Med chem part 6

Question 1

______ is a structural analog of folic acid

Answer 1

methotrexate

Question 2

the active form of methotrexate is…..

Answer 2

polyglutamate - has multiple (5) glutamates oh Y-COOH

Question 3

what enzyme does methotrexate inhibit?

Answer 3

DHFR (dihydrofolate reductase)

Question 4

how does methotrexate work as an immunosuppressant?

Answer 4

inhibits DHFR (dihydrofolate reductase, which in turn inhibits de novo synthesis of thymidine)

doing this prevents the conversion of folate to THF (tetrahydrofolate) which is involved in the conversion of uridine to THYMIDINE, which are involved in DNA/RNA synthesis, respectively

thus, proliferation of T and B immune cells is inhibited, including those responsible for synovial inflammation

Question 5

true or false

methotrexate is a potent immunosuppressant

Answer 5

true

Question 6

methotrexate is said to have ________ properties.
why?

Answer 6

antifolate

prevents conversion of folate to THF by inhibiting dihydrofolate reductase

Question 7

what does the “tetra” in tetrahydrofolate mean

Answer 7

2 double bonds have been reduced

Question 8

“dihydro” what does di mean

Answer 8

1 double bond has been reduced

Question 9

what is a major side effect of methotrexate?

Answer 9

may cause dose-dependent folate deficiency

Question 10

true or false

folate deficiency, induced by methotrexate, does not respond well to replacement therapy

Answer 10

false - it does

Question 11

why is administering NSAIDS and methotrexate TOGETHER not advised?

Answer 11

they compete for the same transporter to be excreted

can lead to accumulation and toxic effects of methotrexate

Question 12

how is methotrexate excreted?
through what transporter?
what else is excreted via this transporter?

Answer 12

excreted unchanged
through folate transporter (human organic anion transporter)

NSAIDS are also excreted with this

Question 13

as mentioned, NSAIDS and MTX compete for the same transporter to be excreted

why is it that this leads to toxic levels of MTX and not NSAIDS?

Answer 13

because MTX is highly potent.
thus, there is much more NSAID and more likely to saturate the transporters, leaving MTX accumulating in the blood

Question 14

aside from inhibiting DHFR, what other minor components of MTX MOA are there?

Answer 14

-increase adenosine levels and receptor activation, leading to decreased inflammation

-inhibit synthesis of polyamines which accumulate in synovial fluid and produce toxic ammonia and H2O2 through metabolism. they also activate NFKB (“on” switch for inflammation)

Question 15

as mentioned, MTX inhibits the synthesis of polyamines
these include what 2 things and what do they do?

Answer 15

spermine and spermidine
they produce toxic ammonia and peroxide through their metabolism in the synovial fluid
AND activate NFKB (“on” switch for inflammation)

thus, MTX inhibiting the synthesis of spermine and spermidine prevents these things from happening

Question 16

blocking what signaling pathway would have antirheumatic effects?
name 4 drugs that are involved with inhibiting this pathway

Answer 16

JAK STAT pathway

Tofacitinib
Baricitinib
Upadacitinib

Question 17

in general, what are JAK inhibitors called

Answer 17

jakinibs

Question 18

explain how the JAK STAT pathway works

Answer 18

cytokine binds to receptor and it dimerizes

the tyrosine residues on JAKS and the receptor itself gets phosphorylated

STAT binds to this complex and undergoes phosphorylation too – TRANSLOCATES TO NUCLEUS where it transcribes the target genes — in this case the transcription of inflammatory genes that produce cytokines

Question 19

name 3 ways in which the JAK STAT pathway can be blocked

Answer 19

bind the cytokine (monoclonal antibodies)

bind to the receptor

block JAK (this is what jakinibs do!!) and prevent activation/phosphorylation of stat

Question 20

name the first in class JAK1 SELECTIVE INHIBITOR

Answer 20

Upadacitinib

Question 21

what is an important component of JAK inhibitors, and kinase inhibitors in general?

Answer 21

have 2 hydrogen bonds

1 part on the molecule (sp2) acts as an acceptor and the other part (sp3) acts as a donor

Question 22

what is the first in class JAK1/JAK3 inhibitor

Answer 22

tofacitinib

Question 23

JAK1/JAK2 selective inhibitor

Answer 23

Baricitinib

Question 24

cytokines ___ and ____ are KEY mediators of immune function in RA and have been major targets of therapies

Answer 24

IL-6 and TNFa

Question 25

name 2 IL-6 blockers

are they biologics?

Answer 25

tocilizumab
sarilumab

yes

Question 26

how do the IL-6 blockers, Tocilizumab and Sarilumab, work?

Answer 26

they bind to the IL-6 RECEPTOR and inhibit IL-6 mediated signaling

Question 27

which IL-6 inhibitor requires higher dose and frequency to achieve the same effects as the other?
why?

Answer 27

tocilizumab

it is less potent than sarilumab

Question 28

name a T-cell costimulatory inhibitor

is it synthetic or a biologic?

Answer 28

biologic

abatacept

Question 29

explain the MOA of Abatacept

why is it called a “costimulatory” inhibitor

Answer 29

it blocks CD28 on the T cell from binding to both CD80 AND CD86 on the antigen presenting cell

thus, it regulates the second signal required for full T cell activation

Question 30

as mentioned, Abatacept modulates the SECOND costimulatory signal required for full T cell interaction

what is the first?

Answer 30

T cell interaction with MHC complex

Question 31

what is the function of Rituximab?
is it synthetic or biologic?

Answer 31

biologic

mediates B cell apoptosis by binding to CD20 on the B cell

Question 32

explain the mechanism of action how corticosteroids are used for rheumatoid arthritis

Answer 32

glucorticoids stimulate the synthesis of LIPOCORTIN

this inhibits PLA2 – which cleaves arachidonic acid from membranes - 1st step in prostaglandin synthesis

blocks production of prostaglandins through COX AND leukotrienes through LOX

Question 33

what is another name for lipocortin

Answer 33

Annexin A1

Question 34

which is a more effective/potent anti inflammatory: steroids or NSAIDS?

Answer 34

STEROIDS!!

blocks production of both prostaglandins AND leukotrienes

NSAIDS just block prostaglandins

Question 35

COX is to prostaglandins as _____ is to leukotrienes

Answer 35

LOX

Question 36

besides having anti inflammatory effects, name 3 other effects of corticosteroids

Answer 36

anti-mitotic
immunosuppressant
vasoconstriction

Question 37

how are corticosteroids immunosuppressants?
how are they vasoconstrictors?

Answer 37

immunosuppressants because they suppress the maturation/differentiation/proliferation of immune cells inc dendritic cells and macrophages and inhibits cytokines

vasoconstrictors bc they reduce blood flow to inflamed site to dc # inflamm mediators being delivered

Question 38

name the 5 required groups for glucocorticoid activity of a steroid

Answer 38

keto at 3
double bond between carbons 4 and 5 in ring A
11 position beta hydroxy
17 position alpha hydroxy
21 position hydroxy

Question 39

from hydrocortisone molecule, what was added to make prednisolone

Answer 39

a double bond was added between carbons 1 and 2

Question 40

name the delta 1 corticosteroids
why are they called this?

Answer 40

prednisolone and prednisone

because they have a double bond at carbon 1

Question 41

what is the only change when looking at the structures of hydrocortisone and prednisolone?

Answer 41

in prednisolone, there is an added double bond between carbons 1 and 2

Question 42

as mentioned, the only difference between hydrocortisone and prednisiolone is the added double bond between 1 and 2 in prednisolone

what is the result of this

Answer 42

LONGER DURATION OF ACTION

due to increased metabolic stability towards reductions —- bc increased resonance

Question 43

which is more potent glucocorticoid - prednisolone or prednisone? why?

Answer 43

the OH (alcohol) group at position 11 is ESSENTIAL for glucocorticoid activity

prednisone has a ketone there instead

Question 44

what occurs when ring A is flattened in corticosteroids

Answer 44

glucocorticoid action increases and mineralcorticoid action decreases

Question 45

what is a side effect of corticosteroids?
it is due to what action?

Answer 45

retention of sodium and water

due to mineralcorticoid activity

Question 46

what is the only difference between the delta1 corticoids and triamcinolone?
what was the result of this?
what was then done?

Answer 46

adding a 9 alpha fluorine group and 16 alpha hydroxyl

however, this has poor bioavailability because it is too hydrophilic

bexamethasone and betamethasone were created to address this

Question 47

as mentioned, dexamethasone and betamethasone were created to address the poor bioavailability of triamcinolone due to the 16 hydroxyl group.

what was done to triamcinolone to create betamethasone and dexamethasone?

Answer 47

instead of a hydroxyl group, a methyl group was inserted at carbon 16

in dexamethasone, the configuration is alpha and in betamethasone it is beta

–only difference between the 2

Question 48

as mentioned ,the only difference between triamcinolone and dexamethasone/betamethasone is the replacement of a hydroxyl group with a methyl group

what is the result of this?

Answer 48

increased lipophilicity, and thus increased antirheumatic properties

Question 49

true or false

16-CH3 OR 16-OH leads to increased glucocorticoid activity and decreased minerolocorticoid activity

Answer 49

TRUE

only issue is that OH is too polar and not well absorbed

Question 50

how is it that adding a 9a-halogen (in the case of hydrocortisone -> betamethosone) increases glucocorticoid activity?

Answer 50

because of electron withdrawing effects on the 11 beta OH — makes it a strong hydrogen bond donor (more acidic properties)