Pharma

• 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, into the synovial cavity

  5. Ultimately leading to joint destruction and other systemic abnormalities characteristic of RA
• Rheumatoid arthritis (RA)


  • 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, a 20-carbon fatty acid, is the primary precursor

  2. Cyclooxygenase pathway: Prostaglandins, thromboxanes, and prostacyclins are synthesized

  3. Lipoxygenase pathway: Leukotrienes or lipoxins are formed

  
• Cyclooxygenase-1 (COX-1)


  • Responsible for the physiologic production of prostanoids, a housekeeping enzyme that 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
• Functions of prostaglandins


  • They control many physiological functions, such as acid secretion and mucus production in the gastrointestinal (GI) tract, uterine contractions, and renal blood flow
  • They are also among the chemical mediators that are released in allergic and inflammatory processes
• Non-steroidal anti-inflammatory drugs (NSAIDs)

  Have anti-inflammatory, analgesic, and antipyretic actions
• All NSAIDs act by inhibiting the cyclooxygenase enzymes that catalyze the first step in prostanoid biosynthesis, leading to decreased prostaglandin synthesis with both beneficial and unwanted effects
• Aspirin


  • Can be thought of as a traditional NSAID, but it exhibits anti-inflammatory activity only at relatively high doses that are rarely used
  • It is used more frequently at lower doses to prevent cardiovascular events such as stroke and myocardial infarction (MI)

  
• Aspirin


  It is an irreversible inhibitor of cyclooxygenase activity, unlike other NSAIDs which are reversible inhibitors

  
• Actions of Aspirin and other NSAIDs

  • Anti-inflammatory effect: Inhibition of cyclooxygenase diminishes the formation of prostaglandins like PGE2 which induce acute inflammation
  • Analgesic action: Decreasing PGE2 synthesis can decrease the sensation of pain
  • Antipyretic action: Lowering body temperature in patients with fever by impeding PGE2 synthesis and release

  
• No single NSAID has demonstrated superior efficacy over another, and they are generally considered to have equivalent analgesic efficacy
• The NSAIDs are used mainly for the management of mild to moderate pain arising from musculoskeletal disorders, with the exception of ketorolac which can be used for more severe pain but for only a short duration
• Fever occurs when the set-point of the anterior hypothalamic thermoregulatory center is elevated, which can be caused by PGE2 synthesis stimulated by endogenous fever-producing agents (pyrogens)
• The NSAIDs lower body temperature in patients with fever by impeding PGE2 synthesis and release, resetting the "thermostat" back toward normal, but they have no effect on normal body temperature
• Therapeutic uses of NSAIDs

  • Anti-inflammatory and analgesic uses: Osteoarthritis, gout, RA, headache, arthralgia, myalgia, dysmenorrhea
  • Antipyretic uses: Fever treatment
  • Cardiovascular applications: Reducing risk of recurrent cardiovascular events, TIAs, stroke, and death
  • External applications: Topical treatment of corns, calluses, warts, arthritis, seasonal allergic conjunctivitis, inflammation and pain related to ocular surgery
• Aspirin


  Irreversibly inhibits COX-1–mediated production of TXA2, thereby reducing TXA2-mediated vasoconstriction and platelet aggregation and the subsequent risk of cardiovascular events

  
• Low doses of aspirin

  75 to 162 mg (commonly 81 mg) are used prophylactically to reduce the risk of recurrent cardiovascular events, transient ischemic attacks (TIAs), stroke, and death in patients with a history of previous MI, TIA, or stroke

  
• Pharmacokinetics of aspirin


  • Rapidly deacetylated by esterases in the body to produce salicylate, which is passively absorbed mainly from the upper small intestine
  • Salicylate is converted by the liver to water-soluble conjugates that are rapidly cleared by the kidney
  • At anti-inflammatory dosages, the hepatic metabolic pathway becomes saturated, leading to a longer half-life

  
• Pharmacokinetics of other NSAIDs

  • Most are well absorbed after oral administration and circulate highly bound to plasma proteins
  • Majority are metabolized by the liver, mostly to inactivate metabolites
  • Excretion of active drug and metabolites is primarily via the urine
• Adverse effects of NSAIDs

  • Gastrointestinal: Increased risk of dyspepsia, bleeding, and ulceration due to reduced prostaglandin-mediated gastric protection
  • Increased risk of bleeding: Antiplatelet effect, especially with aspirin
  • Renal effects: Decreased synthesis of vasodilatory prostaglandins can lead to sodium and water retention, edema, and acute kidney injury

  
• Patients with a history of heart failure or kidney disease are at particularly high risk for the renal effects of NSAIDs

  
• Renal prostaglandins play an important vasoregulatory role, modulating the effects of vasoconstrictors like angiotensin II, vasopressin, and norepinephrine