Pharmacology – DIURETICS (MADE EASY)

Pharmacology – DIURETICS (MADE EASY)

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

100 Replies to “Pharmacology – DIURETICS (MADE EASY)”

  1. tnx to a very precise teachings… can i request that you also make a teaching lesson regarding calcium channel blockers….. tnx in advance..

  2. Hii sir..#pls take a antidiuretic class #your class very interesting and easy#pls more video upload

  3. Thank you sooo much!!!!! You are the best Pharmacology teacher On YouTube!!! Thanksss a lot ❤️❤️❤️

  4. Tq very much sir… But i have a doubt… At 12:21 (regarding cause of hyper calcemia) increase in sodium reabsorption at PCT must decrease calcium reabsorption….as both are positively charged ions…??

  5. Wait, isn't the Thick ascending loop impermeable to H20? If we blocked the Na/K/CL co-transporter with a loop diuretic, we still shouldn't loose water in THIS area either in OR out, even if the sodium were to stay, right?

  6. Thank you sir, this helped me a lot:)
    But I request you to make videos about the anti-microbials and CNS drugs as they are huge topics and difficult to cover quickly, I have my finals soon 😭

  7. 👍👍👍👍👍👍👍👍 👍👍👍👍👍👍👍👍👍👍👍👍👍👍👍👍👍👍👍👍👍👍👍

  8. Man, you are saving lives. I don't know where would I've been if I haven't found your leactures! Thank you so much for all your work, please keep on rocking!!! <3

  9. Well u said spironolactone will stimulate receptos for testosterone n progestrone.. But its not right.. Spironolactone resembles testosterone in structure n hence can competitively inhibit testosterone n progestrone receptors which will lead to impotence n gynecomastia in males n menstrual irregularities in females n moreover bcz it inhibits testosterone receptprs thats why it is also used for tx of hirsuitism

  10. At the end of this lecture you mentioned that the osmotic diuretics can cause volume overload and dehydration? Why would they cause volume overload?

  11. Plz have such less time to even like this effort….so many view but so less likes …u deserve more…keep the good work goin

  12. Sir can you please upload videos on other subjects of pharmacy as your lecture is most interesting and understanding.

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