Hesi NSAIDS_mod_3_updated

Classes within this chapter

• Corticosteroids
• Salicylates
• NSAIDs (Nonsteroidal Anti-Inflammatory Drugs)
• Acetaminophen
• Gold Compounds
• DMARDs (Disease-Modifying Anti-Rheumatic Drugs)

Notes: This set covers the major drug classes used to treat inflammation, arthritis, and related conditions as presented in the transcript. Some slides note content that is testable beyond the book; these points are included here.

Acute Inflammation and Systemic Response

• Systemic response to injury includes several manifestations:
  • Fever: Activated prostaglandins signal the brain to raise temperature. Treatments like acetaminophen (Tylenol), ibuprofen (Motrin), and aspirin inhibit prostaglandin formation.
  • Histamine release contributes to inflammatory processes.
  • Pain, arteriolar vasodilation, lymphadenopathy (swollen lymph nodes), anorexia, sleepiness.
• Inflammatory cascade (simplified):
  • Injury exposes tissue membranes and activates a cascade beginning with Hageman factor (Factor XII) leading to kallikrein and bradykinin release.
  • Activation sequence involves pre-kallikrein and kininogen, resulting in bradykinin release and increased vascular permeability.
  • Release of arachidonic acid follows, leading to downstream products from COX and LOX pathways:
  • Prostaglandins (via COX-1 and COX-2)
  • Leukotrienes
• Treatments target various points in this cascade:
  • Corticosteroids and antihistamines can modulate early inflammatory mediators like histamine.
  • COX inhibitors (Salicylates, NSAIDs) act on the prostaglandin pathway.
  • TNF blockers (e.g., etanercept, anakinra) act on later inflammatory signals (cytokine pathways).
  • Gold salts have a unique mechanism affecting phagocytosis by macrophages.

Salicylates (Aspirin, ASA)

• ASA is an anti-inflammatory agent with multiple actions:
  • Anti-inflammatory, antipyretic (fever reduction), analgesic (pain relief), and antiplatelet effects (inhibits platelet aggregation).
  • At low doses (e.g., 81 mg to 325 mg per tab) ASA is often used for cardioprotection and antiplatelet effects; higher doses for pain/inflammation.
• Common dosing references:
  • Baby aspirin ≈ 81 mg per tablet (note: not for babies; pediatric use is restricted). Adult aspirin ≈ 325 mg per tablet.
• Uses include mild-to-moderate pain, fever, various inflammatory conditions, and prevention of ischemic events.
• Dosing ranges to remember: $81\,\text{mg} \le D \le 325\,\text{mg}$ per tablet (typical).
• Contraindications:
  • Allergy to salicylates, NSAIDs, or tartrazine (dye)
  • Recent surgery (within 1 week)
  • Pregnancy or lactation considerations
• Adverse effects:
  • GI effects (irritation, gastritis, ulcers) and bleeding risk due to platelet inhibition
  • Other: salicylate toxicity (salicylism) with very high ASA levels
• Salicylate Toxicity (Salicylism):
  • Can occur with high ASA levels around the range of $20!-\,25\,\text{g}$
  • Symptoms: dizziness, tinnitus, difficulty hearing, nausea/vomiting, diarrhea, confusion, fatigue; tachypnea, hemorrhage, pulmonary edema, convulsions, coma, etc.

NSAIDs (Nonsteroidal Anti-Inflammatory Drugs)

• NSAIDs include several groups:
  • Propionic acids
  • Acetic acids
  • Fenamates
  • Oxicam derivatives
  • COX-2 inhibitors (selective)
• Mechanism: Block both COX-1 and COX-2 enzymes (COX-1 and COX-2 are inhibited to reduce prostaglandin synthesis).
• COX-1 vs COX-2 roles:
  • COX-1: present in all tissues; involved in blood clotting; protects stomach lining; maintains Na and water balance in kidneys; converts arachidonic acid to prostaglandins.
  • COX-2: induced at trauma/injury; amplifies pain and inflammation; mediates vasodilation and platelet effects; inhibition reduces inflammation and fever but has safety considerations.
• COX-2 inhibitors (COX-2 selectivity):
  • Expected benefits: decreased GI toxicity compared with nonselective NSAIDs
  • Risks: increased risk of cardiovascular events; other CV/GI risks noted
  • Black Box Warning: cardiovascular and GI risks for certain COX-2 inhibitors
• NSAIDs categorization by selectivity (general flavor):
  • COX-2 selective NSAID: celecoxib (Celebrex)
  • SEMISELECTIVE NSAIDs: drugs with higher affinity for COX-2 but some COX-1 activity (e.g., meloxicam, diclofenac, etodolac, et al.)
  • NONSELECTIVE NSAIDs: ibuprofen, naproxen, many traditional NSAIDs
  • Some NSAIDs are aspirin-like (ASA) with unique profiles
• Important safety notes:
  • Contraindications include allergy to NSAIDs or salicylates; celecoxib also contraindicated with sulfonamide allergy; cardiovascular dysfunction or hypertension (especially with COX-2 inhibitors); peptic ulcers or known GI bleeding; pregnancy/lactation; renal or hepatic disease (use caution)
  • Adverse effects depend on COX-1 vs COX-2 inhibition but commonly include GI upset, renal effects, cardiovascular effects, and bleeding risks; monitor closely, especially with elderly or comorbid patients
• COX-2 selectivity and GI safety vs CV risk (conceptual):
  • Higher COX-2 selectivity tends to lower GI toxicity but can raise CV risk; nonselective NSAIDs carry GI risk and some CV risk too; overall balance of harms/benefits is drug-specific
• Celecoxib (Celebrex):
  • A COX-2 selective NSAID; marketed for osteoarthritis and rheumatoid arthritis
  • Common adverse effects: dyspepsia, diarrhea, abdominal pain, URI symptoms, peripheral edema, GI discomfort
  • CV risk: notable association with higher CV event risk; require caution in patients with cardiovascular risk factors
  • Dosing and monitoring tailored to patient risk profile

COX Enzymes: Visualized (conceptual)

• COX-2 selective NSAIDs and their safety profile can be summarized as:
  • Increased CV risk associated with some COX-2 inhibitors
  • GI risk generally lower compared with nonselective NSAIDs, but not zero
  • Nonselective NSAIDs carry GI and renal risks; some carry less CV risk depending on agent and dose
• A simplified view: COX-1 inhibition leads to gastric/renal risks; COX-2 inhibition yields anti-inflammatory benefits with CV/GI safety tradeoffs

NSAIDs: Relative Safety Profiles (summary from slides)

• Least to most GI/renal toxicity by selectivity (illustrative ordering):
  • Very high COX-2 selectivity agents tend to have higher CV risk but lower GI risk
  • Nonselective NSAIDs have higher GI risk, more renal effects, but cardiovascular risks vary by drug and dose
• Example ranking (from the slide visuals):
  • Celecoxib (Celebrex): high COX-2 selectivity; relatively lower GI risk but notable CV risk in some patients
  • Ibuprofen, naproxen: nonselective; variable GI and renal risk; naproxen often considered relatively safer for CV risk at standard doses but still risky
  • Rofecoxib (Vioxx): highly COX-2 selective, removed from the market due to cardiovascular safety concerns
  • Diclofenac, indomethacin, ketoprofen, piroxicam, meloxicam, nabumetone, others: a mix of selectivities with varying risk profiles

Acetaminophen (Paracetamol)

• Not an NSAID; analgesic and antipyretic with limited anti-inflammatory activity
• Uses: moderate to mild pain relief and fever control; often used as an NSAID alternative
• Liver toxicity risk: Extremely hepatotoxic in overdose; death can occur with high intake
• Dosing norms: Typical dosing is $325\,\text{mg} \text{ to } 1000\,\text{mg every 4-6 hours}$; max daily dose often stated as $4000\,\text{mg/day}$ for adults
• Overdose concern and antidote:
  • Acetylcysteine is the antidote (also used as a mucolytic in other contexts)
• Special cautions:
  • Children are especially susceptible to overdose and liver injury
  • Use caution with concurrent hepatotoxic drugs, liver disease, or chronic alcohol use
• Contraindications/Adverse effects:
  • Hepatic dysfunction; chronic alcoholism (increased risk of hepatotoxicity)
  • Potential adverse effects: hepatotoxicity, headaches, hemolytic anemia, renal dysfunction, skin rash, fever

Anti-Arthritis Agents (Overview)

• Gold compounds (Chrysotherapy)

  • Gold compounds used: Auranofin (Ridaura) and gold sodium thiomalate (Aurolate)
  • Mechanism: Gold is taken up by macrophages and inhibits phagocytosis; this reduces release of lysosomal enzymes and tissue destruction
  • Role: Reserved for patients who do not respond to other therapies; do not reverse existing damage, but aim to prevent further damage
  • Considerations: Can be toxic; contraindicated in pregnancy/lactation, allergy to gold, diabetes mellitus, congestive heart failure, renal or hepatic dysfunction, hypertension, etc.

• DMARDs (Disease-Modifying Anti-Rheumatic Drugs)

  • Goal: Slow down or prevent further joint damage before severe damage occurs
  • Some sources classify gold compounds as DMARDs
  • Other classifications include: Tumor Necrosis Factor (TNF) blockers and other agents
  • Adverse effects can be severe to life-threatening; monitoring is essential

TNF Blockers (Tumor Necrosis Factor Blockers)

• Approved TNF blockers include:
  • Adalimumab (Humira), certolizumab (Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade)
• Mechanism:
  • TNF-α is a cytokine that stimulates a wide range of proinflammatory activities; these drugs bind TNF-α to inhibit its activity
• Uses:
  • Rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, plaque psoriasis, ankylosing spondylitis
• Administration:
  • All are given subcutaneously (SQ) except infliximab, which is given intravenously (IV)
• Contraindications and safety concerns:
  • Black box warning for serious risk of fatal infections and risk of lymphoma or other cancers
  • Do not use in the presence of acute infection, cancer, sepsis, TB, hepatitis, myelosuppression, or demyelinating disorders
  • Pregnancy/lactation considerations; live vaccines contraindicated; allergy to animal products (including chicken) can be a concern
  • Cautions: Renal or hepatic disorders, heart failure, latex allergies
• Practical implications:
  • Patients require infection screening (TB testing, hepatitis status) prior to initiation
  • Vaccination status should be reviewed; avoid live vaccines during therapy
  • Monitor for signs of infection or unusual bleeding, and cancer risk due to immunomodulation

Other DMARDs (Additional Agents)

• A broad list of DMARDs beyond TNF blockers includes:
  • Methotrexate, cyclophosphamide (antineoplastic), abatacept (T cell co-stimulation blocker), antimalarial drugs (e.g., hydroxychloroquine), interleukin-1 (IL-1) receptor antagonists (e.g., anakinra)
• Anakinra (Kineret): IL-1 receptor antagonist; blocks IL-1 which contributes to cartilage degradation in RA; often used in combination with other anti-arthritic drugs
• Contraindications: Similar to other DMARDs (individual drug contraindications apply)

Adverse Effects Common to DMARDs

• Fatigue is a common symptom in patients with Rheumatoid Arthritis and can be a side effect of DMARD therapy
• Other potential adverse effects noted in slides: blurred vision, headaches, infections, fatigue, cancer risk, sleep disturbances, cognitive effects (collectively humorously referred to as the 7 dwarfs of RA: Fatigue, Blurred vision, HA, Infections, Cancer, Sleepy, Dopey, etc.)

Anti-Inflammatory Agent Comparisons

• DMARDs vs NSAIDs:
  • DMARDs
  • Onset: Slow onset of action
  • Effect: Arrest progression of the disease and prevent new deformities
  • Use: Chronic management; disease-modifying
  • NSAIDs
  • Onset: Rapid onset of action
  • Effect: Relief of inflammation and pain but do not halt disease progression or prevent deformities
  • Use: Acute relief; symptomatic management
• Practical takeaway: DMARDs address long-term joint damage, while NSAIDs provide symptomatic relief; many patients combine both for comprehensive management while monitoring safety.

Practical and Safety Considerations

• Black Box warnings and monitoring are especially important for TNF blockers due to infection and cancer risks
• For all NSAIDs and salicylates: assess GI, renal, hepatic safety; check for history of ulcers, bleeding disorders, kidney disease, and hypertension
• For acetaminophen: monitor liver function and avoid hepatotoxic combinations; educate about maximum daily dose and risk of overdose
• For corticosteroids (mentioned as a class in the chapter): they are a major anti-inflammatory option but require careful tapering and monitoring to avoid adverse effects; cortical pathways relate to broad anti-inflammatory effects (not detailed further in the slides)

Connections to Foundational Principles and Real-World Relevance

• Inflammation is a multi-step cascade with tissue injury triggering mediator release and enzyme-driven pathways (COX-1/COX-2, LOX, histamine, kallikrein/kinin system)
• Pharmacologic strategies target different nodes in the cascade to achieve anti-inflammatory, analgesic, antipyretic, or disease-modifying effects
• The balance between efficacy and safety drives choices (e.g., COX-2 inhibitors may reduce GI risk but raise CV risk; DMARDs reduce long-term joint damage but carry infection/cancer risks)
• Vaccination status, infection risk, pregnancy status, and comorbid conditions are critical in drug selection and monitoring, especially with biologics and DMARDs

Mathematical and Quantitative References (LaTeX notation)

• Low-dose ASA range per tablet: $81\,\text{mg} \le D \le 325\,\text{mg}$
• ASA toxicity threshold: $D \approx 20\text{ to }25\,\text{g}$ for salicylism
• Acetaminophen maximum daily dose: $\text{Max daily dose} = 4000\,\text{mg/day}$
• Acetaminophen dosing example (typical): $325\,\text{mg} \text{ to } 1000\,\text{mg every } 4-6\,\text{hours}$
• Note: Where applicable, drug-specific selectivity and mechanism are described in terms of COX-1 vs COX-2 actions and downstream effects (no single numeric equation, but the relationship is captured conceptually above)

Summary takeaways

• A broad range of agents targets inflammation and arthritis, from short-term symptom relief (NSAIDs, acetaminophen) to long-term disease modification (DMARDs, TNF blockers, gold compounds)
• Understanding the inflammatory cascade helps explain why different drugs have different targets, benefits, and risks
• Safety monitoring is essential, especially for NSAIDs (GI/renal), acetaminophen (liver), and biologic DMARDs/TNF blockers (infections, cancer risk)
• In clinical practice, combinations of drugs are common to achieve symptomatic relief, disease modification, and prevention of joint damage while balancing safety