1. Diuretic Agents in Hypertension and other disorders
Dr. Thomas Abraham
PHAR 417: Fall 2004

2. Diuretic Agents in Hypertension
Overview of renal function
Filtration of blood in the glomerulus results in significant portion of plasma water being secreted into the proximal convoluted tubules. Much of the bicarbonate, water, glucose and Na+ (65%) are reabsorbed back into circulation from here.
Concentration of urine occurs in the Loop of Henle when water is reabsorbed. This is also the site for major reabsorption of Na+ (25%), K+, and Cl -. Calcium and Mg2+ are reabsorbed here as well and under the influence of PTH more Ca2+ is reabsorbed in distal convoluted tubule.
Na/K/Cl symporter located in the thick ascending limb of the loop.
Further Na+ and Cl- reabsorption is under the control of aldosterone in the collecting tubules while final water reabsorption in the collecting ducts is controlled by ADH.

3. Diuretic Agents in Hypertension
Thiazide Diuretics
Thiazides have oral bioavailability and are secreted by the organic acid transporter in the proximal tubule to reach their active site: the distal convoluted tubule
Thiazides interfere with Na+/Cl- symporter to decrease NaCl reabsorption in the DCT and may also decrease NaCl reabsorption from late PCT.
Thiazides may compete with Cl- binding to the symporter.
Loss of NaCl in the urine results in decreased water reabsoption and a diuresis.

4. Diuretic Agents in Hypertension
Effects of thiazides on urinary excretion
Ø      Less effective than loop diuretics since most of the Na+ has been reabsorbed prior to reaching the DCT.   
Ø      Has some activity on carbonic anhydrase and can lead to increased bicarbonate and phosphate elimination.
  Ø      Increased elimination of Na+ in the DCT leads to K+ wasting and hypokalemia may result; chronic thiazide enhances Ca2+ reabsorption in the DCT possibly by a Na+/Ca2+ exchanger process.
Adverse effects related to thiazide diuretics
Ø      Extracellular volume depletion, hypokalemia, hypotension, hypercalcemia, hyperurecemia.
 Ø      Decrease glucose tolerance, increase plasma LDL levels, allergic reaction in pts. allergic to sulfonamides.

5. Diuretic Agents in Hypertension
Significant Drug Interactions
Ø      Decrease efficacy of anticoagulants, sulfonylurea hypoglycemics, insulin; enhance effects of cardiac glycosides, lithium, loop diuretics and vitamin D.
  Ø      NSAIDS, bile acid sequestrants and methenamine decrease thiazide efficacy.
  Ø      Thiazides may potentiate quinidine-induced ventricular arrhythmias due to the resulting hypokalemia.
 Therapeutic Uses
1. Hypertension (alone or in combination); thiazides appear to have additional effects as vasodilators
Edema due to CHF, liver failure.
Renal stones and failure
Nephrogenic diabetes insipidus esp. due to lithium treatment

6. Diuretic Agents in Hypertension
LOOP DIURETICS
Ø      Selectively inhibit NaCl reabsorption in the thick ascending portion of the loop of Henle. The high capacity of the NaCl reabsorption process results in these diuretic being the most efficacious (also referred to as high ceiling diuretic).
These agents have rapid absorption from the GI tract with torsemide (Demadex®) having the greatest oral bioavailability. These agents are cleared by filtration and secretion by the organic acid transporter and work on the luminal side of the ascending loop.

7. Diuretic Agents in Hypertension
LOOP DIURETICS (cont)
Ø      These drugs inhibit the actions of the Na+/K+/2Cl- transport system of the ascending limb of the loop of Henle.
The potassium-derived positive potential in the lumen normally drives Ca2+/Mg2+ reabsorption. Loss in this potential results in increased elimination of Ca2+ and Mg2+ ions. Active reabsorption of Ca2+ in the DCT prevents severe hypocalcemia but hypomagnesemia can result.
Loop diuretic may have effects to alter blood flow to various vascular beds e.g. renal, venous, that appear independent of the diuretic actions.

8. Diuretic Agents in Hypertension
Ø      Loop diuretic used when rapid and large diuresis is required: acute pulmonary edema, heart failure, hypertension, hypercalcemia, hyperkalemia, acute renal failure.
Ø      Large sodium loss in the ascending loop results in increased K+ and H+ loss in the collecting ducts to cause hypokalemia and metabolic alkalosis. This exchange of Na+ for K+ is also regulated by aldosterone thus the actions of loop agents in the ascending limb of the loop of Henle coupled with aldosterone effects in the collecting ducts leads to significant K+ wasting. This can precipitate arrhythmias and in patients on digoxin: potentiate the effects of the cardiac glycoside.
 Ø      Other toxicities include: ototoxicity (additive with other agents like aminoglycosides, cisplatin), hyperuricemia, allergic reactions, dehydration.
Allergic sensitivities to furosemide, bumetanide and torsemide may occur in patients with sulfonamide (sulfa antibiotics, hypoglycemics) allergies.

9. Diuretic Agents in Hypertension
Potassium-sparing Diuretics
Ø      These agents antagonize the process of Na+ reabsorption at the cortical collecting tubule at the expense of K+. The antagonism may occur at the level of the mineralocorticoid receptor (e.g. for spironolactone) or due to inhibition of Na+ transport through its channel (triamterene and amiloride).
 Ø      Spironolactone is a competitive antagonist of the aldosterone receptor (competes with aldosterone) with relatively slow onset of action due to extensive hepatic metabolism. Triamterene undergoes hepatic metabolism that decreases its plasma t1/2 while amiloride is cleared in the urine unchanged.

10. Diuretic Agents in Hypertension
Ø      Potassium-sparing diuretics decrease Na+ reabsorption in the collecting tubules and consequently prevent the secretion of K+. Aldosterone enhances Na+/K+-ATPase activity and Na+ and K+ channel activities to increase Na+ reabsoption and thereby increase water reabsorption (figure). This process is inhibited by spironolactone which binds to the cytoplasmic mineralocorticoid receptor to prevent the action of aldosterone. Triamterene and amiloride directly interfere with the Na+ channel to prevent the reabsorption of the ion.   
Ø      Other drugs that have K+-sparing activity include NSAIDS, ACE inhibitors, angiotenisin II receptor antagonists and b-adrenoceptor antagonists. Thus K+-sparing diuretic may have additive effects with these agents.
 Ø      Significant toxicities include: hyperkalemia, hyperchloremia, gynecomastia, acute renal failure (esp. triamterene + indomethecin), kidney stones.

11. Diuretic Agents in Hypertension
Eplerenone (Inspra®)
Aldosterone as part of the RAAS causes increased Na+/water retention and hypertension.
Aldosterone may have additional mechanisms to elevated systemic blood pressure.
Eplerenone binds to mineralocorticoid receptors in renal and other tissues to decrease Na/water retention and decrease BP.
Eplerenone may be used alone or in combination with other agents (ACEI and ARBs) to control BP.

12. Diuretic Agents in Hypertension
Osmotic Diuretics
Ø      Mannitol is the most commonly used of these agents. Primarily used to reduce intracranial pressure during stroke or hemorrhage or to increase the renal elimination of toxins (e.g. radiocontrast dyes).   
Ø      These agents are filtered in the glomerulus but are not reabsorbed from the renal tubules. Being highly polar it increases the osmotic pressure in the renal tubules increasing the the loss of water in regions of the nephron that are freely permeable to water (proximal tubule and descending limb of loop of Henle).
Ø      Mannitol has to be administered parenterally to produce diuresis; oral administration leads to osmotic diarrhea.
Ø      Mannitol is used in cases of renal failure, to reduce intracranial pressure, reduce intraocular pressure; not used to treat hypertension.
Toxicity associated with use include pulmonary edema, headache, nausea, vomiting and precipitation of heart failure (all primarily due to extracellular volume expansion).

13. Diuretic Agents in Hypertension
Carbonic Anhydrase Inhibitors
Ø      Carbonic anhydrase is found in many cell types but concentrated in the luminal membranes of proximal convoluted tubules.
Ø      CA is responsible for the conversion of carbonic acid to bicarbonate to limit bicarbonate elimination in the proximal tubule:
Ø      Dehydration of carbonic acid to carbon dioxide and water in the tubular lumen is followed by passive CO2 diffusion back into the proximal tubular cell where it combines with intracellular water to form carbonic acid again.

14. Diuretic Agents in Hypertension
Ø      The cellular carbonic acid dissociates into bicarbonate and hydrogen ions and the H+ becomes available to the tubular Na+/H+ antiporter that pumps in one Na+ ion for every H+ ion it pumps out into the tubular lumen. This allows for the reabsorption of both Na+ and HCO3- ions from the glomerular filtrate and decreases its pH.
Ø      Inhibition of carbonic anhydrase by selective inhibitors results in decreased bicarbonate and Na+ reabsorption. This leads to decreased water reabsorption or greater diuresis.