Central analgesics and Non-steroidal ant-iinflammatory agents

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Analgesics and NSAIDS, Definition-classification, SAR,Synthesis,Uses,Adverse effects.

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Central analgesics and Non-steroidal ant-iinflammatory agents

  1. 1. PRESENTED BY SURYADEVARA SIREESHA B.PHARM . VIGNAN PHARMACY COLLEGE. Approved by PCI,AICTE, New Delhi. Affiliated to JNTU,Kakinada. Vadlamudi -522213, Guntur, A.P.
  2. 2. CONTENTS:  Introduction of Pain.  Pain management.  Treatment.  Opium.  Chemistry of morphine.  SAR.  Synthesis.  Uses.  Adverse effects.  NSAIDs.  New approach.  Conclusion.  References. 2
  3. 3. CENTRAL ANALGESICS Agents that decreases acute and some type of chronic pain are referred as analgesics or analgetics. PAIN: Pain is defined as an unpleasant, sensory and emotional experience associated with actual or potential tissue damage. Pain is apart of our body’s defense system, it produces a reflexive, retraction from the painful stimulus and to protect the affected body part while it heals. 3
  4. 4. ACUTE CHRONIC It is normally predicted physiological response. E.g.: sprains & broken bones etc…, It is unrelenting, not-self limiting and persist from months to years. E.g.: osteoporosis, cancer etc.., 4
  5. 5. MECHANISM OF PAIN 5
  6. 6. PAIN MANAGEMENT MILD If pain persist SEVERE Step:3 potent opioid +/-non opioid or analgesic adjuvant. MODERATE If pain persist Step:2 less potent opioid + non opioid +/- analgesic adjuvant. Step:1 non opioid +/- analgesic adjuvant. 6
  7. 7. TREATMENT:  The pharmacological management of pain is the foundation of pain therapy.  Analgesics can be classified as : 1. Opioids. 2. Non-opioids. 3. Adjuvant or co-analgesics.  Opioids are used for effective treatment of pain.  Non-opioids are effective analgesics for mild to moderate pain.  Adjuvant to some extent they give relief from pain , but are not majorly used as analgesics. 7
  8. 8. OPIUM Opium is the latex obtained from incisions of unripe capsules of “papaver somniferum,” belongs to family papaveraceae. • Opium was well known to the ancients about 77 AD . • It contains 30 alkaloids, the first group is morphine. • Morphine consists of alkaloids which have a phenanthrene nucleus, Whereas papaverine group have a benzylisoquinoline structure. 8
  9. 9. Phenanthrene series Morphine Codeine Thebaine 9 to 14 0.5 to 2 0.2 to 1 Benzyl isoquinoline series Papaverine Noscapine Narcine 0.8 to 1 3 to 10 0.2 to 0.4 CLASS NAME OF DRUG % OF OPIUM PRESENT 9
  10. 10. CHEMISTRY OF MORPHINE:  The morphine contains 5 rings.  It is ‘T’ shaped molecule. IUPAC NAME: (5α, 6α) 7,8-didehydro 4,5-epoxy 17-methyl morphinan 3,6-diol. 10
  11. 11. MORPHINE 11 (S) (R) (R) (S) O N-CH3 HO HO H 1 2 3 4 5 6 7 14 9 10 11 16 17 12 13 8 A D C E B
  12. 12. STEREOCHEMISTRY:  Natural morphine molecule exists as a single isomer.  Naturally occurring levorotatory (-) morphine has 5R, 6S, 9R, 13S, 14R configuration.  It undergoes epimerization at 14-position, but not beneficial to analgesic activity.  Carbons at 5,6,9,13,14 positions are chiral centers. 12
  13. 13. CHEMICAL FEATURES OF OPIUM: POSITION MODIFICATION EFFECTS Phenolic -OH -OH to -OCH3 -OH to -OC2H5 Less analgesic, Cough suppression. Alcoholic -OH -OH to -OCH3 -OH to -OC2H5 5 × morphine. 2.4 × morphine. Allylic unsaturated linkage -CH=CH- to –CH2CH2- 1.2 × morphine. Tertiary nitrogen N-CH3 to NH N-CH3 to NCH2CH3Ph < active than morphine 14 × morphine. 13
  14. 14.  Morphine analogues were developed to combat the problems due to usage of morphine. 1.VARIATION OF SUBSTITUENTS:  Alkylation of phenolic –OH and N-demethylation lead to the loss of analgesic activity. MORPHINE ANALOGUES AS CENTRAL ANALGESICS: 14
  15. 15. 2.DRUG DESECTION:  Introduction of OH group at C-14 increases activity. O O N-CH3 HO OH OXYMORPHINE 15 14
  16. 16.  Introduction of allyl cyclo propyl methylene group have antagonist effect on NITROGEN atom.  E.g: Naltrexone, Naloxone. O O HO N NALTREXONE 16 allyl cyclo propyl methylene
  17. 17.  Phenyl ethyl group increases activity by 14 folds. O HO HO N 17 Phenyl ethyl
  18. 18. 3.SIMPLIFICATION : A. Removing of ring E :-  Complete loss of activity. O HO HO NO ACTIVITY. 18
  19. 19. B.Removing of ring D:- Removal of epoxy Bridge produces morphinan with analgesic activity indicating oxygen is not essential for activity. HO NH LEVORPHANOL LEVALLORPHAN N 19 HO
  20. 20. C.Removing of ring C and D :- Produces group of benzomorphous, which retain analgesic activity. N CH3 CH3 PHENAZOCIN H N CH3 CH3 METAZOCINE OH CH3 20
  21. 21. D.Removing of ring B,C and D :-  It produces series of compounds known as 4- phenyl piperidines.  The activity increases by 6 times by introducing the phenolic group. N N C2H5OOC FENTANYL 21
  22. 22. CLASSIFICATION OF ANALGESICS & SAR: Central analgesics are majorily classified into four types:- 1.Morphine &its analogues . 2.Phenyl piperidines. 3.Diphenyl heptanones . 4.Benzazocin derivatives. SAR OF MORPHINE & ITS ANALOGUES: O N R1 R2 R3 22
  23. 23. DRUG R1 R2 R3 OTHER CHANGES Morphine -OH -OH -CH3 _ Heroin -OCOCH3 -OCOCH3 -CH3 _ Oxymorphine -OH =O -CH3 1,2 Levorphanol -OH -H -CH3 1,3 Codeine -OCH3 -OH -CH3 _ Oxycodone -OCH3 =O -CH3 1,2 1.Single bond instead of double bond between C-7 & C-8. 2. OH added to C-14. 3.No oxygen between C-5 & C-4. 23
  24. 24. SAR OF PHENYL PIPERIDERINES: N R3 R2 R1 NAME R1 R2 R3 ANALGESIC ACTIVITY Meperidine -CH3 -C6H5 -COOC2H5 1.0 Properidone -CH3 -C6H5 -COOCH(CH3)2 15.0 Ketobemidone -CH3 -C6H4OH -OCOC2H5 6.2 α-Prodine -CH3 -C6H5 -OCOC2H5 5.0 24
  25. 25. SAR OF DIPHENYL HEPTANONES: R2 R1 DRUG R1 R2 ANALGESIC ACTIVITY Methadone -COC2H5 -CH2CH(CH3)N (CH3)2 1 Isomethadone -COC2H5 -CH(CH3)CH2N (CH3)2 0.65 Phenadoxone -COC2H5 1.4 Dextromoramide 13 NC H O N CH3 CH3 N O 25
  26. 26. SAR OF BENZAZOCIN DERIVATIVES: N R1 C CH3 CH3 R2 DRUG R1 R2 Pentazocine -CH2CH=C(CH3)2 H Phenazocin -CH2CH2C6H5 H Cyclozocin H Ketazocin =O C C 26
  27. 27. SYNTHESIS OF METHADONE: 27 2-dimethyl aminopropyl chloride METHADONE Diphenyl aceto nitrile
  28. 28. SYNTHESIS OF MPERIDINE: CN + Cl NH2 N CN N COOC2H5 MEPERIDINE Phenyl acetonitrile spiroalkylation EtOH/HCL H2O with NAOH 28 N-(2-chloroethyl)propan-1-amine
  29. 29. MECHANISM OF ACTION: Opioid receptors. Acts on G-Protein coupled receptors. Inhibits Adenyl cyclase. Promotes opening of K+ channels & inhibits opening of Ca+2 channels. Reduces neuronal excitability & increases K+ conductance. Causes hyper polarization & shows inhibitory pathway & relieves pain. 29
  30. 30. RECEPTORS Opioid receptors are of 3 types. They are µ , k , δ. COMPOUND µ k δ PURE AGONIST: Morphine Methadone Codeine + + + + + + + + 0 + + 0 0 PARTIAL ANTAGONIST: Bupreorphine Butraphanol Propiram + + + + + + + _ + + + 0 0 0 0 30
  31. 31. USES: Opium and morphine are widely used as analgesics to relieve pain.  Used as hypnotic.  Used to treat painful myocardial ischemia with pulmonary oedem.  Used to treat cough.  Euphoria, sedation.  Pupillary constriction. 31
  32. 32. ADVERSE EFFECTS:  Respiratory depression.  Hypotension.  Constipation.  Urinary retention.  CNS problems: Mental clouding Nausea. Vomiting. Headache. Fatigue.  Tolerance.  Drug dependence. 32
  33. 33. MANIFESTATION OF OPIATE WITHDRAWL: TIME MANIFESTATION 6-12hrs Intense carving for the drug, lethargy, weakness. 12hrs Yawning, lacrimation, tremors & anorexia. 48hrs Peak of withdrawal syndrome. Fever, increase in B.P & heart rate. 7-10 days Symptoms clear up but restless, insomnia, weakness & pain for several weaks. 33
  34. 34. OPIOID POISONING:  Numerous reasons contribute to poisoning due to opioids.  It may occur due to clinical over dosage & many times when drug is ingested in large amounts with suicidal intentions. SYMPTOMS OF TOXICITY: 1. Coma, decreased respiration, pulmonary oedema. 2. Cyanosis, hypothermia, hypotension. 3. G.I spasm. 34
  35. 35. Toxic & Lethal Dose: Toxic dose-60mg. Lethal dose-250mg. TREATMENT: 1.Re-establishment of vital function such as respiration and blood circulation by the use of ABCD intervention. 2. Gastric lavage, which is done using KMnO4 solution, followed by stomach wash with sodium sulphate. 3. If opioids are ingested through oral route, then emetics and cathartics are used. 4.Respiratory depression can be reversed by the use of specific antidotes like naloxone. 35
  36. 36. DOSAGES:  Dose for diagnosis of poisoning is 0.2-0.4mg intravenously.  Dose should be repeated twice or thrice every 2-3 minutes.  In neonates, respiratory depression which results from administration of morphine to mother during delivery, is treated using 10µg/Kg naloxone given through intravenous/intramuscular/subcutaneous route. 36
  37. 37.  These are typically used to combat inflammation.  The clinical features of inflammation have been recognized since ancient times as swelling, redness, pain & heat.  Inflammation can also cause disease due to damage of healthy tissue. 37
  38. 38. CLASSIFICATION: 1.Salicylic acid derivatives: Aspirin, Salsalate, Diflunisol. 2.P-amino Phenol derivatives: Paracetmol, Phenacetin. 3.Pyrazoline dione derivatives : Phenyl butazone, Oxyphenbutazone. 4.Anthranilic acid derivatives : Mefenamic acid, Flufenamic acid. 5.Arylalkanolic acid derivatives: (a)Indole acetic acid: Indomethacin. (b)Indene acetic acid: Sulindac. (c)Pyrrole acetic acid: Tolmetin. 38
  39. 39. 6.Oxicams: Pyroxicam, Meloxicam. 7.Miscellaneous: Nambumetone, Nimesulide, Analgin. 8.Selective COX-2inhibitors: Celecoxid, Rofecoxid. MECHANISM OF ACTION:  NSAIDs are reversible, competitive inhibitors of co-activity.  Drug inhibit irreversibly by acetylating Co-enzymes.  Inhibits prostaglandins synthesis. 39
  40. 40. DIFFERENT DERIVATIVES: 1. Salicylates. 2. P-amino phenol derivatives. 3. 3,5-pyrazolinediones. 4. Pyrazoline derivatives. 5. Anthranilic acid derivatives. 40
  41. 41. SALICYLATES: DRUG R1 R2 Salicylic acid H H Methyl salicylate CH3 H sodium salicylate Na H Phenyl salicylate C6H5 H COOR1 OR2 41
  42. 42. P-AMINO PHENOL DERIVATIVES: NHCOCH3 ACETANILIDE NHCOCH3 0C2H5 PHENACITIN NHCOCH3 OH PARACETAMOL 42
  43. 43. 3,5-PYRAZOLINEDIONES: DRUG R R4 Phenyl butazone H -C4H9 Oxyphenbutazone OH -C4H9 Sulphinpyrazone H -(CH2)2SOC6H5 N N H O O R4 R 43
  44. 44. PYRAZOLONE DERIVATIVES: DRUG R2 R4 Antipyrine CH3 H Aminopyrine CH3 N(CH3)2 Dipyrone CH3 CH3-N-CH2SO3Na N N O R4 CH3 R2 44
  45. 45. ANTHRANILIC ACID DERIVATIVES: DRUG R1 R2 R3 Mefinamic acid CH3 CH3 H Flufinamic acid H CF3 H Meclofinamic acid Cl CH3 Cl COOH NH R1 R2 R3 45
  46. 46. SYNTHESIS OF ASPIRIN: SALICYLIC ACID ASPIRIN 46
  47. 47. SYNTHESIS OF PARACETAMOL: P-AMINO PHENOL P-ACETAMINO PHENOL 47
  48. 48. SYNTHESIS OF NIMESULIDE: 48
  49. 49. SYNTHESIS OF MELOXICAM: 49
  50. 50. SYNTHESIS OF IBUPROFEN: 50 Benzyl isobutyl. Acetyl chloride IBUPROFEN
  51. 51. USES:  Anti-inflammatory.  Analgesic.  Anti-pyretic.  Inhibition of platelet aggregation.  Rheumatoid arthritis.  Oseto arthritis.  Gout.  Myocardial infraction. 51
  52. 52. 52 NSAIDs GROUP SPECIFIC ADVERSE EFFECTS.
  53. 53. ADJUVANT ANALGESICS IN THE TREATMENT OF PAIN: CLASS DRUGS Antidepressants. Amitriptyline, Imipramine, venlafaxine. Antiepileptic. Gabapentin, Carbamazepine, Phenytoin. Antiarrhythmics. Mexiletine. Topical. Ketorolac, lidocaine Steroids. Prednisone. Muscle Relaxation. Cyclobenzaprine, Baclofen. 53
  54. 54. NEW APPROACHES  Enkephalinase Inhibitors, Such as the experimental drug RB120 Produce analgesia, together with other Morphine – like effect, without causing dependence.  Agonists at nicotinic Ach receptors based on Epibatidine (an alkaloid from frog skin), which is a potent nicotinic agonist & unexpectedly a potent analgesic. 54
  55. 55. CONCLUSION  Pain management is a challenging task, as it adversely affects the patient life style and there cannot be a permanent relief from the pain due to terminal illness like cancer.  Use of medication depends on the symptom associated with disease of the patient.  Now a days a variety of drugs are available in the market to combat the consequences of pain.  They are useful for the treatment of the pain to improve the quality of life of patient. 55
  56. 56. REFERENCES:  Foye’s principals of medicinal chemistry-7th edition(Pg:658-695).  Wilson & Gisvolds textbook of organic , medical & pharmacentical analysis – 12th edition(Pg:776-805).  Remingtions – The science & practice of pharmacy vol-II-22th edition(P.g:2679&2682).  Basic & Clinical pharmacology by katzung – 11th edition(Pg:692-720).  Rang & Dale’s pharmacology-6th edition.  Trease & Evans pharmacognosy(Pg:357-363).  Pharmacology & Pharmacotherapeutics -R.S.Satoskar – 12th edition. 56
  57. 57. 57

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