Opoid Analgesics and Antagonists PDF

OPIOID ANALGESIC AND ANTAGONIST Dr. Angelo Miguel M. Realina OUTLINE INTRODUCTION..............................................................................................1 MORPHINIANS.............................................................................

OPIOID ANALGESIC AND ANTAGONIST Dr. Angelo Miguel M. Realina OUTLINE INTRODUCTION..............................................................................................1 MORPHINIANS........................................................................................... 9 TERMINOLOGIES....................................................................................... 2 BENZOMORPHANS................................................................................... 9 SPECIFIC OPIOIDS..................................................................................... 9 CLASSIFICATION OF OPIOIDS BY EFFECT AT OPIOID RECEPTORS...... 2 AGONIST..................................................................................................... 2 ANTAGONIST.............................................................................................. 2 PARTIAL AGONIST.................................................................................... 2 ENDOGENOUS OPIOID SYSTEM................................................................. 2 PERIPHERALLY ACTING OPIOID ANTAGONISTS................................. 9 ENDORPHINS............................................................................................. 2 ENKEPHALINS............................................................................................ 2 DYNORPHINS............................................................................................. 2 OPIOID RECEPTOR SUBTYPES, THEIR FUNCTIONS, AND THEIR CLINICAL USE OF OPIOID ANALGESIC..................................................... 10 ENDOGENOUS PEPTIDE AFFINITIES.......................................................... 2 ANALGESIA............................................................................................... 10 5 TYPES OF OPIOID RECEPTORS............................................................... 3 MU RECEPTORS......................................................................................... 3 ACUTE PULMONARY EDEMA................................................................. 10 COUGH...................................................................................................... 10 DIARRHEA................................................................................................. 10 SHIVERING................................................................................................ 10 KAPPA RECEPTORS.................................................................................. 3 ANESTHESIA............................................................................................. 10 DELTA RECEPTORS................................................................................... 3 ALTERNATIVE ROUTES OF ADMINISTRATION.........................................11 NOCICEPTIN RECEPTORS........................................................................ 3 PATIENT CONTROLLED ANALGESIA.....................................................11 ZETA RECEPTORS...................................................................................... 3 TRANSDERMAL PATCHES.......................................................................11 OPIOID RECEPTORS AND THEIR ENDOGENOUS LIGANDS AND SUBLINGUAL.............................................................................................11 PRECURSORS................................................................................................. 3 INTRANASAL.............................................................................................11 MECHANISM OF ACTION OF OPIOIDS........................................................ 3 ADVERSE EFFECTS OF OPIOID ANALGESICS...........................................11 OPIOID RECEPTOR DISTRIBUTION IN THE CNS.................................. 4 DEFINITIONS RELATED TO OPIOID USE...................................................11 OTHER DIFFERENT SITE OF ACTIONS OF OPIOID ANALGESIC.......... 5 PHYSICAL DEPENDENCE.........................................................................11 PHARMACOKINETICS OF OPIOIDS............................................................. 5 TOLERANCE...............................................................................................11 ABSORPTION............................................................................................. 5 ADDICTION................................................................................................11 DISTRIBUTION........................................................................................... 5 PSEUDOADDICTION.................................................................................11 METABOLISM............................................................................................. 5 SUBSTANCE ABUSE.................................................................................11 EXCRETION................................................................................................. 6 HIGH-YIELD SUMMARY...............................................................................11 SAMPLE QUESTIONS TO REMEMBER.................................................. 13 ORGAN SYSTEM EFFECTS............................................................................ 6 REFERENCES................................................................................................ 13 CENTRAL EFFECTS.................................................................................... 6 INTRODUCTION United States ○ Over-prescription of opioids ○ ○ PERIPHERAL EFFECTS...............................................................................7 Philippines ○ under-prescription ○ ○ SPECIFIC AGENTS...........................................................................................7 PHENANTRENES.........................................................................................7 PHENYLETHYLAMINES............................................................................. 8 PHENYLPIPERIDINES............................................................................... 8  ANTAGONIST no functional response preventing an agonist from binding Naloxone PARTIAL AGONIST partial functional response ○ Buprenorphine Remember: Note: Icebreaker Discussion ENDOGENOUS OPIOID SYSTEM ○ ENDORPHINS ○ Addiction stress or pain μ-receptors  (mu) analgesia and euphoria ○  ○  Analgesia state of no pain  Analgesic substance that removes ENKEPHALINS or reduces pain δ-receptors mood regulation endogenous pain relief. TERMINOLOGIES OPIUM DYNORPHINS poppy plant (Papaver κ-receptors (kappa pain and somniferum and Papaver album stress responses. alkaloids ○ Morphine Note: Codeine ○ ○ OPIOID RECEPTOR SUBTYPES, THEIR FUNCTIONS, AND THEIR ENDOGENOUS PEPTIDE AFFINITIES OPIOD acts on opioid receptor. OPIATES naturally occurring NARCOTICS Endorphins μ (mu) QUESTIONS: Opium is derived from which plant? Poppy plant Are all opioids, narcotics? True or False? Enkephalins False δ (delta) Are all narcotics, opioids? True or False? False Dynorphins CLASSIFICATION OF OPIOIDS BY EFFECT AT OPIOID RECEPTORS κ (kappa) AGONIST maximal agonist response Morphine Note: Opioid Receptor Subtypes mu-opioid receptors sedation, analgesia, inhibition of respiration.  ○ respiratory depression. 5 TYPES OF OPIOID RECEPTORS MU RECEPTORS ZETA RECEPTORS MU-1 analgesia dependence MU-2 Note: respiratory depression, miosis MU-3 OPIOID RECEPTORS AND THEIR ENDOGENOUS LIGANDS AND vasodilation PRECURSORS Remember: KAPPA RECEPTORS (precursor: Prodynorphin) DELTA RECEPTORS (precursor: Proenkephalin) NOCICEPTIN RECEPTORS (precursor: Prepronociceptin) Morphine (most well- Morphinan series known & gold standard) ○ ○ Diphenylpropylamine ○ ○ Benzomorphan ○ ○ Phenylpiperidine series ○ ○ ○ ○ ○ morphine gold standard MECHANISM OF ACTION OF OPIOIDS G-protein-coupled receptors (GPCRs), Presynaptic calcium influx ○ Glutamate ○ Postsynaptic potassium conductance hyperpolarization ○  hyperpolarization Supplementary Video for MOA of Opioids: rapid potassium efflux hyperpolarization OPIOID RECEPTOR DISTRIBUTION IN THE CNS ○ Periaqueductal gray (PAG)  Primary site for opioid-induced glutamate analgesia ○ Limbic system  ○ Spinal cord  Peripheral receptors ○ preventing calcium entry inhibiting neurotransmitter release OTHER DIFFERENT SITE OF ACTIONS OF OPIOID ANALGESIC inflamed or damaged peripheral tissues spinal cord PHARMACOKINETICS OF OPIOIDS ABSORPTION ○ ○ ○ ○ ○ First-pass metabolism: liver ○ DISTRIBUTION Lipophilicity speed of onset ○ Fentanyl Highly ○ Morphine Less Included in the exam: Lipophilicity Brainstem ○ Fentanyl Highly rapidly GABA release Morphine Less slower METABOLISM liver CYP450 CYP2D6 Active metabolites morphine-6-glucuronide ○ Codeine metabolized to morphine CYP2D6   respiratory depression  ○ Remember: CYP2D6 prolonged sedation Included in the exam: EXCRETION Renal impairment necessary renal Renal impairment accumulation OPIOID ANALGESICS COMMONLY USED FOR SEVERE PAIN ○  Which is the drug of choice for severe acute pain? Fentanyl For post-operative use, Fentanyl Methadone ○ very long onset and duration of action. Mu (morphine-like) Agonist Morphine (μ) Within 20 Fentanyl (μ) Codeine (μ) Hydromorphone (μ) Levorphanol (μ, δ, κ, nociceptin agonist; NMDA antagonist, SNRI) Meperidine (μ) 1,5-Demethyl-2- ethyl-3,3-diphenyl- 1-pyrroline 4-6 initially, 6-8 after Methadone (NMDA) 30-120 10 2-Ethyl-5-methyl- steady state 3,3-diphenyl-1- pyrroline Methadone-N-oxide Oxycodone (MOP and KOP) Tramadol (weak μand weak SNRI) Mixed agonist-antagonist Nalbuphine (κ agonist, μ antagonist) Butorphanol (κ, σ agonist) Pentazocine (σ) Partial Mu agonist Buprenorphine (κ agonist) ORGAN SYSTEM EFFECTS CENTRAL EFFECTS ANALGESIA sensory and affective (emotional) components   Stomach: ○ opioids  Small intestine: ○  Large intestine: EUPHORIA ○ dysphoria ○ does not produce tolerance ○ SEDATION constipation persists regardless of the duration of opioid therapy. Biliary Colic: Sleep elderly Elevated Plasma Amylase and Lipase: RENAL RESPIRATORY DEPRESSION most dreaded side effect of opioids UTERUS labor depressed response to a carbon ENDOCRINE dioxide challenge. Stimulate ADH prolactin somatotropin inhibit luteinizing hormone COUGH SUPPRESSION Men ○ low testosterone Codeine Women PRURITUS TRUNCAL RIGIDITY NAUSEA AND VOMITING IMMUNE TEMPERATURE inhibited by opioids tumor progression SLEEP ARCHITECTURE SPECIFIC AGENTS PHENANTRENES PERIPHERAL EFFECTS STRONG AGONISTS Morphine, Hydromorphone, Oxymorphone CARDIOVASCULAR SYSTEM Heroin Bradycardia ○ ○ MEPERIDINE ○ tachycardia MORPHINE Gold standard for opioid analgesics Hypotension ○ archetypal opioid analgesic agent to which all other painkillers are compared Remember: Which of the following opioids can cause tachycardia? ○ Meperidine first pass effect GASTROINTESTINAL Morphine-6-Glucuronide Constipation ○ ○ ○ ○ Has longer half-life than the parent compound  Morphine-3-Glucuronide Remember: ○ Buprenorphine ○ Lacks analgesic activity ○ Excitatory effects ○ ○ seizure, myoclonus and hyperalgesia ○  MIXED RECEPTOR ACTIONS NALBUPHINE Remember: Morphine Strong kappa-receptor agonist and partial mu antagonist gold standard for opioid analgesics Morphine-6-Glucuronide ○ ○ analgesic activity ○ Longer half-life than the parent compound ○ Morphine-3-Glucuronide ○ primary metabolite ○ excitatory effects ○ Lacks analgesic activity Remember: MILD TO MODERATE Oxycodone CODEINE, DIHYDROCODEINE, HYDROCODONE lower binding affinity to mu-opioid receptors Nalbuphine OXYCODONE PHENYLETHYLAMINES ○ STRONG AGONISTS METHADONE ○ High oral bioavailability: 85% Useful in opioid rotation incomplete cross tolerance with opioids ○ Inhibitors of CYP3A4 ○ avoid saturation of receptors ○ ○ NMDA receptor antagonist activity anti- ○ hyperanalgesic prevent the development Inducers of CYP3A4 of morphine tolerance ○ Plasma half-life: 24 hours ○ Prolong the QTc interval ○ ○ immediate-release controlled-release Remember: Methadone Remember: Oxycodone ○ MILD TO MODERATE AGENTS PROPOXYPHENE BUPRENORPHINE Partial Mu Opioid Receptor agonist ○ ○ ○ PHENYLPIPERIDINES STRONG AGONISTS Long half-life FENTANYL more potent than morphine slow dissociation infusion Oral transmucosal nasal spray buprenorphine induced respiratory depression Transdermal patch  ○ kappa agonist. Partial agonist or antagonist at mu receptor ○ BENZOMORPHANS ○ MIXED RECEPTOR ACTIONS ○ PENTAZOCINE Kappa agonist with weak mu antagonist or partial agonist ○ SUFENTANIL SPECIFIC OPIOIDS TRAMADOL Weak Mu agonist and weak norepinephrine serotonin ALFENTANIL reuptake inhibitor neuropathic chronic REMIFENTANIL TAPENTADOL Weak Mu agonist and weak norepinephrine reuptake inhibitor MEPERIDINE ○ Significant antimuscarinic effects ○ Contraindication: Tachycardia ○ ○ NALOXONE Pure opioid antagonist Normeperidine Higher affinity for mu Anti-shivering ○ Meperidine is the 15-45 minutes most effective Redosed or administered as continuous infusion (IV) ○ MILD TO MODERATE AGENTS DIPHENOXYLATE ○ Difenoxin diarrhea Remember: Checking for Respiratory Depression LOPERAMIDE control diarrhea peripheral opioid mu receptors lack of effect ○ on CNS receptors ○ ○ NALTREXONE Pure opioid antagonist Remember: Meperidine ○ withdrawal symptoms Sufentanil and Alfentanil ○ Maintenance therapy Loperamide ○ Relapsing cases: ○ decreases MORPHINIANS the craving for alcohol in chronic alcoholics STRONG AGONIST LEVORPHANOL PERIPHERALLY ACTING OPIOID ANTAGONISTS Acts on different receptors ○ Agonist METHYLNALTREXONE ○ inhibition ○ antagonist opioid-induced constipation MIXED RECEPTOR ACTIONS NALOXEGOL BUTORPHANOL ALVIMOPAN ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ naloxone CLINICAL USE OF OPIOID ANALGESIC Is nasal administration not allowed? ANALGESIA ○ hypoxemia ○ ACUTE PULMONARY EDEMA WHO 3-STEP ANALGESIC LADDER Non-Opioids + Adjuvants ○ COUGH Dextromethorphan Opioids from mild to moderate pain + Non-opioids + Adjuvants DIARRHEA ○ Loperamide SHIVERING Meperidine Opioids from moderate to severe pain + Non-opioids + Adjuvants ○ ANESTHESIA IV Fentanyl ○ Spinal, epidural Morphine Invasive and Minimally Invasive Treatments Remember: ○ Note: Other Questions from Students What is the drug of choice for opioid overdose?  ALTERNATIVE ROUTES OF ADMINISTRATION PATIENT CONTROLLED ANALGESIA Tolerance, dependence Abuse, addiction DEFINITIONS RELATED TO OPIOID USE PHYSICAL DEPENDENCE state of adaptation fentanyl oxycodone morphine ○ Abrupt cessation ○ Rapid dose reduction ○ administration of an antagonist ○ TRANSDERMAL PATCHES fentanyl TOLERANCE physiologic state resulting from regular use of a drug increased dosage specific effect reduced effect constant dose over time ADDICTION behaviors ○ Impaired control over drug use SUBLINGUAL ○ Craving Philippines, Fentanyl sublingual tablet (Abstral ○ Compulsive use ○ Continued use despite harm INTRANASAL ○ bypassing the first-pass effect ADVERSE EFFECTS OF OPIOID ANALGESICS PSEUDOADDICTION Respiratory depression iatrogenic syndrome ○ Most significant and common adverse effect of misinterpretation of relief-seeking behaviors as though opioid analgesics they are drug-seeking behaviors commonly seen with addiction Pupil constriction (miosis ○ SUBSTANCE ABUSE chronic opioid therapy ○ use of any substance(s) for nontherapeutic purposes use of medication for purposes other than prescribed Constipation Question: When checking patients, observe their pupils—are they showing miosis or HIGH-YIELD SUMMARY mydriasis? ○ Agonist: Morphine ○ Antagonist: Naloxone ○ Partial Agonists: Buprenorphine Respiratory depression ○ Endorphins  stress or pain  Μ-receptors (mu) Constipation  analgesia and euphoria ○ Enkephalins ○ Constipation:  Δ-receptors  mood regulation endogenous pain relief  ○ Dynorphins  Κ-receptors (kappa)  pain and stress responses Phenanthrenes ○ Μ (mu): Endorphins ○ Strong Agonists:    Morphine sedation, analgesia, and  Gold standard for opioid the inhibition of respiration. analgesics   Morphine-6-Glucuronide respiratory depression. analgesic activity  Respiratory depression and miosis longer half-life than the Mu-2 receptors parent compound ○ Δ (delta): Enkephalins  Morphine-3-Glucuronide ○ Κ (kappa): Dynorphins primary metabolite excitatory effects ○ G-protein-coupled receptors (GPCRs). lacks ○ naturally occurring opioid analgesic activity morphine gold ○ Mild to Moderate Agonists standard  Codeine, Dihydrocodeine, ○ Presynaptic calcium influx Hydrocodone  Glutamate ○ Postsynaptic potassium conductance  Oxycodone hyperpolarization ○ periaqueductal gray (PAG) primary and most significant site for opioid- induced analgesia.  Buprenorphine ○ brainstem inhibit pain-inhibitory Safer neurons GABA than morphine (less respiratory depression ○ Fentanyl Highly lipophilic rapidly ○ Mixed Receptor Actions: ○ Morphine Less lipophilic slower  Nalbuphine ○ Liver respiratory depression (higher doses); CYP2D6.  Phenylethylamines ○ Strong Agonist: Methadone ○ Kidneys  high oral bioavailability: 85% ○ Renal impairment  opioid rotation  Long plasma half-life: 24 hours  Prolong the QTc interval dose reduction is Phenylpiperidines essential kidney failure ○ Strong Agonists: ○ Methadone (NMDA): Very long onset and duration  Fentanyl: 100x more potent than of action. morphine patients with  30-120 minutes. advanced cancer  4-6 initially, 6-8 after steady  Meperidine: Antimuscarinic state most effective anti-  10 shivering  1,5-Demethyl-2-ethyl-3,3- normeperidine diphenyl-1-pyrroline; 2-Ethyl-5-methyl-  Sufentanil 3,3-diphenyl-1-pyrroline; Methadone- N-oxide  Alfentanil ○ Analgesia  Remifentanil sensory and affective (emotional) components ○ Mild to Moderate: ○ Respiratory depression: Most serious and  Loperamide Controls diarrhea dreaded mu-opioid receptors ○ but only Morphinians Meperidine tachycardia ○ Strong Agonist Levorphanol   ○ Naloxegol ○ Alvimopan ○ Mixed Receptor Actions  Butorphanol  abdominal pain, diarrhea, nausea, flatulence, vomiting, headache ○ cough: dextromethorphan Benzomorphans ○ diarrhea: loperamide ○ Mixed Receptor Actions Pentazocine ○ Shivering: Miperidine  ○ IV Anesthesia: Fentanyl ○ Spinal, epidural: Morphine  SAMPLE QUESTIONS TO REMEMBER Opioids ○ Tramadol ○ Poppy plant  ○ False, not all opioids are narcotics  ○ False ○ Tapentadol  ○ Miosis  ○ Yes. ○ Fentanyl Opioid Antagonists ○ Naloxone ○ Meperidine tachycardia.  Remember ○ Morphine ○ Naltrexone REFERENCES Peripherally Acting ○ Methylnaltrexone