Questions and Answers
What is the primary effect of NSAIDs on prostaglandins?
What is the role of cyclo-oxygenase in the body?
What is the effect of NSAIDs on pain perception?
What is a common adverse reaction to NSAIDs?
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Which of the following is a contraindication for NSAID use?
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What is the role of Cyp p450 enzymes in NSAID metabolism?
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What is the function of hyaluronic acid in connective tissues?
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What is the anti-inflammatory mechanism of glucosamine?
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What is the primary source of glucosamine in the body?
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What is the potential therapeutic effect of exogenous glucosamine administration?
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Study Notes
Inflammatory Joint Disease
- Inflammatory joint disease, commonly referred to as arthritis, is characterized by inflammatory damage or destruction in the synovial membrane or articular cartilage.
- Systemic signs of inflammation include fever, leucocytosis, malaise, anorexia, and increased levels of fibrinogen in the blood.
- Inflammatory joint disease can be infectious, caused by the invasion of bacteria, etc. through contaminated needles or cuts.
Rheumatoid Arthritis
- Rheumatoid arthritis is a systemic, inflammatory autoimmune disease associated with swelling and pain in multiple joints, tends to be bilateral.
- The disease first affects the synovial membrane, which lines the joint cavity, and then spreads to the articular cartilage, fibrous joint capsule, and surrounding ligaments and tendons, causing pain, joint deformity, and loss of function.
- Rheumatoid arthritis can affect fingers, feet, wrists, elbows, ankles, and knees, as well as the shoulders, hips, and cervical spine, and may also involve the tissues of the lungs, heart, kidneys, and skin.
Pathophysiology of Rheumatoid Arthritis
- The pathophysiology of rheumatoid arthritis involves three processes:
- Neutrophils and other cells in the synovial fluid become activated, breaking down the surface layer of articular cartilage.
- Cytokines, particularly TNF-α, stimulate the release of pro-inflammatory compounds (especially IL-1) and cause the chondrocytes to attack cartilage.
- The synovium digests nearby cartilage, releasing inflammatory molecules.
- The mechanism of synovial and cartilage breakdown involves inflammatory phagocytes (neutrophils, macrophages) ingesting immune complexes and releasing powerful enzymes that degrade synovial tissue and articular cartilage.
Clinical Manifestations
- General systemic manifestations of inflammation include fever, fatigue, weakness, anorexia, weight loss, and generalised aching and stiffness.
- Joints become painful, tender, and stiff.
- Joint swelling is caused by increasing amounts of inflammatory exudate (leucocytes, plasma, plasma proteins) in the synovial membrane, hyperplasia (an increase in cell numbers) of inflamed tissues, and formation of new bone.
- Loss of mobility and range of motion, joint deformity, and complications such as cysts and nodules in the articular cartilage or subchondral bone and on the skin.
Complications
- Rupture of a cyst or of the synovial joint itself, usually caused by strenuous physical activity that places excessive pressure on the joint.
- Rupture releases inflammatory exudate into adjacent tissues, thereby spreading inflammation.
- Rheumatoid nodules, or swellings, are observed in areas of pressure.
Adverse Reactions
- Adverse reactions include anorexia, diarrhoea, loss of taste, nausea, vomiting, abdominal pain, allergic reactions, and stomatitis.
- May also impair renal function.
Sulfasalazine
- Sulfasalazine is a sulfonamide antibiotic (sulfapyridine) linked to an anti-inflammatory (salicylate mesalazine).
- Common adverse reactions include nausea, anorexia, rashes, tinnitus, dizziness, and headache.
- Serious adverse effects include haemolytic anaemia, agranulocytosis, and thrombocytopenia.
TNF-α Antagonists
- TNF-α antagonists prevent the stimulation of pro-inflammatory modulators.
- Infliximab is a monoclonal antibody that prevents TNF-alpha from binding to its receptor.
- Etanercept is a bioengineered fusion protein that binds to TNF-α and blocks its activity.
Cytokine Modulators
- Abatacept binds to antigen-presenting cells and modulates a key co-stimulatory signal required for activation of T lymphocytes.
- Anakinra binds to the interleukin 1 (IL-1) receptor, blocking its activation and reducing the inflammatory response.
- Rituximab is a monoclonal antibody that targets an antigen found on the surface of B lymphocytes, blocking the activation of T-cells and macrophages.
- Tocilizumab binds to IL-6 receptors, thus inhibiting the binding of IL-6 and inhibiting the inflammatory and immunological responses mediated by IL-6.
- Tofacitinib is a kinase 3 inhibitor that blocks cytokine pathways that lead to lymphocyte activation.
Folic Acid Antagonists -- Methotrexate
- Methotrexate is a folic acid antagonist that inhibits DNA synthesis and cell replication by competitively inhibiting the conversion of folic acid to folinic acid.
- Significant side effects include neutropenia, thrombocytopenia, and anaemia.
Glucocorticoid Steroid
- Glucocorticoid steroids bind to glucocorticoid receptor alpha (GR alpha) in the cytoplasm of cells.
- GR alpha -- steroid complex translocates to the nucleus of the cell and binds to glucocorticoid response elements, inducing or repressing the transcription of specific mRNAs.
- The synthesis of specific proteins is increased or decreased, and mediators are generated or suppressed.
Osteoarthritis
- Osteoarthritis is effectively a wearing out of the joint.
- It predominantly affects the weight-bearing joints.
- It tends to occur in men and women older than 40 years of age and becomes more common with increasing age.
Non-Steroidal Anti-Inflammatory Drug
- Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the enzyme cyclo-oxygenase (COX).
- COX catalyzes the oxygenation of arachidonic acid, which is metabolized principally to prostaglandins (PGs) and leukotrienes (LTs).
- PGs are involved in inflammation and pain, and NSAIDs reduce the inflammatory process and provide pain relief.
Adverse Reactions -- NSAIDS
- Adverse reactions include tinnitus, impaired haemostasis, and acid-base imbalances.
- NSAIDs are used with caution in the elderly and in people with compromised cardiac function and/or hypertension.
- Avoid use in persons with a history of hypersensitivity or a severe allergic reaction to aspirin (or to other NSAIDs), asthma, severe renal or liver disease, active ulcer disease, or GI bleeding.
Complimentary Drugs
- Hyaluronic acid injections boost the availability of hyaluronic acid for the production of cartilage and synovial fluid.
- Glucosamine is an endogenous amino-monosaccharide synthesized from glucose naturally in the body.
- Glucosamine is used in the biosynthesis of proteoglycans and glycosaminoglycans, which are the building blocks of cartilage.
- Exogenous administration of glucosamine may assist in regenerating lost cartilage.
- Glucosamine also has significant anti-oxidant activity, reducing reactive oxygen species in the inflammatory stage of osteoarthritis.
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