Opioids Drugs

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Complete source of Opioids presentation from Barash Clinical anesthesia.
By Dr.Khalid Al-Jonaieh

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Opioids Drugs

  1. 1. OPIOIDS Dr.Khalid Al-Jonaieh Demonstrator Anesthesia Department KKUH بسم الله الرحمن الرحيم
  2. 2. Terminology <ul><li>Opiate : </li></ul><ul><li>used to refer to drugs derived from opium including morphine. </li></ul><ul><li>Narcotic : </li></ul><ul><li>not useful in a pharmacologic or clinical context. </li></ul><ul><li>Affinity : </li></ul><ul><li>the ability to bind a receptor to produce a stable complex and intrinsic activity. </li></ul><ul><li>Efficacy : </li></ul><ul><li>the range in magnitude of an effect produced by a drug receptor combination relative to the maximum possible effect. </li></ul><ul><li>Potency : </li></ul><ul><li>the relative dose required to achieve an effect which related to receptor affinity. </li></ul>
  3. 3. Efficacy and Potency <ul><li>described by the dose-effect curve resulting from drug-receptor combination </li></ul>
  4. 4. ENDOGENOUS OPIOIDS AND OPIOID RECEPTORS <ul><li>All of the endogenous opioids are derived from three prohormones : </li></ul><ul><li>Proenkephalin </li></ul><ul><li>Prodynorphin </li></ul><ul><li>Pro-opiomelanocortin ( POMC ) </li></ul><ul><li>All being with the pentapeptide sequences of {Leu} or {Met}-enkephalin </li></ul>
  5. 5. Proenkephalin <ul><li>Widely distributed throughout the brain, spinal cord, and peripheral sites, particularly the adrenal medulla. </li></ul>
  6. 6. The dynorphin <ul><li>All begin with the [ Leu ]- enkephalin sequence and are widely distributed throughout the brain, spinal cord, and peripheral sites . </li></ul>
  7. 7. Pro-opiomelanocortin <ul><li>The common precursor of β - endorphin, ACTH, and melanocyte - stimulating hormone. </li></ul><ul><li>The term endorphin is reserved for peptides of the POMC family. </li></ul><ul><li>The major site of POMC synthesis is the pituitary, but it is also found in the pancreas and placenta . </li></ul>
  8. 8. Receptors <ul><li>The initial classification by Martin of opioid receptors into the three types </li></ul><ul><li>Based on binding activity of the exogenous ligands </li></ul><ul><li>Morphine mu (µ) </li></ul><ul><li>Ketocyclazocine kappa (κ) </li></ul><ul><li>SKF10,047 sigma ( σ ) </li></ul><ul><li>Other Opioid receptors identified : </li></ul><ul><li>Enkephalins delta ( δ ) </li></ul><ul><li>Endorphin epsilon (ε) </li></ul>
  9. 9. Selectivity <ul><li>Very few endogenous opioids exhibit great selectivity for a single receptor type. </li></ul><ul><li>Naloxone, the most commonly used opioid antagonist, is not selective for opioid receptor type. </li></ul><ul><li>Naltrindole ( a δ - opioid receptor antagonist ) </li></ul><ul><li>Nor - binaltorphimine ( a κ - opioid receptor antagonist ) . </li></ul>
  10. 10. Cellular Level <ul><li>Receptor binding initiates a series of physiologic functions resulting in cellular hyperpolarization and inhibition of neurotransmitter release, effects that are mediated by second messengers . </li></ul><ul><li>All opioid receptors appear to be coupled to G proteins, which regulate the activity of adenylate cyclase among other functions. </li></ul><ul><li>G protein interactions, in turn, affect ion channels. </li></ul><ul><li>Different ion may be involved at different opioid receptor types. </li></ul>
  11. 11. Pharmacokinetics & Pharmacodynamic <ul><li>Pharmacokinetics determines the relationship between drug dose and its concentration at the effect site(s). </li></ul><ul><li>Pharmacodynamic variables relate the concentration of a drug at its site of action, in this case opioid receptors in the brain and other tissues, and the intensity of its effects. </li></ul>
  12. 12. Pharmacokinetics <ul><li>The processes of absorption, redistribution, biotransformation, and elimination . </li></ul><ul><li>Compartmental models describe the time course of change in plasma concentration. </li></ul><ul><li>Opioids used in anesthesia are characterized by two - or three - compartment models. </li></ul><ul><li>Distribution phase : The early rapid decline in plasma concentration after the peak. </li></ul><ul><li>Elimination phase : The subsequent slower decline. </li></ul>
  13. 13. Pharmacokinetics <ul><li>Two main mechanisms are responsible for drug elimination </li></ul><ul><li>biotransformation </li></ul><ul><li>excretion </li></ul><ul><li>Opioids are biotransformed in the liver by two types of metabolic processes . </li></ul><ul><li>Phase I reactions include oxidative and reductive reactions, such as those catalyzed by cytochrome P450 system, and hydrolytic reactions . </li></ul><ul><li>Phase II reactions involve conjugation of a drug or its metabolite to an endogenous substrate, such as D - glucuronic acid . </li></ul><ul><li>Remifentanil is metabolized via ester hydrolysis , which is unique for an opioid . </li></ul><ul><li>With the exceptions of the N -dealkylated metabolite of meperidine and the 6- and possibly 3-glucuronides of morphine, opioid metabolites are generally inactive . </li></ul>
  14. 14. Pharmacokinetics <ul><li>Routes of opioid excretion: </li></ul><ul><li>Kidneys </li></ul><ul><li>The biliary system </li></ul><ul><li>Gut </li></ul>
  15. 15. Pharmacodynamic <ul><li>To reach its effector sites in the central nervous system ( CNS ) , an opioid must cross biologic membranes from the blood to receptors on neuronal cell membranes . </li></ul><ul><li>The ability of opioids to cross this blood–brain barrier depends on such properties as </li></ul><ul><li>molecular size </li></ul><ul><li>ionization </li></ul><ul><li>lipid solubility </li></ul><ul><li>protein binding </li></ul><ul><li>Of these characteristics, lipid solubility and ionization assume major importance in determining the rate of penetration to the CNS . </li></ul>
  16. 16. Pharmacodynamic <ul><li>Lipid solubility is measured as an octanol : water or octanol : buffer partition coefficient . </li></ul><ul><li>Drug ionization is also an important determinant of lipid solubility. </li></ul><ul><li>Nonionized drugs are 1,000 to 10,000 times more lipid - soluble than the ionized form . </li></ul><ul><li>The degree of ionization depends on the pKa of the opioid and the pH of the environment . </li></ul><ul><li>Plasma protein binding also affects opioid redistribution because only the unbound fraction is free to diffuse across cell membranes . </li></ul><ul><li>The major plasma proteins to which opioids bind are albumin and α 1-acid glycoprotein. </li></ul>
  17. 17. Morphine <ul><li>Analgesia </li></ul><ul><li>Effect on MAC of Volatile anesthesia </li></ul><ul><li>CNS effects </li></ul><ul><li>Respiratory Depression </li></ul><ul><li>Cough Reflex </li></ul><ul><li>Muscle Rigidity </li></ul><ul><li>Nausea and Vomiting </li></ul><ul><li>GIT Motility and Secretion </li></ul><ul><li>Biliary Track </li></ul><ul><li>Genitourinary Effects </li></ul><ul><li>Histamine Release </li></ul><ul><li>Cardiovascular Effects </li></ul><ul><li>Disposition Kinetics </li></ul><ul><li>Active Metabolites </li></ul>
  18. 18. Analgesia <ul><li>Morphine analgesia results from complex interactions at a number of discrete sites in the brain, spinal cord, and under certain conditions, peripheral tissues. </li></ul><ul><li>Involves both µ1 and µ2 opioid effects. </li></ul><ul><li>Act selectively on neurons that transmit and modulate nociception. </li></ul><ul><li>Leaving other sensory modalities and motor functions intact . </li></ul>
  19. 19. At the spinal cord level <ul><li>Presynaptically : </li></ul><ul><li>acts on primary afferent nociceptors to decrease the release of substance P. </li></ul><ul><li>Postsynaptically : </li></ul><ul><li>hyperpolarizes postsynaptic neurons in the substantia gelatinosa of the dorsal spinal cord to decrease afferent transmission of nociceptive impulses. </li></ul><ul><li>Spinal morphine analgesia is mediated by µ 2 - opioid receptors . </li></ul>
  20. 20. At the Supraspinal level <ul><li>Opioid analgesia originates in </li></ul><ul><li>the periaqueductal gray matter </li></ul><ul><li>the locus ceruleus </li></ul><ul><li>nuclei within the medulla </li></ul><ul><li>notably the nucleus raphe magnus </li></ul><ul><li>Primarily involves µ1-opioid receptors </li></ul><ul><li>Microinjections of morphine into any of these regions activate the respective descending modulatory systems to produce profound analgesia </li></ul><ul><li>Coadministration at the level of the brain and spinal cord increases morphine's analgesic potency nearly tenfold , an effect mediated by µ 2 -opioid receptors </li></ul>
  21. 21. At Peripheral Level <ul><li>An action when acute inflammation is present. </li></ul><ul><li>By activating peripheral opioid receptors </li></ul><ul><li>Mediated by µ 3 - opioid receptors . </li></ul><ul><li>In chronic pain conditions such as neuropathic pain or chronic arthritis, spinal and peripheral receptors may be down - regulated, a state that can decrease morphine analgesia. </li></ul>
  22. 22. Pain Relief <ul><li>The minimum effective analgesic concentration ( MEAC ) of morphine </li></ul><ul><li>For postoperative pain relief is 10 to 15 ng / mL </li></ul><ul><li>For more severe pain, plasma morphine concentrations of 30 to 50 ng/mL are needed to achieve adequate analgesia </li></ul>
  23. 23. Effect on MAC of Volatile Anesthetics <ul><li>Decreases MAC of volatile anesthetics in a dose - dependent manner. </li></ul><ul><li>1 mg / kg administered with 60% nitrous oxide ( N2O) blocks the adrenergic response to skin incision in 50% of patients, a characteristic called MAC-BAR </li></ul><ul><li>Epidural morphine 4 mg given 90 minutes prior to incision reduces halothane MAC by nearly 30%. </li></ul>
  24. 24. Other Central Nervous System Effects <ul><li>Cognitive and fine motor impairment </li></ul><ul><li>Euphoria,dysphoria </li></ul><ul><li>Sleep disturbances including reduction in rapid eye movement and slow-wave sleep. </li></ul><ul><li>slowing of EEG, increased voltage and decreased frequency . </li></ul><ul><li>Pruritus appears to be a µ receptor-mediated effect produced at the level of the medullary dorsal horn. </li></ul><ul><li>Antipruritic effect mediated by κ receptors & not histamine-mediated. </li></ul>
  25. 25. Hormonal Effects <ul><li>Affect the release of several pituitary hormones, both directly and indirectly </li></ul><ul><li>Inhibition of corticotropin - releasing factor </li></ul><ul><li>Inhibition of gonadotropin - releasing hormone </li></ul><ul><li>Which decreases circulating concentrations of : </li></ul><ul><li>ACTH </li></ul><ul><li>β - endorphin </li></ul><ul><li>follicle - stimulating hormone </li></ul><ul><li>luteinizing hormone </li></ul><ul><li>ِ Antidiuretic hormone release is inhibited </li></ul><ul><li>Prolactin and growth hormone concentrations may be increased by opioids. </li></ul>
  26. 26. Respiratory Depression <ul><li>Produce dose - dependent ventilatory depression. </li></ul><ul><li>Primarily by decreasing the responsivity of the medullary respiratory center to CO 2 . </li></ul><ul><li>Similar for young and elderly patients. </li></ul><ul><li>With increasing morphine doses, periodic breathing resembling Cheyne-Stokes breathing, decreased hypoxic ventilatory drive, and apnea can occur. </li></ul>
  27. 27. Cautions <ul><li>Oxygen desaturation </li></ul><ul><li>Obstructive apnea </li></ul><ul><li>Paradoxic breathing </li></ul><ul><li>Slow respiratory rate </li></ul><ul><li>Have been reported in asleep patients receiving morphine infusions for postoperative analgesia. </li></ul><ul><li>Obesity </li></ul>
  28. 28. Cough Reflex <ul><li>Depress by a direct effect on the medullary cough center . </li></ul><ul><li>Receptors mediating this effect appear to be less stereospecific and less sensitive to naloxone than those responsible for analgesia . </li></ul>
  29. 29. Muscle Rigidity <ul><li>Ex. abdominal muscle rigidity and decrease thoracic compliance </li></ul><ul><li>Large doses of IV morphine (2 mg/kg infused at 10 mg/min) </li></ul><ul><li>Increased by the addition of 70% N 2 O </li></ul><ul><li>Mediated by µ receptors at supraspinal sites. </li></ul><ul><li>These effects are reduced or eliminated by : </li></ul><ul><li>naloxone </li></ul><ul><li>muscle relaxants </li></ul><ul><li>drugs that facilitate GABA agonist activity such as thiopental and diazepam </li></ul>
  30. 30. Nausea and Vomiting <ul><li>The incidence appears to be similar if you use it as premedication or intraoperative. </li></ul><ul><li>The incidence appears to be similar what ever the route of administration. </li></ul><ul><li>including oral, IV, intramuscular, subcutaneous, transmucosal, transdermal, intrathecal, and epidural . </li></ul><ul><li>Laboratory and clinical studies comparing the incidence or severity of nausea and vomiting have found no differences among opioids in equianalgesic doses. </li></ul><ul><li>including morphine, hydromorphone, meperidine, fentanyl, sufentanil, alfentanil, and remifentanil . </li></ul>
  31. 31. The vomiting center <ul><li>Receives input from the chemotactic trigger zone ( CTZ ): </li></ul><ul><li>the area postrema of the medulla </li></ul><ul><li>pharynx </li></ul><ul><li>gastrointestinal tract </li></ul><ul><li>mediastinum </li></ul><ul><li>visual center </li></ul><ul><li>The CTZ is rich in opioid, dopamine, serotonin, histamine, and ( muscarinic ) acetylcholine receptors. </li></ul><ul><li>The CTZ receives input from the vestibular portion of the eighth cranial nerve . </li></ul>
  32. 32. Antiemetic <ul><li>At the level of the vomiting center: </li></ul><ul><li>High doses of morphine </li></ul><ul><li>Naloxone </li></ul><ul><li>Propofol </li></ul><ul><li>Benzodiazepines </li></ul><ul><li>Studies suggests that antiemetic effects of morphine are more short-lived than emetic effects. </li></ul><ul><li>Possible explanation for this observation is that the active metabolite morphine-6-glucuronide accumulates and worsens nausea. </li></ul>
  33. 34. Gastrointestinal Motility and Secretion <ul><li>Mediated by µ - , κ - , and δ - opioid receptors. </li></ul><ul><li>Inhibit gastric secretion </li></ul><ul><li>Decrease gastrointestinal motility and propulsion </li></ul><ul><li>Suppress diarrhea </li></ul><ul><li>Delayed gastric emptying </li></ul><ul><li>Decreases lower esophageal sphincter tone </li></ul>
  34. 35. Biliary Tract <ul><li>Increase the tone of the common bile duct and sphincter of Oddi . </li></ul><ul><li>Symptoms vary from epigastric distress to typical biliary colic and may even mimic angina . </li></ul><ul><li>Possibly via histamine release. </li></ul><ul><li>Antagonism of morphine's biliary effects by diphenhydramine supports this hypothesis. </li></ul><ul><li>Reversed by : </li></ul><ul><li>Naloxone </li></ul><ul><li>Atropine </li></ul><ul><li>Nitroglycerine </li></ul>
  35. 36. Genitourinary Effects <ul><li>Urinary retention. </li></ul><ul><li>Results in dyssynergia between the bladder detrusor muscle and the urethral sphincter because of a failure of sphincter relaxation . </li></ul><ul><li>Spinal morphine appears to cause naloxone - reversible urinary retention via µ - and / or δ - , but not κ - opioid receptors . </li></ul>
  36. 37. Histamine Release <ul><li>From circulating basophils. </li></ul><ul><li>From tissue mast cells in skin and lung. </li></ul><ul><li>Morphine - mediated histamine release is dose - dependent. </li></ul><ul><li>Not prevented by pretreatment with naloxone. </li></ul><ul><li>Suggesting that histamine release is not mediated by opioid receptors . </li></ul><ul><li>The decrease in peripheral vascular resistance seen with high - dose morphine ( 1 mg / kg ) correlates well with elevated plasma histamine concentration . Fentanyl </li></ul>
  37. 38. Cardiovascular Effects <ul><li>arteriolar and venous dilation. </li></ul><ul><li>decreased peripheral resistance. </li></ul><ul><li>inhibition of baroreceptor reflexes. </li></ul><ul><li>Lead to postural hypotension. </li></ul><ul><li>Mechanism: </li></ul><ul><li>histamine release. </li></ul><ul><li>morphine - mediated central sympatholytic activity. </li></ul><ul><li>direct action on vascular smooth muscle. </li></ul><ul><li>Caution : morphine's effect on vascular resistance is greater under conditions of high sympathetic tone . </li></ul><ul><li>Carefull with Severe Trauma & Cardiac Patients. </li></ul>
  38. 39. <ul><li>Does not suppress myocardial contractility. </li></ul><ul><li>Produce dose - dependent bradycardia. </li></ul><ul><li>In clinical anesthesia practice, opioids are often used to prevent tachycardia and reduce myocardial oxygen demand . </li></ul><ul><li>Patients undergoing cardiovascular surgery who received 1 to 2 mg / kg of morphine experienced minimal changes in heart rate, mean arterial pressure, cardiac index, and systemic vascular resistance . </li></ul><ul><li>Cautiously in spontaneously breathing patients with head injury or other conditions associated with elevated intracranial pressure. </li></ul>
  39. 40. Disposition Kinetics <ul><li>After IV administration morphine undergoes rapid redistribution </li></ul><ul><li>Mean redistribution half - time between 1.5 and 4.4 min. </li></ul><ul><li>pKa: 7.9 Nonionized 23% </li></ul><ul><li>Clearance: 1050 ml/min </li></ul><ul><li>Terminal elimination half - life between 1.7 and 3.3 hours. </li></ul><ul><li>35% protein bound, mostly to albumin . </li></ul><ul><li>Its steady - state volume of distribution is large, the range of 3 to 4 L / kg in normal adults . </li></ul><ul><li>The MEAC is 10-15 ng / mL. </li></ul>
  40. 41. <ul><li>Morphine's major metabolic pathway is hepatic phase II conjugation, to form morphine-3-glucuronide ( M3G ) and morphine-6 β - glucuronide ( M6G ). </li></ul><ul><li>The rate of hepatic clearance of morphine is high, with a hepatic extraction ratio of 0.7 </li></ul><ul><li>Extrahepatic sites such as kidney, intestine, and lung. </li></ul><ul><li>Unchanged morphine in the urine accounts for only about 10% of the dose . </li></ul><ul><li>A single IV dose, 40% of the dose are excreted in the urine as M3G and and 10% as M6G. </li></ul>
  41. 42. Active Metabolites <ul><li>M6G possesses significant µ receptor affinity and potent antinociceptive activity . </li></ul><ul><li>Because morphine glucuronides are eliminated by the kidney, morphine should be administered cautiously to patients with renal failure . </li></ul>
  42. 43. Dosage and Administration of Morphine <ul><li>Used mainly as a premedicant and for postoperative analgesia. </li></ul><ul><li>For adults range from 0.01 to 0.20 mg / kg . </li></ul><ul><li>When used in a balanced anesthetic technique with N2O, morphine can be given in total doses of up to 3 mg/kg. </li></ul><ul><li>When combined with other inhalation agents, it should not exceed more than 1 to 2 mg / kg. </li></ul><ul><li>The morphine dose associated with apparent cardioprotective effect is a single dose of 40 mg, given before cardioplegia and cardiopulmonary bypass . </li></ul>
  43. 44. Extra Info. <ul><li>Because of its hydrophilicity, morphine crosses the blood–brain barrier relatively slowly. </li></ul><ul><li>Its onset can be observed within 5 minutes </li></ul><ul><li>peak effects may be delayed for 10 to 40 minutes . </li></ul><ul><li>This delay makes morphine more difficult to titrate as an anesthetic supplement than the more rapidly acting opioids . </li></ul>
  44. 45. Meperidine <ul><li>A phenylpiperidine derivative. </li></ul><ul><li>Was the first totally synthetic opioid . </li></ul><ul><li>It was initially studied as an anticholinergic agent. </li></ul><ul><li>Last comment about this opioid was </li></ul><ul><li>Bad-Drug. 3 rd international anesthesia conference . </li></ul>
  45. 46. Analgesia and Effect on MAC of Volatile Anesthetics <ul><li>Potency is about one - tenth that of morphine's. </li></ul><ul><li>Mediated by µ - opioid receptor activation mostly. </li></ul><ul><li>Also has moderate affinity for κ - and δ - opioid receptors. </li></ul><ul><li>The MEAC of meperidine is 200 ng / mL </li></ul><ul><li>A dose - dependent reduction in the MAC of halothane . </li></ul>
  46. 47. <ul><li>Well - recognized weak local anesthetic properties . </li></ul><ul><li>Alters nerve conduction and produces analgesia . </li></ul><ul><li>Neuraxial meperidine may also produce sensory and motor blockade as well as sympatholytic effects that are not seen with other opioids . </li></ul>
  47. 48. Side Effects <ul><li>Therapeutic doses can produce: </li></ul><ul><li>sedation, pupillary constriction, and euphoria. </li></ul><ul><li>Very high doses produce CNS excitement and seizures. </li></ul><ul><li>In equianalgesic doses produce : </li></ul><ul><li>respiratory depression </li></ul><ul><li>nausea & vomiting </li></ul><ul><li>dizziness </li></ul><ul><li>delay in gastric emptying </li></ul><ul><li>increase common bile duct pressure </li></ul>
  48. 49. Cardiovascular Effects <ul><li>Not associated with hemodynamic instability. </li></ul><ul><li>1 mg / kg in patients with cardiac disease decreased heart rate, cardiac index, and rate–pressure product. </li></ul><ul><li>High dose depress contractility and significantly more hemodynamic instability than morphine or fentanyl, partially related to histamine release . </li></ul>
  49. 50. Shivering <ul><li>Causes : </li></ul><ul><li>general and epidural anesthesia </li></ul><ul><li>fever </li></ul><ul><li>hypothermia </li></ul><ul><li>transfusion reactions </li></ul><ul><li>administration of amphotericin B </li></ul><ul><li>Eliminates visible shivering prevent the increase of O2 consumption. </li></ul>
  50. 51. <ul><li>Equianalgesic doses of fentanyl (25 µg) and morphine (2.5 mg) did not reduce postoperative shivering </li></ul><ul><li>Not mediated by µ - opioid receptors . </li></ul><ul><li>Butorphanol effectively reduces postoperative shivering in a dose of 1 mg </li></ul><ul><li>Mediated by κ - opioid receptors . </li></ul>
  51. 52. <ul><li>Low doses of naloxone, sufficient to block µ receptors, did not reverse the antishivering effect of meperidine. </li></ul><ul><li>High - dose naloxone, designed to block both µ and κ receptors, did reverse the antishivering effect. </li></ul><ul><li>α 1-adrenergic agonists (clonidine 1.5 µg/kg), serotonin antagonists, and propofol, can reduce postoperative shivering. </li></ul><ul><li>Suggests that a nonopioid mechanism may be involved. </li></ul><ul><li>Physostigmine 0.04 mg / kg can also prevent postoperative shivering. </li></ul><ul><li>Suggesting a role for the cholinergic system . </li></ul>
  52. 53. Disposition Kinetics <ul><li>Following IV administration, plasma concentration falls rapidly. </li></ul><ul><li>Redistribution half - life is 4 to 16 minutes. </li></ul><ul><li>Its terminal elimination half - life is between 3 and 5 hours. </li></ul><ul><li>pKa : 8.5 nonionized 7% </li></ul><ul><li>Moderately lipid soluble. </li></ul><ul><li>40 to 70% protein bound mostly to albumin and α1-acid glycoprotein. </li></ul><ul><li>Large large Vd ss , range of 3.5 to 5 L/kg in adults. </li></ul>
  53. 54. <ul><li>High hepatic extraction ratio. </li></ul><ul><li>The high clearance rate :10 mL / kg / min. </li></ul><ul><li>It is N -demethylated in the liver to form normeperidine. </li></ul><ul><li>Also hydrolyzed to meperidinic acid. </li></ul><ul><li>Both metabolites may then be conjugated and excreted renally. </li></ul><ul><li>Normeperidine is pharmacologically active and potentially toxic. </li></ul>
  54. 55. Active Metabolites <ul><li>Normeperidine : pharmacological active. </li></ul><ul><li>Produce signs of CNS excitation. </li></ul><ul><li>Mood alterations such as apprehension and restlessness. </li></ul><ul><li>Neurotoxic effects such as tremors, myoclonus, and seizures. </li></ul><ul><li>The elimination half - life of the metabolite normeperidine ( 14 to 21 hours ) . </li></ul><ul><li>Mean plasma normeperidine concentration of 0.81 µg / mL developed seizures even with patients without renal dysfunction. </li></ul>
  55. 56. Dosage and Administration of Meperidine <ul><li>A single IV dose is approximately one - tenth as potent as morphine. </li></ul><ul><li>IV : a shorter duration of action. </li></ul><ul><li>IV analgesic doses for adults range from 0.1 to 1 mg / kg. </li></ul><ul><li>IV doses of 12.5 to 50 mg are effective in reducing postoperative shivering . </li></ul><ul><li>The total daily dose should not exceed 1,000 mg in 24 hours . </li></ul>
  56. 57. Methadone <ul><li>Primarily a µ agonist. </li></ul><ul><li>Pharmacologic properties that are similar to morphine . </li></ul><ul><li>Chemical structure is very different from that of morphine. </li></ul><ul><li>Pseudopiperidine ring for opioid activity. </li></ul><ul><li>Because of its long elimination half-life, mostly used for : </li></ul><ul><li>Long - term pain management </li></ul><ul><li>Treatment of opioid abstinence syndromes . </li></ul>
  57. 58. Analgesia and Use in Anesthesia <ul><li>The onset of analgesia is rapid, within 10 to 20 minutes. </li></ul><ul><li>After single doses of up to 10 mg, the duration of analgesia is similar to morphine. </li></ul><ul><li>Large or repeated parenteral doses, can reach up to 20 hours. </li></ul>
  58. 59. Side Effects <ul><li>Similar in magnitude and frequency to those of morphine . </li></ul><ul><li>Did not appear to have clinically significant respiratory depression . </li></ul><ul><li>About 50% experienced nausea or vomiting, which was easily treated with standard antiemetic therapy. </li></ul><ul><li>Decreases intestinal propulsive activity </li></ul><ul><li>Biliary spasm. </li></ul>
  59. 60. Disposition Kinetics <ul><li>Mean redistribution half - time is 6 min. </li></ul><ul><li>Mean terminal elimination T 1/2 is 34 hrs. </li></ul><ul><li>Well absorbed after an oral dose with bioavailability 90%, and peak plasma concentration at 4 hours. </li></ul><ul><li>90% plasma protein. </li></ul><ul><li>Extensive metabolism in the liver, mostly N -demethylation and cyclization to form pyrrolidines and pyrroline. </li></ul>
  60. 61. Dosage and Administration of Methadone <ul><li>To achieve prolonged postoperative analgesia </li></ul><ul><li>20 mg provide analgesia without significant post-OP respiratory depression. </li></ul><ul><li>Important note: that these long-acting opioids are not currently approved for prophylaxis of postoperative pain. </li></ul>
  61. 62. Fentanyl <ul><li>Structurally related to phenylpiperidines. </li></ul><ul><li>Clinical potency ratio 50 to 100 times that of morphine . </li></ul><ul><li>Progressive EEG changes (slow) with a lag of 3 to 5 minutes. </li></ul><ul><li>Resolution of EEG changes lagged by 10 to 20 minutes after stop of fentanyl infusion. </li></ul>
  62. 63. Analgesia <ul><li>A µ - opioid receptor agonist. </li></ul><ul><li>Dose - dependent analgesia. </li></ul><ul><li>Ventilatory depression. </li></ul><ul><li>Sedation. </li></ul><ul><li>High doses produce unconsciousness. </li></ul><ul><li>In post-OP patients, the mean fentanyl dose requirement was 55.8 µg/hr. </li></ul><ul><li>Mean plasma fentanyl concentration of 1.3 ng / mL reduced experimental pain intensity ratings by 50%. </li></ul>
  63. 64. Use in Anesthesia <ul><li>Reduces the MAC of volatile anesthetics in dose - dependent fashion. </li></ul><ul><li>A single IV bolus dose of fentanyl 3 µg / kg, given 25 to 30 min prior to incision, reduced both isoflurane and desflurane MAC by 50% . </li></ul><ul><li>3 ng / mL provides a 59% reduction of sevoflurane MAC. </li></ul><ul><li>Combining with propofol is a technique for providing general anesthesia, (TIVA). </li></ul>
  64. 65. <ul><li>The potency index for TIVA is described as the plasma concentration required to prevent a response in 50% ( CP 50 ) or 95% (CP 95 ) of patients to various surgical stimuli. </li></ul><ul><li>Fentanyl reduces requirements for both volatile agents and propofol by a similar proportion . </li></ul><ul><li>Spontaneous ventilation returned when the fentanyl concentration dropped to 1.5 to 2 ng / mL . </li></ul>
  65. 66. stress - free anesthesia <ul><li>Fentanyl has been used as the sole agent for anesthesia, a technique that requires a large initial dose of 50 to 150 µg / kg. </li></ul><ul><li>Significantly blunt the “ stress response ”—that is, hemodynamic and hormonal responses to surgical stimuli—while producing only minimal cardiovascular depression . </li></ul><ul><li>Disadvantages : </li></ul><ul><li>early extubation </li></ul><ul><li>“ fast - track” techniques because of prolonged respiratory depression </li></ul><ul><li>intraoperative awareness and recall </li></ul><ul><li>muscle rigidity </li></ul>
  66. 67. Other CNS Effects <ul><li>Increase middle cerebral artery flow. </li></ul><ul><li>Elevation in ICP. </li></ul><ul><li>Hypercarbia from fentanyl-induced respiratory depression influence fentanyl ionization and cerebral blood flow and hence the delivery brain tissue. </li></ul><ul><li>Muscle rigidity. </li></ul><ul><li>Instructed to deep - breathe during fentanyl induction may experience less rigidity. </li></ul><ul><li>Seizurelike movements represent as myoclonus. </li></ul><ul><li>Can activate epileptiform EEG activity in patients having surgery for intractable temporal lobe epilepsy. </li></ul><ul><li>Pruritus typically presents as facial itching. </li></ul>
  67. 68. Respiratory Depression <ul><li>Respiratory depression expressed as </li></ul><ul><li>elevation in end-tidal CO 2 </li></ul><ul><li>a decrease in the slope of the CO 2 response curve </li></ul><ul><li>decrease minute ventilation at an end-tidal CO 2 of 50 mm Hg (VE 50 ) </li></ul><ul><li>Greatly increased when it is given in combination with midazolam. </li></ul><ul><li>Blunts the hypoxic ventilatory drive to a greater extent than the hypercarbic ventilatory drive . </li></ul>
  68. 69. Airway Reflexes <ul><li>Expiration, panting, and coughing decreased, the duration of laryngospasm shortened, in a dose - dependent fashion . </li></ul><ul><li>These protective reflexes return to baseline rapidly after emergence. </li></ul>
  69. 70. Cardiovascular Effects <ul><li>Concentration - dependent negative inotropic effects. </li></ul><ul><li>A very high concentration reduced contractility by 50%. </li></ul><ul><li>In clinical practice up to 75 µg / kg is associated with hemodynamic stability. </li></ul><ul><li>7 µg / kg at induction had a slight decrease in heart rate, but no change in mean arterial pressure. </li></ul><ul><li>20 µg / kg, decreases 15% in heart rate, MAP, systemic and PVR seen in patients with CAD . </li></ul><ul><li>Does not prevent the inflammatory effects associated with cardiopulmonary bypass. </li></ul><ul><li>Does not produce the apparent cardioprotective effects. </li></ul>
  70. 71. Extra Info. <ul><li>Hypertension in response to sternotomy is the most common hemodynamic disturbance during high - dose fentanyl anesthesia and occurs in 40 and 100% in patients receiving 50 to 100 µg / kg . </li></ul><ul><li>Unlike morphine and meperidine, which induce hypotension, at least in part because of histamine release. </li></ul><ul><li>The combination of fentanyl and diazepam produces significant cardiovascular depression, increased central venous pressure significantly. </li></ul><ul><li>Adding 60% N2O to high-dose fentanyl produced a significant decrease in cardiac output and increases in systemic and pulmonary vascular resistance. </li></ul>
  71. 72. Endocrine Effects <ul><li>High - dose fentanyl ( 100 µg / kg ) prevented increases the “ stress response ” during surgery </li></ul><ul><li>plasma epinephrine </li></ul><ul><li>Cortisol </li></ul><ul><li>glucose </li></ul><ul><li>free fatty acids </li></ul><ul><li>growth hormone </li></ul><ul><li>but a lower dose of fentanyl did not . </li></ul><ul><li>( 5 µg / kg followed by an infusion of 3 µg / kg / h ) </li></ul>
  72. 73. Smooth Muscle and Gastrointestinal Effects <ul><li>Fentanyl, significantly increases common bile duct pressure ( the highest ) </li></ul><ul><li>Nausea and vomiting </li></ul><ul><li>Delay gastric emptying </li></ul><ul><li>Intestinal transit </li></ul>
  73. 74. Disposition Kinetics <ul><li>Fentanyl's extreme lipid solubility. </li></ul><ul><li>Rapid crossing of biologic membranes. </li></ul><ul><li>Rapid uptake by highly perfused tissue groups, including the brain, heart, and lung. </li></ul><ul><li>Thus, after a single bolus dose, the onset of effects is rapid and the duration brief. </li></ul><ul><li>pKa 8.4 Nonionized 8.5% </li></ul>
  74. 75. <ul><li>The onset within 10 seconds and correlated with a rapid increase in brain tissue fentanyl concentration, which equilibrated with plasma by 1.5 min . </li></ul><ul><li>Recovery from fentanyl effects started within 5 min and was complete by 60 min . </li></ul><ul><li>Peak muscle concentration was seen at 5 min . </li></ul><ul><li>Fat concentration reached a maximum 30 min , because of the limited blood supply to that tissue . </li></ul><ul><li>With prolonged administration of fentanyl, fat can act as a reservoir of drug . </li></ul>
  75. 76. <ul><li>The terminal elimination half - time ranged from 3.1 to 6.6 hours. </li></ul><ul><li>Significantly bound to red blood cells: 40%. </li></ul><ul><li>Blood: plasma partition coefficient of 1. </li></ul><ul><li>Highly protein bound, 79 to 87%. mostly α1-acid glycoprotein which is pH-dependent. </li></ul><ul><li>Decrease in pH will increase the proportion of fentanyl that is unbound. </li></ul><ul><li>Thus, a patient with respiratory acidosis will have a higher proportion of unbound ( active ) fentanyl, which could exacerbate respiratory depression . </li></ul>
  76. 77. <ul><li>Clearance of fentanyl is primarily by rapid and extensive metabolism in the liver . </li></ul><ul><li>Indicate a high hepatic extraction ratio. </li></ul><ul><li>Which dependent on liver blood flow . </li></ul><ul><li>Metabolism is primarily by N -dealkylation to norfentanyl. </li></ul><ul><li>By hydroxylation of both the parent and norfentanyl. </li></ul><ul><li>6% is excreted unchanged in the urine. </li></ul>
  77. 78. Dosage and Administration of Fentanyl <ul><li>Single bolus dose short - acting opioid. </li></ul><ul><li>Very large doses and multiple doses prolonged respiratory depression and delayed recovery could occur. </li></ul><ul><li>useful as a sedative / analgesic premedication : 25 to 50 µg IV. </li></ul><ul><li>A transmucosal delivery system is effective premedicant for pediatric and adult patients as well as an effective treatment for “breakthrough” pain in chronic pain patients, should be administered in a monitored environment . </li></ul>
  78. 79. Intubation Time <ul><li>Fentanyl blunt the hemodynamic response to laryngoscopy and tracheal intubation, which can be particularly severe in patients with hypertension or cardiovascular disease . </li></ul><ul><li>doses of 1.5 to 5 µg / kg </li></ul><ul><li>Should be complete approximately 3 min prior to laryngoscopy to maximally blunt hemodynamic responses to tracheal intubation . </li></ul><ul><li>Administration of up to 3 to 5 µg / kg / hr will allow recovery of spontaneous ventilation at the end of surgery . 0.5 to 2.5 µg / kg every 30 minutes . </li></ul>
  79. 80. cardiac surgery <ul><li>Prevents hemodynamic changes in response to noxious stimuli, can be achieved with: </li></ul><ul><li>a loading dose of 50 µg/kg, </li></ul><ul><li>followed by a continuous infusion of 30 µg/kg/hr. </li></ul>
  80. 81. Sufentanil <ul><li>A thienyl derivative of fentanyl. </li></ul><ul><li>Has a clinical potency ratio 2,000 to 4,000 times that of morphine. </li></ul><ul><li>Has a clinical potency ratio 10 to 15 times that of fentanyl . </li></ul><ul><li>EEG changes lagged behind plasma concentration changes by 2 to 3 min , after 4-min sufentanil infusion. </li></ul><ul><li>Resolution of the EEG changes lagged behind plasma concentration changes by 20 to 30 min . </li></ul>
  81. 82. Analgesia <ul><li>Highly selective µ - opioid receptor agonist. </li></ul><ul><li>IV infusion rate to adequate postoperative analgesia, mean rate of 8 to 17 µg / hr was required during the first 48 hours . </li></ul>
  82. 83. Use in Anesthesia <ul><li>Decreases the MAC of volatile anesthetics in a dose - dependent manner 70 to 90%. </li></ul><ul><li>In cardiac surgery, high doses ( 10 to 30 µg / kg ) with oxygen and muscle relaxants are needed. </li></ul><ul><li>When used as the sole anesthetic agent, even high doses may not completely block the hemodynamic responses to noxious stimuli. </li></ul>
  83. 84. Other CNS Effects <ul><li>Equianalgesic doses of sufentanil and fentanyl produce similar changes in the EEG. </li></ul><ul><li>With 15 µg / kg, α activity became prominent within a few seconds, and within 3 min, the EEG consisted almost entirely of slow δ activity . </li></ul><ul><li>1 to 2 µg / kg, Rigidity and myoclonic activity reported during induction, and on emergence. </li></ul><ul><li>0.5 µg / kg was not associated with changes in cerebral blood flow. </li></ul>
  84. 85. In patients with intracranial tumors <ul><li>1 µg / kg was associated with an elevation in spinal cerebrospinal pressure, a decrease in cerebral perfusion pressure and arterial pressure had dropped significantly. </li></ul>
  85. 86. Respiratory Depression <ul><li>In spontaneously breathing patients anesthetized with 1.5% halothane and N2O, 2.5 µg reduced mean minute ventilation by 50%, and 4 µg reduced mean respiratory rate by 50%. </li></ul><ul><li>Comparing with fentanyl: </li></ul><ul><li>Changes in end - tidal CO2 were the same for fentanyl and sufentanil </li></ul><ul><li>the slope of the ventilatory response to CO2 was depressed to a greater extent by fentanyl. </li></ul>
  86. 87. CVS Effects <ul><li>Produces vasodilation by : </li></ul><ul><li>A sympatholytic mechanism. </li></ul><ul><li>A direct smooth muscle effect . </li></ul><ul><li>15 µg/kg, decrease in MAP which is used for induction of anesthesia. </li></ul><ul><li>Combining vecuronium and sufentanil can cause a decrease in MAP during induction and significant bradycardia and sinus arrest, but not with pancuronium. </li></ul>
  87. 88. Endocrine Effects <ul><li>Sufentanil, like fentanyl, reduces the endocrine and metabolic responses to surgery . </li></ul><ul><li>However, even a large induction dose ( 20 µg / kg ) did not prevent increases in cortisol, catecholamines, glucose, and free fatty acids during and after cardiopulmonary bypass . </li></ul>
  88. 89. Disposition Kinetics <ul><li>Extremely lipophilic. </li></ul><ul><li>pKa 8 nonionized 20%. </li></ul><ul><li>Smaller degree of ionization at physiologic Ph. </li></ul><ul><li>Protein Binding 93% mostly to α1-acid glycoprotein. </li></ul><ul><li>Vd ss smaller than fentanyl : 1.9 Kg/L. </li></ul><ul><li>Elimination half - life shorter than that of fentanyl : 2.7 hrs. </li></ul><ul><li>Plasma concentration drops very rapidly after an IV bolus dose. </li></ul><ul><li>98% of the drug is cleared from plasma within 30 minutes after IV bolus dose. </li></ul><ul><li>Less red cell bound than fentanyl ( 22 compared with 40% ). </li></ul>
  89. 90. <ul><li>Clearance is rapid. </li></ul><ul><li>As fentanyl high hepatic extraction ratio. </li></ul><ul><li>Metabolism in the liver is by : </li></ul><ul><li>N -dealkylation </li></ul><ul><li>O -demethylation </li></ul><ul><li>Study show clearance and elimination half - life in patients with cirrhosis are similar to controls. </li></ul>
  90. 91. Dosage and Administration <ul><li>Loss of consciousness is seen with total doses between 1.3 and 2.8 µg / kg . </li></ul><ul><li>Doses in the range of 0.3 to 1.0 µg / kg given 1 to 3 minutes prior to laryngoscopy can be expected to blunt hemodynamic responses to intubation </li></ul><ul><li>Balanced anesthesia is maintained with (A)intermittent bolus doses or (B)a continuous infusion </li></ul><ul><li>A:0.1 to 0.5 µg / kg, mean maintenance requirements of 0.35 µg / kg / hr </li></ul><ul><li>B:initial bolus of 0.5 µg / kg followed by an infusion of 0.5 µg / kg / hr </li></ul>
  91. 92. Cardiac Anesthesia <ul><li>Can be used as the sole agent. </li></ul><ul><li>Much higher bolus doses ( 10 µg / kg ) and / or infusion rates ( 0.15 µg / kg / min ) . </li></ul>
  92. 93. Alfentanil <ul><li>A tetrazole derivative of fentanyl. </li></ul><ul><li>Alfentanil is a µ-opioid receptor agonist and produces typical naloxone-reversible analgesia and side effects such as sedation, nausea, and respiratory depression. </li></ul><ul><li>Its clinical potency is 10 times that of morphine. </li></ul><ul><li>Its clinical potency one - fourth to one - tenth that of fentanyl. </li></ul><ul><li>Peak effect of EEG lagged behind peak plasma concentration by <1 minute. </li></ul><ul><li>Resolution of effect followed decreasing serum alfentanil concentration by no more than 10 minutes . </li></ul>
  93. 94. Analgesia <ul><li>Following an adequate loading dose, average alfentanil requirements for postoperative analgesia are approximately 10 to 20 µg / kg / hr . </li></ul>
  94. 95. Use in Anesthesia <ul><li>An infusion rate of 8 µg / kg / min, reduced enflurane MAC by 69%. </li></ul><ul><li>Balance anesthesia : loading dose of 150 µg / kg, followed by an infusion titrated between 25 and 150 µg / kg / hr according to responses to surgical stimuli . </li></ul><ul><li>Comparing to fentanyl, the duration of even very large doses of alfentanil is short, so repeated doses or a continuous infusion of alfentanil is required . </li></ul><ul><li>Did not eliminate responses to intubation and intraoperative stimuli in all patients . </li></ul>
  95. 96. Other CNS Effects <ul><li>Produces the typical generalized slowing of the EEG. </li></ul><ul><li>Increase epileptiform EEG activity in patients with intractable temporal lope epilepsy. </li></ul><ul><li>Produce intense muscle rigidity 150 to 175 µg/kg </li></ul><ul><li>Loss of consciousness. </li></ul><ul><li>Increase CSF pressure in patients with brain tumors, whereas fentanyl does not . </li></ul>
  96. 97. Neurosurgical patients <ul><li>When normocapnia and blood pressure were maintained at baseline. </li></ul><ul><li>no clinically significant changes in ICP. </li></ul><ul><li>no evidence of cerebral vasodilation. </li></ul><ul><li>no evidence of cerebral vasoconstriction. </li></ul><ul><li>MAP and cerebral perfusion pressure decreased in a dose - dependent fashion. </li></ul>
  97. 98. Respiratory Depression <ul><li>Mild ventilatory depression. </li></ul><ul><li>increased end - tidal CO2 </li></ul><ul><li>decreased slope of the CO2 response curve </li></ul><ul><li>At plasma concentrations associated with 50% reduction in pain intensity, respiratory depression was equivalent for alfentanil, fentanyl, and morphine. </li></ul><ul><li>Recovery of ventilatory function was faster with alfentanil compared with fentanyl . </li></ul>
  98. 99. Cardiovascular Effects <ul><li>The cardiovascular effects of alfentanil are influenced by </li></ul><ul><li>preoperative medication, muscle relaxant used, method of administration, and the degree of surgical stimulation. </li></ul><ul><li>In general, heart rate and MAP are unchanged or slightly decreased during induction with alfentanil 40 to 120 µg / kg. </li></ul><ul><li>Rapid induction with 150 to 175 µg/kg alfentanil can decrease mean arterial pressure by 15 to 20 torr. </li></ul><ul><li>With lorazepam premedication or thiopental induction, moderate doses ( 10 to 50 µg / kg ) of alfentanil blunt the cardiovascular and catecholamine responses to laryngoscopy and intubation. </li></ul>
  99. 100. <ul><li>Severe hypotension has been observed when alfentanil is given after 0.125 mg / kg diazepam . </li></ul><ul><li>Alfentanil can also cause bradycardia. </li></ul><ul><li>Minimized by premedication with atropine and by the vagolytic effect of pancuronium . </li></ul><ul><li>Alfentanil 50 µg/kg combined with propofol 1 mg/kg for induction of anesthesia can produce significant bradycardia and hypotension after intubation, but premedication with glycopyrrolate prevents these effects. </li></ul>
  100. 101. Nausea and Vomiting <ul><li>The same incidence of nausea and vomiting as fentanyl. </li></ul><ul><li>But alfentanil - induced nausea and vomiting resolved more quickly. </li></ul>
  101. 102. Disposition Kinetics <ul><li>Alfentanil pharmacokinetics differs from fentanyl and sufentanil in several respects. </li></ul><ul><li>Is a weaker base than other opioids . </li></ul><ul><li>The pKa of alfentanil is 6.8 </li></ul><ul><li>90% of unbound plasma alfentanil is nonionized at pH 7.4 </li></ul><ul><li>Volume of distribution is 4 times smaller than fentanyl's. </li></ul><ul><li>Short terminal elimination half - life. </li></ul><ul><li>Clearance is just half that of fentanyl. </li></ul>
  102. 103. <ul><li>Smaller volume of distribution is a result of </li></ul><ul><li>lower lipid solubility </li></ul><ul><li>high protein binding </li></ul><ul><li>92% of alfentanil is protein bound, mostly to α 1-acid glycoprotein. </li></ul><ul><li>After IV administration, plasma alfentanil concentration falls rapidly; 90% of the administered dose has left the plasma by 30 minutes, mostly because of distribution to highly perfused tissues. </li></ul>
  103. 104. <ul><li>Terminal elimination half - life of 84 to 90 minutes. </li></ul><ul><li>Clearance of alfentanil, 6.4 mL / kg / min </li></ul><ul><li>Intermediate hepatic extraction coefficient 32 to 53% which depends on hepatic plasma flow. </li></ul><ul><li>Mean plasma - brain equilibration half - times : </li></ul><ul><li>Fentanyl : 6.4 min </li></ul><ul><li>Sufentanil : 6.2 min </li></ul><ul><li>Alfentanil : 1.1 min </li></ul>
  104. 105. <ul><li>Alfentanil undergoes N -dealkylation and O -demethylation in the liver to form inactive metabolites. </li></ul><ul><li>Liver disease can significantly prolong the elimination half - life of alfentanil . </li></ul><ul><li>Patients with moderate hepatic insufficiency as a result of cirrhosis have reduced binding to α 1-acid glycoprotein and a plasma clearance one-half that of control patients. </li></ul><ul><li>These changes result in a marked increase in the elimination half-life, 219 min versus 90 min. </li></ul>
  105. 106. <ul><li>Renal disease also decreases alfentanil protein binding, but does not result in decreased plasma clearance or a prolonged terminal elimination half-life. </li></ul><ul><li>Alfentanil's elimination half-life is prolonged by about 30% in the elderly and appears to be much shorter (about 40 minutes) in children 5 to 8 years old. </li></ul><ul><li>Obesity is also associated with a 50% decrease in alfentanil clearance and a prolonged (172 minutes) elimination half-life. </li></ul>
  106. 107. <ul><li>The combination of moderate lipid solubility and short elimination half - life suggests that both redistribution and elimination are important in the termination of alfentanil's effects. </li></ul><ul><li>After a single bolus dose, redistribution will be the most important mechanism. </li></ul><ul><li>After a very large dose, repeated small doses, or a continuous infusion, elimination will be a more important determinant of the duration of alfentanil's effects . </li></ul>
  107. 108. Dosage and Administration <ul><li>120 µg / kg produce unconsciousness in 2 to 2.5 minutes, and muscle rigidity. </li></ul><ul><li>Premedication with a benzodiazepine is associated with: </li></ul><ul><li>a lower dose requirement, 40 to 50 µg / kg </li></ul><ul><li>a faster onset of unconsciousness, within 1.5 minutes. </li></ul><ul><li>hypotension. </li></ul>
  108. 109. Intubation <ul><li>For rapid sequence induction, a bolus dose of 36 µg / kg followed by thiopental and rocuronium can yield ideal intubating conditions within 40 seconds in 95% of patients . </li></ul><ul><li>A lower dose, 15 µg / kg ( range, 13 to 31 µg / kg ) with sevoflurane and N2O, but without muscle relaxants produced good intubating conditions within 90 seconds in 95% of patients. </li></ul><ul><li>With propofol 2.5 mg / kg, an alfentanil dose of 10 µg / kg appears optimal for laryngeal mask insertion, but is accompanied by apnea for about 2 minutes . </li></ul>
  109. 110. <ul><li>Brief duration of action. </li></ul><ul><li>Useful component of general anesthesia in short surgical procedures. </li></ul><ul><li>Loading doses of 5 to 10 µg/kg provide good analgesia with rapid recovery. </li></ul>
  110. 111. For Long Procedures <ul><li>Its pharmacokinetic properties make it ideal for administration as a continuous infusion. </li></ul><ul><li>After induction of anesthesia, a loading dose of alfentanil 10 to 50 µg / kg is followed with </li></ul><ul><li>supplemental bolus doses of 3 to 5 µg / kg as needed. </li></ul><ul><li>continuous infusion starting at 0.4 to 1.7 µg / kg / min with 60 to 70% N2O or a propofol infusion. </li></ul>
  111. 112. Cardiac Surgery <ul><li>High - dose alfentanil is used as the sole anesthetic agent. </li></ul><ul><li>Continuous infusion of up to 150 to 600 µg / kg / h . </li></ul><ul><li>Adjusted according to the patient's responses to stimuli. </li></ul>
  112. 113. Remifentanil <ul><li>A 4-anilidopiperidine with a methyl ester side chain. </li></ul><ul><li>An ultrashort - acting opioid which is due to metabolism rather than to redistribution. </li></ul><ul><li>Because its ester side chain is susceptible to metabolism by blood and tissue esterases. </li></ul><ul><li>Potent, naloxone - reversible µ - selective opioid agonist activity. </li></ul><ul><li>It does not accumulate with repeated dosing or prolonged infusion. </li></ul>
  113. 114. Analgesia <ul><li>Produces dose - dependent analgesic effects. </li></ul><ul><li>Analgesic effects of bolus IV doses ( 0.0625 to 2.0 µg / kg ) </li></ul><ul><li>Bolus doses produced a peak analgesic effect between 1 and 3 minutes and a duration of approximately 10 minutes . </li></ul><ul><li>Remifentanil is 40 times as potent as alfentanil . </li></ul>
  114. 115. <ul><li>Postoperative analgesia study, 80% of patients got satisfied analgesia with remifentanil infusion of 0.05 to 0.15 µg / kg / min . </li></ul><ul><li>Remifentanil may offer an alternative for laboring patients in whom regional anesthesia is absolutely contraindicated . </li></ul><ul><li>PCA with a median effective bolus dose of 0.4 µg / kg ( range, 0.2 to 0.8 µg / kg ) and consumption of 0.066 µg / kg / min ( range, 0.027 to 0.207 µg / kg / min ). </li></ul>
  115. 116. Use in Anesthesia <ul><li>The effect of remifentanil on the MAC of volatile anesthetics is characterized by steep dose - effect or concentration - effect curves. </li></ul><ul><li>Decreases enflurane and isoflurane MAC in a dose - dependent fashion up to a maximum near 65%. </li></ul><ul><li>Effects on the MAC - BAR ( requirement for blunting the sympathetic response to skin incision ) of sevoflurane and desflurane in 60% N2O are similar. </li></ul>
  116. 117. <ul><li>12 µg / kg for loss of consciousness. </li></ul><ul><li>20 µg / kg, 60% of patients had severe muscle rigidity . </li></ul><ul><li>Pediatric patients require twice as much as adults ( 0.15 µg / kg / min vs . 0.08 µg / kg / min ) when it is used with propofol for TIVA. </li></ul><ul><li>Gender differences which female required more in a study with unclear explanation. </li></ul>
  117. 118. <ul><li>For balanced anesthesia, including combination with inhalation agent report similar findings of </li></ul><ul><li>hemodynamic stability. </li></ul><ul><li>easy titratability. </li></ul><ul><li>blunting responses to noxious stimulation </li></ul><ul><li>permitting rapid recovery. </li></ul><ul><li>did not alter desflurane's effect on the bispectral index analysis of the EEG. </li></ul>
  118. 119. TIVA <ul><li>Remifentanil is infused as a component of TIVA more frequently than other opioids . </li></ul><ul><li>Increases in remifentanil dosage to certain level reduced propofol dose requirements. </li></ul><ul><li>Response to intubation was prevented in 80% of patients by approximately doubling the remifentanil. </li></ul><ul><li>A small bolus dose of remifentanil (20 µg) given 30 seconds before induction, can reduce the pain of propofol injection. </li></ul>
  119. 120. Cardiac Anesthesia <ul><li>While high - dose remifentanil ( 1 to 2 µg / kg / min ) has been used as a single agent for cardiac anesthesia. </li></ul><ul><li>It is more commonly administered with propofol or isoflurane for “fast - track cardiac anesthesia. </li></ul><ul><li>Patients require analgesics very soon after an infusion is stopped. </li></ul><ul><li>A continuation of remifentanil to transition to postoperative analgesia can avoid early pain and sympathoadrenal stimulation. </li></ul>
  120. 121. Monitored Anesthesia Care <ul><li>Useful during monitored anesthesia care for conscious sedation such as ESWL and colonoscopy. </li></ul><ul><li>Useful during conjunction with regional anesthesia. </li></ul><ul><li>When compared with propofol, remifentanil provides better analgesia, but results in more nausea and respiratory depression, whereas propofol causes more oversedation. </li></ul><ul><li>Times required for discharge are clinically similar . </li></ul><ul><li>Maintenance of spontaneous respiration during general anesthesia show if low doses of remifentanil are used . </li></ul>
  121. 122. Other CNS Effects <ul><li>Produces effects on the EEG, a concentration - dependent slowing . </li></ul><ul><li>Produce muscle rigidity, especially with bolus doses. </li></ul><ul><li>Not affecting intracranial pressure </li></ul><ul><li>Dose - dependent decreases in MAP . </li></ul><ul><li>Remifentanil 0.5µg/kg/min plus propofol preserved cerebral autoregulation, whereas isoflurane 1.8% did not. </li></ul>
  122. 123. Motor - Evoked Potentials <ul><li>The ability to monitor motor-evoked potentials (MEPs) is important in many cranial and spinal neurosurgical procedures. </li></ul><ul><li>All opioids and propofol suppressed MEPs in a dose - dependent fashion. </li></ul><ul><li>Remifentanil exerted less suppression than the other opioids and propofol . </li></ul><ul><li>Quality and reproducibility of MEPs was preserved with remifentanil. </li></ul>
  123. 124. <ul><li>Has not been shown to produce seizure activity. </li></ul><ul><li>Reduce methohexital requirement in patients having electroconvulsive therapy . </li></ul><ul><li>Remifentanil 1 µg / kg allowed a 50% reduction in methohexital dose, which results in seizure prolongation by 50% . </li></ul>
  124. 125. Respiratory Depression <ul><li>Produces dose - dependent respiratory depression as measured by : </li></ul><ul><li>increases in end - tidal CO2 </li></ul><ul><li>decreased oxygen saturation </li></ul><ul><li>Peak respiratory depression occurred at 5 minutes after each dose of remifentanil and alfentanil. </li></ul><ul><li>The maximal respiratory depressant effect seen after 2 µg / kg remifentanil was similar to that caused by 32 µg / kg alfentanil . </li></ul>
  125. 126. Recovery from Resp. Depression <ul><li>The duration of respiratory depression, measured as time to return of blood gases to within 10% of baseline values. </li></ul><ul><li>10 minutes after 1.5 µg / kg remifentanil </li></ul><ul><li>20 minutes after 2 µg / kg remifentanil </li></ul><ul><li>30 minutes after 32 µg / kg alfentanil </li></ul><ul><li>Recovery was rapid, and minute ventilation returned to baseline by 8 minutes after the infusion was stopped for all infusion rates, compared with 61 minutes after stopped of alfentanil infusion. </li></ul>
  126. 127. Hemodynamic Effects <ul><li>Bolus doses >1.0 µg / kg produce brief increases in systolic BP ( 5 to 20 torr ) and heart rate ( 10 to 25 beats / min ). </li></ul><ul><li>In patients anesthetized, remifentanil ( up to 5 µg / kg ) produces dose - dependent decreases in systolic BP and heart rate around 20% . </li></ul><ul><li>Attenuated by premedication with glycopyrrolate 0.3 to 0.4 mg and reversed with ephedrine or phenylephrine. </li></ul>
  127. 128. <ul><li>These hemodynamic effects were not mediated by histamine release </li></ul><ul><li>Transient and easily treated with fluids and downward titration of propofol . </li></ul><ul><li>A study show : </li></ul><ul><li>Hypotension : 12% with remifentanil 4% with fentanyl </li></ul><ul><li>Bradycardia : 2% with remifentanil 1% with fentanyl </li></ul>
  128. 129. Coronary Artery Disease <ul><li>In a comparison of high - dose remifentanil ( 2 µg / kg / min ) and remifentanil 0.5 µg / kg / min plus propofol. </li></ul><ul><li>Both techniques produced similar changes: </li></ul><ul><li>30% drop in mean arterial pressure </li></ul><ul><li>25% drop in cardiac index. </li></ul><ul><li>30% drop in myocardial blood flow </li></ul><ul><li>40% drop in oxygen consumption </li></ul>
  129. 130. Cardiac Surgery <ul><li>Rapid injection of remifentanil 1 µg / kg followed by a continuous infusion at 0.1 to 0.2 µg / kg / min on induction </li></ul><ul><li>Bradycardia ( heart rate <30 beats / min ) </li></ul><ul><li>Hypotension ( systolic BP <80 mm Hg ) </li></ul><ul><li>Hypotension was effectively treated by ephedrine and temporary discontinuation of remifentanil . </li></ul><ul><li>These severe effects can often be avoided by slower administration ( >60 seconds or longer ) of the loading dose, </li></ul>
  130. 131. Gastrointestinal Effects <ul><li>The incidence of nausea was 44 and 53% for remifentanil and alfentanil, respectively. </li></ul><ul><li>The incidence of vomiting was 21 and 29% for remifentanil and alfentanil, respectively . </li></ul><ul><li>With 0.8% isoflurane, nausea occurred in 18 and 20% of patients with remifentanil and alfentanil, respectively. </li></ul><ul><li>But with propofol reported very low incidence of nausea and vomiting (6 to 22%). </li></ul>
  131. 132. Remifentanil <ul><li>For strabismus surgery in children, vomiting occurred with equal frequency ( 26 to 31% ) with remifentanil, alfentanil, isoflurane, and propofol . </li></ul><ul><li>Produce dose - dependent nausea and vomiting similar to other short - acting µ - agonist opioids that can be attenuated by propofol . </li></ul><ul><li>Delays gastric emptying and biliary drainage. </li></ul>
  132. 133. Other Side Effects <ul><li>Postoperative shivering occurred in about 40% of patients. </li></ul><ul><li>Pruritus in 12% of patients . </li></ul><ul><li>Psychomotor side effects typical of µ opioids. </li></ul><ul><li>Dry mouth. </li></ul><ul><li>Itching. </li></ul><ul><li>Flushing. </li></ul><ul><li>Sweating. </li></ul><ul><li>Turning of the stomach. </li></ul><ul><li>Miosis. </li></ul><ul><li>Some of these effects lasted an hour or more after remifentanil administration was stopped . </li></ul>
  133. 134. Disposition Kinetics <ul><li>Remifentanil is an ester functional group that hydrolyzed by blood and tissue nonspecific esterases and results in very rapid metabolism . </li></ul><ul><li>Because butyrocholinesterase ( pseudocholinesterase ) does not appear to metabolize remifentanil, plasma cholinesterase deficiency and anticholinergic administration do not affect remifentanil clearance . </li></ul><ul><li>Unlike other opioids, redistribution plays only a minor role in remifentanil clearance . </li></ul>
  134. 135. <ul><li>Has a small volume of distribution, approximately 0.3 to 0.5 L / kg 25 L in adult </li></ul><ul><li>Clearance, 3 to 5 L / min, is 3 to 4 times normal hepatic blood flow . </li></ul><ul><li>A rapid distribution phase of 0.9 minutes. </li></ul><ul><li>Slow distribution half-times 6 minutes. </li></ul><ul><li>A very short terminal elimination half - life of 9.5 minutes. </li></ul><ul><li>Doses should be based on lean body mass . </li></ul><ul><li>pKa 7.26 nonionized 58%. </li></ul>
  135. 136. Dosage and Administration <ul><li>Best administered as a continuous infusion. </li></ul><ul><li>Repeated bolus doses can be effective. </li></ul><ul><li>Induction : 0.25–0.5 µg/kg/min or 0.5–1.0 µg/kg . </li></ul><ul><li>Maintenance : 0.25–0.5 µg/kg/min or 25–50 µg . </li></ul><ul><li>PACU : 0.05–0.25 µg/kg/min . </li></ul><ul><li>Monitored Anesthesia Care : 0.01–0.2 µg/kg/min or 12.5–25 µg . </li></ul>
  136. 137. Induction Dosage, Intubation, LMA Placement <ul><li>Unreliability in loss of consciousness and significant muscle rigidity. </li></ul><ul><li>Remifentanil alone has not been found to be a satisfactory single agent for induction of anesthesia. </li></ul><ul><li>Bolus doses of >2 µg / kg can drop arterial pressure 20 to 30%. </li></ul><ul><li>Hemodynamic changes in cardiac patients receiving high - dose infusion are similar to remifentanil plus propofol . </li></ul>
  137. 138. <ul><li>Combined with a potent inhalation agent, a loading dose of 1 µg / kg given slowly ( over 60 seconds ) can provide adequate intubating conditions with hemodynamic stability. </li></ul>
  138. 139. <ul><li>The most commonly reported remifentanil - based regimen for anesthetic induction and laryngoscopy consists of remifentanil 0.5 to 1 µg / kg given over 60 seconds plus propofol 1 to 2 mg / kg , followed by remifentanil infusion of 0.25 to 0.5 µg / kg / min . </li></ul>
  139. 140. Maintenance of General Anesthesia <ul><li>In combination with 70% N2O in O2, remifentanil 0.6 µg/kg/min is generally adequate. </li></ul><ul><li>A lower infusion rate ( 0.2 to 0.25 µg / kg / min ) is needed when remifentanil is combined with inhalation agents. </li></ul><ul><li>For TIVA, maintenance infusion rates for remifentanil and propofol are 0.25 to 0.5 µg / kg / min and 75 to 100 µg / kg / min , respectively . </li></ul><ul><li>If N2O is added, remifentanil infusion rates as low as 0.125 µg/kg/min and propofol infusion of 50 to 75 µg/kg/min can be used. </li></ul>
  140. 141. <ul><li>For elderly patients or those with cardiac disease, a reduction in propofol by about 25% is recommended . </li></ul><ul><li>Children require higher remifentanil doses to block responses to skin incision. </li></ul>
  141. 142. Cardiac Surgery <ul><li>For high - dose opioid anesthesia for cardiac surgery, the remifentanil infusion is maintained at 1 to 3 µg / kg / min and should be adjusted downward for hypothermia. </li></ul><ul><li>Adding a low - dose propofol infusion of 50 µg / kg / min to this high infusion rate effectively suppressed responses to skin incision, sternotomy, and aortic cannulation . </li></ul>
  142. 143. A disadvantage of remifentanil <ul><li>Related to its short duration of action. </li></ul><ul><li>Patients may experience substantial pain on emergence from anesthesia . </li></ul><ul><li>If moderate - to - severe postoperative pain is anticipated, continuing the remifentanil infusion between 0.05 and 0.15 µg / kg / min . </li></ul><ul><li>The use of local and regional anesthetic techniques is also effective . </li></ul><ul><li>Mild postoperative pain is anticipated, intraoperative administration of a NSAID 30 to 60 minutes before the end of surgery. </li></ul>
  143. 144. Monitored Anesthesia Care <ul><li>Used for conscious sedation / analgesia. </li></ul><ul><li>Used an adjunct for sedation or analgesia during regional anesthesia, or for block placement. </li></ul><ul><li>During colonoscopy, a continuous remifentanil infusion of 0.2 to 0.25 µg/kg/min , supplemented with small (10-mg) doses of propofol provided good analgesia but mild respiratory depression was common. </li></ul>
  144. 145. ESWT <ul><li>Patients who received low - dose ( 12.5 to 25 µg ) intermittent bolus injection of remifentanil with or without infusion at 0.05 µg / kg / min reported better analgesia than continuous infusion of 0.1 µg / kg / min alone . </li></ul>
  145. 146. Ophthalmologic Surgery <ul><li>Remifentanil 1 µg / kg with or without a subsequent infusion of 0.2 µg / kg / min administered 90 seconds prior to placement of ophthalmologic block resulted in excellent analgesia. </li></ul><ul><li>14% of patients who received an infusion experienced respiratory depression. </li></ul>
  146. 147. Regional Anesthesia <ul><li>When used as an adjunct to local or regional anesthesia, a much lower maintenance infusion rate, 0.05 to 0.1 µg / kg / min , provides adequate sedation and analgesia . </li></ul><ul><li>Finally, the dose requirement of remifentanil for sedation / analgesia is reduced 50% when combined with midazolam or propofol . </li></ul><ul><li>When 1 to 2 mg of midazolam premedication is given, 0.01 to 0.07 µg / kg / min remifentanil provides good sedation / analgesia. </li></ul>
  147. 148. Partial Agonists and Mixed Agonist–Antagonists <ul><li>Structurally related to morphine . </li></ul><ul><li>Characterized by binding activity at multiple opioid receptors and their differential effects ( agonist, partial agonist, or antagonist ) . </li></ul><ul><li>The clinical effect of a partial agonist at the µ - opioid receptor is complex. </li></ul><ul><li>Administered alone, a partial agonist has a flatter dose - response curve and a lower maximal effect than a full agonist. </li></ul>
  148. 149. <ul><li>The observed effect of the combination of A and B is expressed as a fraction of the maximal effect of the full agonist . As the concentration of the partial agonist increases, the effect of the combination converges on the maximum effect of the partial agonist . When added to a low concentration ( e . g . , [ A ] = 0.25 ) of agonist, the partial agonist increases the response; but when added to a large concentration of the agonist, the response decreases—that is, B acts like an antagonist . </li></ul>
  149. 150. <ul><li>Combined with a low concentration of a full agonist, the effects of the partial agonist are additive up to the maximum effect of the partial agonist . </li></ul><ul><li>Combined with increasing concentrations ([ A ] = 0.67 to 256 ) of full agonist, the partial agonist will act as an antagonist . </li></ul><ul><li>These drugs mediate their clinical effects via µ and κ - opioid receptors. </li></ul>
  150. 151. <ul><li>Nalbuphine and butorphanol have been reported to be antagonists at the µ opioid receptor, they do cause respiratory depression, which is not a function of κ agonists . Thus, they appear to have at least partial agonist activity at the µ - opioid receptor . </li></ul>
  151. 152. Receptors <ul><li>µ RECEPTOR: </li></ul><ul><li>Nalbuphine </li></ul><ul><li>Butorphanol </li></ul><ul><li>Buprenorphine </li></ul><ul><li>Κ RECEPTOR: </li></ul><ul><li>Nalbuphine </li></ul><ul><li>Butorphanol </li></ul>
  152. 153. The major role for using them <ul><li>To be in the provision of postoperative analgesia. </li></ul><ul><li>Used for intraoperative sedation, as adjuncts during general anesthesia. </li></ul><ul><li>To antagonize some effects of full µ opioid agonists . </li></ul>
  153. 154. Nalbuphine <ul><li>Is a phenanthrene opioid derivative . </li></ul><ul><li>Classified as a κ agonist and µ antagonist. </li></ul><ul><li>It is more accurately described as a partial agonist at both κ and µ receptors . </li></ul><ul><li>0.5 mg / kg dose reduced enflurane MAC by 8%. </li></ul><ul><li>This modest MAC reduction, compared with 65% for morphine, suggests nalbuphine may not be a useful adjunct for general anesthesia . </li></ul>
  154. 155. Study <ul><li>Combined with diazepam 0.4 mg / kg and 50% N2O in oxygen, a loading dose of 3 mg/kg was followed by additional doses of 0.25 mg/kg as needed throughout surgery. </li></ul><ul><li>No significant increases in blood pressure, stress hormones, or histamine were seen. </li></ul><ul><li>Emergence from anesthesia was uncomplicated. </li></ul>
  155. 156. Side Effects <ul><li>The most common side effect was drowsiness . </li></ul><ul><li>Respiratory depression. </li></ul><ul><li>Can precipitate withdrawal symptoms in patients who are physically dependent on opioids . </li></ul>
  156. 157. Comparison with fentanyl <ul><li>Fentanyl was found to better attenuate hypertensive responses to intubation and surgical stimulation . </li></ul><ul><li>Significant respiratory depression was seen in 8 of 30 patients who received fentanyl; compared with no respiratory depression in the nalbuphine group. </li></ul><ul><li>Analgesia was similar. </li></ul><ul><li>Postoperative sedation was common in the nalbuphine group. </li></ul>
  157. 158. Features <ul><li>The respiratory depression mediated by µ - opioid receptors. </li></ul><ul><li>Has a ceiling effect equivalent to that produced by ~0.4 mg / kg morphine . </li></ul><ul><li>Analgesia is mediated by both κ and µ receptors . </li></ul><ul><li>Antagonize the respiratory depressant effects of full agonists while still providing analgesic effects . </li></ul>
  158. 159. <ul><li>Have ceiling analgesic and respiratory depressant effects. </li></ul><ul><li>Can be as effective as full µ agonists in providing postoperative analgesia . </li></ul><ul><li>Nalbuphine 5 to 10 mg has also been used to antagonize pruritus induced by epidural and intrathecal morphine . </li></ul><ul><li>The usual adult dose of nalbuphine is 10 mg as often as every 3 hours . </li></ul>
  159. 160. Butorphanol <ul><li>A morphinan congener. </li></ul><ul><li>Has partial agonist activity at κ - and µ - opioid receptors. </li></ul><ul><li>Produced dose - dependent sedation which mediated by κ receptors . </li></ul><ul><li>Decreases enflurane MAC,11%, at 0.1 mg/kg. Increasing the butorphanol dose 40-fold does not produce a further reduction. </li></ul><ul><li>Butorphanol and morphine provided equally satisfactory anesthesia . </li></ul>
  160. 161. <ul><li>Produces respiratory depression with a ceiling effect below that of full µ agonists . </li></ul><ul><li>3 mg produces respiratory depression approximately equal to that of 10 mg morphine . </li></ul><ul><li>Its effectiveness in reversing fentanyl - induced respiratory depression (5 µg / kg followed by an infusion of 3 µg/kg/hr) by butorphanol 1 mg only. </li></ul>
  161. 162. <ul><li>Does not produce significant elevation in intrabiliary pressure. </li></ul><ul><li>Effective in the treatment of postoperative shivering. </li></ul><ul><li>Antipruritic effect that is blocked by a selective κ antagonist . </li></ul><ul><li>Reduce morphine - induced pruritus without completely blocking its analgesic effect . </li></ul><ul><li>Lower incidence of opioid - induced ileus compared with µ - selective opioids. </li></ul>
  162. 163. Extra Info. <ul><li>Use as a sedative as low as 0.5 mg. </li></ul><ul><li>Treatment of moderate postoperative pain . </li></ul><ul><li>Single analgesic doses range from 0.5 to 2 mg. </li></ul><ul><li>Administered as patient - controlled analgesia. </li></ul><ul><li>Can be administered epidurally and transnasally . </li></ul>
  163. 164. Buprenorphine <ul><li>Highly lipophilic thebaine derivative. </li></ul><ul><li>A partial µ opioid agonist . </li></ul><ul><li>At small - to - moderate doses it is 25 to 50 times more potent than morphine . </li></ul><ul><li>Does not appear to have agonist activity at the κ - opioid receptor. </li></ul><ul><li>Its slow dissociation from µ receptors, which can lead to prolonged effects not easily antagonized by naloxone . </li></ul>
  164. 165. <ul><li>Bell - shaped dose - response curve such that, at very high doses, it produces progressively less analgesia . </li></ul><ul><li>10 or 20 µg / kg buprenorphine during surgery were pain - free postoperatively. </li></ul><ul><li>30 or 40 µg / kg had significant postoperative pain . </li></ul>
  165. 166. <ul><li>Have a ceiling effect to its respiratory depressant dose - response curve . </li></ul><ul><li>Buprenorphine - induced respiratory depression can be prevented by prior naloxone administration. </li></ul><ul><li>Not easily reversed by naloxone once the effects have been produced . Which require around 5 to 10 mg to antagonize it which maximum occur after 3 hours. </li></ul>
  166. 167. <ul><li>A dose of 0.3 mg buprenorphine reduces CO 2 responsiveness to about 50% of control values. </li></ul><ul><li>Did not antagonize fentanyl - induced respiratory depression, and appears to increase respiratory rate without antagonizing analgesic effects in slowly administered doses up to 0.5 mg . </li></ul>
  167. 168. Extra Info. <ul><li>Effective in treatment of moderate - to - severe pain. </li></ul><ul><li>Slow onset. </li></ul><ul><li>Analgesic duration can be >6 hours . </li></ul><ul><li>A single dose of 0.3 to 0.4 mg appears to produce analgesia equivalent to 10 mg morphine . </li></ul>
  168. 169. Opioid Antagonists <ul><li>They are competitive inhibitors of the opioid agonists. </li></ul><ul><li>Effect profile depends on: </li></ul><ul><li>The type of agonist administered </li></ul><ul><li>Dose of agonist administered </li></ul><ul><li>The degree to which physical dependence on the opioid agonist </li></ul>
  169. 170. Naloxone <ul><li>The most widely used opioid antagonist. </li></ul><ul><li>Structurally related to morphine and oxymorphone. </li></ul><ul><li>It is a pure antagonist at µ - , κ - , and δ - opioid receptors . </li></ul><ul><li>Administered to antagonize opioid - induced respiratory depression and sedation . </li></ul>
  170. 171. Naltrexone <ul><li>Long - acting oral agent. </li></ul><ul><li>Relatively pure antagonist activity . </li></ul>
  171. 172. <ul><li>Mediated by endogenous opioids: </li></ul><ul><li>reverse “stress analgesia”. </li></ul><ul><li>antagonize analgesia produced by low-frequency stimulation with acupuncture needles. </li></ul><ul><li>reverse analgesia produced by placebo medications. </li></ul><ul><li>Trials in prevention of treatment of opioid - mediated gastrointestinal dysfunction. </li></ul>
  172. 173. Side Effects <ul><li>Producing sudden, severe pain in postoperative patients. </li></ul><ul><li>Severe hypertension. </li></ul><ul><li>Tachycardia and ventricular dysrhythmias. </li></ul><ul><li>Precipitate opioid withdrawal symptoms in opioid-dependent individuals. </li></ul><ul><li>Acute, sometimes fatal, pulmonary edema even in healthy young patients who have received relatively small doses ( 80 to 500 µg ) . </li></ul>
  173. 174. The Mechanism Pulm. Edema <ul><li>The mechanism for this phenomenon is thought to be centrally mediated catecholamine release, which causes acute pulmonary hypertension. </li></ul><ul><li>It is also essential to monitor vital signs and oxygenation closely after naloxone is administered to detect occurrence of any of these potentially serious complications. </li></ul>
  174. 175. <ul><li>Very fast onset of action = easy to titrated. </li></ul><ul><li>Peak effects occur within 1 to 2 minutes. </li></ul><ul><li>Duration is dose - dependent. </li></ul><ul><li>Total doses of 0.4 to 0.8 mg last 1 to 4 hours. </li></ul><ul><li>Suggested incremental doses for IV titration are 20 to 40 µg given every few mins until the patient's ventilation improves, but analgesia is not completely reversed. </li></ul>
  175. 176. Using As Infusion <ul><li>Because naloxone has a short duration of action, respiratory depression may recur if large doses and / or long - acting opioid agonists have been administered . </li></ul><ul><li>When prolonged ventilatory depression is anticipated, an initial loading dose followed by a naloxone infusion can be used . </li></ul><ul><li>Infusion rates between 3 and 10 µg / hr have been effective in antagonizing respiratory depression from systemic and epidural opioids . </li></ul>
  176. 177. Use of Opioids in Clinical Anesthesia <ul><li>The goal of opioid premedication is to provide moderate sedation, anxiolysis, and analgesia while maintaining hemodynamic stability . </li></ul><ul><li>Potential risks of opioid premedication include: </li></ul><ul><li>Oversedation. </li></ul><ul><li>Respiratory depression. </li></ul><ul><li>Nausea and Vomiting . </li></ul>
  177. 178. For induction of anesthesia <ul><li>Opioids are often used to blunt or prevent the hemodynamic responses to tracheal intubation . </li></ul><ul><li>Opioids with rapid onset of action, such as fentanyl and its derivatives, are appropriate for this use . </li></ul>
  178. 179. During maintenance of general anesthesia <ul><li>Opioid dosage is titrated to the desired effect based on : </li></ul><ul><li>the surgical stimulus. </li></ul><ul><li>individual patient characteristics, such as </li></ul><ul><li>age. </li></ul><ul><li>volume status. </li></ul><ul><li>neurologic status. </li></ul><ul><li>liver dysfunction. </li></ul><ul><li>other systemic disease states . </li></ul>
  179. 180. <ul><li>Important pharmacokinetic differences among these opioids include volumes of distribution and intercompartmental (distributional) and central (elimination) clearances. </li></ul><ul><li>A smaller distribution volume tends to shorten recovery time. </li></ul><ul><li>A reduction in clearance tends to increase recovery time . </li></ul>
  180. 181. <ul><li>The major pharmacodynamic differences among these opioids are potency and the equilibration times between the plasma and the site of drug effect . </li></ul><ul><li>Equilibration half - times between plasma and effect site are 5 to 6 minutes for fentanyl and sufentanil. </li></ul><ul><li>Equilibration half - times between plasma and effect site are 1.3 to 1.5 minutes for alfentanil and remifentanil . </li></ul>
  181. 182. <ul><li>The rate of recovery after a continuous infusion will depend on the duration of the infusion as well as the magnitude of decline that is required . </li></ul>
  182. 184. <ul><li>If only a 20% drop in effect site concentration is required, recovery from all three opioids will be rapid, although recovery time increases for fentanyl after 3 hours of drug infusion . </li></ul><ul><li>If a 50% decrease is required, recovery from sufentanil will be fastest for infusions <6 to 8 hours in duration, but more rapid for alfentanil if infusions are continued for >8 hours . </li></ul>
  183. 185. Context - Sensitive Half - Time <ul><li>Defined as the time required for the drug concentration in the central compartment to decrease by 50%, and demonstrated how this half - time changes as drug infusion duration increases . </li></ul>
  184. 186. Explanation <ul><li>During an infusion, the peripheral ( fast and slow ) compartments begin to “fill up . ” After the infusion is stopped, drug will be eliminated, but will also continue to be redistributed as long as the concentration in a peripheral compartment is lower than that in the central compartment . This leads to a rapid drop in central compartment drug concentration . </li></ul>
  185. 187. <ul><li>When central compartment ( plasma ) concentration drops below that of the peripheral compartment ( s ) , the direction of drug redistribution will reverse and will slow the decline in plasma concentration . </li></ul>
  186. 188. <ul><li>The degree to which redistribution will affect the rate of drug elimination depends on the ratio of the distributional to elimination time constants . Thus, a drug that can rapidly redistribute will have a correspondingly larger contribution from the peripheral compartment ( s ) , and plasma concentration will drop progressively more slowly as infusion duration continues . </li></ul>
  187. 189. Context - sensitive half - times
  188. 190. THANK YOU
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