
Dry Nose 51 %
Conjuctivitis 19 %
Impetiginization 7.5 %
Photosensitivity 1-5 %
Arthralgia and Myalgia 15 – 20 %
Headache 5 – 16 %
Case-crossover study
30,496 subjects in the initial cohort, 126 (0.4%) cases met inclusion criteria.
Slight ↑ depression/suicide attempts during during and up to one year after treatment
• 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.
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
BAD Guidelines 2010
Lipid profile
KFT
Special tests :
X-ray wrists, ankles, thoracic spine
Optha examination
Follow up : monthly x 3 months, then 3 monthly
BEXAROTENE
TSH, T4
Agenesis of
Cerebellar Vermis
Abnormal Cortical
Tracts
CARDIOVASCULAR ABNORMALITIES
Hypoplastic or
Interrupted Aortic Arch
VSD
ASD
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:
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
Unstable preparations
• AROTINOID SULPHONES
• Various generation of synthetic retinoids have been developed by changing str. of Vit. A
• 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.