Fitzy: Pharmacology of Gout and Hyperuricemia Flashcards
What transporter in the kidney will let us reabsorb urate?
-URAT1
Where does Uric acid come from?
- Purines
- fructos
- alcohol
What enzyme makes uric acid?
-Xanthine Oxidase
What are some other factors besides hyperuricemia that contribute to gout attacks in the first metatarsal phalangeal joint?
- temperature
- pH
- joint hydration: this is why there’s nocturnal pain
- Presence of altered matrix proteins, exposed cartilage fragments and nucleating debris
What are the two XO inhibitors?
- Allopurinol
- Febuxostat
What are the drugs that turn uric acid into a more soluble form?
- rasburicase
- pegloticase
- uricosolytics
What is the one anti inflammatory gout specific drug?
-colchicine
What is that unique MOA for Colchicine?
- 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
what is the mainstay of therapy of acute gout attacks in patients who have no contraindications to them?
-NSAIDS!
when do we have to use caution with NSAIDs?
- ulcers
- htn
- coronary disease
- fluid retention
- remember that the dose of NSAIDs needed to resolve gout attack are on the higher side
How much ibuprofen should a person with gout take?
-2 tabs three times a day is often insufficent! so they need to take a shit ton
What does colchicine do again?
- binds to tubulin, depolymerizes microtubules, and imparis migration of granulocytes
- thereby blunting inflammation
What is the maximum does for colchicine?
-12 tablets per episode
Is colchicine an analgesic?
-no
Does colchicine modify uric acid levels?
-no
What confers long term risks, such as osteoporosis and infection, but has low risk for short-term risks?
-corticosteroids
What aer the adverse effects of corticosteroids that we have to worry about?
- adverse effects on bp and blood sugar
- so if they have htn or uncontrolled diabetes mellitus
What are the 2 XO inhibitors?
- allopurinol
- febuxostate
- they inhibit urate biosynthesis
What are the 2 drugs that are uricosuric agents (URAT1 inhibitors)?
- Probenecid
- Sulfinpyrazone
- they enhance urate excretion
What are the recombinant urate oxidase enzymes?
- pegloticase
- rasburicase
- they enhance urate metabolism
What is the only uricosuric agent available in US?
-Probenecid
What is the 1st line urate lowering therapy (ULT) in gout?
- XO inhibitors
- allopurinol
- febuxostat
What accumulates as a result of tx with allopurinol and febuxostat?
-hypoxanthine is the best answer
What is the active metabolite of allopurinol?
- oxyurinol
- has long ass half life
Why is febuxostat better than allopurinol?
- has better and different adverse effect profile vs allopurinol
- can be used in patients with renal disease
What is that one wierd paradox thing with ULT?
-during the initial phase of ULT, there is an early increase in acute gout attacks
What do we give as well to people who are beginning ULT to decrease acute gout associated with initiation of ULT?
-colchicine or an NSAID
What is a big thing that we have to worry about with allopurinol and febuxostat?
-they inhibit metabolism of Xanthine drugs use in cancer chemotherapy, immunosuppression, asthma conferring risk of overexposure and requiring dose adjustments
What were the Xanthine drugs that build up when we inhibit XO?
- 6 mercaptopurine
- Azathioprine
- Theophylline
Which xanthine drug makes people edgy when they don’t clear it?
-theophylline
What is the black box warning with allopurinol?
- 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
What genotype do we have to worry about and make them avoid allopurinol?
- HLA-B*5801
- severe hypersensitivity to allopurinol
- Han Chinese, Thai descent
What drug combo is appropriate in some patients to achieve the serum urate target (<6mg/dL)?
- oral ULT
- oral uricosuric agent (probenecid)
What are uricosuric drugs?
- 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
What does probenecid do specifically?
- blocks URAT1 transporter on apical membrane of epithelium
- promotes excretion
When should uricosuric agents (probenecid) be avoided?
-in pts with risk/hx of nephrolithiasis or uric acid nephropathy
Should urate-lowering therapies be initiated during an acute attack?
- no
- they are of no benefit for acute gout
What is the paradox thing with aspirin?
- 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
What kind of a dose of aspirin do we need to give them to have a uricosuric effect?
-a very high dose
Will thiazide and loop diuretics help?
- no!
- they interfere with urate clearance by effects on multiple transporters in the prox renal tubule
- this causes uric acid retention
What is kind of the last stitch effort we use for gout?
-ULT with a urate oxidase recombinant enzyme (pegloticase) is appropriate for severe disease, failure, or intolerance to appropriately dosed XOI options
What does Pegloticase and rasburicase do?
-these drugs augment metabolic degradation of uric acid into allantoin
What do we use pegloticase for?
-hyperuricemia associated with malignancy (tumor lysis syndrome)
What do we use rasburicase for?
-approved for gout-associated hyperuricemia
How is pegloticase and rasburicase given to patients?
-IV… not a pill
What is rasburicase contraindicated in?
- G6PD deficiency
- gives them hemolysis
