drugs for gout

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Drugs for Gout

Pharmacology and Toxicology

Musculoskeletal System

Third Year Medical Students

Faculty of Medicine

The Hashemite University

Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved1

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Gout

• Gout: “the most common crystal-inducedarthropathy”

- Characterized by hyperuricemia andcrystals deposition.

- Inflammatory arthritis.

- Hyperuricemia does not always lead togout, but gout is always preceded byhyperuricemia; study of 990 vs 4200

- Primary or secondary


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Gout

- Recurrent attacks of a red, tender, hot,and swollen joint.

- Rapid progression in <12h.

- Lifestyle

- Genetics: SLC2A9, SLC22A12

- usually >30 yo

- "the disease of kings" or "rich man'sdisease“.


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Gout: Pathophysiology

Uric acid

• End product of purine synthesis

• Eliminated by renal excretion

• Primary hyperuricemia: due to uric acid:

1. Overproduction (rare genetic disorders)

2. Underexcretion (90%)


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• Hyperuricemiaprecipitation of urate salts(needle-like crystals)

• Urate crystal depositionin tissues triggersinflammatory response:

infiltration ofgranulocytes

Needles of urate crystals

Neutrophils attacking the

urate crystals


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Gout: Causes of Secondary Gout

Excessive alcohol consumption

Diet rich in purines

Nephropathy

Starvation or dehydration

Certain drugs


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What Are The Approach Considerations?

Principles of gout management are :

• Treatment of gout flares (4)

• Urate-lowering therapy

• Anti-inflammatory prophylaxis when starting urate-lowering therapy

• Screening and management of comorbidities associated with gout (Type 2 DM, cardiovasculardisease, hypertension, hyperlipidaemia, etc.)


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Treatment of Acute Gout

•NSAIDs: e.g., indomethacin•full dosage for 2-5 days•Stop 2 days after symptoms subside

•Intra-articular/systemic corticosteroids•Colchicine•Anakinra or Canakinumab (interleukin-1receptor antagonist)


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Colchicine

• Plant alkaloid

• Not a uricosuric/not an analgesic – butrelieves pain

Mechanism of action

Binds tubulin depolymerization

Disrupts leukocyte migration

interferes with the inflammasomecomplex found in neutrophils andmonocytes

Blocks cell division

Other therapeutics: ACS, pericarditis,familial Mediterranean fever andrecently trialed for Covid-19


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Colchicine: Mechanism of Action


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Colchicine

Therapeutic uses

1. Relieves acute gout pain within 12 h (given 36 h after onset)

2. Prophylactic agent against gout attacks in patients initiating urate lowering therapy.

Narrow therapeutic window

Pharmacokinetics

• Oral, rapidly absorbed

• Recycles in bile

• Excreted unchanged in feces and urine


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ColchicineAdverse effects

N/V/D and abdominal pain

Myopathy

Neutropenia, aplastic anemia

Alopecia

Should NOT be used in pregnancy!(FDA;C, AU:D)

Used with caution in patients with hepatic, renal disease


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Treatment of Chronic Gout

• Aims to reduce thefrequency of attacks andcomplications of gout

• Options:

Xanthine oxidaseinhibitors (allopurinol,febuxostat) – first-line

Uricosuric agents(probenecid)


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Indications for Uric Acid Lowering Therapy

ACR and EULAR guidelines:

Established diagnosis of gout with one ofthe following:

• Tophus or tophi identified on clinicalexamination or imaging study

• Frequent (≥2/yr) of acute gouty arthritis

• Chronic kidney disease (CKD) stage ≥2

• Previous urolithiasis

Gouty tophus


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Allopurinol

Mechanism of action

• Purine analog

• Xanthine oxidase inhibitor

• Interferes with the last two stepsin uric acid biosynthesis

• Reduces uric acid production


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Allopurinol

Pharmacokinetics

• Oral, completely absorbed

• Primary metabolite: alloxanthine (oxypurinol) (also active inhibitor)

• Half-life 15-18 hours

• Excreted in feces and urine

Adverse effects

• Hypersensitivity

• Administered concurrently with NSAIDs, steroids or colchicine. Why?


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Febuxostat

• Xanthine oxidase inhibitor

• Structurally unrelated toallopurinol (non-purine)

• Similar indication toallopurinol

• Elimination.. Liver > kidney

• Risk of hypersensitivity isless

• Reports of increased CVSevents lead to limited use


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Probenecid

• Uricosuric agent

• Weak organic acid

• Promotes renal clearance ofuric [inhibits urate-anionexchanger]

• Blocks tubular reabsorptionof uric acid

• How does it interact withaspirin/salicylates?


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Pegloticase

• Recombinant urate oxidase

• Converts uric acid to allantoin

• Allantoin is a nontoxicmetabolite excreted renally

• Indicated for patients who failstandard therapy

• Given IV every 2 weeks


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Dietary Restriction

Foods very high in purines:

• Organ meats such assweetbreads (eg, pancreas andthymus)

• Sardines

• Mussels

Foods moderately high in purines

• Trout

• Anchovies

• Haddock

• Scallops

• Mutton

• Veal

• Live

• Salmon

• Kidneys

• Turkey


Weight gain is a significant riskfactor for gout (M), whereasweight loss reduces the risk

Avoid Alcohol and encouragevegetables

drugs for gout

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