Podcast
Questions and Answers
What are the two main isoforms of COX?
What are the two main isoforms of COX?
Which of the following is NOT a characteristic of COX1?
Which of the following is NOT a characteristic of COX1?
Which of these is a COX2 selective NSAID?
Which of these is a COX2 selective NSAID?
Aspirin irreversibly inhibits platelet COX1 activity.
Aspirin irreversibly inhibits platelet COX1 activity.
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Non-acetylated salicylates are a type of COX2 selective NSAID.
Non-acetylated salicylates are a type of COX2 selective NSAID.
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Which of these is a contraindication for aspirin?
Which of these is a contraindication for aspirin?
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What is the mechanism of action of methotrexate?
What is the mechanism of action of methotrexate?
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Which of the following adverse drug reactions (ADRs) is associated with methotrexate?
Which of the following adverse drug reactions (ADRs) is associated with methotrexate?
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Which of the following is NOT a Janus kinase (JAK) inhibitor?
Which of the following is NOT a Janus kinase (JAK) inhibitor?
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What type of DMARD is tofacitinib?
What type of DMARD is tofacitinib?
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Tofacitinib is indicated for the treatment of psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis.
Tofacitinib is indicated for the treatment of psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis.
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Upadacitinib has been shown to have a high degree of metabolism by CYP3A4.
Upadacitinib has been shown to have a high degree of metabolism by CYP3A4.
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Which of these is NOT a TNF-alpha inhibitor?
Which of these is NOT a TNF-alpha inhibitor?
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Certolizumab is a TNF-alpha inhibitor that targets the TNF-alpha receptor, p75.
Certolizumab is a TNF-alpha inhibitor that targets the TNF-alpha receptor, p75.
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Which of the following is NOT a major adverse drug reaction (ADR) associated with TNF-alpha inhibitors?
Which of the following is NOT a major adverse drug reaction (ADR) associated with TNF-alpha inhibitors?
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Anakinra is a:
Anakinra is a:
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Tocilizumab is a monoclonal antibody that binds to and inhibits interleukin-6.
Tocilizumab is a monoclonal antibody that binds to and inhibits interleukin-6.
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Rituximab is a B cell antibody that targets the CD20 antigen. This antigen is present on B cells but not on plasma cells.
Rituximab is a B cell antibody that targets the CD20 antigen. This antigen is present on B cells but not on plasma cells.
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Abatacept is a T cell activation inhibitor.
Abatacept is a T cell activation inhibitor.
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What is the characteristic feature of gout?
What is the characteristic feature of gout?
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Which of the following is a uricosuric drug?
Which of the following is a uricosuric drug?
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Pegloticase, a recombinant uricase, increases excretion of uric acid by converting it into allantoin, a highly water-soluble compound.
Pegloticase, a recombinant uricase, increases excretion of uric acid by converting it into allantoin, a highly water-soluble compound.
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Which of the following drugs competes with methotrexate for OAT in the proximal tubule?
Which of the following drugs competes with methotrexate for OAT in the proximal tubule?
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Allopurinol and febuxostat are both xanthine oxidase (XO) inhibitors.
Allopurinol and febuxostat are both xanthine oxidase (XO) inhibitors.
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Allopurinol is a selective and reversible XO inhibitor
Allopurinol is a selective and reversible XO inhibitor
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Which of the following is NOT a boxed warning associated with febuxostat?
Which of the following is NOT a boxed warning associated with febuxostat?
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Febuxostat is a non-purine analog and a selective, reversible XO inhibitor.
Febuxostat is a non-purine analog and a selective, reversible XO inhibitor.
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What are the two main classes of agents used to treat acute gout attacks?
What are the two main classes of agents used to treat acute gout attacks?
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Which of the following is NOT an anti-inflammatory agent used to treat acute gout attacks?
Which of the following is NOT an anti-inflammatory agent used to treat acute gout attacks?
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Colchicine works by inhibiting microtubule polymerization.
Colchicine works by inhibiting microtubule polymerization.
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Which of the following is an example of a uricosuric drug that can be used to prevent gout attacks by increasing uric acid excretion from the kidneys?
Which of the following is an example of a uricosuric drug that can be used to prevent gout attacks by increasing uric acid excretion from the kidneys?
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Allopurinol inhibits the production of uric acid by blocking the enzyme xanthine oxidase.
Allopurinol inhibits the production of uric acid by blocking the enzyme xanthine oxidase.
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Study Notes
Integrated Sequence VI - Winter Quarter 2024
- Course Topic: Pharmacology of NSAIDs, DMARDs, and Anti-Gout Agents
- Required Reading: Katzung 16th Ed., Chapters 36 & 18
- Recommended Reading: G&G 14th Ed., Chapters 39, 41, 42
- Instructor: Molly Yao, Ph.D., M.S.
Learning Objectives
- Students should be familiar with the effects of PGE2, PGI2, and TXA2.
- Students should compare and contrast the effects of COX1 and COX2.
- Students should be able to state the MOA, ADRs, and contraindications of NSAIDs.
- Identify COX non-selective and COX2 selective NSAIDs.
- Explain the toxicity of acetaminophen in relation to NSAIDs.
- Recognize the different classes of conventional synthetic (cs) and biological (b) DMARDs.
- Understand the MOA, ADRs, drug interactions, contraindications, and boxed warnings of DMARDs.
- Understand the MOA, ADRs, drug interactions, contraindications, and boxed warnings of anti-gout agents.
Review: Osteoarthritis (OA)
- Also known as degenerative joint disease.
- Characterized by cartilage degeneration, leading to structural and functional failure of synovial joints.
- An intrinsic disorder of cartilage, where chondrocytes respond to biochemical and mechanical stresses leading to matrix breakdown and repair failure.
Review: Eicosanoids and Prostaglandins
- Classically refers to unbranched 20-carbon fatty acids, derived from arachidonic acid, a component of phospholipids in plasma membrane inner leaflets of many cell types.
- Extremely prevalent and central to various metabolic pathways.
- Involved in a range of potent biological effects on many body systems, including inflammation, cellular signaling, cardiovascular and inflammatory pathophysiology, and smooth muscle tone.
Pathways of Arachidonic Acid (AA) Release
- Diverse physical, chemical, inflammatory, and mitogenic stimuli trigger the release of AA from membrane phospholipids.
- AA is processed through multiple pathways, including cyclooxygenase (COX) and lipoxygenase (LOX) pathways.
Cyclooxygenase (COX)
- A family of enzymes that convert AA to prostaglandins.
- Two main isoforms: COX1 and COX2.
- COX1 is constitutively expressed in most cells and generates prostanoids for "housekeeping" functions.
- COX2 is readily inducible and is the major source of prostanoids in inflammation and cancer.
Prostanoids Biosynthesis
- Prostaglandins differ from each other in their substituents and number of double bonds in the pentane ring and side chains.
PGE2 Effects
- Pain, fever, inflammation, and central sensitization.
- Crosses the blood-brain barrier and acts on thermosensitive neurons to regulate body temperature.
- Involvement in inflammation, including local blood flow, vascular permeability, and leukocyte chemotaxis.
PGE2 Effects on Kidneys
- Regulates renal function, particularly in marginally functioning kidneys or volume-contracted states.
- Affects renal blood flow and glomerular filtration rate.
- Impacts water and sodium excretion.
Prostanoids: Prostacyclin (PGI2) and Thromboxane (TXA2)
- PGI2 is produced by endothelial cells and inhibits platelet aggregation, opposing TXA2.
- TXA2 is produced by platelets and promotes platelet aggregation.
Prostanoid Receptors
- Five major types of G protein-coupled receptors (GPCRs): DP, EP, FP, IP, and TP, each with different ligands and signal transduction pathways.
Anti-Inflammation by Targeting AA
- Several strategies target AA to reduce inflammation, including steroid (IS3) and protein synthesis inhibitors.
NSAIDs
- Analgesic, antipyretic, and anti-inflammatory agents.
- COX1 and COX2 non-selective NSAIDs include ibuprofen, indomethacin, naproxen, and ketoprofen.
- COX2 selective NSAIDs include celecoxib, diclofenac, meloxicam, and etoricoxib.
- Aspirin irreversibly inhibits platelet COX1 activity, reducing thrombotic events.
NSAIDs: Pharmacology
- Highly metabolized by CYP3A4 and CYP2C enzymes.
- Excreted primarily through the kidneys.
- Exhibit varying degrees of enterohepatic recirculation.
NSAIDs: ADR & Contraindications
- Common gastrointestinal adverse effects, including abdominal discomfort, nausea, bleeding, and dysplasia.
- Contraindications include uncontrolled hypertension, uncontrolled nephrotic patients, and the third trimester of pregnancy.
NSAIDs: Drug Interactions
- Multiple NSAIDs should not generally be used together (except low-dose aspirin for cardioprotection).
- Aspirin should be separated in time from other NSAIDs to avoid drug interactions (at least 1 hour separation).
- NSAIDs can interact with other drugs, such as aminoglycosides or methotrexate.
Non-Aspirin Boxed Warnings
- Increased risk of serious GI adverse events in patients who are elderly.
- Increased risk of serious GI adverse events in patients taking systemic steroids, SSRIs, or SNRIs.
- Non-selective NSAIDs can unbalance TXA2 and PGI2 production.
- COX2 selective inhibitors do not affect TXA2 but do inhibit PGI2 production.
Acetaminophen
- Not an NSAID but has analgesic and antipyretic properties.
- Minimal anti-inflammatory effects.
- Mechanistic understanding is incomplete but likely involves weak COX inhibition and interactions with endogenous systems.
- High doses can be highly toxic to the liver and kidneys, potentially leading to severe hepatotoxicity and even death.
Review: Rheumatoid Arthritis (RA)
- A chronic inflammatory autoimmune disorder characterized by synovitis and often progressive joint destruction.
- Primarily attacks the synovial membrane lining the joint, resulting in inflammation and immune complex formation.
- Extra-articular lesions can affect other tissues and organs.
Review: Pathogenesis of RA
- Autoimmune response.
- Antibodies (i.e., Rheumatoid Factor) targeting self-antigens.
- Activated T-cells stimulate B cells and other inflammatory cells, leading to chronic inflammation.
- Genetic and environmental factors contribute to the condition's development.
Disease Modifying Anti-Rheumatic Drugs (DMARDs)
- NSAIDs provide symptom relief but do not alter the course of the disease.
- DMARDs can slow or halt disease progression.
- Conventional synthetic DMARDs include methotrexate, sulfasalazine, and hydroxychloroquine.
- Biological DMARDs target specific inflammatory pathways.
Disease Modifying Anti-Rheumatic Drugs (DMARDs) continued
- Janus kinase inhibitors (tofacitinib, baricitinib, upadacitinib) target inflammatory signaling pathways, specifically JAKs.
Disease Modifying Anti-Rheumatic Drugs (DMARDs) continued
- Tumor necrosis factor (TNF) inhibitors (etanercept, infliximab, adalimumab, golimumab) target components of the immune response, suppressing inflammatory cytokines like TNF-a.
- Interleukin-1 (IL-1) inhibitors (anakinra) target IL-1's role in inflammation.
Disease Modifying Anti-Rheumatic Drugs (DMARDs) continued
- Interleukin-6 (IL-6) inhibitors (tocilizumab, sarilumab) target IL-6-mediated signaling, reducing associated inflammation.
Review: B Cell in RA
- B cells are a type of white blood cell that produces antibodies.
- CD20 antigen is a protein found on B cells, frequently elevated in patients with certain B-cell malignancies.
bDMARDs: B Cell CD20 Antibody (Rituximab)
- Depletes B cells via several mechanisms including antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.
bDMARDs: T-Cell Activation Inhibitor (Abatacept)
- Abatacept is a fusion protein that blocks T-cell activation and inhibits inflammatory responses.
- MOA involves binding to CD80 and CD86 proteins on antigen-presenting cells (APCs), preventing T-cell activation.
Review: Gout
- Recurrent episodes of acute inflammatory arthritis due to monosodium urate crystal deposition in joints and cartilage.
- Uric acid crystal deposition leads to inflammation.
Gout Treatment: Acute Attacks
- Treatment focus is alleviating pain and inflammation.
- Agents such as NSAIDs, corticosteroids, and colchicine target the inflammatory response, modulating leukocyte activity, and inhibiting inflammation.
Gout Treatment: Prophylaxis
- Prophylactic treatment aims to prevent recurrent attacks by lowering uric acid levels.
- Agents such as probenecid, allopurinol, and febuxostat treat elevated uric acid levels.
Gout Treatment: Acute Attack Therapy (Colchicine), cont.
- Colchicine inhibits tubulin polymerization, disrupting neutrophil activation and migration and inflammatory responses, decreasing platelet aggregation and halting inflammation.
Gout Treatment: Acute Attack Therapy (IL-1 Receptor Antagonist)
- Similar mechanism as Canakinumab, inhibits IL-1a and IL-1ß for inflammatory response inhibition in inflammatory diseases.
Prophylactic Treatment Strategies Chronic Urate Lowering Therapy
- Methods aiming to lower uric acid levels and reduce or prevent crystal deposition in joints.
- Uricosuric drugs (probenecid): increase urinary excretion of uric acid.
- Recombinant uricase (pegloticase): Converts uric acid to allantoin, an easily excreted water-soluble substance.
- Xanthine oxidase inhibitors (allopurinol, febuxostat): prevents uric acid production.
Chronic Urate Lowering Therapy: Probenecid
- Probenecid is a uricosuric drug that increases the excretion of uric acid in the urine.
- Its mechanisms involves preventing reabsorption in the proximal convoluted tubule.
- Has ADRs, such as severe adverse effects of other weak acids.
Chronic Urate Lowering Therapy: Recombinant Uricase (Pegloticase)
- Pegloticase is a recombinant uricase that catalyzes the conversion of uric acid to allantoin.
- The modified PEG attachment increases its plasma half-life allowing improved excretion.
Chronic Urate Lowering Therapy: XO Inhibitors
- Allopurinol and febuxostat are Xanthine oxidase inhibitors.
- They prevent uric acid production by inhibiting xanthine oxidase.
- Allopurinol and Febuxostat decrease the concentration of uric acid
Chronic Urate Lowering Therapy: XO Inhibitors Continued
- Allopurinol causes more soluble (hypoxanthine) rather than less soluble (uric acid)
- May cause or precipitate acute attacks.
- Interactions with other agents may need monitoring.
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