Drug Handling By The Kidney

Drug handling by the kidney Glomerular filtration  Glomerular filtration depends on the molecular size and plasma concentration of the drug. Furthermore, it only applies to free drugs in the bloodstream, as opposed to drugs bound to other molecules (e.g. proteins) Tubular secretion (proximal tubule)   Drug molecules can be actively transferred into the tubular lumen from the plasma. There are 2 such systems, one for acidic drugs (e.g. penicillin, glucuronic acid conjugates, salicylic acid) and another one which handles the organic bases (e.g. amiloride, morphine, quinine) Many drugs that are excreted by the kidney share the same active transport system, and that these transporters are saturable  competition for excretion can arise, leading to drug interactions. (e.g. penicillin and probenecid) Tubular resorption (distal tubule)     Tubular resorption depends on the lipid solubility of the drug Furthermore, it is affected by the pKa of the drug (acid dissociation constant), where reabsorption of weak acids is favoured. Uncharged species can permeate the cellular barrier separating compartments, resulting in similar concentrations in gastric juice, plasma and urine. There is also a variation in fractional ionisation as a function of pH, giving rise to large concentration differences with respect to plasma The pH of the tubule fluid can be exploited to assist with drug elimination, where the excretion of acidic drugs is increased by increasing urinary pH, and the excretion of basic drugs is increased by lowering the pH Drug elimination in disease states  It is important to consider relative importance of renal/hepatic mechanisms for a particular drug when predicting the significance of renal/hepatic disease on its handling by a patient. If drug clearance is totally dependent on the glomerular filtration rate then what determines the GFR will also determine filtration. Determinants of GFR are: o Transglomerular pressure  o Surface area o Oncotic pressure o Filtration membrane characteristics o Hydrostatic pressure Thus, for drugs mainly excreted via filtration, a decrease in GFR will reduce the clearance of the drug – for example, the antibiotics Vancomycin is almost exclusively removed by glomerular filtration, hence for patients on the dialysis or patients with chronic kidney failures, the dosage required is far less than what it would be for normal patients Drugs and renal disease   Given the important role of the kidney in the elimination of some drugs, it is not surprising that renal disease can affect the responses to some drugs. Thus intercurrent kidney disease needs to be taken into account in prescribing of some drugs. Patients with renal disease need to be treated with a variety of drugs, but these drugs also may: o Exacerbate the renal disease o Accumulate due to failure of their elimination by renal excretion o Lose effect (e.g. by actions of diuretics) For example, patients can experience decreased level of consciousness due to accumulated penecillin, an increased nephrotoxicity from drugs accumulating in proximal tubule due to poor renal plasma flow and relative hypoxaemia, and Massive hyperkalaemia in patients with distal tubular acidosis and administration of ACEI or ATII antagonists Drug-induced renal toxicity/disease  The kidney is exquisitely sensitive to toxic damage by some drugs as the kidneys receive 25% of cardiac output, and is thus exposed to potential toxins (e.g. physical damage by Tubulotoxin and Endothelial toxin). Further, due to the blood supply within the kidney – renal cortex is well perfused (hence sensitive to changes in systemic function e.g. renal blood flow, or single nephron blood flow), thus the glomerular/ proximal tubule is prone to damages. Another feature of the kidney – the counter-current mechanism, relies on low blood flow in the vasa recta, which it means that some drugs/chemicals may reach high concentrations in the medulla. Finally, agents that undergo active secretion by the kidney in order to be secreted into the urine, these drugs must be accumulated by the proximal tubule cells  A small number of drugs (+ environmental hazards such as heavy metals) cause specific toxic effects on the kidney. In some cases the nephrotoxicity can limit the therapeutic application of the drug (e.g. aminoglycoside antibiotics, angiotensin converting enzyme inhibitors). For some drugs, nephrotoxic effects lead to acute renal failure, while in other cases, nephrotoxicity can lead to significant kidney damage with chronic use of the drug (e.g. paracetamol) Effects on renal parenchyma include:  Physical damage by toxins (such as Tubulotoxin, Endothelial toxin)  Immune reaction (e.g. causing Acute interstitial nephritis)  Remote changes in systemic function – e.g. renal blood flow, or single nephron blood flow  Dose dependent toxicity (e.g. by NSAIDS including COX2, Aminoglycosides e.g. gentamicin causes nephrotoxicity by inhibiting protein synthesis in renal cells, causing necrosis in the proximal tubule, resulting in acute tubular necrosis and acute renal failure  Idiosyncratic renal damage (e.g. by NSAIDS, Penecillins, Gold, penicillamine)  In particular NSAIDs – can inhibit renal prostaglandins and therefore decrease GFR, alter vasa recta circulation, endanger papilla potentially causing necrosis, and is also associated with renal lesions (such as minimal change lesion and membranous nephropathy)