Gout and NSAIDS

Inflammation

• Inflammation is a response by living, vascularized tissue to remove an injurious agent, including mechanical, chemical, thermal, or radioactive agents.
• It is a mechanism to restore tissue to normal.

Characteristics of Inflammation

• Redness: caused by increased blood flow
• Swelling: caused by fluid retention/edema
• Heat: caused by increased blood flow
• Pain: caused by impingement/pressure on local nerves
• Loss of function: excess of all of the above

Mediators of Inflammation

• Histamine: released by mast cells in tissue and platelets in blood
• Prostaglandins: cause peripheral vasodilation with redness and edema (partly due to bradykinin activation)
• Bradykinin: contributes to edema and pain
• Serotonin: involved in pain modulation

Consequences of Inflammation

• Pain: often accompanied by fever
• Fever: caused by exogenous pyrogens, lymphokines, and TNFα

Pain Modulators

• Nociceptors (pain receptors) are activated mechanically or chemically
• Inflammatory mediators can directly induce pain or decrease pain threshold

Mechanism of Fever

• Exogenous pyrogens increase prostaglandin E2 in the hypothalamus, raising the set point of the temperature regulating center
• This leads to cutaneous vasoconstriction, decreased heat loss, increased heat generation, and increased body temperature

Treatment of Inflammation

• Two major goals: relieve pain and other symptoms, and slow or arrest the tissue-damaging process
• NSAIDs are commonly used to treat inflammation, with aspirin being the original drug; numerous modifications have been made to refine efficacy, safety, and efficiency

NSAIDs

• Classes of NSAIDs:
  • Phenylacetic acid derivatives (e.g. diclofenac)
  • Indols (e.g. indomethacin)
  • Phenylpropionic acid derivatives (e.g. ibuprofen, naproxen)
  • Acetic acid derivatives (e.g. ketorolac)
• Pharmacokinetics: highly protein-bound, well absorbed, and metabolized, with primarily renal elimination
• Mechanism of action: competitive inhibitors of cyclooxygenase, reducing prostaglandin production and resulting in anti-inflammatory, analgesic, and antipyretic effects
• Therapeutic uses: arthritis, gout, antipyretics, analgesics, and cardioprotection

Adverse Effects of NSAIDs

• GI: abdominal pain, nausea, diarrhea, anorexia, ulcers
• Platelets: inhibited platelet activation, increased bruising, and hemorrhage
• Renal: salt and water retention, edema, decreased effectiveness of antihypertensive drugs, and hyperkalemia
• CV: closure of ductus arteriosus, increased risk of thrombotic events (especially with COX2 selective drugs)
• CNS: headache, vertigo, dizziness, confusion, and hyperventilation

Specific NSAIDs

• Aspirin: antiplatelet effect, used in cardioprotection and closure of patent ductus arteriosus
• Diclofenac: very potent anti-inflammatory, used in acute gout, severe osteoarthritis, and rheumatoid arthritis
• Indomethacin: potent anti-inflammatory, used in rheumatoid arthritis, ankylosing spondylitis, and acute bouts of gout
• Ibuprofen: well-tolerated for long-term use, used in children, and available in flavored chewable tablets and suspensions
• Naproxen: generally safe, but can cause GI disturbances, and has a longer half-life than most other NSAIDs
• Ketorolac: potent analgesic with moderate anti-inflammatory effects, used post-operatively, but has a risk of serious GI irritation, renal complications, and bleeding

COX2 Selective Inhibitors

• Developed to inhibit prostaglandin synthesis by the COX2 isozyme at sites of inflammation without affecting COX1
• Example: celecoxib, which is 15-20 times more selective for COX2 than COX1

Acetaminophen

• Non-anti-inflammatory analgesic, primarily used as an antipyretic and analgesic
• Mechanism of action is unclear
• Not useful as anti-rheumatic therapy
• Ideal analgesic for individuals susceptible to gastric irritation of NSAIDs
• Pharmacokinetics: rapid oral absorption, peak plasma levels in 30-60 minutes, and hepatic metabolism

De Novo Synthesis of Purine Bases

• Purines enter a common metabolic pathway leading to production of either nucleic acid or uric acid
• Uric acid accumulates if production exceeds excretion (average production: 600-800mg UA/day)
• Enzyme systems regulate purine metabolism, which can result in overproduction of uric acid

Overproduction of Uric Acid

• Can occur due to increased breakdown of tissue nucleic acids and excessive rates of cell turnover
• Associated with conditions such as:
  • Myeloproliferative and lymphoproliferative disorders
  • Psoriasis
  • Polycythemia vera
  • Certain anemias

Underexcretion of Uric Acid

• Under normal conditions, 2/3 of uric acid is excreted in urine, and 1/3 is eliminated via GI tract after enzymatic degradation by colonic bacteria
• Primary idiopathic hyperuricemia: majority of patients with gout have a relative decrease in renal excretion of uric acid for an unknown reason

Hyperuricemia

• Defined as:
  • Serum levels >416 μmol/L in males
  • Serum levels >357 μmol/L in females
• Overproducers: individuals with hyperuricemia who excrete >1000mg of UA/24hrs

Signs and Symptoms of Gout

• Generally presents as acute inflammatory monoarthritis
• Onset: usually at night
• Duration: 3-14 days (untreated)
• Lower extremity involvement, with 85% of initial attacks involving a single joint
• Most commonly affects the first metatarsophalangeal joint (great toe) = "Podagra" (50%)

Diagnosis

• Definitive: visualization of uric acid crystals in joint fluid by aspiration
• Presumptive diagnosis:
  • Inflammatory monoarthritis
  • Elevated UA
  • Response to colchicine
• Lab test: high UA level, leukocytosis
• Long-standing gout: x-ray – asymmetric swelling

Acute Classic Attack

• Rapid, localized onset of excruciating pain (night), swelling, redness, and inflammation
• Typically monoarticular at first, affecting the big toe, and may include other joints
• Debilitating, with unilateral attack lasting 3-14 days, maximal severity within 12-24 hours
• Complete resolution (untreated): days to weeks

Intercritical Gout

• Most untreated patients experience a second episode within 2 years
• Typically, uric acid-lowering treatments begin if >2 flares per year

Tophaceous Gout/Chronic Gouty Arthropathy

• Bony erosions/deformities may develop, typically associated with chronic tophaceous (crystal) deposits
• Most common sites: base of fingers, olecranon bursae, ulnar aspect of forearm, Achilles tendon, knees, wrists, and hands

Treatment Goals

• Terminate acute attack: goal is to control inflammation and pain
• Prevention of acute and chronic gout: goal is to lower uric acid level to prevent precipitation, acute attacks, and formation of tophi

Nonpharmacologic Therapies

• Awareness of nonpharmacologic therapies is essential for patient education and tailored therapy
• Role in management: acute attack, prevention/chronic management

Pharmacologic Treatment Options

• Acute: NSAIDs, oral colchicine, corticosteroids
• Chronic: xanthine oxidase inhibitors (allopurinol, febuxostat), uricosurics (probenecid)