MedChem of Gout

which purine bases are catabolized to uric acid?

adenine

guanine

what are the precusors of uric acid?

hypoxanthine

xanthine

uric acid has a ____ water solubility than hypoxanthine.

lower

why does uric acid have a lower water solubility than hypoxanthine?

UA has multiple intramolecular interactions that leaves only 1 site for H-bonding; hypoxanthine has 3 available sites for H-bonding

what is the pH of synovial fluid?

7.4

is uric acid mostly ionized or unionized at physiologic pH?

99% ionized

what is the ionized form of uric acid?

urate monoanion (or sodium urate)

as temperature and pH decrease, the solubility of monosodium urate will _____.

decrease

is uric acid ionized or unionized as pH decreases? is it more or less soluble?

unionized; less

where does uric acid crystallization typically occur?

joints (e.g., big toe)

gout is always a result of _______.

hyperuricemia

increased plasma conc. of uric acid leads to.....

deposition of monosodium urate crystals that can cause inflammation

how is inflammation due to gout treated?

anti-inflammatory (NSAIDs, colchicine)

immunosuppression (glucocorticoids)

how are future gout attacks prevented?

uricosuric agents (probenecid)

xanthine oxidase inhibitors (allopurinol, febuxostat)

how can probenecid prevent gout attacks?

increase UA excretion

how can allopurinol and febuxostat prevent gout attacks?

decrease UA production

what are alkaloids?

basic (alkaline) compounds that generally have a nitrogen in their ring structure

is colchicine an alkaloid?

yes

what is the Vd of colchcine?

high Vd; 5-8 L/kg

where does colchicine accumulate to produce its effect?

leukocytes, kidney, spleen and liver

how is colchicine metabolized?

hydroxylation of the methoxy group by CYP3A4

how is colchicine excreted?

renally (~50% unchanged); enterohepatic circulation

colchicine has a ______ therapeutic window.

narrow

there is a risk of toxicity with colchicine serum conc.....

> 3.0

colchicine requires a dose reduction in which patients?

renal or hepatic impairment

colchicine is a substrate of _____ and _____.

CYP3A4; Pgp

how do CYP3A4 and Pgp inhibitors affect colchicine?

increase colchicine conc.; increase risk of toxicity

how do CYP3A4 and Pgp inducers affect colchicine?

decrease colchicine conc.; decrease drug effectiveness

what drugs can increase the risk of myopathy when taken with colchicine?

HMG CoA reductase inhibitors (compete for metabolism by 3A4)

what drugs should be avoided/monitored when taking with colchicine?

clarithomycin

protease inhibitors

grapefruit juice

cyclosporine

which glucocorticoids are used in the treatment of gout?

prednisone, prednisolone (PO)

methylprednisolone (PO, intra-articular)

triamcinolone (intra-articular, IM)

list the glucocorticoids in order of decreasing affinity for GR compared to hydrocortisone:

triamcinolone (5x) > methylprednisolone (4x) > prednisolone (2x)

prednisone is completely metabolized into its _____ form.

active

how is prednisone metabolized?

hydroxylation of the ketone group to a hydroxyl to form prednisolone

taking prednisone with fluroquinolones can increase the risk of...

tendon rupture

taking prednisone with which drugs can increase corticosteroid concentrations?

oral contraceptives

how do strong CYP3A4 inducers affect prednisone?

decreased corticosteroid concentration

what are examples of strong CYP3A4 inducers?

carbamazepine

phenobarbital

phenytoin

rifampin

how do strong CYP3A4 inhibitors affect prednisone?

increased corticosteroid concentration

what are examples of strong CYP3A4 inhibitors?

clarithomycin

some antivirals and antifungals

how do Al/Mg containing antacids affect prednisone?

decreased oral absorption

what is the MoA of probenecid?

URAT1 inhibitor (inhibits UA reabsorption)

probenecid is metabolized into _____ metabolites.

active

probenecid can block renal secretion of which drugs?

methotrexate

penicillin

sulfonylureas

indomethacin

aspirin

probenecid should be used with caution in patients with...

G6DP deficiency (e.g., hemolytic anemia)

peptic ulcer disease

renal impairment

allopurinol is a _____ analog.

purine

how is allopurinol metabolized?

hydroxylation by xanthine oxidase to form the active metabolite oxypurinol

what is the half life of oxypurinol?

18-30 hr

allopurinol should be used with caution in patients with...

renal impairment

what is the rare/serious AE associated with allopurinol?

hypersensitivity syndrome

in which populations is there an increased risk of hypersensitivity syndrome with allopurinol?

HLA-B*58:01 positive carriers; predominantly asian population; consider PGx testing

febuxostat is a ________ structure.

non-purine

what is the MoA of febuxostat?

selective, non-competitive inhibitor of XO

is allopurinol or febuxostat more potent in XO inhibition?

febuxostat

what enzymes are involved in the metabolism of febuxostat?

CYP1A1

CYP1A2

CYP2C9

febuxostat is a ______ inhibitor of xanthine oxidase.

non-competitive

mPEG increases the _____ and decreases the _____

half life; immune response

what is the MoA of pegloticase?

converts uric acid to more soluble allantoin

allopurinol and febuxostat have DIs with substrates of XO such as....

mercaptopurine and azathioprine (myelosuppression)