Treatment of RA and OA (PDF)

Anti-inflammatory Drugs (Rheumatoid Arthritis and Osteoarthritis) Pharmacology and Toxicology Musculoskeletal System Third Year Medical Students Facul...

Anti-inflammatory Drugs (Rheumatoid Arthritis and Osteoarthritis) Pharmacology and Toxicology Musculoskeletal System Third Year Medical Students Faculty of Medicine The Hashemite University Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 1  Anti-inflammatory Drugs Prostaglandins Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Acetaminophen Traditional Disease-Modifying Antirheumatic Drugs (DMARDs) Biologic Disease-Modifying Antirheumatic Drugs (B-DMARDs) Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 2  Inflammation “normal, protective response to a variety of noxious stimuli such as physical trauma, chemicals, or microbiologic agents in effort to inactivate or destroy invading organisms, remove irritants, and set the stage for tissue repair” Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 3  When Can Things Go Wrong? Rheumatoid Arthritis Chronic inflammatory disease affecting the joints. Middle ages (30-50 years) Aetiology still unknown; but environmental and genetic risk factors such as: smoking, obesity and vitamin D deficiency. Inappropriate activation of the immune system → inflammation → immune-mediated/autoimmune disease Activated immune cells secrete proinflammatory cytokines: TNF-α IL-1, IL-6 and IL-8 among others Transforming growth factor beta (TGF-ß) Fibroblast growth factor (FGF) Immunology.org Platelet-derived growth factor (PDGF) Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 4  When Can Things Go Wrong? Rheumatoid Arthritis Proinflammatory cytokines result in: 1. vascular permeability/cellular infiltration due to release of histamines, kinins, and vasodilatory prostaglandins 2. increased hepatic production of C- reactive protein 3. increased production and release of proteolytic enzymes by chondrocytes → cartilage degeneration 4. increased osteoclast activity → focal bone erosions/osteoporosis 5. systemic manifestations: heart, lung. Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 5  When Can Things Go Wrong? Rheumatoid Arthritis Chronic inflammatory response can result in: progressive tissue injury Persistent polyarthritis (synovitis) functional disability significant pain Extra-articular manifestations Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 6  Pharmacological Therapy Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 7  Prostaglandins “unsaturated fatty acid (arachidonic acid) derivatives containing 20 carbons that include a cyclic ring structure (eicosanoids)” Mostly local, minimal systemic effect. Firstly, discovered in seminal fluid. Act as autocrine or paracrine. Related compounds (Prostanoid): thromboxanes, leukotrienes. Tmedweb.org Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 8  Synthesis of Prostaglandins Main precursor: arachidonic acid Released from membrane phospholipids by phospholipase A2 two major pathways: cyclooxygenase and lipoxygenase. Wikipedia.org Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 9  Cyclooxygenase Pathway COX-1 is a constitutive enzyme that regulates normal cellular processes, such as gastric cytoprotection, vascular homeostasis, platelet aggregation, and reproductive and kidney functions. COX-2 is constitutively expressed in tissues such as the brain, kidney, and bone. COX-2 expression at other sites Cyclooxygenase-1 (COX-1): increases during states of chronic physiological prostanoids Cyclooxygenase-2 (COX-2): enhanced inflammation and by prostanoid synthesis Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 10  Cyclooxygenase Pathway Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 11  Lipoxygenase Pathway Anti-leukotriens are used in the treatment of Asthma (Respiratory System). Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 12  Prostaglandins Roles of prostaglandins: ❑Bind to variety of G-coupled protein receptors; effects depend on cell type, tissue, etc. (~10 different receptors) ❑Pain, inflammation and fever ❑Gastric cytoprotection ❑Uterine contractions ❑Renal blood flow Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 13  Some Therapeutic Uses of maintains the patency of the Prostaglandins Reduce gastric acid secretion & stimulate mucus and ductus arteriosus during pregnancy bicarbonate production. Alprostadil Lubiprostone Misoprostol PGE1 PGE1 derivative PGE1 analogue Treatment of erectile Treatment of chronic Protection of gastric dysfunction idiopathic constipation mucosa during chronic Treatment of Treatment of opioid- NSAIDs use. congenital heart associated constipation Induction of labor (off diseases Treatment of IBD- label) (Cardiovascular System) constipation (Gastrointestinal system) (Gastrointestinal system) stimulates chloride channels in the luminal cells Sofian Al Shboul © of theCopyright intestinal epithelium, © 2018 Wolters Kluwer thereby increasing ٠ All Rights Reserved 14 intestinal fluid secretion  Some Therapeutic Uses of Prostaglandins (Ophthalmology) (Cardiovascular System) Bimatoprost, latanoprost Epoprostenol (IV), PGF2α analogs iloprost (inhale) Treatment of open-angle glaucoma as they Prostacyclin (PGI2) analogs reduce intraocular pressure Bimatoprost increases eyelash prominence, length, and darkness and is approved for the Treatment of pulmonary arterial treatment of eyelash hypotrichosis. hypertension AE: Blurred visionIris Produce significant reduction in color change (increased brown pigmentation, pulmonary arterial resistance which may be permanent) with a subsequent increase in Increased number, length, and pigmentation cardiac index and oxygen of eyelashes delivery Ocular irritation (redness, stinging, or AE: discomfort in the eyes) Dizziness, headache, flushing, Foreign body sensation (the feeling of and fainting something in the eye) Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 15  Anti- inflammatory Drugs Prostaglandins Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Acetaminophen Traditional Disease-Modifying Antirheumatic Drugs (DMARDs) Biologic Disease-Modifying Antirheumatic Drugs (B-DMARDs) Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 16  Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 17  Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 18  Aspirin/NSAIDs Mechanism of action Aspirin: weak organic acid, irreversibly acetylates COX Other NSAIDs are reversible inhibitors of COX Main actions: Anti-inflammatory Antipyretic Analgesic Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 19  Aspirin/NSAIDs Anti-inflammatory actions COX inhibition → ↓ prostaglandins (inflammatory mediators). In RA, they inhibit the inflammation NOT the progression of the disease. Antipyretic action Inflammation → cytokines → PGE2 → fever NSAIDS block PGE2 → ↑ heat dissipation (peripheral vasodilation + sweating) NSAIDs effect on normal body temperature? Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 20  Aspirin/NSAIDs Analgesic action PGE2 mediates pain (sensitizes nerve endings to bradykinin, histamine) COX inhibition (mainly COX-2) → ↓ PGE2 → ↓ pain Differences in analgesic efficacy among different NSAIDs? All are used for musculoskeletal pain Ketorlac: can be used for severe pain (short duration) Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 21  The salicylates exhibit analgesic activity at lower doses. Only at higher doses do these drugs show anti-inflammatory activity Aspirin/NSAIDs Therapeutic Uses 1) Anti-inflammatory and analgesic uses: Osteoarthritis Gout (not aspirin) Rheumatoid arthritis Headache Arthralgia Myalgia Dysmenorrhea Cancer pain (in combination with opioids) Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 22  Aspirin/NSAIDs 2) Antipyretic uses: Aspirin, ibuprofen, and naproxen…. Aspirin should NOT be used in pediatric patients --- risk of Reye syndrome Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 23  Aspirin/NSAIDs 3) Cardiovascular applications reduce the risk of recurrent CVS events and/or death in patients with previous MI or unstable angina pectoris reduce the risk of recurring TIAs and stroke or death in those who have had a prior TIA or stroke reduce the risk of cardiovascular events or death in high-risk patients such as those with chronic stable angina or diabetes. Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 24  Aspirin/NSAIDs 3) Cardiovascular applications Low-dose (75-162 mg, 81 mg) aspirin inhibits COX-1–mediated production of TXA2, thereby reducing TXA2-mediated vasoconstriction and platelet aggregation and the subsequent risk of cardiovascular events. the antiplatelet effects persist for the life of the platelet. Chronic use of low doses allows for continued inhibition as new platelets are generated. Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 25  Aspirin/NSAIDs External applications: Salicylic acid → acne, corns calluses, warts Diclofenac (gel)→ OA (knees and hands) Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 26  Aspirin/NSAIDs Pharmacokinetics Aspirin: ❑Oral, deacetylated to salicylate ❑Absorption: passive, upper small intestine ❑Crosses the BBB/placenta Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 27  At low doses of aspirin (less than 2 g/day), uric acid secretion is decreased, whereas a high doses, uric acid secretion may be Aspirin/NSAIDs unchanged or increased. Therefore, aspirin is avoided in gout or in patients taking probenecid. Pharmacokinetics ❑Metabolism: salicylate is converted in the liver to water- soluble conjugates ❑Elimination: -renal, first-order elimination, half- life: 3.5h -at anti-inflammatory dosages (>4 g/d), half-life: 15h Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 28  Aspirin/NSAIDs Pharmacokinetics Other NSAIDs ❑Oral, parenteral ❑Metabolism: hepatic ❑Elimination: renal Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 29  ❖ NSAIDs should be taken with food or fluids to diminish GI upset. ❖ If NSAIDs are used in patients with a Aspirin/NSAIDs high risk for GI events, proton pump inhibitors should be used concomitantly to prevent NSAID-induced ulcers Adverse effects Gastrointestinal: ❑Normally, prostacyclin (PGI2) inhibits gastric acid secretion, PGE2 and PGF2α stimulate synthesis of protective mucus in both the stomach ❑COX-1 inhibitors reduce PGI2 , PGE2 and PGF2α → decreased stomach/intestinal protection. ❑Lead to gastrointestinal bleeding, ulcers Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 30  lifetime of the platelet ? Aspirin/NSAIDs Adverse effects Bleeding: ❑Aspirin irreversibly inhibits COX-1–mediated TXA2 formation, while other NSAIDs reversibly inhibit the production of TXA2 ❑antiplatelet effect with a prolonged bleeding time Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 31  Aspirin/NSAIDs Adverse effects Effects on the kidney: Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 32  Aspirin/NSAIDs Adverse effects reduction in the production of TXA2 Cardiac effects: ❑Aspirin (high COX-1) selectivity → cardioprotective decreasing PGI2 production ❑NSAIDs with higher COX-2 selectivity (or COX-2 selective inhibitors) → ↑ risk of cardiovascular events (MI, stroke). An increased risk for cardiovascular events, including MI and stroke, has been associated with all NSAIDs except aspirin naproxen appears to be the least likely to be harmful Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 33  Aspirin/NSAIDs Adverse effects Other effects: ❑Inhibition of PG synthesis → shift towards leukotrienes synthesis → bronchoconstriction → used with caution in asthma ❑CNS problems: headache, tinnitus, dizziness Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 34  Aspirin/NSAIDs Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 35  Aspirin/NSAIDs Drug interactions Salicylate is 80-90% protein- bound Drugs that are highly protein-bound can displace salicylate (and vice versa) Examples: warfarin, phenytoin, valproic acid…. Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 36  Aspirin/NSAIDs Toxicity Mild salicylate toxicity (salicylism): nausea, vomiting, hyperventilation, headache, mental confusion, dizziness, and tinnitus. Severe salicylate toxicity: Restlessness, delirium, hallucinations, convulsions, coma, respiratory and metabolic acidosis, and death 10 g of aspirin can cause death in children Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 37  Aspirin/NSAIDs Pregnancy First Trimester: Category C Risk of Miscarriage Congenital Malformations: cardiovascular defects and gastroschisis Second Trimester: Category C NSAIDs are generally considered safer during this period compared to the first and third trimesters Third Trimester: Category D NSAIDs should generally be avoided during the third trimester due to the following risks: Premature Closure of the Ductus Arteriosus Oligohydramnios Prolonged Labor or Delayed Onset of Labor Safer Alternatives During Pregnancy: Acetaminophen (Paracetamol) Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 38