Drugs and the Kidneyx

Drugs and the Kidney Renal drug excretion is determined by GFR, tubular secretion and passive diffusion • Only free drugs in plasma can pass through kidney • Plasma protein-bound drugs cant Two Major Carrier Systems Carry Drugs to Tubule • Acidic carrier system: carries weak acids (frusemide, thiazides) • Basic carrier system: carries weak bases (amiloride, dopamine) • These are efficient excreting systems for drugs • They are subject to competitive inhibition o E.g. thiazides and gout o E.g. probenecid and penicillin Passive Diffusion • As plasma is reabsorbed, lipid soluble drugs will also be reabsorbed along their concentration gradient • Hence, lipid soluble drugs take longer to excrete • Whereas polar, water soluble drugs remain in the tubular fluid Factors Affecting Renal Drug Excretion • pH o Alteration of pH changes proportion of drug in unionised, lipid soluble form o pH modulation is used to increase drug excretion in OD e.g. aspirin Weak Acid Weak Base Acidic Urine Reabsorbed Excreted Alkaline Urine Excreted Reabsorbed • Age o Both renal mass and perfusion decrease with age o Glomerular filtration and tubular secretion decrease with age • Disease o Renal impairment alters drugs’ pharmacokinetics/dynamics and can have adverse effects o Dose modification needed and check for interaction o Some drugs have no direct effect on renal function but aggravate metabolic consequences of renal failure:  Hyperkalaemia is worsened with K supplements, K-sparing diuretics, aldosterone antagonists, RAS agents  Na-containing drugs and antidiuretics can lead to fluid overload and HT o Effect of renal impairment on pharmacodynamic mechanisms  Renal impairment often leads to coagulopathy from effects of uraemia on platelet function and may be more prone to bleeding complications of anticoagulant/antiplatelet therapy o Effects of renal impairment on concentration of drug at site of action  Some diuretics and antibiotics become ineffective in patients with renal impairment because they do not achieve adequate concentrations at their site of action at the renal tubules or bladder  Thiazide diuretics, nitrofurantoin or high dose loop diuretics o Method of administration  IV drug administration is undesirable in fluid restricted patients o Drug interactions  Especially important in transplant immunosuppressed patients  The most important: cyclosporine, tacrolimus, everolimus and sirolimus which are all substrates of CYP3A4 enzyme  Hence, interaction in these immunosuppressants will alter their levels which is dangerous to the transplanted kidney  Coprescription of drugs that inhibit these systems: • Azole antifungals • CCBs • Macrolides • Grapefruit juice o These all: ↑absorption, ↓metabolism  toxicity  Coprescription of drugs that induce these systems • Barbiturates • Phenytoin • Carbamazepine • St. John’s wort o These all: ↓absorption, ↑metabolism  rejection Estimating Renal Function for Drug Dosage • Dose modification necessary if GFR<60mL/min o Mild renal impairment: 30-60mL/min o Moderate: 10-30mL/min o Severe: dialysis required • Cockcroft-Gault equation used to calculate dosage modulation • The modification of diet in renal disease (MDRD) or CKD-EPI formula, if not corrected for body SA, can lead to different dosages than those from the Cockcroft-Gault equation • Important to note that single-point estimation of function is somewhat inaccurate as kidney function is constantly changing Cockcroft-Gault Equation (140 − 𝐴𝑔𝑒 [𝑦𝑒𝑎𝑟𝑠]) × 𝑤𝑒𝑖𝑔ℎ𝑡 [𝑘𝑔] 𝐶𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 𝐶𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 [𝑚𝐿/𝑚𝑖𝑛] = ♀ ×0.85 for 0.815 × 𝑠𝑒𝑟𝑢𝑚 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 [𝜇𝑚𝑜𝑙/𝐿] Ideal Body Weight (IBW) • Males: IBW(kg) is 50 + (0.9kg/cm for each cm >152cm) • Females: IBW(kg) is 45.5 + (0.9kg/cm for each cm >152cm) • If individual is under IBW, use actual body weight Medications Requiring Dose Adjustments Haemodynamically Mediated Kidney Injury • Refers to any AKI resulting from acute drop in glomerular pressure, including pre-renal states leading to ↓renal blood flow and medications that affect the RAS • Drug-induced causes of haemodynamically induced kidney injury are caused by either, or both of, AA constriction or EA dilation • ACEIs, ARBs, NSAIDs, are most commonly implicated • Triple whammy: ACEI/ARB + Diuretic + NSAID • Cyclosporine and tacrolimus (calcineurin inhibitors) o Dramatically increased success of transplants o Nephrotoxicity remains dose-limiting adverse effect o Delayed chronic interstitial nephritis also been reported, but acute haemodynamically mediated kidney injury is the most important mechanism of nephrotoxicity • Mechanism o ↑TXA2 and endothelin (vasoconstrictors) + RAS and SNS activation + ↓NO, prostacyclin (PGI2) and PGE2 o Net effect is predominantly AA vasoconstriction with ↓RPF + ↓GFR o Dose related Tubular Cell Damage • Drugs that lead to Renal Tubule Epithelial Cell (RTEC) damage do so via direct cellular toxicity or ischaemia • Damage is most common in PCT and DCT and is termed ATN when cell degeneration and sloughing from PCT and DCT BM are observed • Most common agents associated with this type of injury are aminoglycosides (10-25% of patients receiving therapeutic course get nephrotoxicity) • Critically ill patients have higher risk of nephrotoxicity • Mechanism o Accumulation of high drug concentration within PCT cells  generation of ROS that injure mitochondria  cellular apoptosis and necrosis • Prevention o Patients selection and use of alternate antibiotics o Avoid volume depletion o Limit aminoglycoside dose o Avoid concomitant therapy with other nephrotoxic drugs Radiographic Contrast Mediated Nephrotoxicity (CIN) • Leading cause of hospital acquired AKI (10-13% of cases)  Mechanism: o Renal ischaemia: systemic hypotension and simultaneous acute vasoconstriction caused by disruptive PG synthesis and release of adenosine, endothelin and other renal vasoconstrictors  sustained reduction in RPF o High concentration in tubules  cytotoxicity • Prevention: fix dehydration and sometimes volume expansion • N-acetylcysteine: an antioxidant that may reduce risk of CIN for renal injured patients Obstructive Nephropathy • Drugs  deposition/precipitation in renal tubules or collecting systems • Precipitation of drug crystals in distal tubules can lead to intratubular obstruction, intestinal nephritis and superimposed ATN: collectively called crystal nephropathy • Nephrolithiasis results from abnormal crystal precipitation in kidney  E.g. o Antineoplastic drugs  acute tubular obstruction indirectly, by inducing tumour lysis syndrome, hyperuricaemia, intratubular precipitation of uric acid crystals o Administration of allopurinol 2-3 days prior to chemotherapy Drug Induced Glomerular Disease • Classified as direct cellular toxicity or immune mediated toxicity • Direct o Thrombotic microangiopathy o MCGD o FSGS • Immune o Vasculitis o Membranous GN • Implicating drugs: NSAIDs, pamidronate, lithium, interferon α and β Drug Induced Tubulointerstitial Nephritis • Changes in interstitum rather than tubules  Presentation may be: o Acute and reversible with interstitial oedema, rapid loss of kidney function, and systemic symptoms or; o Chronic and irreversible, associated with interstitial fibrosis and minimal to no systemic symptoms • Acute allergic interstitial nephritis (AIN) o E.g. penicillins, cephalosporin, NSAIDs, PPIs, sulphonamides • Chronic interstitial nephritis o Lithium, analgesics, calcineurin inhibitors