Pharmacotherapy: Gout Flashcards
What is Gout ?
Painful inflammatory
arthropathy of joints & soft
tissue
What joint is most commonly affected ?
Joints of the big toe most commonly affected (podagra)
Intensely painful joint swelling characterised by?
Redness, warmth and tenderness
When is Uric acid created?
End product of purine
degradation in humans
What are the immediate precursors of Uric acid ?
- Immediate precursors are water soluble
- Xanthine & hypoxanthine
Where is the Uric acid filtered ?
Uric acid filtered at the
glomerulus, reabsorbed in the proximal tubule
What is Gout a result from?
High serum uric acid levels
When does the high uric acid levels occur ?
Happens when serum urate exceeds urate solubility (about 0.42 mmol/L)
Why would there be high uric acid levels ?
- Due to uric acid over production; or
- Reduced renal excretion - the most common cause (80%)
What are some general measures to reduce risk ?
- Reduce alcohol intake
- Restrict fructose containing drinks
- Reduce weight if overweight
- Restrict intake of purine-rich foods
What is the Pathogenesis of Acute Gout ?
- Presence of urate crystals in joint
- Positively charged crystals become coated with negatively charged proteins especially IgG & phospholipids
- Phagocytosis by macrophages in synovium
- Promote release of inflammatory mediators from neutrophils e.g. IL-1β
What is another Pathogenesis of Acute Gout?
- Mast cells and endothelial cells are activated
- Chemotactic factors stimulate leucocyte migration into the joint
- Neutrophils release proteolytic enzymes which attack the synovial membrane
- Tissue inflammation, cartilage destruction and joint damage
- Rapid onset of severe joint pain reaching max intensity in 24h
What is the diagnosis of Gout ?
- Confirmed by microscopic finding of urate crystals in synovial fluid from affected joint (not necessary)
- 75% of patients with gout will have features of the metabolic syndrome
- Insulin resistance, central obesity, dyslipidaemia
- Increased risk of CVD
What are the treatment aims of Gout ?
- To relieve pain and terminate an acute attack
promptly - To eliminate secondary causes
- To prevent recurrence
Explain the mechanism of action for the first drug therapy: Non Steroidal Anti-Inflammatory Drugs (NSAIDS)?
- NSAIDs act on the cyclooxygenase (COX)- enzyme system that stimulates synthesis of endoperoxide precursors of prostaglandins
- Inhibit synthesis of prostaglandins & thromboxanes (prostanoids)
- Two enzyme isoforms- COX1 and COX2
- NSAIDs reversibly inhibit both COX-1 & COX-2 enzymes as well as thromboxane synthetase
- Aspirin acetylates and thereby irreversibly inhibits the COXs
Give a brief summary about the COX-1 enzyme ?
- COX-1 constitutive enzyme
present in most cells and tissues - Primarily expressed in non
inflammatory cells - Adverse effects of NSAIDs mainly due to inhibition of COX1
- Inhibition results in side effects e.g. Gastric mucosa and issues in kidney
Give a brief summary about the COX-2 enzyme?
- COX-2 induced at sites of inflammation - Expressed in activated lymphocytes, polymorphonucleocytes and other inflammatory cells - Induces the synthesis of inflammatory cytokines e.g. IL-1 and TNF-a - Anti-inflammatory effect of NSAIDs mainly due to inhibition of COX-2 enzyme - COXIBs selectively inhibit COX-2 enzymes e.g. etoricoxib
What is the first line of acute attack ?
- NSAIDS are 1st line for acute attack
- indomethacin, diclofenac, naproxen - High dose x 3 days, then reduced dose x 10 days until pain relief achieved
What is the only COXIB licensed for gout ?
Etoricoxib
Now explain Colchicine, another gout management?
- Reduces the production of inflammatory mediators by
macrophages and down regulates their receptors on
synovial and endothelial cells - Forms a complex with tubulin in neutrophils cells and selectively inhibits microtubule assembly
- Reducing neutrophil migration into affected joint & phagocytosis of crystals
- If crystals are phagocytosed into the neutrophil, colchicine inhibits release of enzymes that cause joint damage
Briefly explain Glucocorticoids ?
- Anti-inflammatory &
immunosuppressant - Reduce swelling and
tenderness - Oral or parenteral steroids may be used in gout when
other treatments are precluded or not tolerated
Explain how Corticosteroids, another gout management, is administered ?
- Intra-articular injection for acute episodes
- Dose administered dependent on size of joint
- E.g. 5-10mg methylprednisolone (small joint)
- Oral doses can also be used
Explain Canakinumab ?
- Human
