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Diuretics

Definition, Types and Drug Effects

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Defining Natriuretic Agent

Any substance which increases the out put of urinary sodium is called natriuretic agent.


Defining Diuretic Agent

Any substance which increases urine out put or urine volume is called diuretic agent.


Nephron: The Functioning Unit of The Kidney

It is a very specialized tubular structure present in the kidney and is considered with urine formation. One kidney has approximately 1.2 million nephrons. Anything which increases urine or sodium out put that must be working on nephrons. Natriuretic or diuretic agents alter the function of nephrons in such a way that there is increased sodium or urine out put.


Structure of Nephron

As we know nephron is like an epithelial tube made by epithelial cells. There are following parts of a nephron:

  1. Bowman’s capsule: The glomerular capillary tuft and Bowman’s capsule together make the glomerulus. Glomerulus is the area to which the blood comes into the kidney and it acts a filtration unit of the kidney.

  2. Proximal convoluted tubule (PCT).

  3. Descending limb of loop of Henle.

  4. Thin part of ascending loop of Henle.

  5. Thick part of ascending limb of loop of Henle.

  6. Distal convoluted tubule (DCT).

  7. Collecting duct.

When blood comes into glomerulus, small amount of fluid having different plasma components is filtered into Bowman’s capsule; it goes through PCT and enters into descending limb of loop of Henle. The fluid keeps on moving towards the thin part of ascending limb of loop of Henle, thick part of ascending loop of Henle, DCT and eventually reaches in collecting duct. The part of that filtered fluid which appears at the end of the tube is called urine.


To Fully Understand the Function of Nephron, We Have to Clear the Following Concepts

Cardiac Output

The amount of blood pumped by the heart to the circulatory system in a minute is called cardiac out put, i.e. approximately 5000mL.


Renal Blood Flow (RBF)

The amount of blood supplied to the kidneys per minute is called renal blood flow, i.e. 20-25% of cardiac output (1000mL)


Renal Plasma Flow (RPF)

The amount of plasma supplied to the kidneys per minute is called renal plasma flow, i.e. 60% of the renal blood flow (600mL). It means 600mL plasma passes through glomeruli in every minute.


Glomerular Filtration Rate (GFR)

The amount of filtrate appeared in the Bowman’s capsule per minute is called glomerular filtration rate, i.e. 20% of the renal plasma flow (120mL).

Note: 80% of the renal plasma flow goes to peritubular capillary network, i.e. vasa recta.

This 120mL filtrate passes through the tube (nephron), a lot of substances reabsorb back to the blood and some substances are added by the process of secretion. The fluid which passes along the tube (nephron) is called tubular fluid.

As fluid moves forward, the composition of the fluid keeps on changing depending upon what are the substances which are pulled back to the blood and what are the substances which have been added. The tubular fluid which appears at the end of the tube is called urine. Urine is formed in three processes; filtration, reabsorption and secretion.

Nephrons are the master chemical processors which chemically process all the filtrate by reabsorbing or secreting the substances. Normally, out of processing of 120ml of filtrate, only 1mL fluid appears as urine in one minute. During this process nephron keeps fluid balance, electrolyte balance and acid-base balance within the normal range.

If there is more acid in the body, it will make the urine more acidic, on the other hand if there is more alkali in the body, it will make the urine more alkaline. If there is excessive Na in the body, it will bring more Na out.

Natriuretic and diuretic agents usually alter the functions of nephron leading to natriuresis and diuresis.


Oliguria

When urine output is less than 400-500mL/day


Polyuria

When urine output is more than 3500mL/day


Normal Urine Output

Normally urine output is some where between 500mL-3500mL/day (average 1500mL/day).


Functions of Different Parts of Nephron

Nephron is made of epithelial cells which have luminal membrane and basolateral membrane. Each membrane or side has specialized proteins or transporters or channels which differ with functions. Basolateral membrane of all the nephron cells has special type of proteins called Na+/K+ ATPases, which are mainly responsible to pump the Na (3 molecules) out of the cell(into the interstitial fluid) and K (2 molecules) inside the cell. So nephron cells are rich in K and poor in Na, consequently they would like to have high tendency to pick the Na from the tubular fluid at their luminal side by different mechanisms.

As we know PCT is made of epithelial cells having luminal membrane and basolateral membrane. These cells are attached with each other by proteins.

When filtrate passes through PCT, at the luminal side, Na/H-counter transporters reabsorb Na into the cells. Then at the basolateral membrane, this Na is pumped out of the cells by Na+/K+ ATPases and finally Na goes back to the circulation. Na/H-counter transporter reabsorbs Na (1 molecule) from the tubular fluid and secrets one proton into the tubular fluid. About 65% Na is reabsorbed by PCT cells.

In the lumen, this secreted proton (H) constantly reacts with bicarobonate (HCO3) to produce carbonic acid (H2CO3). An enzyme expressed in the luminal side breaks carbonic acid into water (H2o) and carbon dioxide (Co2). This enzyme is called luminal carbonic anhydrase. Co2 concentration progressively becomes more in the lumen. As Co2 is liposoluble so it can easily move into the cell.

Inside the cell, this Co2 reacts with the intracellular water to produce the carbonic acid under the influence of cytoplasmic carbonic anhydrase. Then carbonic acid breaks down into a proton (H) and bicarbonate (HCO3) inside the cell. Proton is further pumped into the lumen by Na/H-counter transporter and bicarbonate (HCO3) is pumped into the interstitial fluid by HCO3/Cl exchanger. Eventually bicarbonate (HCO3) goes back to the circulation from the interstitial fluid.

Proximal convoluted tubule (PCT) and descending limb of loop of Henle are freely permeable to water. When filtrate enters to PCT, water and solutes (glucose, amino acids and Na) are reabsorbed with the same ratio, so filtrate osmolarity does not change in the lumen, this called isotonic reabsorption.

After DCT upto the collecting duct, nephron is impermeable to water. Only solutes are reabsorbed by the nephron, it makes the luminal fluid more diluted.  If there is no ADH, collecting duct is also impermeable to water and vice versa.

From cortex to medulla, interstitium becomes hyperosmolar. When fluid moves from Bowman’s capsule to the end of the PCT, tubular fluid has same osmolarity as that of interstitium. And isotonic reabsorption takes place.

As fluid moves in the initial part of descending limb of loop of Henle, tubular fluid starts losing water and gaining the solutes because this part of nephron is surrounded by hyperosmotic interstitium (medulla). As soon as this tubular fluid moves further to ascending limb of loop of Henle and early part of DCT, the wall becomes impermeable to water. This part of nephron actively throws solutes into the interstitium to keep medullary interstitium hyperosmotic. This segment is responsible to dilute the luminal fluid and concentrate interstitium, so this segment is also called diluting segment of nephron.

When this tubular fluid reaches in the collecting tubule, if there is no ADH, wall of this segment becomes impermeable to water and highly diluted urine will be passed out from the body. If there is high level of ADH, wall of this segment becomes permeable to water and hyperconcentrated interstitium will pull the water from the lumen and concentrated urine will be passed out from the body.

If blood is hyperosmolar, more ADH will be released to reabsorb the water from collecting duct, on the other hand if blood is hyposmolar, less ADH will be released and less water reabsorption takes place in the collecting duct and eventually hypotonic urine (diluted urine) is produced.


Drugs Which Act on Proximal Convoluted Tubule (PCT)

Acetazolamide (Carbonic Anhydrase Inhibitor)

This type of drugs inhibits luminal as well as intracellular carbonic anhydrase. Due to inhibition of these enzymes, Co2 cannot be produced in the lumen and PCT cells cannot produce proton, so Na/H-counter transporters become dysfunctional. Consequently Na will not reabsorb and more sodium will appear in the urine leading to natriuresis. As sodium is also reabsorbed by the other parts of nephron, so it produces mild natriuresis.

Increased bicarbonate concentration in the lumen causes bicarbonaturia and makes the urine alkaline and with the passage of time blood becomes acidic. Along the sodium and bicarbonate more water will appear in the urine leading to diuresis.


Role of Collecting Duct

The cells of collecting duct are called principle cells. These cells are operated by aldosterone and are responsible to secret K into the lumen.

Basolateral membrane of the principle cells has Na+/K+ ATPases, which are mainly responsible to pump the Na (3 molecules) out of the cell (into the interstitial fluid) and K (2 molecules) inside the cell. So the principle cells like other nephron cells are also rich in K and poor in Na. About 2-3% Na is reabsorbed by this part of nephron.

At the luminal side of the principle cells, there are Na-channels as well as K-channels. As these cells are poor in Na and rich in K so Na moves from lumen into the cells through Na-channels, makes the lumen electronegative which attracts proton from the intercalated cells of DCT.

K moves from the cells into the lumen through K-channels. Sodium reabsorption is more than potassium secretion so the last part of nephron becomes electronegative.


Aldosterone and Collecting Duct

In salt and water depleted state, body has tendency to activate rennin-angiotensin-aldosterone axis which produces aldosterone in the body. Finally aldosterone enters into the principle cells through basolateral membrane. This aldosterone binds with its receptor in the cytoplasm and activates its DNA part. Now this complex (aldosterone+receptor) activates different type of genes in the nucleus which eventually produces special type of proteins called as aldosterone induced proteins. These proteins have following functions:

At the luminal membrane

  • Activation of Na-channels

  • Insertion of Na-channels

  • Production of Na-channels

At the basolateral membrane

  • Activation of Na+/K+ ATPases

  • Insertion of Na+/K+ ATPases

  • Production of Na+/K+ ATPases

As a result more Na is reabsorbed into the cell and moves further into the interstitium through Na+/K+ ATPases. More K enters into the cell from interstitium through Na+/K+ ATPases.

  • In this way principle cells become extremely rich in K and extremely poor in Na. Due to reabsorption of Na, lumen will become electronegative which attracts proton from intercalated cells of DCT and K from principle cells leading to kaliuresis.

All the diuretics which act proximal to the collecting tubule are K wasters. For example; Acetazolamide inhibits the carbonic anhydrase leading to extra load of Na, bicarbonate and water in the last part of nephron. Eventually it produces kaliuresis by following mechanisms:

  • Due to extra load of sodium, more sodium is reabsorbed by the principle cells and the functioning of Na+/K+ATPases increases which brings more K into the cell. So, at the luminal side, more K moves into the lumen along the concentration gradient leading to kaliuresis.

  • Due to extra load of anions (HCO3), lumen will become more electronegative which pulls more K from the cell and produces kaliuresis.

  • When more water is present in the last part of nephron, luminal flow will be fast and it rapidly washes K from the lumen. So potassium concentration will be low in the lumen and more K moves from the cells into the lumen through K-channels leading to kaliuresis.


Antikaliuretic or K Sparing Drugs : Drugs Which Act on Collecting Duct

Triamterene and Amiloride

These drugs block the Na-channels, leading to mild natriuresis. Na+/K+ ATPases become slow, less K will enter into the cell, so rate of loss of K is reduced, so these are also called antikaliuretic or K sparing drugs.

Due to no reabsorption of Na, less electronegativity is produced which and less attraction for the K to come out of the cell is also reduced.


Spironolactone (Aldosterone Analogue)

This type of drug binds with aldosterone receptor and its DNA part remains inactive. It means that all the aldosterone depended activity has been reduced. So capability of luminal membrane to reabsorb the Na is reduced and capability of basolateral membrane to throw the Na into interstium and attract the K into the cell is also reduced.


Thick Part of Ascending Limb of Loop of Henle

The cells of this segment like other nephron cells are also rich in K and poor in Na. About 20-25% Na is reabsorbed this segment.At the luminal side, these cells have special transporter called Na+/K+ /2Cl cotransporter. This transporter is mainly responsible to push the Na (1 molecule), K (1 molecule) and Cl (2 molecules) into the cell. At the basolateral side, the cells throw the Na and Cl into the intersitium by special mechanism and make the interstitium more concentrated.

As the cells receive K from the basolateral side as well as from the luminal side, so these cells become richer in K. Due to presence of K-leaky channels at the luminal side, K escapes from the cell into the lumen making it electropositive. Due to this electropositivity, Ca and Mg present in the tubular fluid escape from the lumen through the gap junctions in between the cells.


Transcellular Transport

When substances (Na, K and Cl etc) are reabsorbed through the cell, is called tanscellular transport.


Paracellular Transport

When substances (Ca or Mg etc) are reabsorbed through the gap junctions in between the cells is called paracellular transport.


Cotransporter Inhibitor Na+/K+ /2Cl

What are the Loop Diuretics? (Furosemide, Torsemide, Ethacrynic Acid and Bumetanide etc)

Furosemide inhibits Na+/K+ /2Cl cotransporter, so Na, K and Cl cannot be reabsorbed into the cells. This makes the interstitium less hyperosmotic and urine less diluted. Eventually more Na, K, and Cl reach at the last part of nephron leading to natriuresis, diuresis and kaliuresis.

As K is not reabsorbed due to inhibition of this cotransporter, so less K will escape from the cell into lumen. This makes the lumen less electropositive so less amount of Ca and Mg is reabsorbed and more amount of Ca and Mg will appear at the last part of nephron leading to calciuria and and more Mg in the urine. Calciuria, for long time, may active the PTH which further stimulates the osteoclasts leading to osteoporosis.

In the management of severe hypercalcemia, furosemide is administrated which produces calciuria so that body can get rid of Ca. But due to risk of dehydration, furosemide always should be administrated along with normal saline (0.9%)


DCT (Distal Convoluted Tubule)

Intercalated cells of this segment have carbonic anhydrase, so they have capability to make intracellular carbonic acid which further breaks into proton (H) and bicarbonate. This proton is actively pumped into the luminal fluid making it acidic and bicarbonate is pumped into the interstitial fluid making it alkaline. This proton (H) further reacts with PO4 in the lumen and makes H2PO4, and also reacts with NH3 to form NH4Cl, making the urine acidic.

Due to inhibition of Na+/K+ /2Cl cotransporter, more Na goes to the distal part of nephron near the intercalated cells and principle cells. This will drag more K from the principle cells and H from the intercalated cells into the luminal fluid that will end up into only natriuresis, loss of Cl, but also kaliuresis and acidic urine.


Thiazide and Thiazide Like Diuretics

Intercalated cells like other nephron cells are also rich in K and poor in Na. About 8-10% Na is reabsorbed by this segment of nephron. These cells have Na/Cl cotransporter and Ca-channels at their luminal side. Na/Cl cotransporter is responsible to pump the Na and Cl into the cell, then Na and Cl further move into the interstitium at the basolateral membrane. Ca channels are responsible to take the Ca from the lumen into the cell under the influence of PTH. This hormone secreted by chief cells of parathyroid gland acts on specialized serpentine receptors present on the cell membrane.

At the basolateral membrane, these cells have Na/Ca exchanger. Na moves into the cell and intraceullar Ca moves into the interstitium through this exchanger.

Thiazide and thiazide like diuretics inhibit Na/Cl cotransporter, so more Na and Cl go to the distal part of nephron leading to natriuresis, diuresis and kaliuresis. Due to inhibition of Na/Cl cotransporter, Na cannot move into the cell which leads to overfunctioning of Na/Ca exchanger. As a result, more interstitial Na enters into the cell and more intracellular calcium moves into the interstitium. In this way Ca is being reabsorbed more effectively by DCT cells through Ca-Channels leading to less loss of Ca in urine. So, thiazides are Ca retainers and K wasters.

If a patient suffers from idiopathic hypercalciuria, he/she has high risk of Ca related stones in the urinary system. One of the managements is to administrate low dose of thiazide drug for a long time.


Differences Between Furosemide (Loop Diuretics) and Thiazide Drugs

Furosemide (Loop Diuretics)

Act on thick part of ascending loop of Henle.

Inhibit Na+/K+ /2Cl cotransporter.

Produce calciuria, so also called Ca wasters

Diuretic


Thiazide Drugs

  1. Act on distal convoluted tubule (DCT)

  2. Inhibit Na/Cl cotransporter

  3. Ca retainers

  4. Moderate diuretic


Similarities Between Furosemide (Loop Diuretics) and Thiazide Drugs

  1. Both drugs produce natriuresis, kaliuresis and diuresis.

  2. Both are also called K wasters.

  3. Their action is prostaglandin dependent. If there is low PG (due to use of NSAIDs), the function of these drugs decrease.

  4. In case of impaired renal function, enough concentration of these drugs will not reach to the lumen leading to loss of diuretic function.

  5. Both drugs are secreted into the lumen from peritubular system. This pathway is also shared by uric acid pathway. So long term use of these diuretics may lead to hyperuricemia.

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