1. SYSTEMIC RETINOIDS

2.  The term retinoids includes all natural and synthetic
compounds that have structural or biological activities like
vitamin A
 There are more than 1500 retinoids have been developed
 First generation(nonaromatic): Tretinone: all-trans retinoic
acid , Isotretinoin : 13-cis retinoic acid, Alitretinoin: 9-cis
retinoic acid
 Second generation(monoaromatic): Etretinate, acitretin
 Third generation(polyaromatic): Adapalene, Tazarotene,
Bexarotene

The original second generation retinoid used for psoriasis, etretinate,
was superseded by its natural metabolite, acitretin, which was shown to
have similar efficacy with a better pharmacokinetic profile

4. Approved Systemic Retinoids
Chemical
name
Trade name
Date approval Indication
(removal)
Isotretinoin
Accutane
5/7/1982
Amnesteem
11/2002
Sotret
12/2002
Claravis
4/2003
Etretinate
Tegison
9/30/1986
(12/20/2002)
Severe recalcitrant
psoriasis
Acitretin
Soriatane
10/26/1996
Severe psoriasis
Bexarotene
Targretin
12/29/1999
Refractory CTCL
Severe recalcitrant
nodular acne
4

5.  Retinoids metabolism occurs in the liver
 They are excreted in bile and urine

6. Mechanism of action
 These synthetic hormones bind to nuclear retinoid
receptors , thereby altering gene transcription and
returning keratinocyte proliferation and differentiation to
normal.
 As well as modification of inflammatory responses and
neutrophil function

7. Mayor Retinoid-Responsive Skin
Diseases
 Acne: I,(T)
 Psoriasis: E
 Disorders of keratinization:I,E,(T)
 NMSC:I,E
 Precancerous lesions: T,E,(I)
 Skin aging:T

8. Psoriasis
 Retinoids , since they are not immunosuppressive,
retinoids have a role in the treatment of psoriasis in
children, patients with HIV infection and those who are
prone to cancer. It is generally safe for long-term use and
has no time limit restrictions.
 Retinoids are considered excellent for use in combination
with other treatments and when used with UVB or PUVA,
their dose and the number of phototherapy treatments
can be reduced, with the added benefit of a potential
reduction in skin carcinogenesis

9.  Acitretin is as effective as etretinate .
 Plaque psoriasis : variable response:
30% complete clearance, 50% significant
improvement (60-70% reduction of PASI score)
 Erythrodermic and Pustular psoriasis: retinoids
are the first-line therapy
 Complete clearance usually requires
a combination of therapy such as:
1. Retinoids + topical steroids
2. Retinoids + topical vit D derivatives
3. Retinoids + anthralin
4. Retinoids + PUVA (Re-PUVA): retinoids are
started for 14 days before starting PUVA
5. Retinoids + UVB

10. Psoriasis
 Within few days of
initiating therapy at
dose 30-70mg/day
 An initial worsening of
the disease with
increase of erythema
and/or extent of
involvement
 Initial low dose: 10
mg/day
 Followed by increasing
of dose
 Efficacy of low-dose
acitretin is as placebo
 Effective doses
25,50,75 mg /day
(0.5-1 mg/kg/day)

11. Disorders of keratinization
 Ichthyosis
 PRP
 Darier disease
 Keratoderma
 Papillon-Lefevre syndrome
 Keratosis lichenoids chronica

12. PRP
Systemic Vitamin A had been used with considerable
effectiveness. The advent of synthetic retinoids has
largely supplanted vitamin A therapy
 Isotretinoin:
 Acitretin
 1mg/kg/day
 1mg/kg/day
 80% of patients
showed clearance of
lesions after an
average 25 weeks
treatment
 Alone or in
combination with UVR

14. Acne vulgaris
 Isotretinoin is a systemic retinoid that is highly
effective in the treatment of acne vulgaris.
 Isotretinoin causes normalization of epidermal
differentiation, depresses sebum excretion by 70%,
is anti-inflammatory, and even reduces the presence
of P acnes.
 Treatment with isotretinoin can lead to both marked
improvement
and
long-lasting
remission.
Essentially,
isotretinoin
has
the
capacity to “cure” acne.

15.  Initially with the introduction of isotretinoin, only
patients with severe nodular cystic acne or
severe inflammatory acne, who were not
responding to conventional therapy were given
the drug.
 Now, with more than 20 years of treatment
experience, expanded guidelines for its use
include:
1. Moderate acne relapse (<50% improvement)
after a single adequately-dosed course of
antibiotics or hormonal therapy of 4 months
2. Significant psychosocial impairment
3. Gram negative folliculitis
4. Scarring or persistent dyschromia

16.  Acne conglobata is certainly the best indication for isotretinoin
therapy; however acne fulminans, after initial "calming" of the
exacerbation with oral tapering dose steroids over 4-6 weeks,
responds well to the retinoid.
 Gram-negative folliculitis can be effectively treated not only with
ampicillin, co-trimoxozole or trimethoprim, but with isotretinoin
as well.
 Hidradenitis suppurativa and rosacea patients have benefited
from isotretinoin therapy as well
 Isotretinoin is used in pyoderma faciale after initial oral steroids
for the first 4 weeks.
 Acne excoriee is often quelled with a course of isotretinoin

Good results have been reported in its use for granulomatous
perioral dermatitis.

17. Acne vulgaris
 Isotretinoin therapy should be initiated at a dose of 0.5
mg/kg/d for 4 weeks and increased as tolerated until a
cumulative dose of 120-150 mg/kg is achieved.
 Recommended course of therapy is 4-5 months , but
some dermatologists continue therapy 2 months after
clearance with average 7 months.
 Coadministration with steroids at the onset of therapy
may be useful in severe cases to prevent initial
worsening.
 Initial response can be seen by 8 weeks, But if
comedones is more present than inflammatory lesions
improvement may be delayed until 3 months

18.  Some patients may respond to doses lower
than the standard recommendation dosages.
 A lower dose (0.25-0.4 mg/kg/d) may be as
effective as the higher dose given for the
same time period and with greater patient
satisfaction.
 But may result in higher recurrence rate
 Lower intermittent dosing schedules (1 week
out of each month) are not as effective.

20.  Isotretinoin absorption is increased by
coadministration with lipids. Thus, patients
are instructed to take their doses with a
small, fatty meal.
 Given the half-life of 10 to 20 hours, it is best
to take isotretinoin twice aday.

21.  Non-responding patients to "normal" courses of
isotretinoin may have been responders had the following
potential pit-falls been adequately addressed during the
initial course in assessing response:
1. Compliance: check the lips for signs of cheilitis.
2.
Isotretinoin must be taken with a fat containing food.
3.
Insufficient dosage: clinical experience has shown that the
dosing guidelines given in the product monograph are
inadequate to achieve optimal response in most patients.
4.
Truncal acne, family history, early onset before age 12,
long established acne that has been inadequately treated
for years: all require more aggressive treatment.
5.
Ovarian cause (PCOS) may require hormonal therapy.

22. Hidradenitis suppuritiva (HS)
 Acitretin for HS is barely
mentioned in the
literature; however, its
positive effect is
pharmacologically
reasonable, as the primary
event in HS is follicular
occlusion, and acitretin
induces normalization of
epithelial cell proliferation
and differentiation.
 Not surprisingly,
isotretinoin is ineffective
for HS, as this agent
primarily works on
sebaceous glands, which
are not involved in the
pathogenesis of HS.
 The observation that 35%
of treated patients still
responded to isotretinoin is
more likely to be due to the
immunomodulatory
effects of this retinoid.

23. NMSC pre-malignant lesions
 Chemoprevention of nonmelanoma skin
cancer in patients with a history of numerous
tumors or high-risk skin cancer patients
(Xeroderma pigmentosum, nevoid BCC
syndrome, organs transplant patients )
 Treatment of premalignant skin lesions as HPVinduced tumors (condyloma accuminatum) and
actinic keratoses.
 Etretinate or aciretine 30 mg/day for 6 months

24. Neoplastic
conditions
 BCC
 Advanced SCC
 Keratoacanthoma
 Kaposi sarcoma
 Sebaceous hyperplasia
 Muir-Torre syndrome
 Leukoplakia
 Langerhans cell histocytosis

25. Ichthyosis
 Acitretin
 Ichthyosis vulgaris
 X-linked recessive
Good
 Lammelar ichthyosis
 Non-bullous congenital
Best
ichthyosiform
erythroderma
 Bullous congenital
ichthyosiform
erythroderma
May result in intial increase
of bulla formation

26. A case of KID syndrome treated with systemic
retinoids 3o mg/day and urea-based emollient
for 5 months

27. CTCL
 Bexarotene is a retinoid specifically selective
for retinoid X receptors (RXR), as opposed to
the retinoic acid receptors (RAR).
 Bexarotene is indicated for the treatment of
cutaneous manifestations of cutaneous T-cell
lymphoma in people who are refractory to at
least one prior systemic therapy.

29.  Systemic retinoid toxicity is similar to hypervitaminosis A;
hence, mucocutaneous side-effects (e.g., skin dryness,
conjunctivitis, and hair loss) are common. Other sideeffects include hyperlipidaemia, osteoporosis and
ligamentous calcifications

30. Skin fragility:
 a frequent side effect of
oral synthetic retinoids,
 Light and electron
microscopy showed
fraying or loss of the
stratum corneum and
outer layers of the viable
epidermis, loss of
desmosomes and
tonofilaments, and
intracellular and
intercellular deposits of
amorphous material that
did not stain with stains
for mucin.

31. Side effects

32.  The most common side effects are
mucocutanous effects such as cheilitis and
hair loss, which are dose-dependent.

33. Teratogenicity
 Systemic retinoids should be considered with extreme
caution in females in childbearing peroid and pregnancy
must be avoided.
 Contraception counseling is mandatory, and 2 negative
pregnancy test done at least 21 days after the last
menstrual peroid (serum pregnancy test is more accurate)
results are required prior to the initiation of therapy.
 The length of time the drug is present in the body is of
great importance because of its possible teratogenic
effects

34.  Etretinate is approximately 50 times more
lipophilic than acitretin
 Etretinate is stored in adipose tissues from which
it is released slowly
 Re-esterification of acitretin to etretinate may
occur when acitretin is taken with alcohol
 Isotretinoin and its major metabolites are
present after discontinuation of the drug and
reaches its normal levels within 2 weeks
 The time of compulsory contraception:
1. 1 month in isotretinoin
2. 2-3 years in etretinate and acitretin

35. Checklist for prescribing
isotretinoin
 Adequate sexual history
 Frank explanation of the treatment and potential








pregnancy effects
Assessment of patient comprehension
Oral contraceptive pills
Serum pregnancy test last week of cycle
Stat OCP and retinoids on 2-3 day of next cycle
Consent form signed
Each visit-discuss contraception and avoidance of
pregnancy
OCP continued after therapy
Immediate notification of physician if suspect pregnancy

36. Investigations
 laboratory examination should also include
fasting cholesterol and triglyceride assessment,
hepatic transaminase levels, and a CBC count.
 Pregnancy tests and laboratory examinations
should be repeated monthly during treatment.
 Patients with prior history of hyperlipidemias,
blood sugar or liver abnormalities may require
increased testing frequencies

38.  A recent pharmacogenetic study concluded
that "people who develop hypertriglyceridemia during isotretinoin therapy, as
well as their parents, are at increased risk for
future hyperlipidemia and the metabolic
syndrome.“
 Therefore the physician may take advantage
of this side-effect to predict the risk of the
patient and their first degree relatives of
developing diabetes, high blood pressure and
obesity later in life.

39.  While using isotretinoin, the patient is
considered at high risk for abnormal healing and
the development of excessive granulation tissue
following procedures.
 Many dermatologists delay elective procedures,
such as dermabrasion or laser resurfacing (eg,
with carbon dioxide laser or erbium:YAG laser),
for up to 1 year after completion of therapy.
 Other procedures to be avoided during therapy
include tattoos, piercings, leg waxing, and other
epilation procedures