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Flashcards in Drugs for Gout Deck (28)
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1

What are some of the therapeutic goals for treating gout?

1. Increase excretion of uric acid 2. Inhibit inflammatory cells 3. Inhibit uric acid biosynthesis 4. Provide symptomatic relief (NSAIDs or steroids -- short-term)

2

Used within the first 24 hours 

NSAIDs:

Indomethacin

Naproxen 

3

What should NOT be used to treat gout? 

Aspirin -- inhibits uric acid secretion at low dose

4

Provides symptomatic relief in patients that can't take NSAIDs

Short term use

Adverse effects with extended use

Steroids

5

No effect on uric acid excretion 

Antimitotic: arrests cell division n G1 by interfering with microtubule and spindle formation 

Binds to microtubles in inflammatory cells = neutrophils: inhibits neutrophil activation and migration

Lessens the symptoms of inflammation

Colchicine 

6

How is colchicine metabolized? 

Oral administration

Rapid absorption but variability

Large volume of distribution 

Metabolized by CYP450 

Substrate for P-glycoprotein (transmembrane protein that eliminates drugs) 

7

What are some adverse effects of colchicine? 

Narrow therapeutic-toxicity window

GI: nausea, vomiting, diarrhea, abdominal pain 

Usually a latent period before symptoms 

Effects rapid proliferating cells of GI 

8

What are some contraindications of colchicine? 

Hepatic/renal disease (decrease dose or less frequent dosing)

Elderly patients

Especially if also taking CYP3A4 or P-gp inhibitor

Reasion = increase concentration of colchicine 

9

How is colchicine used therapeutically? 

Acute gout attacks (within hours)

Prophylactically in patients with chronic gout 

 

Tends not to be the drug of choice because of adverse effects

10

When is it appropriate to use prophylactical therapy for gout? 

Frequent attacks

Disabling attacks

Urate nephrolithiasis (uric acid stones) 

Urate nephropathy

Tophaceous gout: nodular masses of uric acid crystals (tophi) are deposited in different soft tissue areas of the body 

11

What are some non-pharmacologial measures individuals with gout should take? 

Abstain from alcohol

Weight loss

Discontinue medicine that impair uric acid excretion (aspirin, thiazide diuretics)

12

Inhibits terminal steps in uric acid biosynthesis 

Blocks xanthine oxidase 

Decreases plasma uric acid concentration, uric acid crystals dissolve

Allopurinol 

13

How is allopurinol metabolized? 

Prodrug

Structural analog of hypoxanthine 

Converted to oxypurinol by aldehyde oxidoreductase

Plasma half-life prolonged: 

allopurinol (1-2 hours) 

oxypurinol (18-30 hours) 

14

What are some adverse effects of allopurinol? 

Hypersensitivity: increases if taken with ACE inhibitors, thiazide diuretics, amoxicillin 

Acute gout attack: mobilizes tissue stores of uric acid, give the drug with colchicine or NSAID 

15

What are the therapeutic uses of allopurinol? 

Prevention of primary hyperurecemia of chronic gout 

Severe forms of gouty nephropathy, tophaceous deposits, renal urate stones 

Prophylactic treatment in secondary forms of hyperurecemia due to hematological disorders of anti-neoplastic therapy 

16

Non-purine xanthine oxidase inhibitor 

Forms a stable complex with both the reduced and oxidized form of xanthine oxidase and inhibits catalytic function in both states 

Febuxostat 

17

Comparison of Allopurinol and Febuxostat. 

  • Febuxostat is more potent than allopurinol 
  • Febuxostat is more effective than allopurinol in the subset of patients with imparied renal function
  • Incidence of adverse events (dizziness, diarrhea, headache, nausea) similar with both drugs
  • Incidence of CV side effects (antiplatelet trialists collaboration events) was numerically higher with febuxostat than allopurinol

18

Converts uric acid to allantoin (an inactive and water soluble metabolite of uric acid) 

PEGylated recombinant form of urate oxidase enzyme (uricase -- normally absent in humans)

Pegloticase

19

What are the pharmacokinetics of Pegloticase? 

Intravenous administration (every 2 weeks) 

Long half-life

20

What are some adverse effects of Pegloticase? 

Infusion site reactions

Gout flare: provide prophylaxis for acute gout flares

Immune response: can form antibodies directed at PEG portion of molecule

21

What is Pegloticase therapeutically used for? 

Refractory chronic gout

22

What are uricosuric agents? 

Give an example.

Something that increases the rate of excretion of uric acid 

 

Probenecid 

23

How does probenecid increase uric acid exretion? 

Increases uric acid secretion by competing with the renal tubular acid transporter so that less urate is reabsorbed 

24

What are the pharmacokinetics of Probenecid? 

Oral administration

Dose-dependent half-life

Plasma protein binding 

25

What are some adverse effects of probenecid? 

Some GI side effects

Ineffective in patients wtih renal insufficiency 

Contraindicated in patient with uric acid kidney stones

26

What is Probenecid therapeutically used for? 

Used for chronic gout but rarely in patients with any kidney disease or overproducers of uric acid...more likely to produce uric acid stones

27

What are some drug interactions with Probenecid? 

Interfere with renal excretion of drugs that undergo active tubular secretion, especially weak acids.

Inhibition of glucuronide conjugation of other drugs.

Methotrexate, Clofibrate, Palatrexate, Penicillin, Salicylates

28

Other gout drug interactions

Plasma levels of drugs that are metabolized by xanthine oxidase increase -- possibly to toxic levels when administered with allopurinol or febuxostat. 

 

Life-threatening toxicities are associated with administration of concomitant therapy with P-glycoprotein or CYP3A4 inhibitors or colchicine