1.7 Gout Pharmacology

Briski :((((((

gout is a form of ____ charcterized by recurrent episodes of joint pain and inflammation

arthritis

gout joint pain and inflammation is caused by…

MSU crystal deposits in joint and soft tissues

MSU crystals form as a result of …

elevated urate concentrations

MSU crystal localization in the urinary tract can lead to…

kidney stones and urinary obstruction

hallmark of gout

tophi

what is tophi

hard nodules of MSU crystals present in peripheral joints

tophi initially start in…

a single joint (usually big toe)

T or F:

hyperuricemia is always the cause of gout

F

uric acid metabolism:

uric acid is the end product of ____ metabolism

purine

what three things can increase serum uric acid concentration

increased uric acid production

reduction in uric acid renal excretion

combination of both

overproduction of serum uric acid accounts for ____ gout cases

10%

overproduction of uric acid can result from…

excessive de novo purine synthesis

excess dietary intake

myeloproliferative derivates

what is a nucleoside

nitrogenous base and sugar

what is a nucleotide

nitrogenous base, sugar, and phosphate groups

purine levels are controlled by…

de novo synthesis and salvage pathways

the first step in de novo syntehsis of purine is…

PRPP + glutamine via amidoPRT

which enzyme is responsible for the first step in the de novo pathway of making purines

amido pRT

amidoPRT is _____ activated by levels of PRPP

allosterically

when PRPP is high, amidoPRT activity is

high

in the salvage pathway ___ transforms dietary adenine and guanine to ATP and GTP for use in nucleic acid synthesis

HGPRT

In the salvage pathway, HGPRT transforms dietary ______ to the nucleotides ATP and GTP, respectively, for use in nucleic acid synthesis.

adenine and guanine

In the salvage pathway, HGPRT transforms dietary adenine and guanine to the nucleotides ____ and ____, respectively, for use in nucleic acid synthesis.

ATP and GTP

purines adenine and guanine are converted to _____

hypoxanthine

hypoxanthine is transformed to ____

xanthine

xanthine is converted to _____ by xanthine oxidase

uric acid

what enzyme is responsible for converting hypoxanthine to xanthine and then xanthine to uric acid?

xanthine oxidase

xanthine oxidase function

conversion of hypoxanthine to xanthine and then xanthine to uric acid

what drug can reduce urate synthesis by blocking xanthine oxidase?

allopurinol

what drug can increase urate excretion

probenecid

what drug can increase the conversion of urate to allantoin

uricase

synovial joint:

the fibrous capsule is continuous with _______

periosteum of adjacent bone

synovial joint:

the _____ is continuous with periosteum of adjacent bones

fibrous capsule

synovial joint:

the synovial membrane lines _____ of the joint

nonarticular surfaces

any variable that decreases the solubility of urate can promote…

urate crystal deposition

urate is LESS soluble at ___ temps

lower

urate is less soluble at lower temps which explains why urate crystals are…

peripherally distrubuted

synovial joint fluid is more ___ than blood which favors crystal formation

acidic

in an acute attack of gout, MSU binds to _____ which activates them

monocyte toll like receptors

in acute attack of gout:
1. MSU binds to monocyte toll like receptors which activates them

2. which leads to…

phagocytosis of MSU crystals w intracellular assembly of inflammatory response enzymes

lowkey slide 9 ????

idk girl

Asymptomatic hyperuricemia plasma urate levels

>6.0 mg/dL in women >7.0 mg/dL in men

Asymptomatic hyperuricemia pharmacological intervention

none

Acute gout features

Acute arthritis, typically 1st metatarsophalangeal joint (big toe), excruciating pain

acute gout pharmacological intervention

NSAIDS, colchicine, glucocorticoids

Intercritical phase features

Asymptomatic hyperuricemia

Intercritical phase pharmacological intervention

none

Chronic gout features

Hyperuricemia, development of tophi, Recurring attacks of acute gout

Chronic gout pharmacological intervention

Allopurinol, probenecid, sulfinpyrazone

Non selective NSAIDs ADE:
GI

GI bleeding or ulceration

nonselective NSAIDs ADE:

platelets

inhibition of platelet aggregation

which non selective NSAID is the least likely to cause GI upset?

ibuprofen

which non selective NSAID is the most likely to cause GI upset?

piroxicam

COX2 inhibitor NSAIDs:

effect on platelets

do not effect platelets at normal doses

which is better for pts with risk of GI bleed or taking chronic anticoagulants with gout?

a. nonselective NSAIDs

b. COX 2 NSAIDs

b

potential adverse CV effects of NSAIDS

aggravation of hypertension, causation of renal failure, inhibition of diuretic-induced increases in renal sodium excretion, and reduction of hypotensive effect of diuretics and other anti-hypertensive drugs.

Colchicine MOA

Inhibition of microtubule polymerization, diminished action of chemokine inflammatory mediators, decreased neutrophil activation.

Colchicine ADE

Diarrhea, nausea, vomiting; myelosuppressive

in the presence of cyanocobalamin, colchicine may…

decrease cyanocobalamin concentrations

in the presence of HMG-CoA reductase inhibitors, colchicine may…

may increase rhabdomyolysis drug effects

in the presence of P-gp/ABCBI inducers, colchicine may…

decrease P-pg substrate levels

in the presence of _______, colchicine may decrease cyanocobalamin concentrations

Cyanocobalamin

in the presence of _______, colchicine may increase rhabdomyolysis drug effect

HMG-CoA reductase inhibitors

in the presence of ________, colchicine may decrease P-pg substrate levels

P-gp/ABCBI inducers

serum colchicine levels may be increased by…

CYP3A4 inhibitors; Digoxin; Fosamprenavir; Grapefruit juice; P-pg/ABCBI inhibitors; Tacrolimus; Tipranavir

in the presence of colchicine: Conivaptan, Mifepristone, Stiripentol may…

increase serum CYP3A4 substrate levels

in the presence of colchicine _____ may increase serum CYP3A4 substrate levels

Conivaptan, Mifepristone, Stiripentol

in the presence of colchicine, _______ may increase colchicine myopathic effects

Fibric acid derivatives

in the presence of colchicine, Fibric acid derivatives may…

increase colchicine myopathic effects

glucocorticoid ADE

osteoporosis; myopathy, peptic ulcer disease, CNS effects, hypertension, predisposition to infections; possible glucose intolerance.

glucocorticoid ADE are minimal with ____ treatments for acute gout attacks

short term

____ are highly effective, rapid-acting anti-inflammatory agents with a favorable risk vs. benefit profile.

glucocorticoids

non-pharma interventions for gout

ice, reduce alcohol use, minor dietary modifications, decreased body weight

allopurinol is a structural analog of _____

xanthine

allopurinol MOA

inhibition of uric acid production

allopurinol is oxidized by XO to produce _____

oxypurinol

oxypurinol inhibits XO by….

preventing molybdenum in the enzyme active site from converting between +4 and +6 oxidation states, thereby ‘freezing’ the enzyme

allopurinol is assoc with which rare and life threatening reaction?

allopurinol hypersensitivity syndrome

symptoms of allopurinol hypersensitivity syndrome

erythematous rash, fever, hepatitis, eosinophilia, leukocytosis, renal failure; usually begin within 8 weeks of therapy

risk factors of allopurinol hypersensitivity syndrome

HLA-B*5801 genotype; renal impairment; concomitant diuretic use; female sex; age

drug interactions:

allopurinol and ampicillin or amoxicillin

Increase Co-administration increases rate of skin rxn

drug interactions:

allopurinol and azathioprine

Increase in azathioiprine metabolite production

drug interactions:

Allopurinol and carbamazepine

Increase serum concentrations

drug interactions:

allopurinol and pegloticase

Adverse toxicity is enhanced, increasing risk of anaphylaxis and infusion rxns

drug drug interactions:

allopurinol and theophylline

Increased plasma levels and possible toxicity

drug drug interactions:

allopurinol and warfarin

Enhanced anti-coagulation effect

drug drug interactions:

allopurinol and ACE inhibitors

Elevated risk of hypersensitivity rxn to allopurinol

drug drug interactions:

allopurinol and loop diuretics

increased serum concentrations and incidence of hypersensitivity rxns to allopurinol

Febuxostat is a non-purine xanthine oxidase inhibitor and is ___ selective than allopurinol

more

Febuxostat does not inhibit…

other enzymes involved in purine/pyrimidine metabolism

Febuxostat ADE ADE

increased liver function, N/D, rash, arthralgias

drug drug interactions:

Febuxostat and didanosine

Increased systemic exposure

drug drug interactions:

Febuxostat and Pegloticase

Increased adverse effects with augmented risk of anaphylaxis and infusion rxns

drug drug interactions:

Febuxostat and XO substrate drugs, Mercaptopurine or, theophylline

Increased plasma concentrations, leading to azathioprine toxicity

uricouric agents MOA

block renal tubular uric acid resorption

probenecid MAIN target

URAT1

probenecid can target…

URAT1 and OATs

probenecid increases renal urate excretion and can predispose….

urate stone formation (kidney stone)

probenecid increases ____

renal urate excretion

probenecid can be antagonized by…

low dose aspirin

Sulfinpyrazone has a similar MOA to…

probenecid