Med Chem - Gout

Question 1

true or false

gout is an inflammatory disease

Answer 1

true

Question 2

gout is an inflammatory disease cause by what

Answer 2

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

Question 3

TRUE OR FALSE

gout is only chronic

Answer 3

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

Question 4

explain the biosynthesis of uric acid

how are purines involved?

Answer 4

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

Question 5

breakdown where urate comes from

Answer 5

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

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

Question 6

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

Answer 6

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

Question 7

name 2 urocosuric drugs

Answer 7

probenecid
lesinurad

Question 8

what is the end metabolic product of purines

Answer 8

uric acid

Question 9

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

Answer 9

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

Question 10

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

Answer 10

xanthine oxidase bc it’s involved with 2 steps:

conversion of hypoxanthine to xanthine and xanthine to uric acid

Question 11

name 2 drugs that are XO inhibitors

Answer 11

allopurinol
febuxostat

Question 12

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

what is this called?

Answer 12

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

Question 13

true or false

changing the diet cannot help gout

Answer 13

false it can

reducing amount of purines in diet can help

Question 14

what does XO do in terms of chemistry

Answer 14

adds OH groups

Question 15

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

Answer 15

indomethacin
ibuprofen
ketorolac
naproxen

Question 16

what is the MOA of colchicine

Answer 16

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

Question 17

what is colchicine derived from and thus what is it called

Answer 17

derived from plants - various colchicum species

thus called an ALKALOID

Question 18

What are the physical properties of colchicine

Answer 18

pale-yellow odorless powder

Question 19

explain the MOA of probenecid

Answer 19

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

Question 20

what is unique about lesinurad

Answer 20

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

Question 21

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

Answer 21

hypoxanthine/6-hydroxypurine

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

Question 22

true or false

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

Answer 22

true

Question 23

what is the end product of purine metabolism in humans

Answer 23

uric acid

Question 24

name 2 things xanthine oxidase catalyzes the conversion of

Answer 24

hypoxanthine to xanthine and xanthine to uric acid

Question 25

explain the metabolism of allopurinol

Answer 25

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!!!!

Question 26

alloxanthine/oxipurinol is a structural analog of what?

Answer 26

XANTHINE while allopurinol is a structual analog of hypoxanthine

Question 27

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

Answer 27

allopurinol only binds the oxidized form of Mo cofactor of XO. oxipurinol only binds the REDUCED form of Mo cofactor on XO

Question 28

Explain the MOA allopurinol

Answer 28

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)

Question 29

why is allopurinol MOA known as "slow binding kinetics"

Answer 29

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

Question 30

oxipurinol is a ______ based inhibitor of XO

Answer 30

mechanism based

Question 31

why is oxipurinol considered a suicide inhibitor

Answer 31

because it covalently binds to the reduced form of XO

Question 32

true or false both XO inhibitors are purine based

Answer 32

FALSE - only allopurinol febuxostat is non-purine based. it is a thiazole derivative

Question 33

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

Answer 33

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

Question 34

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

Answer 34

TRUE remember, allo/oxipurinol are purine based and structurally similar febuxostat is not - non competitive - thiazole derivative

Question 35

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

Answer 35

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

Question 36

true or false febuxostat is a noncompetitive, reversible inhibitor of XO

Answer 36

true

Question 37

true or false febuxostat covalently binds to Mo of xanthine oxidase

Answer 37

FALSE it is not covalent like oxipurinol it is noncompetitive and reversible - not structurally the same

Question 38

true or false allopurinol/oxipurinol are competitive XO inhibitors

Answer 38

TRUE structurally resemble the substrates

Question 39

pegloticase is ___ ___

Answer 39

pegylated uricase

Question 40

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

Answer 40

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

Question 41

explain a big concern with pegloticase

Answer 41

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

Question 42

explain methemoblobinemia

Answer 42

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

Question 43

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

Answer 43

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

Question 44

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

Answer 44

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