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