Urate-lowering Therapy: Mechanism of Action and Gout Management (Nursing)

00:01 Now let's discuss the mechanisms of our urate-lowering therapies.

00:05 First, we're going to start with uricosuric drugs.

00:09 Now these drugs work at the level of the kidney.

00:12 Normally, after uric acid is filtered by the glomerulus, about 90% of it is reabsorbed in the proximal tubule through urate transporters, particularly URAT1 and the other organic transporters that we call OATSs.

00:27 Now uricosuric means a substance or a medication.

00:30 We're talking about medications that increase the excretion of uric acid in the urine.

00:35 So these drugs work by inhibiting the reabsorption of uric acid in the kidneys, which leads to higher levels of uric acid being eliminated in the urine.

00:45 Now this increased excretion of uric acid in the urine effectively lowers the level in the blood.

00:52 So you have lower serum levels.

00:54 Now I want to remind you, it's really important that your patients understand they don't want an additional problem.

01:00 They have to drink water.

01:03 Adequate hydration is essential with these medications because you want to prevent uric acid crystal formation in the urinary tract.

01:11 So that's why they need to drink lots of fluids and water to keep things being flushed through.

01:17 The primary uricosuric drug in the U.S. is probenicid.

01:20 Now there's other medications that have these similar uricosuric effects, right? One of them would include benzobromerone.

01:27 Now that has limited availability in the U.S.

01:30 And there's other medications that are used to treat other diagnoses that can also have a uricosuric effect.

01:37 So things like losartan, that's an antihypertensive, atorvastatin, something we use to control cholesterol, and phenofibrate, a lipid-lowering agent.

01:47 All of these medications can cause a uricosuric effect.

01:51 Another group of medications is xanthine oxidase inhibitors, or XOIs.

01:56 These meds take a different approach because they target uric acid production.

02:01 Xanthine oxidase is an enzyme, and this enzyme catalyzes the oxidation of hypoxanthine to xanthine and then xanthine to uric acid in the purine metabolism pathway.

02:13 So by inhibiting this enzyme, XOIs reduce the amount of uric acid produced by the body.

02:19 So the primary XOIs are allopurinol, our first-line agent, and febuxostat.

02:24 Allopurinol is structurally similar to hypoxanthine, and how allopurinol works is it permanently binds to that enzyme xanthine oxidase, thereby it inhibits the action of xanthine oxidase.

02:38 So after the patient takes the medication, allopurinol is converted in the body to the metabolite oxypurinol.

02:46 Oxypurinol is the compound primarily responsible for the long-term inhibition of xanthine oxidase because it remains active in the body much longer than the allopurinol itself.

02:56 So that's an extra benefit of allopurinol.

02:59 Febuxostat is a selective inhibitor of xanthine oxidase, and it differs from purines in its chemical structure.

03:06 It attaches to a different location on the xanthine oxidase enzyme compared to the allopurinol.

03:12 So this difference in binding location explains why patients who experience allergic reactions to allopurinol usually don't have similar reactions to febexistat, making it a valuable treatment option for those who just can't use the allopurinol.

03:24 If you like animals, this next discussion on uricase drugs is going to be particularly interesting to you.

03:30 You see, uricase is an enzyme, and it's something that most mammals have except humans.

03:37 Now this enzyme is important because it converts uric acid to allantoin, which is much more soluble and easily excreted.

03:44 But remember, we don't have it.

03:47 But the uricase drugs will provide an enzyme that I said most mammals have, but we as humans naturally lack.

03:54 So when I say animals, many animals including dogs, cats, rats, and most primates except humans and great apes naturally produce uricase.

04:04 This allows them to break down uric acid more completely.

04:06 Hence, you're not going to find a lot of gout in those animal populations.

04:11 There are two examples of uricase drugs that I'd like to take a look at.

04:16 The first one is pegloticase.

04:18 Now pegloticase is a modified or pegylated form of the enzyme, and it's used to treat severe gout that hasn't responded to other treatments.

04:28 Rasburicase has an even more special application.

04:30 It's another uricase medication, but it's primarily used to manage high uric acid levels during cancer treatment, for example, from tumor lysis syndrome.

04:39 So it's used to treat the high uric acid levels during cancer treatment rather than for long-term gout management.

04:45 Now when you're thinking about primary indications when you're managing gout with urate lowering therapy, the target is to reduce serum urate levels below six for most patients.

04:57 If they have a tophaceous gout or severe disease, you're going to want to keep that level below five.

05:03 Now tophageous gout, remember that's a chronic and advanced form of gout, and it has those hard nodules called tophi.

05:11 According to the 2020 American College of Rheumatology Guidelines, we consider initiating urate lowering therapy for patients that have the following types of conditions.

05:20 If the patient has recurrent gout flares, that's one or more a year with some certain conditions, if they have a need for long-term prophylaxis, if we have presence of the tophi, if there's evidence of joint damage from gout, if they have a history of urolithiasis or kidney stones, if they have chronic kidney disease, or if they have severe or polyarticular, meaning multiple joints where gout attacks are involved.

05:44 Now remember these guidelines have evolved.

05:46 They've evolved to recommend earlier intervention than previous guidelines, because we learned that with persistent hyperuricemia, even with infrequent attacks, can lead to silent crystal deposits and joint damage.

05:59 For most patients, allopurinol is our first choice because it's effective, it's safe, and it's also cost-effective.

06:06 Febuxostat is an alternative for patients who can't tolerate allopurinol or who have a contraindication to the use of allopurinol.

06:14 Now uric acid drugs like probenecid are particularly useful when under-excretion of uric acid is the primary cause of the elevated uric acid in the blood.

06:24 Now these drugs are less effective in patients with decreased renal function, so keep that in mind.

06:29 Pegloticase is reserved for patients with refractory chronic gout who haven't responded to or cannot tolerate the other therapies.