Gout Tx Flashcards
Discuss the steps of purine metabolism.
- Adenosine to Hypoxanthine then Xanthia via Xanthine oxidase
- Guanine to Xanthine
- Xanthine to uric acid via Xanthine oxidase
* no matter what uric acid is the dead end to purine metabolism
1/3 of uric acid - metabolism of dietary purines
2/3 of uric acid - metabolism of endogenous purines
The majority of the uric acid is produced by the liver,, and excreted by the kidneys. Only a minor portion is excreted in the feces.
What is the pathophysiology of gout?
Uric acid is an insoluble metabolite that when accumulates leads to the formation of urate crystals that deposit in tissues (esp joints and kidney – even more specifically the first metatarsophalangeal joint). The deposition of these crystals initiates an inflammatory process leading to acute gout attacks.
Involvement of gout at the first metatarsophalangeal joint = podagra
Inflammatory rxn..
- Urate crystals recognized by macrophages
- macrophages take up urate crystals
- macrophages release IL-1B
- IL-1B binds endothelium which secretes IL-8 to attract neutrophils
- Neutrophils accumulate in the joint and release more IL-1B to continue the cycle (positive feedback)
Gout is most commonly due to under excretion of uric acid rather than overproduction of uric acid.
What comorbidities are seen with gout?
- CV complications - HTN, Coronary heart disease, HF< stroke
- Renal dysfunction - kidney disease, kidney stone
- Metabolic disorders - DM 2, Metabolic syndrome, Obesity
* Hyperuricemia and gout are independent risk factors of these conditions, but rather these conditions contribute to increased mortality rate within pts with gout
What drugs are used in the management of acute gout?
- NSAIDs
- Colchicine
- Glucocorticoids
What is the first line drug for acute gout?
NSAIDs (esp Indomethacin)
*Do not use Aspirin as it competes with uric acid in the proximal tubule of the kidney thereby increasing gout within the circulation and tissues/decreasing excretion
AE of NSAIDs - bleeding, salt and water retention (why?), renal insufficiency
What is the role of Colchicine in the tx of gout?
Colchicine is an anti-mitotic agent used to treat gout. It binds to tubulin thereby inhibiting its polymerization and preventing formation of microtubules. By inhibiting tubulin function, there is a disruption in mobility of granulocytes to migrate to the affected area, cell division and also inhibits synthesis and release of leukotrienes.
AE Colchicine - nausea, vomiting, abdominal pain, diarrhea
Chronic administration may lead to…. myopathy, neutropenia, aplastic anemia, alopecia
*do not use during pregnancy
**NSAIDs have replaced Colchicine due to effects of GI disturbance (diarrhea) seen with Colchicine therapy
What is the role of glucocorticoids in the treatment of gout?
Glucocorticoids have anti-inflammatory and immunosuppressive effects on gout. When acute attacks occur in a single joint and DO NOT respond to NSAIDs or colchicine, a depot preparation of glucocorticoids are directly injected in to the joint.
What types of drugs lower plasma urate concentration?
- decrease uric acid synthesis - Allopurinol. Febuxostat
- enhance uric acid excretion - Probenecid
- Enhance uric acid metabolism - Pegloticase
Allopurinol?
First line pharmaceutical agent to decrease uric acid level. It is a purine analog that inhibits xanthine oxidase [hypoxanthine to xanthine and xanthine to uric acid]. Allopurinol has also been seen to facilitate the dissolution of tophi.
AE Allopurinol - HSN rxn (esp skin rashes), Steven-Johnson syndrome, increased incidence of acute attacks of gouty arthritis due to mobilization of tissue stores of uric acid
What is co-administered with Allopurinol for the first 4-6 months of administration?
NSAIDs or colchicine to reduce chance of acute attack of gout
What drug interactions should be watched with the use of Allopurinol?
Mercaptopurine (anti-cancer drug) and Azathioprine (immunosuppressant) are purine analogues that are metabolized by xanthine oxidase. Inhibition of xanthine oxidase by Allopurinol can lead to an increased concentration of these drugs to toxic doses. A dose reduction of these drugs is required.
Febuxostat?
Drug that reduces uric acid synthesis, similar to Allopurinol. It has similar AE as well as the same drug interaction with azathioprine and 6-mercaptopurine.
It is structurally unrelated to allopurinol.
Probenecid?
This drug enhances uric acid excretion within the kidneys. Urate is filtered, secreted, and reabsorbed by the kidneys - and over 90% of the urate that is filtered is reabsorbed leaving only 10% to be excreted.
Probenecid is a uricosuric drug that inhibits the Urate transporter 1 (URAT1) in the luminal side of the kidney thereby inhibiting the reabsorption. This leads to a lower plasma urate levels and dissolution of urate crystals.
AE - mild GI irritation, mild HSN rxn, increase risk of uric acid renal stones therefore increased/ample fluid intake should be maintained to minimize risk
What should be co-administered with probenecid to limit renal stone formation?
Sodium bicarb or potassium citrate to maintain alkaline urine. *do not give this drug to pts with nephrolithiasis or with overproduction of uric acid
What drugs inhibit URAT1?
Probenecid
Losartan (only ARB that does this)
Fenofibrate (lipid lowering agent that increases LPL)
**all three of these drugs lower uric acid levels in the plasma
