Tiêu đề 23. DRUG INDUCED RENAL DISORDERS.pdf ✅

PHARMD GURU Page 1 INTRODUCTION: Drug induced kidney disease constitutes an important cause of acute renal failure and chronic kidney disease due to drugs, by virtue of immunological mechanisms or direct toxicity initiate certain stereotyped renal responses. RENAL PATHOPHYSIOLOGICAL ALTERATIONS (DRUG INDUCED): 1) Tubular epithelial cell damage  Acute tubular necrosis  Osmotic nephrosis 2) Hemodynamically mediated kidney injury 3) Obstructive nephropathy  Intratubular obstruction  Nephrolithiasis 4) Glomerular disease 5) Tubulo-interstitial disease  Nephrocalcinosis  Papillary necrosis  Acute allergic interstitial nephritis  Chronic interstitial nephritis 6) Renal vasculitis, thrombosis and cholesterol emboli  Vasculitis and thrombosis  Cholesterol emboli 1) TUBULAR EPITHELIAL CELL DAMAGE:  Caused by either direct toxic or ischemic effects of drugs  Damage is localized in the PCT and DCT epithelia  Acute tubular necrosis: Observed as cellular degeneration and sloughing from PCT and OCT basement membranes  Osmotic nephrosis: Swelling and vacuolization of proximal tubular cells. DRUG INDUCED RENAL DISORDERS
PHARMD GURU Page 2 ACUTE TUBULAR NECROSIS: AMINOGLYCOSIDE - NEPHROTOXICITY: Incidence: 5% to 15% of patients receiving aminoglycoside therapy Clinical Presentation:  Gradual progressive rise in Scr and in CrCI after 6 to 10 days of therapy  Nonoliguria >500 mL/day  Magnesium wasting >10 to 30 mg  Severe kidney injury does not usually develop Pathogenesis:  Binding, intracellular transport in lysosomes  Release of lysosomal enzymes  ROS generation, Altered cell metabolism and membrane fluidity  Cellular dysfunction and death  PCT epithelial cell damage leading to obstruction of the tubular lumen  Back leakage of the glomerular filtrate across the damaged tubular epithelium  Reduction of GFR Risk Factors:  Aggressive aminoglycoside dosing  Combination of nephrotoxic drug therapy  Existing predisposing conditions Prevention:  Alternative therapy: fluoroquinolones,3rd or 4th generation cephalosporins  Limit the total aminoglycoside dose administered  Avoid concomitant therapy with other nephrotoxic drugs  High intermittent dosing: Once daily dosing regimen Management:  Measure Scr every 2 to 4 days  Maintain adequate hydration (Avoid volume depletion)  Discontinue or revised regimen if Scr increase of 0.5 mg/dL or more

PHARMD GURU Page 4 CISPLATIN AND CARBOPLATIN NEPHROTOXICITY: Incidence:  Previously incidence was 50-100%, now it has reduced to 6-13%  20% to 40% decline in GFR is frequently observed Pathogenesis:  Binding to PCT cell proteins and sulfhydryl groups  Disruption of cell enzyme activity, uncoupling of oxidative-phosphorylation  Initially PCT is damaged which progresses to DCT and glomerular necrosis Clinical Presentation:  Scr reaches at peak after 10-12 days of therapy which recovers in 21 days  Dose related toxicity, cumulative response on subsequent cycles  Hypocalcaemia and hypokalaemia  Hypomagnesemia is associated with seizures, neuromuscular irritability, or personality changes, and persist long after chemotherapy Risk Factors:  Age, dehydration, renal irradiation, concurrent use of aminoglycoside antibiotics, and alcohol abuse Prevention:  Dose reduction and decrease frequency of administration  Combination with other safer chemotherapeutic agents  Vigorous hydration (maintain 100 ml/h of urine output)  Start 24 hrs prior therapy: 250 ml/h 1 to 4 L of NS  4-8 hrs after dose: 150 to 250 ml/h  Amifostine: organic thiophosphate  Chelates cisplatin in normal cell, reduces nephrotoxicity, neurotoxicity, ototoxicity and myelosuppression Management:  Cisplatin induced AKI is partially reversible  Daily monitoring of Renal function indices i.e. Scr and BUN  Daily monitoring of serum magnesium, potassium, and calcium concentrations