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dr. Ike - update on opioid pharmacology


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Opioid --> are important drugs used in the pain management.
Employ appropriate pharmacological choice by knowing the pharmacology of the drugs --> both pharmaco dynamic and pharmaco kinetics.
Provide optimal effect and minimize side effects

Published in: Health & Medicine
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dr. Ike - update on opioid pharmacology

  1. 1. Curriculum Vitae Nama : Dr. Ike Sri Redjeki, dr., SpAnKIC,KMN,M.Kes Jabatan : Kepala Departemen Anestesiologi & Terapi Intensif Fakultas Kedokteran Universitas Padjadjaran Bandung Ketua Program Studi Pendidikan Konsultan Intensive Care (KIC) Fakultas Kedokteran Universitas Padjadjaran Bandung Alamat : Departemen Anestesiologi & Terapi Intensif Fakultas Kedokteran Universitas Padjadjaran/RS. Hasan Sadikin Jalan Pasteur no. 38 Bandung 40161 Telp : 022-2038285/0811230514 Fax : 022-2038306 E-mail :
  2. 2. Update on Opioid Pharmacology Ike Sri Redjeki Department of Anesthesiology and Intensive Care Unit Hasan Sadikin Hospital/Medical Faculty of Padjadjaran University BANDUNG
  3. 3. Introduction Opioid • The most effective analgesics are the opioid analgesics • The opioids  interact with opioid receptors in the nervous system • These receptors are the sites of action for the endorphins, compounds that already exist in the body  also site of action for the external opioid drugs • Pharmakokinetics of this specific drugs also influence its efficacy
  4. 4. Ascending fast - Ascending slow – Descending *Opioid Receptor ↓ Site of action of Endorphine and other mediator  Opioid * * * * * *
  5. 5. FSC MO P MID DI C SC Spinal Cord MO Medulla (oblongata) P Pons C Cerebellum MID Midbrain (Mesencephalon) DI Diencephalon (Thalamus + Hypothalamus) F NRPG RVM Forebrain (Cerebral Cortex + Deep nuclei, e.g. amygdala) nucleus reticularis paragigantocellularis Rostral Ventral Medulla PAGRVM NRPG Amygdala Thalamus Hypothalamus Nociceptive Input
  6. 6. Example of physiological control of descending inhibition Stress produced analgesia (SPA) • Many accounts of people ignoring injuries when stressed, e.g. during sports contests, in battle • Animal studies show at least partly due to activation of PAG/RVM system • Possible role for amygdala, hypothalamus, some cortical regions (insula) that are also involved in other aspects of stress responses (hormonal, cardiovascular) • Note that PAG/RVM system is also part of cardiovascular control system for stress responses
  7. 7. Enkephalins are derived from pro- enkephalin relatively selective δ ligands Endorphins are derived from pro-opiomelanocortin (also the precursor for ACTH and MSH) bind to the µ receptor Dynorphins are derived from pro-dynorphins and are highly selective at the µ receptor Presynaptic Postsynaptic Opioid Nociceptins (nociceptin/orphaninFQ [N/OFQ]) (orphanin), have potent hyperalgesic effects Little affinity for the µ, d, κ receptors, (“opioid-receptor-like”) Nociceptin antagonists may be antidepressants and analgesics Kappa receptor  only analgesia and sedation no other side effect
  8. 8. The ORL-1 receptor • the ORL-1 receptor or the “orphan” receptor was very recently discovered • The natural opioid peptide that is a ligand for this receptor is nociceptin which is also called orphanin • The ORL-1 receptor is associated with many different biological effects such as memory processes, cardiovascular function, and renal function • It is thought to have effects on dopamine levels and is associated with neurotransmitter release during anxiety
  9. 9. Opioid Receptor Primary afferent nociceptor terminal Secondary ascending neuron Ca2+ Ca2+ K+ K+ Neurotransmitter glutamate  opioid receptor  opioid receptor Noxious stimulus ATP  cAMP
  10. 10. Opioid Receptor  placed by opioid Secondary ascending neuron Primary afferent nociceptor terminal Ca2+ Ca2+ K+ K+ Neurotransmitter glutamate  opioid receptor  opioid receptor Opioid Opioid x x Noxious stimulus ATP  cAMPX
  11. 11. Classification based on degree of affinity and efficacy at various receptor • Opioid Agonist • Opioid Partial Agonist ( high affinity but low efficacy at the μ receptor) • Opioid Agonist / Antagonist ( poor μ opioid receptor efficacy or μ opioid receptor antagonist and have κ agonist ) • Opioid Antagonist
  12. 12. Analgesic effects at opioid receptors. in the brainstem and medial thalamus in the limbic and other diencephalic areas, brain stem, and spinal cord
  13. 13. Future of Opioid Analgesics • The future of Opioid Analgesics seems to be linked to the study of the Kappa Receptor – The kappa receptor induces analgesia without the dangerous and unwanted side effects that the mu and delta receptors are associated with – However there are not any selectively strong agonists to this receptor as of now • As similar as endogenous morphine  non toxic metabolite
  14. 14. Chemical Structure of Opioid Morphine Phenolic hydroxyl group Alcohol hydroxyl group > Nausea and hallucination Nitrogen Atom Changes to the methyl group  will decrease analgesia and creating antagonists ( nalorphine )
  15. 15. Prototype of opioid Pentazocine High incidence of dysporia Fentanyl, Meperidine Hihgest affinity for the mu receptor Include propoxyphene and metadone Tramadol does not fit in the standard opioid classes  unique analgesic , an atypical opioid  4-phenyl – piperidine analogue of codein Has partial μ agonist, in addition to central GABA catecholamine and serotonergic activity
  16. 16. Pharmacology of opioid Side effect of opioid Drug interaction Morphine ( prototype μ receptor, phenanthrene deriative ) • After oral administration  only 40 – 50% reaches the CNS within 30 minute  other extended release  90 min • Poor penetration  poor lipid solubility • Respiratory acidosis increase brain concentration of morphine caused by increase in CBF • Elimination half life  120 min • Drug inhibit morphine degradation : tamoxifen, diclofenac, naloxone, carbamazepin, tryciclic and heterocyclic antidepressants, benzodiazepine Side Effect : • Decrease sympathetic nervous system tone • Decreased intestinal motility • Spasm of biliary smooth muscle and sphincter Oddi spasm • Induce nausea and vomiting  direct stimulation of CTZ in the floor of 4th ventricle • Skin sign  urticaria ( histamine release)
  17. 17. Pharmacology of opioid Side effect of opioid Drug interaction Codein • Weak affinity to μ receptor • Potency  50% of morphine • Half life 2.5 – 3 hours • Analgesic activity  occurs from metabolism of codein to morphine • Inhibitor  metabolit : celecoxib, cimetidine, cocaine • Inducers : dexamethasone, rifampin • Doses > 65 mg  not well tolerated • Low dose  paradoxically more emetic than higher dose  competing effect in CTZ Side effect : A very rare but serious side effect in nursing infants whose mothers are taking codeine, and are apparent ultra-rapid metabolizers of codeine, resulting in rapid and higher levels of morphine in the breast milk, and the subsequent potentially fatal neonate respiratory depression
  18. 18. Pharmacology of opioid Side effect of opioid Drug interaction Meperidine • Relatively weak opioid μ agonist  only 10% of morphine • Have a significant anticholinergic and local anesthetic properties • Half life 3 hours  half life the metabolite  normeperidine 15 – 30 hour • Must not be given with MAO inhibitor  may produce severe respiratory depression, hyperpyrexia, CNS excitation, delirium, and seizures • side effect : anxiety, tremors, multifocal myoclonus, seizures  especially in patients with renal disease, following repeated administration
  19. 19. Pharmacology of opioid Side effect of opioid Drug interaction Fentanyl • Strong opioid agonist • Available in parenteral, transdermal, transbuccal preparation • Synthetic piperidine opioid agonist • 80x more potent than morphine • Highly lipophylic • Binds strongly to plasma protetin • Transdermal formulation  a lag time 6 – 12 hour to onset of action, reach 3 – 6 days steady state
  20. 20. Notes about the Fentanyl patch • Takes 12 hours for onset of analgesia • Need adequate subcutaneous tissue for absorption • Takes 24 hours to reach maximum effect • Change patch every 72 hours • Dosage change after six days on patch • Suitable for stable pain only
  21. 21. Pharmacology of opioid Side effect of opioid Drug interaction Tramadol • Unique analgesic • An atypical opioid, has a higher affinity to μ receptor than the parent compound • Max doses  400 mg/day • Toxic dose cause CNS excitation • Oral tramadol absorbed rapidly  analgesic potency the same with codein
  22. 22. Addiction • A single exposure to morphine could induce tolerance and dependence • Recent study shows that prolonged ventral tegmental area (VTA), dopamine neuron activities (DA) and opiate receptor desensitization followed single morphine exposure • Cause  the development of dependence and tolerance  cause acute analgesic tolerance and acute addiction of morphine
  23. 23. Withdrawal Sign ( after Physiological Dependence ) Acute Action • Analgesia • Respiratory Depression • Euphoria • Relaxation and sleep • Tranquilization • Decreased blood pressure • Constipation • Pupillary constriction • Hypothermia • Drying of secretions • Reduced sex drive • Flushed and warm skin Withdrawl Sign • Pain and irritability • Hyperventilation • Dysphoria and depression • Restlessness and insomnia • Fearfulness and hostility • Increased blood pressure • Diarrhea • Pupillary dilation • Hyperthermia • Lacrimation, runny nose • Spontaneous ejaculation • Chilliness and “gooseflesh”
  24. 24. Potential problem in  Opioid Therapy • Opioid induced hyperalgesia : hyperalgesia syndrome occur following effective opioid administration  the phenomenon of pharmacological tolerance or may be mediated through mechanism : – Central glutamatergic mechanism – Increase in the synthesis of excitatory neuropeptides such as dynorphine – Descending facilitatory mechanism arising in the medula • Medication overuse headache
  25. 25. Pharmakokinetics Aspect of opioid
  26. 26. Percent of peak effect Site Concentration after bolus injection Minutes since bolus injection 0 5 10 15 20 Percentofpeakeffect siteconcentration 0 20 40 60 80 100 Methadone Remifentanil Fentanyl Sufentanil Alfentanil Hydromorphone Morphine Meperidine
  27. 27. Pharmacokinetic of opioid
  28. 28. Therapeutic Window
  29. 29. Blood levels in Therapeutic Window PCA
  30. 30. Conclusions • Opioid  are important drugs used in the pain management • Employ appropriate pharmacological choice by knowing the pharmacology of the drugs  both pharmaco dynamic and pharmaco kinetics • Provide optimal effect and minimize side effects