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ANALGESICS

ANALGESICS. Analgesic???????. An agent that subdues pain by acting in the CNS or on peripheral pain mechanism. Classification of Analgesics. Opioid Analgesics Non – opioid Analgesics. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS. What are NSAIDs?. Non- opioid; non-narcotic analgesics

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ANALGESICS

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  1. ANALGESICS

  2. Analgesic??????? • An agent that subdues pain by acting in the CNSor on peripheral pain mechanism

  3. Classification of Analgesics • Opioid Analgesics • Non – opioid Analgesics

  4. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

  5. What are NSAIDs? • Non- opioid; non-narcotic analgesics • Analgesic, antipyretic, anti- inflammatory actions • Weaker analgesics than morphine • Do not depress CNS • No dependence • Acts primarily on peripheral pain mechanisms • Weakly acidic compounds • Highly protein bound • Orally absorbed

  6. The major pharmacological actions of these drugs are due to their ability to inhibit the synthesis ofprostaglandins

  7. Beneficial actions due to PG synthesis inhibition: • Analgesia • Antipyretic • Anti-inflammatory • Antiplatelet • Closure of ductus arteriosus

  8. Toxicity due to PG synthesis inhibition: • Gastric mucosal damage • Bleeding • Na+ and H2O retention • Prolongation of labour • Asthma

  9. History • The medicinal properties of willow bark (salix alba) was known since centuries • In the 5th century, people used the bitter powder extracted from willow bark to relieve pain • Salicilin salicylic acid • In 1897 aspirin was discovered by Felix Hofmann • 1949: phenylbutazone • 1950: paracetamol • 1963: indomethacin

  10. I) Non-selective COX inhibitors: • Salicylates: Aspirin, Diflunisal • Paraaminophenol derivatives: Paracetamol • Pyrazolone derivatives: Phenylbutazone • Indole acetic acid derivatives: Indomethacin, Sulindac • Aryl acetic acid derivatives:Diclofenac, Tolmetin • Propionic acid derivatives:Ibuprofen, Naproxen, Ketoprofen • Antranilic acids:Mefenamic acid, Flufenamic acid • Oxicams :Piroxicam, Tenoxicam • Alkanones :Nabumetone • Pyrrolo-pyrole derivative:Ketorolac II) Selective COX-2 inhibitors Nimesulide, Celecoxib, Rofecoxib

  11. ASPIRIN • One of the oldest drugs • Acetylsalicylic acid • Rapidly converted in the body to salicylic acid

  12. Membrane Phospholipids Aspirin: Mechanism of Action Arachidonic Acid Cyclooxygenase Lipooxygenase PGH2 PGG2 Leukotrienes Prostaglandins Thromboxanes

  13. Membrane Phospholipids Aspirin: Mechanism of Action Aspirin Arachidonic Acid Cyclooxygenase Lipooxygenase PGH2 PGG2 Leukotrienes Prostaglandins Thromboxanes

  14. COX-1 • Continuously stimulated by the body • Its concentration in the body remains stable • Creates PGs used for basic housekeeping through out the body • PGs stimulate normal body functions such as stomach mucous production, regulation of gastric acid secretion, Na+ & water excretion…

  15. COX-2 • Induced • Stimulated only as apart of immune response • Used for signaling pain & inflammation • Produces PGs for inflammatory response

  16. Pharmacological actions 1.ANALGESIA ( 0.3- 1.5/day) • Good analgesic, but weaker than morphine • Relieves non-visceral pain such as inflammatory, tissue injury related etc… • Relieve pain from integumental structures • No Euphoria & No Tolerance Analgesic effect is due to: • Inhibition of PG synthesis • ↑ the threshold to pain perception at central subcortical level

  17. 2. Antipyretic action: • ↓ body temperature of patients having pyrexia • Inhibits PG synthesis in hypothalamus • Promotes heat loss by peripheral vasodilatation & sweating

  18. 3. Anti-inflammatory action • Occurs at high doses ( 3-6 g/day) • Potent anti-inflammatory agent • Signs of inflammation are suppressed • Inhibition of PG synthesis • Antagonizes the action of bradykinin

  19. 4. Respiration • Respiration is stimulated Anti-inflammatory dose ↓ ↑ O2 consumption by skeletal muscles ↓ ↑ CO2 production ↓ Respiratory stimulation ↓ Removal of plasma CO2 ↓ Respiratory Alkalosis • High dose : Respiratory centre depression

  20. 5. Acid- Base & Electrolyte balance Anti-inflammatory doses ↓ Alkaline pH ↓ ↑ Excretion of HCO3-,Na+,H2O ↓ Normal pH ↓ Compensated Respiratory Alkalosis

  21. 5. Acid- Base & Electrolyte balance Uncompensated Metabolic Acidosis

  22. 6. Metabolic Effects • Anti-inflammatory doses • ↓ • Uncoupling of oxidative phosphorylation • ↓ • ↑ Cellular Metabolism • ↓ • ↑ Heat production • ↓ • ↑ Utilization of glucose • ↓ • ↓ Blood sugar level Large Dose: a) Negative nitrogen balance b) Hyperglycemia

  23. 7. G.I.T • Gastric irritant: epigastric distress; Nausea; Vomiting • High Doses : Gastritis; Gastric ulceration; GI bleeding

  24. How to avoid GI irritation & Ulcer ? Aspirin should be administered • With plenty of water • With an alkali • With misoprostol, a PGE analogue

  25. 8. CVS • High dose : depress VMC  ↓ BP 9. Uric Acid Excretion • Therapeutic doses: ↓ urate excretion • High doses : ↑ urate excretion

  26. 10. Blood Prostaglandins Thromboxane synthetase TXA2 Inhibit Adenyl cyclase ↓ Platelet cAMP ↑ Platelet aggregation

  27. 10. Blood ___ ASPIRIN Prostaglandins Thromboxane synthetase TXA2 is not synthesized No Inhibition Adenyl cyclase ↑Platelet cAMP ↓ Platelet aggregation

  28. Pharmacokinetics • Absorbed from stomach & upper intestine • Rapid deacetylation→ salicylic acid • 80% plasma protein bound • Crosses BBB & placenta • Metabolism : glycine conjugation • Excretion : kidney • Half life: 3-5 hours

  29. Adverse Effects • Nausea, vomiting, epigastric distress, occult blood loss • Rashes, urticaria, rhinorrhea,angioedema, asthma • SALICYLISM dizziness, tinnitus, vertigo reversible impairment of hearing & vision excitement, mental confusion • Liver damage: Reye’s syndrome • Nephrotoxicity

  30. Acute salicylate intoxication(15- 30g) • Manifestations dehydration, GI irritation, vomiting acid- base imbalance hyperpyrexia restlessness, delirium, hallucination tremor, convulsions haematemesis respiratory failure

  31. Treatment of Acute salicylate Intoxication • Gastric lavage • IV fluids • External cooling • Vit K & blood transfusion • Alkaline diuresis

  32. CONTRAINDICATIONS • Peptic ulcer • Children suffering from influenza • Chronic liver disease • Diabetics • Pregnancy prolongation of labour greater postpartum blood loss premature closure of ductus arteriosus • Stopped 1 week before surgery

  33. Drug Interactions • Displaces Warfarin, Sulfonylureas, Phenytoin, Methotrexate from their protein binding sites. • Antagonizes the action of probenecid • Blunts the action of diuretics

  34. Therapeutic Uses • Head ache, back ache, myalgia, joint pain pulled muscle, neuralgia, dysmenorrhoea • Fever • Acute Rheumatic fever first choice 4-6g/day • Rheumatoid arthritis relieves pain, swelling, morning stiffness 3-5 g/day • Osteoarthritis • Patent ductus arteriosus

  35. Therapeutic Uses Myocardialinfarction • Low dose aspirin started immediately after MI prevents reinfarction and reduce mortality. • Use with or with out Heparin • Clopidogrel/Ticlopidine are alternatives

  36. Therapeutic Uses Unstable Angina • Aspirin (100- 150 mg/day) given along with Heparin followed by Warfarin decreases risk of MI & sudden death in patients with unstable angina. • Clopidogrel/Ticlopidine are alternatives/adjuvant to aspirin.

  37. Therapeutic Uses Cerebrovascular disease • Aspirin has been used to prevent transient ischemic attacks of stroke in patients with cerebrovascular disease, although aspirin do not alter the cause of stroke

  38. Aspirin considered a wonder drug for >50 years (1899-1950), inhibit Cyclo-oxygenase,. . . but found to cause gastrointestinal ulcers and bleeding, to cause CNS “salicylism,” altered acid-base balance (respiratory alkalosis), Reye’s syndrome in children with viral infections. . .

  39. MORPHINE 1. Basic drug 2. Potent analgesic 3. Relieves visceral pain 4. Removes the associated reactions to intense pain 5. No anti-inflammatory/ antipyretic action 6.Produces sedation ASPIRIN 1. Acidic drug 2. Potent analgesic 3.Relieves inflammatory, tissue injury related pain 4. Does not remove the associated reactions to intense pain 5. Potent anti-inflammatory/ antipyretic action 6. No sedation

  40. MORPHINE 7. Produces euphoria 8. Depress respiratory centre 9. Depress cough centre 10. High dose ↓BP 11.Do not cause acid- base imbalance 12.No GI irritation; bleeding 13. Produce constipation 14. Produces miosis 15. Causes tolerance & dependence 16. Precipitate asthma 17. No Salicylism 18. No antiplatelet action 19. Pre- anaesthetic medication ASPIRIN 7. No euphoric effects 8. Stimulates respiratory centre 9. No effect 10. High dose ↓BP 11. Produce acid- base imbalance 12.Cause GI irritation; bleeding 13.No constipation 14.No miosis 15. No tolerance & dependence 16. Precipitate asthma 17. Causes Salicylism 18. Antiplatelet action 19. Not a pre- anaesthetic medication

  41. PARACETAMOL • Acetaminophen • De-ethylated active metabolite of PHENACETIN • Commonly used drug • Over The Counter (OTC) drug • Potent antipyretic & equianalgesic with Aspirin • Weak/no anti-inflammatory action

  42. More active on COX in brain • Poor inhibitor of PG synthesis in peripheral tissues • No GI irritation, acid-base imbalance • No affect on blood • No respiratory stimulation • Not uricosuric

  43. Pharmacokinetics • Well absorbed orally • Metabolism : liver i) glucuronide conjugation ii) sulfate conjugation • Excretion: kidney • Half life: 2-3 hours

  44. Adverse Effects • Safe & well tolerated • Nausea, rashes, anemia • Nephropathy

  45. Acute Toxicity(>150mg/kg) • Early manifestations nausea, vomiting, liver tenderness • After 12-18 hours centrilobular hepatic necrosis renal tubular necrosis hypoglycemia coma • After 2 days jaundice, hepatic failure, death

  46. Mechanism of toxicity

  47. Treatment • Gastric lavage • Activated charcoal • Specific antidote: N-acetylcysteine Replenishes glutathione stores of liver 150mg/kg IV for 15 min; followed by same dose IV over the next 20 hours

  48. Therapeutic uses • Headache, musculoskeletal pain • Dysmenorrhoea • OSTEOARTHRITIS • Fever

  49. ASPIRIN Potent analgesic Good antipyretic Potent anti-inflammatory agent Inhibits COX even in presence of peroxides Stimulate respiratory centre Alter acid- base balance Increase cellular metabolism Produces GI irritation Inhibit platelet function Metabolism: glycine conjugation SALICYLISM Reye’s syndrome Nephropathy No specific antidote for acute poisoning PARACETAMOL Potent analgesic Good antipyretic No anti-inflammatory action Do not inhibit COX in presence of peroxides Do not stimulate respiratory centre Do not alter acid- base balance Do not increase cellular metabolism Do not produce GI irritation Do not inhibit platelet function Metabolism: glucuronide conjugation No SALICYLISM No Reye’s syndrome Nephropathy Specific antidote for acute poisoning : N- acetylcysteine

  50. Ibuprofen • Introduced in 1969 • Analgesic, Antipyretic & Anti-inflammatory activity similar to aspirin • Better tolerated orally • Inhibition of synthesis of PG • 92-99% bound to plasma albumin

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