Diuretics Flashcards
What are diuretics
are drugs that increase the volume of urine excreted.
What is the most common MOA for diuretics
inhibitors of renal ion transporters that decrease the reabsorption of Na+ at different sites in the nephron.
As a result, Na+ and other ions enter the urine in greater than normal amounts along with water, which is carried passively to maintain osmotic equilibrium.
Notes: Diuretics change urine pH, the ionic composition of the urine& blood.
What is the most common use of diuretics
Management of edema
Many diuretics are used for non-diuretic actions indications give some examples
➢ thiazides in hypertension,
➢ carbonic anhydrase inhibitors in glaucoma,
➢ aldosterone antagonists in heart failure
How much of the blood is filtered through the glomerular capillaries into bowman’s capsule
Approximately 16% to 20%
What is the composition of The blood filtrate?
glucose, sodium bicarbonate, amino acids, and
other organic solutes, as well as electrolytes, such as Na+, K+, and Cl-. normally free of proteins and blood cells.
How does the kidney regulates the ion composition and volume of urine
➢ active reabsorption or secretion of ions
➢ and/or passive reabsorption of water at five functional zones along
the nephron
How much of the filtered Na+ (and water) get reabsorbed at the proximal tubule
65%
diuretics working in the proximal tuble have weak diuretic
properties, why?
The presence of a high capacity Na+ and water reabsorption area (loop of Henle) distally to the proximal convoluted tubule allows reabsorption of Na+ and water kept in the lumen by diuretics acting in the proximal convoluted tubule, and limits effective diuresis
Where does Approximately 25% to 30%
of the filtered sodium chloride is absorbed
And is the major site for salt reabsorption
The ascending loop of Henle
When it comes distal tubule:
İs it permeable to water
How much of nacl gets reabsorbed and via what transports
The target of what drug?
- No
- 5%-10% via Na+/Cl- transporter
- Thiazide diuretics
Note: calcium reabsorption happens here
1% to 2% of the filtered sodium enters the principal cells through epithelial sodium channels that are inhibited by what?
amiloride and triamterene.
Aldosterone receptors in the principal cells influence Na+
reabsorption and K+
secretion.how
Aldosterone increases the synthesis of epithelial sodium channels and of the Na•/K•-ATPase pump
to increase Na• reabsorption and K+ excretion.
Why are thiazides the most widely used diuretic
because of their antihypertensive effects.
İs the efficacy of thiazides for HTN depended on their diuretic action
No not entirely
Thiazides reduce peripheral vascular resistance
with long-term therapy.
Ok
What is the main difference between thiazides
all have equal maximum diuretic effects, differing only in potency
Chlorothiazide was the first orally active thiazide, although hydrochlorothiazide and chlorthalidone are now used more commonly due to better bioavailability.
Ok
What’s the potency for the following
Chlorothiazide
Hydrochlorothiazide
Chlorthalidone
Hydrochlorothiazide is more potent than chlorothiazide
Chlorthalidone is twice as potent as hydrochlorothiazide
What are thiazide-like diuretics
Chlorthalidone ,indapamide , and metolazone are referred to as thiazide-like diuretics (lack the characteristic benzothiadiazine chemical
structure)
however, their mechanism of action, indications, and adverse effects are similar to those of hydrochlorothiazide
What is the MOA for thiazides
The thiazide and thiazide-like diuretics act mainly in the distal convoluted tubule to decrease the
reabsorption of Na+ by inhibition of a Na+
/Cl−
cotransporter
As a result, these drugs increase the concentration of Na+ and Cl−
in the tubular fluid.
Thiazides must be excreted into the tubular
lumen at the proximal convoluted tubule to be
effective
Therefore, decreasing renal function reduces the
diuretic effects.
What are the main actions of thiazides
a. Increased excretion of Na+ and Cl−
which can result in the excretion of very hyperosmolar(concentrated) urine.
This effect is unique
b. Decreased urinary calcium excretion
decrease the Ca2+ content of
urine by promoting the reabsorption of Ca2+ in the distal convoluted tubule.
c. Reduced peripheral vascular resistance
An initial reduction in blood pressure results from a decrease in blood volume and, therefore, a decrease in cardiac output.
With continued therapy, blood volume returns to baseline.
However, antihypertensive effects continue, resulting from reduced peripheral vascular resistance caused by relaxation of arteriolar smooth muscle
What are the therapeutic uses for thiazides
a. Hypertension
Clinically, thiazides are a mainstay of antihypertensive treatment, because they are inexpensive, convenient to administer, and well tolerated.
Blood pressure can be lowered with a daily dose of thiazide.
At doses equipotent to hydrochlorothiazide,
chlorthalidone is considered a preferred option by some clinicians because of its longer half-life.
b. Heart failure
Loop diuretics (not thiazides) are the diuretics of choice in reducing extracellular volume in heart failure.
However, thiazide diuretics may be added in patients resistant to loop
diuretics
Metolazone is most frequently utilized as an addition to loop diuretics
c. Hypercalciuria
➢ thiazides inhibit urinary Ca2+ excretion
➢ useful in treating:
➢ idiopathic hypercalciuria
➢ calcium oxalate stones in the urinary tract
what are the pharmacokinetics for thiazides
bioavailability—–60%-70%
chlorthiazide—–bioavailability 15%-30% thw only one with IV form
most thiazides take 1-3 weeks to produce a stable reduction in blood pressure
most thiazides exhibits a long half life (10-15) hours
most thiazides are excreted unchanged by urine
how does the pharmacokinetics of Indapamide differs from other thiazides
its the only one that under goes hepatic metabolism and is excreted by urine and bile
what are the side effects of thiazides
1) hypokalemia (the most frequent)
its is the continual loss of k+ from the body
happens due to the thiazides increase Na+
in the filtrate arriving at the distal tubule, more K+is also exchanged for Na+
Potassium supplementation or combination with a potassium-sparing diuretic may be required.
2)hypomagnesemia (loss of mg)
3)hyponatremia (due to the elevation of ADH)
4)hyperuricemia
➢ Thiazides increase serum uric acid by decreasing the amount of acid excreted through competition in the organic acid secretory system.
➢ may precipitate a gouty attack in predisposed individuals.
➢ thiazides should be used with caution in patients with gout or high levels of uric acid.
5) hypovolemia (orthostatic hypotension and light headedness)
6)hypercalcemia
7)hyperglycemia
➢ Patients with diabetes still benefit from thiazide therapy, but should monitor glucose to assess the need for an adjustment in diabetes therapy if thiazides are initiated.
give examples on loop diuretics and their location of action
Bumetanide , furosemide (most common), torsemide , and ethacrynic acid (not used due to high side effects
on the ascending loop of henle
whats the difference between bumetanide and torsemide and furosemide
bumetanide and torsemide have better bioavailavility and more potent
what is the MOA of loop diuretics
Loop diuretics inhibit the cotransport of Na+
/K+/2Cl−in the luminal membrane in the ascending limb of the loop of Henle
These agents have the greatest diuretic effect of all the diuretics because the ascending limb accounts for reabsorption of 25% to 30% of filtered NaCl and downstream sites are unable to compensate for the increased Na+load
Loop diuretics must be excreted into the tubular lumen at the proximal convoluted tubule to be effective
what are the actions of loop diuritecs
1)diuresis even with renal dysfunction patients
2)increses ca++ excretion
In patients with normal serum Ca2+concentrations, hypocalcemia does not result, because Ca2+ is reabsorbed in the distal convoluted tubule.
3) venodilation due to enhanced prostaglandin synthesis
what are the theraputic uses for loop diuretics
1) edema (drug of choice)
for pulmonary edema and acute/chronic peripheral edema caused from heart failure or renal impairment.
can be given IV in emergency
2)hypercalcemia
3)hyperkalemia
what are the pharmacokinetics of loop diuretics
can be given orally or IV
Furosemide has unpredictable bioavailability of 10% to 90% after oral administration.
Bumetanide and torsemide have reliable bioavailability of 80% to 100%, which makes these agents preferred for oral therapy.
The duration of action is approximately 6 hours for furosemide and bumetanide, and moderately longer for torsemide,
what are the side effects for loop diuretics
1) acute hypovolemia
a severe and rapid reduction in blood volume, with
the possibility of hypotension, shock and cardiac arrhythmias.
2) hypokalemia
The heavy load of Na+ presented to the collecting tubule results in increased exchange of tubular Na+ for K+ leading to hypokalemia, the most common adverse effect of the loop diuretics.
Use potassium-sparing diuretics or supplementation with K+
3)hypomagnesemia
4) ototoxicity (reversible or permanent hear loss)
particulary when
➢ infused intravenously at fast rates,
➢at high doses
➢when used in conjunction with other ototoxic drugs (aminoglycoside antibiotics).
➢Ethacrynic acid is the most likely to cause ototoxicity.
5) hyperuricemia
➢Loop diuretics compete with uric acid for the renal secretory systems, thus blocking its secretion and, in turn, may cause or exacerbate gouty attacks.
what are potassium sparing diuretics
Potassium-sparing diuretics act in the collecting tubule to inhibit Na+reabsorption and K+ excretion
These drugs should be used cautiously in moderate renal dysfunction and avoided in patients with severe renal dysfunction because of the increased risk of hyperkalemia.
Within this class, there are drugs with two distinct mechanisms of action:
aldosterone antagonists
epithelial sodium channel blockers
what is the MOA for spironolactone and eplerenone (potassium sparing , aldosterone antagonists)
antagonize aldosterone receptors.
Resulting in a lack of intracellular proteins that stimulate the Na+/K+exchange sites of the collecting tubule.
Thus, aldosterone antagonists prevent Na+
reabsorption and, therefore, K+ and H+ secretion.
Eplerenone is more selective for aldosterone receptors and causes less endocrine effects (gynecomastia) than spironolactone, which also binds to progesterone and androgen receptors.
what are the actions of spironolactone and eplerenone
antagonize aldosterone receptors at :
renal sites, which causes diuresis,
nonrenal sites, which causes other effects.
In most edematous states, blood levels of aldosterone
are high, causing retention of Na+
Spironolactone antagonizes the activity of aldosterone,
resulting in retention of K+ and excretion of Na+
what are the theraprutic uses for aldosterone antagonists
1)edema
Aldosterone antagonists are particularly effective diuretics when used in high doses for edema associated with secondary hyperaldosteronism, such as:
hepatic cirrhosis and nephrotic syndrome.
Spironolactone is the diuretic of choice in patients with hepatic cirrhosis with fluid in the peritoneal cavity (ascites).
By contrast, in patients who have no significant circulating levels of aldosterone, there is minimal diuretic effect with use of this drug.
2)hypokalemia
Although the aldosterone antagonists have a low efficacy in mobilizing Na+ from the body in comparison with the other diuretics, they have the useful property of causing the retention of K+.
These agents are often given in conjunction with thiazide or loop diuretics to prevent K+ excretion that occurs with those diuretics.
3)heart failure
Aldosterone antagonists are employed at lower doses to prevent myocardial remodeling mediated by aldosterone.
Use of these agents has been shown to decrease mortality associated with heart failure, particularly in those with reduced ejection fraction.
4)Resistant hypertension, defined by the use of three or more medications without reaching the blood pressure goal,
often responds well to aldosterone antagonists.
This effect can be seen in those with or without elevated aldosterone levels
5)Polycystic ovary syndrome
Spironolactone is often used off-label for the treatment of polycystic ovary syndrome.
It blocks androgen receptors and inhibits steroid synthesis at high doses, thereby helping to offset increased androgen levels seen in this disorder.
what are the pharmacokinetics of aldosterone antagonists
Both spironolactone and eplerenone are well absorbed after oral administration.
Spironolactone is extensively metabolized and converted to several active metabolites, which contribute to the therapeutic effects.
Eplerenone is metabolized by cytochrome P450.
what are the side effects of aldosterone antagonists
a. Hyperkalemia
The most common side effect, hyperkalemia, is dose-dependent.
increases with renal dysfunction or use of other potassium-sparing agents such as angiotensin-converting enzyme inhibitors and potassium supplements.
b. Gynecomastia
Spironolactone, but not eplerenone, may induce gynecomastia in approximately
10% of male patients and menstrual irregularities in female patients.
what are Triamterene and amiloride
Triamterene and amiloride block epithelial sodium channels, resulting in a decrease in Na+/K+ exchange.
Although they have a K+-sparing diuretic action similar to that of the aldosterone antagonists,
their ability to block the Na+/K+-exchange site in the collecting tubule does not depend on the presence of aldosterone.
Like the aldosterone antagonists, these agents are not very efficacious diuretics.
Both triamterene and amiloride are commonly used in combination with other diuretics, almost solely for their potassium-sparing
properties.
