NSAIDs, DMARDs, Anti-gout Agents 2024-25 PDF

PHID 1606 – Integrated Sequence VI – Winter Quarter 2024 December 10, 11, 2024 Pharmacology of NSAIDs, DMARDs, and Anti-Gout Agents Required Reading: Katzung 16th Ed., Chpt. 36 & 18 Recommended Reading: G&G 14th Ed, Chpt 39, 41...

PHID 1606 – Integrated Sequence VI – Winter Quarter 2024 December 10, 11, 2024 Pharmacology of NSAIDs, DMARDs, and Anti-Gout Agents Required Reading: Katzung 16th Ed., Chpt. 36 & 18 Recommended Reading: G&G 14th Ed, Chpt 39, 41, 42 Molly Yao, Ph.D., M.S. Professor Phone: 572-3575 Email: [email protected] Office: Glendale Hall 236-10 © MWU 2024 Dr. Yao  Learning Objectives Be familiar with physiological roles of PGE , PGI , & TXA 2 2 2 Compare/contrast the effects of COX1 and COX2 State the MOA, ADR, contraindication of NSAIDs as a class Identify COX non-selective, COX2 selective NSAIDs Explain toxicity of acetaminophen to NSAIDs Recognize classes of conventional synthetic (cs) DMARDs and biological (b) DMARDs Understand MOA, ADR, drug interactions, contraindication, boxed warnings of DMARDs, if any State MOA, ADR, drug interactions, contraindication, boxed warnings of anti-gout agents  Review: Osteoarthritis (OA) Also called degenerative joint Disease Characterized by degeneration of cartilage that results in structural and functional failure of synovial joints An intrinsic disorder of cartilage in which chondrocytes respond to biochemical and mechanical stresses resulting in the breakdown of the matrix and failure of its repair “wear and tear” arthritis; degenerative joint disease Collagen is degraded faster than synthesized; cartilage is lost Mechanical, biochemical, and inflammatory processes  Review: Eicosanoids and Prostanoids Eicosanoids Classically refers to unbranched 20-carbon fatty acids derived from arachidonic acid (fatty acid component of phospholipids in inner leaflet of plasma membrane of many cell types) oxygenation – Extremely prevalent Centrally involved in number of metabolic pathways, leading to wide range of potent biological effects on a wide range of systems Diverse roles in inflammation & cellular signaling Inflammatory, neoplastic, GI, cardiovascular physiology and pathophysiology: inflammation, smooth muscle tone, hemostasis, thrombosis, parturition Can be inhibited by NSAIDs, COX-2 inhibitors, leukotriene inhibitors Chemically diverse family of autacoids Rapidly synthesized in response to specific stimuli, act Pathways of Arachidonic Acid (AA) Release and Metabolism  Cyclooxygenase (COX) Family of enzymes that converts AA to PGH2 Two main isoforms: COX1 and COX2 COX1 Constitutively expressed in most cells Generate prostanoids for “housekeeping” function COX2 Readily inducible expression Immediate early response gene product Major source of prostanoids in inflammation and cancer Prostanoi PGH2 rapidly converted to biologically active ds prostaglandins, thromboxane, Biosynth prostacyclin via various different enzymes esis Expression of enzymes differs in different cell types, hence tissue or cell specificity Most cells make one or two dominant prostanoids  Prostanoids: Prostaglandins Prostaglandins differ from each other in two ways The substituents of the pentane ring (indicated by the last letter, e.g., E and F in PGE and PGF) The number of double bonds in the side chains (indicated by the subscript, e.g., PGE1, PGE2)  PGE2 EffectsPGI 2 has similar effects as PGE2 on Pain pain, fever, inflammation, threshold to stimulation of nociceptors  peripheral and sensitization GI Centrally active PGE2 production and release from spinal cord and brain COX in response to peripheral pain stimuli  central sensitization  excitability of spinal dorsal horn neurons  hyperalgesia Fever PGE2 crosses the blood-brain barrier  act on receptors on thermosensitive neurons  trigger hypothalamus  heat generation, heat loss  body temperature Inflammation Pro-inflammation: local blood flow; vascular permeability & leukocyte infiltration, leukocyte chemoattraction & endothelial adhesion GI (IS2)  PGE2 EffectsPGI2 has similar Kidney effects as PGE2 on Eicosanoid products: PGE2 and PGI2kidney , followed by PGF2α and TXA2 Regulate renal function, particularly in marginally functioning kidneys and volume-contracted states Renal COX2-derived PGE2 and PGI2 maintain renal blood flow and glomerular filtration rate Modulate systemic blood pressure through regulation of water and sodium excretion High salt intake diet medullary COX2 expression  medullary blood flow, tubular salt reabsorption COX1-derived products promote salt excretion in the collecting ducts Low salt intake diet: cortical COX2 expression  renin release  glomerular filtration, salt  Prostanoids: Prostacyclin PGI2 Platelet Effects Endothelial COX2-produced PGI2 potently inhibits platelet aggregation COX2 inhibitors reduce PGI2 production  platelet activation and aggregation Prostanoids: Thromboxane (TXA2) Platelet COX1: the only COX isoform expressed in mature platelets Major product: TXA2 Induce platelet aggregation, amplify effect of other potent platelet agonists, e.g., thrombin Platelet actions of TXA2 are restrained by PGI2 and PGD2  Prostanoid FYI GPCRs Receptors Five main types: ligand DP: PGD2 EP: PGE2 FP: PGF2α IP: PGI2 TP: TXA2 Activate different pathways → complex signaling → paradoxical effects Multiple second messenger systems cAMP: inhibit platelet aggregation; relax smooth muscle IP3/DAG: stimulate platelet aggregation; contract Prostanoid Receptors & Signaling FYI Pathways 3 Anti-Inflammation by Targeting AA Derivatives Steroi ds (IS3) Protei n synthe sis NSAID s  NSAIDs Named so as to differentiate from steroids Analgesic; antipyretic; anti-inflammatory effects Aspirin (Acetylsalicylic acid, ASA): Prototype of NSAIDs Non-acetylated salicylates COX1 and COX2 non-selective NSAIDs Ibuprofen, indomethacin, naproxen, Ketorolac, etc. Vary primarily in their potency, analgesic, anti- inflammatory effectiveness, & duration of action Ibuprofen & naproxen have moderate effectiveness Indomethacin has greater anti-inflammatory effectiveness, used for rheumatic arthritis (RA) Ketorolac has greater analgesic effectiveness ADRs often determine selection COX2 Selective NSAIDs Celecoxib, diclofenac, meloxicam, etc. Developed to lessen GI toxicity Inhibit endothelial COX2-derived PGI2 production  inhibition of TXA2-mediated platelet aggregation   NSAIDs: MOA Aspirin Low range ( 4 g/day or use of multiple acetaminophen-containing products Can require liver transplant or result in death  Review: Rheumatoid Arthritis (RA) of autoimmune origin A chronic inflammatory disorder that principally attacks the joints, producing a nonsuppurative proliferative and inflammatory synovitis. Often progresses to the destruction of the articular cartilage and, in some cases ankylosis (adhesion) of the joints Extraarticular lesions may occur in the skin, heart, blood vessels, and lungs  Review: Pathogenesis of RA Antibodies against self-antigens CD4+ T cell-derived cytokine-mediated inflammation T cells may initiate the autoimmune response Activated CD4+ T cells activate B cells, plasma cells, and other inflammatory cells Genetic Drug factors target Environment al factors Drug target APC, antigen-presenting cell; BAFF, B cell activating factor; BLyS, B lymphocyte stimulator; RF, rheumatoid factor  Review: Pathogenesis of RA Activated CD4+ T cells-produced cytokines  IFN-γ recruit macrophages  cause tissue injury TNF and IL-1 from macrophages activate resident synovial cells (fibroblasts, chondrocytes)  release proteolytic enzymes (collagenases, metalloproteinases), growth factors  destruct cartilage, ligaments and tendons of the joints, nonsuppurative proliferative synovitis  RANKL osteoclasts activity  bone destruction Drug target Proliferation of synovial lining cells  Disease Modifying Anti-Rheumatic Drugs (DMARDs) NSAIDs provide symptomatic relief DMARDs slow down disease progression Conventional synthetic (cs) DMARDs Methotrexate Sulfasalazine Hydroxychloroquine Leflunomide Janus kinase inhibitors: tofacitinib, baricitinib and upadacitinib Biological (b) DMARDs Tumor necrosis factor (TNF) inhibitors: etanercept, infliximab, adalimumab, golimumab, certolizumab Interleukin-1 inhibitors anakinra Interleukin-6 receptor antagonists: tocilizumab, sarilumab  csDMARDs: Methotrexate MOA (MTX) Major MOA in RA Inhibits amino-imidazole-carboxamide-ribonucleotide (AICAR) transformylase  extracellular AMP accumulation  adenosine production  adenosine ‘checks’ overactive immune response and other anti-inflammatory effects  inhibit inflammation, suppress neutrophil, macrophage, dendritic cell, and lymphocyte function      adenosine deaminase (ADA)  csDMARDs: MTX Major MOA in RA Inhibit thymidylate synthase (TYMS)  suppress formation of thymidine residues  reduce DNA synthesis  suppress cell proliferation Minor MOA in RA Inhibit dihydrofolate reductase  inhibit proliferation, ADR stimulate apoptosis Stomatitis; nausea Leukopenia, anemia, GI ulceration, alopecia Dose-related liver enzyme elevations Folate administration to ↓hematological, GI and hepatic side effects Contraindications Pregnancy, breastfeeding, alcohol use disorder, chronic liver disease, blood dyscrasias, immunodeficiency syndrome Boxed warnings  csDMARDs: MTX PK Renal excretion: 90% MTX is excreted unchanged in the urine Any condition or drug that impairs renal blood flow will impair MTX elimination and toxicity potential Hepatic metabolism to 7-hydroxymethotrexate has potential to cause nephrotoxicity High degree (50%) of albumin binding  easily displaced by other drugs with higher albumin binding affinity Drug interactions Loop diuretics can MTX concentration Aspirin/NSAIDs, beta-lactams, probenecid have potential to impair renal function  renal elimination of MTX  MTX toxicity MTX can effectiveness of loop diuretics Sulfonamides, salicylates and phenytoin: free MTX and toxicity Sulfonamides: adverse effects of both 30  csDMARDs: Sulfasalazine MOA Unclear Contraindications Sulfa or salicylate allergy GI or GU obstruction Porphyria  csDMARDs: Hydroxychloroquine internal extern MOA (HCQ) al Stabilize lysosomal enzymes in APCs HCQ enters and accumulates in lysosomes  pH lysosome  prevent activity of lysosomal enzymes  inhibit degradation of cargo  prevent MHC class II-mediated autoantigen presentation  suppress T cell responses to mitogen  csDMARDs: Pro-inflammatory MOA Hydroxychloroquine cytokines (HCQ) Inhibit expression of pro- inflammatory cytokines by preventing TLR signaling and cGAS–stimulator of interferon genes (STING) signaling accumulate in endosomes  alter pH  inhibit pH- dependent Toll-like receptor (TLR) processing bind to DNA or RNA of pro- inflammatory cytokines  prevent RNA and DNA from binding to TLR7 and TLR9, respectively inhibit activity of the nucleic acid sensor cyclic GMP- AMP  csDMARDs: Hydroxychloroquine (HCQ) ADR Dosing ≤ 6 mg/kg/d: retinopathy < 1% for up to 5 yrs, < 2% for up to 10 yrs; 1% per year thereafter Baseline ophthalmologic exam and annual screenings after 5 yrs are recommended  csDMARDs: Leflunomide MOA Prodrug converted to active rate metabolite teriflunomide (A77 limiting step in 1726) in the intestine and pyrimidine plasma  inhibit synthesis Leflunomi dihydroorotate de dehydrogenase (DHODH) in the mitochondria  ↓orotate  ↓uridine monophosphate (UMP)  ↓pyrimidine synthesis necessary for DNA replication of rapidly dividing cells  ↓T-cell proliferation, ↓B-cell antibody production,  csDMARDs: Leflunomide Significant enterohepatic circulation Can take up toLong elimination half-life of 2 weeks 2 years to be completely cleared after discontinuation Accelerate clearance: bile acid resin like cholestyramine or activated charcoal suspension ADR Dose-related diarrhea and liver function abnormalities Mitochondrial dysfunction may account for hepatoxicity Contraindications Pregnancy, severe hepatic impairment, current teriflunomide therapy Boxed warnings: do not use in pregnancy Must have negative pregnancy test and use 2 forms of birth control during treatment If pregnancy is desired, must wait 2 years after  Small Molecule JAK Inhibitor: Tofacitinib MOA Inhibit Janus kinase (JAK)  block JAK-signal transducer and activator of transcription (STAT) pathway  prevent pro- inflammatory gene expression, including TNF-α, interleukins Indicated for psoriatic arthritis, rheumatoid arthritis, UC 37 Targeted Synthetic (ts) DMARDs: Janus Kinase (JAK) Inhibitors Tofacitinib, Baricitinib, Upadacitinib Tofacitinib Baricitinib Upadacitini b MOA Interrupt JAK-STAT signaling pathway by inhibiting Selectivity JAK1, 2, 3 JAK1, 3 > JAK2 JAK1, 2 > JAK 3 Metabolis CYP3A4 (70) CYP3A4 (10) Unchanged (79); m (%) CYP3A4 (