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Intro to D&D Final > Med Chem - Psoriasis Part 1 > Flashcards

Med Chem - Psoriasis Part 1 Flashcards

1
Q

name the areas most commonly affected by psoriasis

A

knees, elbows, and scalp

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2
Q

psoriasis is a ____ ___ skin disorder leading to….

A

chronic inflammatory

leading to erythema, scaling, and thickening of the skin

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3
Q

as mentioned, psoriasis is a chronic inflammatory disease leading to erythema, scaling, and thickening of the skin

what causes this thickening

A

because of the hyperproliferation and abnormal differentiation of keratinocytes and the excessive amount of T cells coming to the surface (epidermis)

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4
Q

what is the cause of inflammation in psoriasis

A

cytokines

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5
Q

name 4 types of SYSTEMIC therapies for psoriasis

A

methotrexate
oral retinoids
PDE4 inhibitor
biologics

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6
Q

name 7 types of topical/external therapies for psoriasis

A

corticosteroids
calcineurin inhibitors
photo(chemo)therapy
AhR (aryl hydrocarbon) agonsit
calcipotriene
vitamin A analogs
anthralin

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7
Q

name a Vitamin A analog used in psoriasis

A

tazarotene

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8
Q

name an AhR (aryl hydrocarbon) agonist used in psoriasis

A

Tapinarof

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9
Q

what is PUVA

A

oral Psoralen + UVA

phototherapy used in psoriasis

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10
Q

what class is tacrolimus

A

calcineurin inhibitor - can be used in psoriasis

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11
Q

name 2 oral retinoids that can be used as systemic agents in psoriasis

A

etretinate
isotretinoin

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12
Q

name 4 biologics that can be used as systemic agents in psoriasis

A

alefacept
efalizumab
ustekinumab
ixekizumab

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13
Q

calcipotriene is a derivative of what? what is the brand name?
is it synthetic/natural/semisynthetic?

A

SYNTHETIC derivative of vitamin D3 (calcitriol)

Dovonex cream

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14
Q

calcipotriene is indicated for what kind of psoriasis

A

moderate plaque psoriasis

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15
Q

name 2 benefits of using calcipotriene cream (dovenox) over topical corticosteroids

A

1 .does not cause tachyphylaxis (when using for long periods of time, efficacy is reduced and need higher and higher strength) – not the case for calcipotriene

  1. less is absorbed systemically compared to steroids
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16
Q

which is more systemic absorption and why – topical corticosteroids or calcipotriene

A

steroids are absorbed more systemically

this is bc calcipotriene has more polar functional groups

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17
Q

differentiate between the structure of corticosteroids vs calcipotriene

A

in calcipotriene, the B ring of the steroid is OPENED through C9-C10 cleavage and is now an open chain

also, calcipotriene has more polar functional groups and is thus less systemically absorbed

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18
Q

another name for vitamin D3

A

calcitriol

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19
Q

what receptors does calcipotriene bind to?
what KIND of receptors are they?

A

vitamin D3 receptors

they are nuclear receptors – located inside of the cell

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20
Q

the vitamin D3 receptor belongs to the _______ receptor superfamily

A

steroid/thyroid receptor superfamily

it is a NUCELAR RECEPTOR

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21
Q

in what tissues/cells is the vitamin D3 receptor located?
what does this say about its efficacy in psoriasis if we target it?

A

vitamin D3 receptor is found inside the cells of many different tissues — including T cells – which are known to play a role in psoriasis!!!

the receptors are widely distributed in tissues all over the body inc in T cells - good target for psoriasis

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22
Q

explain the mechanism of action of calcipotriene

what endogenous molecule does it mimic?

A

mimics vitamin D3

binds to the vitamin D receptor (VDR) which forms a heterodimer with an RXR (retinoic acid receptor)

this transcriptional complex then goes to the nucleus where it modulates gene transcription by binding a palindromic sequence on DNA

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23
Q

what kind of dimer does VDR form when bound to calipotriene/vitamin D3?

A

heterodimer with RXR is preferred, but an alternate dimer is a homodimer with another VDR

heterodimer is more effective

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24
Q

name 3 different things that calcipotriene inhibits through binding to the DNA sequence and modulating transcription

A

inhibits:

-expression of proinflam. cytokines

-cell differentiation and proliferation of keratinocytes

-T cell proliferation

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25
Q

name 1 thing that calcipotriene actually INDUCES (not inhibits)

A

Tregs – they are responsible for SUPPRESSING the immune system and preventing an autoimmune response

26
Q

what does ATRA stand for

A

all trans retinoic acid

27
Q

is ATRA a flexible molecule?

why or why not?

A

YES - it is flexible

this is because of the alternating double bonds – allows the single bonds to rotate and cause the double bonds to isomerize to cis conformations

therefore, there are a wide range of ATRA conformation

28
Q

All trans retinoic acid is the active form of what?

A

vitamin A

29
Q

true or false

retinoic acids, in general , bind ALL RAR’s with no selectivity

A

true

30
Q

differentiate between the structure of tazarotene and ATRA and what this means about its activity

A

tazarotene is RIDGID unlike ATRA

this is due to the carbon carbon triple bond in the middle of the molecule

this rigidity gives tazarotene greater selectivity — selective for RARB and RARY

31
Q

true or false

tazarotene is a synthetic retinoid

A

true

32
Q

acetylenic

A

refers to the carbon triple bond in tazarotene that makes it rigid and non-isomerizable

33
Q

explain the SAR of tazarotene

A

it is a PRODRUG
the COOEt rapidly gets hydrolyzed by skin esterases to COOH – ACTIVE FORM

this COOH is important for RAR binding

also, the -S- was introduced as a weak point for metabolism - quickly gets inactivated to s=o and SO2 – this LIMITS SYSTEMIC TOXICITY FROM THE DRUG

34
Q

true or false

tazarotene is a prodrug

A

true

35
Q

what drug is ATRA

does it have selectivity?

A

tretinoin

no RAR selectivity – it is extremely flexible

36
Q

true or false

isotretinoin and etretinate are conformationally rigid and selective for specific RARs

A

FALSE

they are flexible and can cis trans isomerize – not selective. can rotate across alternate single bonds

37
Q

what drug is 13-cis retinoic acid

A

isotretinoin

38
Q

what is the name of the enzymes that allow for cis-trans isomerization in ATRA

A

retinoid isomerases

39
Q

Etretinate is a _______ analog

explain

A

tretinoin/ATRA analog

it just has an ethyl ester added to the end of it – therefore it is a PRODRUG

also, it is NOT RIGID – not selective for RARs

40
Q

TRUE OR FALSE

all retinoids are teratogenic and should be avoided during pregnancy

A

true

41
Q

etretinate seems to accumulate where after repeated dosing?
why?
what does this mean?

A

in adipose tissue because it’s very lipophilic – therefore, has an EXTREMELY LONG HALF LIFE - 120 days

42
Q

as mentioned, etretinate has an extremely long half life of 120 days due to its high lipophilicity and distribution into adipose tissue

what about its metabolite?

A

its metabolite - acitretin - has a much shorter half life of 49 hours because of the hydrophilic COOH group

43
Q

true or false

the metabolite of etretinate is pharmacologically active

A

true

44
Q

explain the general structure of anthralin and what this says about its mechanism of action

A

planar tricyclic molecule

any molecule like this can slide in between DNA strands and have anti-proliferative effects of skin cells through inhibit DNA synthesis
(sliding is called intercalation)

45
Q

tapinarof is a structural analog of what?

A

resveratrol

46
Q

what class is tapinorof

A

aryl hydrocarbon receptor agonist

47
Q

explain the aryl hydrocarbon receptor and where it is widely expressed

A

cytosolic ligand gated ion channel, widely expressed in the SKIN !! - good target for psoriasis

48
Q

what is the acronym for the response given by an AhR receptor agonist

A

AAD response

anti inflammatory

anti oxidant

development and maintenance of skin barrier

49
Q

explain the MOA of tapinarof

A

goes through the skin and into the cell where it binds AhR receptor in the cytoplasm

the drug-receptor complex goes to the nucleus and, with the help of an AhR nuclear translocator, gets into the nucleus where it modulates gene transcription

causing dec inflamm cytokines, increased antioxidant response, and increased barrier proteins for the skin

50
Q

explain TWO WAYS in which tapinarof has antioxidant activity

A
  1. by modulating transcription and producing more reducing molecules like GSH and NADPH
  2. tapinarof is an antioxidant ITSELF due to the phenolic OH”s
51
Q

name 2 barrier proteins that are increase through the AhR agonist actions of tapinarof

A

fillagrin
loricin

they cross link to keratin filament to make firm barrier

52
Q

name 2 psoriasis agents that have a tricyclic planar structure and what this means about their action

A

anthralin
methoxsalen

both are able to intercalate between DNA strands and inhibit DNA synthesis, having anti-proliferative skin effects

53
Q

Methoxsalen is used in what treatment?

A

photochemotherapy for severe psoriasis

a naturally occurring photactive substance that is activated upon exposure to light

54
Q

true or false

methoxasalen is a synthetic photoactive substance

A

FALSE – naturally occuring photactive substance

55
Q

methoxsalen is classified as a ____ or ___ (chemically)

A

psoralen or furocoumarin

56
Q

true or false

methoxsalen is given orally

A

true

57
Q

the MOA of methoxsalen is______ mediated. be specific

A

UVA mediated, specifically UVA 320-400nm (broad band)

58
Q

explain the MOA of methoxsalen

A

upon exposure to UVA320nm-400nm, there is free redical (1 electron transfer) covalent binding with THYMINE on DNA strands

can be either cross linked (both furan and coumarin bound to thymine) or mono-adducts (only furan or coumarin is bound to thymine)

this binding to thymine on DNA causes decreased DNA synthesis and inhibition of the growth of skin cells

59
Q

tacrolimus is a ____ isolated from ___

A

macrolide isolated from fungal strain

60
Q

explain MOA of apremilast

A

PDE4 inhibitor

in psoriasis patients, PDE4 is overactive and too much cAMP is being converted to AMP. these low cAMP levels trigger the production of proinflammatory cytokines.

apremilast prevents conversion of cAMP to AMP, thus increasing cAMP levels and, in turn, decreasing the production of proinflammatory cytokines

61
Q
A

Intro to D&D Final (22 decks)

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