P1

• Pain is a common complaint from patients seen at the clinics, from headache, dysmenorrhea, and joint pains of rheumatoid arthritis, osteoarthritis, and gouty arthritis
• Arachidonic Acid Pathway


  • Inflammatory signals triggers the hydrolysis of membrane phospholipids by phospholipase A2 to produce arachidonic acid
  • Arachidonic acid can be acted upon by lipoxygenase that will produce the leukotrienes involved in allergic inflammatory reactions like bronchospasm and smooth muscle contractions
  • Cyclooxygenase catalyzes the formation of prostaglandins involved in inflammation, pain, and fever, and the production of thromboxane A2 involved in platelet aggregation

  
• Thromboxane A2


  • Platelet aggregation
• Prostaglandins


  • Inflammation
  • Pain
  • Fever
• Leukotrienes


  • Bronchoconstriction
  • Smooth muscle contraction
• Cyclooxygenase (COX)


  Enzyme involved in the production of prostaglandins involved in pain and inflammation
• COX-1


  • Expressed constitutively in most cells
  • Housekeeping functions like controlling acid production by the parietal cells in the stomach
• COX-2


  • Induced by cytokines, shear stress, and tumor promoters
  • Inflammation and pain
• Uses of NSAIDs


  • Anti-inflammatory (inhibition of COX-1 & COX-2)
  • Analgesic (inhibition of PGE2 and PGI2)
  • Antipyretic (inhibition of prostaglandins induced by IL-1 and IL-6 in hypothalamus)
• NSAIDs


  • First line drugs to arrest inflammation and accompanying pain
  • Suppress the signs of underlying inflammatory response but may not resolve and reverse the inflammatory process
  • Treatment of chronic inflammation requires higher doses than those used in analgesia and antipyresis
• Antithrombotic activity of Aspirin

  • Aspirin reduces the formation of thrombi
  • Aspirin at low doses (80-100 mg) is more selective for COX-1 and has significantly greater antithrombotic activity than other NSAIDs
• Topical use of Salicylic Acid

  • Treatment of plantar warts, fungal infections, and corns
• Adverse effects of NSAIDs

  • Gastrointestinal (nausea, vomiting, diarrhea, constipation, dyspepsia, epigastric pain, bleeding and ulceration)
  • Hypersensitivity (rash, bronchospasm, rhinitis, edema, anaphylactic reaction)
  • Reye Syndrome
  • Renal impairment
  • Cardiovascular (increased risk of serious cardiovascular thrombotic events)
  • Prolonged bleeding time
  • Sulfonamide allergy
• Drug interactions with NSAIDs(CASH ALPS)

  • ACE inhibitors
  • Corticosteroids and selective serotonin reuptake inhibitors (SSRIs)
  • Anticoagulants and antiplatelets
  • Sulfonylureas
  • Methotrexate
  • Alcohol
  • Aspirin and other NSAIDs
  • Lithium
• Classification of NSAIDs(SPAPFEA)


  • Salicylates
  • Para-aminophenol Derivative
  • Acetic Acid Derivatives
  • Propionic Acid Derivatives
  • Fenamates
  • Enolic Acid Derivatives (Oxicams)
  • Aryl Heterocyclics (COX 2 Selective NSAIDs)
• Salicylates


  • Exemplified by Aspirin
  • Oral: Aspirin, Diflunisal
  • Topical: Salicylic Acid, Methyl Salicylate
  • Mechanism of action: Irreversible inhibitor of COX-1 and COX-2
  • Dosage: Antipyretic, Anti-inflammatory, Antiplatelet
  • Indications: Rheumatic fever, Ischemic control, Myocardial infarction
  • Pharmacokinetics: Rapidly absorbed, Peak plasma levels 1-2 hours, Half-life 3-5 hours, Highly protein bound
  • Adverse effects: Gastric irritation and bleeding, Hypersensitivity
• Acetaminophen (Paracetamol)


  • Weak inhibitor of COX-1 and COX-2
  • Reduces fever through inhibition of prostaglandin synthesis in the CNS and by increasing heat dissipation
  • Used for management of mild to moderate pain and temporary reduction of fever
• COX-1 and COX-2


  Enzymes inhibited by NSAIDs
• DOSAGE


  • Antipyretic (usual doses)
  • Anti-inflammatory (usual doses)
  • Antiplatelet (lasts for 8-10 days) in low doses: 80- 100 mg/day
• Antipyretic (usual doses)


  • Adults: 45 mg/Kg/day in divided doses
  • Children: 50-75 mg/kg/day in divided doses
  • Kawasaki Disease: 80-100 mg/day
• INDICATIONS


  • Synergistic with opioids for cancer pain control
  • Rheumatic fever
  • Ischemic control, myocardial infarction
  • Systemic Mastocytosis, Bartter Syndrome, Niacin Toxicity
• PHARMACOKINETICSof SALICYLATES (ASPIRIN)


  • Absorbed rapidly in the stomach and intestines
  • Peak Plasma levels: 1-2 hours
  • Half-life: 3-5 hours
  • Highly Protein Bound
• ADVERSE EFFECTS


  • Gastric irritation and bleeding, hypersensitivity
• Acetaminophen (USP) / Paracetamol (British Pharmacopeia)


  Active metabolite of PHENACETIN
• Acetaminophen


  Used for the management of mild to moderate pain and for temporary reduction of fever
• MOA of Acetaminophen


  • Weak inhibitor of COX-1 and COX-2
  • Reduces fever through inhibition of prostaglandin synthesis in the CNS and by inhibition of endogenous pyrogens in the hypothalamus
• DOSAGE of Acetaminophen


  • CNS Analgesic and antipyretic: Adults: 325-650 mg every 4 to 6 hours, Children: 10-15 mg/Kg/dose every 4 hours
  • Weak anti-inflammatory
• PHARMACOKINETICS of Acetaminophen


  • Well absorbed orally
  • Half-life of 2-3 hours
• ADVERSE EFFECTS of Acetaminophen

  • NAPQI is the toxic metabolite
  • May cause a mild increase in hepatic enzymes; nephrotoxicity, methemoglobinemia
  • Well-tolerated; No clinically relevant effects of cardiovascular and respiratory systems, platelets and GI tract
  • Severe liver damage can occur with overdose due to the accumulation of NAPQI
• Therapeutic uses of acetic acid derivatives

  • Rheumatoid arthritis
  • Osteoarthritis
  • Ankylosing spondylitis
  • Dysmenorrhea
  • Gouty arthritis
  • Bursitis
  • Tendonitis
  • Other forms of Arthritis (Juvenile, Psoriatic, and Reactive)
• Non-COX Selective Inhibitors


  • Indomethacin
  • Sulindac
  • Ketorolac
  • Tolmetin
• COX-2 Selective Inhibitors


  • Diclofenac
  • Etodolac
• Diclofenac


  • Commonly used drug in this group
  • Not recommended for children, nursing mothers and pregnant women
• PHARMACOKINETICS of Diclofenac


  • Hepatotoxic even at therapeutic doses
  • Can cause elevations of hepatic transaminases in plasma by more than 3x the upper normal limit indicating the significant liver damage even at therapeutic doses
  • At 150 mg/day renal blood flow may be impaired
• DOSE of Diclofenac


  • 50-70 mg QID
• INDICATIONS for Diclofenac


  • Osteoarthritis
  • Rheumatoid arthritis
  • Ankylosing spondylitis
  • Primary dysmenorrhea
• ADVERSE EFFECTS of Diclofenac

  • Similar to other NSAIDS: GI disturbances
  • Increased risk for myocardial infarction like in other COX-2 selective inhibitors
  • CNS effects
  • Rashes
  • Fluid retention
  • Edema
  • Renal function impairment
• Indomethacin is approved for closure of persistent patent ductus arteriosus
• Ketorolac


  • Has a rapid onset of action and a short duration
  • It is widely used in post-operative patients, but NOT routinely used for obstetric analgesia
  • Used for seasonal allergic conjunctivitis, postoperative ocular inflammation, and combined with phenylephrine as irrigation during cataract or intraocular lens replacement surgery to maintain pupils dilated, pupil size, prevent myosis, and reduce postoperative pain
• Propionic Acid Derivatives


  • Ibuprofen; Naproxen; Fenoprofen; Ketoprofen; Flurbiprofen
  • All are Non-selective Cyclooxygenase (COX) inhibitors