Med Chem - Acne Flashcards
why is acne more common at puberty?
there is an increase in androgens, which causes oil/sebum production
this can clog pores and form a comedone – causes acne
name 2 things that androgens do that causes acne
increased sebum production
skin thickening
both can clog pores and cause acne
briefly explain the pathology of acne
dead cells and sebum accumulate in the hair follicle, causing a clog
this is a great place for the commensal bacteria - cutibacterium acnes to feed on the sebum and proliferate
the acne in the skin invokes an inflammatory response as well
the result is filled with pus and reddened
excessive ____ + ____ + ____ = acne
cell build up
oil
bacteria
is cutibacterium acnes gram positive or negative?
positive
name 3 treatment goals for acne
-decrease inflammation
-decrease sebum production and c. acnes proliferation
-correct the abnormalities of follicular maturation
name 5 classes of drugs used for acne treatment
systemic antibiotics
retinoids
azelaic acid
benzoyl peroxide
salicylic acid
name 4 retinoids used in acne
tretinoin
adapalene
isotretinoin
trifarotene
name 4 systemic antibiotics used in acne
tetracycline
doxycycline
minocycline
sarecycline
name the 3 dosage forms in which salicylic acid is available
cream
lotion
gel
explain how salicylic acid works to treat acne
it’s a keratolytic agent with anti-inflammatory action
reduces acne by exfoliating the skin and keeping pores clear
what kind of acne severity is salicylic acid indicated for
mild acne
true or false
salicylic acid does not have anti inflammatory action
FALSE - it does
benzoyl peroxide is applied topically in concentrations up to…..
10%
how does benzoyl peroxide have antimicrobial actions?
has an oxidizing effect due to the production of benzoate free radicals
what is azelaic acid indicated for?
mild-moderate inflammatory acne vulgaris
true or false
azelaic acid is naturally occurring
TRUE
naturally occurring acid found in whole grain cereals and animal products
how does azelaic acid work in acne
inhibits the growth of cutibacterum acnes
chemical name azelaic acid
nonanedioic acid
“non” - 9 carbons
“di” - 2 COOH groups
what are the 2 types of retinoid receptors
what are the subtypes?
RARs - retinoic acid receptors
RXRs - Retinoid X receptors
all have a,B,Y subtypes
what kind of receptors are RARs and RXRs
nuclear receptors
RARs and RXRs are activated by what?
natural (endogenous) or synthetic retinoid agonists
true or false
RARs and RXRs are GPCRs involved with the modulation of gene transcription
FALSE
they are nuclear receptors involved with the modulation of gene transcription
what is the dominant RAR subtype present in the skin?
GAMMA (Y)
explain how RARs and RXRs function
RARs dimerize with RXRs to form HETERODIMER. this heterodimer goes to the nucleus where it recognizes RARE DNA sequence in the promoter region of target genes
involved with regulation of cell growth, differentiation, and apoptosis
HOWEVER, while RARs MUST form a HETERODIMER with RXR, RXR can function as a homodimer as well as a heterodimer
true or false
in order to be functional, RARs must form a HETERODIMER with RXR
true
what does the “RARE” DNA sequence stand for
retinoic acid response element
as mentioned, RARY is the most predominant subtype of retinoic acid receptors in the skin
what is the significance of this?
want to have highly selective RARY agonists.
this will lead to less side effects.
also, RARY subtype is not present in the placenta. therefore, a highly selective RARY agonist will not be teratogenic like every other retinoid!!
tretinoin is a _____ form of _____
oxidized (active) form of vitamin A (retinol)
how is tretinoin an oxidized form of vitamin A?
it has exact same structure
only difference is that the -CH2OH in vitamin A (retinol) has been oxidized to COOH in tretinoin
what is retinol
vitamin A
explain the receptor selectivity of tretinoin
NONSELECTIVE RAR agonist
how does tretinoin work in acne
unplugs the hair follicles and keeps the pores clear
also, increases speed that surface skin cells are replaced
explain in detail the conversion of vitamin A to ATRA, as well as the inactivation of ATRA
include all enzymes and whether the steps are reversible or irreversible
retinol <-> retinal by retinol dehydrogenase
retinal -> ATRA (COOH) by retinal dehydrogenase
ATRA inactivated by CYP2D6 into an inactive 4-oxometabolite
as mentioned, CYP2D6 mediates the inactivation of ATRACOOH into an INACTIVE 4-oxometabolite
what potential drugs may be used to block the action of CYP2D6, and thus prolong the action of retinoids by preventing their inactivation?
RAMBAS
(retinoic acid metabolism blocking agents)
where are RAR and RXR receptors located?
what does this mean regarding the drug?
in the NUCELUS, bound to RARE regions on DNA
this means the retinoic acid (drug) has to diffuse into the nucleus and bind to RAR to form the heterodimer and modulate gene transcription
what effect does retinoic acid binding to RARs have
cell differentiation and proliferation
apoptosis
immune modulation
beneficial acne effects
chemical name for isotretinoin
13-cis-retinoic acid
true or false
isotretinoin is a selective RARY agonist
FALSE - non selective bc of rotation
it is a result of ATRA isomerization
retinoids are also called_______
diterpenes
why are retinoids also called diterpenes?
bc they have 20 carbons
true or false
isotretinoin is a 13-cis isomer of ATRA
true
what is isotretinoin indicated for
severe and recalcitrant (stubborn) cases of inflammatory acne
how is isotretinoin useful in acne
inhibits sebaceous gland function and inhibits follicular keratinization
true or false
adapalene is a natural retinoid compound
FALSE
it’s a synthetic retinoid-like compound
does adapalene have any selectivity? why or why not
YES - has selectivity for RARB and RARY subtypes found in the epidermis
this is because the double bonds are locked into the aromatic ring - RIGID. cannot cis-trans isomerize. thus, able to have some selectivity
what is a similarity between adapelene and ATRA
the distance between the C with the bulky group and COOH is ~TEN CARBONS APART
How does adapalene work to reduce the formation of pimples
it affects the growth of skin cells, thus reducing formation of pimples bc clogs not as likely
name of the bulky group on adapalene
adamantyl
what is the retinoid that has RARY selectivity
trifarotene
what group on trifarotene allows it to have RARY selectivity?
hydroxyethoxy group
explain some benefits of trifatorene over other retinoids
- RARY selective: safer than others for teratogenity bc RARY is not expressed in placenta. also less side effects bc RARY selective and its predominantly in the skin
- has poor systemic absorption than other retinoids because of polar hydroxyethoxy group - less systemic side effects!!
what is trifatorene indicated for
ages 9 and older for facial and truncal acne
trifarotene belongs to ______ class of compounds
explain
meta-terphenyl
meaning 3 phenyl rings all meta to each other
