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ANALGESIC DRUGS / 1/ MORPHINE - LIKE DRUGS (OPIOID, NARCOTIC ANALGESICS)

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ANALGESIC DRUGS / 1/ MORPHINE - LIKE DRUGS (OPIOID, NARCOTIC ANALGESICS)

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  1. ANALGESIC DRUGSandNONSTEROIDAL ANTI-INFLAMMATORY DRUGSV. GeršlAccording to: - H.P.Rang, M.M.Dale, J.M.Ritter, P.K.Moore: Pharmacology, 5th ed.- H.P.Rang, M.M.Dale, J.M.Ritter, R.J.Flower: Pharmacology, 6th ed. R.A.Howland, M.J.Mycek: Lippincott’s Illustrated Reviews: Pharmacology,3rd ed. R.A.Harvey, P.C.Champe: Lippincott’s Illustrated Reviews: Pharmacology,4th ed.- B.G.Katzung, S.B.Masters, A.J.Trevor: Basic and Clinical Pharmacology, 11th ed.

  2. ANALGESIC DRUGS /1/MORPHINE - LIKE DRUGS (OPIOID, NARCOTIC ANALGESICS) /2/ ANALGESIC-ANTIPYRETICS AND ANTIINFLAMMATORY DRUGS MECHANISM OF PAIN AND NOCICEPTION: Nociception: mechanism whereby noxious peripheral stimuli are transmitted to CNS. Polymodal nociceptors (PMN): peripheral sense organs that respond to noxious stimuli, mostly nonmyelinated C-fibres whose endings respond to thermal, mechanical and chemical stimuli.

  3. Chemical mediators: - chemical stimuli acting on PMN to cause pain - bradykinin, 5-HT, capsaicin (from pepper) - neurotransmitters released locally in inflammation - 5-HT, histamine, acetylcholine -prostaglandins - sensitization of PMN Transmitters of PMN neurons: fast transmitters (glutamate, ATP) and peptides (substance P, Calcitonin-gene-related-peptide, i.e. CGRP) modulatory transmitters: met- enkephalin, endorphin, 5-HT, Noradrenaline Nociceptive fibres terminate in the dorsal horn (1st neurone), forming synaptic connection with transmission neurones running to thalamus (2nd neurone) then to cortex (3rd neurone).

  4. OPIOIDS (MORPHINE-LIKE) ANALGESICS • AND ANTAGONISTS • Opioids - natural or synthetic compounds - produce morphine-like effects - • binding to specific opioid receptors in the CNS »»» effects mimic the action of endogenous peptide neurotransmitters (e.g., leu- and met-enkephalins). • Morphine and codeine (from the poppy - Papaver somniverum). • The widespread availability of opioids drug abuse. • Although the opioids have a broad range of effects, their primary use is to relieve intense pain and the anxiety that accompanies it, whether that pain is from surgery or a result of injury or a disease, such as cancer. • Antagonists - can reverse the actions of opioids, important clinically (use in cases of overdose).

  5. Summary of opioid analgesic and antagonists OPIOID ANALGESICS AND ANTAGONISTS Mixed agonist-antagonists and partial agonists Strong agonists Alfentanil Fentanyl Heroin Meperidine Methadone Morphine Oxycodone Remifentanil Sufentanil Buprenorphine Butorphanol Nalbuphine Pentazocine Antagonists Nalmefene Naloxone Naltrexone Moderate/low agonists Other analgesics Codeine Propoxyphene T ramadol (according to Lippincott´s Pharmacology, 4th ed., 2009)

  6. OPIOID RECEPTORS Protein receptors on the membranes of certain cells mostly in the CNS and the GIT. All are coupled to inhibitory G proteins, inhibit adenylyl cyclase and  cAMP. They may be also associated (via G protein) with ion channels – to increase K efflux (hyperpolarisation) or reduce Ca influx (impeding neuronal firing and transmitter release). The major effect of the opioids are mediated by 3 families of receptors - each exhibits a different specifityfor the drug(s) it binds. /mu/ - analgesia, euphoria, sedation, depression,dependence /delta/- peripheral action, interaction with enkephalins /kappa/- analgesia at the spinal level Also receptors for endogenous opioid peptides –(endorphins, enkephalins, dynorphins).

  7. A novel receptor-ligand system homologous to opioid peptides found: G-protein-coupled orphanin opioid-receptor-like subtype 1 (ORL1). Ligand: nociceptin (orphanin FQ). Called N/OFQ systém. Nociceptin is structurally similar to dynorphin – acts on ORL1 receptor NOP. System implicated in both pro- and anti-nociceptive activity, modulation of drug reward, learning, mood, anxiety etc.

  8. Mechanism of action of m-opioid receptor agonists in the spinal cord. Activation of the opioid receptor decreases Ca2+ influx in response to incoming action potential. this decreases release of excitatory neurotransmitters, such as glutamate. PRESYNAPTIC NEURON Opioid receptor Synaptic vesicle Ca2+ Ca2+ Glutamate K+ K+ Excitatory response Opioid receptor Activation of the opioid receptor increases K+ efflux and decreases the response of the post-synaptic neuron to excitatory neuro- transdmitters. (according to Lippincott´s Pharmacology, 2006 POSTSYNAPTIC NEURON

  9. Distribution of receptors: The highest density in 5 areas of the brain involved in integrating information about pain. 1. Brainstem:influencerespiration, cough, nausea and vomiting, blood pressure, pupillary diameter, control of stomach secretions. 2. Medial thalamus: mediate deep pain that is poorly localized and emotionally influenced. 3. Spinal cord: In the substantia gelatinosa - involved with the receipt and integration ofincoming sensory information, leading to the attenuation of painful afferent stimuli. 4. Hypothalamus: neuroendocrine secretion. 5. Limbic system: The greatest concentration there is in the amygdala. Receptors probably may influence emotional behaviour. 6. Periphery: binding to peripheral sensory nerve fibers and terminals (inhibition of the Ca-dependent release of pro-inflammatory substances /Substance P/ from endings) – contribution to anti-inflammatory effects of opioids? 7. Immune cells: the role has not been determined

  10. morphine analogues: closely related in structure to morphine - often synthesised from it: they may be agonists (e.g. morphine, diamorphine (heroin) and codeine), partial agonists (e.g. nalorphine and levallorphan) or antagonists (e.g. naloxone, naltrexone) • synthetic derivatives - structures unrelated to morphine: ― phenylpiperidine series, e.g. pethidine and fentanyl ― methadone series, e.g. methadone and dextropropoxyphene • ― benzomorphan series, e.g. pentazocine and cyclazocine • ― semisynthetic thebaine derivatives, e.g. etorphine and • buprenorphine. • Note:diphenoxylate and loperamide - an opiate that does not enter • the brain andlacks analgesic activity. Like other opiates they • inhibit peristalsisused to control diarrhea.

  11. Division (in relation to the activity) 1. Strong agonists (e.g. morphine, meperidine=pethidine, methadone, fentanyl, sufentanil, alfentanil, remifentanil, oxycodone) 2. Moderate agonists (e.g. propoxyphene, codein) 3. Mixed agonist-antagonists (e.g. pentazocine, buprenorphine, nalbuphine, butorphanol) 4. Other analgesics ( tramadol) 5. Antagonists (naloxone, naltrexone)

  12. STRONG AGONISTS • MORPHINE • The major analgesic drug contained in crude opium – theprototype agonist (codeine - present in lower concentrations and is less potent). • The opioid agonists all have similar actions, high affinity for  receptors, varying affinities for  and  receptors. • Mechanism of action: • Major effect via opioid receptors in the CNS and GIT. • Opioids cause hyperpolarization of nerve cells, inhibition of • nerve firing, and presynaptic inhibition of transmitter release.

  13. Morphine also acts at k receptors in lamina I and II of the substantia gelatinosa of the spinal cord release of substance P (which modulates pain perception in the spinal cord). Morphine also inhibits release of many excitatory transmitters from nerve terminals carrying nociceptive (painful) stimuli.

  14. Actions: /1/ CNS: a. analgesia: Opioids relieve pain both by enhancing the pain threshold at the spinal cord level, and more importantly, by altering the brain´s interpretation of pain. Patients are still aware of the presence of pain, but the sensation is not unpleasant. b. Euphoria:strongsense of contentment and well-being (may be caused by stimulation of the ventral tegmentum). c. Respiratory depression: by  the sensitivity of respiratory center neurons to CO2 - occurs with ordinary doses; accentuated as the dose increases; ultimately - respiration ceases. Respiratory depression - the most common cause of death in acute opioid overdose.

  15. d. Depression of cough reflex: Morphine and codeine have antitussive properties - itdoes not correlate closely with analgesic and respiratory depressant properties of opioids. The receptors involved in the antitussive action appear to be different than those involved in analgesia. e. Miosis (pupillary constriction): The pinpoint pupil -typical – from stimulation of  and  receptors. Excitation of the Edinger-Westphal nucleus of the oculomotor nerve »»»  parasympathetic stimulation to the eye. Little tolerance to it (all addicts to morphine have pin-point pupils). Important diagnostically (most other causes of coma and respiratory depression produce dilation of the pupil) ! f. Nausea and emesis: direct stimulationof the chemoreceptor trigger zone in the area postrema »»» vomiting. However, the emesis does not produce unpleasant sensations.

  16. g. Increased polysynaptic spinal cord activity: Increased disposition to convulsions (Straub tail reaction in mice - raising and stiffening of the tail due to the spasm of a muscle at the base of the tail). h. Truncal rigidity: Intensification of tone in the large trunk muscles (supraspinal and spinal (?) mechanism – interference with ventilation. Following high i.v. doses of highly lipid soluble opioids (e.g., fentanil, sufentanil)

  17. /2/ GIT, urogenital s.: • - It decreases motility and increases tone of intestinal smooth muscle ! constipation (little tolerance developing to it). • - M. pressure in the biliary tract (contraction of the gallbladder and constriction of biliary sphincter) harmful in biliary colic due to gallstones !! • - M. also  the tone of the anal sphincter • M. also can cause spasm of ureter and suppresses urinary bladder voiding reflex, increases ADH  retention of urine (catheterization in intoxication with M.)!! • - Labor:M. can prolong 2ng stage (transient  in strength, duration and frequency of contraction) • /3/ Inhibition of cilia motility: • Important in bronchi (disturbed expectoration) and in ovary tube (sterility – interference with ovum transport).

  18. /4/ Cardiovascular system: M.- no major effects on BP or heart rate (high doses – hypotension and bradycardia - action on the medulla). Because of respiratory depression and CO2 retention, cerebral vesselsdilate and increase the cerebrospinal fluid pressure »»» contraindicated in severe brain injury. /5/ Histamine release: Release of histamine from mast cells »»» bronchoconstriction, hypotension, urticaria, itching, sweating. Asthmatics should not receive the drug. /6/ Hormonal actions: Inhibition of the release ofgonadotropin-releasing h. and corticotropin-releasing h.  decrease of luteinizing h., FSH, ACTH, and ß-endorphin. Testosterone and cortisol levels decrease. It increases prolactin and GH release and ADH. /7/ Immunosuppressant activity: Increased susceptibility to infections after long-term abuse.

  19. Therapeutic use: • Analgesia:effective in treatment of pain. Opioids induce sleep, and • in clinical situations when pain is present and sleep is necessary, • opiates may be used to supplement the sleep-inducing drugs. • Note: The hypnotics are not usually analgesic, and may have diminished • sedative effect in the presence of pain. • It is necessary to know origin of the pain !!! • b. Diarrhea: M.  motility of smooth muscle and increase tone • (through the intramuscular nerve plexus). • c. Relief of cough: Suppression of the cough reflex, however codeine • or dextromethorphan are more widely used. • d. Acute pulmonary edema: IV morphine relieves dyspnea caused • by pulmonary edema in LVF - possibly by its vasodilatory effect.

  20. e. Application in anesthesia • Premedication before an. (sedative, anxiolytic, analgesic properties), • intraoperatively (as adjuncts to other or – e.g. high dosee of fentanyl – as • primary component). • Commonly used in high-risk surgery (cardiovascular etc.) to minimize • cardiovascular depression.

  21. Pharmacokinetics: a. Administration: Absorption of M. from the GIT is slow and erratic  usually not given orally (exception: new extended release tablets). Codeine - well absorbed after oral administration. Significant first-pass metabolism of morphine in the liver  i.m., s.c., or i.v. injections - the most reliable responses. [Note: In chronic pain in neoplastic disease - use either the new slow-release tablets orally, transdermal patches or pumps that allow the patient to control the pain through self-administration – PCA (patient-controlled analgesia). Opiates - nonmedical purposes - by inhaling powders or smoke from burning crude opium  rapid onset of action.

  22. b. Distribution: M. rapidly enters all body tissues (incl. the fetuses of pregnant women  should not be used during labor !! Infants born of addicted mothers show physical dependence on opiates and withdrawal symptoms if opioids are not administered. Only a small percentage of M. crosses the blood-brain barrier (morphine is the least lipophilic of the common opioids). More fat-soluble opioids - fentanyl, methadone, heroin - readily penetrate into the brain.

  23. c. Fate: M. is conjugated in the liver to glucuronic acid. Morphine-6-glucuronide - a very potent analgesic; the conjugate at the 3-position - much less active. Conjugates are excreted primarily in the urine, small quantities in the bile. The duration of action of morphine is 4 – 6 hours when administered systemically. Much longer when injected epidurally (its low lipophilicity prevents redistribution from the epidural space). Importance od an age - elderly patients - more sensitive to effects of the drug ( metabolism or other factors, e.g.  lean body mass, renal function, etc.)  use lower doses. Neonates should not receive morphine because of their low conjugating capacity !!!

  24. Adverse effects: • - Severe respiratory depression occurs, coma. • - Constipation. • - Vomiting, dysphoria. • - Allergy, depletion of histamine -bronchoconstriction, hypotensive effects, itching, low blood volume. • Serious in intracranial pressure, particularly in head injury. • It enhances cerebral and spinal ischemia. • In prostatic hypertrophy – M. may cause acute urinary retention. • A serious - stoppage of respiratory exchange in emphysema • or cor pulmonale patients. If employed, respiration must be carefully watched. • In adrenal insufficiency or myxedema – may be extended and • increased effects. • Use with caution in patients with bronchial asthma or liver failure.

  25. Tolerance • itcan be detected within 12-24 hours of morphine administration - tomost of the effects of M. (incl. analgesia, emesis, euphoria, and respiratory depression) but tolerance to constipating and miosisusually not • addicts may take 50 times the normal analgesic dose of M. with relatively little respiratory depression, but marked constipation and pupillary constriction are present. • Tolerance = a general phenomenon of opioid receptor ligands. • Cross-tolerance occurs between drugs acting at the same receptor, but not between opioids that act on different receptors. • In clinical settings, the opiate dose required for effective pain relief may increase, but it is not a major problem.

  26. Physical (and psychological) dependence. Characterised by a clear-cut abstinence syndrome. In animals - abrupt withdrawal of M. after chronic admin. for a few days  irritability, loss of weight and a variety of abnormal behaviour patterns (body shakes, writhing, jumping and signs of aggression). The reactions decrease after a few days, but abnormal irritability and aggression persist for many weeks. Human addicts show a similar abstinence syndrome - somewhat resembling severe influenza, with yawning, pupillary dilatation, fever, sweating, piloerection, nausea, diarrhoea and insomnia. Extreme restlessness and distress are accompanied by a strong craving for the drug.Symptoms are maximal after 2-3 days and largely disappear in 8-10 days; some residual symptoms persist for several weeks. Re-administration of morphine rapidly abolishes the abstinence syndrome. Also strong psychological dependence(craving for the drug). Rapid development.

  27. Many physiological changes: E.g., spinal reflex hyperexcitability occurs in morphine-dependent animals. The noradrenergic pathways emanating from the locus ceruleusmay also play an important role in causing the abstinence syndromea2- agonist clonidine is sometimes used. Detoxification of heroin- or morphine-dependent individuals - usually p.o. administration of methadone, buprenorphine or clonidine.

  28. Drug interactions:The depressant actions of morphine are enhanced, e.g., by phenothiazines, MAO inhibitors, tricyclic antidepressants, BZD.MAO inhibitors – high incidence of hyperpyrexic coma, also hypertension Low doses of amphetamine strangely enhance analgesia.

  29. PETHIDINE = MEPERIDINE a synthetic opioid structurally unrelated to morphine. Used for acute pain. 1. Mechanism of action: It binds particularly to m rec. but also well to k rec. 2. Actions: depression of respiration similar to morphine, but it has no significant cardiovascular action when given orally. i.v. administration -  in peripheral resistance and  in peripheral blood flow  tachycardia. Also dilates cerebral vessels,  CSF pressure. Contractions of smooth muscle - to a lesser extent than does morphine. Meperidine does not cause pinpoint pupils rather, causes the pupils to dilate because of an atropine-like action.

  30. 3. Therapeutic uses: - Analgesia for any type of severe pain. - It is not useful in the treatment of diarrhea or cough. - Lower increase in urinary retention than morphine. - Employed in obstetrics (less effect on uterine muscle). 4. Pharmacokinetics: Unlike morphine, pethidine is well absorbed from the GIT, and is useful when an orally administered, potent analgesic is needed. Mostly administered i.m. Duration of action of 2 - 4 hours (shorter than morphine). It is is N-demethylated to normeperidine (norpethidine) in the liver , excreted in the urine. Norpethidine has hallucinogenic and convulsant effect. Because of its shorter action and different route of metabolism, meperidine is preferred over morphine for analgesia during labor.

  31. 5. Adverse effects: - Large or repetitive doses can cause anxiety, tremors, muscle twitches, rarely convulsions due to the accumulation of normeperidine. - It differs from opioids - in large doses, it dilates the pupil and causes hyperactive reflexes. - Severe hypotension (esp. when administered postoperatively). - Due to its antimuscarinic action - dry mouth and blurred vision may be. - When used with major neuroleptics, depression is greatly enhanced. Administration wiht I-MAO severe reactions (convulsions, hyperthermia). - It can cause dependence, partial cross-tolerance with other opioids occurs.

  32. Differences against morphine: - shorter duration of the action (particularly marked in neonate) »»» preferred during labour - not biotransformed by conjugation (which is deficient in newborns) - N-demethylated in the liver to norpethidine (hallucinogenic and convulsant effects - after large oral dose) - rather restlessness than sedation - no miosis - lower antitussive effect - antimuscarinic (i.e., parasympatholytic) activity »»» lower spasm of smooth muscle, dry mouth, blurring of vision

  33. METHADONEa synthetic, orally effective opioid; approx. equal in potency to morphine - but less euphoria and a longer duration of action. 1. Mechanism of action: - viaμreceptors. Also other mechanisms (block of NMDA rec., block of monoamine reuptake) – sometimes effective when morphine failed2. Actions: The analgesic activity - equivalent to morphine. Well-absorbed orally. Plasma half-life more than 24 hours. It also  biliary pressure and causes constipation.3. Therapeutic uses:Analgesia. In the controlled withdrawal of dependent abusers from heroin and morphine.

  34. It causes a withdrawal syndrome that is milder but more protracted (days to weeks) than with other opioids 4. Pharmacokinetics: Readily absorbed after p.o. administration. It accumulates in tissues, where it remains bound to protein, from which it is slowly released. It is biotransformed in the liver and excreted in the urine, mainly as inactive metabolites. I.e., it has longer duration of action (boundin extravascular compartment) »»» less acute physical abstinence syndrome (psychological dependence similar) »»» used widely in treating morphine and heroine addiction. In presence of methadone, morphine does not cause euphoria. 5. Adverse effects: It can produce physical dependence like morphine.

  35. FENTANYL - chemically related to pethidine, has 100-fold the analgesic potency of morphine, used in anesthesia. A rapid onset and short duration of action (15 - 30 min), usually injected i.v., epidurally, or intrathecally. Epidural use for analgesia postoperatively and during labor. An oral transmucosal preparation and a transdermal patch are also available. The transdermal patch must be used with caution (death from hypoventilation has been known to occur). The transdermal patch creates a reservoir of the drug in the skin the onset is delayed 12 hours, and the offset is prolonged.

  36. Negligible effect on cardiac contractility (used in cardiac surgery)Metabolized to inactive metabolites by the CYP4503A4 - drugs that inhibit this isozyme can potentiate the effect of fentanyl. Most of the drug and metabolites are eliminated through the urine. Adverse effects - similar to those of other μreceptor agonists. - Because of life-threatening hypoventilation, the fentanyl patch is contraindicated in the management of acute and postoperative pain or pain that can be ameliorated with other analgesics. - It causes pupillary constriction. - Used in neuroleptanalgesia (with droperidol)

  37. SUFENTANIL, ALFENTANIL, REMIFENTANIL related to fentanyl Sufentanil, alfentanil and remifentanil - differ in their potency and metabolic disposition. Sufentanil is even more potent than fentanyl, whereas the other two are less potent but much shorter-acting. ETORPHINE - about 1000times more potent than morphine, used to immobilise wild animals.

  38. HEROIN does not occur naturally.Produced by di- acetylation of morphine  a threefold increase in its potency.Great lipid solubility  it crosses HEB more rapidly than morphine (a more exaggerated euphoria, rush when taken by injection). Shorter duration of action (2 hrs), very strong dependence.Converted to morphine in the body, but its effects last about half as long. In most countries it has no accepted medical use.

  39. OXYCODONE a semisynthetic derivative of morphine. Orally active andsometimes formulated with aspirin or acetaminophen. It is used to treat moderate to severe pain. Metabolized to products with lower analgesic activity. Excretion is via the kidney. Abuse of the SR (sustained-release) preparation (ingestion of crushed tablets) - many deaths  the higher-dosage forms of these preparations should be used only by patients who are tolerant to opioids.

  40. MODERATE AGONISTS CODEINE(methylmorphine) much less potent analgesic than morphine (cca 20 %of the analgesic potency of M. »»» mild types of pain).About 10 % of codein metabolized to morphine  analgesic effects. Good antitussive activity (due codein itself) at doses that do not cause analgesia - (In cough preparations frequently replaced by, e.g. dextromethorphan - a synthetic cough depressant without analgesic action and with a low potential for abuse). Well absorbed after p.o. administration. Lower potential for abuse than morphine  rarely dependence. Lower euphoria than morphine. Frequently combined in analgesic-antipyretic preparations with salicylates or acetaminophen. Respiratory depression of low importance. Antitusssive activity, constipation.

  41. PROPOXYPHENE- a derivative of methadone. The dextro isomer - used as an analgesic (in mild to moderate pain). The levo isomer - is not analgesic, but it has antitussive action. A weaker analgesic action than codeine (approx. 50 %). Often used in combination with aspirin or acetaminophen for an analgesia. Absorbed orally, metabolized in the liver. It can produce nausea, anorexia, and constipation. Toxic doses - respiratory depression, convulsions, hallucinations, and confusion. In some individuals - cardiotoxicity and pulmonary edema. Note: When used with alcohol and sedatives  severe CNS depression, and death by respiratory depression and cardiotoxicity can result. The respiratory depression and sedation can be antagonized by naloxone, but the cardiotoxicity cannot. DIHYDROCODEINE– cca 1/6 potency of M., oral SR forms

  42. Opioides used in diarrhea – not for analgesia DIPHENOXYLATE and DIFENOXIN (its metabolite). Poor solubility limits their parenteral use, do not readily penetrate HEB – lack of morphine-like activity on CNS Preparations usually with atropine Not to be use in young children (< 4 years). LOPERAMIDE Relat. selectively on GIT; significant enterohepatic cycling. Also antisecretory action. It reduces frequency of abdominal cramps, passage of faces and shorten duration of illness (firts choice in traveller´s diarrhoea) Action on peripheral µ receptors (and lack of effect on CNS receptors) – renewed interest in the treatment of neuropathic pain.

  43. MIXED AGONIST-ANTAGONISTS AND PARTIAL AGONISTS Stimulate one receptor but block another = mixed agonist-antagonists. The effects of these drugs depend on previous exposure to opioids. In individuals who have not recently received opioids, mixed agonist-antagonists show agonist activity and used to relieve pain. In the patient with opioid dependence, the agonist-antagonist drugs may show primarily blocking effects  produce withdrawal symptoms.

  44. PENTAZOCINE an agonist on kreceptors, a weak antagonist at m and dreceptors. Analgesia by activating receptors in the spinal cord - used to relieve moderate pain. Administered orally or parenterally; less euphoria compared to morphine. Higher doses  respiratory depression and  the activity of GIT. High doses -  BP and can cause hallucinations, nightmares, tachycardia, dizziness (via sigma non-opioid receptors)  decreased use. In AP - it  aortic BP and pulmonary arterial BP and the work of the heart. It decreases renal plasma flow. Despite its antagonist action, pentazocine does not antagonize the respiratory depression of morphine, but it can precipitate a withdrawal syndrome in a morphine abuser. Tolerance and dependence may develop.

  45. BUPRENORPHINE a partial agonist, acting at them receptor. It acts like M. in naive patients; precipitate withdrawal in morphine users. A major use - in opiate detoxication (less severe and shorter duration of withdrawal symptoms compared to methadone). Lower sedation, respiratory depression and  BP, even at high doses. In contrast to methadone (available only at specialized clinics), buprenorphine (sublingual tablets)is approved for oftice-based detoxification or maintenance. Administered sublingually (treatment of dependence) or parenterally (in moderate pain); a long duration of action (tight binding to the receptor). Metabolized by the liver, excreted in the bile and urine. Adverse effects: respiratory depression that cannot be reversed by naloxone, decreased (or, rarely, increased) BP, nausea, and dizziness.

  46. NALBUPHINE and BUTORPHANOL only a limited role in the treatment of chronic pain. Neither is available for oral use. Their propensity to cause psychotomimetic effects is less than that of pentazocine. Nalbuphine does not affect the heart or increase BP, in contrast to pentazocine and butorphanol. A benefit - they exhibit a ceiling effect for respiratory depression.

  47. MEPTAZINOL and DEZOCINE - recently introduced opiates of unusual chemical structure. Meptazinol– it can be given orally or by injection; short plasma half-life. It seems to be relatively free of some morphine-like side-effects, (no euphoria or dysphoria, not severe respiratory depression). It produces nausea, sedation and dizziness, and it has atropine-like side-effects.Because of its short duration of action and lack of respiratory depression, it may have advantages for obstetric analgesia.Dezocine is a partial agonist at μ-receptors; analgesic activity similar to morphine, but with respiratory depressant activity that reaches a 'ceiling' at high doses. It has not yet been fully evaluated.

  48. OTHER ANALGESICS TRAMADOL- in moderate to moderately severe pain. A centrally acting analgesic partially acting by binding to m-opioid receptor. In addition, it inhibits re-uptake of norepinephrine and serotonin. Its respiratory-depressant activity is less than that of morphine. Naloxone can only partially reverse the analgesia produced by tramadol or its active metabolite. Extensive metabolism; one metabolite is active. Concurrent use with carbamazepine  increased imetabolism by induction of the CYP2D6. Quinidine (inhibits isoenzyme)   levels of tramadol.Anaphylactoid reactions have been reported. Important: the seizures that can occur, especially in patients taking selective serotonin re-uptake inhibitors or TCA. Tramadol should also be avoided in patients taking MAO inhibitors.

  49. ANTAGONISTS They bind with high affinity to opioid receptors, but fail to activate the receptor-mediated response. Administration of opioid antagonists - no profound effects in normal individuals. However, in patients dependent on opioids, antagonists rapidly reverse the effect of agonists and precipitate the symptoms of opiate withdrawal.

  50. NALOXONE used to reverse the coma and respiratory depression of opioid overdose. It rapidly displaces all receptor- bound opioid molecules and, therefore, is able to reverse the effect of a heroin overdose. In 30 s of i.v. naloxone, the respiratory depression and coma are reversed. A half-life of 60 to 100 minutes - relatively short duration of action  patient who was recovered may lapse back into respiratory depression. It is a competitive antagonist at m, k and d, receptors, with a ten-fold higher affinity for m receptors than for k( it reverses respiratory depression with only minimal reversal of the analgesia from agonist stimulation of k receptors in the spinal cord). No pharmacologic effects in normal individuals, but it precipitates withdrawal symptoms in opioid abusers. Low doses – treatment of adverse effects associated with i.v. and epidural administration of opioids !!

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