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

1. ANALGESIC DRUGS V. GeršlAccording to: - H.P.Rang, M.M.Dale, J.M.Ritter, P.K.Moore: Pharmacology, 5th ed.- R.A.Howland, M.J.Mycek: Lippincott’s Illustrated Reviews: Pharmacology, 3rd 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; produce morphine-like effects. • They act by binding to specific opioid receptors in the CNS »»» effects mimic the action of endogenous peptide neurotransmitters (e.g., leu- and met-enkephalins). • They relieve severe pain - essential in treatment of major diseases, trauma, and surgery. • Danger of the 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. • Antagonists – they can reverse actions of opioids, important clinically – treatment of overdose.

5. OPIOID ANALGESICS AND ANTAGONISTS STRONG AGONISTS Alfentanil Fentanyl Heroin Meperidine Methadone Morphine Remifentanil Sufentanil MODERATE/LOW AGONISTS Codeine Oxycodone Propoxyphene MIXED AGONIST-ANTAGONISTS AND PARTIAL AGONISTS Buprenorphine Butorphanol Nalbuphine Pentazocine ANTAGONISTS Naloxone Naltrexone (according to Lippincott´s Pharmacology, 2006 OTHER ANALGESICS Tramadol

6. morphine analogues: closely related in structure to morphine; often synthesized 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) • synthetic derivatives with structures unrelated to morphine: ― phenylpiperidine series, e.g. pethidine, fentanyl ― methadone series, e.g. methadone, dextropropoxyphene • ― benzomorphan series, e.g. pentazocine, cyclazocine • ― semisynthetic thebaine derivatives, e.g. etorphine, • buprenorphine. • Loperamide - an opiate – but it does not enter the CNS - it lacks analgesic activity. However, like other opiates it inhibits peristalsis - used to control diarrhea.

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

8. OPIOID RECEPTORS Specific protein receptors on the membranes of certain cells mostly in the CNS and the GIT. All are coupled to inhibitory G proteins, and inhibit adenylyl cyclase. They may be also associated 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 three families of receptors - each exhibits a different specifity for the drug(s) it binds.  /mu/ - analgesic activity, euphoria, sedation, depression, dependence  /delta/ - peripheral action, interaction with enkephalins  /kappa/ - analgesia at the spinal level

9. Distribution of receptors: The highest density – in 5 general areas of the brain involved in integrating information about pain. 1. Brainstem: mediate respiration, cough, nausea and vomiting, maintenance of blood pressure, pupillary diameter, control of stomach secretion. 2. Medial thalamus: mediate deep pain that is poorly localized and emotionally influenced. 3. Spinal cord: In the substantia gelatinosa - receipt and integration ofincoming sensory information, leading to the attenuation of painful afferent stimuli. 4. Hypothalamus: affect neuroendocrine secretion. 5. Limbic system: The greatest concentration 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. 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- transmitters. (according to Lippincott´s Pharmacology, 2006 POSTSYNAPTIC NEURON

11. STRONG AGONISTS • MORPHINE • The major analgesic drug contained in crude opium – the prototype agonist (codeine is 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 - by interacting with opioid receptors. • Opioids cause hyperpolarization of nerve cells, inhibition of • nerve firing, and presynaptic inhibition of transmitter release.

12. Morphine acts at k receptors in the substantia gelatinosa of the spinal cord; it decreases the release of substance P (which modulates pain perception in the spinal cord). It also appears to inhibit the release of many excitatory transmitters from nerve terminals carrying nociceptive (painful) stimuli.

13. Actions: /1/ CNS: a. analgesia:- relief of pain without the loss of consciousness. (both by enhancing the pain threshold at the spinal cord level, and more importantly, by altering the brain’s interpretation of pain). Patients are aware of the presence of pain, but the sensation is not unpleasant. b. Euphoria: powerful sense of contentment and well-being (may be caused by stimulation of the ventral tegmentum). c. Respiratory depression: by reduction of the sensitivity of respiratory center neurons to carbon dioxide. Respiratory depression - the most common cause of death in acute opioid overdose.

14. d. Depression of cough reflex: Morphine and codeine have antitussive properties. The cough suppression does not correlate closely with analgesic and other effects (probably different receptors are involved in the antitussive action than in analgesia). e. Miosis (pupillary constriction): The pinpoint pupil - characteristic of morphine use - results from stimulation of  and  receptors. Excitation of the Edinger-Westphal nucleus of the oculomotor nerve »»» enhanced parasympathetic stimulation to the eye. Little tolerance to the effect (all addicts - except those on meperidine – demonstrate pin-point pupils) - important diagnostically (most other causes of coma and respiratory depression produce dilation of the pupil) ! f. Nausea and emesis: stimulationof the chemoreceptor trigger zone in the area postrema »»» vomiting. However, the emesis does not produce unpleasant sensations.

15. /2/ GIT: • It relieves diarrhea and dysentery. It decreases motility and increases tone of smooth muscle! • Morphine increases pressure in the biliary tract. • !!Morphine also increases the tone of the anal sphincter and ureteric spasm »»» harmful in biliary colic due to gallstones, retention of urine (catheterization in intoxication with M.) !! • Morphine produces constipation, with little tolerance developing. • /3/ Inhibition of cilia motility: • Important in bronchi (disturbances with expectoration) and in ovary tube (sterility).

16. /4/ Cardiovascular system: M. has no major effects on the blood pressure or heart rate (high doses – hypotension and bradycardia - action on the medulla). Because of respiratory depression and carbon dioxide retention, cerebral vessels dilate and increase the cerebrospinal fluid pressure »»» usually contraindicated in severe brain injury. /5/ Histamine release: Morphine releases histamine from mast cells »»» bronchoconstriction, hypotension, urticaria, itching, sweating. Asthmatics should not receive the drug. /6/ Hormonal actions:Inhibition of the release of gonadotropin-releasing h. and corticotropin-releasing h., decrease in the concentration of luteinizing h., follicle-stimulating h., ACTH, and ß-endorphin.Testosterone and cortisol levels decrease. It increases prolactin and growthh. release by diminishing dopaminergic inhibition.

17. It increases antidiuretic hormone- urinary retention. [Note: It also can inhibit the urinary bladder voiding reflex – catheterization may be required.] /7/ 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/. /8/ Immunosuppressant activity: Increased susceptibility to infections after long-term abuse.

18. Therapeutic use: • Analgesia:Only few other drugs that are as effective in treatment of • pain. Opioids induce sleep - in situations when pain is present and sleep • is necessary, they may be used to supplement the properties hypnotics. • Note: The hypnotic drugs are not usually analgesic, and may • have diminished sedative effect in the presence of pain. • b. Treatment of diarrhea: Morphine decreases the motility of smooth • muscle and increase tone (through the intramuscular nerve plexus). • c. Relief of cough: Suppression of the cough reflex (codeine • or dextromethorphan are more widely used). • d. Treatment of acute pulmonary edema:i.v. morphine relieves dyspnea • caused by pulmonary edema in left ventricular failure - possibly by its • vasodilatory effect.

19. Pharmacokinetics: a. Administration: Absorption from GIT is slow and erratic, and the drug is usually not given orally (but new slow-release tablets exist). Codeine - well absorbed after oral administration. Significant first-pass metabolism in the liver - therefore, intramuscular, subcutaneous, or i.v. injections produce the most reliable responses. Note: In cases of chronic pain associated with neoplastic disease – frequent use of the new slow-release tablets orally or pumps that allow the patient to control the pain through self-administration. Opiates - for nonmedical purposes taken by inhaling powders or smoke from burning crude opium (rapid onset of the action).

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

21. c. Fate: M. is conjugated in the liver to glucuronic acid. Morphine-6-glucuronide- potent analgesic; the conjugate at the 3-position is much less active. Conjugates - excreted primarily in the urine(small quantities in the bile). The duration of action of morphine is 4 - 6hours when administered systemically; longer action when injected epidurally (its low lipophilicity prevents redistribution from the epidural space. [Note: A patient's age can influence the response to morphine. Elderly patients are more sensitive to the analgesic effects(decreased metabolism, decreased lean body mass, renal function, etc.)They should be treated with lower doses. Neonates should not receive morphine because of their low conjugating capacity.

22. Adverse effects: • - Severe respiratory depression occurs, coma. • - Constipation. • - Vomiting, dysphoria. • - Allergy-enhanced bronchoconstriction, hypotensive effects, itching, • low blood volume. • - The elevation of intracranial pressure, particularly in head injury, • can be serious. It enhances cerebral and spinal ischemia. • - In prostatic hypertrophy, morphine may cause acute urinary retention. • - A serious action - the stoppage of respiratory exchange in emphysema • or cor pulmonale patients. Respiration must be carefully watched. • In adrenal insufficiency or myxedema – there may be extended and • increased effects. • Use with caution in patients with bronchial asthma or liver failure.

23. Tolerance and physical dependence: Repeated use produces tolerance to the respiratory depressant, analgesic, euphoric, and sedative effects of M. Tolerance usually does not develop to the miosis and constipatiion. Physical and psychological dependence readily occur. Withdrawal symptoms - series of autonomic, motor, and psychological responses that incapacitate the individual and cause serious-almost unbearable-symptoms. However, it is very rare that the effects are so profound as to cause death. Note: Detoxification of heroin- or morphine-dependent individuals - usually methadone or clonidine.

24. TOLERANCE AND DEPENDENCE Tolerance to opioids (i.e. an increase in the dose needed to produce the effect) develops rapidly. Dependence - involves two separate components - physical and psychological dependence. Physical dependence- associated with a physiological withdrawal syndrome (or abstinence syndrome). Morphine also produces strong psychological dependence, expressed as craving for the drug.

25. Tolerance Itcan be detected within 12-24 hours of M. administration. Tolerance - to most of the effects (analgesia, emesis, euphoria, respiratory depression) – none or little effects on the constipating and pupil-constricting actions. Thus, addicts may take 50x the normal analgesic dose with relatively little respiratory depression, but marked constipation and pupillary constriction. The mechanisms of tolerance – some mechanisms can be excluded (e.g., increased biotransformation, reduced affinity for receptors, down-regulation of receptors, inhibition of the release of endogenous opioids). Tolerance - a general phenomenon of opioids - irrespective of which type of receptor they act. Cross-tolerance occurs between drugs acting at the same receptor, but not between opioids that act on different receptors.

26. Physical dependence- characterised by a clear-cut abstinence syndrome. Abstinence syndrome - somewhat resembling severe influenza, yawning, mydriasis, fever, sweating, piloerection, nausea, diarrhoea, insomnia. Extreme restlessness and distress - accompanied by a strong craving for the drug.Maximum- after 2-3 days;mostly disappear in 8-10 days; some residual symptoms and physiological abnormalities persist for several weeks. Re-administration of M. rapidly abolishes the abstinence syndrome. Changes related to the abstinence syndrome: e.g.,spinal reflex hyperexcitability in morphine-dependent animals, and it can be produced by chronic intrathecal as well as systemic administration of morphine. The noradrenergic pathways emanating from the locus ceruleusmay also play an important role in causing the abstinence syndrome - a2- agonist clonidine is sometimes used. The rate of firing of locus ceruleus neurons is reduced by opioids, and increased during the abstinence syndrome. Similar changes affect dopaminergic neurons in the ventral tegmental area that project to the nucleus accumbens.

27. Interactions:The depressant actions of morphine - enhanced by phenothiazines, MAO inhibitors, tricyclic antidepressants.Low doses of amphetamine strangely enhance analgesia, as does hydroxyzine.

28. MEPERIDINE (pethidine) A synthetic opioid structurally unrelated to morphine. Used for acute pain. 1. Mechanism of action:binding particularly to m receptors. It also binds to k receptors. 2. Actions:Depression of respiration, no significant cardiovascular action when given orally. i.v. - a decrease in peripheral resistance and an increase in peripheral blood flow, and increase in cardiac rate. It dilates cerebral vessels, increases CSF pressure, and contracts smooth muscle (the latter to a lesser extent than morphine). Meperidine does not cause pinpoint pupils but causes the pupils to dilate - because of an atropine-like action.

29. 3. Therapeutic uses: Analgesia for any type of severe pain. It is not useful in the treatment of diarrhea or cough. Commonly employed in obstetrics. 4. Pharmacokinetics: Well absorbed from GIT, useful when administered orally. Mostly administered i.m. Duration of action of 2 - 4 hours. It is N-demethylated to normeperidine in the liver; excreted in the urine. Because of its shorter action and different route of metabolism, meperidine is preferred over morphine for analgesia during labor.

30. 5. Adverse effects: Large or repetitive doses - anxiety, tremors, muscle twitches, convulsions (rarely) due to the accumulation of normeperidine. Large doses - it dilates the pupil and causes hyperactive reflexes – difference from opioids. Severe hypotension can occur if administered postoperatively. Due to its antimuscarinic action - dry mouth and blurred vision. When used with major neuroleptics, depression is greatly enhanced. Administration to patients taking monoamine oxidase inhibitors can provoke severe reactions, such as convulsions and hyperthermia. Meperidine can cause dependence.

31. 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

32. METHADONEA synthetic, orally effective opioid, cca equal in potency to morphine but induces less euphoria and has a somewhat longer duration of action. 1. Mechanism of action: by the μreceptors. 2. Actions: The analgesic activity is equivalent to morphine. Well-absorbed orally, in contrast to morphine. The miotic and respiratory-depressant actions have average half-lives of 24 hours. It also increases biliary pressure and is also constipating.3. Therapeutic uses:Used in the controlled withdrawal of dependent abusers from heroin and morphine.

33. It causes a withdrawal syndrome that is milder but more protracted (days to weeks) than with other opioids 4. Pharmacokinetics: Readily absorbed after oral administration. It accumulates in tissues, where it remains bound to protein, from which it is slowly released. Biotransformed in the liver; 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 the normal euphoria) 5. Adverse effects: It can produce physical dependence like morphine.

34. FENTANYL related to meperidine, it has 100-fold analgesic potency of morphine, used in anesthesia. A rapid onset and short duration of action (15 - 30 minutes), 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 transmucosal preparation - used in the treatment of cancer patients. The transdermal patch - use with caution, because death resulting from hypoventilation has been known to occur. The transdermal patch creates a reservoir of the drug in the skin. Hence, the onset is delayed 12 hours, and the offset is prolonged.

35. Metabolized to inactive metabolites by the CYP4503A4 system, and 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. Unlike meperidine, it causes pupillary constriction. It is used in neuroleptanalgesia (with droperidol) !!

36. SUFENTANIL, ALFENTANIL, REMIFENTANIL related to fentanyl - they 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. HEROIN (diamorphine) - does not occur naturally. Produced by di- acetylation of morphine, it leads to a 3-fold increase in its potency. Its greater lipid solubility - it crosses the blood-brain barrier more rapidly than morphine (a more exaggerated euphoria when taken by injection). Pharmacologically similar to morphine. Great lipid solubility »»» rapidly crosses the HEB and gives greater "rush", 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.

37. Time to peak effect and duration of action of several opioids administered intravenously. Time to peak effect Key Duration of action 20 minutes Morphine 4 hours 15 minutes Meperidine 2 – 4 hours 5 minutes Fentanyl 15 – 30 minutes (according to Lippincott´s Pharmacology, 2006

38. MODERATE AGONISTS CODEINE(methylmorphine) a much less potent analgesic than morphine, but a higher oral effectiveness. It shows good antitussive activity at doses that do not cause analgesia. It has a lower potential for abuse than morphine, and rarely produces dependence. Lower euphoria than morphine. In most cough preparations it has been replaced by, e.g. dextromethorphan. Less polar »»» better absorption after p.o. administration. About 20% of the analgesic potency of morphine »»» mild types of pain. Frequently combined in analgesic-antipyretic preparations with salicylates or acetaminophen. . Also respiratory depression, practically of low importance. Antitusssive activity, constipation.

39. OXYCODONE - a semisynthetic derivative of morphine. Orally active; sometimes formulated with aspirin or acetaminophen. Used to treat moderate to severe pain. Metabolized to products with lower analgesic activity. Excretion is via the kidney. Abuse of the sustained-release preparation - many deaths. The higher-dosage forms of the latter preparation should be used only by patients who are tolerant to opioids.

40. PROPOXYPHENE - a derivative of methadone. The dextro isomer - an analgesic to relieve mild to moderate pain. The levo isomer is not analgesic - it has antitussive action. A weaker analgesic action than codeine. Often used in combination with aspirin or acetaminophen for an analgesia. Well absorbed orally, metabolized in the liver. It can produce nausea, anorexia, and constipation. Toxic doses - respiratory depression, convulsions, hallucinations, and confusion. A very serious problem can arise in some individuals, with resultant cardiotoxicity and pulmonary edema. Note: When used with alcohol and sedatives, a severe CNS depression is produced, and death by respiratory depression and cardiotoxicity can result. The respiratory depression and sedation can be antagonized by naloxone, but the cardiotoxicity cannot.

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

42. PENTAZOCINE - agonist on k receptors, a weak antagonist at m and d. It promotes analgesia by activating receptors in the spinal cord - used to relieve moderate pain. Administered orally or parenterally; less euphoria. Higher doses - respiratory depression and decreases the activity of the GIT. High doses increase blood pressure and can cause hallucinations, nightmares, tachycardia, and dizziness ---- its decreased use. In angina, it increases the mean aortic pressure and pulmonary arterial pressure 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 develop.

43. BUPRENORPHINE - a partial agonistat the m receptor. It acts like morphine in naive patients, but it can also precipitate withdrawal in morphine users. A major use - in opiate detoxication (it has a less severe and shorter duration of withdrawal symptoms compared to methadone). It causes little sedation, respiratory depression, and hypotension, even at high doses. In contrast to methadone (available only at specialized clinics) - buprenorphine is approved for office-based detoxification or maintenance. Administered sublingually or parenterally; a long duration of action (tight binding to the receptor). Metabolized by the liver; excreted in the bile and urine. Adverse effects: respiratory depression (cannot be reversed by naloxone), decrease in blood pressure, nausea, dizziness.

44. NALBUPHINE, 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 blood pressure, in contrast to pentazocine and butorphanol. A benefit of all three medications - they exhibit a ceiling effect for respiratory depression.

45. MEPTAZINOL and DEZOCINE - recently introduced; unusual chemical structure. Meptazinol can be given orally or by injection; it has a short plasma half-life. It seems to be relatively free of morphine-like side-effects, causing neither euphoria nor dysphoria, nor severe respiratory depression. But, it produces nausea, sedation and dizziness, and has atropine-like side-effects.Because of its short duration of action and lack of respiratory depression - advantages for obstetric analgesia.Dezocine - a partial agonist at μ-receptors - analgesic activity similar to morphine; but with respiratory depressant activity thatreaches a 'ceiling' at high doses.

46. OTHER ANALGESICS TRAMADOL - a centrally acting analgesic that binds to the m-receptor. In addition, it weakly inhibits re-uptake of norepinephrine and serotonin. Used in moderate to moderately severe pain. Its respiratory-depressant activity is less than that of morphine. Naloxone can only partially reverse the analgesia produced by tramadol. The drug undergoes extensive metabolism, and one metabolite is active. Concurrent use with carbamazepine results in increased imetabolism, presumably by induction of the cytochrome P450 system 2D6. Quinidine (inhibits this isoenzyme), increases levels of tramadol.Anaphylactoid reactions were reported. Important: the seizures - especially in patients taking selective serotonin re-uptake inhibitors or tricyclic antidepressants. Tramadol should also be avoided in patients taking MAO inhibitors.

47. ANTAGONISTS They bind with high affinity to opioid receptors, but fail to activate the receptor-mediated response. Administration of opioid antagonists produces 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.

48. NALOXONE - used to reverse the coma and respiratory depression of opioid overdose. It rapidly displaces receptor- bound opioids - it is able to reverse the effects. Within 30 seconds of i.v. administration, the respiratory depression and coma are reversed. A half-life of 60 to 100 minutes. Because of its relatively short duration of action, a depressed patient who has been treated and 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(explanation of the fact that it reverses respiratory depression with only minimal reversal of the analgesia that results from agonist stimulation of k receptors in the spinal cord). Naloxone produces no pharmacologic effects in normal individuals, but it precipitates withdrawal symptoms in opioid abusers.

49. NALTREXONE • Actions similar to those of naloxone. • Longer duration of action - a single oral dose blocks the effect of injected heroin for up to 48 hours. • Naltrexone in combination with clonidine - and, sometimes, with bruprenorphine - is employed for rapid opioid detoxification. • It may also be beneficial in treating chronic alcoholism by an unknown mechanism, but benzodiazopines and clonidine are preferred. • Adverse effect: hepatotoxicity. • ( NALORPHINE - partial agonist of morphine, used previously as an antidote in acute morphine and heroine overdosage; it can not antagonize effects of pentazocine and other partial agonists, none or few clinical use)

50. Clinical uses of analgesic drugs • Used to treat and prevent pain, e.g. • ― pre- and postoperatively • ― common painful conditions including headache, dysmenorrhoea, labour, trauma, burns • ― many medical and surgical emergencies (e.g. myocardial • infarction, renal colic) • ― terminal disease (especially metatastic cancer). • Opioid analgesics - used also in some non-painful conditions, e.g. acute heart failure (because of their haemodynamic effects) and terminal chronic heart failure (to relieve distress).