Kidney and Drugs

Renal excretion The major organ for the excretion of drugs is the KIDNEY. The functional unit of the kidney is the nephron. Major Excretory Processes in the Nephron Glomerular filtration Increase drug conc. in lumen Tubular secretion Increases drug conc. in lumen Tubular re-absorption Decreases drug conc. in lumen

Effect of Urine pH on tubular re-absorption Many drugs are either weak bases or acids and therefore the pH of the filtrate can greatly influence the extent of tubular re-absorption for many drugs. When urine is acidic, weak acid drugs tend to be reabsorbed. Alternatively when urine is more alkaline, weak bases are more extensively reabsorbed These changes can be quite significant as urine pH can vary from 4.5 to 8.0 depending on the diet (e.g. meat can cause a more acidic urine) or food rich in carbohydrate ↑ pH or drugs (which can increase or decrease urine pH).

Alteration of Urine pH Excretion of some drugs can be increased by suitable adjustment of urine pH e.g. pentobarbital (a weak acid) overdose may be treated by making the urine more alkaline with sodium bicarbonate injection. Effective if the drug is extensively excreted as the unchanged drug. If the drug is extensively metabolized, then alteration of kidney excretion may not significantly alter the overall drug metabolism.

Nephrotoxic Drugs Dose dependant toxicity Idiosyncratic Renal Damage NSAIDs including COX 2 Aminoglycosides Radio opaque contrast materials Idiosyncratic Renal Damage NSAIDs Penicillins Gold, penicillamine

NSAIDs (Non-steroidal anti inflammatory drug( Commonly used Interfere with prostaglandin production, disrupt regulation of renal medullary blood flow and salt water balance Chronic renal impairment Habitual use Exacerbated by other drugs ( anti- hypertensives, ACE inhibitors)

Aminoglycoside Nephrotoxicity • Incidence • 5% to 15% of patients receiving aminoglycoside therapy 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

Prescribing Aminoglycosides Once daily regimen now recommended in patients with normal kidneys High peak concentration enhances efficacy long post dose effect Single daily dose less nephrotoxic

Amphotericin-B Nephrotoxicity • Incidence Toxicity relates to cumulative dosage, starts from 300-400mg, 4g (at higher doses 80% incidence) Prevention • Liposomal amphotericin B formulations (Targeted drug delivery) • IV infusion of NS daily during the course of therapy reduces toxicity Management • Discontinuation and substitution of therapy • Daily monitoring of Renal function indices i.e. Scr and BUN • Daily monitoring of serum magnesium, potassium, and calcium concentrations

CHRONIC INTERSTITIAL NEPHRITIS • A progressive and irreversible lesion Causative agents • Lithium • Cyclosporine

PAPILLARY NECROSIS • Necrosis of the renal papillae (region where collecting ducts enter the renal pelvis) • Risk Factors • Cumulative consumption of combination analgesics, phenacetin, or acetaminophen and aspirin • Caffeine in combination analgesics • Causative agents • Analgesic

Intravenous Contrast Used commonly CT scanning, IV urography, Angiography Unsafe in patients with pre-existing renal impairment Risk increased in diabetic nephropathy, heart failure & dehydration Can precipitate end-stage renal failure Cumulative effect on repeated administration

Prescribing in Kidney Disease Patients with renal impairment Patients on Dialysis Patients with renal transplants

Dosing in renal impairment Loading dose does not change (usually( Maintenance dose or dosing interval does T ½ often prolonged Reduce dose OR Increase dosing interval

Risk Factors Patient-related factors • Age, sex, race • Pre-existent renal disease • Specific disease (diabetes mellitus, multiple myeloma, proteinuric patients) • Sodium-retaining states (cirrhosis, heart failure, nephrosis) • Dehydration and volume depletion • Acidosis, potassium and magnesium depletion • Hyperuricemia, hyperuricosuria • Sepsis, shock • Renal transplantation

• Drug-related factors • Inherent nephrotoxic potential • Dose • Duration, frequency and form of administration • Repeated exposure • Drug interactions • Combined or closely associated use of diagnostic or therapeutic agents with added or synergistic nephrotoxic potential (e.g. Radiocontrast agents, aminoglycosides, NSAIDs, cisplatin, ACEI)

Prevention • Avoid the use of potentially nephrotoxic agents (patients at increased risk for toxicity) • Maintain careful and adequate hydration to establish high renal tubular urine flow rates

Excretion Excretion is the most important pharmacokinetic factor altered in renal insufficiency by: Glomerular filtration, tubular secretion, reabsorption: Net renal excretion of a drug is a composite of these 3 factors. Generally it is assumed that all 3 decline in a parallel manner. Creatinine clearance is, therefore, the guiding factor for drug dosage. Determination of a patient’s 24-hour creatinine clearance by urine collection will confirm the degree of suspected renal insufficiency and frequently assist with safer drug prescribing.

• Identify those patients at risk for renal insufficiency • Measure serum creatinine and either calculate or measure creatinine clearance • Consider whether the patient’s medications should be altered because of the patient’s renal insufficiency • Adjust drug doses if required • Use the least nephrotoxic drug possible • Monitor drug levels and renal function • Keep up-to-date medication lists and be aware of complementary medicines