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Pain, Inflammation, NSAIDs and Analgesics

Pain, Inflammation, NSAIDs and Analgesics. Learning Outcomes. By the end of the lecture the student should be able to Define and discuss the pathobiology of pain pathways Explain the molecular mechanism of action common to all nonsteroidal antiinflammatory drugs (NSAIDs)

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Pain, Inflammation, NSAIDs and Analgesics

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  1. Pain, Inflammation, NSAIDs and Analgesics

  2. Learning Outcomes By the end of the lecture the student should be able to • Define and discuss the pathobiology of pain pathways • Explain the molecular mechanism of action common to all nonsteroidalantiinflammatory drugs (NSAIDs) • Describe the pharmacological effects of each drug in each class. • Describe the pharmacokinetics of salicylates. • Describe the main adverse effects of the drugs of each class. • Describe the clinically important drug interactions of the drugs of each class. • Describe the principal contraindications of the drugs of each class. • Describe the main therapeutic uses of NSAIDs and acetaminophen.

  3. What is inflammation? • INFLAMMATION – is a reaction to tissue injury caused by the release of chemical mediators that cause both vascular response and the migration of fluids and cells to the injured site • It is a protective mechanism in which the body attempts to neutralize and destroy harmful agents at the site of tissue injury and establish condition for tissue repair.

  4. What is Pain Pain: An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage Hyperaesthesia (hypersensitivity): Increased sensitivity to stimulation, excluding the special senses Hyperalgesia: Increased pain in response to a noxious stimulus Allodynia: Pain due to a stimulus that does not normally produce pain From the International Association for the Study of Pain (IASP) definitions (Merskey, and Bogduk 1994)

  5. Physicians Have a Moral Obligation to Provide Comfort and Pain ManagementEspecially for those near the end of life! • Pain is the most feared complication of illness • Pain is the second leading complaint in physicians’ offices • Often under-diagnosed and under-treated • Effects on mood, functional status, and quality of life • Associated with increased health service use

  6. 18% of Elderly PersonsTake Analgesic Medications Regularly(daily or more than 3 times a week) • 71 % take prescription analgesics • 63% for more than 6 months • 72% take OTC analgesics • Median duration more than 5 years • 26% report side-effects • 10% were hospitalized • 41% take medications for side-effects

  7. Common Causes of Pain In Elderly Persons • Osteoarthritis • back, knee, hip • Night-time leg cramps • Claudication • Neuropathies • idiopathic, traumatic, diabetic, herpetic • Cancer

  8. Pain Receptors

  9. Pain Intensity Proportional to number of receptors stimulated

  10. Pain Pathway

  11. Etiological Factors inflammation/tissue damage/nerve lesions Pain Mechanism Pain Sydromes post-operative/arthritic/back pain/neuropathic

  12. Mechanisms associated with peripheral sensitization to pain

  13. Prostaglandins as mediators

  14. • Non-selective (t NSAIDS) inhibit both isozymes. • Side effects occur due to inhibition of COX-1(house keeping” enzyme) ► • With selective COX-2 inhibitors (Coxibs), chances of GIT toxicity are less. • CVS side effects can occur

  15. NSAIDS: Mechanism of action • Main mechanism: Inhibition of COX • Reversible (competitive) inhibitors • Irreversible inactivation (by Aspirin) • Nonselective COX inhibitors (traditional NSAIDS) • Selective COX-2 inhibitors (Celecoxib)

  16. NSAIDS: Effects • Anti-inflammatory effect • reverses vasodilation, edema, tenderness • Analgesic effect • By preventing PG mediated sensitization of nerve endings • Antipyretic effect • Resets the hypothalamic thermostat by decreasing PG synthesis • Vasodilation and heat loss • Do not cause hypothermia

  17. Antiplatelet aggregation effect • Platelets have COX-1 • Aspirin acetylates COX-1 to inhibit its activity in an “irreversible manner”. • All other tNSAIDS-reversible inhibitors • Selective COX-2 inhibitors do not disturb platelet aggregation at therapeutic doses • Acetaminophen do not inhibit platelet aggregation

  18. Common side effects of NSAIDS • Gastrointestinal: Nonselective NSAIDS COX-1 inhibition ↓ gastroprotective PGs • Gastric irritation, erosions, ulcers, gastric bleeding • Misoprostol (PGE1) can be used to prevent gastric ulcers caused by tNSAIDS. • Selective COX-2 inhibitors are safer.

  19. Renal: Sodium water retention, Papillary necrosis • CVS:↑ Na and water retention • Platelet inhibition : bleeding • Selective COX-2 inhibitors and acetaminophen do not disturb platelet function. • CNS: Headache, confusion, seizures • Hypersensitivity:“Pseudoallergic reaction” (due to increased leukotrienes)

  20. Salicylates • Acetylated salicylate: Aspirin (Acetylsalicylic acid) • Non-acetylated salicylates:sodium salicylate, diflunisal, mesalamine (5-ASA) ►Mechanism of action: • Aspirin:non-selective COX inhibitor; “Irreversible inhibition” by acetylation. • Other salicylates: weak COX inhibitors; other mechanisms are involved.

  21. Dose dependent effects of Aspirin Toxic levels High Levels

  22. Effects of aspirin • Antiplatelet effect: • Irreversible inactivation of COX-1 in platelets causes decreased production of TXA2 (aggregation promoter) • Platelets (enucleated) cannot regenerate COX; effect lasts for 7-8 days. • Irreversible inactivation of COX in endothelial cells causes decreased production of PGI2 (aggregation inhibitor) • Endothelial cells can regenerate cyclooxygenase in a matter of hrs. • Net effect is decreased platelet aggregation and increase in bleeding time. • Low doses (80-160mg) are enough to inhibit aggregation without anti-inflammatory effects.

  23. ANTIPLATELET EFFECT OF ASPIRIN Aggregation promotor Aggregation inhibitor Irreversible inhibition by Aspirin. Nucleated endothelial cells can regenerate COX. COX PG I2 COX-1 Irreversible inhibition by Aspirin. Enucleated platelets cannot regenerate COX.

  24. ↑ Plasma uric acid levels (at low dose) • ↓ Plasma uric acid levels (at high dose) • Hyperventilation and compensated alkalosis (At high levels) • stimulates respiratory center, ↓ pCO2, Increased bicarbonate in urine • Metabolic acidosis: (At toxic levels) • Accumulation of salicylic acid due to zero order kinetics at high levels. • Respiratory center depression; ↑ pCO2

  25. Salicylates: Adverse effects • Hypersensitivity reactions • Pts with asthma, nasal polyps, chronic urticaria are more susceptible • Pseudoallergic reaction • Cross reactivity with other NSAIDS • Reye’s syndrome: Encephalopathy, hepatotoxicity. • Do not use aspirin in childrenwith viral fever. • Salicylism: Tinnitus, dimness of vision, mental confusion, lassitude, sweating, hyperventilation, nausea and vomiting, diarrhea

  26. Salicylate intoxication • Tinnitus, Nausea and vomiting, abdominal cramps, gastric bleeding. • Respiratory depression, Acidosis, generalized convulsions. • marked hyperthermia, dehydration. • Skin eruptions, petechial hemorrhages • coma and death (due to respiratory failure) Treatment: Symptomatic and supportive. • External cooling and I.V. fluids with Na, K, and glucose. • Gastric lavage to remove unabsorbed drug • Forced alkaline diuresis to remove absorbed drug

  27. Salicylates: Therapeutic uses • Keratolytic: salicylic acid • Counterirritant: Methylsalicylate • Antiinflammatory, analgesic, antipyretic • Diflunisal: does not enter CNS; no antipyretic effect Mesalamine (5-ASA): • inflammatory bowel diseases Aspirin (Low doses): • MI, Angina • Atrial flutter/fibrillation • Transient ischemic attacks

  28. Other tNSAIDS Ibuprofen, Naproxen: • Widely used NSAID for pain and inflammation • GIT and CNS side effects are less • The mechanism of the antipyretic effect of Ibuprophenis Decreased concentration of prostaglandins in the hypothalamus Diclofenec • Inhibits COX and lipooxygenase (to minor extent) • Decreases free radical production • Accumulates in synovial fluid Ketorolac • Can be administered IV, IM • Used in postoperative pain

  29. Indomethacin • One of the most potent COX inhibitor • Inhibits COX • Inhibits Phospholipase A2 • Reduces neutrophil migration • Reduces T and B cell proliferation • Severe side effects (in 1/3rdpts) • Abdominal pain, diarrhea, GI bleeding • Frontal headache • Dizziness, confusion, depression, hallucinations • Therapeutic Uses: • Arthritis (osteoarthritis, rheumatoid arthritis, Ankylosing spondylitis, Gout) • Closure of ductusarteriosus

  30. Selective Cox-2 inhibitors“Coxibs” • Celecoxib: first selective COX-2 inhibitor • Potent antiinflammatory, analgesic and antipyretic activity • Incidence of GI bleeding and peptic ulcers is lower than tNSAIDS • Does not inhibit platelet aggregation • Increased risk of cardiovascular side effects: Hypertension, Thrombotic events

  31. Acetaminophen • Analgesic and antipyretic agent • Inhibits COX-3 in CNS… ? • Lacks significant anti-inflammatory and antiplatelet activity: very weak COX 1& 2 inhibitor • Metabolized in the liver • Toxic doses deplete glutathione • A metabolite, N-acetyl-p-benzoquinoneimine accumulates and causes hepatic necrosis. • Acetylcysteine administered as antidote.

  32. Acetaminophen: Metabolism MAJOR PATHWAY (Sulphate Conjugation) MAJOR PATHWAY (Glucuronide conjugation) MINOR PATHWAY P450 Enzyme CYP2E1 and CYP1A2 RENAL EXCRETION TOXIC METABOLITE NAPQI N-acetyl-p-benzo-quinoneimine) Therapeutic Doses Toxic Doses (4gm+) Glutathione Available Glutathione Depleted RENAL EXCRETION Hepatic Necrosis

  33. Antiinflammatory agents:Steroids

  34. Glucocorticoids: Mechanism of action

  35. Steroids: Antiinflammatory effect

  36. Therapeutic uses • Adrenal Uses • Non-adrenal uses: • Inflammatory disorders • Asthma • Allergies: Allergic rhinitis, Acute allergic reactions • Autoimmune disorders: RA, SLE, glomerulonephritis • Carcinomas • For immunosuppression

  37. Oral thrush (Candidiasis)

  38. Other Adverse effects of Glucocorticoids • Cushing like syndrome • Psychosis • Peptic ulcers • Osteoporosis • Aseptic necrosis of hip • Easy bruisability, Purple striae on skin • Visceral fat deposition • Posterior subcapsular cataract, glaucoma • Hirsutism • Increased appetite • Growth retardation in children

  39. OPIOID ANALGESICS

  40. History of Opioids • Opium is extracted from poppy seeds • Used for thousands of years to produce: • Euphoria • Analgesia • Sedation • Relief from diarrhea • Cough suppression

  41. Mechanism of action • Activation of peripheral nociceptive fibers causes release of substance P and other pain-signaling neurotransmitters from nerve terminals in the dorsal horn of the spinal cord • Release of pain-signaling neurotransmitters is regulated by opioid agonists by acting presynaptically to inhibit substance P release, causing analgesia

  42. Molecular Effect of Opioid Receptor Activation • Reduction or inhibition of neurotransmission, due largely to opioid-induced presynaptic inhibition of neurotransmitter release • Involves changes in transmembrane ion conductance • Increase potassium conductance (hyperpolarization) • Inactivation of calcium channels

  43. Pharmacological Effects • Sedation and anxiolysis • Drowsiness and lethargy • Apathy • Cognitive impairment • Depression of respiration • Main cause of death from opioid overdose • Combination of opioids and alcohol is especially dangerous • Cough suppression • Opioids suppress the “cough center” in the brain • Pupillary constriction • pupillary constriction in the presence of analgesics is characteristic of opioid use

  44. Pharmacological effects • Nausea and vomiting • Stimulation of receptors in an area of the medulla called the chemoreceptor trigger zone causes nausea and vomiting • Unpleasant side effect, but not life threatening • Gastrointestinal symptoms • Opioids relieve diarrhea as a result of their direct actions on the intestines • Other effects • Opioids can release histamines causing itching or more severe allergic reactions including bronchoconstriction • Opioids can affect white blood cell function and immune function

  45. Three Opioid Receptors • Mu • Kappa • Delta

  46. Delta Receptor • It is unclear what delta’s responsible for. • Delta agonists show poor analgesia and little addictive potential • May regulate mu receptor activity

  47. Mu-1 Located outside spinal cord Responsible for central interpretation of pain Mu-2 Located throughout CNS Responsible for respiratory depression, spinal analgesia, physical dependence, and euphoria Mu-Receptor: Two Types

  48. Kappa Receptor • Only modest analgesia • Little or no respiratory depression • Little or no dependence • Dysphoric effects

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