Opioid Analgesics & Antagonists

1. Opioid Analgesics& Antagonists Dr. Hayder B Sahib Ph.D. Pharmacology

2. The opioids include natural opiates and semisynthetic alkaloids derived from the opium poppy • pharmacologically similar synthetic substitutes, and endogenous peptides. • On the basis of their interaction with opioid receptors, the drugs are classified as agonists, mixed agonist-antagonists, and antagonists.

3. Opioid peptides released from nerve endings modulate transmission in • 1- the brain • 2- spinal cord • 3- primary afferents • via their interaction with specific receptors. • Many of the pharmacologic actions of opiates and synthetic opioid drugs are effected via their interactions with endogenous opioid peptide receptors.

4. CLASSIFICATION A. Spectrum of Clinical Uses • Opioid drugs can be subdivided on the basis of their major therapeutic uses (eg, analgesics, antitussives, and antidiarrheal drugs). • B. Strength of Analgesia • On the basis of their relative abilities to relieve pain, the analgesic opioids may be classified as • 1- strong, moderate, and weak agonists. Partial agonists are opioids that exert less analgesia than morphine, the prototype of a strong analgesic, or full agonist.

5. C. Ratio of Agonist to Antagonist Effects • Opioid drugs may be classified as agonists (receptor activators [full or partial]), antagonists (receptor blockers) or mixed agonist-antagonists, which are capable of activating one opioid receptor subtype and blocking another subtype.

6. PHARMACOKINETICS • A. Absorption and Distribution • Most drugs in this class are well absorbed when taken orally, but morphine, hydromorphone, and oxymorphone undergo extensive first-pass metabolism. • In most cases, opioids can be given parenterally, and sustained-release forms of some drugs are now available, including morphine and oxycodone. Opioid drugs are widely distributed to body tissues. • They cross the placental barrier and exert effects on the fetus that can result in both respiratory depression and, with continuous exposure, physical dependence in neonates.

7. Metabolism • With few exceptions, the opioids are metabolized by hepatic enzymes, usually to inactive glucuronide conjugates, before their elimination by the kidney. • However, morphine-6-glucuronide has analgesic activity equivalent to that of morphine, and morphine-3-glucuronide (the primary metabolite) is neuro-excitatory. • Codeine, oxycodone, and hydrocodone are metabolized by cytochrome CYP2D6, an isozyme exhibiting genotypic variability.

8. In the case of codeine, this may be responsible for variability in analgesic response because the drug is demethylated by CYP2D6 to form the active metabolite, morphine. • The ingestion of alcohol causes major increases in the peak serum levels of several opioids including hydromorphone and oxymorphone. • Meperidine is metabolized to normeperidine, which may cause seizures at high plasma levels.

9. Depending on the specific drug, the duration of their analgesic effects ranges from 1–2 h (eg, fentanyl) to 6–8 h (eg, buprenorphine). • However, long-acting formulations of some drugs may provide analgesia for 24 h or more. • The elimination half-life of opioids increases in patients with liver disease. Remifentanil, a congener of fentanyl, is metabolized by plasma and tissue esterases and has a very short half-life.

10. MECHANISMS OF ACTION • Receptors • Many of the effects of opioid analgesics have been interpretedin terms of their interactions with specific receptors for endogenous peptides in the CNS and peripheral tissues. • Certain opioid receptors are located on primary afferents and spinal cord pain transmission neurons (ascending pathways) and on neurons in the midbrain and medulla (descending pathways) that function in pain modulation • Other opioid receptors that may be involved in altering reactivity to pain are located on neurons in the basal ganglia, the hypothalamus, the limbic structures, and the cerebral cortex.

11. Three major opioid receptor subtypes have been extensively characterized pharmacologically: • μ, δ, and κ receptors. • All 3 receptor subtypes appear to be involved in antinociceptive and analgesic mechanisms at both spinal and supraspinal levels. • The μ-receptor activation plays a major role in the respiratory depressant actions of opioids and together with κ-receptor activation slows gastrointestinal transit κ-receptor activation also appears to be involved in sedative actions; δ-receptor activation may play a role in the development of tolerance.

12. B. Opioid Peptides • Opioid receptors are thought to be activated by endogenous peptides under physiologic conditions. These peptides, which include endorphins such as β-endorphin, enkephalins, and dynorphins, are synthesized in the soma and are transported to the nerve endings where they accumulate in synaptic vesicles. • On release from nerve endings, they bind to opioid receptors and can be displaced from binding by opioid antagonists.

13. Endorphins have highest affinity for μ receptors, enkephalins for δ receptors, and dynorphins for κ receptors. • Although it remains unclear whether these peptides function as classic neurotransmitters, they appear to modulate transmission at many sites in the brain and spinal cord and in primary afferents. • Opioid peptides are also found in the adrenal medulla and neural plexus of the gut.

14. C. Ionic Mechanisms • Opioid analgesics inhibit synaptic activity partly through direct activation of opioid receptors and partly through release of the endogenous opioid peptides, which are themselves inhibitory to neurons. • All 3 major opioid receptors are coupled to their effectors by G proteins and activate phospholipase C or inhibit adenylyl cyclase. At the postsynaptic level, activation of these receptors can open potassium ion channels to cause membrane hyperpolarization (inhibitory postsynaptic potentials). • At the presynaptic level, opioid receptor activation can close voltage-gated calcium ion channels to inhibit neurotransmitter release Presynaptic actions result in the inhibition of release of multiple neurotransmitters, including acetylcholine (ACh), norepinephrine, serotonin, glutamate, and substance P.

16. Strong agonist e.g. morphine , meperidine , fentanyl • Moderate agonist e.g. codeine , oxycodone • Weak agonist e.g. propoxyphene • Partial agonist: are opioids that exert less analgesia than morphine(activate opioid receptor to submaximal response) e.g. buprenorphine

21. b-Sedation and euphoria:- -These effects may occur at doses below those required for maximal analgesia. -The sedation is additive with other CNS depressants, but there is little amnesia. -Some patients show dysphoric effects from opioid drugs.

22. c-Respiratory depression:- -Morphine causes respiratory depression by reduction the sensitivity of respiratory center neurons to CO2 At higher doses, there will be respiratory arrest. -Respiratory depression is the most common cause of death in acute opioids overdose.

23. d-Depression of cough reflex:- -Both morphine and codeine have antitussive properties. -Cough suppression does not correlate closely with analgesic and respiratory depressant properties of opioid drugs. -The receptors involved in the antitussive action appear to be different from those involved in analgesia.

24. e-Miosis:- -The pinpoint pupil (characteristic of morphine use) result from stimulation of μ and κ receptors. -Morphine excites the Edinger-Westphal nucleus of theoculomotor nerve, which causes enhanced parasympathetic stimuli to the eye. -There is little tolerance to this effect, and all morphine abusers demonstrate pinpoint pupil. -

25. f-Emesis:- Morphine directly stimulate the chemoreceptor trigger zone that causes emesis. g-GIT:- -Morphine relieves diarrhea by decreasing the motility and increasing the tone of intestinal smooth muscle. -It can also increase biliary tract pressure due to contraction of gallbladder and constriction of the biliary sphincter.

26. h-Cardiovascular:- -In large doses, morphine may cause hypotension and bradycardia i-Histamine release:- Morphine is contraindicated in patient with asthma. why ?? Morphine may cause urticaria, sweating and vasodilation. why?

27. j-Hormonal actions:- -Inhibit release of gonadotropin-releasing hormone -Inhibit release of corticotrophin-releasing hormone -Decrease the concentration of:- ●luteinizing hormone●FSH●ACTH●and -endorphin ß -Testesterone and cortisol level decrease -Increase prolactin and GH release by diminishing dopaminergic inhibition

28. k-Chronic effects: A-Tolerance: -Marked tolerance can developed to acute pharmacological effects, with exception of miosis and constipation. -Antagonists of glutamate NMDA receptors (e.g. ketamine) and δ receptors antagonists are reported to block opioid tolerance. B-Dependence: -Is a physiological response to chronic therapy with opioid especially strong agonists. -Abstinence syndrome:abrupt discontinuance of opioid may cause rhinorrhae, lacrimation, chills, muscle ache, diarrhea, anxiety and hostility

29. Degrees of Tolerance That May Develop to Some of the Effects of the Opioids. • HighModerate Minimal orNone Analgesia BradycardiaMiosis Euphoria, dysphoria Constipation Mental clouding Convulsions Sedation Respiratory depression Antidiuresis Nausea and vomiting Cough suppression

30. Pharmacokinetics of morphine:-  -Oral morphine is subjected to extensive 1st pass metabolism (only 20% of the dose reach systemic circulation) -Given s.c or i.m morphine is rapidly absorbed but in circulatory shock it is better to be given i.v. -Morphine is metabolized by liver and kidney: the conjugated metabolites include the pharmacologically active morphine-6-glucuronide and morphine-3-glucuronide. -The t½ is 3 h (active metabolites slightly longer) and the duration of useful analgesia is 6 h. -Morphine cross the placenta and suppresses respiration of the fetus at birth.

31. ●Therapeutic uses of morphine:- 1-Analgesia: -Treatment of constant moderate to severe pain. 2-Acute pulmonary edema: -I.V morphine dramatically relieves dyspnea caused by pulmonary edema associated with LVF –possibly by vasodilator effects. 3-Anasthesia: -Opioids are used as preoperative medication and as intraoperative agents. -High –dose I.V morphine and fentanyl are the major components of anesthesia of cardiac surgery.

32. ●Adverse effects of morphine: -Respiratory depression. -Vomiting, dysphoreaand allergy-enhanced hypotensive effect -Elevation of CSF -Acute urinary retention (in prostatic hypertrophy) -Morphine should be used with caution in asthma and liver failure

33. ■Fentanyl: -Administered parenterally -It has shorter duration of action(1-2 h) than morphine -Available as transdermal patch which provide analgesia for 72 hrs

34. ■ Meperidine (pethidine): -It has shorter duration of action (2-3 h) than morphine -1- Produced lessneonatal respiratory depression than morphine (so, it preferred in obstetrics) -2- Has no effects on cough reflex. -3- It is less likely to cause constipation. 4- Has little hypnotic effect. -5- Less likely to cause urinary retention. -6- May cause mydriasis and tachycardia due to weak anticholenergic activity.

35. ■Methadone: -Act mainly at μ receptors -Well absorbed from GIT (morphine is partially absorbed) -It has longer duration of action than morphine (24 h) and this allow using methadone in:- 1-Chronic pain (palliative care) 2-treatment of opioid withdrawal (it allow smoother withdrawal with tapered dose reduction) -Methadone dependency occur, but it is less severe than in morphine -Sedation is less than that of morphine.

36. ■Diamorphine (Heroin): -The most potent of all dependence-producing opioids. -More lipid-soluble than morphine. -Rapid onset of action (than morphine) -Produce greater euphoria than morphine. • -Not approved for clinical use.

37. И-MODERATE AGONISTS: ■Codeine: IS a much less potent analgesic than morphine, but it has higher oral effectiveness -It has good antitussiveactivity at doses that do not cause analgesia. -It has lower potential for abuse and less euphoria than morphine. -Is often used with aspirin and acetaminophine. -In cough preparation, codeine has been replaced by dextromethorphan – a synthetic cough suppressant that has no analgesic action and a low potential for abuse.

38. ■Oxycodone: -Is a semi-synthetic derivative of morphine -Used to treat moderate to severe pain -Usually used with aspirin -Orally effective and undergo less 1st –pass metabolism than morphine. -Less respiratory depression, and dependence liability than morphine.

39. Ш-WEAK AGONISTS: ■Propoxyphene -Is a derivative of methadone. -There is 2 isomer: *Dextro isomer is used is used as analgesic. *Levo isomer is used as antitussive. -It is weaker analgesic than codeine. -Used in combination with aspirin and acetaminophine. -It can produce nausea, anorexia, and constipation. -In toxic doses, respiratory depression, convulsion, and in some individuals, cardiotoxicity and pulmonary edema.

40. ІV-MIXED AGONIST-ANTAGONISTS -The effects of these drugs depend on previous exposure to opioids. -In individuals who have not recently received opioids, it show agonist activity and are used to relieve pain. -In patients with opioids dependency, it shows primarily blocking effects-that is, produce withdrawal symptoms.

41. ІV-MIXED AGONIST-ANTAGONISTS ■Pentazocine: -Act as agonist onκ-Receptors and is a weak antagonist at μ- and δ Receptors. -Produce analgesia by activating receptors in spinal cord. -Used for moderate pain. -High doses increase BP and can cause hallucination, nightmare, tachycardia, and dizziness. -In angina, it increases the mean aortic pressure and pulmonary arterial pressure and thus, increases the work of heart and should not used for pain of MI.

42. -It also decreases the renal plasma flow. -It does not antagonize the respiratory depression of morphine, but it can precipitate withdrawal symptoms in morphine abusers. -Severe respiratory depression, although uncommon is resistance to naloxone reversal.

43. ■Buprenorphine: -Is classified as partial agonist at μ-receptors . -It precipitate withdrawal in morphine abusers. -A major use is in opiate detoxification, because it has less severe and shorter duration of withdrawal symptoms compared to methadone. -It causes little sedation, respiratory depression, and hypotension even at high doses. -Severe respiratory depression, although uncommon, is resistance to naloxone reversal.

44. V-OTHER ANALGESICS(CENTRALLY ACTING) ■Tramadol: -A centrallyacting analgesic that binds to the μ-opioidreceptors. -Also it weakly inhibits re-uptake of norepinephrine and serotonin. -It may have special use for neuropathic pain. -Associated with increased risk of seizures and is contraindicated in patients with epilepsy. -Its action is only partially reversed by naloxone. -Should not administered to patients taking MAOIs.

45. VI-OPIOID ANTAGONISTS -Binds with high affinity to opioid receptors, but fail to activate the receptor-mediated response. -It produce no profound effects in normal individuals. -In patients dependent on opioid, it rapidly reverse the effects of agonist, and precipitate the symptoms of opioid withdrawal.

46. ■Naloxone: --Used to reverse the coma and respiratory depression of opioid over dose and also for diagnoses of opioid dependency. -Has half life of 30-100 min. -Naloxone is competitive antagonist atμ-, κ- and δ Receptors. With 10 fold higher affinity for μ- receptor than for κ- and δ Receptors. -This may explain why naloxone readily reverse respiratory depression with only minimal reversal of analgesia that result from agonist stimulation of κ- receptors in the spinal cord.

47. ■Naltrexone: -It has longer duration of action than naloxone (48 h). -Indication is similar to that of naloxone in addition , it may be used to decrease craving for alcohol.