1.6 Anti Gout agents med chem

su

example of anti-inflammatory anti-gout agent

colchicine

colchicine class

anti-inflammatory agent for gout

Probenecid class

URAT1 inhibitor

lesinurad class

URAT1 inhibitor

allopurinol class

xanthine oxidase inhibitor

febuxostat class

xanthine oxidase inhibitor

pegloticase class

recombinant uricase

what is gout

painful form of inflammatory arthritis caused by excess uric acid in the blood and urine

gout is assoc with elevated levels of ____ in the serum and urine

uric acid

uric acid is an excretory product of ___ metabolism

purine

uric acid is hydrolyzed to _____ by uricase

allantoin

uric acid is hydrolyzed to allantoin by …

uricase

allantoin is hydrolyzed by allantoinase to ____ and then ____

urea; glyoxylic acid

acute gouty arthritis results from the accumulation of needle shaped crystals of ____ in joints, synovial fluid, and periarticular tissue

urate monohydrate (MSU)

what dis

uric acid

what dis

allantoin

what dis

glyoxylic acid

uric acid is weak and with very ____ water solubility

low

at body pH, uric acid exists as a ____ which is more water soluble

monosodium salt (MSU)

monosodium urate water solubility

300 mg/100 mL

uric acid solubility

6 mg / 100 mL

which organ has the dominant role in urate elimination

kidney

excretion of urate requires _____ which is located in renal proximal tubule cells

urate anion transporter (URAT1)

where is URAT1 found

renal proximal tubule cells

what is URAT1

urate anion transporter that is required for excretion of urate, its targeted by anti-gout agents

acute gout attacks can be controlled by drugs that reduce inflammation caused by…

deposited urate crystals

acute gout attacks can be controlled by drugs that inhibit uric acid biosynthesis by inhibiting which enzyme?

xanthine oxidase

acute gout attacks can be controlled by drugs that increase the excretion rate of ____

urate

anti gout therapy aims to…

reduce inflammation

lower urate

is allopurinol competitive or nah?

competitive

is febuxostat competitive or nah?

nah!

colchicine:

stops inflammation initiated by uric acid deposition but does not…

alter serum acid level

which of the following statements about colchicine is true?

a. its light sensitive

b. it decreases serum uric acid levels

c. increases release of lysosomal enzymes

d. all of the above

a

colchicine:

is ____ sensitive

light

colchicine:

why is it light sensitive?

extended conjugation

colchicine MOA:

diminishes phagocytosis by ________ to decrease inflammation

polymorphonuclear leukocytes

colchicine MOA:

diminishes phagocytosis by polymorphonuclear leukocytes to _____

decrease inflammation

colchicine MOA:

increases pH of synovial fluid due to _____ which leads to decreased uric acid deposition

decreased lactic acid production

colchicine MOA:

increases pH of synovial fluid due to decreased lactic acid production which leads to…

decreased uric acid deposition

colchicine MOA:

increases pH of _____ due to decreased lactic acid production which leads to decrease uric acid deposition

synovial fluid

colchicine MOA:

inhibits release of ____ during phagocytosis to decrease inflammatoin

lysosomal enzymes

colchicine:

typically combo with which gout agent?

probenecid

colchicine metabolism:

metabolized in the liver by CYP3A4 via ______ to make a primary amine metabolite

CYP3A4 N-deacetylation

colchicine Metabolism:

metabolized in the liver by CYP3A4 N-deacetylation to make…

primary amine

colchicine:
toxicity can be increased by…

urine alkalinization

colchicine inhibits: (select all that apply)

a. CYP3A4

b. URAT1

c. OAT4

d. P-gp

a and d

colchicine toxicity can be decreased by urine ____

acidification

probenecid is _____in water and acidic solutions

insoluble

probenecid is ____ in alkaline solutions

soluble

probenecid promotes ____ in the renal tubules and reduces it deposition in the joint

uric acid excretion

probenecid promotes excretion of uric acid by…

inhibiting URAT1

probenecid inhibits URAT1 which leads to reabsorption of ____ into the plasma instead of uric acid

probenecid

probenecid is a ____ benzoate

N-dialkylsulfamyl

probenecid:
increased uric acid excretion occurs with ____ substituents

smaller N alkyl

probenecid:

competitively inhibits the reabsorption of uric acid through ____ at the proximal tubules

OAT (organic anion transporter)

probenecid inhibits OAT which leads to…

increased urate excretion

what is an OAT and what it do

transports drugs and metabolites from blood into proximal tubules as the first step of tubular secretion

overall effect of probenecid

increased urate excretion

probenecid inhibits ____which plays a role in intercellular communication of inflammation

pannexin 1

probenecid inhibits pannexin 1 which leads to…

reduced inflammation

T or F:

probenecid lowers urate levels and reduces inflammation

T

probenecid metabolism:

almost completely absorbed and is hella plasma protein _____

bound

probenecid metabolites include…

w-1 OH

N-dealkylation products

glycine conjugate

acyl glucuronide conjugation (major)

what is probenecid’s major metabolite

acyl glucuronide conjugation

probenecid metabolites:
if the metabolite contains ___ then it is an active URAT1 inhibitor

COOH (CO2H)

probenecid metabolite:

if the metabolite contains COOH then it is an active _____ inhibitor

URAT1

probenecid metabolites:

the ____ metabolite is an active OAT inhibitor

glycine conjugate

the glycine metabolite of probenecid is an active ____ inhibitor

OAT

Lesinurad inhibits both ___ and ___

URAT1 and OAT4

Lesinurad inhibits URAT1 and OAT4 which are both sodium independent transporters that are involved in…

excretion of organic acid

Lesinurad is associated with ____ caused by diuretics

hyperuricemia

Lesinurad is a _____ steroisomer

atropisomer

what the f word is an atropisomer???

stereoisomers made from hindered rotation about a single bond or axial chirality where the energy differences are due to steric strain or other contributors that create a barrier to rotation leading to the isolation of individual rotamers

Lesinurad is metabolized by which enyzme?

CYP2C9

Lesinurad is metabolized by CYP2C9 to make ___ metabolites

inactive

lesinurad is ____ by CYP2C9 to M3 and M4

oxidized

lesinurad interacts with drugs that inhibit ____

CYP2C9

Allopurinol is an isomer of _____

hypoxanthine

Allopurinol acts as a ______ of xanthine oxidase

substrate/ reversible inhibitor

Allopurinol leads to uric acid synthesis ____

inhibition

Allopurinol leads to serum levels of xanthine and hypoxanthine _____

elevations

T or F

Xanthine and hypoxanthine are substantially less H2O soluble than urate

F

xanthine and hypoxanthine are both ____ H2O soluble than urate

much more

Allopurinol major metabolite

oxypurinol (alloxanthine)

what is alloxanthine (oxypurinol)

active metabolite of allopurinol that is also an xanthine oxidase inhibitor

chronic allopurinol admin leads to accumulation of ___ which leads to increased uricosuric activity

alloxanthine

chronic allopurinol admin leads to accumulation of alloxanthine which leads to…

increased uricosuric activity

early treatment with allopurinol must be combo with which drug

colchicine

Febuxostat was the first ____ XO selective inhibitor

nonpurine

Febuxostat is a noncompetitive inhibitor of both___ and ___ forms of xanthine oxidase

oxidized and reduced

what drug is a non competitive inhibitor of both oxidized and reduced forms of xanthine oxidase?

Febuxostat

Febuxostat MOA

Noncompetitive xanthine oxidase inhibitor blocks the entry of xanthine or hypoxanthine, or any other substrate, into the catalytic cleft

Febuxostat does not inhibit enzymes involved in _____ so it has less ADE than allopurinol

purine or pyrimidine metabolism

Febuxostat does not inhibit enzymes involved in purine or pyrimidine metabolism so it has…

less ADE than allopurinol

Febuxostat has a ___ step metabolism

2

febuxostat is metabolized by which enzymes in the first step?

CYP1A2

CYP1A1

CYP2C9

febuxostat is metabolized by which enzyme in the second step?

xanthine oxidase

Pegloticase indicated for tx of chronic gout in pts who failed…

traditional small molecule therapy

Pegloticase is a _____ uricase

recombinant porcine like

Pegloticase MOA

enhances elimination of uric acid by converting it to allantoin