Exam 3 Drugs 2.docx

OPIOIDS AGONISTS Drug Drug Specifics Organ System Effects There is a large interpatient variability for the response amongst all opioids Cardiovascular Opioids are generally considered to provide cardiovascular stability Usually not significant with opioids alone Potential for significant depression...

OPIOIDS AGONISTS Drug Drug Specifics Organ System Effects There is a large interpatient variability for the response amongst all opioids Cardiovascular Opioids are generally considered to provide cardiovascular stability Usually not significant with opioids alone Potential for significant depression when combined with VAs, benzodiazepines Huge synergism results in myocardial depression Opioid itself is not a concern Myocardial Depression Morphine-induced bradycardia Stimulation of vagal nuclei in medulla Specific to morphine Direct depressant effect on SA/AV nodes Morphine-induced histamine release Results in decreased venous tone Variable decreases in SVR, MAP MAP drops more if the patient is dry Morphine is the only opioid that produces histamine Myocardial Protection Enhanced resistance to oxidative and ischemic stresses, preconditioning effect MONA therapy for chest pain Cardiovascular depression via synergism with benzodiazepines Opioids given alone do not cause these effects Fentanyl given with diazepam Huge drop in SVR and MAP with compensatory increase in HR Not blunting response Bigger dose does not cause much more difference The difference is giving them together (synergism) Morphine-induced histamine release Large increase in serum histamine with morphine only Immediate effect Large standard deviation with morphine histamine release Interpatient variability Ventilation Depression of ventilation Corresponding increase in etCO2 and decrease in MV in patients receiving opioids Factors that increase the magnitude/duration of opioid-induced respiratory depression Renal insufficiency Excreting active metabolites Increased ventilatory depression with renal insufficiency Hyperventilation / hypocapnia Drugs are weak bases alkalotic state means increased pH more percentage of nonionized drug Respiratory acidosis Increased CBF despite large amounts of ionized drug Can overcome ionization effect All opioids produce dose-dependent ventilatory depression μ receptor activation results in direct depression of ventilation centers in brainstem Increase in resting PaCO2 with shift of CO2 response curve to right Curve looks at etCO2 and MV Increase in MV to increased etCO2 Right shift means it takes more etCO2 to cause an increase in MV with opioids in patients spontaneously breathing Most patients we control their ventilation need to consider this curve shift during emergence An increase in hydrogen ions will stimulate CNS to breathe Decrease in ventilation rate with potential of prolonged pauses Incomplete compensatory increase in Vt, evidenced by predictable increase in PaCO2 Decrease in ciliary activity Pathogens beneath the glottis can’t get out with ETT Prone to atelectasis Increase in airway resistance Direct effect on bronchial smooth muscle vs indirect histamine effect Histamine causes bronchoconstriction Cough suppression Direct, depressant effects on medullary cough centers Greatest effect in opioids with “bulky substitutions” at number 3 carbon Codeine (antitussive) Dextrorotatory isomers suppress cough with no analgesia or ventilatory depression Most opioids are levorotary Dextromethorphan (Robitussin) Dextro isomer Can be opioid sparing Produces some sedation but no ventilatory depression Rigidity Rapid IV administration of large dose can cause generalized skeletal muscle rigidity Most common with fentanyl and derivatives “Wooden chest syndrome” Likely related to laryngeal musculature contraction Heavy opioid induction if you can’t ventilate, there could be airway constriction in laryngeal muscles (not chest) Treatment with muscle relaxant or opioid antagonist Or instrument the airway Central Nervous System Autonomic Effects Increased vagal tone Decreased sympathetic tone Suppress sympathetic outflow during induction/laryngoscopy using opioids Intracranial Pressure In absence of hypoventilation; decrease cerebral blood flow, possible decrease in ICP Won’t see this unless we are controlling ventilation Hypoventilation, hypercapnia can increase cerebral blood flow, ICP In spontaneously breathing patients Caution in head injury And uncontrolled airways EEG Effects Resemble patterns of sleep No indication of seizure activity with occasional myoclonus Myoclonus is less significant than with etomidate or propofol Miosis Pupil constriction Excitatory stimulation of ANS component of Edinger-Westphal nucleus in oculomotor nerve (CN3) Hypoxia will cause mydriasis Overcomes this miosis effect Sedation Precede production of analgesia, not tied to analgesic effect Variability is significant No correspondence Decreased NE release from LC 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%) Fentanyl will increase biliary colic pain Cautious use if planned intraoperative cholangiogram During cholecystectomy, angiogram assesses patency of biliary duct under fluoro If you give fentanyl, may cause biliary duct spasm that would occlude flow Treatment with opioid antagonist (naloxone), nitroglycerin, glucagon Nitro and glucagon produce smooth muscle relaxation Gastrointestinal Tract GI smooth muscle spasm Delayed gastric emptying Due to increased pyloric tone (aspiration risk) Time of injury is initial NPO time but once opioids are given, new NPO time is last dose Constipation Due to decreased peristalsis and prolonged transit time Peristalsis = smooth muscle contraction and relaxation Transit time = increased water reabsorption in intestines Harder to pass stool Sphincter of Oddi spasm can also increase biliary pressure and cause biliary colic Nausea and Vomiting Direct stimulation of CTZ via δ-opioid receptor and/or by acting as partial agonist at dopamine (D2) receptor CTZ = chemoreceptor trigger zone IM = getting to CTZ before emetic center and may actually be able to throw up Effect on vestibular apparatus Increased GI secretions and delayed transit Depresses vomiting center in medulla Emetic reflex is suppressed May be nauseous without need to throw up Genitourinary Urinary urgency/ retention Increased tone and peristalsis of ureter Augmentation of detrusor muscle tone Urinary urgency Increased urinary sphincter tone Urinary retention Cutaneous Changes Histamine release *morphine only* Skin, face, chest flushing Urticaria/erythema at injection site, along vein Not an allergic reaction if localized Rapid onset and offset of symptoms Provocation of cough Preinduction administration of fentanyl, sufentanil, alfentanil Imbalance between sympathetic and vagal innervation of airways Stimulation of juxtacapillary irritant receptors Hormonal Changes Prolonged therapy may impair H-P-A/H-P-G axes ↑prolactin ↓ cortisol, LH, FSH, testosterone, estrogen Short term decrease Placental Transfer Readily transported across placenta Fetal ion trapping Neonatal depression from placental transfer (morphine>meperidine) Morphine, we are concerned about metabolites Dependency with chronic maternal use If mom is opioid dependent, neonate will be opioid dependent Don’t immediately reverse, will cause seizures and increased SNS response Drug Interactions Ventilatory depression exaggerated by amphetamines, phenothiazines (Thorazine), MAOIs, TCAs Significant concern of CNS depression and hyperpyrexia with MAOI + meperidine Enhanced analgesia with sympathomimetics Don’t give these to increase effects Overdose Symptoms Classic triad Hypoventilation Miosis Coma Skeletal muscle flaccidity with potential airway obstruction Acute hypoxia/hypercapnia increases mortality Hypotension, seizure activity, mydriasis in presence of hypoxemia Treatment order Airway management Correct O2 debt and hypercapnia first Ventilatory support Opioid antagonist 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 Treats visceral pain Effective against visceral and somatic pain Analgesia more prominent when administered prior to stimulus Not normally given prophylactically May produce dysphoria when administered in the absence of pain 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) Morphine has a very distinct hysteresis INH Similar timing to IV administration High incidence and degree of respiratory depression Plasma/ CSF Concentrations Peak pharmacologic effects lag behind peak plasma concentration Hysteresis 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 Lipophobic, hydrophilic High degree of ionization at physiologic pH Ionized wont cross Protein binding Not a lot of free drug to reach CNS Rapid conjugation with glucuronic acid Immediate conjugation = decreased concentration gradient 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 Drug is not sequestered in lung tissue CSF peak and decay Delayed onset of analgesia Late respiratory depression Has to do with metabolites, not morphine itself Plasma levels rapidly drop after 6 hours After 6 hours, there is still a large amount in the CSF etCO2 is mirrored to CSF concentration Metabolism Primary conjugation with glucuronic acid in liver and kidneys Immediate Primary elimination in urine, with minimal biliary excretion Metabolites Morphine-3-glucuronide (75-85%) Most common Pharmacologically inactive Detectable in plasma 1 min after IV administration Rapid glucuronidation Morphine-6-glucuronide (5-10%) Most potent Pharmacologically active, μ receptor agonist Similar ventilatory depression to morphine Similar affinity to μ receptor, but 650x analgesic potency More potent than morphine Analgesic effect is from morphine 6 metabolite, not morphine Prolonged duration of action 3 or 6 = carbon Elimination Half-Time Elimination of metabolites longer than unchanged drug Rapid decrease in plasma concentration of morphine primarily due to glucuronidation Morphine is the prodrug Concerns Accumulation of morphine-6-glucuronide is significant issue with renal dysfunction Be very careful using with renal patients Clearance decreased in neonates, more sensitive to respiratory depression Minimal excretion/low concentration in breast milk Elderly maintain higher plasma concentrations Decreased serum protein = increased free drug Conjugation impaired by MAOIs Female gender Greater analgesic potency Prolonged duration Decreased slope of ventilation/CO2 response Flattened slope meperidine (Demerol) Overview μ and κ opioid receptor agonist Phenylpiperidine derivative Similar chemical structure to local anesthetics and atropine LA = Na channel blockade intrathecal injection motor blockade and analgesia Atropine = increase in HR, dry mouth, blurred vision Tachycardia is specific to Demerol Anticholinergic effects 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 Metabolism Extensive hepatic metabolism (90%) Demethylation to normeperidine Active metabolite 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 Don’t use with renal patients Normeperidine half time is longer than meperidine itself Elimination Half-Time Large doses may override hepatic, enzyme-dependent metabolism and prolong effect Highly protein bound (70%) Elimination half-time 3-5 hrs, primarily via pH dependent urinary excretion Clinical Use Large, unreliable variations in peak plasma concentrations after IM administration Toxicity potential with patient-controlled analgesia Due to long elimination half time Neuroexcitatory toxicity Postoperative shivering (neurogenic) κ receptor activation, agonist activity at α2-receptor, decrease in shivering threshold Alternatives Direct α2-agonists Precedex RNs can’t give this IVP Butorphanol Kappa receptor agonist 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 serum serotonin (MAOIs, SSRIs) SSRIs block serotonin reuptake Autonomic instability, HTN, HR, temp, diaphoresis, confusion, agitation, hyperreflexia Severe outcomes Seizures, coma, coagulopathy, metabolic acidosis fentanyl Overview Phenylpiperidine derivative Roughly 100x more potent than morphine Pharmacokinetics Highly lipid soluble Rapid onset Although well-defined hysteresis Shorter onset than morphine Large volume of distribution Long elimination half-time Short duration related to rapid redistribution to fat, skeletal muscle Similar to propofol High clearance but take a long time for all of it to be eliminated 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 Rapid redistribution Metabolism Extensive metabolism by N-demethylation Dependent on CYP3A enzymes and susceptible to enzyme interference Ramping or suppressing enzymes with change pharmacologic effect Metabolites No active metabolites! Norfentanyl, hydroxyproprionyl-fentanyl, hydroxyproprionyl-norfentanyl Minimal, clinically insignificant pharmacologic activity Elimination Half-Time Highly protein bound Prolonged elimination half-time despite short duration of action Slow reuptake from inactive tissue sites Short duration due to redistribution to tissues 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 Don’t use on outpatient surgeries as an infusion Return from peripheral tissue compartments to plasma Clinical Uses Anxiolysis Transmucosal= 15-20 mcg/kg, 30-45 min preop Fentanyl lollipops are used for pediatrics and chronic pain Can result in ventilatory depression, PONV Analgesia Postoperative intermittent bolus doses Short duration in bolus doses Labor 25 mcg (max) IT/up to 100 mcg epidural Intrathecal morphine is effective but watch for rostral spread Morphine is water soluble moves in CSF to other spinal levels Large concentration of opioid receptors in dorsal horn Chronic transcutaneous patch, steady 72 hr plasma concentration Take off patch 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 No amnesia No immobility or unconsciousness unless very large dose is used Prolonged ventilatory depression Side Effects Cardiovascular Effects Hypotension Dilation of venous capacitance unlikely, no histamine release Bradycardia Due to depression of carotid sinus baroreceptor reflex This is what causes hypotension Ventilatory Effects Significant, persistent ventilatory depression Ventilatory depression outlives analgesic effect Potential for recurrent depression of ventilation from release of sequestered drug Gastric fluid when trapped, ionized drug released in more alkaline small intestine Moves back into plasma and then becomes active again Skeletal muscle as recovery allows movement Lung tissue when V/Q discrepancies improve 75% is in the lung tissue Re-perfuse lung areas that have fentanyl molecules sequestered there after extubating 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 Pay close attention to MAP (especially in chronic HTN patients) Drug Interactions Benzodiazepines Decreased propofol requirements for GA Marked synergism in hypnotic and ventilatory depression effects sufentanil (Sufenta) Most potent and highly protein bound Overview Phenylpiperidine derivative 5-10x more potent than fentanyl 500-1,000x more potent than morphine Pharmacokinetics Very lipid soluble Rapid penetration of blood-brain barrier Rapid CNS effect Rapid onset Rapid redistribution to inactive tissue Terminates action of small dose Large doses or infusion may accumulate Not as much as fentanyl First-pass pulmonary uptake ~60% Highly protein bound Principal portion binds α1-acid glycoprotein Wide range of α1-acid glycoprotein levels in healthy adults Decreased in neonates & infants Also decreased in elderly More free drug is available in these populations Highly variable effects Metabolism Very high hepatic-extraction ratio Sensitive to changes in hepatic blood flow How much is delivered to the liver vs how much comes out of the liver N-dealkylation and O-demethylation Metabolites Products of N-dealkylation are pharmacologically inactive Product of O-demethylation, desmethyl sufentanil ~10% activity of parent drug Pharmacologically inactive Clinically insignificant Excretion Excreted in urine/feces, 30% conjugated form Significant tubular reabsorption due to high lipophilicity Goes back into the tissue (then into plasma again) Impaired renal function results in increased plasma concentration Don’t give to renal patients Elimination Half-Life Fentanyl > sufentanil > alfentanil > remifentanil Measured after single dose 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 Sufentanil or remifentanil used as an infusion in OR Comparison to other opioids Prolonged dose/saturated tissues Sufentanil versus fentanyl Longer duration of analgesia Less depression of ventilation Sufentanil versus equipotent fentanyl or morphine More rapid induction More rapid emergence Earlier extubation Side Effects Cardiovascular Effects Hemodynamic stability Bradycardia (may decrease CO) Ventilatory Effects Potential for delayed depression of ventilation Less than fentanyl or morphine Chest wall/skeletal muscle rigidity, difficult PPV Wooden chest from laryngeal muscles CNS Effects Decreased CMRO2 with maintenance or decrease in CBF Potential increase ICP with decreased MAP in head injury Control ventilation to overcome ICP changes alfentanil (Alfenta) 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 Hydrophilic Affects CSHT Renal failure does not alter clearance or elimination half-time Safe to give to renal patients Metabolism No clinically significant active metabolites Wide (10-fold) interindividual variability Likely reflects variability in hepatic intrinsic clearance CYP3A4 activity Variability due to enzyme activity Context- Sensitive Half-time Longer than sufentanil for infusion up to 8 hr Smaller and more rapid equilibration of Vd of alfentanil Highly protein bound Clinical Uses Bolus for anticipated acute, but brief noxious stimulus Infusion for adjunct to GA Side Effects Lower incidence of PONV Potential for acute dystonia in untreated Parkinson’s disease remifentanil (Ultiva) Overview Unique, phenylpiperidine derivative Functional group = ester Selective μ receptor agonist 1-2x more potent than fentanyl 100-200x more potent than morphine Fast onset, rapid titration, fast off Pharmacokinetics Rapid blood:brain equilibrium time Steady state achieved within 10 min Rapid steady state = easy to titrate Very small Vd Very high rate of clearance Low interindividual variability Similar in lean and obese patients Base dose on lean body weight Metabolism Metabolized by non-specific plasma and tissue esterases No effect on butyrylcholinesterase/pseudocholinesterase Primarily renal excretion Unchanged by hepatic or renal dysfunction Safe to use in renal and liver patients Decreased ~20% with hypothermia Enzymes are temperature dependent Metabolite Remifentanil acid 300-4,600x less potent than parent Clinically inactive Context- Sensitive Half-Time Fast, ~4 min Independent of duration of infusion Basically context-insensitive Clinical Uses Rapid and profound short duration analgesia= 1 mcg/kg IV Used as an infusion 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 Staying below 0.1 Not traditionally used as a PCA because it is short lived other than L&D 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 Good alternative if epidural can’t be achieved Fetus can also break down remifentanil Ion trapping is not problematic Side Effects Ventilatory Effects Depression of ventilation Significant but short lived Synergistic with propofol Remifentanil and propofol have synergistic ventilatory depression Decreased slope and right shift CNS Effects Muscle rigidity ↓CBF & ↓CMRO2 Maintenance of CBF/CO2 curve No change in ICP/IOP Favorable to use in craniotomy and neuro cases Other Effects N/V Mild bradycardia No histamine release Abrupt discontinuation of analgesia OIH Going from profound analgesia to nothing opioid induced hyperalgesia hydromorphone (Dilaudid) Overview 5x more potent than morphine Very similar pharmacology to morphine Same considerations Suitable for PCA and intrathecal administration Pharmacokinetics pKa 8.6 Protein binding 19% Vd 303 L Partition coefficient 525 500 times more lipid soluble than morphine Will stay at segment of spinal cord when given intrathecal Metabolism Primary conjugation with glucuronic acid in liver Hydromorphone-3-glucuronide (95%) Neuroexcitatory effects Not as much as normeperidine Minimal (<5%) hydroxy-6-metabolites Clinically insignificant potency methadone Prolonged duration Wide interindividual effects Opioid withdrawal (less sedation, euphoria), chronic pain Satiates opioid receptors no euphoria or withdrawal codeine Mild analgesia Antitussive Also available IM oxymorphone (Opana) 10x potency of morphine Increased N/V Greater chance of physical dependence Similar to oral morphine but less subject to first pass Opioid crisis from oxymorphone and oxycodone oxycodone 2x potency of morphine High abuse potential Available in sustained release and tamper resistant forms hydrocodone Equipotent with morphine Often combined with acetaminophen Makes it dangerous 5-325 = 5 mg hydrocodone and 325 mg Tylenol Max tylenol = 4g daily High abuse potential Reclassified as Schedule II Oral, commonly given postop tramadol Moderate μ agonist, weak κ and δ agonist Descending inhibitory pathway Inhibition of neuronal uptake of NE and 5-HT3 Stimulation of presynaptic 5-HT3 release Serotonin = primary excitatory NT in descending pathway Minimal depression of ventilation, low incidence of physical dependence High incidence of N/V Concurrent ondansetron may affect analgesia Serotonin blocker decreases tramadol potency Seizure potential From serotonin syndrome heroin Synthetic analogue of morphine, diacetylmorphine High lipid solubility Rapid BBB penetration Rapid metabolism in brain to morphine and monoacetylmorphine Relative to morphine More rapid onset Less N/V Greater physical dependence OPIOID AGONISTS-ANTAGONISTS Drug Drug Specifics Opioid Receptor Activity Bind μ receptor Produce limited response partial agonist Produce no response competitive antagonist Displaces agonist Often exert partial agonist actions at κ and δ receptors Kappa receptors = dysphoria Advantages Analgesia with less depression of ventilation Partial Mu agonist at most Less potential for dependence Ceiling effect with depression of ventilation Concerns Modest production of analgesia Potential to limit effects of subsequent pure opioids May precipitate withdrawal in chronic user Higher incidence of dysphoria Related to kappa receptor Pentazocine (Talwin) Weak agonist at κ and δ receptors PO, IM, IV, and epidural routes Extensive first-pass hepatic metabolism Increase in plasma catecholamines ↑ HR, ↑ BP, ↑ PA pressure, ↑ LVEDP Significant dysphoria Not used much anymore Used to be used in patients with opioid tolerance Butorphanol (Stadol) Low affinity antagonist at μ receptor Moderate affinity agonist at κ receptor Analgesia and anti-shivering effects Alternative to Demerol Minimal affinity agonist at δ receptor Minimal dysphoria Rapid and complete absorption via IM route Migraine cocktail Potential for similar hemodynamic/catecholamine effects as pentazocine Increases catecholamines Limited use as anesthesia adjunct due to minimal effect on MAC requirements and antagonism of subsequent pure opioid analgesia Makes opioids less effective Nalbuphine (Nubain) Antagonist at μ receptor Agonist at κ receptor Equipotent to morphine Ceiling effect to ventilatory depression Can reverse ventilatory depression caused by fentanyl while preserving analgesia Partial agonist at Mu receptor No evidence of catecholamine release Buprenorphine (Buprenex) High affinity partial agonist at μ receptor 50x > affinity of morphine Resistant to naloxone Not problematic due to ceiling respiratory effect 33x more potent than morphine Ceiling effect to ventilatory depression Increasing dose only decreases Mu activity to an extent Partial Mu agonist Peak ventilatory depression ability not as high as fentanyl 5x more lipid soluble than morphine ↓ concern of late ventilatory depression in SAB OPIOID ANTAGONISTS Drug Drug Specifics Opioid Antagonist Created by modifying chemical structure of opioid agonist High affinity for opioid receptor Displaces agonist on receptor binding site Reversal effect Increasing opioid concentration could bump antagonist off receptor Binding produces no effect Clinical Uses Reverse detrimental effects of opioid agonists Ventilatory depression Right shift to curve Goal is to decrease ventilatory depression while preserving analgesia N/V Pruritis Urinary retention Postoperative ileus Biliary spasm naloxone (Narcan) Antagonist at μ, κ, and δ receptors Greatest affinity for μ recptor Dose/ Administration Incremental IV bolus Attempts to reverse untoward opioid effects, preserve analgesia Small doses for IV boluses 2mg to reverse overdose IV bolus Reverses untoward effects and analgesia A higher IV bolus dose will reverse analgesia Effective routes PO (5x IV dose), ETT, IT, nasal Onset 1-2 min Duration 30-45 min Concerns “Renarcotization” Duration of agonist > duration of antagonist SNS stimulation from abrupt reversal of analgesia/sedation Can cause brain bleeds in neonates N/V Precipitation of neonatal withdrawal syndrome Reversal of GA in large doses Other Uses Hypovolemic/septic shock Dose-related improvement in myocardial contraction Corrects the vasoplegia in shock Doses > 1 mg/kg, likely not mediated by μ receptor, potential κ and δ receptors May reduce anterior cord syndrome, combined with CSF drain, with aortic cross-clamp Ischemic anterior cord if clamped for too long causes paralysis Narcan reduces this Potential value in management of heat stroke naltrexone Orally active antagonist at μ, κ, and δ opioid receptors Up to 24 hr duration Treatment of alcoholism And heroin addiction Reduces desire to drink Reduces or prevents N/V associated with spinal morphine Use regional anesthesia if patient is taking this Difficult to control their pain 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 Used for withdrawal methylnaltrexone Quaternary structure Reverses peripheral effects (delayed gastric emptying, some components of N/V) Spares central opioid effects