Bahouth - Hyperuricemia/Gout Pharm Flashcards
1
Q
What is hyperuricemia?
A
- Concentration of uric acid in the plasma is >7mg/dL
- Rubbing of crystals against soft tissues of the joint can cause pain
2
Q
What are the causes of hyperuricemia?
A
- Metabolic (10%):
1o: enzyme abnormalities -> PRPP surplus (rate-limiting step) or HGPRT deficiency
2o: increased purine biosynthesis -> certain blood disorders or chemo/radiation
- Renal (90%): excreting <0.7g/d (1.0g/d is normal)
1o: kidney disease (renal failure) -> low GFR, excrete normal levels of UA only at higher than normal plasma levels
2o: long-term diuretic therapy (vol depletion + enhanced tubular reabsorption of UA) or toxemia of pregnancy (swollen glomerular tufts)
3
Q
What are the therapeutic aims in the tx of gout?
A
- Terminate an acute attack
- Prevent recurrence of gouty arthritis (flare-ups)
- Reverse or prevent complications of deposited ureate crystals -> can deposit in joints and behind the ear, causing pain
- Prevent other factors associated with disease: treat HTN, obesity, and hyper-TG
- Prevent formation of (ureate) kidney stones bc these can cause kidney failure
- Remember: 1st line of therapy is behavioral change (i.e., consuming less red meat and chicken)
4
Q
What is Colchicine? MOA?
A
- Natural product for the tx and prevention of acute gouty arthritis
1. Does NOT treat any other form of arthritis bc no anti-inflammatory or anti-pyretic effects, and doesn’t lower uric acid concentration in blood - MOA: depolymerization of microtubules
1. Poly’s move by depolymerizing/repolymerizing their MT’s, so colchicine prevents their mvmt
2. Poly’s normally die when trying to destroy the crystals and release pro-inflam & pain cytokines
3. Phagocytosis also requires depolymerization of MT’s —> colchicine blocks immune response, terminating acute gout attack - Sometimes taken 1x per day, 5d/week for up to 1 yr
5
Q
What are the therapeutic uses and side effects of Colchicine?
A
-
Therapeutic uses:
1. To terminate acute attacks of gout and prevent receurrence of gouty arthritis
2. In familial Mediterranean fever -
Side effects:
1. GI disturbances, like N/V, diarrhea, anorexia, cramping (acute): sign you have given too much (can be difficult to dose correctly)
2. Blood dyscrasias/bone marrow suppression, multi-organ damage (chronic)
3. Monitoring: CBC, serum ALK PHOS -
NOTE: no specific antidote agent for colchicine, so impaired renal/hepatic func can lead to elevated serum drug levels and INC toxicity -> myopathy (prox weakness and elevated serum CK), peripheral neuropathy, and rhabdomyolysis, esp. if overdose (NOT removed by dialysis)
1. De-acetylated in liver, excreted via biliary and renal mechs
6
Q
What is the MOA of Indomethacine, and how is it used therapeutically to treat gout?
A
-
COX-INH used to tx a variety of inflam conditions -> blocks ability of immune response to attack ureate crystals, helping w/pain
1. Analgesic, antipyretic, INH leukocyte motility - Preferred agent of some physicians for acute gouty arthritis due to the AE profile of colchicine
7
Q
What are the dosing regimen, and potential toxic effects of Indomethacin?
A
- 50mg 3x daily w/effective antacid regimen -> only given 3-5 days, then switch to milder NSAID like Ibuprofen to prevent devo of peptic ulcer
- Other toxic effects:
1. GI: N/V, ulcers
2. Hematopoietic disorders
3. CNS severe frontal headaches
4. Antagonizes Furosemide and HCTZ
8
Q
What is the MOA of Allopurinol?
A
-
Suicide INH of biosynthesis of uric acid
1. Competitive INH of xanthine oxidase: binds active site, and reversibly INH enzyme
2. Metabolized to oxypurinol bc also a substrate for XO: metabolite is a non-competitive INH of XO that binds enzyme irreversibly, and kills it - Xanthine, hypoxanthine very soluble in H2O, so you can raise their concentrations to high levels w/o them precipitating out
9
Q
What are the therapeutic effects of Allopurinol?
A
- Reduces plasma level and urinary excretion of UA
- INC plasma levels and urinary excretion of oxypurine precursors like xanthine and hypoxanthine
-
Facilitates dissolution of UA crystals in joints, kidney
1. Crystals dissolve into UA bc plasma conc below solubility (crystals pose a danger to the pt)
2. Note: flare-ups can occur, so may give NSAIDs - Prevents formation of UA kidney stones, which can cause renal failure
10
Q
What are the therapeutic uses for Allopurinol?
A
-
1o hyperuricemia of gout from enzyme abnormalities (HGPRT, PRPP), and kids w/familial juvenile hyper-uricemic nephropathy
1. Only drug available for these kids, and usually prescribed for life (can save them from nephropathy and/or renal failure) - 2o hyperuricemia due to hematologic disorders (MM) or chemo
- Pts w/crystals in joints can also benefit, but need NSAIDs to prevent flare-ups during mobilization of ureate crystal
11
Q
What are the AE’s with Allopurinol?
A
- INC incidence of acute gout: from dissolved crystals
- Hypersensitivity rxns like dermatitis (2%) & exfoliative dermatitis (potentially lethal) -> desensitize w/low dose of allopurinol or substitute oxypurinol
- LFT’s e/6 wks, then e/6 months
- Interacts w/6-MP, which is metabolized by XO -> DEC 6-MP dose by at least 70%
- DO NOT give these pts Ampicillin and related AB’s bc INC risk of dermatitis and exfoliative dermatitis
12
Q
What is Febuxostat? MOA?
A
- XO inhibitor approved last year
- Potent INH of both oxidized AND reduced forms of XO -> enzyme-INH complex very stable (Allopurinol only INH oxidized form)
- Structurally unrelated to Allopurinol; direct inhibitor rather than allosteric
- Lowers urate concentrations by DEC urate levels
13
Q
What are the clinical uses and indications for Febuxostat?
A
- More potent than Allopurinol in lowering UA levels, and has less side effects at regular, 80mg dose
- Main indication to lower urate levels in pts who have adverse symptoms w/Allopurinol, like hypersensitivity
- Can be used in patients with mild to moderate renal impairment (unlike Allopurinol)
- Have to give a prophylactic med for acute attacks like NSAID or Colchicine, just like with Allopurinol
- Few patients cannot tolerate taking this drug
14
Q
What are the side effects of Febuxostat?
A
- Generally mild
- 2-3% of pts have transaminase elevations >3x the upper limit
15
Q
What is a uricosuric agent? How is UA handled in the kidney?
A
- INC urinary excretion of uric acid
- UA is freely filtered at glomerulus -> small molecule
1. In PCT, all filtered uric acid is reabsorbed by early segments, then secreted again from blood into tubular fluid, then partially reabsorbed in the brush border
2. Difference between what is secreted and reabsorbed at brush border is what is lost
16
Q
What is the MOA of Probenecid?
A
- Uricosuric agent: INC excretion of uric acid
- INH transport of organic (anions) across epi barriers
-
Interferes with UA reabsorption by organic acid transporter in brush border of the proximal tubule
1. Sm molecule secreted in tubules via organic acid transporters (does NOT affect UA secretion)
2. Interferes/competes w/UA for reabsorption by the brush border transporter, which has limited ability to transport the two molecules -> more uric acid remains in tubular fluid, and thus in urine
19
Q
What is Pegloticase?
A
- Bio-uricolytic (urate oxidase analog) agent
1. Urate oxidase enzyme in almost all mammals, but not ppl -> lowers UA levels by converting it to allantoin, benign end metabolite easily excreted in urine - Recombinant, PEGylated formulation (urate oxidase + polyethylene glycol to INC half-life) of a modified pig urate oxidase
- New way of reversing severe complications of uric acid deposition in the joints
- Given IV since it is an enzyme -> for small subset of pts in whom all other drugs have failed (with tophi)
