J O Pi Oid


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J O Pi Oid

  1. 1. Opioid Analgesics <ul><li>Roger McFadden 2007 </li></ul><ul><li>Click mouse to move show forward </li></ul>
  2. 2. Opioid Analgesics <ul><li>The body has its own analgesic system that has evolved to kick-in when an animal is injured </li></ul><ul><li>This in-built analgesia provides short-term relief from pain that enables an animal to escape from predators or extract themselves from a dangerous situation without being crippled with pain </li></ul><ul><li>Opioid analgesics utilise this system to provide controlled pain-relief </li></ul><ul><li>This system is stimulated by other stimuli beside pain, including exercise and stress </li></ul>
  3. 3. Reticular formation in brain stem Target area for opioid analgesia
  4. 4. Neuromodulation of nociceptive pathways <ul><li>The body possesses its own analgesic system which is centred in the periaqueductal grey matter of the brain </li></ul><ul><li>Efferent neurons from this area synapse in the reticular formation of the brain stem and then to the first order afferent neurons in the spinal cord </li></ul><ul><li>Here they release neurotransmitters which block the synaptic transmission of the afferent fibres and so attenuate the experience of pain </li></ul><ul><li>This area is a key target for analgesic drugs including opioids and (probably) paracetamol </li></ul>
  5. 5. Neuromodulation of nociceptive pathways <ul><li>Inhibitory neurotransmitters include GABA, norepinephrine and a family of endogenous opioid peptides </li></ul><ul><li>The endogenous opioid peptides vary in influence with location and include… </li></ul><ul><li>Brain –  -endorphin, dynorphin and enkephalins </li></ul><ul><li>Spinal cord </li></ul><ul><li>interneurons - esp. dynorphin </li></ul><ul><li>descending pathways – esp. enkephalins </li></ul>
  6. 6. Neuromodulation of nociceptive pathways <ul><li>Endogenous opioid peptides bind to several sub-types of opioid receptor… </li></ul><ul><li> (mu) </li></ul><ul><li> (delta) </li></ul><ul><li> (kappa) </li></ul><ul><li>Opioid drugs can bind to these receptors as agonists and produce similar effects to the endogenous opioid peptides </li></ul><ul><li>Most analgesic effects associated with  receptors </li></ul>
  7. 7. Neuromodulation of nociceptive pathways <ul><li>Most analgesic effects associated with  receptors </li></ul><ul><li>The following opioid analgesics are specific for  receptors… </li></ul><ul><li>morphine </li></ul><ul><li>codeine </li></ul><ul><li>methadone </li></ul><ul><li>buprenorphine </li></ul><ul><li>Fentanyl </li></ul><ul><li> and  receptors also contribute to analgesia </li></ul><ul><li>Nalbuphine and pentazocine also have specificity for  and  receptors </li></ul>
  8. 8. Mechanism of Neuromodulation <ul><li>The binding of endogenous or exogenous opioids to opioid receptors promotes the opening of K + channels and inhibits the opening of Ca 2+ channels </li></ul><ul><li>Opening K + channels hyperpolarises membranes and reduces neuronal activity </li></ul><ul><li>Closing Ca 2+ channels inhibits synaptic activity by reducing the release of neurotransmitters </li></ul>
  9. 9. Synapses between afferent nociceptive neurons and secondary ascending neurons relay pain signals to the brain. The entry of Ca 2+ into the pre-synaptic primary neuron and the release of K + from the post-synaptic secondary neuron are processes involved in signal transmission across the synapse .
  10. 10. Mechanism of Neuromodulation <ul><li>Opioids bind to  receptors associated with these channels </li></ul><ul><li>This firstly enhances the opening of K + channels and secondly inhibits the opening of Ca 2+ channels </li></ul><ul><li>This hyperpolarises the membrane and inhibits the release of neurotransmitters respectively </li></ul><ul><li>Both of these events inhibit the transmission of nociceptive signals to ascending pathways to the brain </li></ul>
  11. 11. Opioids binding to ion channel associated  receptors inhibit the influx of calcium ions into the pre-synaptic terminal and increase the outflow of potassium ions from the post-synaptic membrane. This has the effect of reducing the release of the neurotransmitter glutamate and hyperpolarising the post-synaptic membrane. Synaptic transmission is inhibited.
  12. 12. Physiological action of opioids <ul><li>The effects of opioids on neurological pathways is complex… </li></ul><ul><li>1. attenuation of nociceptive synapses in the dorsal horn </li></ul><ul><li>2. attenuation of nociceptive stimulation in periphery </li></ul><ul><li>3. stimulation of descending pathways that inhibit nociceptive synapses </li></ul>
  13. 13. Opioids – side effects <ul><li>Most opioid side effects associated with  receptors </li></ul><ul><li>respiratory depression (reduces sensitivity of respiratory centres in brain stem to CO2) </li></ul><ul><li>euphoria (and dysphoria via  receptors) </li></ul><ul><li>sedation </li></ul><ul><li>dependence </li></ul><ul><li>reduction in GI motility </li></ul><ul><li>bronchoconstriction (histamine release stimulated) </li></ul><ul><li>Different opioid drugs interact with different subspecies of receptor producing different actions and side effects </li></ul>
  14. 14. Opioids - tolerance <ul><li>Tolerance can develop rapidly with opioid use, requiring an increase in dose for effective analgesia. </li></ul><ul><li>Tolerance may be observed in side-effects too… </li></ul><ul><li>Tolerance may be observed in the mechanism that results in respiratory depression but constipation is worsened by large doses. </li></ul>
  15. 15. Pharmacokinetics <ul><li>Morphine is erratically absorbed but oral administration may be acceptable for chronic pain </li></ul><ul><li>Codeine is well absorbed orally but subject to considerable first-pass metabolism in the liver </li></ul><ul><li>The half life of most morphine analogues is around 3-6 hours </li></ul>
  16. 16. Opioid antagonists <ul><li>Opioid antagonists such as naloxone (short acting) and naltrexone (long-term), block  receptors and reverse the action of opioids </li></ul><ul><li>However, antagonists can make clinical pain worse </li></ul>
  17. 17. <ul><li>End of Presentation </li></ul>