Dr. Sumit Kr.

Ghosh
Asst. Professor Department of Medicine Medical College & Hospital, Kolkata

INTRODUCTION
   

Renal Physiology and Pharmacokinetics Drugs and normal kidney Drugs toxic to kidney Prescribing drugs in kidney diseases

RENAL PHYSIOLOGY
1. Extra Cellular Fluid Volume control 2. Electrolyte balance 3. Waste product excretion 4. Drug and hormone elimination/metabolism 5. Blood pressure regulation 6. Regulation of haematocrit 7. Regulation of calcium/phosphate balance (vitamin D3 metabolism)

PHARMACOKINETICS
1. 2. 3. 4.

Absorption Distribution Metabolism Elimination

Renal Excretion
Total amount of excretion of a drug depends on 1) Glomerular filtration: ~ plasma protein binding ~ renal blood flow 2) Tubular reabsorption ~ lipid solubility ~ ionization 3) Tubular secretion active transport of organic acids & bases If renal clearance of a drug >120ml/min (GFR), additional tubular secretion can be assumed to be occurring

DRUGS & NORMAL KIDNEY



Diuretics: - Loop - Thiazide - Aldosterone antagonist - Osmotic Antidiuretics

Indications for use of diuretics

 Heart failure ( acute or chronic )
   

Pulmonary oedema Hypertension Nephrotic syndrome Hypercalcaemia

Thiazide

Amiloride Loop

DRUGS TOXIC TO KIDNEY (NEPHROTOXIC DRUGS)



Drug related renal pathology can affect any / all kidney compartments 1) Tubulointerstitium is commonly involved, best known examples NSAID and antibiotics - drugs should be considered in all primary tubulointerstitial diseases 2) Glomeruli 3) Vasculature (only infrequently affected) - mimicks many primary renal diseases Mechanism: - immunologically mediated - toxic/ischemic damage dose is important for the later Dose dependent vs Idiosyncratic

Patterns of Drug-induced Lesions

Tubulointerstitium Acute tubular injury - Osmotic nephrosis - Nephrocalcinosis - Chrystal NP Acute interstitial nephritis Chronic tubulointerstitial nephropathy Glomeruli Minimal change disease Focal segmental glomerulosclerosis Membranous GN Crescentic GN Thrombotic microangiopathy Blood vessels Hyalinosis Thrombotic microangiopathy Vasculitis

TubuloTubulointerstitium
NSAID ACEACE-I Antibiotics Lithium Diazepam Bisphosphonate Cisplatin Methotrexate

Glomeruli
NSAID Lithium Bisphosphonate Propyithiouracil Cisplatin Mitomycin C Tamoxifen

Blood vs
Clopidogrel Quinine Phenytoin Sulfasalazine Propyithiouracil Mitomycin C Penicillamine

PRESCRIBING DRUGS IN KIDNEY DISEASES

  

Patients with renal impairment Patients on Dialysis Patients with renal transplants

Clearance of drugs that are primarily excreted unchanged (aminoglycosides, digoxin) is reduced parallel to decrease in CrCL Loading dose of such a drug is not altered but maintenance doses should be reduced or dose interval prolonged proportionately Rough guide:
CrCL (ml/min) 5050-70 3030-50 1010-30 5-10 dose to be reduced by 1.5times 2 times 3 times 6 times

 

Dose rate of drugs, partly excreted unchanged in urine also needs reduction, but to lesser extent Plasma proteins, esp albumin, are often low or altered in structure in patients with renal diseases binding of acidic drugs is reduced but not that of basic drugs Permeability of BBB is increased in renal failure - Sedatives causes more CNS depression - Antihypertensive drugs produce more postural hypotension

Drugs worsen existing clinical condition in renal failure Antimicrobials requiring dose reduction in renal failure Even in mild failure Aminoglycosides Ethambutol Vancomycin Amphotreicin B Acyclovir Only in severe failure Cotrimoxazole Cefotaxime Ciprofloxacin, Norfloxacin Metronidazole

Diuretics : Thiazide diuretics tends to reduce GFR, ineffective in renal failure and can worsen uremia Potassium sparing diuretics are cotraindicated; can cause hyperkalemia

ASSESSMENT
Clinical features : Oliguria, anuria, hematuria Freqency Pedal swelling, facial puffiness, ascites Bone pain Vomitting Altered sensorium H/O drug intake CoCo-morbidities Pallor, BP, edema, volume status, flapping tremor Investigations


    

Routine tests : Hb%, serum albumin, urea, creatinine, electrolytes Urine R/E, M/E, C/S Urinary ACR Imaging : X-ray, USG, CT XClearance tests Nuclear scan Kidney biopsy

Two formulas are widely used to estimate GFR: 1) Cockcroft-Gault formula Cockcroft-

2) MDRD (Modification of Diet in Renal Disease)