(16) Anti-Gout Drugs

What 2 diseases we talk about here?

• Gout

• Arthritis

What we talk about in Gout?

• Patho

• Treatment Goals

• Treatment

Gout

Patho

Gout = too much uric acid → urate crystals deposit in joints → inflammation + severe pain

Hyperuricemia can result from:

• Overproduction of uric acid

• Underexcretion of uric acid (Most patients with gout are underexcreters)

Urate crystals deposit in the joints/cartilage and cause recurrent acute arthritis.

Gout

Treatment Goals

• Relieve an acute gout attack

• Prevent future attacks

• Lower uric acid

Gout

Gout drug groups (TREATMENT)

Drug/class	Main job
NSAIDs / corticosteroids	↓ pain + inflammation (DO NOT FIX HIGH URIC ACID)
Colchicine (Colbenemid)	↓ inflammatory-cell migration ((DO NOT FIX HIGH URIC ACID)
Allopurinol (Zyloprim)	↓ uric acid synthesis
Probenecid (Benemid)	↑ uric acid excretion

 NSAIDs

Know:

• First-line for acute gout pain/inflammation

• Work best when started within the first 24 hours

Examples:

• celecoxib

• indomethacin

• naproxen

• ibuprofen

Corticosteroids

Used when NSAIDs cannot be used.

Can be:

• injected into the joint

• given systemically/orally

Arthritis

topics discussed

• Treatment options

  • NSAIDs

  • DMARDs

    • Non-biologic

      • Methotrexate (Rheumatrex)

    • Biologic

      • Etanercept (Enbrel) - MAIN

        • TNF-α blockers

Arthritis

NSAIDs vs DMARDs

NSAIDs → ↓ pain/inflammation

BUT: Do NOT stop the disease from getting worse.

🔴 DMARDs (Disease-Modifying Anti-Rheumatic Drugs)

→ slow/stop disease progression

→ ↓ future joint damage

Easy memory

NSAIDs = symptoms

DMARDs = disease

MASTER CHART - Gout

C

A
P

MASTER CHART - RA

M
E

STOP HERE

COLCHICINE

topics discussed

• main use/idea

• mechanism

• side effects

• PK

COLCHICINE

main use/idea

• Acute gout

• Prevention/prophylaxis

COLCHICINE

Mechanism

Colchicine binds tubulin

→ causes microtubule depolymerization

→ neutrophils cannot move normally

→ ↓ neutrophil migration into the inflamed joint

→ ↓ inflammation

Also:

• blocks cell division by binding mitotic spindles

• inhibits LTB₄ synthesis

COLCHICINE

side effects

GI effects are DOSE-LIMITING.

Know:

• Nausea

• Vomiting

• abdominal pain

Long-term use

Because colchicine inhibits cell division:

→ rapidly dividing cells are affected

→ possible:

• Agranulocytosis

• Aplastic anemia

• Alopecia

• Bone marrow suppression

COLCHICINE

PK

Enterohepatic circulation

→ drug gets recycled in bile

→ long half-life of about 30 hours

Only 10–20% is excreted in urine.

ALLOPURINOL

topics discussed

• main use/idea

• mechanism

• side effects

• PK

• IMPORTANT DRUG INTERACTIONS

ALLOPURINOL

main use/idea

• Used for chronic gout

  • Does not mainly treat the immediate pain of an acute gout attack

• Helps dissolve tophi/crystals

• Helps prevent further kidney damage (nephropathy)

  • Cannot fix kidney damage that already happened

ALLOPURINOL

MECHANISM

• Allopurinol blocks xanthine oxidase (XO) → ↓ uric acid production

• Normal pathway:

  • Purines → hypoxanthine → xanthine → uric acid

• Important details:

  • Allopurinol = competitive XO inhibitor

  • Alloxanthine/oxypurinol = active metabolite → long duration of action

  • Oxypurinol = noncompetitive XO inhibitor

ALLOPURINOL

SIDE EFFECTS

INITIAL GOUT FLARE

• When allopurinol is first started:

  • ↓ uric acid in blood
    → uric acid crystals in tissues begin to dissolve/mobilize
    → can trigger an acute gout attack

• So initially:

  • NSAID and/or colchicine may be used to help prevent/manage the flare.

ALLOPURINOL

PK

• Active orally

• Neither allopurinol nor oxypurinol is bound to plasma proteins

ALLOPURINOL

IMPORTANT DRUG INTERACTIONS

6-Mercaptopurine (6-MP)
Allopurinol ↓ 6-MP metabolism
→ ↑ 6-MP levels
→ reduce 6-MP dose by about 75%

Oral anticoagulants
Allopurinol ↓ their metabolism
→ ↑ anticoagulant effect

Cyclophosphamide
→ can increase risk of bone marrow suppression

Febuxostat

topics discussed

• main use/idea

• Allopurinol vs. Febuxostat

• side effects

Febuxostat

main use/idea

nonpurine XO inhibitor → ↓ uric acid production

Febuxostat

Allopurinol vs. Febuxostat

Allopurinol

• purine analog

• active metabolite

Febuxostat

• nonpurine

• inactive metabolites

Both:

→ ↓ uric acid

→ used for chronic gout

Febuxostat

side effects

Black Box: Cardiovascular risk

Know:

• MI

• Stroke

Other side effects:

• nausea

• diarrhea

• liver abnormalities

• headache

Can also cause an initial gout flare.

PROBENECID

topics discussed

• main use/idea

• mechanism

• drug interactions

PROBENECID

main use/idea

Probenecid = uricosuric

Uricosuric = increases uric acid excretion

PROBENECID

Mechanism

• Normally: uric acid gets filtered → much of it gets reabsorbed

• Probenecid: competes with uric acid at URAT-1

  • → ↓ uric acid reabsorption

  • → ↑ uric acid stays in urine → ↑ uric acid excretion

PROBENECID

drug interactions

1. Low-dose salicylate + Probenecid → ↓ probenecid effect

2. Penicillin + Probenecid → ↓ penicillin secretion → penicillin stays in the body longer

PEGLOTICASE

main topics discuessed

• main use/idea

• mechanism

• side effects

PEGLOTICASE

main use/idea

Severe chronic refractory gout = gout that did not respond to other treatments.

PEGLOTICASE

 Mechanism

Uric acid

→ Pegloticase

→ Allantoin

→ soluble

→ excreted

→ ↓ uric acid

PEGLOTICASE

side effects

• Anaphylaxis

• hypersensitivity

• infusion reaction

• initial gout flare

Methotrexate

topics discussed

• main use/idea

• mechanism

• side effects

Methotrexate

main use/idea

First-line for moderate-to-severe RA

Know:

• low weekly dose

• NOT daily

• can be combined with other DMARDs

Methotrexate

Mechanism

folate antimetabolite

→ ↓ DNA synthesis

→ ↓ immune activity

→ ↓ inflammation

Methotrexate

side effects

Common

• GI: nausea, vomiting, diarrhea

• Fatigue

• Mouth/mucosal ulcers

• ↑ liver enzymes

Serious

• Hepatotoxicity = liver damage

• Kidney damage

• Bone marrow suppression

• Lymphoma

Pregnancy — BIG one

• Contraindicated in pregnancy

• Men: avoid fathering a child for at least 3 months after the last dose

Leucovorin Used after methotrexate → helps ↓:

• GI side effects

• liver-test abnormalities

LEFLUNOMIDE

topics discussed

• main use/idea

• mechanism

• side effects

• Methotrexate vs. Leflunomide

LEFLUNOMIDE

main use/idea

• use when methotrexate cannot be used

• can add it if methotrexate is not working enough

LEFLUNOMIDE

Mechanism

Leflunomide inhibits dihydroorotate dehydrogenase

→ ↓ ribonucleotide synthesis

→ cell stops in G1

→ ↓ T-cell growth

→ ↓ inflammation

LEFLUNOMIDE

Side effects

• Diarrhea

• ↑ liver enzymes

• ↑ BP

• flu-like symptoms

• alopecia

• contraindicated in pregnancy

Hydroxychloroquine/chloroquine

• antimalarial

• slows bone damage

• RA mechanism = unclear

D-penicillamine

• cysteine analog

• slows bone destruction

• mechanism = unclear

ETANERCEPT

topics discussed

• mechanism

• side effects

• combinations

ETANERCEPT

Mechanism

• Etanercept are TNF-α blockers and binds to TNF-α (inflammatory cytokine)

  • TNF cannot bind its receptor (TNFR1/TNFR2)

  • ↓ inflammation

  • ↓ joint damage progression

Easy memory

Etanercept traps TNF.

ETANERCEPT

Side Effects

🔴 Biggest concern = INFECTION

Etanercept suppresses immune activity → ↑ serious infection risk

Therefore:

• Screen for TB before starting

• Do NOT start if the patient already has an active infection.

🔴 Black Box warnings

• Serious infections

• Malignancy

Other effects to recognize:

• lymphoma

• skin cancers

• demyelinating disease

• heart failure

• liver disease

ETANERCEPT

Combinations

• Do NOT combine with another biologic BUT:

• Can combine with a non-biologic, such as methotrexate.