Pain, Inflammation, NSAIDs and Analgesics

1. Pain, Inflammation, NSAIDs and Analgesics BY DR KAUKAB AZIM

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

14. Prostaglandins as mediators √

15. ▼ • 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

16. 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)

17. 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

18. 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

19. 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.

20. 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)

21. 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.

22. Dose dependent effects of Aspirin Toxic levels High Levels

23. 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.

24. ANTIPLATELET EFFECT OF APIRIN 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.

25. ↑ 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

26. 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, sweating, hyperventilation, nausea and vomiting, diarrhea

27. 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

28. 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

29. Other tNSAIDS Ibuprofen, Naproxen: • Widely used NSAID for pain and inflammation • GIT and CNS side effects are less 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

30. 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 1/3rd pts) • Abdominal pain, diarrhea, GI bleeding • Frontal headache • Dizziness, confusion, depression, hallucinations • Therapeutic Uses: • Arthritis (osteoarthritis, rheumatoid arthritis, Ankylosing spondylitis, Gout) • Closure of ductus arteriosus

31. 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

32. 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.

33. 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

34. Antiinflammatory agents:Steroids

36. Glucocorticoids: Mechanism of action

37. Steroids: Antiinflammatory effect

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

39. Oral thrush (Candidiasis)

40. 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

41. OPIOID ANALGESICS

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

43. 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

44. 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

45. 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

46. 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

47. Three Opioid Receptors • Mu • Kappa • Delta

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

49. 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

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