Inflammation and NSAIDs

Inflammation

• Inflammation is a localized protective response to tissue injury, which aims to destroy, dilute, or wall off the injurious agent and injured tissue.
• Symptoms of inflammation include pain, fever, loss of function, redness, and swelling.
• Endogenous compounds involved in inflammation include proteins of the complement system, histamine, serotonin, bradykinin, leukotrienes, and prostaglandins.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

• NSAIDs are a large and chemically diverse group of drugs with analgesic, anti-inflammatory, antipyretic, and aspirin-platelet inhibition properties.
• Common uses of NSAIDs include:
  • Mild to moderate headaches
  • Myalgia
  • Neuralgia
  • Arthralgia
  • Postoperative pain
  • Pain associated with arthritic disorders (e.g., rheumatoid arthritis, osteoarthritis)
  • Gout and hyperuricemia
• All NSAIDs share antipyretic, analgesic, and anti-inflammatory properties.

Salicylates

• Examples of salicylates include aspirin, diflunisal (Dolobid), and others.
• Aspirin is an irreversible inhibitor of COX-1 receptors and reduces thromboxane A2 formation, promoting platelet aggregation.
• Other NSAIDs lack this antiplatelet effect.

Mechanism of Action of NSAIDs

• NSAIDs inhibit the leukotriene pathway, prostaglandin pathway, or both.
• Blocking the chemical activity of the enzyme COX, which has two isoforms:
  • COX-1: involved in maintaining the gastrointestinal (GI) mucosa
  • COX-2: involved in inflammation

Adverse Effects of NSAIDs

• Gastrointestinal: heartburn to severe GI bleeding
• Renal: acute renal failure
• Cardiovascular: increased risk of myocardial infarction (MI) and stroke
• Hematological: altered hemostasis
• Hepatic: hepatotoxicity
• Dermatological: skin eruption, sensitivity reaction
• Otological: tinnitus, hearing loss

Interactions of NSAIDs

• Serious interactions can occur with:
  • Anticoagulants
  • Aspirin
  • Corticosteroids and other ulcerogenic drugs
  • Protein-bound drugs
  • Diuretics and ACE inhibitors
  • Others

Renal Function and NSAIDs

• Renal function depends partly on prostaglandins, which can be disrupted by NSAIDs, leading to acute or chronic renal failure.
• NSAIDs can compromise existing renal function, especially in patients with dehydration, heart failure, liver dysfunction, or those taking diuretics or ACE inhibitors.

Black Box Warning for NSAIDs

• All NSAIDs (except aspirin) carry a black box warning regarding the increased risk of adverse cardiovascular thrombotic events, including fatal MI and stroke.
• NSAIDs may counteract the cardioprotective effects of aspirin.

Salicylate Toxicity

• Cardiovascular: increased heart rate
• Central nervous system: tinnitus, hearing loss, dimness of vision, headache, dizziness, mental confusion, lassitude, and drowsiness
• Gastrointestinal: nausea, vomiting, diarrhea
• Metabolic: sweating, thirst, hyperventilation, hypoglycemia, or hyperglycemia

Aspirin

• Uses:
  • Reduce cardiac death after myocardial infarction (MI)
  • Should be administered at the first sign of MI
• Contraindications:
  • Known drug allergy
  • Conditions that place the patient at risk of bleeding (e.g., vitamin K deficiency, peptic ulcer disease)
  • Reye's syndrome: an acute and potentially life-threatening condition involving progressive neurologic deficits, triggered by viral illnesses and salicylate therapy.

Misoprostol (Cytotec)

• Prevents GI bleeding by:
  • Inhibiting gastric acid secretion
  • Having a cytoprotective component
• Mechanism of action: unclear

Acetic Acid Derivatives

• Examples: diclofenac sodium (Voltaren), indomethacin (Indocin), sulindac (Clinoril), tolmetin (Tolectin), etodolac (Lodine), ketorolac (Toradol)
• Uses:
  • Rheumatoid arthritis (RA)
  • Osteoarthritis (OA)
  • Acute bursitis or tendonitis
  • Ankylosing spondylitis
  • Acute gouty arthritis
  • Patent ductus arteriosus (PDA)
  • Treatment of preterm labor
• Adverse effects:
  • Renal impairment
  • Edema
  • GI pain
  • Dyspepsia
  • Nausea

Cyclooxygenase-2 (COX-2) Inhibitors

• Example: celecoxib (Celebrex)
• Indicated for:
  • OA
  • RA
  • Acute pain symptoms
  • Ankylosing spondylitis
  • Primary dysmenorrhea
• Adverse effects:
  • Headache
  • Sinus irritation
  • Diarrhea
  • Fatigue
  • Dizziness
  • Lower extremity edema
  • Hypertension
• Little effect on platelet function
• Contraindication: known sulfa allergy

Enolic Acid Derivatives

• Examples: nabumetone (Relafen), meloxicam (Mobic), piroxicam (Feldene)
• Uses:
  • Mild to moderate OA
  • RA
  • Gouty arthritis
• Adverse effects:
  • GI distress
  • Renal impairment

Propionic Acid Derivatives

• Examples: fenoprofen (Nalfon), flurbiprofen (Ansaid), ibuprofen (Motrin, Advil, others)
• Uses:
  • Analgesic effects in RA, OA, primary dysmenorrhea, gout, dental pain, musculoskeletal disorders
  • Antipyretic actions
• Adverse effects:
  • GI distress
  • Renal impairment
  • Headache
  • Dizziness
  • Nausea

Gout

• Condition resulting from inappropriate uric acid metabolism:
  • Underexcretion of uric acid
  • Overproduction of uric acid
• Uric acid crystals are deposited in tissues and joints, resulting in pain and hyperuricemia.

Antigout Drugs

• Allopurinol (Zyloprim):
  • Used to prevent uric acid production and prevent acute tumor lysis syndrome
  • Adverse effects: exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis
• Febuxostat (Uloric):
  • Nonpurine selective inhibitor of xanthine oxidase
  • May pose a greater risk of cardiovascular events than allopurinol
• Colchicine (Colcrys):
  • Reduces inflammatory response to the deposits of urate crystals in joint tissue
  • Used for short-term management or prevention of gout
  • Adverse effects: short-term leukopenia and bleeding into the GI or urinary tracts
• Probenecid (Benemid):
  • Inhibits the reabsorption of uric acid in the kidneys and thus increases the excretion of uric acid
  • Uricosuric
  • Must have good renal function
• Lesinurad (Zurampic):
  • Uric acid transporter inhibitors
  • Inhibits the transporter proteins involved in renal uric acid reabsorption resulting in lower serum uric acid levels and increased renal clearance of uric acid
  • Given in combination with xanthine oxidase inhibitor
  • Teaching: at least 2 liters of fluid a day

Nursing Implications

• Assess for conditions that may be contraindications to therapy, especially GI lesions or peptic ulcer disease, bleeding disorders, and sulfa allergy.
• Perform laboratory studies as indicated (cardiac, renal, and liver function studies; complete blood count; platelet count).
• Perform a medication history to assess for potential drug interactions.
• Educate patients about the various adverse effects of NSAIDs and inform them to notify their prescribers if these effects become severe or if bleeding or GI pain occurs.
• Inform patients to watch closely for the occurrence of any unusual bleeding, such as in the stool.