in this lecture I'm going to talk about diuretics so let's get right into it so diuretics also known as water pills simply promote the elimination of water from the body now in order to understand how diuretics work first we need to review the basic physiology of nephron so as you may already know nephron is the structural and functional unit found within the kidneys each nephron has five distinct regions that has specific function first we have Bowman's capsule surrounding a network of capillaries called glomerulus here blood comes into the afferent arteriole where components of the blood
get filtered out of the capillaries into the capsule filtered blood is then carried away from the glomerulus by efferent arteriole next glomerular filtrate which contains mostly water amino acids glucose sodium bicarbonate and electrolytes flows through proximal convoluted tubule in this region almost 100% of the amino acids glucose and about 90% of bicarbonate get reabsorbed as well as about 65% of electrolytes such as sodium and potassium along with water as a side note here remember wherever sodium ions go chloride and water tend to follow the next major region through which the filtrate travels is the descending
and ascending loop of Henle which passes into the medulla of the kidney now the descending limb has walls permeable to water but impermeable to sodium so as the filtrate travels down water leaves but sodium tends to stay making the filtrate more concentrated on the other hand the opposite takes place in the ascending limb particularly in the thick limb which is permeable to sodium but impermeable to water so as the filtrate travels up about 25% of sodium gets reabsorbed passively as well as via active reabsorption mediated by the sodium-potassium-2-chloride cotransporter next the filtrate travels through the
distal convoluted tubule here about 5 to 10% of sodium chloride gets reabsorbed mainly via sodium-chloride cotransporter this part is also relatively impermeable to water so at this point the filtrate becomes more diluted finally the filtrate travels through the late distal tubule and collecting duct here we find two types of cells the principal cells and the intercalated cells now the functions of the principal cells are regulated by two hormones aldosterone which increases sodium reabsorption and increases potassium secretion and antidiuretic hormone which increases water permeability and thus increases water reabsorption now on the other hand the intercalated
cells are regulated by aldosterone but their primary function is to secrete hydrogen ions and reabsorb potassium so now let's switch gears and let's talk about diuretics diuretics simply increase the volume of produced urine by acting on different parts of nephron so in other words diuretics help us to remove salt and water from the body which makes them very useful for treatment of hypertension and abnormal fluid retention referred to as edema now based on their mechanism of action diuretics can be divided into five major classes and these are carbonic anhydrase inhibitors loop diuretics thiazide diuretics potassium
sparing diuretics and osmotic diuretics so let's look at each class in more detail starting with carbonic anhydrase inhibitors carbonic anhydrase inhibitors produce their diuretic effect mainly by reducing reabsorption of bicarbonate in the proximal convoluted tubule now let's zoom in on the epithelial cell of the proximal tubule to see how they exactly do that so to the left of the epithelial cell we have lumen where urine is being formed and to the right we have interstitium which contains blood vessels now here bicarbonate reabsorption is initiated by the action of sodium-hydrogen ion exchanger which allows sodium to
enter the cell in exchange for hydrogen ion next reabsorbed sodium is pumped by sodium potassium ATPase out of the cell where the secreted hydrogen ion combines with the luminal bicarbonate ion to form carbonic acid carbonic acid is then rapidly dehydrated to carbon dioxide and water by an enzyme carbonic anhydrase now carbon dioxide enters the epithelial cell by simple diffusion and gets rehydrated back to carbonic acid by intracellular carbonic anhydrase finally intracellular carbonic acid dissociates to form hydrogen ion which can be transported by sodium-hydrogen exchanger to the lumen and bicarbonate ion which is transported out of
the cell now when carbonic anhydrase inhibitor comes around it inhibits carbonic anhydrase enzyme and as a result bicarbonate gets retained in the lumen since bicarbonate reabsorption utilizes the sodium-hydrogen exchanger inhibition of carbonic anhydrase leads to significant reduction in proximal tubule sodium reabsorption which ultimately results in mild diuresis now the reason why the diuretic effect is only mild is because the majority of the sodium that doesn't get reabsorbed in proximal tubule still gets reabsorbed by distal parts of the nephron however this late reabsorption also leads to increase potassium secretion which is one of the side effects
associated with this class additionally because bicarbonate is a major component of the acid-base buffering system in the circulation it's wasting leads to increase in plasma acidity known as metabolic acidosis now one of the most popular drugs that belongs to this class is a Acetazolamide however due to its relatively weak diuretic effect Acetazolamide is commonly used for its other pharmacologic actions now let's move on to loop diuretics so loop diuretics just like their name suggests work in the loop of Henle specifically in the ascending limb where they inhibit sodium-potassium-2-chloride cotransporter out of all diuretics these agents
produce the greatest diuretic effect because as much as 25% of sodium gets reabsorbed in the ascending limb and at this point other parts of nephron can no longer compensate for increased levels of tubular sodium so now let's zoom in on the cell that lines the thick ascending limb to see what exactly happens there so upon reaching the thick ascending limb some of the filtered sodium potassium and chloride get reabsorbed by sodium-potassium-2-chloride cotransporter this among other things leads to accumulation of potassium within this cell however potassium also tends to leak out through potassium channels back into
the lumen which contributes to a more positive charge there now this positivity in the lumen produces electrical driving force for paracellular reabsorption of cations such as magnesium and calcium so when loop diuretic comes around and blocks sodium-potassium-2-chloride cotransporter we not only lose sodium and water but also potassium calcium and magnesium now keep in mind that potassium loss takes place mainly in the late distal tubule where sodium rich fluid enhances sodium potassium exchange and I'll talk about this more later drugs that belong to this class include Bumetanide Ethacrynic acid Furosemide and Torsemide now when it comes
to side effects besides causing electrolytes imbalance loop diuretics can cause rapid and excessive reduction in blood volume also known as acute hypovolemia this can lead to hypotension shock and even cardiac arrhythmias next because loop diuretics inhibit sodium-potassium-2-chloride cotransporter which also happen to exist in the inner ear their use has been associated with the damage to the hearing also referred to as ototoxicity lastly Ethacrynic acid and Furosemide in particular compete with a transport of uric acid at the same site thus blocking its secretion which ultimately can lead to hyperuricemia and thus worsening of gout symptoms now
let's move on to thiazide diuretics so thiazides are probably the most commonly prescribed diuretics they work mainly in the early part of the distal tubule where they increase sodium chloride excretion by inhibiting sodium-chloride cotransporter however since over 90% of sodium is reabsorbed before reaching the distal tubule in general thiazides produce rather weak diuresis on the other hand thiazides are capable of causing vasodilation which reduces peripheral vascular resistance by mechanism that unfortunately is not clearly understood yet now let's zoom in on the epithelial cell of the early distal tubules to see what exactly happens there so
here sodium and chloride enter the cell via sodium-chloride cotransporter once inside the cell sodium gets transported to the blood via the sodium-potassium ATPase while chloride diffuses out on the other side via chloride channel now when thiazide diuretic comes around and inhibits this sodium-chloride cotransporter the result is decreased sodium chloride reabsorption and ultimately since water follows the salt we get increased urine output drugs that belong to this class include Chlorothiazide and Hydrochlorothiazide which are structurally similar sulfonamide derivatives and we also have Chlorthalidone Metolazone and Indapamide which are often referred to as thiazide-like drugs because they don't
have true thiazide ring but share the same mechanism of action now when it comes to side effects just like loop diuretics thiazides can cause hypokalemia which results from increased delivery of sodium to the distal parts of the tubule moreover similarly to loop diuretics thiazides can also lead to hyperuricemia by interfering with uric acid transport which in turn may exacerbate gout now while loop diuretics can cause calcium excretion leading to hypocalcemia thiazides on the other hand can cause the opposite that is hypercalcemia there are two mechanisms that are thought to be responsible for this first takes
place in the proximal tubule where thiazide induced volume depletion leads to a compensatory increase in sodium reabsorption which in turn produces electrical gradient which leads to passive calcium reabsorption the second mechanism involves the sodium-calcium exchanger located on the basolateral side of the distal tubule so because thiazides block sodium-chloride cotransporter there will be decreased concentration of sodium inside the cell which then in turn causes the sodium calcium exchanger to bring in more sodium in exchange for calcium which is then excreted into the bloodstream lastly thiazides may worsen glucose control leading to hyperglycemia and they may also
elevate cholesterol leading to hyperlipidemia some of the mechanisms thought to be responsible for these effects include decreased insulin secretion and insulin sensitivity as well as increased hepatic glucose production now let's move on to potassium-sparing diuretics so potassium-sparing diuretics work primarily in the collecting tubule where they inhibit sodium reabsorption and potassium excretion although these potassium-sparing agents are relatively weak diuretics they are often used in combination with diuretics from the other classes in order to enhance their effects now let's zoom in on the collecting tubule principal cell to see what exactly happens there so principal cell has
separate channels for sodium and potassium as well as sodium-potassium ATPase on the basolateral side under normal conditions here sodium enters the cell through sodium channel and then is transported by sodium-potassium ATPase into the bloodstream in exchange for potassium now because this sodium entry predominates here the lumen negative electrical potential is generated and chloride is driven into the bloodstream through paracellular pathway this in turn drives potassium out of the cell through potassium channel so as a side note here this illustration should also help you understand how loop diuretics and thiazides lead to potassium loss so increased
sodium load caused by loops and thiazides enhances sodium reabsorption which makes lumen more negative this in turn generates driving force for increased potassium secretion and ultimately lower potassium levels in the blood stream hence hypokalemia now going back to potassium-sparing diuretics agents within this class can be separated into two groups based on their distinct mechanisms of action so the first group works simply by blocking sodium channel which results in decreased sodium potassium exchange and thus retention of potassium drugs that belong to this group include Amiloride and Triamterene now the second group on the other hand works
by antagonizing aldosterone aldosterone is a hormone which gets into the cell binds to the intracellular receptor and stimulates transcription of genes encoding sodium channel and sodium potassium ATPase thus increasing their expression in other words aldosterone leads to increased reabsorption of sodium and water and increased secretion of potassium so because aldosterone antagonists compete for binding to that intracellular receptor the result is reduced synthesis of proteins that activate sodium channels and decreased number of sodium potassium ATPases which ultimately leads to potassium retention drugs that belong to this group include Spironolactone and Eplerenone now when it comes to
side effects as you may already guessed hyperkalemia is the biggest problem especially when these diuretics are combined with other drugs that can also increase potassium levels lastly due to its chemical structure that resembles our natural steroid hormones Spironolactone can stimulate receptors for testosterone and progesterone leading to effects such as menstrual irregularities in females and gynecomastia in males now before we end I wanted to briefly discuss the last class of diuretics namely osmotic diuretics which work by interfering directly with osmosis as you may recall from your basic biology class water has tendency to move across membrane
from lower osmolarity or the dilute side to a higher osmolarity or the concentrated side so these osmotic agents are filtered from glomerulus they are very water soluble or hydrophilic and they undergo very limited reabsorption due to their large molecular size this leads to increased osmolarity of the tubular fluid and thus decreased water reabsorption now because osmotic diuretics increase water excretion rather than sodium excretion they're not very effective for treating edema caused by sodium retention instead they are mainly used for reduction of intracranial pressure promotion of urinary excretion of toxic substances as well as promotion of
urine production in patients with acute kidney failure examples of osmotic diuretics are Mannitol and Urea as for the side effects use of osmotic diuretics can lead to significant fluid changes such as volume overload or dehydration and thus electrolyte imbalances and with that I wanted to thank you for watching I hope you enjoyed this lecture and as always stay tuned for more
