Opioid analgesics (VK)

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Opioid analgesics (VK)

  1. 1. Narcotic analgesics – opium plant – poppy plant - capsule
  2. 2. Pain Signaling   These neurons release excitatory neurotransmitters which relay signals from one neuron to another. “The signals are sent to the thalamus, in which pain perception occurs. From the thalamus, the signal travels to the somatosensory cortex in the cerebrum, at which point the individual becomes fully aware of the pain (2).”
  3. 3. Types of Pain
  4. 4. Types of Pain – contd.
  5. 5. Opioids Narcotic analgesics Prototype: MORPHINE Major action - CNS/spinal cord Potent analgesia–Mu receptor agonist Mu, Kappa, Sigma, Delta Opioid receptor  decreased calcium  decreased glutamate  decreased excitation
  6. 6. Opioid Analgesics – important terms    Analgesics: Drugs -selectively relieves painacting in the CNS or on peripheral pain mechanisms(without significantly altering the consciousness) – Opioids and NSAIDS Opioids: drug binds -opioid receptorsantagonized by Naloxone . – Natural, Synthetic and semi-synthetic Narcotics: Drugs-opium or opium like compounds-potent analgesic effects-a/w significant alteration of mood and behavior-with the potential for dependence and tolerancerepeated administration.
  7. 7. Agonist Antagonist Mu Strong: Morphine, Pethidine, Methadone, Levorphanol, fentanyl, alfentanil, sufentanil, remifentanil Moderate: Oxycodone, codeine Weak: Propoxyphene PA: Buprenorphine- (long) Naloxone Naltrexone Nalmefene Nalbuphine Pentazocine Nalorphine – weak antagonist Butorphanol – weak antagonist kappa Nalbuphine,Pentazocine Butorphanol, Nalorphine Naloxone, Naltrexone Nalmefene Delta Naloxone, Naltrexone , Nalmefene Nalorphine (weak antagonist) Butorphanol – weak antagonist Sigma Naloxone, Naltrexone, Nalmefene
  8. 8. OPIOID/OPIATE RECEPTORS Mu = µ Delta = δ supraspinal analgesia, euphoria, respiratory depression, physical dependence µ1 = mainly analgesia µ2 = mainly respiratory depression Kappa = κ = spinal analgesia, miosis, sedation Sigma = σ = Dysphoria, halluci, respiratory depr and vasomotor stimulation
  9. 9. Where are the receptors ?     Limbic system including amygdaloid nucleus, hypothalamus Medial and lateral thalamus, area postrema (CTZ) Nucleus of tractus solitarious (cough center) Substantia nigra, and spinal cord
  10. 10. Terminology     Opioid agonist = activates some or all opioid receptors and do not block any. Partial agonist = a drug that can activate opioid receptor, but the response is submaximal Mixed agonist-antagonist = a drug that activates some receptor subtypes and blocks some other subtypes Pure antagonist = a drug that blocks all receptor subtypes
  11. 11. OPIOID RECEPTOR TRANSDUCER MECHANISMS
  12. 12. Mechanism of action      Opioid drug bind to opioid receptor widely distributed in CNS & other tissues A part of family of G-protein complex receptor Open K+ channels Prevent opening of Ca 2+ channels Inhibit the release of other neurotransmitters
  13. 13. Endogenous Opioid Peptides  3 distinct families of peptides Enkephalins Endorphins Dynorphins Each family -derived - distinct precursor of polypeptide
  14. 14. Acute effects -Analgesia -Dose dependent CNS depression -Respiratory depression– medulla -Histamine release – hypotension, peripheral vasodilation (decreased preload,afterload) bronchospasm -Cough suppressant -Decrease GI motility – constipation
  15. 15. Stimulant actions Euphoria, CTZ – N, V  Increased ICT  PINPOINT PUPILS - III N nucleus  NOTE : Meperidine (Pethidine) (ATROPINE- LIKE – MYDRIASIS)  Biliary sphincter contraction  Increased detrusor, sphincter tone urgency but retention  Uterine stimulation 
  16. 16. Uses Severe acute shooting visceral pain  MI  Terminal stages in malignancy  Severe crush injuries  Postoperative pain 
  17. 17. Contraindications/A/E Respiratory depression  -Old, young,COPD, kyphoscoliosis  Hypovolemia, hypotension  Increase ICT  HEAD INJURY  Increased intrabiliary pressure  UNDIAGNOSED ACUTE ABDOMEN  Liver disease, renal disease  Labor: respiratory depression in newborn 
  18. 18. Acute morphine poisoning Respiratory depression, hypoxia  Profound CNS depression, coma  Hypotension, PINPOINT PUPILS  Use antagonist  NALOXONE 0.4 mg IV q 2-3 min – pure anta- competitive – all receptors  VENTILATORY SUPPORT  NARROW MARGIN OF SAFETY 
  19. 19. Chronic effects      Dependence – physical, psychic Tolerance – Effect goes on decreasing on chronic use. Tissue tolerance – means - some tissues do not get tolerant. CNS develops tolerance, but GIT (constipation) and EYE (pinpoint pupils) do not develop tolerance !! So, Opiate addict has constipation and pinpoint pupils
  20. 20. How to treat – Morphine dependence  Substitute an agonist !  Which will be less potent than original drug – and which will have long duration of action This will give similar pleasure and withdrawing this drug will be easier due to long duration of action       (withdrawal symptoms will be less severe) So – 1. Methadone (long duration of action) or 2. Buprenorphine (mild withdrawal)
  21. 21. Opiate withdrawal symptoms  Hyperalgesia muscle cramps, stomach pain Mydriasis Diarrhea, Insomnia, Anxiety, Craving, Sweating, Rhinorrhea, Tachycardia, increased blood pressure  Treat with –  Methadone or buprenorphine (as replacement) Clonidine Beta blockers Benzodiazepines       
  22. 22. What is heroin?
  23. 23. Heroin, not heroine !!
  24. 24. What is heroin? Synthetic derivative of morphine  (diacetyl morphine)  Similar properties  Treatment of overdose or withdrawal – same as morphine 
  25. 25. Heroin’s effects on the body
  26. 26. Important opioids         Analgesia (MI, terminal cancer pain, post-op) -Meperidine(pethidine)- atropine-like -fentanyl (also as patches) -methadone, buprenorphine Others: -oxycodone, hydrocodone, propoxyphene Diarrhea – diphenoxylate, loperamide Cough-codeine, dextromethorphan
  27. 27. Pethidine (agonist) Opioid agonist, but is an atropine substitute  So, atropine-like effects: Less spasmogenic, less sphincter contraction  No urinary retention, produces MYDRIASIS  Less histamine release, safe in asthma  PO, IV, IM 50-100 mg. Short duration – 2-3 hours  Slow tolerance and dependence  Uses:  Preanesthetic medication  Post-operative pain, other severe pains  For analgesia during labor 
  28. 28. Fentanyl (agonist)          Congener of pethidine, Rapidly enters brain Short duration of action: 30-40 min During anesthesia as analgesic - IV Post-operative pain - IV Along with droperidol (neuroleptanalgesia)-IV Cancer pains – as patch Chronic pains – as patch IV: 1-2 mcg/kg Transdermal patch – 25-50 mcg per hour – this acts for 2-3 days
  29. 29. Methadone (agonist) (long duration)  T1/2 – 24-36 hours, Slow persistent action Less abuse potential  Withdrawal gradual, prolonged, less severe  1 mg methadone = 4 mg morphine = 2 mg heroin = 20 mg Pethidine  Is also Analgesic  2.5 – 10 mg oral or im   Used as substitute to treat morphine addiction
  30. 30. Mixed agonist-antagonists         Commonly used: Pentazocine Mu antagonist, K agonist: So, Good analgesic Oral (50-100 mg),IV IM (30-60 mg) Short duration of action Post-operative pain Pain due to burn, trauma, fracture, cancer Analgesia during anesthesia and other procedures Increases heart rate, BP, Remember: Do not use in MI Remember: such a drug can precipitate withdrawal in a morphine addict due to Mu antagonistic effect
  31. 31. Diphenoxylate (Lomotil)  therapeutic use is as antidiarrheal drug (treats diarrhea)  meperidine type drug  has very little analgesic properties at therapeutic dose  no antitussive effect  at high doses- analgesic problems  causes respiratory depression and euphoria at high doses
  32. 32. Codeine  change in the methyl group on 3 position  one tenth the potency of morphine  the absorption is more regular than morphine and more predictable  metabolized like morphine through glucuronic acid  tolerance and physical dependence is protracted from morphine since potency of codeine is low  withdrawal from codeine is mild in relation to morphine  antitussive drug for cough
  33. 33. Structural Activity Relationship HO- Group is needed for activity Inefficiently converted to HO group in the liver 2 HO 3 11 4 12 O 13 5 HO CH3O 1 10 15 O 9 14 H 8 6 16 H N H CH3 7 Morphine (Astramorph) HO- Group not important to activity H N CH3 HO Codeine (5X LESS potent than morphine)
  34. 34. PURE ANTAGONIST
  35. 35. Pure antagonists  Naloxone – for acute morphine poisoning – 0.4 mg IV q 2-3 min Naltrexone – tablet 50 mg qd - is of more benefit to decrease the sensation of craving during treatment of addiction – opiates, alcohol, and other drugs of abuse  Nalmefene 
  36. 36. Naloxone        no analgesic activity at all competitive antagonist at mu, kappa, and sigma receptor displaces morphine and other OPIOID from receptor site reverses all actions of the OPIOID and does it rather quickly it will precipitate withdrawal increases blood pressure metabolized same as morphine through glucuronic acid conjugation and excreted through kidney
  37. 37. Naltrexone         same effect of naloxone except -used orally so can't be used for person with acute toxicity long duration of activity single dose block action of heroin-24 hours used for emergency treatment once stabilized, give patient naltrexone After giving naltrexone patient- no euphoric effect from heroin so person gets off heroin (negative reinforcement) approved for use by the FDA also used for treatment of alcoholism
  38. 38. Pharmacokinetics of opoids Absorption  from GI tract, nasal mucosa, lung.  Also through subcutaneous, intramuscular, and intravenous route Distribution   Bound/free morphine accumulates- kidney, lung, liver, and spleen CNS is primary site of action (analgesia/sedation)
  39. 39. Metabolism/Excretion        metabolic transformation -liver conjugates with glucuronic acid excreted by kidney - glomerular filteration half life -2.5 to 3 hours morphine 3 glucuronide - main excretion product 90% is excreted in first day. duration of 10 mg dose- 3 to 5 hours
  40. 40. Drug interactions with Opioids  in general, the coadministration of CNS depressants with OPIOID often produces at least an additive depression (potentiation)
  41. 41. OPIOID and phenothiazines produces an additive CNS depression as well as enhancement of the actions of OPIOID (respiratory depression)  this combination - orthostatic hypotension  OPIOID and tricyclic antidepressants produce increased hypotension  meperidine and MAO inhibitors - severe and immediate reactions that include excitation, rigidity, hypertension, and severe respiratory depression 
  42. 42. OPIOID and barbiturates  increased clearance morphine and amphetamine  enhanced analgesic effect

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