Anti-inflammatory, Antipyretic and Analgesic Agents PDF

ANTI-INFLAMMATORY, ANTIPYRETIC Chris Hall MSPAS, PA-C Chem 306 AND ANALGESIC AGENTS Spring 2025 OBJECTIVES Book Chapter 38 – Anti-inflammatory, Antipyretic and Analgesic Agents 1. Describe normal and abnormal inflammatory pathways 2. Understand the uti...

ANTI-INFLAMMATORY, ANTIPYRETIC Chris Hall MSPAS, PA-C Chem 306 AND ANALGESIC AGENTS Spring 2025 OBJECTIVES Book Chapter 38 – Anti-inflammatory, Antipyretic and Analgesic Agents 1. Describe normal and abnormal inflammatory pathways 2. Understand the utility of DMARDs in treating autoimmune disease 3. Describe the cyclooxygenase pathway and the physiologic role of prostaglandins in fever, pain, and inflammation OBJECTIVES CONTINUED 4. Discuss the mechanism of action, adverse effects, and pertinent drug-drug interactions associated with the following:  Methotrexate  Non-steroidal anti-inflammatory drugs (NSAIDs)  Non-selective NSAIDs  COX-2 inhibitors  Benefits of selective NSAIDs  Salicylates including aspirin  Salicylate toxicity – signs/symptoms and management  Acetaminophen  Acetaminophen toxicity – signs/symptoms and management WHAT IS INFLAMMATION? Normal body response Occurs in response to  Infection (viral/bacterial/fungal)  Physical trauma injury  Noxious chemicals Goal  Prevent damage from invading organisms  Sets stage for tissue repair  Removes toxins infectedwound WHAT IS INFLAMMATION? Inflammatory response is very COMPLEX and involves immune system and other agents such as:  Prostaglandins  Bradykinin  Histamine  Chemotactic factors When healing is complete, the inflammatory process subsides (USUALLY) PROSTAGLANDIN SYNTHESIS Prostaglandins  Produced by almost all cells in the body  Derived from unsaturated fatty acid present in cell membranes  Work like “local hormones” or chemical massagers locallyactinghormone  Produced locally and act locally ❖Different from endocrine gland produced “traditional hormones” that are produced locally but act at distant sites in the body. PROSTAGLANDIN SYNTHESIS inflammatorymarkers Prostaglandins  Derived from arachidonic acid in phospolipidbilayer  Component of the cell membrane phospholipid  Proinflammatory  In response to inflammatory stimuli, arachidonic acid is separated from plasma phospholipids by phospholipase setsoffinflammation process A2 breaksdownarachidonicacid PROSTAGLANDIN SYNTHESIS Phospholipase A2 1ststep stopinflammationatthe  Inhibited by steroids which reduce inflammation mostpotentanti inflammatories  “anti-inflammatories” prostaglandins  PROSTAGLANDIN SYNTHESIS  Arachidonic acid is pro-inflammatory  Once freed from cell membrane can follow 1 of two pathways  Lipoxygenase pathway allergiesmastcells immune response  Leukotrienes  Cyclooxygenase pathway shiitemmation  Prostaglandins seditied  Thromboxanes (procoagulant)  Prostacyclines (anticoagulant) PROSTAGLANDIN SYNTHESIS  Two isoforms of cyclooxygenase enzyme exist  Cyclooxygenase 1 (COX-1) gastric plateletfunction withpaininflammation pathggal  Cyclooxygenase 2 (COX-2)  PROSTAGLANDIN SYNTHESIS Prostaglandins (produced locally and act locally)  Cell type matters a iiiiiiiiiii.it ii ❖COX 1 and COX 2 have different binding sites allows selective targeting PROSTAGLANDIN SYNTHESIS  Cyclooxygenase 1 (COX- 1) gastricsecretion mucus  GI protection  Platelet function  Vascular homeostasis  Reproductive and kidney fxn  Pain, fever, inflammation  Cyclooxygenase 2 (COX- 2)  Pain  Fever  Inflammation  Bone formation VASCULAR HOMEOSTASIS Cyclooxygenase 1 (COX-1) affectsTXA2alittlemore  Responsible for production of  Prostacyclin (PGI2) prostaglandin  Vascular endothelium produced  Anticoagulant keeps plateletsinactive  Thromboxane A2 (TX A2) team  Platelet produced PGI2  Procoagulant turnson platelets TX A2 VASCULAR HOMEOSTASIS Prostacyclin  Keeps platelets inactive  Prevents platelet aggrigation  Promotes vasodilation Thromboxane A2  Activates platelets  Recruits platelets at site of injury  Promotes vasoconstriction GASTRIC PROTECTION  Prostacyclin (PGI2)  Inhibits gastric acid secretion  PG2 and PGF2a  Stimulate production of protective mucus in small intestine and stomach What does this mean for your patients? TX A2 complainaboutheartburnreflux PROSTAGLANDIN SYNTHESIS Cyclooxygenase 2 (COX-2)  Responsible for Prostaglandin E2 production  Prostaglandin E2 is responsible for  Temperature regulation  Pain  Inflammation  Bone healing  Vasodilation PROSTAGLANDIN SYNTHESIS  Cox 1 and Cox 2 both impact  Pain  Fever  Inflammation  Only cyclooxygenase 1 (COX-1) impacts  GI protection  Platelet function  Vascular homeostasis  usedto facts Yrhekehpkegf.PH a  topical NONSTEROIDAL ANTI- INFLAMMATORY DRUGS (NSAIDS) WHY CALLED NSAIDS? antiinflammatoriesthatarenotsteroids NSAIDS are so called to distinguish them from steroids like prednisone Steroids have powerful anti-inflammatory actions notusedlongtermbcsideeffects NSAIDS have weaker anti-inflammatory action  More suitable for long term therapy  Less toxic effects NSAIDS – MECHANISM OF ACTION Competitive cyclooxygenase inhibitors (except aspirin) Block the hydrophobic channel by which the substrate arachidonic acid accesses the active enzyme site Three primary therapeutic effects  Anti-inflammatory  Analgesia  Anti-pyrexia rewatch NSAID PROPERTIES ANTI-INFLAMMATORY  COX inhibition decreases formation of prostaglandins  NSAIDS  1st line drugs for inflammation and pain seen with rheumatic and non-rheumatic diseases  NSAIDs alone DO NOT significantly reverse the progress of rheumatic diseases NSAIDsdonotfixtheproblem  Treatment of chronic inflammation requires higher dosages of NSAIDS  Dose increase = more adverse events NSAID PROPERTIES ANALGESIA Pain COX-2 inhibition thought to be responsible for analgesia  PGE2 sensitizes nerve endings to actions of chemomediators (bradykinin, histamine, etc.) released by inflammatory process  PGE2 and PGI2 are the most important prostaglandins involved in pain  There production can be inhibited by NSAIDS NSAID PROPERTIES ANALGESIA But there are so many…  Ibuprofen (Motrin/Advil)  Naproxen (Aleve)  Indomethacin (Indocid)  Diclofenac (Voltaren) Which should I choose?  NSAIDs have relatively equivalent efficacy  NSAIDS best for pain of muscular, bone, and vascular pain  Not helpful with visceral pain rewatch NSAID PROPERTIES FEVER (ANTIPYREXIA)  PGE2 synthesis leads to elevated set-point of anterior hypothalamus thermoregulatory center (cause of fever)  NSAIDs inhibit PGE2 synthesis and release  Also leads to increased heat dissipation as a result of peripheral vasodilation and sweating  “Resets” thermostat (thermoregulatory system)  NSAIDS have little effect on normal body temperature NSAIDS – CLASSIFICATION ON BASIS OF CHEMICAL STRUCTURE won'tbeaskedthespecificsthatfit ineachclass Salicylates Acetic acids  Aspirin  Diclofenac (Voltaren, Cataflam)  Etodolac (Lodine) Propionic acids  Indomethacin (Indocin)  Ibuprofen (Motrin, Advil)  Ketorolac (Toradol)  Ketoprofen (Orudis)  Nabumetone (Relafen)  Naproxen (Aleve, Naprosyn)  Sulindac (Clinoril)  Oxaprozin (Daypro) Fenamic acids Enolic acids (oxicam class)  Mefenamic acid (Ponstel)  Meloxicam (Mobic)  Piroxicam (Feldene)  onlyCox2 inhibition More COX-1 effects and less COX-2 NSAIDS – PHARMACOKINETICS Nearly complete GI absorption Absorbed fairly rapidly after administration  Food reduces rate not extent of absorption Extensive protein binding Most metabolized by the liver CYPmetabolism  NSAIDS – PHARMACOKINETICS CONTINUED Renal excretion Variable half-lives  Short (< 6 hours)  Diclofenac, ketoprofen, ibuprofen, and indomethacin  Long (> 10 hours)  Naproxen, sulindac, nabumetone, and piroxicam  Most NSAIDS peak in 1-2 hours won'taskwhichare shortorlong NSAIDS – ADVERSE EFFECTS Nausea, vomiting, gastrointestinal distress, peptic ulceration, GI innature bleeding  Concomitant use of H2 receptor blockers or PPIs may help to preventeffectsof NSAIDs  Take with food or milk teratogens 78 Headache, dizziness, drowsiness Elevated liver function tests NSAIDS – ADVERSE EFFECTS (CONTINUED) Headache, dizziness, drowsiness Elevated liver function tests Affects platelet aggregation  Increased bleeding risk  Stops platelets from sticking together NSAIDS – ADVERSE EFFECTS (CONTINUED) Nephrotoxicity  Inhibition of vasodilation prostaglandins  Decreases renal blood flow and GFR  May cause tissue injury  Leads to retention of sodium and water → edema, high blood pressure, increased creatinine, and hyperkalemia Hypersensitivity reactions (rash, bronchospasm); especially with asthmatics COX -2 INHIBITORS COX-2 INHIBITORS onlytargetcoxz COX-2 inhibitors are unique in their selectivity  Inhibit COX 2 while leaving COX 1 unaffected  Less GI bleeding and dyspepsia  No effect on platelet function  May increase the risk of cardiovascular thrombotic events including MI and stroke eventhoughit affect doesn't platelets  Risk with all agents with higher COX-2 selectivity ❖Celecoxib (Celebrex) is contraindicated in patient with sulfa allergy COX-2 INHIBITORS Agents  Celecoxib (Celebrex)  Meloxicam (Mobic)  Rofecoxib (Vioxx) and valdecoxib (Bextra) removed from market  Doubled incidence of MI and CVA in patients using drugs  Indications  Rheumatoid arthritis  Osteoarthritis  Acute pain musculoskeletalpain ASPIRIN ASPIRIN (ACETYLSALICYLIC ACID; ASA) Irreversible inhibitor of cyclooxygenase (COX-1) at low doses  Decrease thromboxane A2 production  Suppression lasts the life of the platelet shutsthemofffortheirwholelife last57days platelets  ~7-10 days Anti-inflammatoryeffect only at HIGH doses  Lacks significant COX-2 effect  Far better antiplatelet than analgesic or anti-inflammatory ASPIRIN – ADVERSE EFFECTS Higher relative specificity for COX-1 → higher risk for GI events  Gastrointestinal adverse effects are most common due to decreased mucus secretion  Especially in high doses  Nausea, heartburn  Dose-related GI bleeding  Ulcer bleeding, gastric perforation ASPIRIN HOW TO DECREASE GI SIDE EFFECTS Co-administration of ASA with proton pump inhibitor reduces GI complications  Omeprazole (Prilosec)  Esomeprazole (Nexium)  Lansoprazole (Prevacid) Also, can uses enteric coated ASA to decreased effect on GI tract however this may impact its function as an antiplatelet ASPIRIN – ADVERSE EFFECTS (CONTINUED) Inhibits platelet aggregation and clot formation leading to prolonged bleeding time  Bleeding risk  Hold 1 week prior to surgery  IRREVERSIBLE effect for life of platelet ❖Caution if combining ASA with NSAIDs  NSAIDs have greater affinity for COX-1  May antagonize protective effects of aspirin (as an antiplatelet) ASPIRIN ADVERSE EFFECTS – HYPERSENSITIVITY Bronchospasm or hypersensitivity  Uncommon overall but more common in patients with asthma, nasal polyps, and recurrent rhinitis  Patients develop rash, bronchospasm, rhinitis, edema, and even anaphylaxis with shock ASPIRIN ADVERSE EFFECTS – REYE’S SYNDROME Aspirin is contraindicated in children (