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Analgesic Nephropathy

Analgesic Nephropathy. Lecture Overview. A. Background NSAIDs: Overview and clincial use Targets of NSAIDs: The Cyclooxygenase (COX) enzymes The role of prostaglandins in inflammation, pain & fever The role of prostaglandins in housekeeping functions B. The Pharmacology of NSAIDs

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Analgesic Nephropathy

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  1. Analgesic Nephropathy

  2. Lecture Overview A. Background • NSAIDs: Overview and clincial use • Targets of NSAIDs: The Cyclooxygenase (COX) enzymes • The role of prostaglandins in inflammation, pain & fever • The role of prostaglandins in housekeeping functions B. The Pharmacology of NSAIDs • Aspirin and the Salicylates • Traditional non-selective NSAIDs e.g. Ibuprofen/naproxen • Coxibs: Selective COX-2 inhibitors e.g. Celecoxib C. Related Non-NSAID Analgesic - Acetaminophen

  3. NSAIDs: An Overview • NSAID Facts: • Amongst the most widely prescribed and used drugs in the US • 1 in 7 Americans treated with NSAIDs for a chronic Rheumatologic disorder • >80 million NSAID prescriptions written/year - ~4.5% of all prescriptions • >30 billion OTC sales of NSAIDs/year • >1% of Americans use NSAIDs on a daily basis

  4. However, there are significant risks of adverse effects with NSAID use: • NSAIDs-induced adverse effects result in >100,000 hospitalizations, ~16,500 deaths and ~45% of drug-related emergency room visits per year • ~33% of Hospitalizations for GI bleeds are caused by NSAIDs • 20-30% of hospitalizations of patients over the age of 60 are due to complications from NSAID use

  5. Therapeutic Applications of NSAIDs GENERAL INDICATIONS: INFLAMMATION, PAIN & FEVER 1. Mild to moderate pain associated with inflammation 2. Chronic inflammatory diseases: a) Rheumatoid Arthritis b) Osteoarthritis c) Acute gout 3. Pain relief -muscle strains, sprains and lower back pain - headache and migraine - Dysmenorrhoea/menstrual cramps - metastatic bone cancer pain - post-operative pain/dental procedures 4. Fever reduction - e.g. common cold/influenza virus 5. Aspirin-Specific Use: Prophylactic treatment to reduce the risk of myocardial infarction and stroke by inhibitingplateletaggregation

  6. Inflammatory Mediators e.g. Cytokines & Prostaglandins NSAIDS Inflammation Pain Fever NSAIDs work by blocking Prostaglandin production: Critical mediators of the inflammatory response Tissue Damage Affected Tissue N.A.C

  7. { a) Cyclooxygenase NSAIDs PG PGG2 b) Peroxidase PGH2 NSAIDs block PG synthesis By inhibiting COX enzymes PG/TX synthases PGI2 PGE2 PGD2 TXA2 PGF2a (Prostacyclin) (Thromboxane) Biological Response NSAID drugs act by inhibiting COX-dependent Prostaglandin synthesis Plasma Membrane Phospholipids Phospholipase A2 Arachidonic Acid Cyclooxygenase Enzymes (PGH2 synthase)  Inflammation  Pain  Fever But also  Adverse Effects N.A.C

  8. NSAIDs: Mechanism of Action All NSAIDs work by inhibiting the activity of cyclooxygenase enzymes Two distinct cyclooxygenase (COX) enzymes: COX-1 & COX-2. - Both enzymes catalyze the conversion of membrane-derived Arachidonic Acid into Prostaglandins and Thromboxane Prostaglandins and Thromboxane are lipid mediators - regulate numerous homeostatic and inflammatory processes. COX-1 - associated with regulating homeostatic functions COX-2 - primarily associated with inflammatory responses.

  9. Distinct physiological roles of COX-1 and COX-2 Inflammatory Stimuli Arachidonic Acid Constitutive Inducible COX-1 COX-2 Constant Low level PG production Acute High level PG production Housekeeping Functions Platelet regulation (blood clotting) Kidney Function Regulation stomach acid/mucous production Inflammation Pain Heat Swelling N.A.C

  10. Pathophysiological functions of COX-2 Increased COX-2 activity promotes: A) Inflammation B) Pain C) Fever Mediated by the actions of COX-2-derived Prostaglandins

  11. Risk factors for NSAID induced Acute vasomotor renal failure • Decreased effective arterial blood volume • CHF • CIRRHOSIS • NEPHROTIC SYNDROM • SEOSIS • HEMORRHAGE • DURITIC • POSTOPRATIVE PATIENTS WITH THIRD SPACE • HYPOTENSION • Normal or increased effective arterial blood volume • CRF • GN • ELDERLY • CIN • OBSTRACTIVE UROPATHY • CYCLOSPORIN A

  12. Predisposing factor for NSAIS nephrotoxicity in old adult • Age related change in renal function • ↓ GFR • ↓ Renal blood flow • ↑ Renal vascular resistanc • Age related change in pharmacokinetics • ↑ Free drug concentration • Hypoalbuminemia • Retaindmetabolits • ↓ Total body water • ↓Hepatic metabolism with longer half- life

  13. Renal syndrome with NSAID • Vasomotor ARF • Nephroticsybdrom with TIN • CRF • Salt retention • Hyponatremia • Hyprekalemia

  14. CLINICAL FEATURE Of NSAID INDUCES VASOMOTOR RENAL FAILURE OLIGURIE Usually occurs whit in a few days Hyperkalemia out of proportion of renal failure Low FeNa Usually dose not require dialysis Usually reversible

  15. NSAID induced TIN VS. typical TIN

  16. What should we do?

  17. خسته نباشید روز خوش

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