Drugs for pain and inflammation notes

• Pain


  Serves as a protective function by signaling the presence of noxious, tissue-damaging conditions
• Px complaint


  Pain will be determined by asking PAIN SCALE RANGES 1-10 (10 being the most painful)
• Nociception


  Detection of painful stimuli
• Dorsal Root Ganglia (DRG) and Trigeminal ganglia


  • Terminate or project to a target organ
  • End connection is always at the SKIN and TISSUE
  • Detect for extreme heat and coldness
  • Alert body from touching potential danger
• Ganglia


  • Connected to a target organ or an effector organ
  • Have receptors that stick with receptor organ
• Nociception


  1. Dangerous stimuli - ion channels opening can cause conversion of that signal into action potential

  2. Propagate action potential to spinal cord

  3. Detection of painful stimuli

  4. CNS will detect the incoming pain and react
• Nociceptors


  • Receptors for pain
  • Free nerve endings found in every tissue of the body except the brain
  • Intense thermal, mechanical, or chemical stimuli can activate nociceptors
• Agents that can activate nociceptors

  • Prostaglandins
• Tissue irritation or injury


  • Prostaglandins, kinins and K+ ions released
  • Stimulate nociceptors
• Nociception


  Detection of a painful stimuli due to a presence of a substance or an agent that stimulates the nociceptor
• Prostaglandins (Autacoids)


  Capable of stimulating nociceptors since from COX 2, it could trigger nociception
• COX 1


  Mucus protection
• COX 2


  Pain and inflammation
• Mild to moderate arthritic pain (nociceptive pain)


  Treated with non-opioid analgesics (NSAIDs)
• Neuropathic pain


  Can be treated with opioids often at higher doses, but responds best with anticonvulsants, TCAs, or SNRIs
• Chronic or Severe Malignant/Non-Malignant pain


  Treated with opioids
• Opioids


  • Natural, semi-synthetic or synthetic compounds with morphine-like effects
  • Bind to specific opioid receptors in the CNS to produce effects that mimic the action of endogenous peptide neurotransmitters (like endorphins, enkephalins, and dynorphins)
• Primary use of opioids


  Relieve intense pain (pain that results from surgery, injury, or chronic disease)
• Main source of opioids


  • Papaver somniferum and P. album (poppy)
  • Incision of poppy seed pod exudates a white substance that turns into a brown gum that is crude opium (contains many alkaloids, the principal one is Morphine which is about 10% in opium)
• Opioid Receptors


  • Major effects of opioids are mediated by three receptor families
  • The three opioid receptors are membrane of the G-protein-coupled receptor family and inhibit adenylyl cyclase
  • Also associated with ion-channels, increasing post-synaptic K+ efflux (increase = hyperpolarization) and reducing pre-synaptic Ca+2 influx
  • Impeding neuronal firing and transmitter release
• Mu (μ) Receptor


  • Mediates analgesic properties of opioids
  • Modulates responses to thermal, mechanical, and chemical nociception
  • Involved in the rewarding and unwanted effect of morphine
• Kappa (κ) Receptor


  • Found in the dorsal horn
  • Contribute to analgesia by modulating the response to chemical and thermal nociception
  • Not involved in mechanical nociception
• Delta (δ) Receptor


  • Interacts with enkephalins in the periphery
  • Involved in mechanical nociception and inflammatory pain
• Endogenous Opioid Peptides


  Painful stimuli can evoke release of endogenous opioid peptides under the stress associated with pain or the anticipation of pain and they diminish the perception of pain
• Endorphins


  • Hormones released by the body to relieve pain, reduce stress, and improve sense of well-being
  • Have greater affinity for the Mu receptor
• Enkephalins


  • Act as neurotransmitters and neuromodulators
  • Provide analgesia, regulate Blood Pressure, involve in memory processes, and in neuroprotection
  • Have greater affinity for the Kappa receptor
• Dynorphins


  • Involved in negative emotional states, pain, addiction, and mood regulation
  • Have greater affinity for the Kappa receptor
• Opioid Receptor Subtypes


  • Mu: Supraspinal and spinal analgesia; sedation; inhibition of respiration; slowed GI transit; modulation of hormone and neurotransmitter release
  • Kappa: Supraspinal and spinal analgesia; modulation of hormone and neurotransmitter release
  • Delta: Supraspinal and spinal analgesia; psychotomimetic effects; slowed GI transit
• Opioids: Pharmacokinetic Properties


  • Absorption: most are well-absorbed when given SQ, IM or oral route; first pass effect is evident hence oral dose may need to be higher than parenteral dose to elicit therapeutic effect
  • Distribution: localize in highest concentrations in highly perfused tissues (organs that has high levels of blood flow) such as brain, lungs, kidneys and spleen
  • Metabolism: converted in large part to polar metabolites (mostly glucuronides)
  • Excretion: polar metabolites are excreted mainly in the urine; glucuronide conjugates are found in the bile
• Codeine and Oxycodone


  Effective orally due to reduced first pass metabolism
• Morphine


  Metabolized to Morphine-6-glucuronide (very potent analgesic) and Morphine-3-glucuronide (does not have analgesic activity)
• Metabolism of opioids


  1. PHASE 1: OXIDATION, REDUCTION, HYDROLYSIS

  2. PHASE 2: GLUCURONIDATION ETC.
• Opioid Agonists


  • Morphine: major analgesic drug contained in crude opium; prototype strong μ receptor agonist
  • Acts on Kappa receptors to decrease the release of Substance P
• Mechanism of Action of Morphine

  1. Morphine and other opioids exert their major effects by interacting stereospecifically with opioid receptors on the membranes of certain cells in the CNS and other anatomical structures (GI tract and urinary bladder)

  2. Morphine acts at κ receptors in lamina I and II of dorsal horn of spinal cord, decreases release of substance P which modulates pain perception in spinal cord and inhibit the release of excitatory transmitters from nerve terminals carrying nociceptive (painful) stimuli
• Morphine-6-glucuronide


  Metabolite of morphine that is more potent than morphine itself, responsible for 85% of the response produced by morphine
• Opioid Agonists: Actions


  • Analgesia: Raise pain threshold and alter brain's perception of pain
  • Euphoria: Produce powerful sense of contentment and well-being
  • Respiration: Cause respiratory depression by reduction of sensitivity of respiratory center neurons to CO2
  • Depression and Cough Reflex: Have antitussive properties (stop coughing mechanism)
  • Emesis: Directly stimulate chemoreceptor trigger zone in the area postrema that causes vomiting
  • Miosis: Cause pinpoint pupil (constriction of pupil) through stimulation of μ and κ receptors
  • Cardiovascular: Have no major effects on blood pressure or heart rate at lower doses, but may cause hypotension and bradycardia at large doses
  • Histamine Release: Release histamine from mast cells causing urticaria, sweating, and vasodilation
  • Hormonal Actions: Increase growth hormone release, enhance prolactin secretion, and increase antidiuretic hormone leading to urinary retention
  • Labor: May prolong 2nd stage labor by decreasing duration and frequency of uterine contraction
• Morphine is contraindicated in individuals with head trauma or severe brain injury due to its ability to increase cerebrospinal fluid pressure
• Bronchoconstriction


  Narrowing of the bronchioles which interferes with normal breathing mechanism
• Bronchoconstriction


  Causes double jeopardy
• Beta blockers


  Similar mechanism to bronchoconstriction - beta 1 (heart) and beta 2 (lungs) - if both beta is blocked, it is beneficial with hypertension (beta 1)