OPIOID AGONISTS AND ANTAGONISTS

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OPIOID AGONISTS AND ANTAGONISTS

  1. 1. OPIOID AGONISTS AND ANTAGONISTS Dr. Robert L. Copeland
  2. 2. <ul><li>Narcotics Those drugs which possess both an analgesic (pain relieving) and sedative properties. </li></ul><ul><li>Opioid refer to drugs in a generic sense, natural or synthetic, with morphine- like actions </li></ul>
  3. 3. Classification of OPIOIDS <ul><li>Natural </li></ul><ul><ul><li>phenanthrene </li></ul></ul><ul><ul><ul><li>morphine 10% </li></ul></ul></ul><ul><ul><ul><li>codeine 0.5% </li></ul></ul></ul><ul><ul><ul><li>thebaine 0.2% </li></ul></ul></ul><ul><li>semisynthetic </li></ul><ul><ul><li>heroin </li></ul></ul><ul><ul><li>oxymorphone </li></ul></ul><ul><ul><li>Hydromorphone </li></ul></ul><ul><li>synthetic </li></ul><ul><ul><li>meperidine </li></ul></ul><ul><ul><li>methadone </li></ul></ul><ul><ul><li>morphinians </li></ul></ul><ul><ul><li>benzamorphans </li></ul></ul>
  4. 4. Chemistry <ul><li>Morphine </li></ul><ul><li>pentacyclic alkaloid (five ring structure) </li></ul><ul><li>oxygen bridge at 4,5 position </li></ul><ul><li>three major rings (a, b, c) </li></ul><ul><li>phenolic groups (s/a hydroxyl, alcoholic, OH) at position 3 and 6 </li></ul><ul><li>modifications at those positions changes pharmacokinetics and potency of drug </li></ul><ul><li>nitrogen at 16 position (n16) </li></ul><ul><li>changing it by adding an alkyl group converts it to naloxone (i.e. go from a agonist to an antagonist) </li></ul>
  5. 6. Receptor Stimulation <ul><li>mu </li></ul><ul><ul><li>P hysical dependence </li></ul></ul><ul><ul><li>E uphoria </li></ul></ul><ul><ul><li>A nalgesia (supraspinal) </li></ul></ul><ul><ul><li>R espiratory depression </li></ul></ul>
  6. 7. <ul><li>kappa </li></ul><ul><ul><li>S edation </li></ul></ul><ul><ul><li>A nalgesia (spinal) </li></ul></ul><ul><ul><li>M iosis </li></ul></ul>
  7. 8. <ul><li>delta </li></ul><ul><ul><li>a nalgesia (spinal & supraspinal) </li></ul></ul><ul><ul><li>re lease of g rowth h ormone    </li></ul></ul><ul><li>sigma </li></ul><ul><ul><li>d ysphoria (opposite of euphoria) </li></ul></ul><ul><ul><li>h allucination (both visual & auditory) </li></ul></ul><ul><ul><li>r espiratory and vasomotor stimulation </li></ul></ul><ul><ul><li>m ydriasis </li></ul></ul>
  8. 9. OPIOID receptors <ul><li>CNS distribution is not uniform </li></ul><ul><li>they are at areas concerned with pain </li></ul><ul><li>receptor locations beginning with highest concentration areas </li></ul><ul><li>1. cerebral cortex </li></ul><ul><li>2. amygdala </li></ul><ul><li>3. septum </li></ul><ul><li>4. thalamus </li></ul><ul><li>5. hypothalamus </li></ul><ul><li>6. midbrain </li></ul><ul><li>7. spinal cord </li></ul>
  9. 10. Endogenous Opioid Peptides <ul><li>Three distinct families of peptides have been identified: the enkephalins, the endorphins, and the dynorphins. Each family is derived from a distinct precursor polypeptide </li></ul><ul><li>These precursors are now designated as proenkephalin (also proenkephalin A), proopiomelanocortin (POMC), and prodynorphin (also proenkephalin B) </li></ul>
  10. 11. Endogenous Opioid Peptides <ul><li>Enkephalins </li></ul><ul><li>they are 5 amino acids long </li></ul><ul><li>also have met enkephalin (methionine at 5' position) and leu enkephalin (leucine at 5' position) </li></ul><ul><li>enkephalins are neuromodulators since they are small peptides, it was found that they came from larger peptides (pro enkephalins) proenkephalin gene codes for peptide 276 amino acid in length </li></ul><ul><li>cleavage of proenkephalin gives 4 to 5 pieces of activated enkephalins </li></ul>
  11. 12. <ul><li>Endorphin </li></ul><ul><li>POMC is processed into melanocyte-stimulating hormone (g-MSH), adrenocorticotropin (ACTH), and b-lipotropin (b-LPH); within the 91-amino-acid sequence of b-LPH are found b- endorphin and b-MSH </li></ul><ul><li>30 amino acid peptide </li></ul><ul><li>last 5 amino acids are the same sequence as enkephalins </li></ul><ul><li>endorphins are neurohormones </li></ul><ul><li>conservation between species </li></ul><ul><li>little difference in humans </li></ul>
  12. 13. <ul><li>Prodynorphin yields more than seven peptides that contain leu-enkephalin, including dynorphin A(1-17), which can be cleaved further to dynorphin A(1-8), dynorphin B(1-13), and a- and b-neoendorphin, which differ from each other by only one amino acid. </li></ul>
  13. 14. Pharmacokinetics <ul><li>absorption </li></ul><ul><li>readily absorbed from GI tract, nasal mucosa, lung subcutaneous, intramuscular, and intravenous route </li></ul><ul><li>distribution </li></ul><ul><li>bound free morphine accumulates in kidney, lung, liver, and spleen </li></ul><ul><li>CNS is primary site of action (analgesia/sedation) </li></ul>
  14. 15. <ul><li>metabolism/excretion </li></ul><ul><li>metabolic transformation in liver </li></ul><ul><li>conjugation with glucuronic acid </li></ul><ul><li>excreted by kidney </li></ul><ul><li>half life is 2.5 to 3 hours (does not persist in body tissue) </li></ul><ul><li>morphine 3 glucuronide in main excretion product </li></ul><ul><li>lose 90% in first day </li></ul><ul><li>duration of 10 mg dose is 3 to 5 hours </li></ul>
  15. 17. <ul><li>Morphine administration </li></ul><ul><li>oral morphine not given due to erratic oral availability </li></ul><ul><li>significant variable first pass effect from person to person and have intraspecies effect (same dose will vary in person day to day) </li></ul><ul><li>IV morphine acts promptly and its main effect is at the CNS </li></ul>
  16. 18. CNS is primary site of action of morphine <ul><li>analgesia </li></ul><ul><li>sedation </li></ul><ul><li>euphoria </li></ul><ul><li>mood change </li></ul><ul><li>mental cloudiness </li></ul>
  17. 19. Morphine analgesia <ul><li>** Changes our reaction and our perception of pain </li></ul><ul><li>severe cancer pain is tolerated more when person is given morphine </li></ul><ul><li>relieves all types of pain, but most effective against continuous dull aching pain </li></ul><ul><li>sharp, stabbing, shooting pain also relieved by morphine </li></ul><ul><li>Morphine given to a pain free individual </li></ul><ul><li>first experience is dysphoric </li></ul><ul><li>not experienced in person in pain </li></ul>
  18. 20. <ul><li>Morphine sedation - morphine causes sedation effect, but no loss of consciousness </li></ul><ul><li>Morphine euphoria </li></ul><ul><li>sense of well being </li></ul><ul><li>reason why morphine is abused </li></ul>
  19. 21. Effects of morphine on respiration <ul><li>There is a primary and continuous depression of respiration related to dose </li></ul><ul><li>decrease rate </li></ul><ul><li>decrease volume </li></ul><ul><li>decrease tidal exchange </li></ul>
  20. 22. <ul><li>mu receptor activation produces respiratory depression; with increase in dose can cause further respiratory depression </li></ul><ul><li>CNS becomes less responsive to pCO2 thereby causing a build up of CO2 </li></ul><ul><ul><li>rhythm and responsiveness causes irregular breathing patterns; one will see periods of apnea </li></ul></ul>
  21. 23. <ul><li>nausea and vomiting – Stimuation of CTZ, in area postrema of medulla </li></ul><ul><li>stimulation by stretch receptors causes nausea and vomiting </li></ul><ul><li>has afferents from gut and ear </li></ul><ul><li>involved in motion sickness </li></ul>
  22. 24. pupil size <ul><li>morphine causes miosis (pinpoint pupils) </li></ul><ul><li>kappa receptor effect </li></ul><ul><li>pinpoint pupils still responsive to bright light </li></ul><ul><li>oculomotor nerve (CN3) is stimulated by kappa receptor site </li></ul><ul><li>if kappa receptor is blocked, mydriasis from sigma effect will result </li></ul><ul><li>atropine partially blocks effect indicating parasympathetic system involved </li></ul>
  23. 25. Acute overdose <ul><li>High doses (overdose situation) of morphine </li></ul><ul><li>excitatory and spinal reflexes </li></ul><ul><ul><li>high doses of many OPIOID cause convulsions </li></ul></ul><ul><li>due to stimulation at sigma receptor </li></ul>
  24. 26. Cardiovascular effects <ul><li>Cardiovascular effects of morphine lead to vasodilation, thus a decrease in blood pressure </li></ul><ul><li>morphine causes the release of histamine and </li></ul><ul><li>suppression of central adrenergic tone and </li></ul><ul><li>suppression of reflex vasoconstriction </li></ul>
  25. 27. Morphine effects on the gastrointestinal system <ul><li>increase in tone and decrease in mobility leads to constipation </li></ul><ul><li>decreased concentration of HCl secretion </li></ul><ul><li>increased tone in stomach, small intestine, and large intestine </li></ul><ul><li>delay of passage of food (gastric contents) so more reabsorption of water </li></ul><ul><li>**tolerance does not develop (i.e. same amount of effect each time) to this constipation effect </li></ul>
  26. 28. Morphine effects on various smooth muscles <ul><li>biliary tract </li></ul><ul><ul><li>marked increase in the pressure in the biliary tract </li></ul></ul><ul><ul><li>10 fold increase over normal (normal is 20 mm H 2 0 pressure) </li></ul></ul><ul><ul><li>increase due to contraction of Sphincter of Oddi </li></ul></ul><ul><li>urinary bladder </li></ul><ul><ul><li>tone of detrusor muscle increased </li></ul></ul><ul><ul><li>feel urinary urgency </li></ul></ul><ul><ul><li>have urinary retention due to increased muscle tone where sphincter closed off </li></ul></ul><ul><li>bronchial muscle </li></ul><ul><ul><li>bronchoconstriction can result </li></ul></ul><ul><ul><li>**contraindicated in asthmatics, particularly before surgery </li></ul></ul><ul><li>uterus </li></ul><ul><ul><li>contraction of uterus can prolong labor </li></ul></ul>
  27. 29. Neuroendocrine Effects <ul><li>inhibit the release of gonadotropin-releasing hormone (GnRH) and corticotropin-releasing factor (CRF), thus decreasing circulating concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), ACTH, and b- endorphin; the last two peptides are usually released simultaneously from corticotrophs in the pituitary. As a result of the decreased concentrations of pituitary trophic hormones, the concentrations of testosterone and cortisol in plasma decline. Secretion of thyrotropin is relatively unaffected. </li></ul>
  28. 30. Tolerance to morphine <ul><li>nausea </li></ul><ul><li>analgesia </li></ul><ul><li>sedation </li></ul><ul><li>respiratory depression         </li></ul><ul><li>cardiovascular </li></ul><ul><li>euphoric </li></ul><ul><li>not to: </li></ul><ul><ul><li>miosis </li></ul></ul><ul><ul><li>constipation </li></ul></ul>
  29. 31. Toxicity of morphine <ul><li>acute overdose </li></ul><ul><li>respiratory depression </li></ul><ul><li>pinpoint pupils (miosis) </li></ul><ul><li>coma </li></ul><ul><li>Treatment </li></ul><ul><li>1. establish adequate ventilation </li></ul><ul><ul><li>1a. 4 point restraints needed </li></ul></ul><ul><li>2. give OPIOID antagonist (naloxone) </li></ul>
  30. 32. <ul><li>Naloxone </li></ul><ul><li>it has no agonist activity </li></ul><ul><li>it displaces morphine from all receptors, reverses all of the effects of morphine </li></ul><ul><li>its effects are immediate (3-5 min) </li></ul><ul><li>duration is 30-45 minutes must be reinjected often </li></ul>
  31. 33. Therapeutic uses of morphine <ul><li>relief of pain </li></ul><ul><li>terminal illness </li></ul><ul><li>preoperative medications </li></ul><ul><li>postoperative medications </li></ul><ul><li>acute pulmonary edema </li></ul><ul><li>constipating effect </li></ul><ul><li>cough </li></ul><ul><li>obstetrical analgesia </li></ul>
  32. 34. Drug interactions with Opioids <ul><li>**in general, the coadministration of CNS depressants with OPIOID often produces at least an additive depression (potentiation) </li></ul>
  33. 35. <ul><li>OPIOID and phenothiazines </li></ul><ul><li>produces an additive CNS depression as well as enhancement of the actions of OPIOID (respiratory depression) </li></ul><ul><li>this combination may also produce a greater incidence of orthostatic hypotension </li></ul><ul><li>OPIOID and tricyclics antidepressants </li></ul><ul><li>can produce increased hypotension </li></ul><ul><li>meperidine and MOA inhibitors </li></ul><ul><li>results in severe and immediate reactions that include excitation, rigidity, hypertension, and severe respiratory depression </li></ul>
  34. 36. <ul><li>OPIOID and barbiturates </li></ul><ul><li>increased clearance </li></ul><ul><li>morphine and amphetamine </li></ul><ul><li>enhanced analgesic effect </li></ul>
  35. 37. <ul><li>Codeine </li></ul><ul><li>change in the methyl group on 3 position (substituted for the hydroxyl group) </li></ul><ul><li>one tenth the potency (analgesic properties) of morphine </li></ul><ul><li>absorbed readily from GI tract </li></ul><ul><li>the absorption is more regular than morphine and more predictable </li></ul><ul><li>given orally </li></ul><ul><li>metabolized like morphine through glucuronic acid </li></ul><ul><li>physical dependence is necessity of drug so you don't go through withdrawal </li></ul><ul><li>tolerance and physical dependence is protracted from morphine since potency of codeine is low </li></ul><ul><li>withdrawal from codeine is mild in relation to morphine </li></ul><ul><li>antitussive drug for cough </li></ul>
  36. 38. <ul><li>Heroin (diacetylmorphine) </li></ul><ul><li>at 3 and 6 hydroxy positions, there are acetyl groups instead of hydroxyl groups </li></ul><ul><li>it is anywhere from 3 to 4 times the analgesic potency of morphine </li></ul><ul><li>heroin is the most lipophilic of all the OPIOID </li></ul><ul><li>morphine is the least lipophilic of all the OPIOID </li></ul><ul><li>OPIOID withdrawal is NOT fatal </li></ul>
  37. 39. <ul><li>When heroin is ingested, it crosses the blood brain barrier rapidly (morphine crosses slow) where it is hydrolyzed to monoacetyl morphine (acetyl group got cleaved off) and then it is hydrolyzed to morphine making more of the drug in the brain making it 3 to 4 times more potent </li></ul><ul><li>withdrawal symptoms of heroin similar to morphine, but more intense (rebound effect) </li></ul><ul><ul><li>mydriasis </li></ul></ul><ul><ul><li>diarrhea </li></ul></ul><ul><ul><li>vasoconstriction </li></ul></ul><ul><ul><li>dysphoria </li></ul></ul><ul><ul><li>etc. </li></ul></ul>
  38. 40. <ul><li>Hydromorphone (trade name is dilaudid) </li></ul><ul><li>have ketone at 6 hydroxyl position of morphine </li></ul><ul><li>also strong agonist </li></ul><ul><li>9 times more potent than morphine </li></ul><ul><li>more sedation than morphine so less euphoric feeling so not abused much </li></ul><ul><li>less constipation </li></ul><ul><li>does not produce miosis </li></ul><ul><li>tolerance and physical dependence is more intense than morphine because of its high potency </li></ul><ul><li>respiratory depression same as morphine </li></ul>
  39. 41. <ul><li>Fentanyl (Sublimaze) </li></ul><ul><li>synthetic drug </li></ul><ul><li>different structure than morphine </li></ul><ul><li>80 to 100 times more potent than morphine </li></ul><ul><li>rapidly acting drug </li></ul><ul><li>used as preoperative medication </li></ul><ul><li>short acting (30-45 min) </li></ul><ul><li>onset of action is 5 minutes </li></ul><ul><li>very high potency </li></ul><ul><li>highly abused ,known as china white as street name </li></ul>
  40. 42. <ul><li>Meperidine </li></ul><ul><li>produced in 1940's </li></ul><ul><ul><li>wanted drug with less addictive liability than morphine, but it has same addictive liability as morphine </li></ul></ul><ul><li>same CNS actions as morphine </li></ul><ul><li>sedation, analgesia, respiratory depression </li></ul><ul><li>potency same as morphine </li></ul>
  41. 43. <ul><li>unlike morphine: </li></ul><ul><li>more respiratory depression </li></ul><ul><li>more bronchoconstriction activity </li></ul><ul><li>less constipation </li></ul><ul><li>no antitussive activity </li></ul><ul><li>**it causes mydriasis (not miosis) </li></ul><ul><li>toxic effects similar to atropine </li></ul><ul><ul><li>dry as a bone, blind as a bat, red as a beet, mad as a hatter </li></ul></ul><ul><ul><li>have dry mouth </li></ul></ul><ul><li>drug absorbed orally </li></ul><ul><li>drug most abused by health care professionlas due to its availability </li></ul><ul><li>withdrawal similar to morphine </li></ul>
  42. 44. <ul><li>Methadone </li></ul><ul><li>pharmacological activity similar to morphine, same potency as morphine </li></ul><ul><li>long duration of activity </li></ul><ul><li>absorbed well orally </li></ul><ul><li>16 to 20 hour duration of action </li></ul><ul><li>powerful pain reliever </li></ul><ul><li>used in maintenance program for narcotic treatment </li></ul>
  43. 45. <ul><li>Diphenoxylate (Lomotil) </li></ul><ul><li>can be OTC drug now </li></ul><ul><li>**therapeutic use is antidiarrhea drug (treats diarrhea) </li></ul><ul><li>meperidine type drug </li></ul><ul><li>has very little analgesic properties at therapeutic dose </li></ul><ul><li>no antitussive effect </li></ul><ul><li>at high doses it has analgesic problems </li></ul><ul><li>causes respiratory depression and euphoria at high doses </li></ul>
  44. 46. Antagonism of Morphine <ul><li>two drugs: naloxone and naltrexone (pure antagonist) </li></ul>
  45. 47. <ul><li>Naloxone </li></ul><ul><li>no analgesic activity at all </li></ul><ul><li>competitive antagonist at mu, kappa, and sigma receptor </li></ul><ul><li>displaces morphine and other OPIOID from receptor site </li></ul><ul><li>reverses all actions of the OPIOID and does it rather quickly </li></ul><ul><li>it will precipitate withdrawal </li></ul><ul><li>person on heroin, then naloxone will precipitate withdrawal, but naloxone effects are seen in the first five minutes and it only lasts for 30 minutes: </li></ul><ul><li>increased blood pressure </li></ul><ul><li>metabolized same as morphine through glucuronic acid and excreted through kidney </li></ul>
  46. 48. <ul><li>Naltrexone </li></ul><ul><li>same effect of naloxone except it is used orally so can't use it if for person with acute toxicity </li></ul><ul><li>long duration of activity </li></ul><ul><li>single dose block action of heroin effects for 24 hours </li></ul><ul><li>used for emergency treatment </li></ul><ul><li>once stabilized, give patient naltrexone </li></ul><ul><li>patient get no euphoric effect from heroin so person gets off heroin (negative reinforcement) </li></ul><ul><li>approved for use by the FDA </li></ul><ul><li>also used for treatment of alcoholism  </li></ul>

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