Rheumatology: Pharmacology - Anti-gout agents

Question 1

What is gout? List some of the clinical features

Answer 1

Metabolic disease characterised by recurrent episodes of acute arthritis due to deposits of monosodium urate in joints and cartilage

May also develop:
- Uric acid renal calculi
- Interstitial nephritis
- Tophi (subcutaneous deposits)
- Adverse CV outcomes

Question 2

List seven classes of drugs used in gout, giving examples where relevant

Answer 2

1. Colchicine
2. NSAIDs (e.g. indomethacin)
3. Uricosuric agents (e.g. probenecid, sulfinpyrazone)
4. Corticosteroids
5. Xanthine oxidase inhibitors (e.g. allopurinol, febuxostat)
6. Pegloticase
7. IL-1 antagonists

Question 3

Describe the pathophysiology of gout

Answer 3

Urate crystals (end-product of purine metabolism) are phagocytosed by synoviocytes, which then release of inflammatory markers (prostaglandins, IL-1, lysosomal enzymes)
Neutrophils are attracted resulting in amplification of the inflammatory process
In later phases of the attack, macrophages ingest urate crystals and release more inflammatory mediators

Question 4

What is the effect of colchicine in gout? What type of medication is colchicine?

Answer 4

Alkaloid medication
Relieves pain and inflammation of acute gout within 12-24hrs without alteration of urate metabolism or excretion, and without other analgesic effects
Also used for prevention of recurrence at lower doses

Question 5

Which NSAID lowers serum uric acid?

Answer 5

Oxaprozin

Question 6

Which three NSAIDs cannot be used to treat gout?

Answer 6

Aspirin
Salicylates
Tolmetin

Question 7

What is the mechanism of action of colchicine?

Answer 7

Binds intracellular tubulin to prevent formation of microtubules, thereby inhibiting leukocyte migration and phagocytosis
Also inhibits LTB4 and IL-1B formation

Question 8

Five clinical uses of colchicine

Answer 8

1. Gout prophylaxis (most common)
2. Acute gout
3. Prevention of recurrent familial Mediterranean fever
4. Prevention and treatment of pericarditis, pleurisy and coronary artery disease
5. Mild beneficial effect in sarcoid arthritis and hepatic cirrhosis

Question 9

Describe the pharmacokinetics of colchicine

Answer 9

Absorption: readily absorbed, peak levels within 2hrs, t1/2 = 9hrs
Excretion: metabolites excreted in GIT and urine

Question 10

What is the dosage of colchicine used for gout prophylaxis vs treatment of acute flare?

Answer 10

Prophylaxis: 0.6mg 1-3x daily
Acute gout: 1.2mg followed by single 0.6mg dose

Question 11

What is the potentially lethal dose of colchicine?

Answer 11

8mg
Narrow therapeutic index

Question 12

List 10 adverse effects of colchicine

Answer 12

GI upset: diarrhoea (common), nausea, vomiting, abdo pain
Hepatic necrosis
Acute renal failure
DIC
Seizures

Rarely:
Hair loss
Bone marrow depression
Peripheral neuritis
Death

Question 13

Describe the toxicity syndrome seen with colchicine

Answer 13

Burning throat pain
Bloody diarrhoea
Shock
Haematuria
Oliguria
May cause fatal ascending CNS depression

Question 14

What is the treatment for colchicine toxicity?

Answer 14

Supportive

Question 15

What is the mechanism of action of probenecid?

Answer 15

Prevents uric acid reabsorption in proximal tubule (inhibits both secretory and reabsorptive transporters but net effect is increased secretion)

Question 16

Why should aspirin not be used in combination with probenecid for management of pain in acute gout flare?

Answer 16

Aspirin inhibits secretory transporters only
In combination with probenecid, which inhibits both secretory and reabsorptive transporters, net effect is increased reabsorption and therefore elevated serum uric acid

Question 17

When is probenecid used in gout?

Answer 17

Prophylaxis only (can be started 2-3 weeks post acute flare)

Question 18

What is the mechanism of action of allopurinol?

Answer 18

Xanthine oxidase inhibitor: decreases urate burden

Question 19

When is allopurinol used in gout? What are some caveats to commencing allopurinol?

Answer 19

Used for prophylaxis only
Can precipitate gout so needs NSAID/colchicine cover for 6/12 post achieving target uric acid levels (<6mg/dL)

Question 20

What uric acid level is targeted for prophylaxis of gout?

Answer 20

<6mg/dL

Question 21

Describe the pharmacokinetics of allopurinol

Answer 21

Absorption: ~80% oral absorption, t1/2 = 1-2hrs, once daily dosing
Metabolism: by xanthine oxidase to alloxanthine (which still retains capacity to inhibit XO)

Question 22

Two important medications interactions with allopurinol

Answer 22

Increases effect of chemotherapeutic purines and cyclophosphamide (should be dose reduced when given concomitantly)
Inhibits probenecid and oral anticoagulant metabolism

Question 23

Five adverse effects of allopurinol

Answer 23

GI upset: nausea, vomiting, diarrhoea
Peripheral neuritis
Necrotising vasculitis
Bone marrow suppression
Aplastic anaemia