Pharmacology of agents used for the treatment of common joint problems Flashcards
What are the three key inflammatory mediators targeted by anti-inflammatory drugs?
Eicosanoids (e.g., prostaglandins, thromboxanes)
Biological oxidants
Cytokines
🧠 Mnemonic: “Eat Bright Carrots” (Eicosanoids, Biological oxidants, Cytokines).
Which COX isoform is primarily involved in inflammatory prostaglandin synthesis?
COX-2 (cyclooxygenase-2).
🖼️ Dominant in inflammation; NSAIDs inhibit COX-2 to reduce pain/swelling.
Explain the mechanism of action of NSAIDs in treating inflammation.
NSAIDs block COX-2, inhibiting prostaglandin/thromboxane synthesis. This reduces:
Vasodilation
Vascular permeability
Pain signaling
Leukocyte migration
🧠 “No COX-2 → No PGs → No Inflammation!”
What initiates the inflammatory process?
Cellular damage from stimuli like infection, physical stress, autoimmune reactions, or chemicals. This activates transcription factors (e.g., NF-κB) that trigger inflammatory mediator release.
What are common adverse effects of NSAIDs?
GI ulcers/bleeding (reduced protective PGs)
Kidney damage (impaired renal blood flow)
Increased cardiovascular risk (e.g., with COX-2 inhibitors)
Allergic reactions (e.g., aspirin-induced asthma)
Contraindications for NSAID use?
Peptic ulcer disease
Severe kidney/liver disease
Aspirin allergy (avoid salicylates)
Pregnancy (3rd trimester: risk of premature ductus arteriosus closure)
Indications for NSAIDs in joint disorders?
Osteoarthritis pain
Rheumatoid arthritis inflammation
Acute gout flares
Ankylosing spondylitis
Trade vs. generic names of NSAIDs: Examples?
Ibuprofen: Advil, Motrin
Celecoxib: Celebrex
Aspirin: Bayer, Ecotrin
Naproxen: Aleve
What are the three classifications of NSAIDs based on COX selectivity?
Non-selective COX-1/COX-2 inhibitors (e.g., ibuprofen, diclofenac)
Selective COX-2 inhibitors (e.g., celecoxib, rofecoxib)
Salicylates (e.g., aspirin).
Why do COX-2 inhibitors cause fewer gastrointestinal (GI) adverse effects than non-selective NSAIDs?
COX-2 inhibitors spare COX-1, which maintains protective prostaglandins (PGE₂) in the stomach lining.
🧠 “COX-2 spares COX-1 → Happy Stomach!”
Explain the mechanism of diclofenac-induced gastric ulceration and how to mitigate it.
Cause: Diclofenac inhibits COX-1, reducing PGE₂ (protects gastric mucosa).
Prevention: Combine with omeprazole (PPI) or misoprostol (PG analog) to reduce acid/ulcer risk.
Why is ibuprofen not recommended with aspirin for cardioprotection?
Ibuprofen competes with aspirin for COX-1 binding, blocking aspirin’s irreversible antiplatelet effect.
🧠 “Ibuprofen blocks aspirin’s heart shield!”
Adverse renal effects of NSAIDs (e.g., COX-2 inhibitors)?
Reduced renal blood flow (inhibits vasodilatory PGs).
Sodium retention → hypertension.
Risk of acute kidney injury (especially in volume-depleted patients).
Key uses of indomethacin?
Acute gout (rapid pain/inflammation relief).
Rheumatoid arthritis.
🖼️ High potency but limited by frequent side effects (e.g., headache, GI issues).
Why is aspirin contraindicated in gout?
Aspirin impairs uric acid excretion by inhibiting renal tubular secretion, worsening hyperuricemia.
Advantages and disadvantages of celecoxib (COX-2 inhibitor)?
Advantages: Fewer GI ulcers, no antiplatelet effect (safer for bleeding risk).
Disadvantages: No cardioprotection, expensive, risk of hypertension/edema.
What makes acetaminophen different from other NSAIDs?
Weak anti-inflammatory activity.
No COX inhibition in peripheral tissues (works centrally).
Safe for GI but risky in overdose (hepatotoxicity).
How does aspirin’s antiplatelet effect last 8–10 days?
Aspirin irreversibly inhibits COX-1 in platelets. Platelets lack nuclei to regenerate COX.
Formulations of NSAIDs?
Oral (tablets, capsules).
Topical (diclofenac gel).
Injectable (ketorolac).
Suppository (indomethacin).
Trade vs. generic names:
Celecoxib
Ibuprofen
Diclofenac
Celecoxib → Celebrex
Ibuprofen → Advil, Motrin
Diclofenac → Voltaren
What are rheumatic diseases?
Chronic inflammatory disorders (e.g., rheumatoid arthritis, systemic lupus erythematosus) characterized by immune-mediated tissue damage and increased phagocyte activity.
What are the primary goals of rheumatic disease management?
Relieve pain/symptoms.
Arrest disease progression.
Maintain mobility/quality of life.
🧠 “Relieve, Arrest, Maintain!”
Therapeutic strategies for rheumatic diseases?
Symptom control: NSAIDs, corticosteroids.
Disease modification: DMARDs (e.g., methotrexate, TNF-α inhibitors).
🖼️ NSAIDs = quick relief; DMARDs = long-term control.
What are DMARDs?
Disease-Modifying Antirheumatic Drugs (e.g., methotrexate, sulfasalazine) that slow/stop immune-mediated joint damage (no direct anti-inflammatory/analgesic effects).
Why are corticosteroids not first-line for rheumatic diseases?
Long-term use causes severe adverse effects (osteoporosis, hyperglycemia, immunosuppression). Used short-term for acute flares.
Key DMARD categories and examples?
Immunosuppressants: Methotrexate, cyclosporine.
Cytokine inhibitors: TNF-α blockers (etanercept), IL-1 antagonists (anakinra).
Others: Hydroxychloroquine, sulfasalazine.
Second-line DMARDs?
Less commonly used due to toxicity (e.g., gold salts, penicillamine, cyclophosphamide).
How do TNF-α inhibitors (e.g., infliximab) work?
Block TNF-α (pro-inflammatory cytokine), reducing joint inflammation/damage.
🖼️ “Neutralize TNF → Save the Joints!”
Methotrexate in rheumatic disease: Mechanism and key risk?
Mechanism: Inhibits folate metabolism → suppresses T-cell/B-cell proliferation.
Risk: Hepatotoxicity, bone marrow suppression (requires folate supplementation).
What is gout?
Arthropathy caused by monosodium urate crystal deposition in joints (often due to hyperuricemia).
Acute gout treatment options?
NSAIDs (indomethacin).
Colchicine (inhibits neutrophil migration).
Corticosteroids (prednisone).
Colchicine mechanism?
Inhibits microtubule polymerization → blocks neutrophil chemotaxis and inflammatory mediator release.
🧠 “Stop microtubules → Stop inflammation!”
Trade vs. generic names:
Etanercept
Infliximab
Anakinra
Etanercept → Enbrel
Infliximab → Remicade
Anakinra → Kineret
Why are DMARDs started early in rheumatoid arthritis?
Joint damage occurs within 18 months of symptom onset; early use slows irreversible damage.
Hydroxychloroquine use and risk?
Use: Mild rheumatoid arthritis, lupus.
Risk: Retinal toxicity (requires annual eye exams).
What is gout?
Gout is an arthropathy caused by monosodium urate crystal deposition in joints, leading to inflammation and pain, often due to hyperuricemia.
Acute gout treatment options and their key considerations.
NSAIDs (e.g., indomethacin, diclofenac): Avoid aspirin (↑ uric acid).
Colchicine: Inhibits neutrophil migration; use low-dose (1.2 mg + 0.6 mg after 1 hr).
Corticosteroids: For NSAID/colchicine contraindications (e.g., prednisone, intra-articular injections).
🖼️ “Acute = Stop Inflammation Fast!”
Colchicine mechanism of action?
Inhibits microtubule polymerization → blocks neutrophil chemotaxis and phagocytosis.
🧠 “No Microtubules → No Neutrophils!”
What are the two primary causes of hyperuricemia?
Overproduction of uric acid.
Underexcretion of uric acid.
🧠 Mnemonic: “Produce or Excrete?”
Why is aspirin avoided in gout management?
Aspirin inhibits uric acid excretion (↑ hyperuricemia) and may worsen acute attacks.
Long-term gout management strategies.
Xanthine oxidase inhibitors: Allopurinol (adjust for renal impairment), febuxostat.
Uricosurics: Probenecid (↑ uric acid excretion; avoid in renal stones).
Combination therapy: Lesinurad + allopurinol for refractory cases.
Uricase analogs: Pegloticase (reserved for severe, refractory gout).
Allopurinol key points.
Mechanism: Inhibits xanthine oxidase → ↓ uric acid production.
ADR: Rash, hepatotoxicity (monitor LFTs).
Contraindication: Hypersensitivity.
When is pegloticase used?
For refractory gout unresponsive to xanthine oxidase inhibitors.
🖼️ Risk: Anaphylaxis (contraindicated in G6PD deficiency).
Lesinurad (Zurampic) mechanism and use
Mechanism: Blocks URAT1/OAT4 transporters → ↑ uric acid excretion.
Use: Combined with xanthine oxidase inhibitors for inadequate response.
Trade vs. generic names:
Allopurinol
Febuxostat
Pegloticase
Allopurinol → Zyloprim
Febuxostat → Uloric
Pegloticase → Krystexxa
What is the target serum uric acid level in long-term gout management?
<6 mg/dL to prevent crystal formation and recurrent attacks.
Probenecid limitations.
Avoid in renal impairment (CrCl <50 mL/min), renal stones, or overproducers.
Alkalinize urine to ↓ stone risk.
Why do urate-lowering therapies initially trigger gout flares?
Rapid changes in uric acid levels destabilize tissue deposits → crystal shedding → inflammation.
🧠 “Start Low, Go Slow!”
Febuxostat vs. allopurinol.
Febuxostat: Non-purine analog, no dose adjustment in mild-moderate renal impairment.
Allopurinol: Purine analog, requires renal dose adjustment.
Corticosteroids in acute gout.
Use: Oral (prednisone), IM, or intra-articular (triamcinolone).
Avoid long-term: Risk of osteoporosis, hyperglycemia, immunosuppression.
