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.

Continue to "Hypertension" or take a quiz: [Q1].

Need more practice? Answer the review questions below.

Questions:

1- List 4 pharmacologically significant areas of the nephron.

2- List 3 general sites of actions of diuretics in the nephrone.

3- List 2 classes of diuretics that act on the proximal tubule.

4- List 1 class of diuretics that act on the loop of Henle.

5- List 2 classes of diuretics that act on the distal tubule/collecting duct.

6- What is the main outcome of diuretic therapy?

7- What are the clinical uses of diuretics?

8- List 8 possible complications of diuretic therapy.

9- List 5 classes of drugs that interact with diuretics

10- What is the general mechanism buy which diuretics increase urine volume?

11- What is the "breaking phenomenom"?

12- What is reabsorbed in the proximal tubule?

13- What is secreted in the proximal tubule?

14- List 1 carbonic anhydrase inhibitor.

15- What is the function and mechanism of action of carbonic anhydrase in th kidneys?

16- What are the general effects of acetazolamide?

17- What are the adverse effects of acetazolamide?

18- What are the clinical uses of acetazolamide?

19- List 2 xanthine diuretics.

20- What is the mechanism of xanthine diuretics?

21- What is the clinical use of xanthine diuretics?

22- What is reabsorbed in the loop of henle?

23- What is the result of "dry" electrolyte reabsorption in the loop of Henle?

24- What drives electrolyte reabsorption in the loop of Henle?

25- List 2 loop diuretics.

26- What is the mechanism of action of loop diuretics?

27- What are the general effects of loop diuretics?

28- Wha is the special characteristic of loop diuretics regarding distribution?

29- What are the adverse effects of loop diuretics?

30- Why is hypocalcemia a possible adverse effect of loop diuretics?

31- What is hypochloremic metabolic alkalosis?

32- Which types of diuretics may cause hypochloremic metabolic alkaloysis?

33- What is reabsorbed in the distal tubule/collecting duct?

34- What modulates water reabsorption in the distal tubule/collecting duct?

35- What is secreted in the distal tubule/collecting duct?

36- What is the role of aldosterone in the distal tubule/collecting duct?

37- List 1 thiazide.

38- What is the mechanism of action of thiazides?

39- What are the general effects of the thiazides?

40- What are the adverse effects of the thiazides?

41- What are the clinical uses of thiazides?

42- What is nephrogenic diabetes insipidus?

43- What is the role of ADH in the kidney?

44- What is the rationale to use thiazide as treatment of nephrogenic diabetes insipidus?

45- What is the mechanism of non-nephrogenic diabetes insipidus?

46- What is the treatment for non-nephrogenic diabetes insipidus?

47- What is a potassium-sparing diuretic?

48- What are the general side effects of pottassium-sparing diuretic?

49- List 3 potasium-sparing diuretic

50- What is the mechanism of action of amiloride and triamterene?

51- What is the mechanism of action of spironolactone?

52- What is the effect of aldosterone in the kidney?

53- What is the mechanism of osmotic diuretics?

54- What is the effect of osmotic diuretics?

55- What are the clinical uses of osmotic diuretic?

56- List 4 osmotic diuretics.

57- What is the mechanism of action of acidifying salts?

58- What are the general effects and clinical use of acidifying salts?

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Hey! DON'T PEEK!!! Finish the questions fist!

Answers:

1- List 4 pharmacologically significant areas of the nephron.
glomerulus
proximal tubule
loop of henle
distal tubule/collecting duct

2- List 3 general sites of actions of diuretics in the nephrone.
proximal tubule
loop of henle
distal tubule/commecting duct

3- List 2 classes of diuretics that act on the proximal tubule.
carbonic anhydrase inhibitors
xanthines

4- List 1 class of diuretics that act on the loop of Henle.
loop diuretics

5- List 2 classes of diuretics that act on the distal tubule/collecting duct.
thiazides
potassium-sparing diuretics

6- What is the main outcome of diuretic therapy?
increase urine volume

7- What are the clinical uses of diuretics?
edema
nephrogenic diabetes insipidus
hyper/hypocalcemia
hypertension

8- List 8 possible complications of diuretic therapy.
volume depletion
hypo/hypernatremia
hypo/hyperkalemia
metabolic acidosis or alkalosis
hyper/hypocalcemia. Abnormalities of lipid metabolism may occur, like
elevated LDL or VLDL
increased VLDL synthesis
hypokalemia may decrease insulin secretion

9- List 5 classes of drugs that interact with diuretics
nonsteroidal anti-inflammatories
sulfas,
anticoagulants,
cancer chemotherapy
antibiotics

10- What is the general mechanism buy which diuretics increase urine volume?
by increasing the excretion of solutes, thus water will follow in iso-osmotic proportion.

11- What is the "breaking phenomenom"?
Situation were the solute targeted by the diuretic agent for elimination 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).

12- What is reabsorbed in the proximal tubule?
60-90% of the glomerular filtrate
Na, Cl and water in isoosmotic proportions
K and bicarbonate

13- What is secreted in the proximal tubule?
H

14- List 1 carbonic anhydrase inhibitor.
acetazolamine

15- What is the function and mechanism of action of carbonic anhydrase in th kidneys?
Cytosolic carbonic anhydrase converts CO2 from the tubular lumen to carbonic acid. The acid dissociates readily into bicarbonate and H. Bicarbonate is transported across the basolateral membrane while H is secreted into the tubular lumen in exchange for Na. In 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 cycle starts again.

16- What are the general effects of acetazolamide?
Increase Na, K, and HCO3 excretion, and decrease excretion of H and ammonia.

17- What are the adverse effects of acetazolamide?
metabolic acidosis
refractoriness

18- What are the clinical uses of acetazolamide?
open-angle glaucoma, to reduce intraocular pressure
metabolic acidosis

19- List 2 xanthine diuretics.
caffeine
pamabrom

20- What is the mechanism of xanthine diuretics?
reduce salt and water reabsorption in the proximal tubule and increase renal blood flow

21- What is the clinical use of xanthine diuretics?
over the counter remedies to relief fluid retention associated with menstruation.

22- What is reabsorbed in the loop of henle?
30% of filtered Na and Cl without iso-osmotic absorption of water
calcium and magnesium

23- What is the result of "dry" electrolyte reabsorption in the loop of Henle?
creates an osmotic gradient in the medulla, used to concentrate urine in the distal tubule.

24- What drives electrolyte reabsorption in the loop of Henle?
Electrolite reabsoption is driven by the luminal Na/K/2Cl triplicate transporter.

25- List 2 loop diuretics.
furosemide
ethacrynic acid

26- What is the mechanism of action of loop diuretics?
inhibit the Na/K/2Cl triplicate transporter

27- What are the general effects of loop diuretics?
greately increase excretion of Na and Cl
increase excretion of HCO3 , K, H and NH4
increase glomerular filtration and renal blood flow

28- Wha is the special characteristic of loop diuretics regarding distribution?
Loop diuretics are weak acids actively transported into the tubular lumen at the later proximal tubule and into inner ear hair cells.

29- What are the adverse effects of loop diuretics?
extream diuresis
hypochloremic metabolic alkalosis
hypokalemia
hypocalcemia
ototoxicity

30- Why is hypocalcemia a possible adveerse effect of loop diuretics?
Hypocalcemia occurs because the loop of Henle is the main site of Ca reabsorption, which follows Na reabsorption.

31- What is hypochloremic metabolic alkalosis?
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.

32- Which types of diuretics may cause hypochloremic metabolic alkaloysis?
loop diuretics
thiazides

33- What is reabsorbed in the distal tubule/collecting duct?
8-10% of filtered Na
Cl, water

34- What modulates water reabsorption in the distal tubule/collecting duct?
aldosterone and antidiuretic hormone (ADH)

35- What is secreted in the distal tubule/collecting duct?
H and K

36- What is the role of aldosterone in the distal tubule/collecting duct?
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.

37- List 1 thiazide.
hyddrochlorothiazide

38- What is the mechanism of action of thiazides?
I nhibit the Na/Cl contransporter that moves ions from the lumen into the cell.

39- What are the general effects of the thiazides?
increase Na and Cl excretion
increase bicarbonate, K and ammonium excretion

40- What are the adverse effects of the thiazides?
hypochloremic metabolic alkalosis
hypokalemia

41- What are the clinical uses of thiazides?
nephrogenic diabetes insipidus
hypertension

42- What is nephrogenic diabetes insipidus?
Diabetes insipidus (aka vasopressin-independent diabetes insipidus) occurs when the nephron no longer responds to antidiuretic hormone (ADH).

43- What is the role of ADH in the kidney?
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.

44- What is the rationale to use thiazide as treatment of nephrogenic diabetes insipidus?
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 compensatory 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 excretion will persist as long as the deficit in extracellular fluid volume is maintained.

45- What is the mechanism of non-nephrogenic diabetes insipidus?
In the case of non-nephrogenic diabetes insipidus (aka vasopresssin-sensitive diabetes insipidus), there is a pituitary deficiency of ADH.

46- What is the treatment for non-nephrogenic diabetes insipidus?
Vasopressin-like peptides are used, and may be naturally occurring (arginine vasopressin, lypressin) or synthetic (desmopressin).

47- What is a potassium-sparing diuretic?
Inhibit Na reuptake from the filtrate in the collecting duct. Increase excretion of Na and Cl while decreasing excretion of K, H and NH4.

48- What are the general side effects of pottassium-sparing diuretic?
metabolic acidosis
hyperkalemia

49- List 3 potasium-sparing diuretic
amiloride
triamterene
spironolactone

50- What is the mechanism of action of amiloride and triamterene?
Inhibit luminal Na channels.

51- What is the mechanism of action of spironolactone?
Blocks the aldosterone receptor.

52- What is the effect of aldosterone in the kidney?
Regulates the expression of multiple gene products that increase Na reuptake: activation of "silent" channels, increased expression of proteins and transporters, etc.

53- What is the mechanism of 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.

54- What is the effect of osmotic diuretics?
Cause excretion of a high volume of diluted urine, leading to contraction of the extracellular and intracellular fluid volumes.

55- What are the clinical uses of osmotic diuretic?
acute renal failure,
glaucoma, and
during ophtralmic or neurosurgery to dry the surgical field

56- List 4 osmotic diuretics.
mannitol
urea
glycerine
isosorbide

57- What is the mechanism of action of acidifying salts?
Ammonium chloride, administered IV, dissociates into ammonium and chloride. The cloride is cotransported with Na into the urine. 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.

58- What are the general effects and clinical use of acidifying salts?
Increase salt and water excretion and are used to increase excretion of weak acids when treating poisoning.