SPR24_OPIOIDS_NRAN80424.pptx

OPIOID AGONISTS & ANTAGONISTS Gregory Collins, DNP, CRNA ADVANCED PHARMACOLOGY OF ANESTHETIC AGENTS 1 OPIOID AGONISTS & ANTAGONISTS READING: OBJECTIVES: FLOOD / 7 BARASH / 20 MILLER / 24 CLASSIFICATION MECHANISM OF ACTION OPIOID RECEPTOR ENDOGENOUS MECHANISMS ORGAN SYSTEM EFFECTS AGONISTS AGONIST-AN...

OPIOID AGONISTS & ANTAGONISTS Gregory Collins, DNP, CRNA ADVANCED PHARMACOLOGY OF ANESTHETIC AGENTS 1 OPIOID AGONISTS & ANTAGONISTS READING: OBJECTIVES: FLOOD / 7 BARASH / 20 MILLER / 24 CLASSIFICATION MECHANISM OF ACTION OPIOID RECEPTOR ENDOGENOUS MECHANISMS ORGAN SYSTEM EFFECTS AGONISTS AGONIST-ANTAGONISTS ANTAGONISTS INTENDED/UNINTEDED EFFECTS OIH/TOLERENCE/ DEPENDENCE 2 CLASSIFICATION DEFINITION All exogenous substances, natural and synthetic, that bind specifically to any of several subpopulations of opioid receptors and produce at least some agonist(?)effect Chiral molecules, levorotatory isomer biologically active at opioid receptor CLASSIFICATION BY ORIGIN: BY ACTION: Naturally occurring Agonist Semisynthetic Agonist-antagonist Synthetic Antagonist 3 CLASSIFICATION ORIGIN: ACTION: MILLE R FLO OD 4 MECHANISM OF ACTION ANTINOCICEPTION Mimic the action of endogenous ligands: endorphins, enkephalins, dynorphins PRESYNAPTIC action results in hyperpolarization and decreased G PROTEIN-COUPLED RECEPTOR release of neurotransmitter BINDING Ca2+ CHANNEL SUPRESSION/ K+ CHANNEL ACTIVATION HYPERPOLARIZED MEMBRANE MILLE R DECREASED RELEASE OF EXCITATORY NEUROTRANSMITTERS 5 MECHANISM OF ACTION RECEPTOR LOCATIONS BRAIN: Locus coeruleus Periaquaductal gray (PAG) Rostral ventral medulla (RVM) SPINAL CORD: Dorsal horn → Primary afferent neurons → Interneurons PERIPHERY: FLOO D 6 MECHANISM OF ACTION PERIPHERAL ACTIVITY BARA SH Chemokines and cytokines attract opioid-containing leukocytes to inflamed tissue These leukocytes migrate through the endothelium and interact with releasing agents (CRF, NE) to secrete opioid peptides Opioid peptides bind peripheral opioid receptors which were synthesized in the dorsal root ganglia and transported to peripheral nerve endings Binding results in hyperpolarization 7 of the nerve ending with a MECHANISM OF ACTION OPIOID RECEPTORS FLOO D 8 MECHANISM OF ACTION ENDOGENOUS MODULATION OPIOID PEPTIDES Endorphins are direct opioid receptor agonists Analgesic placebo effect DESCENDING MODULATION PATHWAYS TREATMENT EXPECTANCY BARASH 9 CHECK YO-SELF… HYPERPOLARIZATION of neurons in afferent pain pathways results in activation of __________ channels and suppression of __________ channels. a)Sodium; potassium b)Potassium; calcium c)Calcium; potassium d)Potassium; sodium 10 ORGAN SYSTEM EFFECTS CARDIOVASCULAR Opioids are generally considered to provide cardiovascular stability MYOCARDIAL DEPRESSION Usually not significant with opioids alone Potential for significant depression when combined with VAs, benzodiazepines 11 ORGAN SYSTEM EFFECTS CARDIOVASCULAR MYOCARDIAL DEPRESSION Morphine-induced bradycardia: → Stimulation of vagal nuclei in medulla → Direct depressant effect on SA/AV nodes Morphine-induced histamine release: → Results in decreased venous tone → Variable decreases in SVR, MAP MYOCARDIAL PROTECTION Enhanced resistance to oxidative and ischemic stresses, preconditioning effect 12 ORGAN SYSTEM EFFECTS CARDIOVASCULAR Cardiovascular depression via synergism with benzodiazepines FLOO D 13 ORGAN SYSTEM EFFECTS CARDIOVASCULAR Morphine-induced histamine release FLOO D 14 ORGAN SYSTEM EFFECTS VENTILATION DEPRESSSION OF VENTILATION ALL OPIOIDS produce dose-dependent ventilatory depression receptor activation results in direct depression of ventilation centers in brainstem Increase in resting PaCO2 with shift of CO2 response curve to right Decrease in ventilation rate with potential of prolonged pauses Incomplete compensatory increase in Vt, evidenced by predictable increase in PaCO2 15 ORGAN SYSTEM EFFECTS VENTILATION DEPRESSSION OF VENTILATION MILLE R 16 ORGAN SYSTEM EFFECTS VENTILATION DEPRESSSION OF VENTILATION MILL ER 17 ORGAN SYSTEM EFFECTS VENTILATION DECREASE IN CILIARY ACTIVITY INCREASE IN AIRWAY RESISTANCE Direct effect on bronchial smooth muscle vs indirect histamine effect COUGH SUPRESSION Direct, depressant effects on medullary cough centers Greatest effect in opioids with “bulky substitutions” at number 3 carbon…codeine Dextrorotatory isomers suppress cough with no analgesia or ventilatory depression 18 ORGAN SYSTEM EFFECTS RIGIDITY Rapid IV administration of large dose can cause generalized skeletal muscle rigidity Most common with fentanyl and derivatives “Wooden chest syndrome”, but likely related to laryngeal musculature contraction Treatment with muscle relaxant or opioid antagonist 19 ORGAN SYSTEM EFFECTS CENTRAL NERVOUS SYSTEM AUTONOMIC EFFECTS Increased vagal tone, decreased sympathetic tone INTRACRANIAL PRESSURE In absence of hypoventilation; decrease cerebral blood flow, possible decrease in ICP Hypoventilation, hypercapnia can increase cerebral blood flow, ICP Caution in head injury 20 ORGAN SYSTEM EFFECTS CENTRAL NERVOUS SYSTEM EEG EFFECTS Resemble patterns of sleep No indication of seizure activity with occasional myoclonus MIOSIS Excitatory stimulation of ANS component of EdingerWestphal nucleus in oculomotor nerve SEDATION Precede production of analgesia, not tied to analgesic effect 21 ORGAN SYSTEM EFFECTS BILIARY TRACT Biliary smooth muscle spasm, increased biliary pressure, epigastric distress – overall incidence 3% Increase in common bile duct pressure with equal analgesic doses: fentanyl (99%), meperidine (61%), morphine (53%) Cautious use if planned intraoperative cholangiogram Treatment with opioid antagonist (naloxone), nitroglycerin, glucagon 22 ORGAN SYSTEM EFFECTS GASTROINTESTINAL TRACT GI smooth muscle spasm Delayed gastric emptying due to increased pyloric tone (aspiration risk) Constipation due to decreased peristalsis and prolonged transit time Sphincter of Oddi spasm can also increase biliary pressure and cause biliary colic 23 ORGAN SYSTEM EFFECTS NAUSEA & VOMITING Direct stimulation of CTZ via -opioid receptor and/or by acting as partial agonist at dopamine (D2)receptor Effect on vestibular apparatus Increased GI secretions and delayed transit Depresses vomiting center in medulla 24 ORGAN SYSTEM EFFECTS GENITOURINARY URINARY URGENCY/RETENTION Increased tone and peristalsis of ureter Augmentation of detrusor muscle tone Increased urinary sphincter tone CUTANEOUS CHANGES HISTAMINE RELEASE Skin, face, chest flushing Urticaria/erythema at injection site, along vein PROVOCATION OF COUGH Preinduction administration of fentanyl, sufentanil, alfentanil Imbalance between sympathetic and vagal innervation of airways 25 ORGAN SYSTEM EFFECTS HORMONAL CHANGES Prolonged therapy may impair H-P-A/H-P-G axes: ↑ prolactin ↓ cortisol, LH, FSH, testosterone, estrogen PLACENTAL TRANSFER Readily transported across placenta Neonatal depression from placental transfer (morphine>meperidine) Dependency with chronic maternal use DRUG INTERACTIONS Ventilatory depression exaggerated by amphetamines, phenothiazines, MAOIs, TCAs Significant concern of CNS depression and hyperpyrexia with MAOI + 26 meperidine ORGAN SYSTEM EFFECTS OVERDOSE SYMPTOMS Classic triad: hypoventilation, miosis, coma Skeletal muscle flaccidity with potential airway obstruction Hypotension, seizure activity, mydriasis in presence of hypoxemia TREATMENT Airway management Ventilatory support Opioid antagonist 27 CHECK YO-SELF… Nausea and vomiting after a single dose of IV opioids is related to all EXCEPT: a) b) c) d) Direct stimulation of CTZ Effect on vestibular apparatus Increased GI secretions and delayed transit Direct stimulation of vomiting center in medulla Bradycardia after morphine administration is secondary to stimulation of: e) Edinger-Westphal nucleus f) Vagal nuclei in medulla g) Purkinje network 28 OPIOID AGONISTS “The most notable feature of the clinical use of opioids is the extraordinary variation in dose requirements for effective treatment of pain” OPIOID POTENCY Morphine Meperidine 1 0.1 Fentanyl 100 Sufentanil 500-1000 Alfentanil 10-20 Remifentanil Hydromorphone Buprenorphine (75-125) 100-200 5 30 Methadone Tramadol 0.1-0.2 18 29 FLOO D POTEN CY OPIOID AGONISTS SUFENTANIL REMIFENTANIL FENTANYL (BUPRENORPH INE) ALFENTANIL HYDROMORPH ONE MORPHINE 30 MORPHINE 18 31 MORPHINE OVERVIEW Prototype for opioid agonists Produce analgesia, euphoria, sedation, decreased ability to concentrate Produce sensations of nausea, feeling of warmth, heaviness of extremities, dry mouth, pruritis Continuous, dull pain relieved more effectively than sharp, intermittent pain Effective against visceral and somatic pain Analgesia more prominent when administered prior to stimulus May produce dysphoria when administered in the absence of pain 32 MORPHINE PHARMACOKINETICS ROUTES OF ADMINISTRATION: IM: Well-absorbed Onset 15-30 min / Peak 45-90 min / Duration 4 hr PO: First-pass hepatic metabolism decreases bioavailability to ~ 25% IV: Peak 15-30 min (poor penetration into CNS) INH: Similar timing to IV administration High incidence and degree of respiratory depression 33 MORPHINE PHARMACOKINETICS PLASMA/CSF CONCENTRATIONS Peak pharmacologic effects lag behind peak plasma concentration CSF concentration peak 15-30 min after IV injection and decay more slowly Less than 0.1% of IV morphine gains access to CSF at time of peak plasma concentration → Poor lipid solubility → High degree of ionization at physiologic pH → Protein binding → Rapid conjugation with glucuronic acid 34 MORPHINE PHARMACOKINETICS PLASMA/CSF CONCENTRATIONS Hyperventilation/alkalosis/hypocarbia increases nonionized fraction, yet higher brain concentrations seen with hypoventilation/acidosis/hypercarbia (↑CBF) Rapid accumulation in kidneys, liver, skeletal muscle – no significant first-pass uptake in lungs 35 MORPHINE PHARMACOKINE TICS FLOO D PLASMA/CSF CONCENTRATIONS CSF peak and decay → Delayed onset of analgesia → Late respiratory depression 36 MORPHINE METABOLISM Primary conjugation with glucuronic acid in liver and kidneys Primary elimination in urine, with minimal biliary excretion METABOLITES  Morphine-3-glucuronide (75-85%)  Morphine-6-glucuronide (5-10%) 37 MORPHINE METABOLISM METABOLITES: Morphine-3-glucuronide (75-85%) → Pharmacologically inactive → Detectable in plasma 1 min after IV administration Morphine-6-glucuronide (5-10%) → Pharmacologically active, receptor agonist → Similar ventilatory depression to morphine → Similar affinity to receptor, but 650x analgesic potency → Prolonged duration of action 38 MORPHINE METABOLISM ELIMINATION HALF-TIME Elimination of metabolites longer than unchanged drug Rapid decrease in plasma concentration of morphine primarily due to glucuronidation FLOOD 39 MORPHINE METABOLISM CONCERNS Accumulation of morphine-6-glucuronide is significant issue with renal dysfunction Clearance decreased in neonates, more sensitive to respiratory depression Minimal excretion/low concentration in breast milk Elderly maintain higher plasma concentrations Conjugation impaired by MAOIs Female gender: → Greater analgesic potency → Prolonged duration → Decreased slope of ventilation/CO2 response 40 CHECK YO-SELF… List 2 properties of morphine that contribute to very limited entry into CSF and delayed peak pharmacologic effects: 1) 2) Which compound has the greatest analgesic potency: a) Morphine b) Morphine-3-glucuronide c) Morphine-6-glucuronide 41 MEPERIDINE 18 42 MEPERIDINE OVERVIEW and opioid receptor agonist Phenylpiperidine derivative Similar structure to local anesthetics and atropine PHARMACOKINETICS Roughly 1/10th potency of morphine Duration of action 2-4 hrs Equivalent sedation, euphoria, N/V as equianalgesic dose of morphine Extensive first-pass hepatic metabolism (~80%), poor oral bioavailability 43 MEPERIDINE METABOLISM Extensive hepatic metabolism (90%): → Demethylation to normeperidine → Hydrolysis to meperidinic acid → Subsequent hydrolysis of normeperidine to normeperidinic acid METABOLITES Normeperidine → Pharmacologically active, 50% analgesic properties of meperidine → CNS stimulant (myoclonus, seizures, delirium, confusion, hallucinations) → Elimination half-time of 15 hrs (35 hrs in renal failure) 44 MEPERIDINE METABOLISM ELIMINATION HALF-TIME Large doses may override hepatic, enzymedependent metabolism and prolong effect Highly protein bound (70%) Elimination half-time 3-5 hrs, primarily via pH dependent urinary excretion 45 MEPERIDINE CLINICAL USE Large, unreliable variations in peak plasma concentrations after IM administration Toxicity potential with patient-controlled analgesia Postoperative shivering: → receptor activation, agonist activity at 2-receptor, decrease in shivering threshold → Alternatives: direct2-agonists, butorphanol 46 MEPERIDINE SIDE EFFECTS Depression of ventilation (>morphine) Large dose results in decrease myocardial contractility Promptly crosses placenta Serotonin Syndrome: → Potentially dangerous interaction with drugs that increase serotonin (MAOIs, SSRIs) → Autonomic instability, HTN, HR, temp, diaphoresis, confusion, agitation, hyperreflexia → Severe outcomes: seizures, coma, coagulopathy, metabolic acidosis 47 CHECK YO-SELF… Which is the LEAST likely untoward effect of meperidine administration? a) Ventilatory depression b) Seizure c) Hypertension d) Bradycardia e) Hallucination 48 FENTANYL 18 49 FENTANYL OVERVIEW Phenylpiperidine derivative Roughly 100x more potent than morphine PHARMACOKINETICS Highly lipid soluble: → Rapid onset (although well-defined hysteresis) → Large volume of distribution → Long elimination half-time Short duration related to rapid redistribution to fat, skeletal muscle 50 FENTANYL PHARMACOKINETICS Lungs also serve as large reservoir → ~75% of bolus dose taken up by pulmonary first-pass effect → Saturation of lung tissue reservoir with multiple bolus doses, infusion → May prolong duration of analgesia and depression of ventilation After IV bolus, more than 80% leaves plasma in < 5 min 51 FENTANYL METABOLISM Extensive metabolism by N-demethylation Dependent on CYP3A enzymes and susceptible to enzyme interference METABOLITES Norfentanyl, hydroxyproprionyl-fentanyl, hydroxyproprionyl-norfentanyl Minimal, clinically insignificant pharmacologic activity 52 FENTANYL METABOLISM ELIMINATION HALF-TIME Highly protein bound Prolonged elimination half-time despite short duration of action → Slow reuptake from inactive tissue sites More prolonged in elderly due to no change in Vd, ↓hepatic blood flow, ↓enzyme activity CONTEXT-SENSITIVE HALF-TIME Prolonged, especially after infusion of > 2hr Return from peripheral tissue compartments to plasma 53 FENTANYL FLOO D FLOO D 54 FENTANYL CLINICAL USES ANXIOLYSIS Transmucosal: 15-20 mcg/kg, 30-45 min preop Can result in ventilatory depression, PONV ANALGESIA Postoperative: intermittent bolus doses Labor: 25 mcg (max) IT/up to 100 mcg epidural Chronic: transcutaneous patch, steady 72 hr plasma concentration 55 FENTANYL CLINICAL USES COMPONENT OF ANESTHESIA 2-20 mcg/kg blunts hemodynamic response to laryngoscopy and surgical incision Marked reduction in MAC of VA or dose of propofol for GA Sole anesthetic agent: → Advantages: stable hemodynamics, suppression of stress response → Disadvantages: potential recall under anesthesia, prolonged ventilatory depression 56 FENTANYL SIDE EFFECTS CARDIOVASCULAR EFFECTS Hypotension from dilation of venous capacitance unlikely, no histamine release Bradycardia due to depression of carotid sinus baroreceptor reflex VENTILATORY EFFECTS Significant, persistent ventilatory depression Potential for recurrent depression of ventilation from release of sequestered drug: → Gastric fluid when trapped, ionized drug released in more alkaline small intestine → Skeletal muscle as recovery allows movement → Lung tissue when V/Q discrepancies improve 57 FENTANYL SIDE EFFECTS CNS EFFECTS Skeletal muscle rigidity or myoclonus with no EEG evidence of seizure No clinically significant change in SSEPs Modest increase in ICP with head injury → Typically accompanied by decreases in MAP and CPP → Potentially due to disruption of cerebral blood flow autoregulation DRUG INTERACTIONS Benzodiazepines: → Decreased propofol requirements for GA → Marked synergism in hypnotic and ventilatory depression effects 58 CHECK YO-SELF… The short duration of a single IV bolus of fentanyl is secondary to: a) Low pKa b) Immediate N-demethylation in liver c) Minimal protein binding d) Redistribution into fat, skeletal muscle Select the TRUE statements regarding fentanyl. e) Fentanyl is highly protein bound. f) Context sensitive half- time is brief due to rapid elimination from all tissues. g) Fentanyl reduces MAC of VAs, but not GA dose of propofol. h) Metabolism of fentanyl can be prolonged with CYP3A enzyme interference. 59 SUFENTANIL 18 60 SUFENTANIL OVERVIEW Phenylpiperidine derivative 5-10x more potent than fentanyl 500-1,000x more potent than morphine 61 SUFENTANIL PHARMACOKINETICS Very lipid soluble: → Rapid penetration of blood-brain barrier, rapid CNS effect Rapid redistribution to inactive tissue: → Terminates action of small dose → Large doses or infusion may accumulate First-pass pulmonary uptake ~60% Highly protein bound: → Principal portion binds -acid glycoprotein → Wide range of -acid glycoprotein levels in healthy adults, ↓ in neonates & infants 62 SUFENTANIL METABOLISM Very high hepatic-extraction ratio → Sensitive to changes in hepatic blood flow N-dealkylation and O-demethylation METABOLITES Products of N-dealkylation are pharmacologically inactive Product of O-demethylation, desmethyl sufentanil, ~10% activity of parent drug 63 SUFENTANIL METABOLISM EXCRETION Excreted in urine/feces, 30% conjugated form Significant tubular reabsorption due to high lipophilicity Impaired renal function results in increased plasma concentration ELIMINATION HALF-TIME fentanyl > sufentanil > alfentanil > remifentanil 64 SUFENTANIL METABOLISM CONTEXT-SENSITIVE HALF-TIME Less than alfentanil for infusions up to 8 hr → Moderate Vd → Decreased volume in central compartment from clearance, redistribution to fatty tissues More favorable recovery profile over long infusion FLOO D 65 SUFENTANIL METABOLISM CONTEXT-SENSITIVE HALF-TIME Comparison to other opioids: → Sufentanil (0.1-0.4 μg/kg IV) versus fentanyl (1-4 μg/kg IV)  Longer duration of analgesia  Less depression of ventilation → Sufentanil (18.9 μg/kg IV) versus equipotent fentanyl or morphine  More rapid induction  More rapid emergence  Earlier extubation 66 SUFENTANIL SIDE EFFECTS CARDIOVASCULAR EFFECTS Hemodynamic stability Bradycardia (may decrease CO) VENTILATORY EFFECTS Potential for delayed depression of ventilation Chest wall/skeletal muscle rigidity, difficult PPV CNS EFFECTS Decreased CMRO2 with maintenance or decrease in CBF Potential increase ICP with decreased MAP in head injury 67 CHECK YO-SELF… The rapid onset of a single dose of sufentanil IV is related to which property? a) Lipid solubility b) pKa c) Protein binding d) Volume of distribution 68 ALFENTANIL 18 69 ALFENTANIL OVERVIEW Phenylpiperidine derivative 1/5 to 1/10 as potent as fentanyl 10-20x more potent than morphine PHARMACOKINETICS Rapid onset due to low pKa, thus high-degree of nonionized drug at physiologic pH Very small Vd due to low lipid solubility, high protein binding Renal failure does not alter clearance or elimination half-time 70 ALFENTANIL METABOLISM No clinically significant active metabolites Wide (10-fold) interindividual variability → Likely reflects variability in hepatic intrinsic clearance, CYP3A4 activity CONTEXT-SENSITIVE HALF-TIME Longer than sufentanil for infusion up to 8 hr → Smaller and more rapid equilibration of Vd of alfentanil 71 ALFENTANIL CLINICAL USES Bolus for anticipated acute, but brief noxious stimulus: 15-30 mcg/kg Infusion for adjunct to GA: 25-150 mcg/kg/hr SIDE EFFECTS Lower incidence of PONV Potential for acute dystonia in untreated Parkinson’s disease 72 CHECK YO-SELF… Wide interindividual variability related to dosing of alfentanil is likely secondary to: a) Large volume of distribution b) Renal insufficiency c) Low pKa d) Hepatic enzyme activity 73 REMIFENTANIL 18 74 REMIFENTANIL OVERVIEW Unique, phenylpiperidine derivative Selective receptor agonist 1-2x more potent than fentanyl 100-200x more potent than morphine Fast onset, rapid titration, fast off 75 REMIFENTANIL PHARMACOKINETICS Rapid blood:brain equilibrium time → Steady state achieved within 10 min Very small Vd Very high rate of clearance Low interindividual variability Similar in lean and obese patients – base dose on lean body weight 76 REMIFENTANIL METABOLISM Metabolized by non-specific plasma and tissue esterases → No effect on butyrylcholinesterase/pseudocholinesterase Primarily renal excretion Unchanged by hepatic or renal dysfunction Decreased ~20% with hypothermia METABOLITE Remifentanil acid (300-4,600x less potent than parent) CONTEXT-SENSITIVE HALF-TIME Fast, ~4 min FLOO D 77 REMIFENTANIL CLINICAL USES Rapid and profound short duration analgesia: 1 mcg/kg IV Analgesic component of a balanced anesthetic: 0.05 – 1.0 mcg/kg/minute → ~ 0.1 μg/kg/minute patients typically maintain spontaneous respirations Postoperative analgesia: 0.05 – 0.1 mcg/kg/minute Patient controlled analgesia for labor and delivery: 0.1 – 0.5 mcg/kg with 2 min lockout → Low dose infusion of 0.025 – 0.05 0.1 μg/kg/minute 78 REMIFENTANIL SIDE EFFECTS VENTILATORY EFFECTS Depression of ventilation, synergistic with propofol CNS EFFECTS Muscle rigidity, ↓CBF & ↓CMRO2, maintenance of CBF/CO2 curve, no change in ICP/IOP OTHER EFFECTS N/V, mild bradycardia, no histamine release, abrupt discontinuation of analgesia, OIH 79 REMIFENTANIL FLOO D FLOO D 80 CHECK YO-SELF… Prolongation of context-sensitive half-time following a 120 min remifentanil infusion should be expected in which context? a) Hypothermia b) Renal failure c) Hepatic failure d) Pseudocholinesterase deficiency 81 HYDROMORPHONE OVERVIEW 5x more potent than morphine Very similar pharmacology to morphine Suitable for PCA and intrathecal administration PHARMACOKINETICS pKa 8.6, protein binding 19%, Vd 303 L, partition coefficient 525 METABLOLISM Primary conjugation with glucuronic acid in liver Hydromorphone-3-glucuronide (95%), neuroexcitatory effects Minimal ( affinity of morphine), resistant to naloxone 33x more potent than morphine, ceiling effect to ventilatory depression 5x more lipid soluble than morphine, ↓concern of late ventilatory depression in SAB MILLE R 90 OPIOID AGONISTSANTAGONISTS MILLE R 91 CHECK YO-SELF… Choose the analgesic agent that stimulates presynaptic serotonin release in the descending inhibitory pain pathways. a) Buprenorphine b) Pentazocine c) Hydromorphone d) Tramadol Select the opioid agonist-antagonist agent(s) that precipitate(s) catecholamine release. e) Pentazocine f) Butorphanol g) Nalbuphine 92 OPIOID ANTAGONISTS OPIOID ANTAGONIST Created by modifying chemical structure of opioid agonist High affinity for opioid receptor Displaces agonist on receptor binding site Binding produces no effect 93 OPIOID ANTAGONISTS CLINICAL USES Reverse detrimental effects of opioid agonists: → Ventilatory depression → N/V → Pruritis → Urinary retention → Postoperative ileus → Biliary spasm 94 OPIOID ANTAGONISTS NALOXONE Antagonist at , receptors; greatest affinity for recptor DOSE/ADMINISTRATION 10-40 mcg, incremental IV bolus → Attempts to reverse untoward opioid effects, preserve analgesia 1-4 mcg/kg IV bolus → Reverses untoward effects and analgesia Effective routes: PO (5x IV dose), ETT, IT, nasal Onset 1-2 min, duration 30-45 min 95 OPIOID ANTAGONISTS NALOXONE CONCERNS “Renarcotization”; duration of agonist > duration of antagonist SNS stimulation from abrupt reversal of analgesia/sedation N/V Precipitation of neonatal withdrawal syndrome Reversal of GA in large doses OTHER USES Hypovolemic/septic shock: dose-related improvement in myocardial contraction → Doses > 1 mg/kg, likely not mediated by μ receptor, potential receptors May reduce anterior cord syndrome, combined with CSF drain, with 96 aortic cross-clamp OPIOID ANTAGONISTS NALTREXONE Orally active antagonist at μ, κ, and δ opioid receptors; up to 24 hr duration Treatment of alcoholism Reduces or prevents N/V associated with spinal morphine NALMEFENE Orally active, equipotent with naloxone IV Similar to naloxone in receptor activity – active at all, greatest effect at μ Longer acting than naloxone (elimination t1/2 = 8.5 hours vs 1 hour for naloxone) Prophylactic for N/V, pruritis with IV PCA morphine METHYLNALTREXONE Quaternary structure 97 Reverses peripheral effects (delayed gastric emptying, some components OPIOID TOLERANCE ACUTE TOLERANCE Can develop within hours with the highly potent opioids CHRONIC TOLERANCE Develops over days to weeks Decreasing analgesic effect results in dose escalation and increased incidence of OIH Develop tolerance to analgesic, euphoric, sedative, respiratory depressant & emetic effects Tolerance does not develop to effects on pupil size or bowel motility PSEUDO-TOLERANCE Seen in chronic pain patients with disease progression and neuropathic pain increasing the nociceptive stimulus 98 OPIOID TOLERANCE MECHANISMS OF TOLERANCE Downregulation: desensitization or internalization of the opioid receptors induced by certain ligands Uncoupling of G proteins Upregulation of the cAMP system Long term, persistent neural adaptation; high synaptic concentrations of glutamate & NMDA receptor activation MILLE R Not a function of enzyme induction (no increase in the metabolism of opioids) 99 OPIOID PHYSICAL DEPENDENCE Dependent on the agonist effects (less likely with agonistantagonists) Can begin to develop within ~48 hours of continuous use, but requires ~ 25 days (with morphine) to develop completely Partially dependent on the patient’s emotional state Discontinuation of the drug produces withdrawal symptoms: →Yawning, diaphoresis, lacrimation, rhinitis (initial) →Insomnia, restlessness (prominent, persistent) →Abdominal cramps, N/V, diarrhea (peak in 72 hr, last 7-10 days) 100 OPIOID INDUCED HYPERALGESIA OPIOID INDUCED HYPERALGESIA (OIH) A paradoxical increase in pain sensitivity with escalation of opioid dose IMPLICATIONS Long-term or high-dose opioid treatment Rapid escalation of dose Use of an opioid with rapid onset/offset (remifentanil) 101 OPIOID INDUCED HYPERALGESIA OPIOID INDUCED HYPERALGESIA (OIH) A paradoxical increase in pain sensitivity with escalation of opioid dose PROPOSED MECHANSIMS Activation of the glutamatergic system Central production of nitric oxide Activation of descending facilitation pathways (PAG/RVM) Not a function of changes in the μ receptor CONSIDERATIONS Most commonly seen after remifentanil infusion Prevention after remifentanil: longer acting opioid 102 OPIOID CONCERNS OPIOID ALLERGY True allergy to any opioid is rare True allergy to fentanyl is very rare Common side effects confused with allergies No cross-sensitivity between morphine and phenylpiperidines 103 OPIOID CONCERNS OPIOID IMMUNE MODULATION Opioid receptors are present on immune cells (peripheral mechanism of action) Opioids impact development, differentiation, and function of immune cells Depression of NK (natural killer) cells, tumor surveillance Consider the fact that pain can also impair immune function REDUCTION IN ANESTHETIC REQUIREMENTS Marked synergism between opioids and IV sedatives/hypnotics Reduction in MAC of VAs in dose-dependent manner 104 SEROTONIN SYNDROME MECHANISM Combination of certain opioids with SSRI or MAOI can result in increased availability of serotonin at 5-HT1A receptors in the CNS Weak serotonin reuptake inhibitors → Meperidine → Tramadol → Methadone → Fentanyl SIGNS/SYMPTOMS Confusion Fever, shivering, diaphoresis Ataxia Myoclonus, hyperreflexia Diarrhea 105 CHECK YO-SELF… Naloxone exhibits greatest affinity for the _________ opioid receptor. Which is LEAST likely to contribute to opioid-induced hyperalgesia? a) Use of rapid onset/offset opioid agent b) Physical changes in μ receptor configuration c) Activation of glutamatergic system d) Increased production of nitric oxide in CNS T or F Opioid tolerance develops secondary to induction of hepatic metabolic/enzymatic pathways. 106 SUMMARY STUDY GUIDE WILL BE POSTED TO D2L! 107