2. Analgesic Nephropathy

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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.

10. 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

11. 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

12. 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

13. 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

14. Renal syndrome with NSAID Vasomotor ARF Nephrotic sybdrom with TIN CRF Salt retention Hyponatremia Hyprekalemia

15. 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

16. 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

17. What should we do?

18. خسته نباشید روز خوش