opioid analgesics n.
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  1. OPIOID ANALGESICS Dr. Naila Abrar

  2. LEARNING OBJECTIVES After this session, you should be able to: • Classify opioids • Describe opioid receptor distribution and the mechanism of action of opioid analgesics • Discuss pharmacological effects, adverse effects and contraindications of opioids • Outline salient features of various opioid agonists, partial agonists and opioid antagonist.


  4. SOURCE • OPIUM • Poppy • Papaversomniferum • P album • Prototype: Morphine

  5. OPIUM “Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium”

  6. CHEMISTRY of OPIUM ALKALOIDS • Phenanthrene der. • Morphine • Codiene • Thebaine • Benzylisoquinoline der. • Papaverine • Noscapine

  7. CLASSIFICATION (Based on source) Naturally Occurring Opium Alkaloids: • Morphine, Codeine Semisynthetic Derivatives: • Diamorphine (Heroin), Etorphine, Buprenorphine, Hydromorphone, Oxymorphone, Hydrocodone, Oxycodone (phenanthrenes)

  8. Synthetic Morphine Substitutes: • Phenylpiperidine series: • Pethidine • Fentanyl, sufentanil, alfentanil, remifentanil • Diphenoxylate, Loperamide • Phenylheptylamines • Methadone, d– Propoxyphene • Morphinans • Levorphanol, levallorphan • Benzomorphan compounds • Pentazocine, Cyclazocine

  9. Terminology (recall) • Pure Agonist: has affinity for binding plus efficacy • Pure Antagonist: has affinity for binding but no efficacy; blocks action of endogenous and exogenous ligands • Mixed Agonist-Antagonist: produces an agonist effect at one receptor and an antagonist effect at another • Partial Agonist: has affinity for binding but low efficacy

  10. CLASSIFICATION OF OPIOID ANALGESICS OPIOID AGONISTS • Morphine • Methadone • Levorphanol • Fentanyl gp- sufentanil, remifentanil • Hydromorphone • Meperidine • Tramadol

  11. PARTIAL AGONIST/weak agonist • Codeine • Oxycodone • Hydrocodone • Propoxyphene • Dextropropoxyphene • Diphenoxylate

  12. MIXED AGONIST-ANTAGONIST • Nalbuphine • Nalorphine • Butorphenol • Pentazocine • Buprenorphine ANTAGONISTS • Naloxone • Naltrexone • Nalmefene

  13. Opioid alkaloids produce analgesia through actions at regions in the brain that contain peptides which have opioid-like pharmacologic properties ENDOGENOUS OPIOID PEPTIDES • Naturally occurring ligands for opioid receptors (endorphins) • Pentapeptides met-enkephalin & leu–enkephalin • These endogenous opioid peptides are derived from three precursor proteins

  14. PRECURSOR PROTIENS 1. Pre-proopiomelanocortin (POMC) Met-enkephalin sequence, B-endorphin, ACTH, B-lipotropin& MSH 2. Preproenkephalin Six copies of met-enkephalin & one copy of leu- enkephalin 3. Preprodynorphin Dynorphin A, dynorphin B, alpha & beta neoendorphins Endomorphins

  15. PHARMACOKINETICS ABSORPTION • Well absorbed • First-pass metabolism oral dose higher than parenteral dose DISTRIBUTION • Bind to plasma proteins but rapidly leave the blood and localize in highest concentrations in tissues that are highly perfused

  16. METABOLISM • Polar metabolites excreted by kidneys • Morphine conjugated to morphine-3-glucuronide (neuroexcitatory) • 10% metabolized to morphine-6-glucoronide(more potent analgesic) • Esters hydrolyzed by common tissue esterase • Heroin hydrolyzed by common tissue esterases to monoacetylmorphine (contd.)

  17. Phenylpiperidines hepatic oxidative metabolism • Meperidine is demethylated to normeperidine (seizures in high conc.) • Codiene-CYP2D6 (genetic polymorphism) EXCRETION • Polar metabolites, including glucuronide conjugates are excreted mainly in the urine

  18. PHARMACODYNAMICS MECHANISM OF ACTION • Opioid agonists produce analgesia by binding to specific GPCRs • Located primarily in brain & spinal cord regions involved in the transmission and modulation of pain

  19. Mechanism of action • Activation of peripheral nociceptive fibers- release of substance P and other pain-signaling neurotransmitters from nerve terminals in the dorsal horn of the spinal cord • Release of pain-signaling neurotransmitters is regulated by endogenous endorphins or by exogenous opioid agonists by acting presynaptically to inhibit substance P release, causing analgesia

  20. CELLULAR EFFECTS of Opioid Receptor Activation • Inhibition of neurotransmission due to opioid-induced presynaptic inhibition of neurotransmitter release • Involves changes in transmembrane ion conductance • Close voltage-gated Ca2+ channels on pre-synaptic nerve terminals reduce transmitter release • Open K+ channels thus hyperpolarize and inhibit postsynaptic neurons

  21. RECEPTOR TYPES • Three major classes • mu () • kappa (k) • delta (d) • GPCRs

  22. Majority of the opioid analgesics act primarily at the  receptors • Analgesia, euphoria, respiratory depression & physical dependence properties of morphine result principally from actions at the  receptor • Endogenous opioid peptides have more affinity for the k & d receptors • Reduced incidence for respiratory depression and addiction & dependence with k receptors but dysphoric effects

  23. RECEPTOR DISTRIBUTION • Dorsal horn of the spinal cord • Receptors present both on: • spinal cord pain transmission neurons & • primary afferents that relay the pain message to them

  24. NEUROANATOMY OF PAIN 1.Afferent pathways a) nociceptors (pain receptors) b) afferent nerve fibres c) spinal cord network 2.CNS-limbic system, reticular formation,thalamus, hypothalamus and cortex 3.Efferent pathways- fibres connectingthereticular formation, midbrain & substantia gelatinosa (responsible for pain modulation)

  25. Theory of pain production and modulation • Gate control theory(created by Melzack and Wall) • Nociceptive impulses are transmitted to the spinal cord through large A- delta& small C- fibers • Synapses in the SG • Cells in this structure function as a gate, regulating transmission of impulses to CNS

  26. Theory of pain production and modulation (contd.) • Stimulation of larger nervefibers (Aa, Ab) causes thecells in SG to "close the gate“ • A closed gate decreasesstimulation of 2nd afferent neuron, which decreases the transmission of impulses, & diminishes pain perception

  27. Theory of pain production and modulation (contd.) • Stimulation of small fiber input inhibits cells in SG and "open the gate". • An open gate increases the stimulation of 2nd order neuron cells & increases transmission of impulses and enhances pain perception • In addition to gate control through large and small fibers stimulation, the CNS, through efferent pathways, may close, partially close, or open gate • Cognitive functioning may thus modulate pain perception

  28. NEURAL MECHANISM OF ANALGESIA • Opioid agonists inhibit the release of excitatory transmitters from the primary afferents that relay the pain message to them • They directly inhibit the dorsal horn pain transmission neurons • Thus opioids exert a powerful analgesic effect directly on the spinal cord (contd.)

  29. Inhibit neurons in pain- modulating descending pathways • Inhibition of inhibitory neurons in several location • Neurons that send processes to the spinal cord & inhibit pain transmission are activated

  30. ORGAN SYSTEM EFFECTS OF MORPHINE & ITS SURROGATES CNS EFFECTS • Principal effects of opioid analgesics with affinity for  receptors are on CNS • Analgesia, euphoria, sedation & respiratory depression, cough suppression, miosis, truncal rigidity, nausea vomiting, temperature

  31. MIOSIS • Valuable in the diagnosis of opioid overdose (no tolerance) • Can be blocked by opioid antagonists • Mediated in part by parasympathetic pathways

  32. TRUNCAL RIGIDITY • Increase in tone of the large trunk muscles • Reduces thoracic compliance & thus interferes with ventilation • Prevented by concomitant use of neuromuscular blocking agents

  33. NAUSEA & vomiting • Activate brainstem CTZ TEMPERATURE - Homeostatic regulation of body temperature is mediated in part by endogenous opioid peptides • Hypothermia

  34. PERIPHERAL EFFECTS CARDIOVASCULAR SYSTEM • No significant direct effect on the heart & cardiac rhythm except bradycardia • Meperidine may result in tachycardia due to its antimuscarinic action • Blood pressure is usually well maintained unless the CVS is stressed, in which case hypotension may occur (due to peripheral arterial & venous dilation)

  35. GASTROINTESTINAL TRACT • Constipation • Tolerance does not develop • Opioid receptors present in high density • Stomach motility decreases but tone increases • Nonpropulsive contractions of intestine • Delayed passage of fecal mass

  36. BILIARY TRACT • Constrict biliary smooth muscle, which may result in biliary colic • Sphincter of Oddi may constrict, resulting in reflux of biliary & pancreatic secretions and elevated plasma amylase & lipase levels

  37. RENAL • Renal function is depressed • Due to decreased renal plasma flow • Opioids have an anti-diuretic effect • Enhance renal tubular sodium absorption • Ureteral & bladder tone are increased • Increased sphincter tone

  38. UTERUS • May prolong labor NEUROENDOCRINE • Stimulate release of ADH, prolactin, & somatotropin • Inhibit release of LH PRURITIS • Flushing & warming of the skin accompanied sometimes by sweating & itching

  39. MISCELLANEOUS • Modulate the actions of the immune system • Natural killer cell cytolytic activity & lymphocyte proliferative responses usually inhibited • Mediated by the sympathetic NS in acute administration & by the hypothalamic-pituitary-adrenal system in prolonged administration

  40. CLINICAL USE OF OPIOID ANALGESICS • Analgesia • Severe, constant pain • Sharp, intermittent pain is not as effectively controlled • Useful in the management of pain associated with cancer & other terminal illnesses • Used during obstetric labor (meperidine)

  41. Acute pulmonary edema • Remarkable relief in dyspnea from pulmonary edema associated with left ventricular failure • Involves reduced perception of shortness of breath & reduced patient anxiety as well as reduced cardiac preload (reduced venous return) and afterload (decreased peripheral resistance) • Useful in treating painful myocardial ischemia with pulmonary edema • morphine

  42. Relief of anxiety & apprehension in pts with MI, internal bleeding • They are NOT anxiolytics or hypnotics CARDIAC ASTHMA OR acute LVF • Reduce preload & after load – VD • Shift blood from pulm to systemic circuit • Relieves air hunger by depressing resp centre • Calms pt - decreases symp response – decrease workload

  43. Cough • Suppression of cough (obtained at doses lower than those needed for analgesia) • Both central & peripheral effects • Codeine, dextromethorphan, levopropoxyphene, noscapine • Diarrhea • Diarrhea from any cause • Crude opium preparations used in the past • Synthetic surrogates with more selective GI effects & few or no CNS effects are used (diphenoxylate, loperamide)

  44. Anesthesia • Frequently used as preanesthetic medication because of their sedative, anxiolytic, and analgesic properties • Also used intra-operatively both as adjuncts to other anesthetic agents and in high doses • Fentanyl, as a primary component of anesthetic regimen, most commonly in cardiovascular surgery • Neuroleptanesthesia ( contd. )

  45. Used as regional analgesics due to their direct action on the neurons of the spinal cord dorsal horn- epidural or subarachnoid space • Morphine is most frequently used • Adverse effects are less common • Respiratory depression, pruritis, nausea & vomiting may occur and can be reversed with naloxone • Fentanyl + LA- pain management • Post op shivering-meperidine used

  46. PATIENT CONTROL ANALGESIA (PCA) Parenteral infusion device controlled by the patient by pressing a button to deliver a programmed dose of the desired opioid analgesic

  47. TOXICITY & UNDESIRED EFFECTS • Direct toxic effects are extensions of their pharmacologic actions • Include respiratory depression, nausea, vomiting & constipation • Tolerance & dependence • Overdosage ( diagnosis & treatment) • Contraindications

  48. Stupor------- coma • RR low------- apnea, cyanosis • Hypotension • Pinpoint pupil • Hypothermia • Death due to resp. failure • TRIAD of pinpoint pupils, coma & resp. depression strongly suggests opioid poisoning