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Opioids Drugs

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Complete source of Opioids presentation from Barash Clinical anesthesia. …

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

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