Drugs and Kidney NEPHROTOXIC DRUGS Nephrotoxic drugs Direct

Drugs and Kidney

NEPHROTOXIC DRUGS

Nephrotoxic drugs : Direct nephrotoxic drugs : Glomerulopathy : penicillamine, gold : these cause proteinuria, and sometimes nephrotic syndrome due to deposition of immune complexes. Glomerulitis and proteinuria may also rarely occur with drug-induced SLE caused by hydralazine or procainamide. Proximal tubule damage: cisplastin, cyclosporine, aminoglycosides, iodinated radiocontrast media (esp. in RF): can cause decline in renal function, & sometimes ARF. Tetracyclines, esp. outdated preparations, may cause Fanconi syndrome with impaired proximal renal tubule reabsorption of glucose, amino acids, phosphate, & bicarbonate.

Damage to distal tubules : Amphotericin B causes distal renal tubular acidosis with increase in creatinine; partially reversible on stopping drug Interstitial nephritis : NSAIDs (except salicylates) (due to high concentration in medulla and inhibition of synthesis of medullary vasodilator PGs). May also be due to allergic reaction to some penicillins (esp. methicillin), cephalosporins, allopurinol. Papillary necrosis: this occurs usually with NSAIDs esp with analgesic mixtures. Nephrogenic diabetes insipidus : due to demeclocycline , lithium; there is loss of renal concentrating power leading to polyuria.

Indirect nephrotoxicity Precipitation of drugs or their metabolites in lumen of renal tubules (after their filtration by glomeruli) causing tubular obstruction which may lead to tubular damage and RF: This occurs in following : - Precipitation of the crystals of the inactive hepatic acetyl metabolites of sulfonamides in renal tubules in cases of oliguria or acid urine p. H. The cytotoxic drug methotrexate may precipitate at acid urine p. H since it becomes poorly soluble. Precipitation may also occur with IV acyclovir, used against severe herpes virus infection , & with protease inhibitor indinavir used in AIDs patients.

- Urate nephropathy : when there is precipitation of urate crystals due to formation of large amounts of uric acid in liver from nucleoproteins as a result of destruction of large number of cancer cells in chronic leukemia or lymphoma or myeloma by cytotoxic drugs. It is preventable by allopurinol. - Tubular obstruction by pigment may occur leading to acute tubular necrosis and RF : this occurs with severe drug-induced intravascular hemolysis causing hemoglobinemia & hemoglobinuria; also occurs with severe drug-induced rhabdomyolysis causing myoglobinuria - Hypovolemia following severe diarrhea which can lead to acute tubular necrosis and RF, as in acute poisoning with iron, Pb, or Arsenic.

Severe potassium depletion (caused by prolonged use of diuretics or laxatives) : may also impair renal concentrating power leading to polyuria. Renal calcification : may occur due to prolonged hypercalcemia in hypervitaminosis D; it can lead to renal impairment Allergic vasculitis: due to sulfonamides, allopurinol Renal vascular thrombosis: e. g. by tranexamic acid. Renal bleeding with hematuria my occur in overdose with anticoagulants e. g. warfarin

Changes in drug pharmacology in RF: Pharmacokinetics: Decreased renal excretion of drugs by kidney. Plasma drug level increases & its t½ is prolonged. Remember that in RF, the GFR, CLcr, and CLrenal. drug are all reduced; plasma Cr level rises since it is inversely related to CLcr. Decreased plasma albumin binding of acidic drugs due to acidosis, retention of nitrogenous products, may require initial dose adjustment of drug Dehydration reduces Vd of drug, thus initial loading doses need to be reduced. Binding of basic drug to alpha-1 acid glycoprotein in plasma is not affected, so no need to change initial dose of drug

Drug Normal t½ (h) (GFR < 5 ml/min) t½ in severe RF (h) Amoxicillin 1. 2 25 Gentamicin 2. 5 > 50 Digoxin 36 90 Captopril 2 25 Atenolol 9 100

Pharmacodynamics: Brain is more sensitive to CNS depressants esp. in advanced RF, so lower doses of sedatives, tranquilizers and opioids are used, if needed. Impairment of control of body fluid volume. If hypovolemic: patient becomes very sensitive to hypotensive effect of α 1 - blockers e. g. prazosin and ACEIs (so decrease dose).

DRUG PRESCRIBING IN RENAL FAILURE 1. Nephrotoxic drugs must be avoided 2. Some drugs are not effective when renal function deteriorates: many diuretics e. g. thiazides, uricosuric agents, some urinary antiseptics: so avoid 3. Avoid drugs that may cause dangerous systemic toxicity if they accumilate in RF. e. g. pethidine, lithium, nitroprusside, oral hypoglycemics, sucralfate, nitrofurantoin, methotrexate.

4. Otherwise, Decrease maintenance dose or increase dose interval or both for some drugs to prevent their dose-related accumulation & toxicity e. g. some antimicrobials like penicillins or aminoglycosides, antihypertensives, digoxin, H 2 - blockers , procainamide. Alternatively, specific drug nomograms may be available to guide doses and therapy in RF. Drug therapy is guided by Therapeutic response and measurement of drug plasma levels.