Pharm5 – Opioids – Flashcards
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*!* Locations of opioid receptors (x5)
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-*Substantia gelatinosa of the spinal cord -Periaqueductal gray matter of the brainstem -Hypothalmus -Amygdala of the limbic system -Corpus striatum of the basal ganglia system
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Is meperidine more like a cholinergic or anticholinergic?
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Anticholinergic (structurally similar to atropine)
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Analogues of Meperidine (x4)
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-Fentanyl -Sufentanil -Alfentanil -Remifentanil
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IV doses (x3) for Fentanyl
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1-2 mcg/kg IV for analgesia 2-20 mcg/kg as adjunct to inhaled agents for laryngoscopy or surgical stimulation 50-150 mcg/kg alone for surgical anesthesia
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Opioid agonist-antagonists (x5)
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Nalbuphine (Nubain®) Buprenorphine (Buprenex®) Butorphanol (Stadol®) Dezocine (Dalgan®) Pentazocine (Talwin®)
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Drug & dose for complete opioid reversal
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Naloxone 1-4 mcg/kg (give over 2-3 minutes to reduce nausea)
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Mu? vs Mu?
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Mu?: Analgesia Mu?: Side effects (hypoventilation, bradycardia, physical dependence)
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What are the endogenous opioid receptor ligands & which receptor is activated by each? (x3)
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endorphins - mu receptors dynorphins - kappa receptors enkephalins - delta receptors
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What are the opioid receptors? (x3) & What is activation of each associated with?
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Mu - Analgesia, euphoria, hypoventilation, bradycardia Kappa - Analgesia, dysphoria, diuresis, stops shivering Delta - Alters response to Mu
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Opioids in what ionic state bind most strongly to the receptor site & why?
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Opioids in the ionized state -because the receptors are anionic (non-ionized state helps drug reach site of action, ionized state makes drug work better at receptors)
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How does activation of opioid receptors effect neurotransmission?
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Inhibits release of presynaptic excitatory neurotransmitters (postsynaptic inhibition may also occur) Decrease in neurotransmission by presynaptic inhibition of neurotransmitters although postsynaptic inhibition may also occur.
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What is the function of each of the Mu receptors?
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Mu?: analgesia, euphoria Mu?: hypoventilation, bradycardia, dependence -no loss of touch, proprioception, consciousness (Principally responsible for supraspinal and spinal analgesia.)
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What is the function of kappa receptors? (x4)
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-analgesia -dysphoria -diuresis -stops shivering Activation results in inhibition of neurotransmitter release via N Ca channels which results in analgesia although dysphoria and diuresis may also occur.
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What is the function of the delta receptors?
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Modulate the Mu receptor.
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What are the clinical uses for opioid receptor agonists (narcotics)?
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Endogenous pain suppression. (same as endorphins)
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What are the anesthesia indications for narcotics? (x4)
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-surgical analgesia -to blunt responses from surgical stimulation & laryngoscopy -epidural & spinal for acute & chronic pain management -high doses for surgical anesthesia (Injected into the epidural and subarachnoid space for acute and chronic pain management.)
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What are the Mu receptor agonists used by anesthesia? (x6)
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morphine meperidine fentanyl sufentanil alfentanil remifentanil (not used as much by anesthesia: codeine, oxycodone, hydromorphone, dextromethorphan, methadone, propoxyphene, & opioid agonist-antagonists)
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What is the MOA of neuroaxial administration? (x3)
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-Injected into epidural or subarachnoid space -Mu receptors in substantia gelatinosa of spinal cord -Also systemic absorption similar to an equal IV dose (Injection into the epidural and subarachnoid space knowing that Mu receptors are found in the substantia gelatinosa of the spinal cord. The neuroaxial route is not associated with sympathetic denervation, skeletal muscle weakness or loss of proprioception.)
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What are the S.E. of neuraxial opioid administration? (x5)
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Dose dependent: -pruritis (most common) -respiratory depression (most severe- 1% occurance but much greater if synergistic from additional narcotic use) -sedation -N&V -urinary retention (in males)
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How is the S.E. of pruritis caused by neuraxial opioid administration be prevented (x1) & treated (x2)?
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-pt should avoid coughing to cause cephalad migration -subtherapeutic dose of an opioid antagonist such as naloxone -can also use agonist-antagonist like buprenorphine (buprenex)
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What is the onset of effect & peak effect of morphine?
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Onset: 15-30 minutes Peak: 45-90 minutes (The peak effect after IV administration is delayed when compared to other opioids [15-30 minutes])
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Under what conditions would morphine cause CV depression & hypotension? (x6)
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CV depression, bradycardia, & hypotension IF: -very large dose (1mg/kg) -orthostatic -given rapidly (>5mg/min) -dehydrated -given with nitrous -given with a benzodiazepenes (More histamine release than fentanyl)
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What mechanism explains flushing that can occur with morphine?
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-Morphine causes cutaneous vessels to dilate (d/t partial release of histamine) (The skin of the face, neck, upper chest become flushed & warm)
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What are the genitourinary effects of morphine? How can this effect be reversed?
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?s the tone & peristaltic activity of the ureters -an anticholinergic such as atropine can reverse these effects (B&O)
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What are the S.E. of all opioids? (x7)
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-Respiratory depression [dose dependent] (cant get Mu? without Mu?) -Skeletal muscle rigidity, especially of thoracic and abdominal areas. (makes ventilating more difficult) -Spasms of biliary smooth muscle. -Spasms of the GI smooth muscles. (constipation & delayed gastric emptying) -N&V (stimulation of chemoreceptor trigger zone) -Fetal effects (crosses placenta) -Tolerance and physical dependence. Withdrawal.
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Which opioid causes the most biliary spasm?
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Fentanyl (Fentanyl increases common bile duct pressure the greatest followed by morphine, meperidine, and pentazocine.)
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Which opiate has the least effect on the fetus
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-Meperidine (Morphine causes greater neonatal depression than meperidine.)
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What is the duration of meperidine?
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2-4 hours. (shorter duration than morphine)
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How is morphine metabolized?
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-Hepatic & Renal (more respiratory depression if RF) (Renal metabolism has a significant contribution to the total metabolism. Principle pathway is conjugation with glucuronic acid in hepatic and extra hepatic sites, especially the kidneys.)
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How is meperidine metabolized?
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-Liver (Hepatic metabolism is extensive with 90% of drug metabolized to normeperidine and meperidinic acid. Urinary excretion if the primary route of elimination and is pH dependent.)
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How is elimination of meperidine affected by urinary pH?
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If urinary pH is <5 then 25% of meperidine is eliminated unchanged in the urine. (otherwise meperidine must be metabolized in the liver first)
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What S.E. are unique to meperidine? (x3)
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-Negative cardiac inotropic effects & histamine release at high doses (why anesthesia doesn't use much) -Tachycardia rather than bradycardia (similar in structure to atropine) -Mydriasis rather than miosis
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Why does meperidine cause tachycardia instead of bradycardia like other opiates?
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Due to its atropine-like structure.
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How do the S.E. of meperidine compare to the S.E. of morphine? (x5)
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-Hypotension is more frequent and more profound with meperidine than with morphine. -More ventilatory depression than morphine. -Less constipating -Less urinary retention than morphine -Biliary tract spasms less with meperidine compared to morphine but is greater than codeine.
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What is the peak effect of fentanyl?
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6.4 minutes.
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How is fentanyl metabolized?
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-Redistribution occurs -Metabolized in the liver to norfentanyl -Norfentanyl excreted by the kidneys (Metabolized by N-demethylation producing norfentanyl, which is structurally r/t normeperidine. Norfentanyl is excreted in the urine.)
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How does the elimination half time of fentanyl differ from morphine?
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-It is longer than morphine d/t the larger Vd for fentanyl (clearance for both opioids is similar)
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How is the plasma concentration of opioids affected by cardiopulmonary bypass? Which drug is most ; which is least affected?
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-All opioid plasma concentrations decrease -Fentanyl decreases the most (adheres to surface of bypass circuit) -Alfentanil ; Sufentanil will have more stable plasma concentrations (larger Vd)
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What are the disadvantages of fentanyl for general anesthesia? (x3)
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-Failure to prevent sympathetic response to painful surgical stimulation at any dose, esp. in patients with good LVF. -Possible patient awareness. -Post-op respiratory depression.
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What are the S.E. of fentanyl? (x5)
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-Bradycardia -Myoclonus -?ICP -Carotid sinus baroreceptor reflex control of HR is depressed (caution in neonates) -Others similar to morphine
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How do the S.E. of fentanyl compare with morphine? (x2)
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-less histamine release -more bradycardia (Fentanyl even in large doses doesn't evoke histamine release, dilation of venous vessels leading to hypotension is unlikely. Bradycardia is more prominent with fentanyl than morphine.)
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What does rapid IV doses of fentanyl or alfentanil cause?
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-Appearance of seizure activity (no EEG evidence of seizures) -Skeletal muscle rigidity? (Seizure activity, difficult to distinguish myoclonus or skeletal muscle rigidity from seizures (no EEG evidence of seizures).)
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What 2 opioids are associated with ?ICP, ?MAP, ?CPP in pts with head injuries?
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-Fentanyl -Sufentanil
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How is alfentanil metabolized?
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Metabolized in liver by cytochrome P-450 3A
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What is unique about remifentanil?
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-It's the only opioid that is not metabolized by the liver. =Fast onset ; fast offset
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What are the clinical uses of codeine?
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Post-op pain, and antitussive.
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What is hydromorphone? (x4)
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(Dilaudid®) -A derivative of morphine -8 times as potent -shorter duration than morphine -S.E. similar to morphine.
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What are the clinical uses of dextromethorphan?
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-Antitussive (robitussin DM, delsyn) Equal in potency to codeine as an antitussive but lacks analgesic properties or physical dependence.
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What are the S.E. of methadone?
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Similar to morphine Depression of ventilation, miosis, constipation, biliary tract spasm similar to morphine.
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What is the clinical use of propoxyphene?
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(Darvon®) Only indicated for relief of mild to moderate pain unrelieved by aspirin or acetaminophen.
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What is tramadol?
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(Ultram®) A centrally acting analgesic with low affinity to mu receptors. (5-10 x less potent as morphine)
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What is a potential drug interaction associated with tramadol?
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-Seizures if pt on antidepressants (Seizures have been reported with concomitant antidepressants.)
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What are the S.E. of opioid agonist-antagonists?
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Similar to morphine, in addition they may cause dysphoria.
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What are the clinical indications for opioid agonist-antagonists?
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Partially reverse opioids but maintain some amount of analgesia
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What are the opioid receptor antagonists? (x4)
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Naloxone (Narcan®) Naltrexone (Revia®) Methylnaltrexone Bromide (Relistor®) (peripheral only- for constipation with narcotic use) Nalmefene (Revex®) (longer duration of action)
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What are the disadvantages of naloxone? (x2)
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-Short duration of action (may require repeat doses or cont. infusion) -N/V with high doses ; rapid administration Has a short DOA which may make supplemental doses or continuous infusion necessary for sustained antagonism.
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What is the advantage of nalmefene over naloxone?
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Longer DOA than naloxone.
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What are the most common adverse reactions (;10%) of methylnaltrexone?
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GI: abdominal pain, flatulence, nausea.
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What are the adverse reactions of methylnaltrexone that occur in 1-10% of patients?
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CNS: dizziness GI: diarrhea.
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What are the adverse reactions of methylnaltrexone that occur in ;1% of patients (limited to important or life threatening)?
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abdominal cramps body temperature increased muscle spasm syncope
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What are the contraindications of methylnaltrexone?
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Known or suspected mechanical bowel obstruction.
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What is the most serious S.E. of neuraxial opioids?
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Respiration depression, occurs 1% of patients.
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Which opioid causes the most histamine release?
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Morphine has more than fentanyl.
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What is the induction dose of remifentanil?
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1 mcg/kg IV over 60-90 seconds (if pushed quickly associated with more bradycardia.)
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How is remifentanyl metabolized?
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By plasma esterases (Due to ester linkage susceptible to hydrolysis by plasma esterases.)
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What can occur if a pregnant woman chronically use opioids? (x2)
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dependence ; ventilatory depression -Opioids can transfer from mother to fetus resulting in ventilatory depression of the fetus. -Physical dependence may also result in the neonate as result of chronic opioid use by the mother.
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What can increase the risk of respiratory depression with neuraxial opioids? (x2)
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-Coughing may increase the cephalad migration of opioid. -Additional narcotics can cause synergistic respiratory depression
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What are the CV S.E. of morphine ;why do they occur? (x2)
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? in BP Bradycardia -d/t histamine release
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How can histamine release (x1) and hypotension (x3) with morphine be minimized?
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-Limit the rate of administration to 5mg/min -H1 ; H2 blockers (doesn't prevent histamine release but prevents change in SVR & BP) -supine position -keep patient well hydrated.
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What drug can be given to antagonize respiratory depression caused by opioids without reducing analgesia? What are the side effects of this drug?
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Physostigmine (ACh-esterase inhibitor) -causes cholinergic SE: diarrhea, bradycardia, etc.
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How long does it normally for tolerance & physical dependence to opioids to develop?
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Tolerance: 2-3 weeks Physical dependence: 25 days (some dependence in 2 days)
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Which opioid has the least effect on neonatal respiratory depression?
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Meperidine.
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What are the S/S of opioid withdrawal?
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Initial: (uncomfortable): yawning, diaphoresis, lacrimation, coryza, insomnia, and restlessness. 72hrs: (GI) abdominal cramps, N/V, diarrhea
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What can occur with abrupt withdrawal if opioids? What can be to help reduce this effect?
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-? in SNS activity [BP, HR] (usually not fatal like with benzos or alcohol) -Clonidine can reduce withdrawl symptoms
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How to administer Naloxone for opioid overdose
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-0.4-2 mg every 2-3 minutes as needed -may need to repeat every 20-60 minutes (short DOA) or a continuous infusion. -If no response after 10mg- question the diagnosis
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Which opioids should only be used in opioid tolerant patients? (x2)
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MS Contin Kadian
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What can occur if meperidine is given too quickly IV?
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More histamine release than morphine.
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What is a possible drug interaction associated with fentanyl?
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fentanyl + benzos = be careful -Effects of opioid and benzos on respiratory depression is synergistic. -Analgesic doses potentiate the effect of benzos and decrease dosing requirements for proposal.
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What is the post-op analgesia dose of methadone?
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20 mg IV (produces postop analgesia lasting >24 hours)
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What are the S.E. of Tapentadol (Nucynta®)?
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CNS effects--dizziness somnolence, fatigue; nausea.
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Why does neuraxial opioid administration cause itching?
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-Pruritis not from histamine release but likely cephalad migration -usually localized to the face, neck, & upper thorax
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Remifentanil vs Alfentanil
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-Both rapid onset & offset -Remifentanil metabolized in the blood, alfentanil in liver -Remifentanil more potent (300x morphine) than alfentanil (10-20x morphine)
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What is unique about methylnaltrexone?
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-An opioid agonist-antagonist that does not cross the BBB (used to treat constipation for those on chronic narcotics)
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Which drug is something between a narcotic and an antidepressant
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Tapentadol (Nucynta®)
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How does Tapentadol (Nucynta®) compare to other opioids?
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Structurally similar to tramadol but stronger (like lortab or meperidine) with a dual analgesic & antidepressant effect (NE reuptake inhibitor)
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At what rate can you give morphine without risk of CV depression & hypotension
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Less than 5 mg/min
