(11) Anti-Gout Drugs

What is Gout?

• ↑ uric acid → monosodium urate crystals form → crystals deposit in joints → inflammation + pain

• inflammatory arthritis common in men

Gout: Lifestyle factors

• high meat/seafood intake

• excessive alcohol

• emotional stress/physical trauma

Why crystals form?

• Uric acid is not very water-soluble.

• Urate monoanion is much more soluble.

• But if urate gets too high, even it cannot stay dissolved.

• It precipitates → forms crystals → deposits in joints → gout.

uric acid facts

• uric acid pKa = 5.7 (more acidic group) and 10.3 (more basic group)

• At body pH, it is mainly the urate monoanion.

Treatment Strategies

Strategy	What you are doing	Drugs
Acute gout/prophylaxis	↓ inflammation	Colchicine
Chronic gout	↑ uric acid excretion	Probenecid, Lesinurad
Chronic gout	↓ uric acid formation	Allopurinol, Febuxostat

• Also know acute gout can involve NSAIDs such as indomethacin/naproxen and glucocorticoids.

COLCHICINE

topic overview

• structure

• metabolism

• fun facts

COLCHICINE

fun facts

• treats the inflammation, NOT the uric acid.

• Can be used with probenecid.

COLCHICINE

Structure

• Several methoxy groups (oxygen attached to a methyl group (CH₃):)

• Contains an amide (a carbonyl (C=O) attached to a nitrogen (N).

COLCHICINE

Metabolism

Phase I metabolism

• CYP3A4 O-dealkylation = minor

  • remove the carbon group from O

• Esterase amide hydrolysis = major

  • break the amide bond with water

PROBENECID

topics discussed

• mechanism

• structure

• metabolism

• fun facts

PROBENECID

mechanism

• URAT1 normally reabsorbs uric acid in the kidney.

  • Reabsorption = uric acid goes from the kidney tubule back into the body.

• Probenecid blocks URAT1 → ↓ reabsorption → ↑ uric acid excretion → ↓ serum uric acid.

PROBENECID

Structure

Recognize:

• Carboxylic acid = acidic

• Tertiary sulfonamide = neutral, NOT acidic

• 2 propyl groups

REFRESHER ONLY:

• Primary sulfonamide: N has 2 H

• Secondary sulfonamide: N has 1 H

• Tertiary sulfonamide: N has 0 H

PROBENECID

fun facts

• Poorly soluble in water/acidic media (like stomach)

• Highly soluble in alkaline media (it loses H and becomes -)

• Can cause mild GI irritation.

PROBENECID

Metabolism

• ALL metabolites are ACTIVE → extended/longer duration of action (THAT’S WHY MOST IMPORTANT)

• Phase 1:

  • (1) Propyl group → ω-oxidation → primary alcohol → aldehyde → carboxylic acid

    • Primary alcohol → alcohol dehydrogenase

    • Aldehyde → aldehyde dehydrogenase

  • (2) N-dealkylation can also occur

• Phase II → glycine conjugation

PROBENECID

Metabolism - draw it out

LESINURAD

topics discussed

• mechanism

• structure

• fun facts

• metabolism

LESINURAD

mechanism

• same uric-acid-excretion mechanism as probenecid.

Atropisomers

the same molecule can exist in two stable 3D shapes because rotation around a bond is restricted.

LESINURAD

Structure

• 2 stable atropisomers

• Similar idea to chirality, BUT no chiral centers, — the difference comes from restricted bond rotation

• Form 1 half-life = ~3.8 hr

• Form 2 half-life = ~6.2 hr

  • Therefore form 2 lasts longe

LESINURAD

Metabolism

• CYP2C9 = main Phase I CYP

  • CYP2C9 can oxidize near the cyclopropyl group (3-carbon ring.)

  • It can also oxidize the aromatic ring → epoxide

    • Epoxide → can form reactive oxygen species → possible connection to kidney toxicity

LESINURAD

Metabolism - show me

LESINURAD

fun facts

1. Black-box warning - ACUTE KIDNEY FAILURE

2. Lesinurad MUST be used with a xanthine oxidase (XO) inhibitor.

   1. Do not use alone → kidney-failure concern increases!

3. Drug interactions

   1. CYP2C9 inhibitor → ↓ lesinurad metabolism → ↑ lesinurad concentration → ↑ toxicity risk

      
      

   2. CYP2C9 substrates (like NSAIDS) can also compete.

      1. Professor connected this to NSAIDs, because many NSAIDs use CYP2C9 and may be used with gout drugs.

Explain the route to make uric acid - verbally

• key route: Hypoxanthine → XO → Xanthine → XO → Uric acid

  • XO = xanthine oxidase

• they are multiple purine routes to uric acid. examples below:

  • Adenine (purine) → hypoxanthine → xanthine → uric acid

  • Guanine (purine) → xanthine → uric acid

Explain the key route to make uric acid - draw it out

What is the mainw way to ↓ uric acid formation?

Block XO, which is done by ALLOPURINOL and FEBUXOSTAT

ALLOPURINOL

topic overview

• mechanism

• structure

• metabolism

ALLOPURINOL

mechanism

• Allopurinol =purine like/ hypoxanthine mimic

• Hypoxanthine + xanthine ↑ and are excreted.

ALLOPURINOL

Structure

• Allopurinol looks very similar to hypoxanthine.

  • Hypoxanthine = XO substrate
    Allopurinol = XO inhibitor

• The important structural difference discussed is the position of a nitrogen.

ALLOPURINOL

Metabolism

• Allopurinol is BOTH:

  • XO inhibitor

  • XO substrate

• Allopurinol → XO → Alloxanthine

• Then: Alloxanthine also inhibits XO

• Therefore: active metabolite → extended duration of action.

ALLOPURINOL

Metabolism - draw it out

FEBUXOSTAT

topics overview

• fun facts

• structure

• metabolism

FEBUXOSTAT

fun facts

• Major comparison 1

  • Allopurinol = purine-like / hypoxanthine mimic

  • Febuxostat = first NONPURINE

  
  

• Comparison 2

  • Fewer side effects than allopurinol

  • used when a patient cannot tolerate allopurinol

  • Allopurinol is generally used first.

• Comparison 3 = Duration

  • Allopurinol → active metabolite → longer duration

  • Febuxostat → more inactive metabolites → shorter duration than allopurinol

FEBUXOSTAT

Structure - draw it out

Remember, Neha Chopra is OG, but Neha Sharma is Copy Cat

FEBUXOSTAT

Metabolism

• Phase 1

  • CYP1A1:

    • O-dealkylation → phenol

    • ω−1 oxidation

  • CYP2C9:

    • ω oxidation

      • Primary alcohol → carboxylic acid

• Phase II → glucuronide conjugation

FEBUXOSTAT

Metabolism - draw it out