Opioid Analgesics Munir Gharaibeh MD Ph D MHPE
Opioid Analgesics Munir Gharaibeh, MD, Ph. D, MHPE Faculty of Medicine, The University of Jordan April, 2014
Opioid Analgesics Opioid Analgesic Narcotic Opium: Papaver somniferum Morphine, Morpheus , -ine Endorphins Enkephalins October 20 Munir Gharaibeh MD, Ph. D, MHPE 2
Opioid Analgesics Dependence(Abuse, Addiction, Habituation): Psychological (Psychic, Craving, Compulsive) Physiological (Physical, Adaptive. . . ) Tolerance. Cross Dependence. Cross Tolerance. October 20 Munir Gharaibeh MD, Ph. D, MHPE 3
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History of Opium Papaver semniferum Morphine Heroin ﺷﺮﻛﺔ ﺍﻟﻬﻨﺪ ﺍﻟﺸﺮﻗﻴﺔ ﺣﺮﺏ ﺍﻷﻔﻴﻮﻥ ﺍﺧﺘﺮﺍﻉ ﺍﻟﺴﻴﺮﻧﺞ 3000 BC 1806 1898 1600 1839 -1842 1853 Morphine Receptors ”Goldstein” 1973
Comparison of Analgesics Opioids Nonopioids Efficacy Strong Weak Prototype Morphine Aspirin Pain Relieved Any Type Musculoskeletal Site of Action Central Peripheral and Central Mechanism Specific Receptors PG Synthesis Danger Tolerance & Dependence G. I irritation Anti-inflammatory No Yes Antipyretic No Yes Antiplatelets No Yes October 20 Munir Gharaibeh MD, Ph. D, MHPE 6
Opiate Receptor Effects Mu 1 Mu 2 Morphine Kappa Sigma Delta Bemazocine N-allylcyclazocine Morphine, Leu-enkephalin Analgesia No analgesia Analgesia; No excessive analgesia heat Apnea Tachypnea Apnea Indifference Sedation Delirium Miosis Mydriasis Miosis Nausea &Vomiting October 20 No analgesia Nausea &Vomiting Munir Gharaibeh MD, Ph. D, MHPE 7
Opiate Receptor Effects Mu 1 Mu 2 Kappa Sigma Delta Constipation Urine retention Diuresis Pruritus Temperature increase Tolerance Little tolerance Tolerance Cross tolerance No mu cross tolerance Mu cross tolerance October 20 Munir Gharaibeh MD, Ph. D, MHPE 8
Opioid Analgesics Peptides Alkaloids : Natural Semi synthetic Synthetic October 20 Munir Gharaibeh MD, Ph. D, MHPE 9
Opioid Peptides “ 1970 s” Peptides helped in the understanding of: Mechanism of actions of opioids. Placebo effect of drugs. Acupuncture. Stimulation induced analgesia. Regulation of the release of pituitary hormones. October 20 Munir Gharaibeh MD, Ph. D, MHPE 10
Opiate Receptor Interactions October 20 Munir Gharaibeh MD, Ph. D, MHPE 11
Sites of Action Substantia gelatinosa Periventricular area Periaqueductal grey Hypothalamus Thalamus Striatum Limbic System Nucleus accumbens October 20 Munir Gharaibeh MD, Ph. D, MHPE 12
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Receptor mechanisms of analgesic drugs The primary afferent neuron originates in the periphery and carries pain signals to the dorsal horn of the spinal cord, where it synapses via glutamate and neuropeptide transmitters with the secondary neuron. Pain stimuli can be attenuated in the periphery (under inflammatory conditions) by opioids acting at mu -opioid receptors (MOR) or blocked in the afferent axon by local anesthetics. Action potentials reaching the dorsal horn can be attenuated at the presynaptic ending by opioids and by calcium blockers, alph 2 agonists. Opioids also inhibit the postsynaptic neuron, as do certain neuropeptide antagonists acting at tachykinin (NK 1) and other neuropeptide receptors. October 20 Munir Gharaibeh MD, Ph. D, MHPE 14
Sites of action of opioid analgesics Inflamed or damaged peripheral tissues. Spinal cord. Thalamus. October 20 Munir Gharaibeh MD, Ph. D, MHPE 15
Brainstem local circuitry underlying the modulating effect of opioids on descending pathways. The pain-inhibitory neuron is indirectly activated by opioids (exogenous or endogenous), which inhibit an inhibitory (GABAergic) interneuron. This results in enhanced inhibition of nociceptive processing in the dorsal horn of the spinal cord. October 20 Munir Gharaibeh MD, Ph. D, MHPE 16
Opioid analgesic action on the descending inhibitory pathway Sites of action of opioids on pain-modulating neurons in the midbrain and medulla including the midbrain periaqueductal gray area (A), rostral ventral medulla (B), and the locus caeruleus indirectly control pain transmission pathways by enhancing descending inhibition to the dorsal horn (C). October 20 Munir Gharaibeh MD, Ph. D, MHPE 17
Cellular Mechanisms of Action Inhibit adenylate cyclase, so decrease c. AMP. Inhibit Ca++ entry by decreasing phosphorylation of voltage operating Ca++channels. Enhance K+ efflux. The net result is an increase in release of DA, 5 HT, nociceptive peptides like substance P, resulting in blockage of nociceptive transmission. October 20 Munir Gharaibeh MD, Ph. D, MHPE 18
Depressant Effects of Morphine Suppression of pain, analgesia. Drowsiness and decreased mental alertness, sedation Decreased respiration. Increased intracranial pressure. Decreased myocardial oxygen demand. Suppression of cough, antitussive. October 20 Munir Gharaibeh MD, Ph. D, MHPE 19
Depressant Effects of Morphine Decreased peristalsis. Inhibition of fluid and electrolyte accumulation in the intestinal lumen. Decreased gastric acid secretion. Inhibition of emetic center. Slight decrease in body temperature. Decreased release of LH and FSH October 20 Munir Gharaibeh MD, Ph. D, MHPE 20
Stimulant Effects of Morphine Euphoria. Constriction of pupils, miosis. Stimulation of chemoreceptor trigger zone. Increased tone of intestinal smooth muscle. Increased tone of sphincter of Oddi, increased biliary pressure. October 20 Munir Gharaibeh MD, Ph. D, MHPE 21
Stimulant Effects of Morphine Increased tone of detrusor muscle. Increased tone of vesical sphincter. Increased release of prolactin and antidiuretic hormone. Proconvulsant in overdose. October 20 Munir Gharaibeh MD, Ph. D, MHPE 22
Pharmacokinetics October 20 Munir Gharaibeh MD, Ph. D, MHPE 23
Therapeutic Uses Acute Pain. Chronic Pain: but we should try: Nonopiates Weaker opiates. Regular fixed schedule. Myocardial Infarction. Obstetric Anesthesia. Pulmonary Edema: Relieve anxiety. Cause peripheral pooling Constipating Effect. October 20 Munir Gharaibeh MD, Ph. D, MHPE 24
Adverse Effects of Opioids Behavioral restlessness, tremulousness, and hyperactivity. Respiratory depression. Nausea and vomiting. Increased intracranial pressure. Postural hypotension accentuated by hypovolemia. Constipation. Urinary retetion. Itching and urticaria. October 20 Munir Gharaibeh MD, Ph. D, MHPE 25
Contraindications Head Injury. Shock and decreased blood volume. Chronic Hypoxic Conditions. October 20 Munir Gharaibeh MD, Ph. D, MHPE 26
Tolerance to Opioids Factors Affecting Development of Tolerance: Rate of Administration Dose Agent used. October 20 Munir Gharaibeh MD, Ph. D, MHPE 27
Tolerance to Opioids Tolerance develops to almost all actions of opioids, EXCEPT: Miosis. Constipation. Convulsions. October 20 Munir Gharaibeh MD, Ph. D, MHPE 28
Tolerance to Opioids Exact mechanism of tolerance to opioids is unknown, but it is: Not metabolic Not immunologic Homeostatic October 20 Munir Gharaibeh MD, Ph. D, MHPE 29
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Opioid Withdrawal 6 -12 hr: Drug seeking (purposive) behavior, non purposive signs, such as restlessness, lacrimation, rhinorrhea, sweating, yawning. 12 -24 hr: Restless sleep for several hours (yen) and feeling more miserable than before after awakening; irritability, tremor, dilated pupils, anorexia, gooseflesh skin. October 20 Munir Gharaibeh MD, Ph. D, MHPE 31
Opioid Withdrawal 24 -72 hr: Increased intensity of previous signs plus weakness, depression, nausea, vomiting, intestinal cramps, diarrhea, alternate chills and flushes, various aches and pains, increased heart rate and blood pressure, involuntary movements of arms and legs, dehydration and possible electrolyte imbalances. October 20 Munir Gharaibeh MD, Ph. D, MHPE 32
Opioid Withdrawal Later: Symptoms of autonomic hyperactivity alternate with brief periods of restless sleep and gradually decrease in intensity until addict feels better in 7 -10 days but may still exhibit strong craving for the drug. Some mild signs may be detectable for up to 6 months. Delayed growth and development of infants born to addicted mothers may be detected for up to one year. October 20 Munir Gharaibeh MD, Ph. D, MHPE 33
Treatment of Opioid Dependence Suppression of Withdrawal Syndrome Morphine Heroin Methadone Clonidine Opioid Substitution: Methadone LAAM Detoxification: Gradually decreasing the dose of methadone. Naloxone Narcotic Antagonists: Naltrexone for 2 -6 months following detoxification. October 20 Munir Gharaibeh MD, Ph. D, MHPE 34
Opioid Agonists Morphine Codeine Oxycodone Hydrocodone Heroin Meperidine (Pethidine) Methadone & L Acetyl Methadone (LAAM) d- Propoxyphene. Tramadol October 20 Munir Gharaibeh MD, Ph. D, MHPE 35
Comparison of Opioid Agonists Analgesia Antitussive Constipation Respiratory Abuse Liability Depression Morphine +++ Heroin +++ Codeine + ++ ++ +++ +++ ++++ ++ ++ + +, -- Oxycodone ++ ++ +++ Meperidine ++ -- +, - +++ ++ Methadone +++ ++ D-propoxyphene + -- +, - + + October 20 Munir Gharaibeh MD, Ph. D, MHPE 36
Partial Agonists-Antagonists Pentazocine. Buprenorphine. Nalbuphine. October 20 Munir Gharaibeh MD, Ph. D, MHPE 37
Antagonists Nalorphine Naloxone Naltrexone October 20 Munir Gharaibeh MD, Ph. D, MHPE 38
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