Anti-Inflammatory & Anti-Gout Drugs – Comprehensive Study Notes

Objectives

  • Understand inflammatory response & its role in pain generation
  • Differentiate inflammatory disorders vs. gout
  • Master:
    • Mechanisms of action (MOA), indications, dosage, routes, AE, cautions/CI, drug–drug interactions (DDI), toxicities of anti-inflammatory & antigout drugs
    • Complete nursing process (assessment → diagnosis → planning → implementation → evaluation) for pts on these agents

Fundamentals of Inflammation

  • Protective, localized reaction to tissue injury
    • Purposes: destroy, dilute, or wall-off injurious agent + injured tissue
  • 5 classic signs: pain, fever, loss of function, redness, swelling
  • Key endogenous mediators:
    • Complement proteins, histamine, serotonin, bradykinin, leukotrienes, prostaglandins

NSAIDs – Core Properties & Uses

  • Large, chemically diverse class possessing:
    • Analgesic, anti-inflammatory, antipyretic activity
    • Aspirin-specific platelet inhibition
  • Common indications:
    • Mild  –  moderate\text{Mild\;–\;moderate} headache, myalgia, neuralgia, arthralgia
    • Post-op pain, primary dysmenorrhea
    • Arthritides → RA, OA, juvenile arthritis, ankylosing spondylitis, bursitis
    • Treatment of gout / hyperuricemia

Cyclo-oxygenase (COX) & Inhibition

  • COX converts arachidonic acid → prostanoids (prostaglandins, prostacyclin, thromboxane A2)
  • COX-1 ("good COX")
    • Physiologic roles: gastric mucosal protection, renal blood flow, platelet TXA2 synthesis
    • Inhibition → AE: gastric ulcer, bleeding, renal impairment
    • BUT benefits: ↓MI / stroke risk (low-dose ASA)
  • COX-2 ("bad COX")
    • Inducible at injury sites → pain, inflammation, fever
    • Inhibition → desired: ↓pain, ↓inflammation, ↓fever, possible colorectal CA protection
  • Classification
    1. Drugs with anti-inflammatory activity = NSAIDs (aspirin, celecoxib, ibuprofen, naproxen…)
    2. Drugs without = acetaminophen (analgesic/antipyretic only)

First-Generation NSAIDs (non-selective COX-1/2)

  • Treat inflammatory disorders, mild–moderate pain, fever
  • Risk: significant GI, renal, bleeding complications

Aspirin (Acetylsalicylic Acid, ASA)

  • Irreversible, non-selective COX inhibitor
  • Unique irreversible platelet inhibition via TXA2 blockade (duration = platelet life ~77 days)
  • Therapeutic uses
    • Analgesic, antipyretic, anti-inflammatory
    • Cardioprotection: primary/secondary MI, ischemic stroke, TIA, unstable angina
    • Dysmenorrhea; possible colorectal/other cancer prevention
  • Dosage examples
    • 81  mg81\;\text{mg} daily (low-dose) → thromboprophylaxis
    • 325  mg325\;\text{mg} q4–6h PRN → pain/fever (max 4  g / day4\;\text{g}\,/\,day)
  • Adverse effects (dose-related)
    • GI: dyspepsia → ulcer → bleed; tinnitus (salicylism), sweating, HA, dizziness
    • Bleeding, anemia (pregnancy), prolonged labor
    • Renal impairment
    • Reye syndrome in children w/ viral infection
    • Hypersensitivity, bronchospasm (esp. asthma + nasal polyps)
  • Drug interactions
    • Anticoagulants (warfarin, heparin) → ↑bleed
    • Alcohol, glucocorticoids, other NSAIDs, ACE-Is/ARBs → renal & GI risk
  • Acute toxicity → triad: respiratory depression, hyperthermia, metabolic acidosis + dehydration → supportive care

Non-Aspirin 1st-Gen NSAIDs

  • >20 agents, reversible COX blockade
  • Similar analgesic/antipyretic/anti-inflammatory efficacy
  • NO cardioprotection; may ↑CV risk
  • Example: Ibuprofen (Advil®, Motrin®)
    • Usual adult: 200–800  mg200–800\;\text{mg} q6–8h (max 3200  mg/day3200\;\text{mg/day})
    • Black-box: GI bleed, CV thrombosis

Second-Generation NSAIDs (COX-2 selective, "coxibs")

  • Equally effective for pain/inflammation; ↓GI ulcer risk vs. 1st-gen
  • ↑ risk: renal impairment, HTN, edema, MI/stroke
  • Celecoxib (Celebrex®)
    • Only U.S. coxib remaining
    • Indications: OA, RA, ankylosing spondylitis, acute pain, dysmenorrhea, familial adenomatous polyposis
    • AE: dyspepsia, abd pain, renal impairment, sulfa allergy cross-reactivity, CV events; avoid late pregnancy
    • Interactions: warfarin ↑INR, ↓furosemide/ACE-I efficacy, ↑lithium levels; levels ↑ w/ fluconazole
    • LAST-line for chronic pain per AHA stepped approach

Other Chemical Classes & Key Agents

  • Salicylates: diflunisal, salsalate, topical/rectal forms; risk of Reye’s syndrome
  • Acetic acid derivatives: diclofenac, indomethacin, sulindac, etodolac, tolmetin, ketorolac
    • Ketorolac: potent analgesic comparable to morphine; IV/IM/PO; limit to ≤5\le 5 days → severe renal & GI AE
  • Propionic acid derivatives: naproxen, ketoprofen, fenoprofen, flurbiprofen, oxaprozin
    • Naproxen: longer t½ (BID); fewer ACE-I interactions
  • Enolic acid (oxicam) derivatives: piroxicam, meloxicam, nabumetone (GI-friendly)
  • Misc. COX-2 > COX-1 bias: nabumetone, meloxicam (not strict coxibs)

Mechanistic Summary

  • NSAIDs block:
    1. Leukotriene pathway
    2. Prostaglandin pathway via COX inhibition
  • Aspirin uniquely, irreversibly inhibits platelet COX-1 → ↓TXA2 → antithrombotic

Contraindications & Cautions

  • Known NSAID or aspirin allergy
  • Bleeding risk: vitamin K deficiency, PUD, hemophilia
  • Advanced renal/hepatic disease, severe HF, pregnancy (especially 3rd trimester)

Adverse Effects (Class wide)

  • GI: heartburn → ulcer → bleed/perforation
  • Renal: acute failure, ↓creatinine clearance; highest risk dehydration, HF, liver disease, ACE-I/diuretics use
  • CV: Black-box (all except ASA) → ↑thrombotic events (fatal MI/stroke)
  • Pulmonary edema (non-cardiogenic)
  • Hepatotoxicity
  • Skin: rash → photosensitivity → SJS/TEN (notably allopurinol but also NSAIDs)
  • Auditory: tinnitus, hearing loss (salicylates)

GI Protection Strategy

  • Misoprostol (Cytotec®)
    • Synthetic PGE1\text{PGE}_1 analogue; ↓acid & ↑mucus/bicarb
    • Prevents NSAID-induced ulcers; pregnancy category X (uterine contractions)

Important Drug Interactions

  • Anticoagulants, antiplatelets, alcohol → bleeding
  • Corticosteroids/ulcerogenic drugs → additive GI injury
  • Highly protein-bound meds → displacement
  • Diuretics & ACE-Is → ↓antihypertensive effect + renal insult

Renal Considerations

  • Prostaglandin-dependent renal perfusion; NSAID blockade may precipitate AKI
  • Monitor BUN/Cr, I+O, elderly, dehydrated, HF, liver dz, ACE-I/diuretics users

Herbal: Glucosamine & Chondroitin (OA)

  • Possible cartilage support / pain relief
  • AE: GI upset; glucosamine → drowsiness, HA, skin rxn
  • DDI: potentiates warfarin, may ↑insulin resistance

Gout Pathophysiology & Targets

  • Hyperuricemia: overproduction or under-excretion of uric acid → monosodium urate crystal deposition in joints/soft tissue
  • Acute flares: intense pain, inflammation

Antigout Pharmacology

  • Goals: ↓serum uric acid (sUA) <66 mg/dL, ↓flare frequency/intensity

Xanthine Oxidase (XO) Inhibitors

  • Allopurinol (Zyloprim®)
    • Purine analogue; blocks XO → ↓uric acid production; prevents tumor lysis syndrome
    • AE: pruritic rash → SJS/TEN, exfoliative dermatitis, hepatotoxicity, bone marrow suppression
  • Febuxostat (Uloric®)
    • Non-purine selective XO inhibitor; more selective vs. allopurinol
    • Concern: ↑CV events; liver function monitoring

Microtubule Inhibitor

  • Colchicine (Colcrys®)
    • Blocks neutrophil motility/mitosis → ↓inflammatory response to crystals
    • Uses: acute flare & prophylaxis (short-term)
    • AE: GI N/V/D, abd pain, myelosuppression, neuromuscular toxicity; monitor CBC; caution renal/hepatic impairment

Uricosurics – Promote Renal Excretion

  • Probenecid (Benemid®)
    • Blocks renal tubular reabsorption URAT-1 → ↑UA excretion; needs good renal function
  • Lesinurad (Zurampic®)
    • UA transporter (URAT-1, OAT4) inhibitor; only combo w/ XO inhibitor
    • Teach: hydrate ≥2  L/day2\;\text{L/day}; monitor renal labs
  • Sulfinpyrazone (Anturane®) – similar to probenecid (less common)

Nursing Process: Key Points

Assessment

  • Complete med history (OTC, herbals, alcohol)
  • Screen for GI lesions/PUD, bleeding disorders, renal/cardiac/hepatic issues, pregnancy, sulfa allergy (celecoxib)
  • Baselines: CBC, platelets, LFTs, BUN/Cr, VS, pain scale

Planning & Implementation

  • Give with food, milk, or antacid to ↓GI upset
  • Avoid crushing enteric-coated ASA
  • No salicylates in children/teens (Reye’s risk)
  • Ketorolac ≤55 days
  • Hydration counseling with antigout uricosurics

Evaluation/Monitoring

  • Therapeutic: ↓pain, ↓inflammation, ↓fever, ↓joint swelling
  • Labs: renal, liver, CBC, sUA (gout)
  • Observe for AE: GI bleed (melena, hematemesis), unusual bruising, tinnitus, rash, edema, ↑BP

Patient Education

  • Report black/tarry stools, coffee-ground emesis, persistent abdominal pain
  • Avoid alcohol & smoking (GI bleed risk)
  • ASA low-dose is preventative; higher doses for symptom relief – know why prescribed
  • Time to full effect for OA supplements/uric acid therapy may be 3–43–4 weeks

NCLEX-Style Review (based on transcript Qs)

  • Low-dose ASA 8181 mg → thromboprevention; high-dose 650  mg650\;\text{mg} QID → pain/fever/OA
  • Salicylate toxicity hallmark: tinnitus; may also see hyperventilation, ↑HR, N/V/D, confusion, hypo/hyperglycemia
  • Ketorolac limited to ≤5\le 5 days due to severe renal & GI risks
  • Most critical monitor for elderly on high-dose ibuprofen: renal function (BUN/Cr, GFR, urine output)
  • Life-threatening skin reactions (SJS/TEN) strongly linked to allopurinol
  • Alcohol + NSAID → ↑GI bleed risk > nephrotoxicity

American Heart Association Stepped Care for Pain

  1. Non-drug measures (RICE, PT, weight loss)
  2. ASA or acetaminophen
  3. Non-selective NSAIDs (naproxen, ibuprofen, non-acetylated salicylates)
  4. COX-2 inhibitor (celecoxib) as last resort for chronic use