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Intro to D&D Final > Med Chem - Gout > Flashcards

Med Chem - Gout Flashcards

1
Q

true or false

gout is an inflammatory disease

A

true

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2
Q

gout is an inflammatory disease cause by what

A

elevated levels of uric acid (as urate ion) in the plasma and urine

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3
Q

TRUE OR FALSE

gout is only chronic

A

false - it can also be acute

acute gout can be reversed and is the accumulation of needle-like crystals of monosodium urate within the joints and synovial fluid

chronic gout associated with permanent erosive joint deformity

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4
Q

explain the biosynthesis of uric acid

how are purines involved?

A

hypoxanthine is converted to xanthine through xanthine oxidase.

xanthine is converted to uric acid, ALSO through xanthine oxidase.

adenine and guanine are purines. they’re involved because adenine is converted into hypoxanthine through adenine deaminase, and guanine is converted to xanthine through guanine deaminase

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5
Q

breakdown where urate comes from

A

1/3 comes from our diet – meat, veil, fish, cheese, etc

1/4 comes from purine breakdown (adenine, guanine)

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6
Q

name 2 ways that uric acid can be excreted from the body through use of drugs

A

when urocosuric drugs are taken, urinary excretion is facilitated

pegloticase is a drug that converts uric acid into ALLANTOIN – more polar and water soluble – that gets excreted

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7
Q

name 2 urocosuric drugs

A

probenecid
lesinurad

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8
Q

what is the end metabolic product of purines

A

uric acid

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9
Q

name 3 ways drugs can be utilized to decrease uric acid levels in the body to treat gout

A
  1. XO (xanthine oxidase) inhibitors
  2. Pegloticase - converts uric acid to more water soluble allantoin
  3. urocosuric drugs - enhance urinary excretion of uric acid
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10
Q

what is the most important enzyme in the synthesis of uric acid

A

xanthine oxidase bc it’s involved with 2 steps:

conversion of hypoxanthine to xanthine and xanthine to uric acid

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11
Q

name 2 drugs that are XO inhibitors

A

allopurinol
febuxostat

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12
Q

explain why cancer patients taking chemotherapy are at a higher risk for developing gout

what is this called?

A

adenine and guanine come from cell breakdown

thus, someone on chemo is gonna have a lot of dead cells and thus a lot of purines and hence a lot of UA synthesis

called tumor lysis syndrome

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13
Q

true or false

changing the diet cannot help gout

A

false it can

reducing amount of purines in diet can help

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14
Q

what does XO do in terms of chemistry

A

adds OH groups

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15
Q

name 4 NSAIDS that are commonly used in gout to reduce pain and inflammation

A

indomethacin
ibuprofen
ketorolac
naproxen

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16
Q

what is the MOA of colchicine

A

it’s unclear – thought to be a blockade of microtubule assembly

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17
Q

what is colchicine derived from and thus what is it called

A

derived from plants - various colchicum species

thus called an ALKALOID

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18
Q

What are the physical properties of colchicine

A

pale-yellow odorless powder

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19
Q

explain the MOA of probenecid

A

it’s a uricosuric drug - enhances the urinary excretion of uric acid

does this by inhibiting the URAT1 transporter. this transporter, if not blocked, would reabsorb uric acid back into the body instead of excreting it

since probenecid is blocking the reabsorption transporter, the uric acid is excreted instead in the urine

20
Q

what is unique about lesinurad

A

it was accidentally discovered

a discontinued NNRTI HIV drug was given to pts and it was noticed that they had low UA levels

turns out that upon metabolism, amide hydrolysis gave rise to an active carboxy metabolite - LESINURAD – that inhibited the URAT1 transporter and thus prevented the reabsorption of uric acid back into the body and facilitated its excretion

21
Q

allopurinol, a xanthine oxidase inhibitor, is an isostere of what?
what is the only difference between the 2?

A

hypoxanthine/6-hydroxypurine

only difference is that in hypoxanthine the N is on carbon 7 and in allopurinol it is on carbon 8

22
Q

true or false

allopurinol is a structural analog of the natural purine base, hypoxanthine

A

true

23
Q

what is the end product of purine metabolism in humans

A

uric acid

24
Q

name 2 things xanthine oxidase catalyzes the conversion of

A

hypoxanthine to xanthine and xanthine to uric acid

25
Q

explain the metabolism of allopurinol

A

is metabolized by both XO and aldehyde oxidase (mostly aldehyde oxidase) into OXIPURINOL (aka alloxanthine)

oxipurinol is an ACTIVE METABOLITE of allopurinol that also inhibits xanthine oxidase!!!!

26
Q

alloxanthine/oxipurinol is a structural analog of what?

A

XANTHINE

while allopurinol is a structual analog of hypoxanthine

27
Q

explain the difference between the binding preferences of allopurinol vs its pharmacologically active metabolite, oxipurinol

A

allopurinol only binds the oxidized form of Mo cofactor of XO.

oxipurinol only binds the REDUCED form of Mo cofactor on XO

28
Q

Explain the MOA allopurinol

A

allopurinol inhibits oxidized form of Mo cofactor on xanthine oxidase

XO or aldehyde oxidase transfers an OH from Mo cofactor onto allopurinol to form OXIPURINOL.

oxipurinol does 180 flip

the Mo cofactor is now in a REDUCED form – oxipurinol will only covalently bind to this form (after flips 180 degrees)

29
Q

why is allopurinol MOA known as “slow binding kinetics”

A

there are long effects – covalent binding to Mo cofactor on xanthine oxidase

30
Q

oxipurinol is a ______ based inhibitor of XO

A

mechanism based

31
Q

why is oxipurinol considered a suicide inhibitor

A

because it covalently binds to the reduced form of XO

32
Q

true or false

both XO inhibitors are purine based

A

FALSE - only allopurinol

febuxostat is non-purine based. it is a thiazole derivative

33
Q

state the MOA of febuxostat and how it differs from allopurinol/oxipurinol

A

it inhibits BOTH the reduced and oxidized forms of XO — REVERSIBLY

it is a NONCOMPETITIVE inhibitor of XO. works by blocking the access of the substrate to the active site

34
Q

true or false

allopurinol/oxipurinol are competitive inhibitors of xanthine oxidase while febuxostat is a noncompetitive inhibitor of xanthine oxidase

A

TRUE

remember, allo/oxipurinol are purine based and structurally similar

febuxostat is not - non competitive - thiazole derivative

35
Q

which is more selective to XO – allopurinol/oxipurinol or febuxostat??

explain

A

febuxostat is more selective for XO

this is bc allo/oxipurinol are structurally very similar to endogenous purines. therefore, it’s possible they can be incorporated into DNA and cause possible toxicity

febuxostat, however, does not resemble endogenous purines and is instead a thiazole derivative

36
Q

true or false

febuxostat is a noncompetitive, reversible inhibitor of XO

A

true

37
Q

true or false

febuxostat covalently binds to Mo of xanthine oxidase

A

FALSE

it is not covalent like oxipurinol

it is noncompetitive and reversible - not structurally the same

38
Q

true or false

allopurinol/oxipurinol are competitive XO inhibitors

A

TRUE

structurally resemble the substrates

39
Q

pegloticase is ___ ___

A

pegylated uricase

40
Q

true or false

humans do not naturally have the uricase enzyme to breakdown uric acid into allantoin

A

TRUE

supposedly we used to have it before evolution, but not anymore

41
Q

explain a big concern with pegloticase

A

by converting uric acid into allantoin, several bad things occur, particularly if the patient has a deficiency in G6PDH

uric acid is a well known endogenous anti oxidant. when it degrades, produces oxidative stress like H2O2. also, as mentioned, uric acid is an antioxidant so converting it into allantoin is depriving us of this useful antioxidant molecule

the redox stress produced can cause hemolytic anemia and methemoglobinemia, particularly in patients that have G6PDH deficiency - an important molecule that produces reducing molecules like NADH and GSH

42
Q

explain methemoblobinemia

A

iron in hemoglobin is typically in its reduced form bc it binds oxygen better — FE2+

however, when it oxidizes to Fe3+, less affinity for oxygen —- methemoglobinemia
can be caused by too much oxidative stress like in the case of a G6PDH pt taking pegloticase

43
Q

give 3 reasons that the uricase enzyme was pegylated to produce pegloticase

A
  1. the PEG chains hide the surface of uricase from B cell receptors – hide from the immune system - dont want immune response produced bc uricase would be recognized as foreign - humans dont produce
  2. the chains impede access by proteases, thus increasing the half life
  3. the small urate molecules can easily diffuse into the active site of uricase to be hydrolyzed into more soluble allantoin to be excreted
44
Q

true or false

if pts are NOT deficient in G6PDH, giving pegloticase is not really a concern

A

true - they still have essential reducing pathways by G6PDH producing NADH and GSH

45
Q
A

Intro to D&D Final (22 decks)

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