Diuretic Agents in Hypertension and other disorders

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Diuretic Agents in Hypertension and other
disorders

• Dr. Thomas Abraham
• PHAR 417 Fall 2005

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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.

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Diuretic Agents in Hypertension
Overview of renal function

• 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.

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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.

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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.
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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

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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).
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Diuretic Agents in Hypertension
LOOP DIURETICS

• 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.

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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.

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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.  
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Diuretic Agents in Hypertension

•  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.

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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.
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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.
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Diuretic Agents in Hypertension

•   
• 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.
•   Significant toxicities include
  hyperkalemia, hyperchloremia, gynecomastia, acute
  renal failure (esp. triamterene indomethecin),
  kidney stones.

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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.

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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).    
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Diuretic Agents in Hypertension

• Osmotic Diuretics
•  
• 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).

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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.
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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.