Pharmacology

• Inflammation


  A normal, protective response to tissue injury caused by physical trauma, noxious chemicals, or microbiologic agents
• Inflammation


  • It is the body's effort to inactivate or destroy invading organisms, remove irritants, and set the stage for tissue repair
  • When healing is complete, the inflammatory process usually subsides
• Inappropriate activation of the immune system


  Can result in inflammation and immune-mediated diseases such as rheumatoid arthritis (RA)
• Rheumatoid arthritis (RA)


  1. White blood cells (WBCs) initiate an inflammatory attack

  2. WBC activation leads to stimulation of T lymphocytes

  3. T lymphocytes recruit and activate monocytes and macrophages

  4. These cells secrete proinflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-1

  5. This leads to joint destruction and other systemic abnormalities characteristic of RA

  
• In addition to T lymphocyte activation, the B lymphocytes are also involved and produce rheumatoid factor and other autoantibodies to maintain inflammation

  
• Pharmacotherapy for RA


  Includes anti-inflammatory and/or immunosuppressive agents that modulate/reduce the inflammatory process, with the goals of reducing inflammation and pain, and halting or slowing disease progression
• Prostaglandins


  Unsaturated fatty acid derivatives containing 20 carbons that include a cyclic ring structure
• Lipids related to prostaglandins

  • Thromboxanes
  • Leukotrienes
  • Hydroperoxyeicosatetraenoic acids (HPETEs)
  • Hydroxyeicosatetraenoic acids (HETEs)

  
• Synthesis of prostaglandins


  1. Arachidonic acid is the primary precursor

  2. Cyclooxygenase pathway produces prostaglandins, thromboxanes, and prostacyclins

  3. Lipoxygenase pathway produces leukotrienes and lipoxins

  
• Cyclooxygenase-1 (COX-1)


  Responsible for the physiologic production of prostanoids, regulates normal cellular processes

  
• Cyclooxygenase-2 (COX-2)


  Causes the elevated production of prostanoids that occurs in sites of disease and inflammation, its expression is increased during states of inflammation

  
• Prostaglandins


  • Control many physiological functions, such as acid secretion and mucus production in the gastrointestinal (GI) tract, uterine contractions, and renal blood flow
  • Are also among the chemical mediators that are released in allergic and inflammatory processes

  
• Non-steroidal anti-inflammatory drugs (NSAIDs)


  A chemically heterogeneous group of organic acids that share certain therapeutic actions and adverse effects

  
• Actions of NSAIDs


  • Anti-inflammatory, analgesic, and antipyretic

  
• All NSAIDs act by inhibiting the cyclooxygenase enzymes that catalyze the first step in prostanoid biosynthesis, leading to decreased prostaglandin synthesis

  
• Aspirin


  A traditional NSAID that exhibits anti-inflammatory activity only at relatively high doses, used more frequently at lower doses to prevent cardiovascular events

  
• Mechanism of action of aspirin


  It is a weak organic acid that irreversibly acetylates and inactivates cyclooxygenase, while other NSAIDs are reversible inhibitors of cyclooxygenase

  
• Major therapeutic actions of NSAIDs


  • Reduce inflammation (anti-inflammatory)
  • Reduce pain (analgesic effect)
  • Reduce fever (antipyretic effect)

  
• Anti-inflammatory action of NSAIDs


  • Inhibition of cyclooxygenase diminishes the formation of prostaglandins, which induce acute inflammation through mast cell activation

  
• Analgesic action of NSAIDs


  Decreasing PGE2 synthesis can decrease the sensation of pain, as PGE2 sensitizes nerve endings to the action of other chemical mediators

  
• No single NSAID has demonstrated superior analgesic efficacy over another, they are generally considered to have equivalent analgesic efficacy

  
• Antipyretic action of NSAIDs

  They lower body temperature in patients with fever by impeding PGE2 synthesis and release, resetting the "thermostat" back toward normal
• Therapeutic uses of NSAIDs


  • Anti-inflammatory and analgesic uses (e.g. osteoarthritis, gout, rheumatoid arthritis, headache, arthralgia, myalgia, dysmenorrhea)
  • Antipyretic uses (e.g. aspirin, ibuprofen, naproxen)
  • Cardiovascular applications (e.g. aspirin for reducing risk of cardiovascular events)
  • External applications (e.g. salicylic acid for corns, calluses, warts; methyl salicylate in liniments; diclofenac gel or solution for osteoarthritis; ketorolac eye drops)

  
• Pharmacokinetics of aspirin


  Rapidly deacetylated to salicylate, which is passively absorbed mainly from the upper small intestine, crosses the blood-brain barrier and placenta, and is cleared by the kidney

  
• Pharmacokinetics of other NSAIDs


  Most are well absorbed orally, highly bound to plasma proteins, mostly metabolized by the liver, and excreted primarily via the urine

  
• Adverse effects of NSAIDs


  • Gastrointestinal (e.g. dyspepsia, bleeding)
  • Increased risk of bleeding (antiplatelet effect)
  • Renal effects (e.g. sodium and water retention, acute kidney injury)
  • Cardiac effects (increased risk of cardiovascular events)
  • Other effects (e.g. caution in patients with asthma)

  
• NSAIDs should be used at the lowest effective dose for the shortest duration possible due to the adverse event profile

  
• Cardiac effects


  Agents with high COX-1 selectivity (e.g. aspirin) have cardiovascular protective effect due to reduced TXA2 production

  Agents with higher COX-2 selectivity have increased risk of cardiovascular events, possibly due to decreased PGI2 production

  
• Increased risk of cardiovascular events, including MI and stroke, has been associated with all NSAIDs except aspirin

  
• Use of NSAIDs, other than aspirin, is discouraged in patients with established cardiovascular disease

  
• For patients with cardiovascular disease in whom NSAID treatment cannot be avoided, naproxen may be the least likely to be harmful

  
• Other adverse effects


  NSAIDs should be used with caution in patients with asthma as inhibition of prostaglandin synthesis can cause a shift toward leukotriene production and increase the risk of asthma exacerbations

  Central nervous system (CNS) adverse events, such as headache, tinnitus, and dizziness, may occur

  Approximately 15% of patients taking aspirin experience hypersensitivity reactions

  
• Drug interactions


  Salicylate is plasma protein bound and can be displaced, resulting in increased concentration of free salicylate

  Aspirin can displace other highly protein-bound drugs, resulting in higher free concentrations
• Toxicity


  Mild salicylate toxicity (salicylism) is characterized by nausea, vomiting, hyperventilation, headache, mental confusion, dizziness, and tinnitus

  Severe salicylate intoxication may result in restlessness, delirium, hallucinations, convulsions, coma, respiratory and metabolic acidosis, and death from respiratory failure

  Children are particularly prone to salicylate intoxication
• Pregnancy


  NSAIDs should be used in pregnancy only if benefits outweigh risks

  In the third trimester, NSAIDs should generally be avoided due to the risk of premature closure of the ductus arteriosus
• Celecoxib


  A selective COX-2 inhibitor, significantly more selective for COX-2 than COX-1

  Inhibition of COX-2 is reversible, unlike the irreversible inhibition of COX-1 by aspirin

  Approved for the treatment of RA, osteoarthritis, and acute pain

  Has similar efficacy to NSAIDs in the treatment of pain

  
• Celecoxib pharmacokinetics


  Readily absorbed after oral administration

  Extensively metabolized in the liver by CYP2C9

  Half-life is about 11 hours, may be dosed once or twice daily

  Dosage should be reduced in moderate hepatic impairment, avoided in severe hepatic or renal disease
• Celecoxib adverse effects


  Headache, dyspepsia, diarrhea, and abdominal pain are the most common

  Associated with less GI bleeding and dyspepsia than other NSAIDs, but this benefit is lost when aspirin is added

  Patients at high risk of ulcers requiring aspirin for cardiovascular prevention should avoid celecoxib

  Patients with anaphylactoid reactions to aspirin or nonselective NSAIDs may be at risk for similar effects with celecoxib

  Inhibitors of CYP2C9 may increase serum levels of celecoxib

  Similar risk for cardiovascular events as other NSAIDs

  
• Acetaminophen


  Inhibits prostaglandin synthesis in the CNS, leading to antipyretic and analgesic effects

  Has less effect on cyclooxygenase in peripheral tissues, accounting for its weak anti-inflammatory activity

  Does not affect platelet function or increase bleeding time

  
• Acetaminophen therapeutic uses


  Used for the treatment of fever and the relief of pain

  Useful in patients with gastric complaints/risks with NSAIDs and those who do not require the anti-inflammatory action of NSAIDs

  Analgesic/antipyretic of choice for children with viral infections or chickenpox (due to the risk of Reye syndrome with aspirin)