Pharmacology of Gout and DMARDS

Question 1

How can gout be managed without taking medication?

Answer 1

• Lower urate levels with lifestyle modification/risk reduction
  
  • dietary changes
  • weight loss
  • reduce alcohol intake
  • examine medication list
    
    • (salicylates, diuretics etc.)

Question 2

What are 3 drugs used to treat acute gout attacks?

Answer 2

Mainly want to suppress inflammation and try and decrease symptoms (pain)

1. NSAIDs
2. Colchicine (if NSAID C/I)
3. Glucocorticoids

Question 3

• Which NSAIDs are recommended to treat acute gout?
  
  • MOA?
• Why wouldn’t you use aspirin?

Answer 3

• Naproxen or indomethacin
• NO ASPIRIN (at low doses)
  
  • because it is a salicyate so it will retain uric acid; so uric acid levels increase

MOA:

• Reversibly inhibit COX1 and COX2
  
  • block prostoglandin synthesis (anti-inflammatory)

Question 4

Main side effects of NSAIDs?

Answer 4

• Cardiovascular events
• GI toxicity

Question 5

• Colchicine used to treat?
  
  • MOA?
  • Major Side effects?

Answer 5

• Used to treat:
  
  • acute gout (2nd line after NSAIDs)
  • prophylactic value
• MOA:
  
  • binds and stabilizes tubulin to inhibit microtubule polymerization (G1 arrest)
    
    • impair neutrophil chemotaxis (adhesion) and degranulation
• Side effects:
  
  • GI (diarrhea)

Question 6

• What are two glucocoticoids that can be used to treat acute gout?
  
  • Administered?

Answer 6

• Prednisone, triamicnolone
• Administered:
  
  • oral, intra-articular or parenteral

Question 7

MOA of glucocorticoids?

Answer 7

• Metabolic, catabolic, anti-inflammatory and immunosuppressive effects
  
  • mediated by interaction with:
    
    • glucocorticoid response elements
    • inhibition of phospholipase A2
    • inhibition of transcription factors like NF-kB

Question 8

• Chronic gout is due to what two scenarios?
  
  • What can occur during treatment of chronic gout?
  • What is recommended for this?

Answer 8

• Due to either:
  
  • uric acid overproduction
  • uric acid under-excretion (mostly)
• Possibility of:
  
  • acute gout flares during treatment initiation
    
    • crystals can be broken down in the joint they are in and lead to an inflammatory response
• Recommended:
  
  • prophylactic colchicine/NSAIDs

Question 9

What two drugs inhibit xanthine oxidase in chronic gout treatment?

Answer 9

1. Allopurinal
2. Febuxostat

Question 10

• MOA of Allopurinal?
• Used to treat?
  
  • What does it increase the concentration of?

Answer 10

• MOA:
  
  • competitive inhibitor of xanthine oxidase
    
    • decreases conversion of hypoxanthine and xanthene to urate
      
      • deals with both excretion and production issues
• Used for:
  
  • Chronic gout
• Increases concentration of:
  
  • azathioprine and 6-MP
    
    • used in chemo; both normally metabolized by xanthine oxidase
    • can increase risk of toxicity

Question 11

• Probenecid is a uricosuric drug.
  
  • Used to treat?
  • MOA?
  • What else does it have an effect on?
  • Side effect?

Answer 11

• Used for:
  
  • chronic gout
    
    • 2nd line agents for under excreters
• MOA:
  
  • inhibits reabsorption of uric acid in proximal convoluted tubule in kidney
    
    • competitively inhibits URAT-1 transporter
• Drug interactions:
  
  • competes with same transporter as penicillins, MTX
    
    • can delay/inhibit excretion of penicillins
• Side effects:
  
  • exacerbate gouty attack
  • uric acid stone formation
    
    • ​need to stay hydrated because excreting lots of uric acid

Question 12

• What is Pegloticase and Rasburicase(MOA)?
  
  • What is it used to treat?
  • When is it used?

Answer 12

• Used for:
  
  • Rasburicase: hyperuricemia associated with malignancy
  • Pegloticase: chronic gout
• MOA:
  
  • recombinant uricase that catalyzes metabolism of uric acid to allantoin
    
    • more water soluble product
    • promotes excretion
• 3rd line treatment (IV)
  
  • if other treatments fail; severe cases

Question 13

Treatment of pseudogout?

Answer 13

• Due to pyrophosphate crystal deposition
  
  • in large joint, like knee
• Treatment similar to gout:
  
  • NSAIDs
  • Glucocorticoids
  • Colchicine (if necessary)

Question 14

• What are the 5 non biological DMARD drugs?
  
  • First line treatment?

Answer 14

1. Methotrexate (MTX)
2. Hydroxychloroquine (HCQ)
3. Sulfasalazine (SSZ)
4. Leflunomide
5. Azathioprine, cyclophosphamide (less common)

Question 15

4 biological DMARDs

Answer 15

1. TNFa inhibitors
2. IL receptor antagonists
3. Co-stimulation inhibitors
4. JK inhibitor (small molecule)

Question 16

What are the RA recommendation for treatments of early disease?

Answer 16

Methotrexate + (HCQ or SSZ)

Question 17

Methotrexate for RA: (non biological drug)

• MOA?
• Adverse effects?

Answer 17

• MOA:
  
  • Inhibits production of folic acid by competitively inhibiting dihydrofolate reductase (decrease DNA synthesis)
  • Inhbits DHFR and AICR transformylase
    
    • cause accumulation of extracellular adenosine
    • suppress B and T- cells
• Adverse effects:
  
  • hepatotoxic

Question 18

• How is hydroxychloroquine (nonbiological; HCQ) used in RA treatment?
• Major side effect?

Answer 18

• Not first line (made for malaria)
  
  • approved for people who haven’t responded to other drugs
  • usually combined with MTX
• Side effects:
  
  • Retinal toxicity
  • GI

Question 19

• Mechanism of Sulfasalazine (SSZ; nonbiological) in treatment of RA?
  
  • activated by?

Answer 19

• Combination of sulfapyridine (antibacterial) and 5-aminosalicylic acid (anti-inflammatory)
  
  • activated by colonic bacteria
• Sulfa drug to salicylate

Question 20

• Leflunomide (nonbiological DMARD) is used to treat?
• MOA?
• Adverse effects?

Answer 20

• Used for:
  
  • rheumatoid arthritis only
• MOA:
  
  • reversibly inhibits dihydroorotate dehydrogenase, preventing pyrimidine synthesis
    
    • suppress T cell proliferation
• Side effects:
  
  • Hepatotoxicity
  • Respiratory tract infections
  • Diarrhea

Question 21

• Azathioprine (non biological DMARD) is used to treat?
  
  • MOA?
  • Drug interactions?

Answer 21

• Used for:
  
  • RA
• MOA:
  
  • antimetabolite precursor of 6-mercaptopurine (6-MP)
    
    • inhibits lymphocyte proliferation by blocking nucleotide synthesis
• Drug interactions:
  
  • 6-MP is degraded by xanthine oxidase
    
    • toxicity is increased by allopurinal (inhibits XO)

Question 22

What are common side effects of the non biological DMARDs?

Answer 22

• GI effects,
• infection
• malignancy

(MTX, HCQ, SSZ, Leflunomide, Azathioprine)

Question 23

• What are the 5 TNFa inhibitor (biological DMARD) used to treat RA?
  
  • all of them are?

Answer 23

1. Etanercept
2. Infliximab
3. Adalimumab
4. Certolizumab
5. Golimumab

All monoclonal antibodies

Question 24

All TNFa inhibitors predispose patients to getting?

Answer 24

• infection; including reactivation of latent TB
  
  • since TNF is important in granuloma formation and stabilization

Question 25

* Etanercept is a TNFa inhibitor used to treat? * MOA?

Answer 25

* _Used for:_ * RA * **Fusion protein** * receptor for TNFa + IgG Fc) * produced by recombinant DNA * _MOA_: * **TNF decoy receptor**

Question 26

General MOA for TNFa inhibitors? (Infliximab, adalimumab)

Answer 26

* Anti-TNFa monoclonal antibodies * _MOA_: * **decrease TNFa receptor activation** so decrease inflammatory and immune response * decrease macrophage and T cell function * decrease joint inflammation, cartilage degredation and bone erosion

Question 27

* What are two IL receptor inhibitors used to treat RA? (biologic) * side effects for each?

Answer 27

1. **_Anakinra: anti IL-1 receptor_** * injection site reaction (IV) 2. **_Tocilizumab: anti IL-6 receptor_** * hyerlipidemia * TB (infections)

Question 28

* Co-stimulatory inhibitor (biological DMARD) to treat RA? * MOA?

Answer 28

* Abatacept * MOA: * binds to CD80/86 to prevent co-stimulatory signal on T cells

Question 29

* Rituximab can be used as biological DMARD to treat RA. * MOA? * Side effect?

Answer 29

* _MOA_: * **anti-CD20** monoclonal antibody * induce apoptosis of B-cell * _Side effect:_ * infusion reaction * **infection** * myelosuppression

Question 30

Side effects of Allopurinal?

Answer 30

* Steven Johnson Syndrome (drug reaction) * rash * Can cause drug reaction with eosinophilia and systemic symptoms

Question 31

* Side effect of Pegloticase? * Administered?

Answer 31

* Need to be administered **IV** * _Side effects:_ * anaphylaxis * can cause **hemolysis** in **G6PD deficiency** (bite cells when spleen removes Heinz bodies)