lesson 12

• Inflammation


  Immune response is the body's way to defend itself from invading bacteria, fungi, and non-living substances that appear foreign and harmful (toxin, chemicals, drugs and foreign particles)

  
• Fever


  Abnormally high temperature associated with infection and is triggered by the release of prostaglandins

  
• Fever is always associated with infectious disease

  
• Mechanism of action of NSAIDs

  1. Inhibit the synthesis of prostaglandins

  2. Reduce pain

  3. Reduce inflammation

  4. Reduce fever

  
• Therapeutic uses of NSAIDs

  • Analgesics
  • Anti-inflammatory
  • Antipyretic

  
• COX-1


  Functioning is important in the maintenance of homeostasis
• COX-2


  Synthesis only increases when an inflammatory process occurs
• Side effects of NSAIDs

  • GI Ulceration
  • Effect on serum urate
  • Reversible decrease in GFR
  • Hypersensitivity reactions

  
• NSAIDs must be taken after eating
• Salicylates


  Non-acetylated: Methyl salicylate

  Acetylated: Aspirin (ASA) OR Acetylsalicylic acid

  
• Aspirin


  Absorbed wholly upon administration and hydrolyzed into active form in the systemic circulation. The hydrolytic product is acetic acid and salicylic acid. The main hydrolytic product responsible for its therapeutic effect is salicylic acid. Excretion is enhanced by urinary alkalinization.

  
• Signs and symptoms of salicylate poisoning

  • Tinnitus
  • Hyperventilation

  
• Treatment for salicylism


  • Emesis and gastric lavage to remove unabsorbed drug
  • IV NaHCO3 - Sodium Bicarbonate is a Systemic alkalinizer
  • Administration of fluid, electrolytes and supportive case

  
• Side effects of salicylates

  • Salicylism
  • Severe Anaphylactic Reactions
  • Reye's Syndrome

  
• Indomethacin


  One of the most potent inhibitor of COX isozyme

  
• Indomethacin


  • Closes ductus arteriosus
• Prostaglandin is responsible for maintaining the patency or opening/close of ductus arteriosus when baby is still in the womb
• Once baby is born, the lungs will be filled with air because of first breath hence there will be pulmonary vascular resistance and the blood flow to the right ventricle towards the lungs will be higher thus ductus arteriosus will close
• Oxicam derivatives


  Selective Cox-1 Inhibitor

  Long half life (OD)

  Relatively higher risk for PUD (Piroxicam) and NSAIDS than ends in OXICA

  
• Diclofenac


  Very common to market
• Nabumetone


  Only non-acidic NSAID (the rest are weak acidic drug)
• Sulindac


  Prodrug

  Active form: Sulindac Sulfoxide
• Ketorolac


  Potent analgesic activity: Comparable to Morphine

  1st NSAID used parenterally

  
• Indications for Ketorolac


  • Eye analgesic

  Short term management for moderate pain-severe

  Should be used in less than 5 days

  Common used in hospital
• Propionic acid derivatives


  Most widely used NSAIDs
• Naproxen


  Naproxen Test - a screening test to determine if a patient is suffering from an infection of neoplastic disease. It is a simple, non-invasive, inexpensive test. We dispense Naproxen Sodium 200mg orally every 8 hours for 3 days and there will be a sharp tick line in fever within 24 hours from infection. The sharp tick line or resolution of fever within 24 hours can suggest Neoplastic disease.

  
• Pyrrole alkanoic acid derivatives

  Contraindicated in patients with gout as they have an ability to increase uric acid level like tolmetin & aspirin

  
• Coxibs


  Also known as specific COX-2 inhibitors

  Celecoxib - most common

  Etodolac - common

  Etoricoxib

  Rofecoxib

  Parecoxib

  Valdecoxib

  
• Advantages of Coxibs


  • Lesser risk for NSAID induced PUD

  Less gastric irritating
• Disadvantages of Coxibs


  • Greater risk of acute thrombotic events, stroke and MI

  That's why Rofecoxib & valdecoxin is withdrawn in the market

  
• COX-2 is responsible for synthesizing prostacyclin hence the effect of antiaggregant will dominate because it will be hard to stop the thrombosis. Prostacyclin is the main antagonist of thromboxane A2 (pro aggregant of platelets).

  
• Paracetamol


  Analgesic and antipyretic activity

  Weak anti-inflammatory activity

  MOA: weak peripheral inhibitor at the peripheral circulation (of COX)

  
• Paracetamol metabolism


  Toxic form: NAPQI

  Antidote: N-Acetyl cysteine

  
• Mefenamic acid


  Analgesic only

  Should not be considered as an NSAID

  Taken with food

  
• Mefenamic acid should not be used for greater than 5 days and there is no study proving it is safe for children