Drugs that affect on kidney

• The most important physiological functions of the kidney include (i) regulating extracellular fluid volume, (ii) maintaining the concentration of electrolytes (e.g. Na , Cl , K+, Ca2+, Mg2+), (iii) regulating acid-base balance, (iv) excreting waste products (e.g. urea, drugs, uric acid), (v) conserving essential nutrients and (vi) synthesising erythropoietin, vitamin D and renin
• The key functional units of the kidney are nephrons consisting of a glomerulus, proximal convoluted tubule, Loop of Henle, distal convoluted tubule and collecting duct, which together reabsorb around 99% of the plasma filtered at the glomerular capillaries
• Important hormones that act on renal tubules are aldosterone (which stimulates Na+ reabsorption in the distal tubule), vasopressin (which stimulates water reabsorption in the collecting duct) and parathyroid hormone (which stimulates Ca2+ reabsorption)
• The renin-angiotensin system is a key local defence of glomerular filtration, especially when it is threatened by reduced renal perfusion, and has wider systemic effects that preserve extracellular fluid volume and blood pressure
• Renal function is expressed as the glomerular filtration rate which is normally greater than 100 mL/min but declines progressively with age
• Chronic renal impairment may be the consequence of systemic or renal disease but acute reversible deteriorations may occur because of pre-renal (e.g. dehydration), renal (e.g. drug toxicity), or post-renal (e.g. ureteric obstruction) causes
• Diuretics reduce the reabsorption of sodium and water by the renal tubules and consequently increase urinary flow and are indicated for diseases associated with sodium chloride and water overload (e.g. heart failure, hypertension, ascites, renal failure)
• Loop diuretics (e.g. furosemide) are particularly efficacious because they inhibit sodium and chloride ion reabsorption in the thick ascending limb of the Loop of Henle, which is responsible for 25% of the sodium chloride and water filtered at the glomerulus
• Thiazide diuretics (e.g. bendroflumethiazide) inhibit reabsorption of around 5–10% of the filtered sodium chloride and water at the distal convoluted tubule
• Potassium-sparing diuretics (e.g. spironolactone) inhibit reabsorption of the remaining 2–3% of sodium in exchange for potassium or hydrogen ions in the late distal tubule and early collecting duct
• Osmotic diuretics (e.g. mannitol) are small inert molecules that are not reabsorbed by the renal tubules and act by creating an osmotic drag that reduces water reabsorption
• Carbonic anhydrase inhibitors (e.g. acetazolamide) reduce the release of hydrogen and bicarbonate ions in the proximal tubule causing a mild natriuresis and metabolic acidosis
• Angiotensin-converting enzyme inhibitors (e.g. ramipril) and angiotensin receptor antagonists (e.g. losartan) inhibit the generation or actions of angiotensin II at its receptor and are widely used to reduce renin-angiotensin system activity in hypertension and heart failure - they are not used to treat renal disease and may impair renal function
• Uricosuric drugs (e.g. febuxostat) inhibit uric acid reabsorption and sodium-glucose co- transporter-2 (SGLT-2) inhibitors (e.g. canagliflozin, dapagliflozin) inhibit glucose reabsorption in the proximal convoluted tubule and are indicated for the treatment of gout and type 2 diabetes respectively
• Vasopressin analogues (e.g. desmopressin) and vasopressin inhibitors (e.g. demeclocycline, tolvaptan) influence the expression of aquaporins and water reabsorption in the collecting ducts
• Drugs given to replace kidney products in patients with renal disease include epoietins, which are erythropoietin analogues, vitamin D analogues (e.g. alfacalcidol, calcitriol) and sodium bicarbonate
• Drugs are an important cause of renal impairment and this may occur by three main mechanisms: (i) secondary to excessive fluid losses leading to dehydration and poor renal perfusion, (ii) because of local effects of drugs on renal vasculature that reduce glomerular filtration, or (iii) because of direct toxic effects on the kidney (e.g. acute tubular necrosis, acute interstitial nephritis)
• The most common drugs causing dehydration are loop diuretics, and to a lesser extent thiazide diuretics, which reduce the reabsorption of sodium and water by the renal tubules and significant fluid losses may also result from drug-induced diarrhoea or vomiting
• The commonest drug classes that alter renal perfusion are those that suppress the renin- angiotensin system such as angiotensin-converting enzyme inhibitors (e.g. ramipril) and angiotensin receptor antagonists (e.g. losartan), and non-steroidal anti-inflammatory drugs (e.g. ibuprofen), which impair cortical blood flow by removing the vasodilator influence of prostaglandins
• There are many drugs that can have direct toxic effects on renal tissues by causing acute tubular necrosis (e.g. aminoglycoside antibiotics, ciclosporin, radio-contrast agents) or acute interstitial nephritis (e.g. cephalosporins, non-steroidal anti-inflammatory drugs)
• The kidney is an important route of drug elimination and caution is required when giving drugs to patients with renal problems who may have reduced clearance rates leading to a prolonged elimination half-life and a danger of accumulation
• Drugs that are likely to accumulate are typically small water-soluble molecules that are freely filtered at the glomerulus (e.g. ) and drugs that are normally secreted in the proximal convoluted tubule (e.g. methotrexate)
• • Drugs that are likely to accumulate may still be given but may need to be given in lower doses or with longer intervals between doses but in some cases may need to be avoided altogether
• Reduction in dose leads to lower peak plasma concentration but has less impact on trough concentration while extending the dose interval has minimal impact on peak plasma concentrations but significantly reduces trough concentration