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New Pharmacological Technologies in the Clinical Management of Narcotic Dependencies

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New Pharmacological Technologies in the Clinical Management of Narcotic Dependencies New pharmacological technologies in the clinical management of narcotic dependencies פרמקולוגיה של תכשירים לטיפול בהתמכרות לאופיאטים (מתדון, בופרינורפין, בופרינורפין\נלוקסון) יעילות ובטיחות Basic Pharmacology An opioid is a chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract. Opioid classification Natural opiates Opium Morphine Codeine Thebaine, Papaverine, Nescapine Semi-synthetic opioids Heroin, Oxycodon, Hydrocodon, Oxymorphone, Hydromorphone Synthetic opioids Methadone, Mepiridine, Fentanyl Mixed antagonists Buprenorphine, Pentazocine Antagonists Naltrexone, Naloxone Bentley compounds Bentley compounds are a class of semi-synthetic opioids that were first synthesized from thebaine by K. W. Bentley. The compounds include: oxycodone, oxymorphone, nalbuphine, naloxone, naltrexone, buprenorphine and etorphine. Compounds Possessing Morphine-Antagonising or Powerful Analgesic Properties. Bentley KW et al. Nature (1965) 206:102-3. Bentley compounds Etorphine - Immobilon is often used to immobilize elephants and other large mammals. Etorphine is available legally only for veterinary use and is strictly governed by law. Diprenorphine – Revivon is an opioid receptor antagonist that can be administered in proportion to the amount of etorphine used (1.3 times) to reverse its effects. Veterinary-strength etorphine is fatal to humans. For this reason the package as supplied to vets always includes the human antidote as well as Etorphine. Opioid activity profiles indicate similarities between the nociceptin/orphanin FQ and opioid receptors: Hawkinson JE et al. European Journal of Pharmacology (2000) 18:107-14. Endogenous opioids Four classes of endogenous opioids: enkephalins, endorphins, endomorphins, dynorphins Endogenios opioids have a range of functions, including: . Pain relief . Induction in euphoria . Regulation Basic Pharmacology Opioids bind to specific opioid receptors in the nervous system and other tissues. There are three principal classes of opioid receptors, μ, κ, δ (mu, kappa, and delta), although up to seventeen have been reported, and include the ε, ι, λ, and ζ (Epsilon, Iota, Lambda and Zeta) receptors. Opioid Receptors Opioid Receptors Subtypes with known clinical significance • µ (mu) • (delta) • (kappa) • NOP1 (ORL-1) • They are involved in the functioning of distinct physiological processes Opioid Receptors µ(mu)-opioid receptor β-endorphins are endogenous ligands which exert their effects primarily through the μ-opioid receptor. µ(mu) -opioid receptor (μ1, μ2, μ3) mediates: μ1: analgesia and physical dependence μ2 : respiratory depression, euphoria, miosis, reduced GI motility and physical dependence μ3 : unknown Endomorphins are two novel endogenous opioid peptides. Endomorphin-1 and endomorphin-2 are tetrapeptides with the highest known affinity and specificity for the μ opioid receptor. Opioidergic projections to sleep-active neurons in the ventrolateral preoptic nucleus: Greco MA et al. Brain research (2008) 1245: 96–107. Opioid Receptors δ (delta)-opioid receptor Leu-enkephalins, Met-enkephalins and deltorphins are endogenous ligands which exert their effects primarily through the delta-opioid receptor δ (δ 1 and δ 2) receptor mediates: Analgesia Antidepressant effects Physical dependence Many delta agonists may also cause seizures at high doses although not all delta agonists produce this effect The delta-opioid receptor: molecular pharmacology, signal transduction, and the determination of drug efficacy: Quock RM et al . Pharmacol. Rev .32–503 :1999 51) Opioid Receptors K (kappa)-opioid receptor Dynorphins are endogenous ligands which exert their effects primarily through the κ-opioid receptor. Kappa receptor (K1, K2 and K3) mediates: analgesia sedation miosis inhibition of ADH (anti-diuretic hormone) release dysphoria Salvinorin A12 is a potent and selective κ-opioid receptor agonists. The κ-opioid receptor also mediates the action of the hallucinogenic side effects of opioids such as pentazocine (Talwin NX) . Selectivity of dynorphin for kappa opioid receptors: James IF et al . Life Sci. (4–1331 :31 (1982 Opioid Receptors Nociceptin opioid receptor (NOP1- OLR-1) Nociceptin is the endogenous ligand for the nociceptin receptor (NOP1) Nociceptin is an opioid-related peptide, but it does not act at the classic opioid receptors and its actions are not antagonized by the opioid antagonist naloxone. Nociceptin is a potent anti-analgesic. There is some evidence that nociceptin may be involved in the phenomenon of opioid-induced hyperalgesia Individuals taking opioids might develop an increasing sensitivity to noxious stimuli, even evolving a painful response to previously non-noxious stimuli (allodynia). NOP1 receptor mediates: • Anxiety • Depression • Development of tolerance to mu agonists • Nociception • Food intake • memory processes • cardiovascular and renal functions • spontaneous locomotor activity • gastrointestinal motility Pharmacology of nociceptin and its receptor: a novel therapeutic target: Calo G et al . Br. J. Pharmacol.83–1261 :129 (2000) Opioid Receptors Epsilon – opioid receptor Epsilon receptor is stimulated by the endogenous opioid peptide beta-endorphin, which induces the release of Met-enkephalin, which, in turn, acts on spinal delta 2-opioid receptors to produce antinociception. Role of protein kinase C (PKC) in agonist-induced mu-opioid receptor down-regulation: II. Activation and involvement of the alpha, epsilon, and zeta isoforms of PKC: Kramer HK and Simon EJ J Neurochem. (1999) 72:594-604. Evidence for epsilon-opioid receptor-mediated beta-endorphin-induced. Analgesia: Tseng LF et al. Trends Pharmacol Sci. (2001) 22:623-30. Buprenorphine blocks epsilon- and micro-opioid receptor-mediated antinociception in the mouse: Hirokazu Mizoguchi, et al. Pharmacol Exp Ther (2003) 306:394-400. Opioid Receptors • Receptor affinity How tightly the drug binds to the receptor • Dissociation How fast the drug leaves the receptor • Intrinsic activity How much the drug stimulates the receptor Agonist and antagonist • Full agonists – bind to the µ receptor producing an almost linear increase in physiological effect: Opium, morphine, codeine, heroin, methadone • Partial agonists – bind to the µ receptor but have a ‘ceiling’ effect on receptor activation: Buprenorphine : The agonist effects of buprenorphine (32 mg) increase linearly with increasing doses until it reache a plateau and no longer continue to develop respiratory depression with further doses, meaning “ceiling effect”. A compound that has an affinity for & stimulates physiological activity at the same cell receptors as opioid agonists but that produces only a partial (i.e., submaximal) bodily response. • Antagonists – bind to the µ receptor but do not produce a biological response and are able to block agonist effects: naloxone, naltrexone, nalmefene Nalmefene (Revex) is an opioid receptor antagonist and used primarily in the management of alcohol dependence, and also has been investigated for the treatment of other addictions such as pathological gambling and shopping. Selective antagonists • All of the opioid antagonists used in medicine are non-selective, either blocking all three opioid receptors, or blocking the mu-opioid receptor but activating the kappa receptor. • However for scientific research selective antagonists are needed which can block one of the opioid receptors but without affecting the other two. • This has led to the development of antagonists which are highly selective to one of the three receptors; • Cyprodime is a selective mu opioid receptor antagonist • Naltrindole is a selective delta opioid receptor antagonist • Norbinaltorphimine is a selective kappa opioid receptor antagonist Mu-opioid receptor specific antagonist cyprodime: characterization by in vitro radioligand and [35S] GTP gammaS binding assays. Márki A et al. European Journal of Pharmacology (1999) 383:209 Naltrindole, a highly selective and potent non-peptide delta opioid receptor antagonist. Portoghese PS et al. European Journal of Pharmacology (1988) 146:185-6. Binaltorphimine and nor-binaltorphimine, potent and selective kappa-opioid receptor antagonists. Portoghese PS et al. Life Sciences (1987) 40:1287-92. Understanding Opioid Effects Super agonist - Full agonist - fentanyl morphine/heroin hydromorphone Positive Potentially lethal dose effect Agonist + partial agonist = Partial agonist addictive - buprenorphine potential Antagonist - naltrexone dose Negative effect Antagonist + agonist/partial agonist Opioid use characteristics.. • Abused primarily for euphoric (“rush”) and analgesic (“Nirvana”) effects • Effects might be influenced by: . Route of administration . Onset of action - Rate of transfer across blood-brain barrier/lipophilicity . Level of intrinsic activity . Duration of action/half-life Opioid use characteristics.. • Dependence diagnosis is strictly defined by DSM-IV-TR (2000) and ICD 10 (1992) criteria. • Continuous unsupervised (legal and illegal) use might lead to the necessity to increase needed dose in order to reach desired effect: “tolerance”. • Tolerance elevates plateau. • Doses beyond plateau lead to overdose. • Inverse tolerance means that decreasing doses elevates effects. • Reduction or cessation of used narcotic substances might lead to withdrawal symptoms and signs (syndrome): Yawning Mydriasis sweating Lacrimation Anxiety Pilorection Diarrhea rhinorrea Buprenorphine
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