{"id":692,"date":"2020-02-17T20:49:46","date_gmt":"2020-02-17T15:19:46","guid":{"rendered":"https:\/\/medicineplexus.com\/?p=692"},"modified":"2020-02-17T20:49:46","modified_gmt":"2020-02-17T15:19:46","slug":"opioid-receptors-and-drugs","status":"publish","type":"post","link":"https:\/\/medicineplexus.com\/opioid-receptors-and-drugs\/","title":{"rendered":"Opioid receptors and Drugs"},"content":{"rendered":"\n<p><strong>Opioid receptors<\/strong><\/p>\n\n\n\n<ul><li>substances obtained from the crude extract of Papaver somniferum (poppy plant).<\/li><li>Morphine is the prototype opioid and acts by agonistic activity on \u03bc, k and d receptors.<\/li><li>critical in the modulation of pain behaviour and anti-nociception<\/li><\/ul>\n\n\n\n<p><strong>Types<\/strong><\/p>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"397\" height=\"103\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-263.png?w=397\" alt=\"\" class=\"wp-image-719\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-263.png 397w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-263-300x78.png 300w\" sizes=\"(max-width: 397px) 100vw, 397px\" \/><\/figure>\n\n\n\n<p>Recently a new endogenous peptide, <strong>nociceptin<\/strong> is isolated that <strong>acts on nociceptin\/orphanin FQ (N\/OFQ) or orphanin like receptors (ORL1)<\/strong><\/p>\n\n\n\n<p><strong>Role of Endogenous Ligands:<\/strong><\/p>\n\n\n\n<p><strong>Enkephalins &#8211; DOP<\/strong><\/p>\n\n\n\n<ul><li>CNS and Adrenal medulla<\/li><li>Hypothalamus, Nucleus accumbens, Ventral tegmental area, Neocortex<\/li><li>Pain Modulation, Memory and emotions, feeding, immune Response, control of gonadal functions<\/li><\/ul>\n\n\n\n<p><strong>Endorphins &#8211; MOP<\/strong><\/p>\n\n\n\n<ul><li>Analgesia and neuroendocrine functions, Modulation of cardiovascular responses.<\/li><li>Trigger: Hypoxia, acidosis, stress and inflammation<\/li><\/ul>\n\n\n\n<p><strong>Dynorphins &#8211; KOP<\/strong><\/p>\n\n\n\n<ul><li>CNS &amp; GIT.<\/li><li>Modulation of stress, cognitive function and motor integration.<\/li><\/ul>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"594\" height=\"182\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-264.png?w=594\" alt=\"\" class=\"wp-image-720\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-264.png 594w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-264-300x92.png 300w\" sizes=\"(max-width: 594px) 100vw, 594px\" \/><\/figure>\n\n\n\n<p><strong>Opioid receptor transducer mechanisms<\/strong><\/p>\n\n\n\n<ul><li>all are GPCRs located mostly on prejunctional neurons<\/li><li>Opioid receptor activation reduces intra cellular cAMP formation and opens K+ channels<\/li><li>(mainly through \u00b5 and d receptors) or suppresses voltage gated N type Ca2+ channels (mainly k receptor<\/li><li>result in neuronal hyperpolarization and reduced availability of intracellular Ca2+ \u2192 decreased neurotransmitter release by cerebral, spinal, and myenteric neurones (e.g. glutamate from primary nociceptive afferents<\/li><\/ul>\n\n\n\n<p><strong>Pharmacokinetics<\/strong><\/p>\n\n\n\n<ul><li>Sufentanil is the most potent whereas meperidine (pethidine) and propoxyphene are the least potent opioids.<\/li><li><strong>Morphine<\/strong> is <strong>metabolized<\/strong> mainly to <strong>morphine-3-glucuronide (M3G)<\/strong> that has <strong>neuroexcitatory <\/strong>properties. Approximately 10% of morphine is metabolized to active product M6G. <strong>Renal failure can lead to accumulation of these metabolites <\/strong>and can <strong>result in seizures (due to M3G<\/strong>) or prolonged opioid action (due to M6G).<\/li><\/ul>\n\n\n\n<ul><li>Pethidine is metabolized mainly to meperidinic acid by MAO and very little is demethylated to norpethidine.<\/li><li>Latter has seizure inducing and cumulative properties.<\/li><li>Pethidine can result in seizures if used for prolonged periods, in patients with renal failure or those taking MAO inhibitors (due to accumulation of norpethidine).<\/li><\/ul>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"330\" height=\"221\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-265.png?w=330\" alt=\"\" class=\"wp-image-721\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-265.png 330w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-265-300x201.png 300w\" sizes=\"(max-width: 330px) 100vw, 330px\" \/><\/figure>\n\n\n\n<p><strong>Actions of pure opioids<\/strong><\/p>\n\n\n\n<p><strong>Pure agonists<\/strong> include <strong>morphine, methadone, pethidine, levorphanol, codeine, hydrocodone,<\/strong><\/p>\n\n\n\n<p><strong>oxycodone and propoxyphene<\/strong>.<\/p>\n\n\n\n<p><strong>1. CNS Actions<\/strong><\/p>\n\n\n\n<ul><li>Morphine produces <strong>spinal and supraspinal analgesia<\/strong> by acting on \u03bc, \u03ba and \u03b4 receptors.<\/li><li><strong>\u03bc receptor<\/strong> opioids have <strong>dependence producing actions due to euphoric action<\/strong>.<\/li><li><strong>\u039a receptors<\/strong> mediate <strong>psychomimetic effects (dysphoria<\/strong>).<\/li><li>Tolerance develops to all actions of opioids except 3C (Constipation, convulsions and constriction of pupil)<\/li><li>Opioids <strong>produce marked sedation<\/strong> but chances of sedation are less with pethidine and fentanyl.<\/li><li>Opioids can produce <strong>respiratory depression and cough suppression<\/strong>.<\/li><li><strong>Miosis<\/strong> can occur with morphine use and <strong>pin point pupil<\/strong> is a valuable sign in diagnosis of <strong>opioid poisoning.<\/strong><\/li><li><strong>Highly lipid soluble<\/strong> drugs like <strong>fentanyl, alfentanyl and sufentani<\/strong>l can result in <strong>truncal rigidity<\/strong> on <strong>rapid i.v. infusion.<\/strong><\/li><li>By stimulating CTZ, opioids can result in <strong>nausea and vomiting.<\/strong><\/li><\/ul>\n\n\n\n<p><strong>2. Peripheral Effects<\/strong><\/p>\n\n\n\n<ul><li>Opioids have <strong>no direct effect on heart except pethidine and pentazocine (that increase heart rate<\/strong>).<\/li><li><strong>Blood pressure may decrease<\/strong> due to <strong>depression of vasomotor system<\/strong> and <strong>release of histamine.<\/strong><\/li><li>There is a shift of blood from pulmonary to systemic circuit due to greater vasodilatation in the latter<\/li><li><strong>Constipation<\/strong> can result due to decreased motility and increased tone of GIT.<\/li><li><strong>Alvimopan<\/strong> is a <strong>peripheral opioid antagonist developed for paralytic ileus.<\/strong><\/li><\/ul>\n\n\n\n<ul><li>Opioids <strong>increase intrabiliary pressure by constricting biliary smooth muscle. (C\/I in biliary colic).<\/strong><\/li><li>may <strong>aggravate bronchoconstriction in asthmatics by releasing histamine. <\/strong>(<strong>C\/I in asthmatics).<\/strong><\/li><\/ul>\n\n\n\n<ul><li>Spinal or epidural administration of opioids may result in intense pruritus over lips and torso (due to histamine release).<\/li><\/ul>\n\n\n\n<p><strong>Actions of Mixed Agonists-antagonists<\/strong><\/p>\n\n\n\n<p><strong>Buprenorphine<\/strong><\/p>\n\n\n\n<ul><li>partial <strong>agonist at m receptor<\/strong> with k and d antagonistic property<\/li><li>useful as an <strong>analgesic<\/strong> and as an <strong>alternative to methadone for the management of opioid withdrawal.<\/strong><\/li><\/ul>\n\n\n\n<p><strong>Nalbuphine, pentazocine and dezocine<\/strong> &nbsp;(K analgesic)<\/p>\n\n\n\n<ul><li>k agonists and \u03bc receptor antagonists.<\/li><li>can produce psychomimetic effects with hallucinations, nightmares and anxiety.<\/li><li>Pentazocine \u00e0 weak \u03bc antagonistic and more marked \u03ba agonistic actions.<\/li><\/ul>\n\n\n\n<p>profile of action is similar to morphine; important differences are:<\/p>\n\n\n\n<ul><li>Analgesia caused by pentazocine is primarily spinal (\u03ba1) and has a different character than that caused by morphine.<\/li><li>Parenterally 30 mg pentazocine = 10 mg morphine<\/li><li>Sedation and respiratory depression is 1\/3 to 1\/2 of morphine at lower dose<\/li><li>Tachycardia and rise in BP are produced at higher doses due to sympathetic stimulation<\/li><li>Biliary spasm and constipation are less severe.<\/li><li>Vomiting is less frequent<\/li><li>Abuse liability is rated lower than morphine<\/li><\/ul>\n\n\n\n<p><strong>Butorphanol<\/strong><\/p>\n\n\n\n<ul><li>predominant k agonist that produces equivalent analgesia but more sedation than morphine.<\/li><\/ul>\n\n\n\n<p><strong>Clinical uses<\/strong><\/p>\n\n\n\n<ul><li>These are used as analgesic agents.<\/li><li><strong>Visceral, dull and constant pain<\/strong> is relieved <strong>more effectively than inflammatory pain<\/strong>.<\/li><li>Opioids are however <strong>contraindicated in biliary colic.<\/strong><\/li><li>Morphine (i.v.) is <strong>useful in myocardial infarction as well as in acute pulmonary edema.<\/strong><\/li><li><strong>Codeine, pholcodeine, dextromethorphan<\/strong> and noscapine are <strong>effective cough suppressants.<\/strong><\/li><li><strong>Dextromethorphan is devoid of constipating action<\/strong> unlike other drugs in this group.<\/li><li><strong>Loperamide and diphenoxylate<\/strong> can be used for the treatment of <strong>non-infective diarrhea.<\/strong><\/li><li><strong>Morphine<\/strong> is useful as a <strong>pre-anaesthetic medication<\/strong> whereas highly lipid soluble drugs (like fentanyl, alfentanil, sufentanil etc) are used as adjuncts to other anaesthetic agents.<\/li><li><strong>Pethidine<\/strong> is used to <strong>reduce shivering after anaesthesia [by its action on a2 receptor]<\/strong><\/li><\/ul>\n\n\n\n<p><strong>Routes of Administration<\/strong><\/p>\n\n\n\n<ul><li>Morphine can be administered by <strong>oral, rectal, i.v., i.m., intrathecal or epidural routes.<\/strong><\/li><li><strong>Fentanyl <\/strong>can be applied as <strong>transdermal patch<\/strong> or can be administered by buccal transmucosal route.<\/li><li><strong>Butorphanol<\/strong> is the only opioid available in <strong>nasal formulation.<\/strong><\/li><\/ul>\n\n\n\n<p><strong>Adverse Effects and Toxicity<\/strong><\/p>\n\n\n\n<ul><li>Respiratory depression, nausea, vomiting, constipation, urinary retention, itching and dysphoria are important adverse effects of opioids.<\/li><li>Tolerance develops to most of the actions of opioids except miosis, constipation and convulsions.<\/li><li>Opioids are highly addictive substances and can lead to development of <strong>psychological as well as physical dependence.<\/strong><\/li><\/ul>\n\n\n\n<ul><li>Sudden discontinuation \u00e0 <strong>withdrawal syndrome<\/strong><\/li><li>rhinorrhoea, lacrimation, yawning, chills, mydriasis, vomiting, diarrhea and anxiety.<\/li><\/ul>\n\n\n\n<p><strong>Contraindications and Precautions<\/strong><\/p>\n\n\n\n<ul><li>Morphine \u00e0 <strong>absolutely contraindicated in head injury<\/strong> because it increases intracranial tension by causing retention of CO2 (due to respiratory depression).<\/li><li>also interferes with the assessment of neurological function by masking the important pupillary signs (causes miosis).<\/li><li>should be used <strong>cautiously<\/strong> in patients with <strong>pulmonary, hepatic or renal dysfunction.<\/strong><\/li><li>Use of opioids in <strong>infants<\/strong> and elderly also require caution.<\/li><\/ul>\n\n\n\n<ul><li>Prolonged use of opioids in pregnancy may lead to in-utero physical dependence of fetus and severe withdrawal symptoms may be precipitated after birth.<\/li><\/ul>\n\n\n\n<p><strong>Important Points about Specific Agents<\/strong><\/p>\n\n\n\n<p><strong>Methadone<\/strong><\/p>\n\n\n\n<ul><li>long acting opioid analgesic that can be administered by oral, i.v., s.c. and rectal routes.<\/li><li>Apart from potent agonistic actions at \u03bc receptors, it <strong>also blocks NMDA receptors<\/strong> and reuptake of monoamines.<\/li><li>relieve neuropathic and cancer pain that are not controlled with morphine.<\/li><li>Due to its <strong>long t1\/2, development of dependence and tolerance is very slow<\/strong>, making it useful for the <strong>treatment of opioid abuse.<\/strong><\/li><li>&nbsp;It is also useful for <strong>opioid rotation therapy.<\/strong><\/li><\/ul>\n\n\n\n<p><strong>Pethidine and pentazocine<\/strong><\/p>\n\n\n\n<ul><li>possess anticholinergic activity (can result in tachycardia).<\/li><li>These drugs are therefore <strong>C\/I in MI<\/strong>.<\/li><li><strong>Because of anticholinergic properties, these are relatively safer in biliary colic<\/strong> as compared to other agents.<\/li><li>Accumulation of active metabolite of pethidine (<strong>norpethidine) can produce seizures.<\/strong><\/li><\/ul>\n\n\n\n<p><strong>Propoxyphene<\/strong><\/p>\n\n\n\n<ul><li>least potent and least efficacious analgesic agent.<\/li><\/ul>\n\n\n\n<ul><li>Diphenoxylate and its active metabolite difenoxin, as well as loperamide are useful for diarrhea.<\/li><\/ul>\n\n\n\n<ul><li><strong>Buprenorphine<\/strong> dissociates slowly from \u03bc receptors and is thus <strong>resistant to naloxone reversal.<\/strong><\/li><\/ul>\n\n\n\n<p><strong>Tramadol<\/strong><\/p>\n\n\n\n<ul><li><strong>weak m receptor agonist<\/strong>. It <strong>also inhibits reuptake of NA and 5-HT.<\/strong><\/li><li>These effects are responsible for its analgesic action, which can be abolished by 5-HT3 antagonists like ondansetron.<\/li><li><strong>analgesic action is only partially reversed by the opioid antagonist naloxone.<\/strong><\/li><li>At high doses, it can lead to seizures.<\/li><li>Tramadol causes less respiratory depression, sedation, constipation, urinary retention and rise in intrabiliary pressure than morphine.<\/li><li>Tramadol should not be given to patients taking SSRI therapy because of risk of \u2018<strong>serotonin syndrome<\/strong><\/li><\/ul>\n\n\n\n<p><strong>Tapentadol<\/strong><\/p>\n\n\n\n<ul><li>new analgesic drug with \u03bc-receptor agonistic action and NA reuptake inhibiting action.<\/li><\/ul>\n\n\n\n<p><strong>Opioid Antagonists<\/strong><\/p>\n\n\n\n<p><strong>Naloxone, naltrexone and nalmefene<\/strong> are potent m receptor antagonists with significant<\/p>\n\n\n\n<p>blocking action at k and d receptors also.<\/p>\n\n\n\n<p><strong>Alvimopan and methylnaltrexone<\/strong> are peripheral opioid antagonists.<\/p>\n\n\n\n<ul><li>Naloxone is given parenterally (ineffective orally) and is a very short acting drug.<\/li><li>Nalmefene is also given parenterally but has a longer half life.<\/li><li>Naltrexone is long acting orally effective opioid antagonist.<\/li><\/ul>\n\n\n\n<p><strong>Actions<\/strong><\/p>\n\n\n\n<ul><li>have no action in the absence of agonists but promptly reverses the opioid effects when administered i.v.<\/li><\/ul>\n\n\n\n<p><strong>Uses<\/strong><\/p>\n\n\n\n<ul><li><strong>Naloxone<\/strong> is the <strong>drug of choice for acute opioid poisoning<\/strong> but it has to be repeated frequently.<\/li><li><strong>Naltrexone <\/strong>is used as a <strong>maintenance drug for opioid poisoning<\/strong>.<\/li><li>It is also used to prevent relapse after opioid de-addition.<\/li><li>It is also used to <strong>decrease craving in chronic alcoholics.<\/strong><\/li><li><strong>Naltrexone plus bupropion<\/strong> has recently been approved for <strong>treatment of obesity<\/strong><\/li><\/ul>\n\n\n\n<ul><li><strong>Naloxone <\/strong>is also used in <strong>neonatal resuscitation to reverse the effects of opioids<\/strong> (if used during labour). &nbsp;<\/li><li>However, it should not be used for this purpose if mother is dependent on opioids. (Baby is also dependent in utero and naloxone can precipitate withdrawal).<\/li><\/ul>\n\n\n\n<ul><li>Naloxone is being <strong>added to opioids meant for oral use to minimize their addictive potential<\/strong>.<\/li><li>&nbsp;If the patient takes the combination orally, only opiod is absorbed not naloxone. Thus, it will produce the desired action. However, if the person takes it by i.v. route for addiction, naloxone also reaches the blood and stops euphoria.<\/li><\/ul>\n\n\n\n<ul><li><strong>Methylnaltrexone and alvimopan<\/strong> are peripheral opioid antagonists indicated for <strong>opioid-induced constipation.<\/strong><\/li><\/ul>\n\n\n\n<ul><li><strong>Naloxegol<\/strong> is a new drug recently approved for same indication<\/li><\/ul>\n\n\n\n<p><strong>Opiod De-addiction<\/strong><\/p>\n\n\n\n<ul><li>Chronic intake \u00e0 physical and psychological dependence. I<\/li><li>Suddenly stopped \u00e0 withdrawal symptoms<\/li><li>For de-addiction of opioids (or any addictive drug), first aim is to stop the further use of the drug by the patient followed by maintainance of de-addiction (i.e., to prevent relapse).<\/li><\/ul>\n\n\n\n<ul><li>If addiction is of short duration and with small doses of addictive drug, sudden stoppage of drug therapy can be attempted and the <strong>mild withdrawal<\/strong> symptoms can be treated with <strong>b-blockers or clonidine (or lofexidine).<\/strong><\/li><\/ul>\n\n\n\n<ul><li>If addiction is of <strong>long duration<\/strong> or with large dose of opioids, sudden withdrawal of the offending drug may be dangerous (due to <strong>severe withdrawal<\/strong> symptoms).<\/li><li>In such patients, the addictive drug is <strong>replaced by equivalent dose of methadone (known as methadone maintenance)<\/strong>.<\/li><li>It prevents withdrawal symptoms by stimulating opioid receptors but is much less addictive. The dose of methadone is then gradually decreased and finally stopped.<\/li><li><strong>To prevent relapse after de-addiction, naltrexone is used.<\/strong><\/li><li>Naltrexone prevents euphoric action by blocking \u03bc receptors. If the person again takes opioids (after deaddiction), there will be no euphoria and the person\u2019s resolution to quit addiction will be strengthened.<\/li><\/ul>\n\n\n\n<p><strong>Note:<\/strong><\/p>\n\n\n\n<p>\u2022 b-blockers and clonidine treat withdrawal symptoms.<\/p>\n\n\n\n<p>\u2022 Methadone prevents withdrawal symptoms. \u2022 Naltrexone is used to prevent relapse.<\/p>\n\n\n\n<p>\u2022 Methadone is used as maintenance therapy in opioid dependence whereas naltrexone is used as<\/p>\n\n\n\n<p>maintenance therapy in opioid poisoning.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Opioid receptors substances obtained from the crude extract of Papaver somniferum (poppy plant). Morphine is the prototype opioid and acts by agonistic activity on \u03bc, k and d receptors. critical in the modulation of pain behaviour and anti-nociception Types Recently a new endogenous peptide, nociceptin is isolated that acts on nociceptin\/orphanin FQ (N\/OFQ) or orphanin[&#8230;]\n","protected":false},"author":3,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_seopress_robots_primary_cat":"","_seopress_titles_title":"","_seopress_titles_desc":"","_seopress_robots_index":"","footnotes":""},"categories":[3],"tags":[],"_links":{"self":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/692"}],"collection":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/comments?post=692"}],"version-history":[{"count":0,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/692\/revisions"}],"wp:attachment":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/media?parent=692"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/categories?post=692"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/tags?post=692"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}