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Intro to D&D Midterm > Med Chem part 5 > Flashcards

Med Chem part 5 Flashcards

1
Q

what is the PRIMARY insult of GI due to NSAIDS?

A

direct acid damage

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2
Q

has mentioned, direct acid damage is the primary insult of GI irritation in case of NSAIDS name 2 mechanisms in which this occurs

A

ion trapping in gastric epithelial cells causes cell injury. NSAIDS with their acidic functional group can get into these cells.

also, mitochondrial oxidative desphosphorylation can be uncoupled, resulting in decreased cellular ATP

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3
Q

what is the secondary mechanism in which NSAIDS cause GI irritation/damage

A

by inhibiting prostaglandins in the GI. these prostaglandins have protective action here.

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4
Q

explain the mechanism of “ion trapping” - part of primary mechanism of GI irritation/damage with NSAIDS

A

The pH of the stomach is 1-2.
ibuprofen, an acidic drug, will not ionize. it will be absorbed.

within the cell, the pH is 6-7. here, it will ionize and be trapped inside the cells

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5
Q

true or false

it is desirable to block prostaglandins in the GI

A

FALSE - undesirab;e

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6
Q

as mentioned, PGE1 has protective roles in the stomach.

knowing this, why is there not a PGE1 to take concimitantly with NSAIDS to prevent primary mechanism GI irritation?

A

because as mentioned earlier, prostaglandins have a VERY SHORT HALF LIFE of 1-5 minutes

a drug can’t be developed

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7
Q

as mentioned, a PGE1 drug cannot be produced because it has such a short half life

what have drug designers come up with instead?

A

a semisynthetic derivative of PGE1 —— MISOPROSTOL

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8
Q

Name 4 components of drug design in which PGE1 was converted into the semisynthetic derivative, misoprostol

explain the logic behind all 4 changes

A

COOH was esterified to OCH3 — more enhanced oral absorption

(thus it is a prodrug! - active drug ends in COOH)

CH3 added at carbon 16 – increases bioavailability

1 mechanism in which PGS are inactivated so quickly is through PG-15-OH dehydrogenase!!!!
therefore, moving the OH to carbon 16 ENHANCES METABOLIC STABILITY!!!!!

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9
Q

RECAP: what are the 2 methods of prostaglandin inactivation?

which is bypassed in the designing of misoprostol?

A
  1. C13=C14 reduction by delta13 reductase
  2. oxidation of C15-OH to C-15KETO by PG-15-OH dehydrogenase (bypassed in misoprostol by moving OH to C16)
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10
Q

In which patients is misoprostol administered?

name 3 effects

A

adjunctive preventative therapy in patients at high risk for GI bleeding

3 effects:

-reduced gastric acid secretion
-stimulates secretion of mucus and bicarbonate
-vasodilation and thus increased mucosal blood flow

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11
Q

as mentioned, part of the MOA of misoprostol is the secretion of mucus and bicarbonate

what is the purpose of the bicarbonate?

A

to capture the H+ ions and precent GI irritation

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12
Q

COX1 is ______ while C2 is ______

A

COX1 is CONSTITUTIVE while COX2 is INDUCIBLE

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13
Q

what does it mean that COX1 is constitutive and COX2 is inducible

what can you say about our knowledge now

A

COX1 is expressed in all tissues and promotes PHYSIOLOGICAL prostaglandin production

COX2 is inducible. produces PATHOGOLOGICAL prostaglandin production and not normally detected under normal conditions

however, we now know that COX2 DOES have important prostaglandin functions such as the production of prostacyclin or PGI2

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14
Q

name 3 physiologic things that can induce COX2

A

cytokines
growth factors
mitogens

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15
Q

name 3 effects of COX1 producing physiologic prostaglandins

A

normal renal function
platelet functions
protects gastric mucosa

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16
Q

nonselective NSAIDS, including aspirin, tend to be more selective towards which COX?

A

COX1

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17
Q

what side effects are associated with nonselective NSAIDS and why

A

they tend to be more selective to COX1

therefore, inhibiting important functions like normal renal function, platele functions, and the production of gastric mucosa

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18
Q

explain how only LOW DOSE aspirin is used as a prophylactic measure for heart attack and stroke

A

as mentioned, nonselective NSAIDS like aspirin tend to be more selective for COX1

COX1 is the enzyme that produces TXA2, a vasoconstrictor and clot inducer.

however, high dose aspirin does NOT have the same prophylactic benefit as low dose. this is because at higher doses both COX1 and COX2 are being blocked and the “balances” of TXA2 and PGI2 are essentially level.

high dose aspirin therefore is only used for pain

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19
Q

what is the warning that comes with COX-2 selective inhibitors

A

may cause heart attack and stroke. thrombosis

“balance” is lost. inhibiting COX2 also inhibits the production of PGI2, a preventor of clots and a vasodilator
TXA2’s clotting and vasoconstriction is a concern

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20
Q

the greater the COX2 selectivity, the ________ the TXA2/PGI2 ratio

A

GREATER

TXA2 levels will be higher and PGI2 lower because COX2 is inhibited

21
Q

why is there a need for COX2 selective inhibitors?

A

concept that therapeutic effects of traditional NSAIDS are by the inhibition of COX2 and the adverse effects are because of the inhibition of COX1

however, we now know the issue of “balancing” TXA2 and PGI2

22
Q

name the MAIN COX2 selective inhibitor

A

celecoxib

23
Q

explain the design choices in celebrex

A

the precursor molecule that was originally designed had too long of a half life (211 hours) and was greater than 1000fold more selective for COX2

this is obviously an issue
half life of 211 hours is too long for too selective for COX2 is not good due to increased risk of thrombosis and heart attack/stroke

therefore, there were 2 chemical modifications done to this precursor

flourine at para position was changed to methyl, reducing half life because fluorine is very stable to metabolism

CH3 (part of a methane sulfide) was changed to NH2 (amino) this is because methane sulfide is not easily excreted (neutral), but sulfonamides ARE readily excretable (acidic)

the t1/2 then changed to 8-12 hours and the COX2 selectivity is now only 375 fold

24
Q

explain the metabolism of celecoxib

A

CH3->CH2OH->CHO->COOH

now inactive because has 2 polar groups: sulfonamide and carboxylic acid

oxidation mediated by CYP2D6

25
Q

explain the difference in shape between nonselective NSAIDS and COX2 selective

A

nonselective - linear model.

COX2 selective - arrowhead shape
center heteroaromatic ring with EWG. 2 aryl groups - 1 lipophilic and 1 that is sulfonamide or sulfone

26
Q

how is it possible to design drugs that are selective for COX2?

A

The difference in amino acids between the 2 enzymes

COX1 has 2 isoleucines and COX2 has 2 valines

valines are SMALLER, therefore, there is more room and creates a HYDROPHILIC pocket for a larger molecule, like an aryl sulfone, arrowhead shape, to bind. this molecule cannot fit into COX1 due to the large isoleucines in the way

27
Q

true or false

rheumatoid arthritis is chronic and systemic

A

true

28
Q

RA is associated with severe damage of what 3 things?

A

cartilage, bone, and joints

29
Q

in RA, what infiltrates into the synovium?
what occurs as a result of this?

A

immune cells like T cell, B cells, macrophages, etc infiltrate

B cells produce AUTOANTIBODIES and secrete cytokines that activate OTHER antigen presenting cells.

cytokines also induce chemotaxis and secretion of collagenase, MMPS and hydrolases —– leading to DESTRUCTION OF CARTILAGE (connective tissue around joint)

30
Q

the antibodies in RA are formed against what?

A

citrullinated proteins

arginine residues get citrullinated and the immune system recognizes as foreign, producing antibodies against the entire protein/tissue

31
Q

what is the class of drugs that stops the underlying progression of arthritis in RA patients

A

DMARDS

disease modifying antirheumatic drugs

32
Q

TRUE OR FALSE

NSAIDS can be used in RA patients, but they do NOT prevent the underlying cause of the inflammatory process

A

TRUE

33
Q

TRUE OR FALSE

DMARDS have anti inflammatory and analgesic effect

A

FALSE - THEY DO NOT
this is the job of NSAIDS in RA patients

they try to prevent the UNDERLYING CAUSE of the inflammatory process

34
Q

is long term use advised in DMARDS?
why or why not?

A

NOT ADVISED

takes a long time to show clinical benefits and has potentially dangerous side effects

35
Q

is hydroxychloroquine a synthetic or biologic DMARD?

A

synthetic

36
Q

the biologic DMARDS are also called…..

A

monoclonal antibodies (most of them)

37
Q

aside from hydroxychloroquine, name 2 other synthetic DMARDS

A

leflunomide
methotrexate

38
Q

briefly explain how hydroxychloroquine works as a DMARD in RA patients

A

mechanism is largely unsolved, but what is known:

increases pH of vesicles in the cytoplasm (4->6). this interferes with the functions of macrophages

they block IL1 IL6 TNFa signaling

interfer with LPS induced TNFa expression

inhibits PLA2 (enzyme that releases arachidonic acid from cell membrane)

39
Q

what is DHODH and what drug inhibits it?

A

DHODH is Dihydroorotate dehydrogenase
this enzyme is involved with synthesizing URIDINE, which is involved with RNA synthesis

Uridine is also the precursor for thymidine. thymidine is involved with DNA synthesis

it is INHIBITED by the active metabolite or leflunomide - teriflunomide

40
Q

Explain the pathway of thymidine synthesis and include the enzymes/cofactors involved

A

Dihydroorotic acid is converted into Orotic acid through DHODH (dihydroorotate dehydrogenase) and cofactor ubiquinone

orotic acid undergoes ribosylation to produce URIDINE which is involved with RNA synthesis

uridine undergoes methylation through Methyl THFto produce THYMIDINE, which is involved with DNA synthesis

41
Q

what is the precursor for thymidine? how is it converted?

A

uridine is coverted into thymine through the addition of a methyl group by Methyl THF

42
Q

_________ is involved with RNA synthesis while ______ is involved with DNA synthesis

A

uridine - RNA synthesis

thymidine - DNA synthesis

43
Q

how is it that teriflunomide (active metabolite of leflunomide) inhibiting DHODH works in RA patients as a DMARD?

A

it inhibits the synthesis of URIDINE which is involved with DNA and RNA synthesis AND the proliferation of B cells. this produces immunosuppressant effects

44
Q

leflunomide (active metabolite) inhibits purine synthesis

true or false

A

FALSE - pyrimidine synthesis

45
Q

what does THF stand for and how does it relate to leflunoide

A

tetrahydrofolate
enzyme that converts uridine into thymidine through the addition of a methyl group

the active metabolite of leflunomide (teriflunoide) blocks this through the inhibition of the beginning of the cascade (DHODH)

46
Q

is leflunomide a prodrug?

A

NO
it IS a little active itself, its active metabolite, teriflunomide, is a lot more effective tho

47
Q

in the conversion of leflunomide to teriflunomide, what bond is cleaved?
what makes this possible?

A

N-O bond

due to CH3-H

48
Q
A

Intro to D&D Midterm (29 decks)

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