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Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
Opioid Pharmacology
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Opioid Pharmacology

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  • 1. Comparative Opioid Pharmacology
  • 2. Disclosure <ul><li>Analgesia is a labeled indication for all of the approved drugs I will be discussing. </li></ul><ul><li>I’ve consulted with Glaxo (remifentanil), Abbott (remifentanil), Janssen (Duragesic), Alza (Duragesic), Anesta (Actiq), and Delex (liposomal fentanyl) </li></ul>
  • 3. Classical Opioid Pharmacology <ul><li>Analgesia </li></ul><ul><ul><ul><li>modest to profound with no ceiling effect </li></ul></ul></ul><ul><li>Sedation </li></ul><ul><ul><ul><li>modest to profound, but has a ceiling effect </li></ul></ul></ul><ul><ul><ul><ul><ul><li>unconsciousness cannot be assured </li></ul></ul></ul></ul></ul><ul><li>Reduces MAC </li></ul><ul><ul><ul><li>with a ceiling effect </li></ul></ul></ul><ul><li>Synergy with hypnotics </li></ul><ul><ul><ul><li>modest at causing sedation </li></ul></ul></ul><ul><ul><ul><li>profound at suppressing movement response to noxious stimulation </li></ul></ul></ul>
  • 4. Classical Opioid Pharmacology <ul><li>High dose opioids are associated with hemodynamic stability </li></ul><ul><li>High dose opioids attenuate the stress response </li></ul>
  • 5. Classical Opioid Pharmacology <ul><li>Urinary retention </li></ul><ul><li>Ileus </li></ul><ul><li>Addiction potential </li></ul><ul><li>Ventilatory depression </li></ul><ul><li>Muscle Rigidity </li></ul><ul><li>Nausea, Vomiting </li></ul><ul><li>Pruritis </li></ul>
  • 6. Pure  agonists <ul><li>Intraoperative </li></ul><ul><ul><li>Fentanyl </li></ul></ul><ul><ul><li>Alfentanil </li></ul></ul><ul><ul><li>Sufentanil </li></ul></ul><ul><ul><li>Remifentanil </li></ul></ul><ul><li>Postoperative </li></ul><ul><ul><li>Morphine </li></ul></ul><ul><ul><li>Hydromorphone </li></ul></ul><ul><ul><li>Methadone </li></ul></ul>
  • 7. Morphine The prototypical opioid
  • 8. Morphine <ul><li>Endogenous Ligand </li></ul><ul><li>Slow rise to peak effect </li></ul><ul><ul><ul><li>Absolute peak analgesic effect is at 90 minutes after bolus injection! </li></ul></ul></ul><ul><li>Active metabolite </li></ul><ul><ul><ul><li>Morphine-6-glucuronide is unlikely to contribute to analgesic effects at standard OR doses. Will contribute to effects with chronic dosing </li></ul></ul></ul><ul><ul><ul><ul><li>Especially in renal failure </li></ul></ul></ul></ul><ul><li>Not as full efficacy as fentanyl series of opioids </li></ul>
  • 9. Simulation of Morphine Time Course Dahan et al. Anesthesiology. 2004 Nov;101(5):1201-9.
  • 10. Fentanyl The ever morphing molecule
  • 11. Fentanyl <ul><li>Among the pharmacologically cleanest opioid </li></ul><ul><li>The first of the “fentanyl” series (obviously…) </li></ul><ul><li>Available in transdermal, submucosal, sublingual, and (soon) inhaled forms. </li></ul>
  • 12. How we think of fentanyl: (small part of the market)
  • 13. Fentanyl morph 1: Duragesic
  • 14. Fentanyl morph 2: Actiq
  • 15. Fentanyl morph 3: E-trans fentanyl Viscusi et al, JAMA 2004 291:1333
  • 16. Fentanyl morph 4: Inhaled liposomal fentanyl Hung et al, Anesthesiology 1995 83:277-84
  • 17. Fentanyl morph 5: Inhaled fentanyl aerosol Mather et al, Br J Clin Pharmacol 1998 46:37
  • 18. Fentanyl morph 6: Effervescent Fentanyl (OraVescent) Pather et al, http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=5
  • 19. Sufentanil Newly morphing molecule
  • 20. Sufentanil <ul><li>10 fold more potent than fentanyl </li></ul><ul><li>Slightly slower onset </li></ul><ul><li>More rapid recovery </li></ul><ul><li>Very clean pharmacologically </li></ul>
  • 21. Sufentanil morph 1: Implantable sufentanil delivery http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=115
  • 22. Meperidine <ul><li>Bad Drug! Little role in the management of pain </li></ul><ul><li>Toxic metabolite </li></ul><ul><ul><li>Normeperidine  seizures </li></ul></ul><ul><ul><li>Renally excreted </li></ul></ul><ul><li>Negative inotrope </li></ul><ul><li>Causes tachycardia (anticholinergic) </li></ul><ul><li>Complex interactions </li></ul><ul><ul><li>MAO syndrome when combined with MAO inhibitors </li></ul></ul><ul><li>Useful for shivering, perhaps as a local anesthetic </li></ul>
  • 23. Hydromorphone A better morphine
  • 24. Hydromorphone <ul><li>A rapid onset morphine </li></ul><ul><li>No histamine release </li></ul><ul><li>About 8 fold more potent than morphine </li></ul><ul><li>No active metabolite </li></ul><ul><li>Good choice for PCA, post-op analgesia </li></ul>
  • 25. Alfentanil <ul><li>Less potent than fentanyl </li></ul><ul><li>Much more rapid onset (including more rapid onset of rigidity and respiratory depression) </li></ul><ul><li>Much more evenascent effect with a single bolus </li></ul><ul><li>With brief infusions will be almost indistinguishable from fentanyl, except for potency </li></ul>
  • 26. Remifentanil <ul><li>Similar potency to fentanyl </li></ul><ul><li>Pharmacokinetics are in a class by themselves (ester metabolism) </li></ul><ul><li>Reduce the dose by about 2/3s in the elderly </li></ul><ul><li>No pharmacokinetic interactions </li></ul><ul><li>Onset is similar to alfentanil </li></ul>
  • 27. Methadone The Under-Utilized Opioid
  • 28. Methadone <ul><li>Longest terminal half-life (about 1 day) </li></ul><ul><li>May accumulate during titration to steady state </li></ul><ul><li>Supplied as a racemic mixture </li></ul><ul><ul><li>L methadone is an opioid antagonist </li></ul></ul><ul><ul><li>D methadone is an NMDA antagonist </li></ul></ul>
  • 29. Fundamental PK/PD Parameters
  • 30. Comparative Opioid PK
  • 31. Comparative Opioid PK
  • 32. Comparative Onset of Opioid Drug Effect
  • 33. Context Sensitive Half Time
  • 34. 50% Effect Site Decrement Time
  • 35. 20% Effect Site Decrement Time
  • 36. Rise to Steady State
  • 37. Relative Potency
  • 38. 50  g fentanyl at 10 minutes
  • 39. 50  g/hour fentanyl at 2 hours
  • 40.  Opioid Receptor
  • 41. Evidence of  opioid subtypes <ul><li>Only about 50% cross tolerance between morphine, methadone, fentanyl </li></ul><ul><ul><ul><li>Explains why rotating opioids in chronic pain is probably a good idea </li></ul></ul></ul><ul><li>CXBK mouse is insensitive to morphine, but has normal response to M6G and fentanyl </li></ul><ul><li>Selective response to opioid antagonists </li></ul><ul><li>Morphine-6-glucuronide, the outlier </li></ul>Gavril Pasternak, Life Sciences 2001:68, 2213
  • 42. Naloxonazine <ul><li>Selectively antagonizes morphine analgesia in animals </li></ul><ul><ul><li> 1 is considered naloxonazine sensitive </li></ul></ul><ul><li>Does not antagonize morphine-induced ventilatory depression or GI effects </li></ul><ul><ul><li> 2 is considered naloxonazine insensitive </li></ul></ul>Gavril Pasternak, Life Sciences 2001:68, 2213
  • 43. Morphine-6-glucuronide <ul><li>Active metabolite of morphine, about 100 fold more potent intrathecally, but enters the CNS VERY slowly </li></ul><ul><li>Has analgesic activity in the CXBK mouse that is insensitive to morphine </li></ul><ul><li>Actions blocked by naloxonazine (hence,  1 ) </li></ul><ul><li>Has a unique antagonist, 3-O-methylnaxtrexone </li></ul><ul><ul><ul><li>Also antagonizes heroin self administration, little affect on morphine </li></ul></ul></ul><ul><li>Subtype of  1 </li></ul><ul><li>MOR-1 knockout (exon 1) has normal sensitivity to morphine-6-glucuronide </li></ul>Gavril Pasternak, Life Sciences 2001:68, 2213
  • 44. MOR-1 gene splice variants (gene=OPRM) Gavril Pasternak, http://www.mskcc.org/mskcc/html/11384.cfm
  • 45. Antisense lowers morphine analgesia (no effect on m6g) Gavril Pasternak, Life Sciences 2001:68, 2213
  • 46. Antisense lowers m6g analgesia (no effect on morphine) Gavril Pasternak, Life Sciences 2001:68, 2213
  • 47. Morphine-6-glucuronide <ul><li>Very slow transit across blood brain barrier. </li></ul><ul><li>Not a substrate for p-glycoprotein, but appears to be a substrate for probenecid inhibited transporters (Anesthesiology 2004:101 1394) </li></ul><ul><li>Recently a peptide based carrier demonstrated 4 fold increase in uptake and potency (JPET 2005:12 epub). </li></ul><ul><li>Some data show higher affinity for  1 , and lower affinity for  2 , compared to morphine. </li></ul><ul><li>Some suggestion that M6G is associated with less ventilatory depression for the amount of analgesia </li></ul><ul><ul><li>(e.g., Romberg et al, Anesthesiology 2004 100:120) </li></ul></ul>
  • 48.  1 selective agonists? <ul><li>Despite evidence now 25 years old of differential response to antagonists, nobody has found a  1 selective agonist </li></ul><ul><li>Biggest argument against it: Paul Janssen spent years looking for one, screening over 70,000 possible ligands </li></ul><ul><li>Reason for hope: perhaps our improved knowledge of MOR-1 splice variants will help identify the required pharmacophore </li></ul><ul><ul><ul><li>Don’t hold your breath… </li></ul></ul></ul>
  • 49. “ Power corrupts, PowerPoint corrupts absolutely” dr shabeel pn

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