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Opiod analgesics Med Chem Lecture


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Lecture Notes for Med Chem/ CNS drugs/ B pharmacy of Purbanchal University, Nepal

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Opiod analgesics Med Chem Lecture

  1. 1. Opiod Analgesics
  2. 2. • Analgesics- substance that relieves pain • Narcotic analgesics are drugs that can relief pain without causing narcosis (loss of consciousness)
  3. 3. Uses • Choice of drugs for managing chronic pain as with cancer or RA • Used as inducing agent (fentanyl) or analgesic supplement with General anesthetics • They have clinical use as anti-diarrheal and antitussive eg Loperamide and Dextromorphan • Some opioids such as methadone and buprenorphine are used to counter addiction of more potent opioids such as heroin
  4. 4. • Opium - is a Greek word meaning “juice,” or the extract of seeds from the poppy Papaver somniferum • Morphine was the first Narcotic analgesic isolated from opium which contains over twenty distinct alkaloids • Opiates – synthetic/natural compounds both structurally and pharmacologically similar to Morphine • Opiods – synthetic/natural compounds not structurally but only pharmacologically similar to Morphine
  5. 5. Pain and its types • Pain is an uncomfortable/unpleasant physical or psychological sensation in the body. • Pain is a good thing. It warn us of something damaging our body so we take proper medical care • However, constant pain can reduce quality of life
  6. 6. Pain has a psychological side . Once you accept pain, it may not be painful anymore
  7. 7. • Acute pain : sharp, short term pain – Surgery, Broken bones, Burns, Sprain, Labor It is cured if the caused of the pain is removed or treated • Chronic pain: dull, long term pain – Cancer, arthritis, chronic back pain and knee pain, Migraine Pain exists for months even when the injury is healed. Cause not well understood
  8. 8. How do we feel pain? • Pain receptors or Nociceptors are found on the free nerve endings of primary sensory fibers that detect unpleasant stimuli and pass the information to CNS to be interpreted as pain • They are distributed all over the body (skin, muscles, joints, internal organs but not brain) • When tissue gets damaged by certain (mechanical, thermal or chemical) stimuli, it releases inflammatory mediators (eg bradykinin, serotonin, prostaglandins, cytokines, and H+) which can activate primary nociceptors • When these neurons reach the spinal cord, they pass the pain signal to 2ndary sensory fibers located around the spinal cord where key NT is substance P. • The 2ndary sensory fibers transmits information to brain where it is interpreted as pain.
  9. 9. Ways to relieve Pain • GA – affect chemical component of neuro transmission ( GABA n NMDA receptor) • LA – block electrical component of neuro transmission (VG Na+ channel) (especially for pain) • NSAIDS – Block local pain messenger such as prostaglandin • Opiods- block both chemical and electrical component of nerve transmission Except NSAIDS all three are CNS depressents
  10. 10. Analgesic receptors • Body has mechanism to naturally relief pain • There are three types in brain and spinal cord • µ (mu) --> most widely occurring and target of most drugs • Κ (kappa) --> lack respiratory depressing effect and can counter analgesic effect of µ agonist • δ (delta) --> reduced GIT motility, respiratory depression, convulsant effect limited clinical use • Only µ and Κ have clinical use
  11. 11. Mechanism of action • Opiod analgesic agonize opiod receptors µ,κ and δ which are G-protein couples receptors. This leads to a series of event which ultimately block neuronal pain transmission by: 1. Inhibition of activation of voltage gated Ca+2 channels which depresses NT release 2. Increases K+ conductance outside the cell to cause hyper polarization of cell thus reducing it’s excitability 3. Inhibtion of adenyl cyclase (adenyl cyclase--> cAMP --> PKA --> phosphorylation of ion channels --> increase chances of channel opening)
  12. 12. Three effects of opiod receptors
  13. 13. Opioids - Classification 1. Natural Opium Alkaloids: Morphine and Codeine 2. Semi-synthetic: Buprenorphine, Oxycodone, Diacetylmorphine(Heroin) 3. Synthetic Opioids: • 4-Phenylpiperidines: Loperamide and Fentanyl and Meperidine • Diphenylpropylamine derivatives: Loperamide and Methdone • Benzomorphans: Pentazocine, Phenazocine • Morphinan : Levorphanol and Butorphanol 4. Endogenous opioid : natural pain relieving peptides of the body, such as endorphins, enkephalins and dynorphins 5. Miscellaneous : Tramadol, Meptazinol
  14. 14. SAR Modification to Morphine
  15. 15. 1. Morphine has 5 Chiral centers. Only the Levo(-) rotatory isomer is active
  16. 16. 2. The OH group in the phenolic ring and basic Nitrogen is needed for activity and seen in all potent µ agonist. Activity can be preserved or enhanced by removing other rings Changing -OH to just –H or -OCH3 lowers activity as seen with codeine R= C3 substituent Activity effect -H 10X Decrease -OH morphine -OCH3 (codeine) Decrease
  17. 17. Morphinans Benzomorphine 4-Phenylpiperidines Fig: Loss of other rings doesn’t effect analgesic activity.
  18. 18. How many chiral centres?
  19. 19. 3. The Nitrogen is mostly tertiary with a methyl substitution in morphine. The size of substituent on Nitrogen dictates potency and agonist or antagonist activity. a) Increasing size from methyl (ie 1 C) to 3 or 5 carbon (especially with double bonds or small cyclic/aromatic rings) results in antagonist activity b) Still larger substitution restores agonist activity in more potent form
  20. 20. •If R = 3-5 carbons then µ antagonist effect (more valid if presence of double bond or Small carbo-cyclic ring) •If R = > 5 carbon (in chain or ring ) then increased µ agonist effect R= Nitrogen subtituent effect CH2CH=CH2 (3 C with double bond) Becomes µ antagonist CH2CH2Ph (Total 8 C) µ agonist (10X more potent than morphine)
  21. 21. 4. Reduction of 7,8 double bond increases activity 5. Inclusion of Hydroxyl group at 14 increases activity Activity increases Activity increases OH at C14 7,8 Reduction of double bond to single bond
  22. 22. 6. Removal of Hydroxyl at 6 increases activity 7. Oxidation of Hydroxyl to keto group at 6 increases activity, if there is also reduction of 7,8 double bond eg hydrocodone 8. Acetylation of Hydroxyl at 6 increases activity R= C6 substituent Effect in activity H increase =O (keto) =O (keto) with 7,8 redcution (change double bond to single) Decreases Increases (10X more potent than morphine H3CC=O (acetyl) Increase
  23. 23. 9. Removal of the ether linkage produces compounds called morphinans that has increases activity Activity increases No ether linkage Levorphanol (10X potent than morphine)
  24. 24. Morphine • It is a naturally occurring analgesic alkaloid extracted from opium of poppy plant • Modification to it’s structure has resulted more potent compound • Used in chronic pain management • It’s 3-O-glucoronidation metabolite is inactive • But it’s 6-O-glucoronidation form is active and thus does reduction is needed in case of renal damage (coz it’s rate of clearance is reduced) • It is potent enough that it’s 60mg oral dose has analgesic effect equal to parental administration • MOA: agonizes µ receptor which depresses pain signals by • inhibiting VGCC and prevent release of Neurotransmitters • Opening VGPC and causing hyperporalization of nerves cells • Inhibiting adenyl acylase
  25. 25. Codeine • It is weak µ agonist formed by modification of 3OH in morphine into H3CO. This results in loss of activity. Thus codeine is used in moderate to mild pain only. • It s metabolic product is morphine and thus abused by addicts. • The does requires to produce analgesia after parental dose causes release of histamine that in turn causes allergic responses. Thus not used parenterally • Use limited as antitussive drug
  26. 26. Heroin • It is 3,6-diacetyl derivative of morphine • By itself is a weak U agonist but the diacetyl form increases its lipophilicity and enhances its penetration into brain • Also it metabolic product, 6 acetyl morphine, is more active than morphine • These two factors make it more potent than morphine but it’s use it limited by extreme addiction to it (more potent = more addictive)
  27. 27. Meperidine • It is a 4-Phenylpiperidines based derivative of morphine • A weak µ agonist, 1/10th as potent as morphine • Doesn’t inhibit cough • rapid onset of action but high 1st pass metabolism • Thus used in obstetrics, where given in small does to mother it won’t cause respiratory depression to the newborn
  28. 28. Fentanyl • It is a 4-(Phenylpropionamido)piperidines based derivative of morphine • It is about 80 times more potent than morphine • It Does not cause histamine release on IV injection (ie no skin inflammation) • It Inhibits p-glycoprotein mediated efflux of digoxin (ie increases conc of digoxin in blood)
  29. 29. Buprenorphine • It has a mixed Agonist/antagonist effect • It produces 50% analgesic effect about 20-50 times than morphine but can NEVER produce 100% effect • Potent Partial agonist of µ and κ receptor but antagonizes δ receptors • Advantage of less severe respiratory depression and less incidence of tolerance or addiction • Used to block effects of high dose of heroin • It itself can’t be antagonized by Naloxone
  30. 30. Pentazocine • A mixed agonist/antagonist effect (µ antagonist and κ agonist) • weak analgesic effect - 1/6 as potent as morphine • Since it is a κ agonist it produces dysphoric effects and also increases blood pressure and heart rate • Abused drug – when injected with tripelennamine (an antihistaminic) it increases euphoric effect and decreases dysphoric effect
  31. 31. Tramadol • not a true opiod analgesic • (+) isomer has activity 1/3800 that of morphine! • (-) isomer blocks norepinephrine and serotonin (excitatory NT) reuptake and thus show some analgesic activity. But the effect is weak • It’s metabolite is active and 1/35 as effective as morphine. • Non-addictive, no respiratory depression or constipation • Used with other analgesic for synergistic effect
  32. 32. Naloxone • It is a strong opiod antagonist • High affinity for µ but low affinity for κ and δ • It is used as a emergency drug to counteract life- threatening depression of the CNS and respiratory system due to morphine or heroine overdose • It itself is not anxiolytic but can potentiate the subtherapeutic dose of the anxiolytic drug busiprone (ie less does of busiprone can be given)
  33. 33. Preparation of Morphine from Poppy plant 1. 10-15 kg of raw opium plant is boiled with 115 kg of water. The opium alkaloids are eventually extracted into the boiling water 2. calcium hydroxide, Ca(OH)2, is added to the solution. This converts the water insoluble morphine into the water soluble calcium morphenate. Codeine is slightly water soluble and gets carried over with the calcium morphenate in the liquid. The other opium alkaloids are neither water soluble nor react with the lime to form soluble calcium salts. They are filtered off and now there is only morphine salt and codeine in the solution
  34. 34. 4. The clear liquid is filtered and reheated and Ammonium chloride (NH4Cl) is added to adjust the alkalinity to a pH of 8 to 9, and the solution is then allowed to cool. Within one or two hours the salt form of morphine turns into insoluble neutral form and precipitate out of the solution 5.The solution is filtered and the residue containing the morphine is dried in the sun. When dry, the crude morphine base is a coffee-colored powder. Approximately 13 kg of opium, from one hectare of opium poppies, are needed to produce 1.3 kg of morphine
  35. 35. 1) Morphine + Ca(OH)2 = calcium morpheate 2) Calcium morpheate + NH4Cl = CaCl2 + NH3 + neutral morphine
  36. 36. Physical dependence/Addiction to narcotics • All forms of drug addiction are driven by stimulation of brain’s self-reward system • Self reward system refers to activity of neurotransmitter Dopamine(DA) which has euphoric effect (intense feelings of happiness, excitement, and joy) • Any Drug that concentrate DA in the synapse by – stimulate DA release, – Inhibit DA reuptake or – Inhibit DA degradation have addition potential
  37. 37. • µ agonist stimulate release of DA, ie causes euphoria, whereas κ agonist prevent DA release ie causes dsyphoria (this effect limited its clinical use) • Cocaine prevents reuptake of Dopamine at the synapse and thus prolong the duration and intensity of reward response
  38. 38. • But the self reward system is self-limiting ie after prolonged or repeated activation feedback mechanism blocks the euphoric effect. Thus the effect lasts for a short while but with opiods, the euphoric effect is very intense. This short but intense feeling of happiness is termed as “euphoric rush” and is very addictive. • Drugs that slowly distribute to the brain have less addiction potential because the feedback system can respond quickly • Only fast distributing drugs, that are potent too, are successful to cause a “euphoric rush” • Distribution into the brain is governed by the lipophilicity and thus abused drugs are very lipophillic to allow quick distribution and quick action. • Also route of administration is lungs or IV to cause quick distribution (thus oral dosage has less addiction potential)
  39. 39. Tolerence • Tolerance means the need for higher doses to produce same level of effect • When an agonist binds to µ receptor, – G second messenger proteins are activated – and adenyl cyclase are inhibited • On continuous binding, tolerance develops due to – Decreases synthesis of G protein subunits – upregulation of adenyl cyclase to compensate the decreases cellular levels of cAMP.
  40. 40. Withdrawal • Stopping intake of opiods produces unwanted physiological effects called withdrawal symptoms • Within 24 hrs following effects are seen – muscle aches, restlessness, anxiety, lacrimation (eyes tearing up) runny nose, excessive sweating, inability to sleep • After 24 hrs more intense effects are seen – Diarrhea, high BP, nausea, vomiting rapid, heart beat
  41. 41. • Cells resist opiod mediated decrease in adenyl cyclase by upregulating (increases production) adenyl cyclase. • If opiods are withdrawn, this upregulated adenyl cyclase in turn generates more cAMP. • This increased cellular levels of cAMP causes many abnormal effects
  42. 42. Revision • Body has pain receptors that recognize pain stimuli • But Opiod analgesics don’t work by blocking these pain receptors
  43. 43. • Body also has opiod receptors (anti- pain receptors) • Opiod drugs bind to them and strengthen their anti pain functions (ie they agonize opiod receptors)
  44. 44. • Blocking pain receptors can also produce analgesic effect but….. • …….No analgesic drugs exist that block pain receptors
  45. 45. • The reason for addictive nature of opiods is not because they help manage pain • But because they cause euphoria through stimulation of dopamine
  46. 46. • There are 3 opiod receptors: µ (mu), κ (kappa), δ (delta) • Most clinical analgesic bind to µ • κ has dysphoric (extreme depression) effect • δ has high respiratory and convulsive effects
  47. 47. • µ agonist promotes dopamine release that causes addiction • κ agonist blocks dopamine release leading to extreme depression that can cause suicidal tendency • δ agonist do not exist seems like we are stuck with addictive analgesics!!!
  48. 48. Mixed agonist/antagonist Q) How can some opiod drugs be both an agonist and antagonist at same time? Ans. There is not 1 but 3 opiod receptors. It is possible to Agonize at one opiod receptor and Antagonize another opiod receptor Eg Buprenorphine is agonist of µ and κ receptor but antagonizes δ receptors
  49. 49. Q) Are people addicted to opiod analgesics for their pain managing effects? Ans) No. Opiod drugs potentiate the effects of dopamine at the synapse. Dopamine is a neurotransmitter that can induce euphoria which is an intense feeling of happiness, excitement, and joy. The addiction is for this euphoric effect.
  50. 50. Q) Why do addicts prefer IV or inhalation than oral route? Ans) With oral route, there is 1st pass metabolism and slow absorption. Thus the drug does not accumulate in brain quickly or at enough concentration to produce the level of euphoric rush that other routes can do because they bypass 1st pass metabolism and directly put drug in blood.
  51. 51. Q) What are the two important characteristics of drugs that cause addiction? i) Their receptors must be involved in potentiating dopamine effects at the synapse ii) They must have access to the brain ie must be lipophillic enough to cross the BBB
  52. 52. Q) Heroine is only 1/10th as potent as morphine. So why do addict prefer heroine than more potent morphine? Two reasons • Heroine is more lipophilic than morphine ie quicker BBB penetration • It’s metabolite is more potent than morphine • These two factors work together to provide a intense and quick occuring ‘euphoric rush’ that addicts seek
  53. 53. HOMEWORK Rank potency of these compounds
  54. 54. Future of analgesics : addiction free age • Recycling opiod receptors • +Naloxone TLR4 receptors • Nav1.7 receptors • P2X receptors • Glial cells • Snail cone venom • Opiorphin
  55. 55. Recycling opiod targets • κ agonists that don’t penetrate the brain but act on peripheral NS don’t cause dysphoria and are a promising approach since they have no addiction potential • Ref : Clin J Pain Volume 26, Number 1, January 2010 Supplement
  56. 56. +Naloxone and morphine • + Naloxlone has no activity on opiod receptors • Research indicates that cause of opiod addiction involves other receptors beyond opiods • It antagonizes toll-like receptor 4 (TLR4) • Given together with morphine, it has shown to reduce addiction of morphine without interfering it’s analgesic activity • Ref: J Neurosci. 2012 August 15; 32(33): 11187–11200
  57. 57. P2X7 receptors • P2X receptors are ATP-gated ion channels whose roles is in pain following nerve damage and inflammation. • Inhibiting a subtype, P2X7 seems to cure – tactile allodynia (pain caused by touch) – chronic inflammatory pain in animal model
  58. 58. Role of Glial cells in pain signalling • Glial cells are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain and peripheral nervous system • Neuroscience currently identifies four main functions of glial cells: • To surround neurons and hold them in place • To supply nutrients and oxygen to neurons • To insulate one neuron from another • To destroy pathogens and remove dead neurons.
  59. 59. • They also have function in glutaminergic and dopaminergic release pathways • If morphine can be given with drugs like AV411, that block glial cells, then no side effects of morphine can be seen
  60. 60. • Systemically active human opiorphin,which protects enkephalins from degradation, is a potent yet non- addictive analgesic without drug tolerance effects • Ref: J Physiol Pharmacol. 2010 Aug;61(4):483-90.
  61. 61. What is obstacle in new analgesic drugs research? Bad interpretation from animal models A 2013 research found Oreo biscuits were more addictive than cocaine in rats!  drugs did not penetrate correct compartment in man Invalid target Inappropriate patient population for mechanism
  62. 62. Animal based study of anti-inflammatory effect First Induce inflamation Then give drug n check if Inflamation is reduced or not
  63. 63. Effective drugs for Neuropathic pain Neuropathic pain chronic pain due to damaged nerves it is described as sensation of burning, stabbing, shooting or like an electric shock. NSAIDS are useless in this case Useful drugs are • Pregabalin – anticonvulsant • Amitriplline – tricyclic antidepressants • Duloxetine – antidepressant