Learning Objectives: After studying the material of this lecture, the student should: 1. Be able to list the precursors of the endogenous Introduction to opioids and the opioid receptors with which the endogenous opioids interact. Opioids/Opiates 2. Know the effects mediated by the interaction of opioids with each of the specific opioid receptors. 3. Learn the mechanism of the analgesic action of morphine. Sandra Welch, Ph.D. 4. Know the similarities and differences in the profile of Professor, Pharmacology and Toxicology clinically observed effects of the opioids. McGuire Hall 305, 828-8424, [email protected] 5. Understand the clinical signs associated with opiate overdose and with opiate withdrawal and the therapies used for each condition. 6. Know the most common drugs used in the maintenance of opiate abstinence. 7. Understand therapeutic precautions when administering opiates. NOTE: ALL TESTS WILL USE ONLY GENERIC NAMES OF DRUGS. ANY TERM IN BOLD OR UNDERLINED IS ABSOLUTELY REQUIRED INFORMATION FOR TESTING. ALL DIAGRAMS ARE REQUIRED INFORMATION FOR TESTING. 1 opium morphine narcotine codeine thebaine papaverine narceine opium opium morphine morphine narcotine narcotine codeine codeine thebaine thebaine papaverine papaverine narceine narceine DIACETYLMORPHINE heroin I. TERMINOLOGY A. Narcotics “Narcosis" = sleep II. HISTORY Legalistic term, proper pharmacological term is “Opioid Analgesics” B. Opium 1806 - Serturner - isolated morphine extract of opium poppy 1832 - Robiquet - isolated codeine C. Opiates 1951 - Nalorphine- the first opiate antagonist drugs derived from opium. Examples are and treatment for overdose morphine, codeine. 1967 - William R. Martin first described opiate D. Opioids receptor subtypes any drug or peptide that has opiate-like effects via binding to opiate receptors. Examples are the endogenous opioids. 2 Lots of things can modify pain sensitivity III. ENDOGENOUS OPIOIDS Figure 1. Schematic representation of the structures of the protein precursors of the three families of opioid peptides. i.e. those opioid peptides which occur naturally in the body Abbreviations: ENK - enkephalin; DYN = dynorphin; END = endorphin. The sequence of met- enkephalin is Tyr-Gly-Gly-Phe-Met, while that of leu-enkephalin is Tyr-Gly-Gly-Phe-Leu. A. Beta-Endorphin (modified from Akil et al., 1984) γ -MSH Goldstein, 1975 ACTH β -LPH 31 amino acids α -LPH β -END pituitary/hypothalamus/adrenal B. Met-Enkephalin α -MSH β -MSH MET-ENK Hughes and Kosterlitz, 1975 MET-ENK LEU-ENK Leu-Enkephalin Hughes and Kosterlitz, 1975 5 amino acids MET-ENK MET-ENK ARG 6 -GLY 7 -LEU 8 ARG 6 -PHE 7 C. Dynorphin important in modulation of analgesia LEU-ENK D. Orphanin FQ -- anti-analgesic α -NEOENDORPHIN E. Endomorphins 1 and 2 -- mu receptor endogenous ligands - DYN DYN A B analgesic β -NEOENDORPHIN Figure 1. Schematic representation of the structures of the protein Four genes are involved: precursors of the three families of opioid peptides. 1. Pro-opiomelanocortin Abbreviations: ENK - enkephalin; DYN = dynorphin; END = endorphin. The sequence of met- enkephalin is Tyr-Gly-Gly-Phe-Met, while that of leu-enkephalin is Tyr-Gly-Gly-Phe-Leu. (modified from Akil et al., 1984) γ -MSH ACTH β -LPH 2. Proenkephalin α -LPH β -END 3. Prodynorphin α -MSH β -MSH MET-ENK MET-ENK LEU-ENK 4. Pronociceptin/orphanin FQ MET-ENK MET-ENK ARG 6 -GLY 7 -LEU 8 ARG 6 -PHE 7 LEU-ENK α -NEOENDORPHIN DYN DYN A B β -NEOENDORPHIN 3 Figure 1. Schematic representation of the structures of the protein precursors of the three families of opioid peptides. Abbreviations: ENK - enkephalin; DYN = dynorphin; END = endorphin. The sequence of met- enkephalin is Tyr-Gly-Gly-Phe-Met, while that of leu-enkephalin is Tyr-Gly-Gly-Phe-Leu. (modified from Akil et al., 1984) γ -MSH ACTH β -LPH α -LPH β -END α -MSH β -MSH MET-ENK MET-ENK LEU-ENK MET-ENK MET-ENK ARG 6 -GLY 7 -LEU 8 ARG 6 -PHE 7 LEU-ENK α -NEOENDORPHIN DYN DYN A B β -NEOENDORPHIN Figure 1. Schematic representation of the structures of the protein precursors of the three families of opioid peptides. Abbreviations: ENK - enkephalin; DYN = dynorphin; END = endorphin. The sequence of met- enkephalin is Tyr-Gly-Gly-Phe-Met, while that of leu-enkephalin is Tyr-Gly-Gly-Phe-Leu. (modified from Akil et al., 1984) γ -MSH ACTH β -LPH α -LPH β -END α -MSH β -MSH MET-ENK MET-ENK LEU-ENK MET-ENK MET-ENK ARG 6 -GLY 7 -LEU 8 ARG 6 -PHE 7 LEU-ENK α -NEOENDORPHIN DYN DYN A B β -NEOENDORPHIN NEW “KIDS” ON THE BLOCK ! D. Orphanin FQ -- anti-analgesic E. Endomorphins 1 and 2 - mu receptor endogenous ligands - analgesic 4 MU1 endomorphins-endogenous ligands MU2 AGONISTS: morphine Agonists: Same as Table 1. Multiple Opiate Receptors codeine MU1 (mu, delta, and kappa opioid receptors meperidine fentanyl Antagonists: Same have been cloned) methadone as MU1 propoxyphene oxycodone tramadol EFFECTS: ANTAGONISTS: Respiratory Naloxone depression Naltrexone (medulla) EFFECTS: Analgesia Bradycardia Euphoria Physical dependence KAPPA 1,2,3 Dynorphins - endogenous ligands AGONISTS SIGMA Pentazocine Butorphanol NOT an opioid receptor ANTAGONISTS EFFECTS Naloxone* Naltrexone* Dysphoria *(much higher doses needed for antagonism, compared to Mydriasis the mu receptor) Hallucinations EFFECTS Miosis Sedation Spinal Analgesia DELTA 1&2 Met and Leu Enkephalin - Endogenous ligands EPSILON AGONISTS: ALL MU AGONISTS ALSO ACT AT DELTA RECEPTORS Beta-endorphin - Endogenous ligand NO SPECIFIC DELTA AGONISTS AVAILABLE FOR CLINICAL USE Effects similar to Mu1 ANTAGONISTS Naloxone Naltrexone EFFECTS Spinal analgesia Respiratory rate DECREASED 5 Endomorphins β R 30 γ H2N α GDP INACTIVE G-PROTEINS EXTRACELLULAR Agonist A R β γ α GTP GDP GTPase P P β R P γ α P GTP INTRACELLULAR HOOC ACTIVATED G-PROTEINS IV. MECHANISM OF ACTION MORPHINE mu receptor G AC i (-) POTASSIUM K+ c-AMP CHANNELS Calcium CALCIUM ENTRY [Ca] BLOCKED i Decreased release of neurotransmitters 6 A. Decrease cyclic AMP 1. mu and delta receptors are coupled to adenylate cyclase (AC) via a G protein (GTP-binding protein) 2. changes in phosphorylation of proteins resulting in decreases in calcium entry. 3. mu and delta receptor activation decreases c-AMP B. Increase potassium efflux 1 1. results in decreased firing of neurons (hyperpolarization). This also decreases calcium entry. 2. All opioid receptor activation increases potassium efflux C. Decreases calcium entry to neurons 2 1. mu, delta, and kappa receptor activation decreases calcium entry 2. blocks release of neurotransmitters since intracellular calcium levels ([Ca]i) levels fall. Opioid peptides hyperpolarize cells to decrease action potential firing Gate Control Theory of Pain from RVM enk projection neuron Glut afferent fiber Sub P V. Pain pathways from Brody et al., 1995 Somatosensory cortex (postcentral gyrus): sensory-discriminative aspects of pain To limbic areas and frontal cortex: arousal, emotional, affective components of pain Intralaminar thalamic nuclear complex Vertebrobasilar thalamic complex Midbrain periaqueductal gray Paleospinothalamic tract (both ascend in anterolater quadrant of spinal cord) Neospinothalamic tract Nucleus raphe magnus in lower brainstem Descending pain-suppressing pathway in dorsolateral funiculus Pain stimulus entering dorsal horn via C and Aδ fiber . 7 VII. CLINICAL EFFECTS A. Summary of clinical responses produced by opioid analgesics: Drug Analgesia Antitussive Constipation Respiratory Abuse morphine +++ ++ +++ +++ +++ heroin +++ ++ +++ +++ ++++ codeine + ++ ++ + ± oxymorphone +++ + ++ +++ +++ meperidine ++ - ± +++ ++ propoxyphene + - ± + + pentazocine ++ - ± + ± butorphanol ++ + ± +++ ± buprenorphine ± + ±±± ++++ (strongest effect); + (weak effect); ± (weak and variable effect); - (no effect) B. Other effects of the opioid analgesics: VIII. CLINICAL SIGNS OF OPIATE OVER- 1. Miosis DOSE 2. Nausea A. Coma 3. Constipation – may be particularly B. Pin-point pupils (miosis) problematic in older people, concomitant use of a C. Respiratory depression stimulant laxative is advised. D. Decreased blood pressure E. Decreased body temperature 4. Histamine release F. Convulsions with some opiates 5. Tolerance and Physical dependence VI. TREATMENT OF OVERDOSE IX. MAINTENANCE OF OPIATE ABSTINENCE A. Naloxone i.v. rapid reversal, but rapid offset. May require repeated A. Methadone administration. 1. long acting mu agonist 2. orally active B. Clonidine - alpha-2 agonist which decreases the release of NE (norepinephrine) and thus, decreases some of B. Ventilate the adrenergic effects of opiate withdrawal C. Naltrexone - oral or long acting depo-injection (experimental) C. Drugs to control hypotension. D. Buprenorphine - “First-line drug”mixed agonist/antagonist, blocks self-administration in opiate addicts, low abuse potential, mild physical dependence. 8 X. WITHDRAWAL FROM OPIATES XI. THERAPEUTIC USES OF A. GENERALLY not life threatening SELECTED OPIATES B. "Flu-like", emesis, diarrhea, chills A. Opiate Agonists C. Due to release of NE and ACh (acetylcholine) 1. Morphine (cont.) 1. Morphine f. also administered by patient-controlled infusion pumps. a. used for severe pain The use of corticosteroids by the patient should be halted for at least 2 weeks prior to the insertion of the catheter to prevent b. duration of action 4-5 hrs infection since morphine increases the immunosuppressive effects of the steroids. c. active i.v. and i.m., and epidurally, LOW activity if given orally ( high "first pass" effect) g.Clearance of morphine depends upon adequate renal function to clear the glucuronidated form of the morphine. The d. elevate head