OPIOIDS

1. LINDA WUNDER,MSN,CRNA NURSE ANESTHESIOLOGY FLORIDA INTERNATIONAL UNIVERSITY OPIOIDS

2. OPIOIDS First, morphine in 1803 with active component opium Narcotic is greek for stupor and is referred to morphine-like analgesics with potential to produce physical dependence.

3. OPIOIDS-OBJECTIVES Explain the mechanisms for pain relief provided by opioid agonist and opioid agonist-antagonist. Describe the Pharmacodynamics and pharmacokinetics for the opioid agonist, opioid agonist-antagonist, and opioid antagonist. Identify the most common adverse effects of various opioids by mode of delivery. Discuss the mechanisms of metabolism and elimination of opioid agonists, opioid agonist-antagonists, and opioid antagonist. Summarize the effects of opioids on the stress response.

4. OPIODS Opioids act at stereospecific opioid receptors at presynaptic and postsynaptic sites in the central nervous system� brain(periaqueductal gray, amygdala, corpus striatum, and hypothalmus) and spinal cord (substantia geltinosa) and in the peripheral tissues. Endogenous ligands for the opioid receptors are collectively known as endorphins. The term endorphin comes from endo, meaning inside, and m-orphine, indicating opioid agonist.

5. OPIOIDS The endorphins are peptides that are released upon a painful stimuli They bind to opioid receptors to decrease the individuals perception of pain Endorphines include enkephlins, endorphines and dynorphins The opioid agonist mimic the endogenous endorphins and bind to the opioid receptors hence inhibiting pain transmission

6. OPIOIDS Ionized state is necessary for strong bonding at the anionic receptor site Only the levorotatory forms of the opioid exhibit agonist activity The affinity of most opioid agonists for receptors correlates well with their analgesic potency

7. OPIOIDS Opioids receptor activation decreases neurotransmission Mostly decreasing presynaptic release of acetylcholine,dopamine,norepinephrine ,substance P(postsynaptic can occur) Substance P is an excitatory neurotransmitter presumed to be released by terminals of pain fibers that synapse in the substantia gelatinosa of the spinal cord

8. OPIOIDS Opioid receptors are classified as mu, delta, kappa An ideal opioid agonist would have have high specificity for receptors, producing desirable responses (analgesia) and little or no specificity for receptors associated with side effects ( hypoventilation, nausea, physical dependence)

11. OPIOIDS

12. OPIOIDS EFFECTS Cv � not a negative inotrope Respiratory- decrease respiratory rate and increase tidal volume. Decrease the CO2 response in the medulla Chest wall rigidity-rapid administration of opioids increases airway pressure Spasm of biliary smooth muscle-sphincter of Oddi GI-constipation, N/V(stimulation of the chemotrigger zone floor of fouth ventricle) Placenta-opioid cross and produce fetal respiratory depression Miosis-excitatory action of edingerwestphal nucleus of the occularmottor nerve Awareness-not a hypnotic Decreases MAC requirements for inhalational anesthetics Tolerance �occurs 2-3 weeks, dependence 25 days Opioids block the normal stress release of catecholamines, anidiuretic hormone and corisol to surgical stimulation Opioids block the hemodynamic response to intubation

13. OPIOIDS Onset 15-30min,1/2 time 1.7-3.3 hr 75-85% metab to morphine-3-glucuronide inactive 5-10% metab to morphine 6-glucuronide, produces analgesia and resp depression via mu activation Metab conjugationwtih glucuronic acid Releases histamine MORPHINE

14. OPIOIDS MEPERIDINE 1/10 as potent as morphine Duration 2-4 hours Mu and kappa receptor agonist Structurally similar to atropine, derived from phenylepiperidine 90% metabolized to normeperidine,1/2 as active as a analgesic Normeperidine toxicity causes myoclonus and seizures No miosis, causes mydriasis, large doses causes decrease in myocardial contractility Do not administer if patient is taking moa inhibitors,cns excitation hypotension Treatment for postop shivering

15. OPIOIDS Hydromorphone- derivative of morphine that is 5 times as morphine with a slightly shorter � life. Produces more sedation that morphine with less euphoria. Rapid elimination and redistribution. Great alternative to morphine when moderate to severe pain is opioid responsive. IV 1-2 mg, � life 1-3 hours, onset 15-30 mins

16. OPIOIDS FENTANYL

17. OPIOIDS FENTANYL-phenylpiperidine derivative 75-125 more potent than morphine Rapid onset, highly lipid soluble First pass-75% initial dose to lungs Duration of action is by redistribution rather than elimination, slowly released and elimination by the liver-N-demethylation and excreted by the urine

18. OPIOIDS FENTANYL Elimination half time is longer than morphine because Vd is larger and is more lipid soluble Stable hemodynamic�no cardiac depressant effects, absence of histamine release, suppression of stress response during surgery

19. OPIOIDS 12 times more potent than fentanyl 60% first pass pulmonary uptake Smaller Vd than fentanyl Metabolized N dealkylation ,O demethylation SUFENTANIL

20. OPIOIDS ALFENTA�to fentanyl but 1/5-1/10 as potent with 1/3 duration Rapid onset 1.4 mins�low PK 90% nonionized, Vd 4-6 times smaller than fentanyl, lower lipid solubility Bound to alpha1 acid glycoprotein Metabolized � piperidine N-dealkylation to noralfentanil and amide N-dealkylation to N-phenylpropionamide Interindividual variability �inhibit metabolism especially alteration in P-450 for those taking erythromycin

21. REMIFENTANIL Potency similar to fentanyl Metab�nonspecific plasma esterases inactive metabolites Small Vd Context-sensitive half-time is independent of its infusion about 4 min (this is unlike fent, sufent, and alfent in which it is dependent on duration of infusion) Not used for neuraxial placement

22. OPIOIDS MORPHINE� .1-1mg/kg intaop FENTANYL� 2-150ug/kg intraop SUFENANIL-- .25-30ug/kg intraop ALFENTANIL� 8-100ug/kg intraop REMIFENTANIL� loading dose-1ug/kg, maintenance.5-20ug/kg/min intraop

24. OPIOIDS AGONIST/ANTAGONIST NALBUPHINE-NUBAIN Chemically related to oxymorphine and naloxone-as potent as morphine and � as an antagonist Metabolized in liver with half time of 3 to 6 hours 10-20 mg IV Reverses postop ventilatory depression effects of fentanyl maintaining the analgesia Relieves itching produced by peripheral opioid mu receptors and maintains analgesia

25. OPIOIDS Butorphanol (Stadol) Agonist-antagonist opioid Agonist effects 20 times >than pentazocine Antagonist effects 20-30 times >the pentazocine Low affinity for mu receptors to produce antagonism Moderate affinity for kappa receptors to produce analgesia IM 2-3mg, � life 2.5-3.5 hours, (similar analgesic effects to 10mg of morphine) Metabolites inactive via bile and urine.

26. OPIOIDS Opioid induced respiratory depression Metabolized conjugation-glucuronic acid to form naloxone 3-glucuronide Half time 60-90 minutes 1-4uq/kg IV Side effects: tachycardia,hypertention,pulmonary edema,cardiac dysrhythmias,vfib Crosses placenta Pure opioid antagonist NALOXONE (Narcan)

27. OPIOIDS NEURAXIAL Epidural or subarachnoid placement of opioids are based on mu receptors in the substancia gelatinosa of the spinal cord Epidural placement of opioids reflect diffusion of the drug across the dura to gain access to the mu opioid receptors on the spinal cord as well as systemic absorption to produce effects similar to those that would follow IV administration

28. OPIOIDS Side effects Pruritus N/V Urinary retention Depression of ventilation Sedation Central nervous system excitation Neonatal morbidity Viral reactivation Ocular dysfunction Sexual dysfunction GI dysfunction Thermoregulatory dysfunction Water retention

29. OPIOIDS Factors that increase risk of respiratory depression High opioid dose Low lipid solubility Concomitant administration of parental opiods or other sedatives Lack of opioid tolerance Advance age

30. ENTEREG ANTAGONIZES the peripheral effects of opioids on the GI tract u-opioid receptors. Does not reverse opioid analgesia

31. KETOROLAC NSAIDs possess analgesic, antiinflamatory, antipyretic,and platelet inhibitory effects NSAIDs inhibition of cyclooxygenase activity and the resulting decrease in peripheral synthesis of prostaglandins

32. KETOROLAC NSAID potent analgesic, moderate antiinflammatory 30mg IM,produces analgesia that is equivalent to 10 mg of morphine Has no ventilatory depression or biliary spasm Metabolized by glucuronic acid conjugation Clearance is decreased in elderly and dosed less in younger patients

33. KETOROLAC SIDE EFFECTS Bleeding Life �threatening bronchospasm may follow if administered to patients with Nasal polyposis, asthma, and aspirin sensitivity