Med Chem - Gout Flashcards
true or false
gout is an inflammatory disease
true
gout is an inflammatory disease cause by what
elevated levels of uric acid (as urate ion) in the plasma and urine
TRUE OR FALSE
gout is only chronic
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
explain the biosynthesis of uric acid
how are purines involved?
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
breakdown where urate comes from
1/3 comes from our diet – meat, veil, fish, cheese, etc
1/4 comes from purine breakdown (adenine, guanine)
name 2 ways that uric acid can be excreted from the body through use of drugs
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
name 2 urocosuric drugs
probenecid
lesinurad
what is the end metabolic product of purines
uric acid
name 3 ways drugs can be utilized to decrease uric acid levels in the body to treat gout
- XO (xanthine oxidase) inhibitors
- Pegloticase - converts uric acid to more water soluble allantoin
- urocosuric drugs - enhance urinary excretion of uric acid
what is the most important enzyme in the synthesis of uric acid
xanthine oxidase bc it’s involved with 2 steps:
conversion of hypoxanthine to xanthine and xanthine to uric acid
name 2 drugs that are XO inhibitors
allopurinol
febuxostat
explain why cancer patients taking chemotherapy are at a higher risk for developing gout
what is this called?
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
true or false
changing the diet cannot help gout
false it can
reducing amount of purines in diet can help
what does XO do in terms of chemistry
adds OH groups
name 4 NSAIDS that are commonly used in gout to reduce pain and inflammation
indomethacin
ibuprofen
ketorolac
naproxen
what is the MOA of colchicine
it’s unclear – thought to be a blockade of microtubule assembly
what is colchicine derived from and thus what is it called
derived from plants - various colchicum species
thus called an ALKALOID
What are the physical properties of colchicine
pale-yellow odorless powder
explain the MOA of probenecid
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
what is unique about lesinurad
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
allopurinol, a xanthine oxidase inhibitor, is an isostere of what?
what is the only difference between the 2?
hypoxanthine/6-hydroxypurine
only difference is that in hypoxanthine the N is on carbon 7 and in allopurinol it is on carbon 8
true or false
allopurinol is a structural analog of the natural purine base, hypoxanthine
true
what is the end product of purine metabolism in humans
uric acid
name 2 things xanthine oxidase catalyzes the conversion of
hypoxanthine to xanthine and xanthine to uric acid
explain the metabolism of allopurinol
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!!!!
alloxanthine/oxipurinol is a structural analog of what?
XANTHINE
while allopurinol is a structual analog of hypoxanthine
explain the difference between the binding preferences of allopurinol vs its pharmacologically active metabolite, oxipurinol
allopurinol only binds the oxidized form of Mo cofactor of XO.
oxipurinol only binds the REDUCED form of Mo cofactor on XO
Explain the MOA allopurinol
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)
why is allopurinol MOA known as “slow binding kinetics”
there are long effects – covalent binding to Mo cofactor on xanthine oxidase
oxipurinol is a ______ based inhibitor of XO
mechanism based
why is oxipurinol considered a suicide inhibitor
because it covalently binds to the reduced form of XO
true or false
both XO inhibitors are purine based
FALSE - only allopurinol
febuxostat is non-purine based. it is a thiazole derivative
state the MOA of febuxostat and how it differs from allopurinol/oxipurinol
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
true or false
allopurinol/oxipurinol are competitive inhibitors of xanthine oxidase while febuxostat is a noncompetitive inhibitor of xanthine oxidase
TRUE
remember, allo/oxipurinol are purine based and structurally similar
febuxostat is not - non competitive - thiazole derivative
which is more selective to XO – allopurinol/oxipurinol or febuxostat??
explain
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
true or false
febuxostat is a noncompetitive, reversible inhibitor of XO
true
true or false
febuxostat covalently binds to Mo of xanthine oxidase
FALSE
it is not covalent like oxipurinol
it is noncompetitive and reversible - not structurally the same
true or false
allopurinol/oxipurinol are competitive XO inhibitors
TRUE
structurally resemble the substrates
pegloticase is ___ ___
pegylated uricase
true or false
humans do not naturally have the uricase enzyme to breakdown uric acid into allantoin
TRUE
supposedly we used to have it before evolution, but not anymore
explain a big concern with pegloticase
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
explain methemoblobinemia
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
give 3 reasons that the uricase enzyme was pegylated to produce pegloticase
- 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
- the chains impede access by proteases, thus increasing the half life
- the small urate molecules can easily diffuse into the active site of uricase to be hydrolyzed into more soluble allantoin to be excreted
true or false
if pts are NOT deficient in G6PDH, giving pegloticase is not really a concern
true - they still have essential reducing pathways by G6PDH producing NADH and GSH
