Medical Pharmacology Topics   

Renal Pharmacology: Diuretics

The nephron has four pharmacologically significant areas: glomerulus, proximal tubule, loop of Henle and distal tubule/colecting tube. Although there are no drugs that act directly on the glomerulus, some agents (ex. ACE inhibitors) can modulate glomerular filtration rate by vasodilation or vasoconstriction of renal arterioles.

Diuretics will act on either the proximal tubule (carbonic anhydrase inhibitors, xanthines), loop of Henle (loop diuretics) or distal tubule/collecting duct (thiazides, potassium-sparing diuretics) to increase urine volume, and are used to treat edema and non adematous states like nephrogenic diabetes insipidus, hyper/hypocalcemia and hypertension. Some agents act by simpler mexhanism, like increasing plasma osmotic pressure or acidifying urine.

Diuretic therapy may be complicated by pathological excretion of water and solutes, metabolic abnormalities, and drug interactions. Renal patjoligies associated with the ude f diuretics include volume depletion, hypo/hypernatremia, hypo/hyperkalemia, metabolic acidosis or alkalosis and hyper/hypocalcemia. Abnormalities of lipid metabolism may occur, like elevated LDL or VLDL, or increased VLDL synthesis.Hypokalemia may de3crease insulin secretion. Diuretics interact with many drugs: nonsteroidal anti-inflammatories, sulfas, anticoagulants, cancer chemotherapy and antibiotics.

Diuretics increase water excretion by increasing the excretion of solutes, thus water will follow in iso-osmotic proportion. The "breaking" phenomena in diuretic treatment refers to a situation were the solute targeted by the diuretic agent for elimination (ex. Na) is near depleated. Since there is little else to eliminate, water excretion will not occur. In the case of Na, the kidneys will tend to conserve Na, thus adjust to new electrolite levels acordingly, and decreasing the effectivenes of natriuretics (diuretics that increase Na elimination).

Proximal Tubule

Reabsorption of 60%-90% of the glomerular filtrate occurs in the proximal tubule. Na, Cl and water are reabsorbed there at iso-osmotic proportions. Reabsorption of K and HCO3, and secretion of H also occur in the proximal tubule.

Carbonic anhydrase inhibitors like acetazolamine increase diuresis by disturbing the homeostasis of bicarbonate in the proximal tubule. Carbonic anhydrase converts CO2 (which difusses into the cell from the tubular lumen) to carbonic acid. The acid dissociates readsily into bicarbonate and H. Bicarbonate is transported across the basolateral membrane while H is secreted into the tubular lumen in exchange for Na. UIn the lumen, brush border carbonic anhydrase catalyzes the opposite reaction as the cytosolic enzyme: the conversion of carbonic acid (from bicarbonate in the glomerular filtrate) to CO2 and water. The newly formed CO2 then diffusses into the cell and the ycle starts again.

Acetazolamide will increase Na, K, and HCO3 excretion, and decrease excretion of H and ammonia. Adverse effects include metabolic acidosis and refractoriness. Acetazolamide by itself has low efficacy treating systemic edema, thus is usually administered in combination with another diuretic for this purpose. The main indication is open-angle glaucoma, to reduce intraocular pressure. It is also useful in the treatment of metabolic alkalosis.

The xanthine diuretics like caffeine and pamabrom reduce salt and water reabsorption in the proximal tubule and increase renal blood flow, yet their diuretic effect is modest. They are indicated as over-the-counter remedies to relief fluid retention associated with menstration.

Loop of Henle

Reabsorption of 30% of filtered Na+ and Cl- occurs in the loop of Henle without any reabsorption of water. This creates an osmotic gradient in the medulla, used to concentrate urine in the distal tubule. Electrolite reabsoption is drven by the luminal Na/K/2Cl triplicate transporter, Ca and Mg are also reabsorbed in the loop of Henle.

Loop diuretics like furosemide and ethacrynic acid inhibit the Na/K/2Cl triplicate transporter. They greately increase excretion of Na and Cl. Excretion of HCO3 , K, H and NH4 also increases, as do glomerular filtration and renal blood flow (?). Loop diuretics are weak acids actively transported into the tubular lumen at the later proximal tubule and into inner ear hair cells.

Loop diuretics may cause extream diuresis, hypochloremic metabolic alkalosis, hypokalemia. hypocalcemia and ototoxicity. Hypocalcemia occurs because the loop of Henle is the main site of Ca reabsorption, which follows Na reabsorption.

The hypochloremic metabolic acidosis potentially caused by loop diuretics and thiazides is also known as substitution alkalosis. It develops because of a disproportionbate reduction of plasma Cl levels relative to the positive ions. Bicarbonate (HCO3) is thus accumulated in plasma as a way to "substitute" for the Cl lost and maintain electrical balance.

Distal Tubule and Collecting Duct

Reabsorption of Cl, water and 8-10% of filtered Na occurs in the distal tubule and collecting duct. Water reabsorption is modulated here by aldosterone and antidiuretic hormone (ADH, aka vasopressin). There is also H and K secretion. An aldosterone-sensitive antiporter in the basolateral membrane exchanges extracellular K for intracellular Na, thus driving the luminal reabsorption of Na and excretion of K.

The thiazides, like hydroclorothiazide, act on the distal tubule by inhibiting the Na/Cl contransporter that moves ions from the lumen into the cell. They increase Na and Cl excretion, as well as HCO3 , K, H and NH4 excretion. Side effects include hypochloremic metabolic alkalosis and hypokalemia.

Thiazides can be used to treat nephrogenic diabetes insipidus (aka vasopressin-independent diabetes insipidus). This disease occurs when the nephron no longer responds to antidiuretic hormone (ADH). ADH is released by the pituitary and binds to receptors in the collecting duct that activate adenylyl cyclase. The high cAMP levels open water pores, increasing water reabsorption. If the tissue is no longer responsive to ADH, thiazides may be used to prevent water loss by depleating the extracellular fluid volume around the distal tubule to an extent that a compensdatory increase in proximal tubule reabsorption of salt and water occurs. Since all the water that leaves the proximal tubule in such patients will be lost in the urine, an increase in water reabsorption at the proximal tubule from the usual 60% to 80-90% will substantially reduce urine flow. The reduction in water excrtetion will persist as long as the deficit in extracellular fluid volume is maintained.

In the case of non-nephrogenic diabetes insipidus (aka vasopresssin-sensitive diabetes insipidus), there is a pituitary deficiency of ADH. Vasopressin-like peptides are used , and may be naturally occurring (arginine vasopressin, lypressin) or synthetic (desmopressin). The naturally occurring agents may cause allergies. ADH receptor antagonists are available but have no clinical application.

The potassium-sparing diuretics like amiloride, triamterene and spironolactone inhibit Na reuptake from the filtrate in the collecting duct. Amiloride and triamterene inhibit luminal Na channels. Spironolactone blocks the aldosterone receptor. Aldosterone regulates the expression of multiple gene products that increase Na reuptake: activation of "silent" channels, increased expression of channel proteins and transporters, etc.

The potassium-sparing diuretics increase excretion of Na and Cl while decreasing excretion of K, H and NH4. Side effects include metabolic acidosis and hyperkalemia.

"Simple" Diuretics

Osmotic diuretics increase the osmotic pressure of plasma, expand the extracellular fluid volume, increase renal blood flow (?) reduce salt and water reabsorption in the proximal tubule and reduce medullary tonicity. They do not normally increase glomerular filtration (?). Osmotic diuretics cause excretion of a high volume of diluted urine, leading to contraction of the extracellular and intracellular fluid volumes. They are used to treat acute renal failure, glaucoma, and during ophtralmic or neurosurgery to dry the surgical field. Mannitol and urea are administered IV, glycerine and issosorbide are taking orally.

Acidifying salts increase salt and water excretion and are used to increase excretion of weak acids when treating poisoning. Ammonium chloride, administered IV, dissociates into ammonium and chloride. The cloride is cotransported with Na into the urine thrroughout the nephrone. The NH4+ releases a proton that is picked up by bicarbonate to form carbonic acid, which is then converted to water and CO2 by cytosolic arbonic anhydrase, and water is excreted following Cl- and Na+. Ammonia is secreted by diffusion in the distal tubule and collecting duct.

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