NSAIDs Lecture Notes PDF

NSAIDs Block inflammation via inhibition of the synthesis of prostaglandins – Analgesia – Anti-inflammatory – Anti-pyretic Widely used agents best for mild to moderate pain – Long term use possible but are they totally safe? GI prob, Hepatotoxicity, nephrotoxicity ...

NSAIDs Block inflammation via inhibition of the synthesis of prostaglandins – Analgesia – Anti-inflammatory – Anti-pyretic Widely used agents best for mild to moderate pain – Long term use possible but are they totally safe? GI prob, Hepatotoxicity, nephrotoxicity  NSAIDs 400 BC Hippocrates prescribes the bark from the willow tree for pain and fever. Contains salicin Salicin isolated in 1829 by Henri Leroux. Salicin -- glucose + salicylic alcohol -- salicylic acid  NSAIDS Salicylic acid synthesized in 1859 Salicylic acid – Bad taste and Highly irritating GI In 1875 for rheumatic fever, antipyretic Uricosuric effects for Gout soon after  NSAIDS Chemist at Bayer named Felix Hoffman synthesized pure acetylsalicylic acid – Better tolerance (father had arthritis) Syn 1897, no value at time, Heroin, dental patient with tooth ache and fever, self admin. Heinrich Dreser Felix Hoffman Arthur Eichengrun  NSAIDS Para-aminophenols (acetaminophen) soon followed 1948 Dr. Lawrence Craven – 400 patients taking aspirin – 1988 FDA approved Aspirin use to prevent heart attack. This was expanded in 1998 to include stroke, reduce damage during a heart attack and any TIAs  Mechanism 1970s aspirin and indomethacin inhibited prostaglandins Prostaglandins associated with inflammation and fever and were released at sites of cell damage Prostaglandins are prostanoids (TXA 2 + Prostacyclin PGI2 etc Eicosanoids—prostanoids and leukotrienes – they are involved in the inflammatory response.  Arachidonic acid metabolism Cell membrane Phospholipids Phospholipases, PLA2 Arachidonic acid Lipoxygenase Cyclooxygenases COX-1 and COX-2 Leukotrienes Prostaglandin H2 LTB4, E4, C4, D4, PGI2, PGE2, PGF2, PGD2, TXA2 PGI2 = prostacyclin PGE2 etc. = prostaglandin E2 TXA2 = Thromboxane A2  Arachidonic acid metabolism Glucocorticoids block Cell membrane Phospholipids Phospholipases, PLA2 Arachidonic acid Lipoxygenase Cyclooxygenases COX-1 and COX-2 Leukotrienes Prostaglandin H2 LTB4, E4, C4, D4, PGI2, PGE2, PGF2, PGD2, TXA2, PGI2 = prostacyclin PGE2 etc. = prostaglandin E2 TXA2 = thromboxane A2  Arachidonic acid metabolism Glucocorticoids block Cell membrane Phospholipids Phospholipases, PLA2 NSAIDs block Arachidonic acid Lipoxygenase Cyclooxygenases COX-1 and COX-2 Leukotrienes Prostaglandin H2 LTB4, E4, C4, D4, PGI2, PGE2, PGF2, PGD2, TXA2, PGI2 = prostacyclin PGE2 etc. = prostaglandin E2 TXA2 = thromboxane A2  Cyclooxygenase COX-1 is constitutively active and expressed in most cells. – Housekeeping function: renal gi blood flow, renal function, mucosal proliferation, platelet function – Source of cytoprotective PGs in GI tract COX-2 is induced in inflammation – Constitutively active for renal development and in brain – Vascular prostacyclin production (vasodilation) Smooth muscle – Vascular TXA2 vasoconstriction PGE2 and I2 vasodilators – Airways PGE2 and PGI2 relax TXA2 and PGF2α contract – LTs contract In asthma aspirin (and others) can cause: – Bronchospasm, dyspnea, wheezing – Non allergenic drug-sensitive asthma caused by excessive production of cysteinyl leukotrienes Gastric cells – COX1 (constitutive) PGs epithelial cells PGs parietal cell NSAIDs most common SA Gastrointestinal distress + bleeding, gastritis – Acid production, mucus/bicarb secretion – COX-1 – COX-2 and Tylenol less problem Platelets – COX-2 in endothelium makes PGI2 which Inhibits clotting So COX-2 inhibition can increase clotting and can cause thrombotic events (Very big problem when COX2 selective inhibitors came to the market! – COX-1 Stimulates TXA2 which increases clotting TXA2 is increased in M.I. So: NSAIDs block TXA2 and reduces clotting most effective is low doses of aspirin Non selective NSAIDs can block both thromboxane A2 and Prostacyclin SO…..  Black Box Warning! 7-9-2015: – FDA Drug Safety Communication: FDA strengthens warning that non-aspirin nonsteroidal anti- inflammatory drugs (NSAIDs) can cause heart attacks or strokes. 10-50% increased risk Improve warnings on OTC No difference between drugs but increased association with higher doses for longer duration Kidney – Regulate hemodynamics and glomerular and tubular function COX inhibitors can reduce renal function in marginally functioning kidneys Worsen hypertension and Congestive heart failure Uterus: increases uterine contractions – Prostaglandins stimulate and initiate labor (can induce abortion) – PGS from endometrium cause cramping (NSAIDS help) NSAIDS can prolong labor PGs maintain a patent ductus arteriosus in utero So if NSAIDS are given late in pregnancy they cause premature closure which can cause pulmonary hypertension in the newborn – However, if the baby is born premature NSAIDS can help close High dose indomethacin and ibuprofen are used for this  Nervous system – PGE1 and PGE2 increase body temperature at hypothalamus Pyrogens (bacteria, cytokines) increase PG synthesis – PGEs inhibit NE from postganglionic sympathetic nerve endings Increased vasoconstriction w/ NSAIDS may be due to increased NE and reduction in vasodilators – PGE2 can cause hyperalgesia at sites of inflammation. Terminal membrane is hyperexcited. NSAIDs acutely block hyperalgesias but it is thought that most analgesic actions are due to the antinociceptive effects directly on peripheral or central neurons in the dorsal horn (decreases PGE2 induced inhibition of glycinergic inhibition) From Goodman and Gilman’s “Pharmacological basis of therapeutics” 12th ed. McGraw Hill publishing.  General characteristics Organic acids (except Nabumetone) Organic acids accumulate at sites of inflammation Reversible (not aspirin) – Some short acting: t½ 10 hrs Aspirin short ½ life long action  Shared therapeutic effects Uses: – Reduce inflammation Except acetaminophen (Tylenol) – Antipyretic Aspirin (salicylates) are contraindicated in children for viral induced fever. Reyes syndrome Acetaminophen is choice in children -young adults – Analgesic Best when inflammation is directly correlated with pain. Effect of Opioid vs Nonopioid Medications on Pain- Related Function in Patients With Chronic Back Pain or Hip or Knee Osteoarthritis Pain The SPACE Randomized Clinical Trial Erin E. Krebs, MD, MPH1,2; Amy Gravely, MA1; Sean Nugent, BA1; Agnes C. Jensen, MPH1; Beth DeRonne, PharmD1; Elizabeth S. Goldsmith, MD, MS1,3; Kurt Kroenke, MD4,5,6; Matthew J. Bair4,5,6; Siamak Noorbaloochi, PhD1,2 Other uses: – Gout– Not Aspirin or Tolmetin – Closure of Patent Ductus Arteriosus Acetylsalicylic acid (Aspirin) Non-selective irreversible COX inhibition – Aspirin irreversible 170x more for COX1 than 2 – Saturable protein binding and metabolism – ~600 mgs – More results in much longer ½ life  Aspirin Antiplatelet effects – Acetylation irreversibly blocks COX-1 blocking TXA2 formation – COX2 is also inhibited PGI2 but COX1 action dominates – Irreversible inhibition in platelets is long (8-11 days) The platelets need to be replaced they are anucleated cells and have limited protein synthesis Remove before surgery (7days) – Can increase risk for CAD  Aspirin Clinical Uses – Mild to moderate pain (not visceral) Headache, myalgia, arthritis, dysmenorrhea, migraine With opioids like oxycodone (Percodan) for moderately severe pain (dentistry) – Rheumatic fever salicilates w/ steroids – Arthritis (lowest effective dose… could still be high) – Acute myocardial infarction, prophylactic use for coronary artery disease, TIAs, angina, thrombosis following bypass 40-80mg/day –TXA2 Acute MI 325mg on suspicion Acute ischemic stroke  Toxicities Should not be used in children with acute viral fever because of risk of Reyes syndrome 1986 required warning for potent than aspirin Indications: – Rheumatoid arthritis, osteoarthritis, acute gouty arthritis, ankylosing spondylitis – Patent ductus arteriosus closure Adverse effects – 33% intolerant GI pain + hemorrhage, diarrhea, pancreatitis, severe headache (15-25%) – Rare psychosis, hallucinations, renal problems  Propionic acid derivatives Ibuprofen (Motrin) Naproxen (Aleve, Naprosyn, Na+ Anaprox) Fenoprofen (Nalfon) Ketoprofen (Orudis) Flurbiprofen (Ansaid, Ocufen)  Propionic acid derivatives > tolerated than aspirin + indometh – Efficacy = aspirin Indications: – Rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, gouty arthritis, tendinitis, bursitis and dysmenorrhea. Non-selective COX inhibitors  Propionic acid derivatives All are anti-inflammatory, analgesic and antipyretic Best? – Naproxen may have edge in analgesia and tolerance All display high protein binding ~99%  Ibuprofen (Motrin) Up to 3200 mg/day – Usual dose 400mg/4-6hrs – w/ food to reduce GI effects; t ½ 2 hrs. – Newly approved IV version for debilitated ptns. 5-15% intolerant GI problems – Not during pregnancy – Toxicity is similar to salicylism Uses: – Rheumatic dis – Patent ductus arteriosus closure Naproxen (Aleve, Naprosyn) Fully absorbed peak in 2-4 hrs. – Antacids can alter absorption times ½ life 14 hrs – 2 xs higher in elderly requires reduction Very similar to Ibuprofen Alzheimer’s trial showed increased risk of Cardiovascular events FDA warning  Ketorolac (Toradol) Very Potent analgesic, moderately effective anti- inflammatory – Postoperative pain, in place of opioids (as efficacious as morphine) – Not for chronic pain only for short term Potency Increases adverse effects – GI + platelets, Renal  COX-2 Selective agents Inhibit COX-2 at inflammation not constitutively active COX-1. – Anti-inflammatory, analgesic and antipyretic actions Uses: Osteoarthritis, Rheumatoid Less GI problems, does not inhibit platelet aggregation (increases) – Risk of thrombotic events has resulted in the removal of some of these This potential is there with all that have COX -2 activity Relative Selectivity  COX-2 Selective agents Celecoxib (Celebrex) 10-20 times more selective COX2 Efficacy = NSAIDs Pfizer: No prothrombotic effects at therapeutic doses. Diclofenac (Cataflam, Voltarin) – High potency -- COX2 selective – Long term treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis – Arthrotec: with Misoprostol (GI) also PPIs – Patch and topical formulations too – Associated with liver problems Para-Aminophenol Derivatives Acetaminophen (Tylenol) Alternative to aspirin for analgesia and antipyretic effects Analgesia—increases pain threshold Antipyretic—hypothalamus No peripheral COX inhibition – Due to peroxide levels High inhibits (inflammation) works in low peroxide (hypothalamus). – No platelet, uric acid or GI effects – No anti-inflammatory effects  Acetaminophen toxicity Minor problems e.g. rashes High Dose: Fatal Hepatic Necrosis and renal failure can occur – Toxic metabolite NAPQI accumulates hepatic and renal necrosis Normally NAPQI is eliminated by conjugation with glutathione – Depletion of glutathione (high doses) NAPQI accumulates and causes hepatotoxicity – 10-15 grms hepatotoxic—25grms fatal (maybe lower depends on pt.) Estimates vary: 78k ER visits, 33K Hospitalizations, 110 -980 deaths/yr) – Moderate to heavy drinkers-Alcoholics (even in the therapeutic range) depleted glutathione and enzyme induction more NAPQI – Renal tubular necrosis Symptoms – Early, nausea, vomiting, diarrhea and pain.(1st 2 days) then liver damage Treatment: (immediate) – Activated charcoal w/in 1st hrs or gastric lavage – Replenish glutathione N-acetylcysteine (Mucosil) FDA recommendations 7/1/09 Black box on OTC for liver toxicity Reduce OTC dose formulations Removal of Opioid combinations? – Oxycodone + acetamin : Percocet – Hydrocodone + acetamin: Vicoden – Limit to 325mg/pill  Quest. Which of the following NSAIDs would be the best choice for analgesia in a patient with duodenal ulcers? – Naproxen (Aleve) – Celecoxib (Celebrex) – Aspirin (Ecotrin) – Diflunisal (Dolobid) – Colchicine