Gout Study Guide Answers- Khan

Causes of Gout (Risk Factors)

• Purine rich diet

• Obesity

• Kidney Disease

• Drugs that increase uric acid

• male

• age

• etc.

Know the pathway of uric acid synthesis and metabolism

• start with adenine or guanine/ Adenine has 1 extra step

• IF adenine: Adenine→ Hypoxanthine→Xanthine→Uric Acid→Allantoin→ Urea+Glyoxylic Acid

• IF Guanine: Guanine→Xanthine→Uric Acid→Allantoin→ Urea+Glyoxylic Acid

be able to identify the structure of adenine

be able to identify the structure of guanine

Discuss treatment strategies of gout

• Prevent/Relief pain and inflammation

• Increase renal excretion of uric acid

• Reducing formation of uric acid

• Enhance metabolism of uric acid

*****Summary: reduce pain/swelling and reduce uric acid in body

List agents used to treat gout

• NSAIDs

• Colchicine

• Steroids

• Uricosurics- Probenecid

• Xanthine Oxidase Inhibitors- Allopurinol, Febuxostat

• Enzymes- Pegloticase

List commonly used NSAIDs used to treat gout

• Indomethacin

• Naproxen

• Sulindac

• Celecoxib

NSAID ADRs

• renal

• GI

• CV

• bleeding

List commonly used steroids for treatment of gout

• prednisone

• prednisolone

• Methylprednisolone

ROAs for steroids used for gout

• PO

• IM

• IV

• Intra-articular

ADRs for steroids for gout

• elevated blood glucose

• elevated BP

• CNS

  • insomnia

  • mood changes

Receptors used by steroids for gout

• Nuclear receptors

  • Steroid binds to CBG outside cell. Steroid comes in an binds to HSP90. HSP90 leaves and dimer is formed (steroid-receptor dimer is activated). Dimer travels inside nucleus and effects transcription.

Advantage of using Intraarticular Injections for Gout

• More localized, so less GI ADRs

Prednisone is converted to Prednisolone in what organ?

liver

Colchicine MOA

• MOA: prevents the formation of microtubules!

  •  Why does that matter? No microtubules= no cell division= no neutrophils = less inflammation

Colchicine Therapeutic Effects

• ONLY ANTINFLAMMATORY

  • NOT AN ANALGESIC

  • NO effects on renal excretion of uric acid or conc in blood

Colchicine GI ADRs

• nausea

• vomiting

• diarrhea

• stomach pain

• hemorrhagic enteropathy

WHY GI effects? Significant enterohepatic circulation

Colchicine Contraindications

• liver/kidney impairments

Colchicine Drug Interactions

• CYP34A Inhibitors

• P-gp Inhibitors

What are uricosurics? Name the drug from this category.

• uricosurics are agents that increase excretion of uric acid

• Drug - Probenecid

Probenecid:

• MOA

• Drug Interactions

• Precautions

• MOA- decrease reabsorption, Probenecid competes with urate for URAT1 protein, urate cannot be reabsorbed

  • URAT1 is an ANTIPORTER

• Drug Interactions- Inhibits renal clearance of:

  • MTX

  • Aspirin

  • PCN

• Precautions- not for patients with:

  • Nephrolithiasis (kidney stones

  • CrCl <30 ml/min

Probenecid ADRs

• GI irritation(take w food),

• Hypersensitivity,

• INCREASE FLUID INTAKE,

• Acute GOUTY ATTACK

How is Allopurinol different from febuxostat structurally?

-        Allopurinol is derived from purines, Febuxostat is non-purine.

-        Febuxostat is completely synthetic it has two rings, one phenyl, one thiazole

-        Allopurinol is 2 nitrogen heterocycles

Structure of allopurinol

Structure of oxypurinol

MOA of Febuxostat versus Allopurinol

• Allopurinol MOA:

  • inhibits xanthine oxidase

    • enzyme used in oxidation of hypoxanthine and xanthine to uric acid

  • xanthine oxidase metabolizes allopurinol to oxypurinol and that inhibits the enzyme

  • decrease uric acid levels in plasma and pee

• Febuxostat MOA:

  • Forms complex with xanthine oxidase

Drug Interactions of Xanthine Oxidase Inhibitors (Allo and Feb)

DO NOT TAKE:

• Azathioprine,

• 6-mercatopurine

ADRs of Xanthine Oxidase Inhibitors (Allo and Feb)

For both: hypersensitivity rxns, acute gout attack, nausea

ONLY Febuxostat: INCREASE RISK OF CV DEATH

Pegloticase:

• MOA

• ADRs

MOA: converts uric acid to allantoin

ADRs: gout flares, Ab formation

Boxed Warnings of Pegloticase

• Anaphylactic Rxns

• In patients with G6PDH deficiency- hemolytic anemia, methemoglobinemia

How is rasburicase different from pegloticase?

-        Rasburicase is used to treat tumor lysis syndrome

-        Not attached to polyethylene glycol

-        ADRs and warnings same as pegloticase

For probenecid as you increase alkyl substitution on the nitrogen in its structure you ___________ activity.

a. increase

b. decrease

a. increase