Pharmacology Lecture on NSAIDs (PDF)

NON-OPIOID ANALGESICS AND ANTI-INFLAMMATORIES Dr. Adam Gratton NMT150 MSc ND February 2, 2023 LECTURE COMPETENCIES Describe the mechanism of action of selective and non- selective COX inhibitors Describe the adverse effects associated with NSAID use Define gastroprotection within...

NON-OPIOID ANALGESICS AND ANTI-INFLAMMATORIES Dr. Adam Gratton NMT150 MSc ND February 2, 2023 LECTURE COMPETENCIES Describe the mechanism of action of selective and non- selective COX inhibitors Describe the adverse effects associated with NSAID use Define gastroprotection within the context of NSAID and describe strategies to reduce serious adverse effects Contrast the presented NSAIDs based on their adverse effect profiles NON-OPIOID ANALGESICS NonSteroidal Anti-Inflammatory Drugs (NSAIDs) Non-specific COX inhibitor like acetylsalicylic Acid (ASA) and ibuprofen COX-2 Specific Inhibitors like celecoxib Non-specific COX inhibitors without anti-inflammatory effect like acetaminophen INTRODUCTION NSAIDs are one of the most commonly prescribed medications for pain and inflammation They make up 5 – 10% of all medications prescribed each year Up to 96% of patients over the age of 65 use NSAIDs in the family practice setting  IL-1 TNF Arachidonic Acid Growth Factors + Glucocorticoids IL4 - COX-1 COX-2 Constit Induced utive Inhibition Undesirable Inhibition Desirable Homeostatic Functions INFLAMMATION GI Tract Kidneys Neurodegeneration Platelet Function Neoplasia Macrophage differentiation COX-2 COX-1 Specific Specific NON-OPIOID ANALGESICS COX-2 prostaglandins are inflammatory and participate in inflammatory responses which can produce pain The biggest issue with COX-1 inhibition is with GI function, particularly mucus secretion in the stomach COX-1 inhibition leads to ulcers and increases the risk for major GI bleeds NON-OPIOID ANALGESICS ASA and Ibuprofen have significant COX-1 inhibitor activity and are known to have a substantial risk for dose dependent GI side effects Celecoxib is substantially more specific to COX-2 and lacks the GI side effects Both classes still increase the risk of cardiovascular disease and mortality Trelle S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis BMJ 2011 ASA ASA is notable in that it causes irreversible inhibition of COX by covalently bonding its acetyl group to the active binding site of COX This effectively produces non-competitive inhibition The remaining salicylate is a competitive inhibitor of COX ASA Short plasma half life as it is rapidly hydrolyzed to salicylic acid by plasma esterase Eliminated in the urine after conjugation (primarily to glycine) Rate of excretion is affected by urine pH Alkalinizing urine will increase ionization and increase elimination in overdose scenarios ASA Contraindicated in children with viral infections GI irritation/ulcers/bleeding Tinnitus – early sign of salicylate toxicity High doses can cause hyperventilation, fever, dehydration, metabolic acidosis, impairment of hemostatis Hypersensitivity reactions are uncommon but potentially fatal 5% cross reactivity to other NSAIDs ASA DOSING Adults: 325 – 650 mg Q4H PO to a maximum of 4 g/day Onset of action: 1 hour Duration of action: 4 – 6 hours IBUPROFEN Adverse effects include: GI irritation, nausea, dyspepsia, bleeding Hepatic toxicity Renal toxicity including acute renal failure if dehydration occurs IBUPROFEN DOSING Adults: 200 – 400 mg Q6 – 8 hours PO to a maximum of 1200 mg/d Onset of action: 30 – 60 minutes Duration of action: 4- 6 hours ACETAMINOPHEN Little effect on COX-1 or COX-2 A third isoform, COX-3, recently discovered and acetaminophen has affinity for COX-3 May explain analgesic and antipyretic effect Little anti-inflammatory effect as it is rapidly inactivated by peroxides produced in inflamed tissue ACETAMINOPHEN Rapidly absorbed from the gut Minimal plasma protein binding Widely distributed to peripheral tissue and the CNS Toxic intermediate formed with CYP1A2, 2E1, 3A isoenzymes Normally conjugated with glutathione and renally excreted Glutathione depletion can lead to hepatic necrosis ACETAMINOPHEN DOSING Adults: 325 – 650 mg Q4H PO or PR for acute pain 325 – 1000 mg Q4-6 hours PO for osteoarthritis Maximum daily dose: 4 g/d Onset of action: under 1 hour Duration of action: 4 – 6 hours CELECOXIB Selective COX-2 Inhibitor Potent anti-inflammatory activity without significant GI toxicity Increased risk of cardiovascular disease and mortality Does not inhibit platelet aggregation CELECOXIB DOSING 100 mg BID PO or 200 mg daily PO for osteoarthritis GASTROPROTECTION Risk of major GI bleeding: Increased age Concomitant use of systemic corticosteroids or warfarin History of GI bleeding or peptic ulcer disease 1 - 2% of people who use NSAIDs will develop GI complications, an annual rate 3 to 5 times higher than among those who do not use NSAIDs GASTROPROTECTION Strategies: Using COX-2 selective NSAIDs Using prostaglandin analogues: misoprostol Using proton pump inhibitors: omeprazole SAMPLE QUESTION Which of the following NSAIDs acts through non- competitive inhibition of COX enzymes? A. Acetaminophen B. Acetylsalicylic acid C. Ibuprofen D. Celecoxib