Opioid analgesics

opioid analgesics

1. Analgesics Drugs that relief pain without loss of conciousness . Opioid or Narcotic analgesics Non- opioid or NSAIDS

2. Basic Pharmacology of Opoid Analgesic

3. Source Opium ( Morphine Source ) is obtained from Poppy, Papaver somniferum and P album. Poppy seed pod exudes white substance that turns into brown gum i.e crude opium Morphine is present in high concentration (10%). Codeine is commercially synthesized from Morphine

4. Classification Action Full agonists Partial Agonists Antagonists Receptors Mu- opoid receptor Delta- opoid receptor Kappa- opoid receptor Morphine Full mu-receptor agonist Codeine Partial mu-receptor agonist Nalbuphine Mixed Agonist-Antagonist and Partial Agonist

5. Chemistry Substitution of allyl group on the nitrogen of morphine and addition of single hydroxyl group Form naloxone(strong mu-receptor antagonist) Certain opoid analgesics modified in liver form compounds with greater analgesic action Most of the synthetic opoids are simpler molecules

6. Endogenous Opoid Peptides Opoid receptors are having drifferent affinities for endogenous peptides Opoid receptors Endogenous peptides Mu-receptor Endorphins> Enkephalins > Dynorphins Delta-receptor Enkephalins >Endorphins and dynorphins Kappa-receptor Dynorphins >>Endorphins and enkephalins Families of Endogenous opoids Endorphins Enkephalins Dynorphins

7. Endogenous peptides are derived from three precursor proteins: Prepro-opiomelanocortin (POMC) Preproenkephalin ( Proenkephalin A) Preprodynorphin ( Proenkeohalin B) POMC contains Preproenkephalin contains Preprodynorphin contains Met- enkephalin sequence Six copies of met enkephalin active opoid peptides containg leu-enkephalin sequence Beta-endorphin one copy of leu-enkephalin Active peptides are dynorphin A, dynirohin B and alpha and beta- nonendorphins nonopoind peptides including adenocorticotropic hormone, Beta- lipotropin , melanocyte stimulating hormone met and leu have slightly high affinity for delta then mu receptor

8. Dynorphin A found in dorsal horn of spinal cord play role in sensitization of nociceptive neurotransmission. Increased dynorphin causing increase pain and long lasting hyperalgesia due to tissue injury and inflammation Endogenous opoid precursor molecule and endopmorphins are present at CNS sites that have been implicated with pain modulation Pronociceptive action of dynorphin independent of opoid receptor…..but dependent on bradykinin receptor activation Endogenous peptides, endomorphin-1 and endomorphin-2 selectively activate central and peripheral mu- opoid receptors

9. Pharmacokinetics

10. Absorption Opioid agonist are well absorbed when given by subcutaneous,intramuscular and oral route. Oral route needs high dose as compared to parenteral route Certain analgesics such as codeine and oxycodone are effective orally because they have reduced first-pass metabolism. Other routes includes oral mucosa via lozenges and transdermal via transdermal patches. Recently an iontophoretics transdermal system has been introduced.

11. Distribution All opioids bind to plasma proteins with varying affinity. T he drugs rapidly leave the blood compartment and localize in highest concentrations in tissues. Drug concentrations in skeletal muscle may be much lower, but this tissue serves as the main reservoir because of its greater bulk.

12. Metabolism The opioids are converted in large part to polar metabolites (mostly glucuronides ). Morphine is metabolized to M3G and M6G. M3G, a compound with neuroexcitatory property and M36, a compound with analgesic property. Esters are rapidly hydrolyzed by tissue esterases e.g remifentanil . Heroin (diacetylmorphine) is hydrolyzed to monoacetylmorphine and finally to morphine, which is then conjugated with glucuronic acid.

13. Cont … Hepatic oxidative metabolism is the primary route of degradation of the phenylpiperidine opioids . The P450 isozyme CYP3A4 metabolizes fentanyl by N- dealkylation in the liver. Codeine, oxycodone , and hydrocodone undergo metabolism in the liver by P450 isozyme CYP2D6. Metabolic disposition of naloxone is chiefly by glucronides conjugation like that of the agonist .

14. Excretion Polar metabolites, including glucuronide conjugates of opioid analgesics, are excreted mainly in the urine. Small amounts of unchanged drug may also be found in the urine. Glucuronide conjugates are also found in the bile. Enterohepatic circulation represents only a small portion of the excretory process.

15. Pharmacodynamics

16. Mechanism of Action Opioid agonists produce analgesia by binding to specific G protein-coupled receptors Receptors located primarily in brain and spinal cord regions (transmission and modulation of pain). Receptor Types Multiple receptor subtypes have been proposed based on pharmacologic criteria, including µ1,µ2 δ 1, δ 2 κ 1, κ 2, κ 3

17. Pharmacodynamics O pioid receptors form a family of proteins that physically couple to G-proteins This interaction affect ion channel gating They close voltage-gated Ca2+ channels on presynaptic nerve terminals and thereby reduce transmitter release They hyperpolarize and thus inhibit postsynaptic neurons by opening K+ channels.

18. gg Mu, delta, and kappa agonists reduce transmitter release from presynaptic terminals. Mu-agonists also hyperpolarize second-order pain transmission neurons by increasing K+ conductance, evoking an inhibitory postsynaptic potential.

19. Tolerance and Physical Dependence Tolerance With frequently repeated administration of therapeutic doses of morphine there is a gradual loss in effectiveness Physical dependence O ccurrence of a characteristic withdrawal when the drug is stopped or an antagonist is administered.

20. Organ System Effects

21. Central Nervous System Effects Analgesia: Opioids reduce both sensory and affective aspects of pain. Specially affective aspects. Euphoria: IV morphine – euphoria…reduce anxiety and distress

22. Sedation: Drowsiness Clouding of mentation Induce more sleep in elders than youngs Morphine + sedative-hypnotics = Deep sleep Phenanthrene derivatives > synthetic agents Morphine disrupts REM and Non-REM sleep patterns

23. Repiratory Depression: Direct action on brain stem respiratory centre Increases alveolar CO 2 Respiratory rate = 3-4 beats/min Cough supression : Cough treatment Ventilation via endotracheal tube – codiene Secretion Airway obstruction

24. Miosis : Induce pupillary constriction in awake state Block pupillary reflex dilation during anasthesia Nausea and Vomiting: Opioids activates CTZ in area prostema of medulla Temperature: Endogenous opioids – maintain body temperature Morphine – hyperthermia K- agonists - hypothermia

25. Peripheral Effects CVS: No direct effect on heart (cardiac rhythm) Morphine – release of histamines – peripheral vasodilation - preload, ionotropy & chronotropy – cardioprotective GIT: Stomach- motility tone HCL secretion Intestine- resting tone with spasm – constipation

26. Biliary tract: Contracts biliary smooth muscles – biliary colic Renal: Depress renal function – renal plasma flow – ADH release – Na+ reabsorbtion – urinary retention Uterus: uterine tone –prolong labour Neuroendocrine : + release of ADH, prolactin and somatotropins - release of LH

27. Skin: Histamine release – dilation of cutaneous blood vessels – flushing, warming of skin Miscellaneous: Opioids modulate immune system Lymphocyte proliferation Antibody production Chemotaxis Leucocyte migration- opioid peptides – inflammatory pain.

28. CLINICAL PHARMACOLOGY

29. ANALGESIA: Relieve constant pain. In cancer, terminal illness, labor, renal and biliary colic pain. Sustained release dosage forms MSContin and OXYContin . In GIT disturbances we use fentanyl transdermal or transmucosal patches. Amphetamine. Morphine and mepridine in labor. Strong opiod agonist for renal and biliary pain. Nalaxone – antagonist

30. ACUTE PULMONARY EDEMA: Morpine and furosemide are used. Furosemide when only pulmonary edema. Morphine (IV) when pulmonary edema with myocardial ischemia as decreases anxiety, cardiac preload and afterload . COUGH: Low dose like 15mg codeine. Diminished use.

31. DIARRHEA: Paregoric, diphenoxylate and loperamide . Not used when infection is there.. SHIVERING: Mepridine - more pronounced effect. Alpha-2 adrenoreceptor .

32. ANESTHESIA: Along with analgesic opiods have sedative and anxiolytic property. Direct action on superficial nerves of dorsal horn of spinal cord through epidural and subarachanoid route. Epidural route is preferred – morphine. Nalaxone – Antagonist. CVS surgery. Thoracic and upper abdominal surgery local anesthetic + fentanyl thoracic epidural catheter Continuous infusion.

33. ADVERSE EFFECTS OF OPIOD ANALESICS: Respiratory depression Nausea Vomiting Constipation Itching around nose Postural hypotention Hypovolemia Restlessness Tremulousness Hyperactivity Increased intracranial pressure Urinary retention Urticaria (spinal and parenteral administration)

34. TREATMENT: Antagonist – nalaxone (IV). Reverse coma due to opiods only.

35. CONTRAINDICATIONS: USE OF PURE AGONIST WITH WEAK PARTIAL AGONIST Morphine + pentazocine . Diminished analgesia and withdrawl effects. USE IN PATIENTS WITH HEAD INJURY: Respiratory depression – CO2 retention – cerebral vasodilation – brain function alters. USE DURING PREGNANCY: Physical dependence and withdrawl effects with 6mg heroin daily. Irritability, shrill crying, diarrhea, seizure with 12mg heroin. Treated with diazepam, methadone & camphorated tincture of opium.

36. USE IN PATIENTS WITH IMPAIRED PULMONARY FUNCTION: Respiratory failure. USE IN PATIENTS WITH IMPAIRED HEPATIC FUNCTION: Effects drug metabolism. USE IN PATIENTS WITH IMPAIRED RENAL FUNCTION: Increased half life and accumulation of active glucoronide metabolites. USE IN PATIENTS WITH ENDOCRINE DISEASES: Prolonged and exaggerated response to opiods .

37. DRUG INTERACTIONS: SEDATIVE – HYPNOTICS: Increased CNS depression Increased respiratory depression ANTIPSYCHOTICS TRANQUILIZERS: Increased sedation Respiratory depression Anti-muscarinic CVS effects Alpha blocking CVS effects MAO INHIBITORS: Hyperpyrexic coma Hypertension

38. SPECIFIC AGENTS

39. Phenanthrenes This class includes drugs as Morphine, hydromorphone and oxymorphone . Strong mu-R agonist although shows binding affinity to other opioid receptors.

40. Heroin: It is also called diamorphine , diacetylmorphine. It is potent and fast acting. More effective than morphine in relieving pain by IM route.

41. Phenylheptylamines This class includes agents such as Methadone. Potent mu-R agonist. Exists as racemic mixture i.e. in form of D and L isomers of methadone. Can block NMDA and Monoaminergic reuptake transporter thus helpful in treatment of neuropathic pain.

42. Methadone- Clinical uses Used in treatment of opioid abuse. Treatment of mild to severe pain. For detoxification of heroin dependent addict it is given 5-10 mg orally two to three times a day for 2-3 days. Its use as analgesic has increased due to less effect on CNS functions compared to Morphine.

43. Phenylpiperidines This class include Fentanyl and its subgroup includes agents like sufentanil , alfentanil , remifentanil . Sufentanil is 5 to 7 times more potent than fentanyl . Alfentanil is less potent than fentanyl but rapidly acting and with shorter duration of action. Remifentanil is rapidly metabolized by blood and tissue esterases thus exhibiting shorter half life.

44. Meperidine : Shows anti- Muscarinic effects which can be a contraindication in case of tachycardia. Negative inotropic action on heart. Can produce seizures Due to increased side effect profile its rarely used as an analgesic.

45. Phenantherenes CODIENE, DIHYDROCODEINE, HYDROCODONE: Are less efficious than morphine. OXYCODONE: Semisynthetic derivative of codeine that acts as a narcotic analgesic’ more potent. COMBINATION: Hydrocodone / oxycodone with acetaminophen=> for treatment of mild to moderate pain, used orally

46. Phenylheptylamines PROPOXYPHENE: Chemically related to methadone Low analgesic properties Low efficiancy

47. Phenylpiperidines Diphenoxylate loperamide Used as Anti-diarrheal agents. Diphenoxylate is used in combination with atropine. DOSE: two tablets to start and then one tablet after each diarrheal stole.

48. Phenantherenes NALBUPHINE: K-receptor agonist u-receptor antagonist Given parenterally Causes such respiratory depression which cannot Be reversed by naloxone . BUPRENORPHINE: Partial u agonist K- antgonist Slow dissociation from u- receptors long duration of action Used for detoxification Maintaince of heroin abuse

49. Morphinans BUTORPHANOL: K-receptor agonist Partial u-receptor agonist/antagonist. Produces analgesia equivalent to nalbuphine and buprinorphine . PENTAZOCIN: K-receptor agonist u- antagonist/ partial antagonist. Orally or parenterally . No sub cutaneous injection becaucse of irritant properties. Benzomorphans

50. Antagonists They are receptor antagonist that acts on opioid receptors (µ,,k). These agents in the treatment of opioid overdose

51. Clinical Uses NALOXONE Initial dose: 0.1 to 0.4mg IV for life threatning CNS and respiratory depression NALTREXONE Used in maintainence programs Blocks heroin effects upto 48hours FDA approved for alcohol abuse Used to prevent relapse of alcohol drinking Effective for weight lose

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