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OPIOIDS

OPIOIDS. GROUP 10 ( Cranfield University) RUELLA D’COSTA SWAROOP JOHNSON TEJASHREE BANE TANISHA GHORPADE VARSHA GHASE. CONTENTS. Introduction Opioid Receptors Agonists Antagonists Addiction and its treatment Recent Advances Conclusion. INTRODUCTION.

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OPIOIDS

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  1. OPIOIDS GROUP 10 (Cranfield University) RUELLA D’COSTA SWAROOP JOHNSON TEJASHREE BANE TANISHA GHORPADE VARSHA GHASE

  2. CONTENTS • Introduction • Opioid Receptors • Agonists • Antagonists • Addiction and its treatment • Recent Advances • Conclusion

  3. INTRODUCTION • Natural and semi synthetic derivatives of opium poppy, as well as similar synthetic compounds that have an analgesic or pain relieving properties because of their effect on the CNS • SOURCE : Opium poppy plant • CONSTITUENTS: • Morphine • Codeine • Thebaine • Papaverine • Noscapine

  4. HISTORY OF OPIOIDS Used as early as 1500 BC Poppy extensively grown in Egyptian, Roman , Chinese civilizations Biggest opium market was the British market Used for years to produce - sedation - Analgesia - Euphoria - Relief from diarrhea - Cough suppression

  5. CHEMISTRY Morphine • Pentacyclic Alkaloid • Oxygen bridge at 4 and 5 position • Three major rings ( a, b , c) • Phenolicgropus ( s/a hydroxyl, Alcoholic, OH) at position 3 and 6 • Nitrogen at position 16 • Changes at the 3 and 6 position change the potency of drug

  6. OPIOID RECEPTORS Opioid receptors are a group of G protein coupled receptors with opiods as ligands The opioid receptors are ~40% identical to somatostatin receptors (SSTRs) Endogenous peptides which bind opiod receptors: -Endorphins -Enkephalins -Dynorphins Discovery: The receptors were first identified as specific molecules through the use of binding studies in which opiates that had been labelled with radioisotopes were found to bind to brain membrane homogenates

  7. RECEPTOR SUBTYPES

  8. Morphine was the first chemical shown to bind to mu receptors. The first letter of the drug morphine is m, thus turning the m to μ. • Ketocyclazocine was first shown to attach itself to kappa receptors • Delta receptor was named after the mouse vas deferens tissue in which the receptor was first characterised • Nociceptin receptor was later identified and cloned based on homology with the cDNA. is known as the or ORL 1 receptor.

  9. ADDITIONAL RECEPTORS • Sigma receptors (σ) were once considered to be opioid receptors due to the antitussive actions • Zeta (ζ) opioid receptor has shown to be a cellular growth factor modulator • Epsilon (ε) opioid receptor produces strong analgesia and release of met-enkephalin

  10. PHARMACOKINETICS

  11. PHARMACODYNAMICS CENTRAL NERVOUS SYSTEM • Stimulation of the medullarychemotrigger zone (CTZ) with nausea and vomiting • Potential for physical dependance with repeated doses of opiods CARDIOVASCULAR SYSTEM • High doses result in Bradycardia • Increased heart rate • Myocardial Depression • Vasodilation

  12. RESIPIRATORY SYSTEM • Depress ventilatory function • Decreased respiratory ventilatory response • Increased apneic threshold • Decreased hypoxic drive GASTOINTESTINAL • Delay gastric emptying • Induced contraction of the sphincter ENDOCRINE • Blocks the release of stress hormones elevated during surgery (catecholamines, ADH, and cortisol)

  13. DRUG INTERACTIONS • Opiods with MAO inhibitors may result in: -respiratory arrest -hypertension -hypotension -coma -hyperpyrexia • Opiods with benzodiazepines, barbiturates, and other CNS depressants can cause synergistic cvs, resp, and sedative effects

  14. CLASSIFICATION OF OPIOIDS BASED ON RECEPTORS PURE AGONISTS - Morphine - Codeine - Meperidine - Fentanyl AGONIST – ANTAGONISTS - Nalbuphine - Butorphanol PURE ANTAGONISTS - Nalaxone - Naltrexone PARTIAL AGONISTS - Pentazocine BASED ON SOURCES • NATURAL Phenanthrene - Morphine ( 10%) - Codeine ( 0.5 %) - Thebaine ( 0.2%) • SEMI SYNTHETIC - Heroin - Oxymorphone - Hydromorphone • SYNTHETIC - Meperidine - Methadone - Morphinians - Benzamorphans

  15. MECHANISM OF ACTION • Pure opioid agonists bind to opioid receptors avidly and demonstrate high intrinsic activity at the cellular level. • Partial opioid agonists bind to opioid receptors but produce a sub-maximal effect compared to pure agonists.

  16. PHARMACOLOGICAL EFFECTS OF OPIOID AGONISTS CNS EFFECTS • Analgesia – alters perception of pain and patients reaction to pain • Dysphoria/euphoria – floating sensation, free from anxiety • Inhibition of cough reflex – useful as antitussive • Miosis (except meperidine causes mydriasis) • Physical dependence • Respiratory Depression – often dose-limiting factor • Sedation – causes drowsiness and impairs thinking CVS EFFECTS •  myocardial oxygen demand • vasodilation & hypotension

  17. GI/BILIARY EFFECTS Constipation – due to decreased motility and decreased HCl secretion Increased biliary sphincter tone & pressure – caution in patients with gall stones Nausea and vomiting (via stimulation of CTZ)  GENITOURINARY EFFECTS Increased bladder sphincter tone Prolongation of labor Urinary retention

  18. NEUROENDOCRINE SYSTEM EFFECTS Inhibition of release of LH & FSH – decreases ovarian and testicular function Stimulation of release of ADH and prolactin IMMUNE SYSTEM EFFECTS Suppression of function of natural killer cells  DERMAL EFFECTS Flushing Pruritis Urticaria (hives) or other rash

  19. OPIOID ANTAGONIST • An opioid antagonist is an receptor antagonist that acts on opioid receptors • Naloxone and naltrexone are competitive antagonists that bind to the opioid receptors with higher affinity than agonists but do not activate the receptors. • Weak opioid partial agonist: Nalorphine and Levallorphan • Naloxone is used for treating opioid overdose • Naltrexone is the only treatment which can reverse the long-term after effects of opioid addiction, which otherwise tends to produce depression and anxiety that may lead to eventual relapse

  20. SELECTIVE ANTAGONISTS • Cyprodime is a selective µ opioid receptor antagonist • Naltrindole is a selective δopioid receptor antagonist • Norbinaltorphimine is a selective Κopioid receptor antagonist

  21. PURE OPIOID ANTAGONISTS • Naloxone (Narcan) • used parenterally only, T ½ about 1 hour • Naltrexone (Revia) • Orally effective, longer acting • Nalmefene (Revex) • Long acting injectable form

  22. NALOXONE • no analgesic activity at all • competitive antagonist at mu, kappa, and sigma receptor • displaces morphine and other OPIOID from receptor site • reverses all actions of the OPIOID and does it rather quickly • it will precipitate withdrawal • person on heroin, then naloxone will precipitate withdrawal, • naloxone effects are seen in the first five minutes and it only lasts for 30 minutes • increased blood pressure • metabolized same as morphine through glucuronic acid and excreted through kidney

  23. NALTREXONE • Same effect of naloxone except it is used orally so can't use it if for person with acute toxicity • Long duration of activity • Single dose block action of heroin effects for 24 hours • Used for emergency treatment • Once stabilized, give patient naltrexone • Patient get no euphoric effect from heroin so person gets off heroin (negative reinforcement) • Approved for use by the FDA USES:- (a) Treatment of alcoholism  (b) Treat opioid overdose toxicity (c) Reverse opioid-induced anesthesia (d)Adjuncts in drugs abuse programs

  24. PARTIAL AGONISTS AND MIXED AGONIST-ANTAGONISTS • Compounds structurally related to morphine • Developed to reduce addiction potential while retaining analgesic properties • Used for moderate pain, anesthetic premed, supplement to surgical anesthesia • Characterized by binding activity at multiple opioid receptors and differential effects at each site • Analgesia generally related to agonistic activity at κ receptors and to a lesser extent µ receptors

  25. PARTIAL AGONISTS AND MIXED AGONIST-ANTAGONISTS • Differ from morphine • Can produce excitability and hallucinogenic effects (κ receptor effects) • Lower degree of physical dependence potential • Can ppt withdrawal in morphine dependence (partial agonists at µ receptors) • Increase some SNS activity to produce positive inotropic effects

  26. ACTIONS OF PARTIAL AGONIST, AGONIST – ANTAGONISTS AT OPIOID RECEPTORS

  27. ADDICTION Weak personality or a chronic brain disease? 1. SUBSTANCE DEPENDENCE(psychological) - behavioral syndrome; compulsive drug-seeking behavior 2. PHYSICAL DEPENDENCE - defined by abstinence syndrome (withdrawal) 3. SUBSTANCE ABUSE: Use of any drug in a manner that deviates from approved medical or social patterns within a given culture 4. DRUG ADDICTION: “…is a primary, chronic,neurobiologic disease, with genetic psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviours that include one or more of the following; impaired control over drug use, compulsive use, continued use despite harm, and craving.” (American Academy of Pain Medicine)

  28. WHAT DOES IT FEEL LIKE? "I was stared at, hooted at, grinned at, chattered at, by monkeys, by paroquets, by cockatoos. I ran into pagodas, and was fixed, for centuries, at the summit, or in secret rooms: I was the idol; I was the priest; I was worshipped; I was sacrificed. I fled from the wrath of Brama through all the forests of Asia: Vishnu hated me; Sevalaid wait for me. I came suddenly upon Isis and Osiris: I had done a deed, they said, which the ibis and the crocodile trembled at. I was buried for a thousand years, in stone coffins, with mummies and sphinxes, in narrow chambers at the heart of eternal pyramids. I was kissed, with cancerous kisses, by crocodiles; and laid, confounded with all unuttemble slimy things, amongst reeds and Niloticmud.“ Thomas de Quincey (1785 - 1859) Confessions of an English Opium-Eater

  29. TREATMENT ALGORITHM

  30. TREATMENT APPROACHES • There are two medical approaches to treatment, i.e. maintenance treatment and medically supervised withdrawal (detoxification) • Other psychosocial approaches, mutual help programme’s and the 12-step programs are used in combination with pharmacotherapy to treat addiction to heroin and other opioids • The maintenance treatment with buprenorphine, methadone or LAAM for opioid addiction has three phases induction, stabilization, and maintenance • According to federal regulations, during induction methadone should initially be given under daily observation for either 6 or 7 days per week

  31. TREATMENT OF OPIATE ADDICTION • Long acting opiate agonists (e.g. Methadone) and long acting benzodiazepines (e.g. diazepam or chlordiazepoxide) used in opiate dependence, were found to be better than short acting drugs or preparations • Psychosocial interventions may be provided in combination with pharmacological intervention for polydrug (more than one drug) and alcohol abusers. There is evidence that themethadone maintenance is more effective if psychosocial interventions and family support are provided • Methadone or buprenorphine have been found effective as maintenance treatment, at optimal doses. Injectableopioid treatment is used in patients who fail oral treatment.

  32. DETOXIFICATION • Detoxification treatment normally lasts for 28 days as inpatient and upto 12 weeks as outpatient, and has been thought of as a safe and effective treatment minimizing withdrawal symptoms, in dependent opiate users • During detoxification psychosocial support is provided and a whole programme for it is in place • Methadone and Buprenorphine are used normally as part of detoxification. Following stabilization, doses can be reduced at the rate of 5mg every one or two weeks for methadone, resulting in zero in about 12 weeks, whereas for buprenorphine, doses are reduced initially at 2mg every 2 weeks or so, with final reductions amounting to 400mcg

  33. TREATMENT OF OPIATE ADDICTION • Patients (including young people) who have decided against detoxifying using methadone or buprenorphine can opt for Lofexidine (NICE,2007b). The treatment lasts for 7-10 days starting at 800mcg daily and going to a maximum of 2.4mg in divided dose • Naltrexone is an opioid antagonist which, when taken regularly, can prevent relapse. With a usual maintenance dose of 50mg , it has been found to be effective in enabling patients maintain abstinence following detoxification

  34. REFERENCES • Comparision In The treatment used to tackle drug abuse in US, Uk and Singapore, Swaroop Johnson, 2008 2. Essentials of Medical Pharmacology, K.D. Tripathi, 5th edition, Jaypee Publishers, 2003 3. Treatment Approaches for Drug Addiction, National Institute Of Drug Abuse, June 2008

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