Transcript The Effects of Isotetrinoin

The Debate on Isotretinoin
Carol Chyau
What is Isotetrinoin?
Also known as Accutane, licensed by FDA in
1982
Oral drug used to treat acne

Taken 1x/2x a day, 16-20 weeks
Synthetic molecule from vitamin A

Vitamin A involved in growth and maintenance of
skin
Expensive but top selling drug worldwide,
prescribed to 12 million people
Manufactured by Hoffman-La Roche
Why is Isotetrinoin Important?
Topic of persisting debate between
dermatologists and FDA
The only effective treatment for severe
acne
Very effective but may have severe side
effects
Facts about Acne
Most common skin disease - effects nearly
17 million people in US
Common in adolescents with rising hormone
levels of androgens (male sex hormones)
during puberty
Often hereditary
Not caused by dirty skin
What is Acne?
Disorder of sebaceous
(oil) glands that plugs
pores and causes
outbreaks of lesions
(pimples)
Disease of
pilosebaceous units


Sebaceous gland
connected to a follicle
(hair-containing canal)
Units most common on
face, upper back, and
chest
Normal pilosebaceous
unit
What Causes Acne?
Change in inner lining
of follicle

Cells shed too fast, clump
together, plug opening of
follicle
Sebum cannot reach
surface of skin

Mixture of oils and cells
fosters Propionibacterium
acnes (P. acnes) to grow
in plugged follicles
P. acnes produces
chemicals and enzymes
that cause inflammation
Types of Acne
Comedo – enlarged follicle plugged with oil and
bacteria


Whitehead – comedo beneath skin
Blackhead – comedo that opens up on surface of skin
Papules – inflamed lesions that are small pink bumps,
could be tender
Pustules – inflamed pus-filled lesions, red at base
Nodules – large, painful, solid lesions deep within
skin
Cysts – deep, inflamed, pus-filled lesions, can cause
pain and scarring
Commons Drugs for Acne
Topical medication

Benzoyl peroxide
cream/gel/lotion, salicylic
acid, sulfur, resorcinol
Oral medication


Antibiotics such as
tetracycline, minocycline,
doxycycline,
erythromycin
Isotretinoin
Isotretinoin and Vitamin A
Vitamin A is also known
as retinoic acid
The most active
metabolite of retinol is
the main factor in skin
regeneration
Isotretinoin is 13-cisretinoic acid, the less
toxic of the retinoids
Discovery revolutionized
acne treatment
Isotretinoin Treatment
Treats severe nodular or cystic acne
Reduces size of oil glands, decreases sebum
production, reduces cells shedding and
sticking in follicles -> less P. acnes.
After treatment, acne almost, if not
completely goes away, though may come
back for some people

Decreases scarring
Molecular Action
Human organism not capable of synthesizing retinol

Must in take with food
Through digestion retinal absorbed in the liver in an inactive esterized form
On demand, retinol attaches to a specific transport protein transported to the
target cells
Links to receptor at keratinocyte cell membrane to penetrates the cell, where it
is bound to CRBP

Stored inactive as retinylester or enzymatically oxidized to retinaldehyde
Made active as retinol acid (RA)through additional enzymatic oxidation
Transported to nucleus via CRABP to attaches itself to the specific retinoic acid
receptor RAR.

RARs belong to a "superfamily" of receptors considered to be a skin
hormone
RA/RAR complex is attached to DNA via RARE (retinoic acid response element)
to regulate epidermal cell functions through induction of protein synthesis
99.9% bound to plasma proteins, particularly albumin

Single polypeptide chain wit multiple binding sites for many lipophilic
metabolites
Side Effects?
Mild: Dry mouth, nose, or skin; itching;
nosebleeds; muscle aches; rarely, decreased
night vision and headaches; tendonitis
Serious: Fatigue, increased blood cholesterol,
lipid, and triglyceride levels and abnormal
liver enzymes, teratogenic (serious birth
defects), *depression, *suicide
What’s the Debate?
1. Seriousness of birth defects
2. Whether or not isotretinoin can really
cause depression and suicide
-
Democrat Bart Stupak, blamed his 17year-old son’s suicide on Accutane
3. Regulation of the “dangerous drug”
Birth Defects
25-30% of female users during pregnancy
report birth defects
Large doses of vitamin known to cause birth
abnormalities
Preventive measures


Must have bright yellow label for female
prescriptions
Must use two birth control methods starting from
one month before therapy until one month after
therapy
Can Isotretinoin Cause Psychological Problems?
Evidence




19% of adverse events reported to Roche were
psychiatric
Numerous “personal” stories
Last month, MedWatch reported 140 users
worldwide that committed suicide during
prescription period or soon after
Current study at Emory University
 Depression may be caused by affecting the brain’s frontal
cortex
 Use PET scans of 40 users to observe signs of decreased
functioning in frontal cortex
How Valid is the Evidence?
Hoffmann – La Roche sponsored extensive
study



Accutane users no more likely than others to be
depressed or suicidal
Self-image actually increased without acne
First population based study
Suicide and depression have many
environmental causes that often go unnoticed
Suicide common to teenagers, largest risk
group to acne to begin with

May be false correlation
Current Regulation
Patients must acknowledge in writing
the awareness of psychiatric side effects
– implemented last year.
Pharmacists must give out medication
guide in lay terms
Other Regulation Issues
Should be weary of prescribing the “miracle”
but “dangerous” drug
While issue of birth defects always provided,
few doctors inform about relations with
depression and suicide.
In many cases, was prescribed to less severe
acne problems
FDA tightly regulates it in the US – what
about 3rd world countries?
Bibliography
"Accutane Is this Acne Drug Treatment Linked to Depression and
Suicide?” Congressional Hearing on Accutane. December 5, 2000
http://www.accutane-suicide-help.com/pages/burton.html
Duenwalk, Mary. “After 20 Years, Debate Over Drug Persists.” New
York Times. January 22, 2002
Jick SS. Kremers HM. Vasilakis-Scaramozza C. “Isotretinoin use and
risk of depression, psychotic symptoms, suicide, and attempted
suicide.” Archives of Dermatology. 136(10):1231-6, Oct. 2000.
O'Donoghue MN. “Update on acne therapy.” Dermatology Nursing.
11(3):205-8, June 1999.
“Product Information.” Roche USA
http://www.rocheusa.com/products/accutane/pi.pdf
“Questions and Answers About Acne.” National Institute of Health.”
http://www.niams.nih.gov/hi/topics/acne/acne.htm