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Published byAlice Hunt Modified over 9 years ago
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Analgesic Nephropathy
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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 Lecture Overview
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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
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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
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Therapeutic Applications of NSAIDs 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 inhibiting platelet aggregation GENERAL INDICATIONS: INFLAMMATION, PAIN & FEVER
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NSAIDs work by blocking Prostaglandin production: Critical mediators of the inflammatory response Affected Tissue Inflammatory Mediators e.g. Cytokines & Prostaglandins Tissue Damage Inflammation PainFever N.A.C NSAIDS
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Arachidonic Acid Phospholipase A2 Plasma Membrane Phospholipids N.A.C PGH2 PGI2PGE2 PGF2 PGD2TXA2 PG/TX synthases (Prostacyclin)(Thromboxane) a) Cyclooxygenase { PGG2 b) Peroxidase Biological Response NSAIDs NSAIDs block PG synthesis By inhibiting COX enzymes NSAID drugs act by inhibiting COX-dependent Prostaglandin synthesis PG Inflammation Pain Fever Cyclooxygenase Enzymes (PGH2 synthase) But also Adverse Effects
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NSAIDs: Mechanism of Action cyclooxygenase enzymes 1.All NSAIDs work by inhibiting the activity of cyclooxygenase enzymes 2.Two distinct cyclooxygenase (COX) enzymes: COX-1 & COX-2. - Both enzymes catalyze the conversion of membrane-derived Arachidonic Acid into Prostaglandins and Thromboxane 3.Prostaglandins and Thromboxane are lipid mediators - regulate numerous homeostatic and inflammatory processes. 4.COX-1 - associated with regulating homeostatic functions COX-2 - primarily associated with inflammatory responses.
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Distinct physiological roles of COX-1 and COX-2 Arachidonic Acid COX-1COX-2 Constitutive Inflammatory Stimuli Housekeeping Functions Platelet regulation (blood clotting) Kidney Function Regulation stomach acid/mucous production Inflammation Pain Heat Swelling N.A.C Inducible Constant Low level PG production Acute High level PG production
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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
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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
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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 – Retaind metabolits ↓ Total body water ↓Hepatic metabolism with longer half- life
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Renal syndrome with NSAID Vasomotor ARF Nephrotic sybdrom with TIN CRF Salt retention Hyponatremia Hyprekalemia
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CLINICAL FEATURE Of NSAID INDUCES VASOMOTOR RENAL FAILURE 1.OLIGURIE 2.Usually occurs whit in a few days 3.Hyperkalemia out of proportion of renal failure 4.Low FeNa 5.Usually dose not require dialysis 6.Usually reversible
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NSAID induced TIN VS. typical TIN خصوصیت نفریت بینابینی ناشی از NSAID نفریت بینابینی معمول طول مدت تماس 5 روز تا یک سال 5 تا 26 روز علائم حساسیتی 7 تا 8 درصد 80 درصد ائوزینوفیلی 17 تا 18 درصد 75 تا 80 درصد پروتیئنوری بیش از 3/5 گرم بیش از 90 درصدکمتر از 10 درصد ائوزینوفیلوری تا 5 در صد 80 تا 85 درصد حد اکثر غلظت سرمی کراتینین 1/5 تا 10 میلی گرم 3/7 تا 10 میلیگرم
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What should we do?
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خسته نباشید روز خوش
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