21-23 PCol 1

• Analgesics


  Drugs designed to relieve pain without causing the loss of consciousness
• Anti-inflammatory analgesics


  • Reduce inflammation
• Opioid analgesics


  • Change the way the brain perceives pain by interacting with opioid receptors
• Drug Classifications


  • Opioids (CNS)
  • Nonopioids (PNS)
• Opioids


  • Natural opioids
  • Semisynthetic opioids
  • Synthetic opioids
• Opioids


  Have a narcotic effect, inducing sedation and effective for managing many types of pain
• Opioid receptors


  • Found extensively in the brain, spinal cord, vascular system, gut, lungs, airway, cardiac system, and some immune system cells
• Natural (Endogenous) Opioid peptides

  • Enkephalins
  • Endorphins
  • Endomorphine
  • Dynorphine
• Opioid receptors


  • Mu (u)
  • Kappa (k)
  • Delta (δ)
• Mu (u) receptors


  Responsible for majority of narcotic effects such as euphoria, sedation, addiction, miosis, constipation and respiratory depression
• Kappa (k) receptors


  Produce additional analgesia in women, activation produces dysphoria
• Delta (δ) receptors


  Induce spinal analgesia and modulation of rapid tolerance to mu (u) opioid agonists, bind to enkephalins
• Opioid overdose symptoms


  • Coma
  • Miosis (pinpoint pupils)
  • Respiratory depression
• Naloxone (Narcan®)


  An opioid antagonist used to reverse the toxic effects induced by opioids
• Approved clinical uses of opioids

  • Analgesics
  • Anesthetic agents
  • Antidiarrheals (Loperamide, Diphenoxylate)
  • Antitussive agents (Dextromethorphan)
• Morphine


  Standard of comparison as analgesic, extensive first pass effect, poor oral bioavailability (25-30% BA)
• Codeine


  Standard of comparison as antitussive drug, weaker analgesic than morphine
• Thebaine


  Precursor in synthesis of Naloxone
• Heroin/Diacetylmorphine/Diamorphine


  Recreational purpose, common drug of abuse
• Apomorphine


  Degradation product of morphine, not analgesic because it doesn't bind to u receptors, antiparkinson drug: D2 agonists, emetic drug for oral poisoning
• Hydromorphone, Oxymorphone


  1. 12x more potent than morphine
• Hydrocodone, Oxycodone


  1. 12x more potent than codeine
• Levorphanol


  1. 7x more potent than morphine, D-isomer: Dextromethorphan (antitussive)
• Loperamide, diphenoxylate


  Antidiarrheal agents
• Tramadol


  Weak u derivative of codeine
• Fentanyl, Alfentanyl, Sulfentanyl


  100x more potent than morphine
• Pentazocine


  Partial kappa agonist, u antagonist if combined with full agonist
• Methadone


  Same efficacy as morphine, good oral BA, longer duration of action, used to wean off patients addicted to Morphine and Heroin
• Meperidine/Pethidine (Demerol®)


  No cardiac and biliary effects, toxic metabolite: Normeperidine can cross BBB and causes seizure
• Phenacetin


  Prodrug metabolized into active drug Acetaminophen, withdrawn due to nephrotoxicity and methemoglobinemia
• Acetaminophen


  Weak PG synthesis inhibitor in the periphery by blocking Cyclooxygenase, used as analgesic agent and antipyretic, safe for pregnant and lactating women, toxic effect: hepatotoxicity (NAPQI)
• Nonsteroidal anti-inflammatory drugs (NSAIDs)


  Weak organic acids that inhibit prostaglandin synthesis by blocking the cyclooxygenase enzyme
• NSAID classifications


  • Nonselective NSAIDs (inhibit both COX-1 and COX-2)
  • Selective NSAIDs (inhibit only COX-2)
• Cyclooxygenase (COX)


  Central enzyme involved in the synthesis of prostanoids from Arachidonic acid, COX-1 involved in production of prostanoids under normal physiologic conditions, COX-2 involved in production of prostanoids in the presence of inflammation and at sites of chronic disease
• Aspirin (Acetylsalicylic acid or ASA)

  Prototype NSAID, irreversible COX inhibitor, adverse effects: gastritis, reversible decrease in GFR, hypersensitivity reactions, hyperuricemia and uricosuria
• Phenylbutazone, Dipyrone, Sulfinpyrazone

  Powerful analgesic and anti-inflammatory, withdrawn due to hematotoxicities and nephrotoxicities
• Indomethacin


  Blocks COX-1 > COX-2, higher risks of GI effects
• Tolmentin


  Uricosuric, contraindicated in gout
• Sulindac, Diclofenac, Ketorolac, Etodolac, Nabumetone

  Phenylacetic acid derivative NSAIDs, Sulindac may cause toxicity like Steven-Johnson Syndrome and Toxic epidermal necrolysis, Ketorolac commonly used for acute pain after surgery, reduces opioid dose requirements by 25% when co-administered
• Mefenamic acid, Meclofenamic acid

  Fenamate NSAIDs, analgesics only, maximum use: 5 days