Diuretics and Renal Physiology

• Electrolyte and fluid volume abnormalities can be life-threatening if not treated.
• Diuretics inhibit renal tubule transport functions to treat these disorders.
• "Diuresis" means an increase in urine volume, while "natriuresis" means an increase in renal sodium excretion.
• Natriuretic drugs often function as diuretics, increasing sodium and water excretion.
• Under normal conditions, less than 1% of filtered sodium is excreted.
• Diuretics increase the excretion of sodium chloride, sodium bicarbonate, and water.
• Diuretics act on specific membrane transport proteins or produce osmotic effects to prevent water reabsorption, while others interfere with hormone receptor interaction in renal epithelial cells.
• Diuretics act on a single anatomical segment of the nephron, informing their pharmacology.

Tubule Transport Mechanisms

• Sodium bicarbonate, sodium chloride, glucose, amino acids, and other organic solutes are selectively reabsorbed in the proximal tubule via specific-mediated transport systems.
• Water reabsorption occurs passively, maintaining constant osmolality in the proximal tubule.
• Sodium bicarbonate and sodium chloride are important regarding diuretic effects.
• Acetazolamide blocks sodium bicarbonate reabsorption in the proximal tubule and is the only diuretic known to predominantly act there.
• Sodium bicarbonate reabsorption begins with the sodium/hydrogen exchanger in the apical membrane of tubule epithelial cells.
• Hydrogen is secreted into the lumen and combines with bicarbonate to form carbonic acid, which is then dehydrated to carbon dioxide and water.
• Carbon dioxide and water cross the cell membrane into proximal tubule cells, accelerated by carbonic anhydrase.
• Carbon dioxide is re-hydrated to carbonic acid, dissociates, and the proton (hydrogen) is exchanged with sodium via the sodium/hydrogen exchanger.
• The sodium/potassium ATPase pump maintains low intracellular sodium by pumping reabsorbed sodium into the interstitium-blood.
• Bicarbonate reabsorption is dependent on carbonic anhydrase activity, inhibited by acetazolamide.
• The proximal tubule has both organic acid and organic base secretory systems that play a role in delivering diuretics to their site of action and are also sites of interaction between diuretics, uric acid, and other exogenous organic compounds, such as probenecid.

Loop of Henle

• The loop consists of the thin and thick ascending limbs.
• The thin limb is involved in water reabsorption via osmotic forces in the hypertonic medullary interstitium but does not participate in active salt reabsorption.
• Osmotic diuretics such as mannitol or glucose act here by opposing water extraction and increasing water delivery to distal sites.
• The thick ascending limb actively reabsorbs sodium chloride (~35% of filtered sodium) and is impermeable to water.
• Sodium/potassium/2chloride cotransporter is responsible for sodium chloride transport.
• "Loop" diuretics such as furosemide selectively block this transporter.
• The cotransporter leads to excess potassium accumulation within the cell.
• The sodium/potassium ATPase pump is active, pumping potassium into the cell, and the subsequent back diffusion of potassium into the tubular lumen leads to a lumen-positive electrical potential.
• Electrical potential drives the reabsorption of divalent cations (Mg2+ and Ca2+).
• Diuretics inhibiting the pump will result in the excretion of divalent cations and sodium chloride.

Distal Convoluted Tubules

• Around 10% of filtered sodium chloride is reabsorbed.
• It is impermeable to water, the reabsorption of sodium chloride dilutes the tubular fluid further.
• The mechanism for sodium chloride reabsorption involves an electrically neutral sodium and chloride cotransport system, distinct from the sodium/potassium/2chloride cotransporter.
• Thiazide diuretics inhibit this sodium/chloride cotransport.
• The sodium/calcium exchanger is responsible for the active reabsorption of calcium.
• Calcium transport mechanism is different in the distal convoluted tubule and the loop of Henle.

Collecting Tubule

• 2%-5% of sodium chloride is reabsorbed.
• The final site for sodium chloride reabsorption, determining the final concentration of sodium in urine.
• The site where mineralocorticoids exert a significant action regulating volume, and the major site of potassium secretion by the kidney.
• The types of cells are principal cells and intercalated cells.
• Sodium, potassium, and water transport occur in principal cells, while proton (hydrogen) secretion occurs in intercalated cells.
• Sodium and water enter principal cells through sodium and water channels.
• Potassium exists via the potassium channels.
• Sodium is then transported into the blood by the sodium/potassium ATPase.
• Lumen-negative charge drives chloride back into the blood via a paracellular pathway, as potassium leaves the cells via potassium channels.
• Diuretics increase sodium delivery at collecting tubules, enhancing potassium secretion; sodium delivered with non-readily reabsorbed anions enhances potassium secretion by increasing the lumen's negative potential.
• Enhanced aldosterone secretion due to volume depletion is a basis for diuretic-induced potassium wasting.
• Sodium reabsorption and potassium secretion are regulated by steroid hormones.
• Antidiuretic hormone (ADH, vasopressin) contributes to urine concentration; without it, the collecting tubule is impermeable to water, leading to diluted urine.
• Serum osmolality and volume stimulate ADH secretion.

Pharmacology of Diuretics

• Carbonic anhydrase is located in the luminal membrane of the proximal tubule in nephrons and catalyzes the dehydration of carbonic acid.
• Carbonic Anhydrase Inhibitors (acetazolamide, dichlorphenamide) reduce bicarbonate reabsorption in the proximal tubule.
• Independent bicarbonate reabsorption exists at other nephron sites.
• Enzyme inhibition causes significant bicarbonate losses, resulting in hyperchloremic metabolic acidosis.
• Diuretic effectiveness decreases with use over several days due to acidosis and enhanced sodium chloride reabsorption in other nephron regions.
• Carbonic anhydrase inhibitors are not effective diuretics clinically; they see use in locations other than the kidney.
• In terms of glaucoma, CA inhibitors decrease the rate of aqueous humor formation, leading to a decrease in intraocular pressure.
• Acetazolamide alkalinizes.
• Urinary alkalinization increases uric acid excretion which is relatively insoluble in acidic urine.
• Acetazolamide can treat mountain sickness by reducing cerebrospinal fluid formation and CSF pH, with prophylactic treatment initiated 24 hours prior to climbing.
• Acetazolamide is useful in correcting metabolic alkalosis due to excessive diuretic use.
• Loop Diuretics (furosemide, bumetanide, piretanide, torasemide, ethacrynic acid) inhibit sodium chloride reabsorption in the thick ascending loop of Henle.
• Loop diuretics can cause 15-20% of filtered sodium excretion and act as inhibitors of the sodium/potassium/2chloride exchanger in the luminal membrane.
• Furosemide, bumetanide, piretanide, and torasemide directly inhibit the chloride binding site and ethacrynic acid forms a complex with cysteine that inhibits the carrier system.
• This type of diuretics can cause an increase in magnesium excretion.
• The clinical use includes edematous states and acute hypercalcemia.
• In the condition of hyperkalemia, they can enhance urinary potassium excretion.
• Loop diuretics can increase urine flow and enhance potassium excretion in acute renal failure, converting oliguric to non-oliguric failure.
• Loop diuretics are useful in treating toxic ingestion of the anions by essentially stopping extracellular volume depletion; saline solution must replace lost sodium and chloride ions.
• They increase the delivery of sodium chloride and water to the collecting duct This can enhance renal potassium and hydrogen secretion, causing hypokalemic metabolic alkalosis.
• This can be reversed by potassium replacement or correction of hypovolemia.
• Loop diuretics can cause dose-dependent hearing loss as a result of ototoxicity.
• This is common with reduced renal function, or aminoglycoside antibiotics are in use.
• Loop diuretics can cause hyperuricemia resulting in gout attacks; this is due to extensive volume depletion and enhancement of uric acid reabsorption in the proximal tubule (can be avoided by use of lower doses).
• Hypomagnesemia can occur as a consequence of chronic use and is corrected by administration of oral magnesium.
• Allergic reactions include skin rashes and eosinophilia.
• Hyperglycemia is likely due to inhibited glucose transport and/or metabolism.
• Overuse is dangerous in congestive heart failure, hepatic cirrhosis or, borderline renal failure.
• Furosemide and bumetanide may show cross-sensitivity in patients who are sensitive to other sulfonamides.

Thiazide Diuretics (Chlorothiazide, Benzthiazide

• Chlorthalidone, Trichlormethiazide) have a moderately powerful diuretic effect.
• They act at the distal convoluted tubule, decreasing the reabsorption of sodium and chloride by binding and inhibiting the chloride site of the sodium/chloride exchanger system, and do not appear to have any impact on the thick ascending loop of Henle.
• The main use is in hypertension, congestive heart failure, nephrolithiasis, and nephrogenic diabetes insipidus.
• The unwanted effects associated with use include, hypokalemic Metabolic Alkalosis, and Hyperuricemia similar to loop diuretics.
• Impaired carbohydrate tolerance and hyperglycemia can occur in patients who are diabetic or individuals who have abnormal glucose tolerance.
• This is due to impaired insulin release from the pancreatic gland and reduced tissue glucose utilization, but is reversible with correction of hypokalemia.
• Thiazides can increase serum cholesterol and low-density lipoproteins between 5% to 15%.
• Hyponatremia is an important adverse effect that can sometimes be life-threatening that is common in patients over 70 years of age and more frequently in females than males.
• The mechanisms by which thiazides induce hyponatremia can be a reduction of kidney diluting capacity, sustained release of ADH, and increased thirst.
• The effect can be prevented by reducing the dose of drug or reducing water intake.
• Risk of hyponatremia has been associated with combined use of thiazides and SSRIs, due to SSRIs causing the release of ADH.
• Rarely skin rashes, hemolytic anemia and thrombocytopenia.
• The overuse of diuretics can be dangerous in congestive heart failure, hepatic cirrhosis or borderline renal failure.
• Potassium-Sparing Diuretics (Spironolactone, Eplerenone, Triamterene, Amiloride).
• Spironolactone and eplerenone are antagonists of aldosterone at the cortical collecting tubule and late distal tubule.
• Eplerenone is an analogue of spironolactone with greater selectivity for the aldosterone receptor.
• Triamterene and amiloride are inhibitors of sodium transport through ion channels in the luminal membrane.
• The class sees use in the conditions of mineralocorticoid excess such as Conn's Syndrome or secondary aldosteronism, congestive heart failure, hepatic cirrhosis, and nephrotic syndrome.
• Hyperkalemia can been known to occur, and is greater with drugs that reduce renin (e.g. β-blockers, NSAIDs), angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists.
• There is an inhibition of hydrogen secretion in concert with potassium secretion cause metabolic acidosis.

Osmotic Diuretics (Mannitol)

• These drugs are filtered in the glomerulus but are incompletely/not reabsorbed, where as such they cause water retention in segments of the nephron (proximal tubule and descending limb of Henle's loop) - leading to a larger volume of fluid remaining within the tubule that secondarily reduces sodium reabsorption.
• Mannitol is poorly absorbed orally and must be given parenterally, where it will cause somatic diarrhea; it is not metabolized and is excreted by glomerular filtration within 30-60 minutes.
• Osmotic diuretics are used to increase water excretion in preference to sodium excretion in patients with compromised renal hemodynamics or avid sodium retention.
• Reduces total body water more than the total cation content, reducing intracellular volume and intracranial pressure.
• Used to lower intraocular pressure before ophthalmologic procedures.
• Extracellular Volume Expansion can cause complications in a condition such as congestive heart failure.
• Dehydration and Hypernatremia can occur with excessive mannitol, but careful attention to serum ion composition and fluid balance can circumvented it.

Vasopressin Receptor Antagonists (Vaptans)

• Act as vasopressin (antidiuretic hormone) receptor antagonists used in hospitalized patients with congestive heart failure, but may be limited to those with hyponatremia.
• Useful for treating edema associated with liver cirrhosis; will reduce urine osmolarity (approximately 50%), and increase urine flow by two folds.
• Side effects include thirst and dry mouth, and increased gastrointestinal bleeds in patients with liver disease.
• Monitor serum sodium ion concentration, since the compounds can cause severe hypernatremia and nephrogenic diabetes insipidus.
• When cardiac function is decreased in congestive heart failure, there is over-activation of the sympathetic nervous system, and the renin-angiotensin-aldosterone system.
• The over-activation of these systems results in the expansion of plasma volume leading to edema.
• Diuretics are useful for treating pulmonary edema and congestion, off-loading volume in systemic and pulmonary circulation.
• Excessive use may result in the extensive reduction in venous return and could reduce cardiac function.
• Diuretic-induced metabolic alkalosis and hypokalemia can compromise cardiac function, treated by potassium supplementation and some degree of intravascular fluid replacement with saline.
• Serum potassium should be monitored, and potassium-sparing diuretics is another option.
• Diuretics use in patients with heart failure work essentially as adjuncts with other drugs.
• Kidney disease causes salt and water retention, which can be treated with diuretic agents in patients with mild renal insufficiency.
• Diuretic agents are of little benefit in cases of severe function loss, due to insufficient filtration to sustain a natriuretic response.
• Glomerular disease such as that found in patients with diabetes mellitus impairs volume homeostasis.
• Frequently, there is also hyperkalemia early on before renal failure in diabetic nephropathy.
• In such case, the use of thiazide or loop diuretics will enhance potassium secretion by increasing the delivery of salt to the potassium-secreting collecting tubule.
• In many patients with nephrotic syndrome, there is primary retention of salt and expansion of plasma volume causing hypertension despite low oncotic pressure, and it is beneficial to use diuretics to control volume.
• When selecting a diuretic in patients with kidney disease, avoid acetazolamide and potassium-sparing diuretics as their use will accentuate acidosis and hyperkalemia.
• Thiazide diuretics are ineffective when the glomerular filtration rate falls below 30 ml/min, where as loop diuretics are the best choice in treating edema in patients with kidney failure.
• In liver disease, edema with ascites, elevated portal hydrostatic pressure, and reduced plasma oncotic pressure.
• The mechanism for edema and salt retention is multifactorial; it most likely involves diminished renal perfusion resulting from systemic vascular alteration, diminished plasma volume as a result of ascites, and diminished oncotic pressure due to hypoalbuminemia.
• There may also be sodium retention due to the effects of high circulating aldosterone levels.
• Diuretic therapy is useful in conditions of severe edema and ascites in patients with cirrhosis of the liver.
• Cirrhotic edema is responsive to actions of spironolactone, but it is important to stress that extensive use of diuretics in this population can cause significant depletion of intravascular volume, and manifestation of hypokalemia, and metabolic alkalosis.
• Idiopathic Edema is a condition that occurs exclusively in women and consists of fluctuation in salt retention and edema, and despite extensive investigation of the pathophysiology of this syndrome the condition remains to be determined.
• Diuretics can be used treat the syndrome although it has also been suggested that diuretic use may contribute to idiopathic edema; the best way to deal with this syndrome is with mild salt restriction.

Hypertension

• Diuretics are useful due to vasodilator actions and moderate salt restriction potentiates hypotensive actions.
• Diuretics are still a first-line of drugs for the treatment of high blood pressure and play an important role in patients that require multiple drug treatment.
• Patients treated with powerful vasodilator require concomitant diuretics to prevent significant retention and thus edema.
• Nephrolithiasis can be treated with thiazide diuretics, which enhances calcium reabsorption in the distal convoluted tubule by reducing the urinary calcium concentration.
• The loop of Henle is important for calcium reabsorption, making loop diuretics helpful in promoting calcium excretion.
• Saline has to be administered concomitantly with loop diuretics if an effective calcium excretion is to be produced; the addition of potassium is considered if needed.
• Thiazide diuretic agents can significantly reduce urine flow in diabetes insipidus, reduce polyuria and polydipsia in patients.
• Thiazides may increase the expression of sodium transporter in distal convoluted and cortical collecting tubules.
• Actions could lead to the maximum volume of diluted urine produced is lowered.