Opioids Dr. Daniels

OPIOIDS Don Daniels COL MC OPIOIDS • • • • • Mu Kappa Delta sigma epsilon Don Daniels COL MC OPIOIDS • • • • • • T shaped Phenanthrene - T + 5-6 rings Morphinans - T + 4 Benzomorphans - T + 3 Phenylpiperidines - T + 2 Tyramine moiety - T - 1 Don Daniels COL MC OPIOIDS: Factors that influence CNS effects • • • • Molecular size *Ionization* *Lipid solubility* Protein binding Don Daniels COL MC OPIOIDS: Drug Elimination • Biotransformation by liver – Phase I -oxidize & redux – Phase II - conjugation – Ester hydrolysis - Remifentanil only • Excretion – metabolites excreted primarily by kidney – biliary and gut are other minor routes Don Daniels COL MC MORPHINE: Analgesia • Sites include brain, spinal cord, & peripheral tissues • Mu 1 & 2 receptor sites • Spinal cord – acts presynaptically – @ Mu 2 receptor – decrease substance P – decrease nocioceptive impulses Don Daniels COL MC MORPHINE: Analgesia • Supraspinal analgesia – Periaqueductal grey matter – Locus ceruleus & nuclei wn the medulla • Involves mu 1 receptors • Peripheral analgesia – Activate primary afferent neurons – Active only when inflammation present Don Daniels COL MC MORPHINE: Effect on MAC • Dose dependent reduction w volatile anesthetics, max 65% • 1 mg/kg blocks adrenergic response to skin incision in 60% N2O • Neuraxial morphine decrease halothane MAC by 30% Don Daniels COL MC MORPHINE: CNS Effects • Sedation, impairs cognitive and fine motor • High dose produce slowing EEG • Dose dependent pupillary constriction – Mediated at Edinger-Westphal nucleus of oculomotor nerve • Pruitis – mediated at the medullary dorsal horn Don Daniels COL MC MORPHINE: Pulmonary • Dose dependent ventilatory depression – Decreases the responsivity of the medullary respiratory center to CO2 • Cough reflex – Depress reflex at the medullary cough center Don Daniels COL MC MORPHINE: Other effects • Muscle rigidity – 2mg/kg over 10 min can produce abdominal rigidity & decrease pulm compliance – Myoclonus w/o EEG evidence of seizure – Mu mediated at supraspinal sites, nucleus raphe pontis and hindbrain – Reduced or reversed w naloxone, thipental, diazepam or muscle relaxants Don Daniels COL MC MORPHINE: Other • N & V equal to other opioids – Induces nausea by stimulation of the chemotactic trigger zone in the area postrema of the medulla & by producing increased vestibular sensitivity • Decrease GI motility, propulsion & secretion – – – – Affect mu, kappa and delta receptors Decrease lower esophageal sphincter tone Epidural morphine may delay gastric emptying Increase common bile duct tone & sphincter of Oddi Don Daniels COL MC MORPHINE: Other • Histamine release – Not prevented by naloxone – Result in decreased SVR • Cardiovascular effects – Arterial and venous dilation – Inhibition of baroreceptor reflexes – No effect on cerebral circulation • Urinary retention Don Daniels COL MC MORPHINE: Dosage • IV Analgesia – 0.01-0.2 mg/kg • N2O:narcotic – Up to 3 mg/kg • With volatile anesthesia – 1-2 mg/kg Don Daniels COL MC Meperidine • 1/10 the potency of Morphine • Analgesia mediated by Mu receptor activation • Also has moderate kappa and delta receptors • Weak local anesthetic – sole agent for SAB Don Daniels COL MC Meperidine: Side effects • • • • • • Sedation, pupillary constriction and euphoria CNS excitement & seizures w high doses Respiratory depression N&V Delayed gastric emptying Less increased CBD pressure/delay gall bladder emptying than other opioids • Pts w cardiac disease experience decreases in HR, CI & rate pressure product • High doses causes significantly more hemodynamic instability than morphine Don Daniels COL MC Meperidine: Shivering • Reduces shivering from any cause • 12.5 – 50 mg will reduce or eliminate • Probably kappa receptor mediated Don Daniels COL MC Meperidine: Active Metabolites • Normeperidine has significant activity • Causes CNS excitation • Elimination half life (14-21 hrs)is longer than parent compound, therefore acculumates • Myoclonus & seizures reported in post op patients or those using drug for chronic pain • Pts at risk; daily dosage of 1000 mg Don Daniels COL MC Meperidine: Dosage • 0.1 – 1 mg/kg • High dose intraoperative use is not recommended due to hemodynamic instability • Daily dose should not exceed 1000 mg/24 hr (may cause seizure) Don Daniels COL MC Methadone • • • • • • Mu agonist Onset 10 – 20 min Similar mg dose analgesia to morphine Median duration can be 20 hrs Effect on MAC not reported Side effects are sedation, N&V, decreased intestinal activity, biliary spasm Don Daniels COL MC Methadone: Dosage • Present focus is postop analgesia • Initial dose 20 mg • 5 mg incremental doses q 30 min Don Daniels COL MC FENTANYL • 50-100 x’s more potent than morphine • Mu agonist • Reduces MAC of volatile anesthetics – 3 mcg/kg reduces isoflurane & desflurane MAC by 50% – Epidural 1,2,4 mcg/kg reduces halothane MAC by 45, 58, 71% – IV 1,2,4 mcg/kg reduces halothane MAC by 8, 40, 49% • Can be used as sole anesthetic agent – 50-150 mcg/kg – Reliable hemodynamics COL MC Don Daniels FENTANYL • Disadvantages of sole drug use – Recall – Does not completely block hemodynamic or hormonal responses in all patients – Muscle rigidity Don Daniels COL MC FENTANYL: CNS effects • Normal patients: 16 mcg/kg increased middle cerebral artery flow by 25% • 3 mcg/kg resulted in elevation in ICP in ventilated patients with head trauma • 5 mcg/kg did not result in elevated CSF pressure in brain tumor pts anesthetized w N2O • *All pts with increased ICP and CBF also had decreases in MAP which may have contributed to changes Don Daniels COL MC FENTANYL: Other CNS Effects • Muscle rigidity – May occur with as low as 7-8 mcg/kg w/o unconsciousness or apnea – Hypercarbia may influence incidence, may be wise to maintain normocarbia at induction • Myoclonus w/o EEG activity • Itching, primarily facial Don Daniels COL MC FENTANYL:Other • Respiratory depression – Decrease in slope of CO2 response curve – Elevation of ETCO2 – Magnitude is increased in combination with other resp depressants • Cardiovascular – In vitro models show negative inotropic effects – In clinical practice, we see hemodynamic stability – May see slight decrease in HR, no change in MAP w low dose – At 20-25 mcg/kg = decrease HR, MAP , SVR, PVR & PCWP by 15% in Cardiac Pts. – No histamine release & high dose decrease neurohormonal response during surgery Don Daniels COL MC FENTANYL • Significantly increases common bile duct pressure • Cause nausea and vomiting • Delay gastric emptying and intestinal transit Don Daniels COL MC FENTANYL: Dosage • Balanced anesthesia – 0.5-2.5 mcg/kg at induction – Repeat 0.5 mcg/kg q 30 min per surgical stimulus – Infusion: 3-5 mcg/kg/hr • High Dose 50-150 mcg/kg Don Daniels COL MC Sufentanil • 2000 – 4000 times more potent than Morphine • 10-15 times stronger than fentanyl • Highly selective mu agonist • Max reduction enflurane or halothane MAC 70-90% • Max isoflurane MAC reduction is 89% Don Daniels COL MC Sufentanil • EEG is slowed , rigidity and myoclonus have been reported • No effects on ICP, those who had elevation in CSF pressure also had decrease in MAP • Causes respiratory depression at doses assoc w clinical analgesia. MV decreases up to 50% w pts breathing spont on volative anesthetics • May cause less resp depression than noted with fentanyl Don Daniels COL MC Sufentanil • Hemodynamic stability at high doses (30 mcg/kg) • Modest decrease in MAP (15 mcg/kg) • Does not completely decrease response to sternotomy • May see profound brady with vecoronium. Brady not seen with coadministration of pancuronium • Reduces neurohumoral response to surgery Don Daniels COL MC Sufentanil • Induction: 0.3-1 mcg/kg • Maintainence – Intermittent bolus: 0.1-0.5 mcg/kg – Infusion: 0.3-0.5 mcg/kg/hr • Cardiac anesthesia, sole anesthetic – 8-50 mcg/kg Don Daniels COL MC Remifentanil • Ultra short acting • Ester side chain renders it susceptible to blood and tissue esterases • Mu agonist • Decreases enflurane MAC 70%, isoflurane by up to 90% • High incidence of chest wall rigidity • Recovery is rapid, on order of 2-7 minutes Don Daniels COL MC Remifentanil • Causes concentration dependent slowing of EEG • Dose dependent respiratory depression • Nausea and vomiting • Muscle rigidity in 70% or subjects given high infusion rates Don Daniels COL MC Remifentanil: Dosage • With 66% N2O: 0.3-1 mcg/kg/min Don Daniels COL MC