Fitzy: Pharmacology of Gout and Hyperuricemia

Question 1

What transporter in the kidney will let us reabsorb urate?

Answer 1

-URAT1

Question 2

Where does Uric acid come from?

Answer 2

• Purines
• fructos
• alcohol

Question 3

What enzyme makes uric acid?

Answer 3

-Xanthine Oxidase

Question 4

What are some other factors besides hyperuricemia that contribute to gout attacks in the first metatarsal phalangeal joint?

Answer 4

• temperature
• pH
• joint hydration: this is why there’s nocturnal pain
• Presence of altered matrix proteins, exposed cartilage fragments and nucleating debris

Question 5

What are the two XO inhibitors?

Answer 5

• Allopurinol

- Febuxostat

Question 6

What are the drugs that turn uric acid into a more soluble form?

Answer 6

• rasburicase
• pegloticase
• uricosolytics

Question 7

What is the one anti inflammatory gout specific drug?

Answer 7

-colchicine

Question 8

What is that unique MOA for Colchicine?

Answer 8

• binds to tubulin and depolimerizes microtubules
• disrupts granulocyte function; inhibits LTB4 formation
• *kind of paralyzes neutrophils… they can’t migrate to the site inflammation… this is used specifically for gout

Question 9

what is the mainstay of therapy of acute gout attacks in patients who have no contraindications to them?

Answer 9

-NSAIDS!

Question 10

when do we have to use caution with NSAIDs?

Answer 10

• ulcers
• htn
• coronary disease
• fluid retention
• remember that the dose of NSAIDs needed to resolve gout attack are on the higher side

Question 11

How much ibuprofen should a person with gout take?

Answer 11

-2 tabs three times a day is often insufficent! so they need to take a shit ton

Question 12

What does colchicine do again?

Answer 12

• binds to tubulin, depolymerizes microtubules, and imparis migration of granulocytes
• thereby blunting inflammation

Question 13

What is the maximum does for colchicine?

Answer 13

-12 tablets per episode

Question 14

Is colchicine an analgesic?

Answer 14

-no

Question 15

Does colchicine modify uric acid levels?

Answer 15

-no

Question 16

What confers long term risks, such as osteoporosis and infection, but has low risk for short-term risks?

Answer 16

-corticosteroids

Question 17

What aer the adverse effects of corticosteroids that we have to worry about?

Answer 17

• adverse effects on bp and blood sugar

- so if they have htn or uncontrolled diabetes mellitus

Question 18

What are the 2 XO inhibitors?

Answer 18

• allopurinol
• febuxostate
• they inhibit urate biosynthesis

Question 19

What are the 2 drugs that are uricosuric agents (URAT1 inhibitors)?

Answer 19

• Probenecid
• Sulfinpyrazone
• they enhance urate excretion

Question 20

What are the recombinant urate oxidase enzymes?

Answer 20

• pegloticase
• rasburicase
• they enhance urate metabolism

Question 21

What is the only uricosuric agent available in US?

Answer 21

-Probenecid

Question 22

What is the 1st line urate lowering therapy (ULT) in gout?

Answer 22

• XO inhibitors
• allopurinol
• febuxostat

Question 23

What accumulates as a result of tx with allopurinol and febuxostat?

Answer 23

-hypoxanthine is the best answer

Question 24

What is the active metabolite of allopurinol?

Answer 24

• oxyurinol

- has long ass half life

Question 25

Why is febuxostat better than allopurinol?

Answer 25

- has better and different adverse effect profile vs allopurinol - can be used in patients with renal disease

Question 26

What is that one wierd paradox thing with ULT?

Answer 26

-during the initial phase of ULT, there is an early increase in acute gout attacks

Question 27

What do we give as well to people who are beginning ULT to decrease acute gout associated with initiation of ULT?

Answer 27

-colchicine or an NSAID

Question 28

What is a big thing that we have to worry about with allopurinol and febuxostat?

Answer 28

-they inhibit metabolism of Xanthine drugs use in cancer chemotherapy, immunosuppression, asthma conferring risk of overexposure and requiring dose adjustments

Question 29

What were the Xanthine drugs that build up when we inhibit XO?

Answer 29

- 6 mercaptopurine - Azathioprine - Theophylline

Question 30

Which xanthine drug makes people edgy when they don't clear it?

Answer 30

-theophylline

Question 31

What is the black box warning with allopurinol?

Answer 31

- Allopurinol should be discontinued at the first appearance of skin rash or other signs of an allergic rxn - it is not recommended for tx of asymptomatic hyperuricemia

Question 32

What genotype do we have to worry about and make them avoid allopurinol?

Answer 32

- HLA-B*5801 - severe hypersensitivity to allopurinol - Han Chinese, Thai descent

Question 33

What drug combo is appropriate in some patients to achieve the serum urate target (<6mg/dL)?

Answer 33

- oral ULT | - oral uricosuric agent (probenecid)

Question 34

What are uricosuric drugs?

Answer 34

- weak organic acids that promote renal clearance of uric acid by inhibiting urat-anion exchangers in the proximal tubule that mediates urate reabsorption - Probenecid remember that

Question 35

What does probenecid do specifically?

Answer 35

- blocks URAT1 transporter on apical membrane of epithelium | - promotes excretion

Question 36

When should uricosuric agents (probenecid) be avoided?

Answer 36

-in pts with risk/hx of nephrolithiasis or uric acid nephropathy

Question 37

Should urate-lowering therapies be initiated during an acute attack?

Answer 37

- no | - they are of no benefit for acute gout

Question 38

What is the paradox thing with aspirin?

Answer 38

- do not use standard dose aspirin as an anti-inflammatory agent for acute gout attacks - aspirin blocks tubular secretion>tubular absorption and thereby aggravates hyperuricemia

Question 39

What kind of a dose of aspirin do we need to give them to have a uricosuric effect?

Answer 39

-a very high dose

Question 40

Will thiazide and loop diuretics help?

Answer 40

- no! - they interfere with urate clearance by effects on multiple transporters in the prox renal tubule - this causes uric acid retention

Question 41

What is kind of the last stitch effort we use for gout?

Answer 41

-ULT with a urate oxidase recombinant enzyme (pegloticase) is appropriate for severe disease, failure, or intolerance to appropriately dosed XOI options

Question 42

What does Pegloticase and rasburicase do?

Answer 42

-these drugs augment metabolic degradation of uric acid into allantoin

Question 43

What do we use pegloticase for?

Answer 43

-hyperuricemia associated with malignancy (tumor lysis syndrome)

Question 44

What do we use rasburicase for?

Answer 44

-approved for gout-associated hyperuricemia

Question 45

How is pegloticase and rasburicase given to patients?

Answer 45

-IV... not a pill

Question 46

What is rasburicase contraindicated in?

Answer 46

- G6PD deficiency | - gives them hemolysis