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Diuretic drugs 2


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In general, what is the intent of a diuretic?
increase urine flow by decreasing the amount of Na+ reabsorbed at different sites of the nephron
Name the 5 classes of diuretics
Thiazides, Loop, Potassium-sparing, Carbonic Anhydrase Inhibitors, and Osmotic Diuretics
What are the major clinical uses of diuretics?
managing disorders involving abnormal fluid retention (edema), or treating hypertension
Name the 5 functional zones of the kidney
1) proximal convoluted tubule
2) descending loop of Henle
3) ascending loop of Henle
4) distal convoluted tubule
5) collecting duct
What does glomerular filtrate contain?
low-molecular-weight plasma proteins in the same concentrations found in plasma; Includes: glucose, sodium bicarbonate, amino acids, and electrolytes
In which portion of the nephron does carbonic anhydrase inhibitor function? How does it work?
proximal tubule - inhibits the reabsorption of HCO3 by inhibiting carbonic anhydrase located both in the cytoplasm and apical membrane of proximal tubular epithelium. This decreases the exchange of Na+ for H+ resulting in a weak diuretic effect.
Name an anhydrase inhibitor
acetazolamide - there's only one in this class
What are the adverse effects seen in Acetazolamide therapy?
1) Mild metabolic acidosis (hyperchloremic)
2) Potassium depletion
3) Renal stone formation
4) drowsiness
5) possible paresthesia
Avoid in patients w/ hepatic cirrhosis - could lead to decreases excretion of NH4.
What are the therpeutic uses of Acetazolamide?
1) Treatment of chronic glaucoma (most common use) - reduces the elevated intraocular pressure of open-angle glaucoma by decreasing the production of aqueous humor; should not be used in an acute attack (too slow)
2) Mountain sickness (weakness, breathlessness, dizziness, nausea, and crebral & pulmonary edema) - prophylaxis treatment given nightly 5 days prior to ascent
In which specific portion of the nephron does a loop diuretic function?
Ascending Loop of Henle - thick portion
How does a loop diuretic work?
They inhibit the Na+/K+/2Cl- cotransport, resulting in water and electrolyte retention
They are the most efficatious of the diuretics because the ascending limb accounts for the reabsorption of 25-30% of filtered NaCl, and downstream sites can not compensate for the increased Na+ load.
Name the 4 most commonly used Loop Diuretics
Bumetanide, furosemide, Torsemide, and ethacrynic acid
Name the 2 Loop Diuretics that are sulfonamide derivatives. Which is the more potent? Which is the most commonly used?
Furosemide and bumetanide. Bemetanide is more potent, but furosemide is the most commonly used.
Which electrolytes are lost in the urine?
Na+, Ca++, Mg++
Which kind of diuretic can be used to decrease the serum Ca++ load?
Loop diuretics
What kind of diuretic can be used to increase serum Ca++?
Thiazide diuretics
Why should NSAIDs be avoided in patients with renal disease?
NSAIDs reduce the synthesis of prostaglandins dampening vasoconstriction effects thereby preventing ischemia
How do prostaglandins and loop diuretics interact?
loop diurectis increase prostaglandin synthesis, which in turn dampen vasoconstriction effects
What are the therapeutic uses of Loop Diuretics?
1) acute pulmonary edeam of heart failure - drug of choice due to rapid onset of action
2) hypercalcemia
What are the pharmacokinetics of Loop Diuretics?
oral or IV administration every 2-4 hours. It'secreted into the urine.
What are the 5 main adverse effects of loop diuretics?
1) otoxicity
2) hyperuricemia
3) Acute volemia
4) hypokalemia
5) hypomagnesemia
Which two loop diuretics may exacerbate gouty attacks?
Furosemide and Ethacrynic Acid compete with uric acid for the renal & biliary secretory systems
Which loop diuretic has the highest incidence of causing deafness?
Ethacrynic Acid (most common), particularly when used in conjunction with aminoglycoside antibiotics; However, all loop diuretics can have this adverse effect.
Under what conditions may Hypercalcemia develop?
Acute hypovolemia - severe rapid reduction in blood volume - due to loop diuretic use. Hypotension, shock, and cardiac arrhythmias may develop as well.
In what portion of the nephron do Thiazides work? How do they work?
Distal convoluted tubule - they inhibit reabsorption of Na+ and Cl-; most commonly used diuretic
Which diuretics are sulfonamide derivatives?
Thaizides, furosemide, and bumetanide
Name the 5 Thiazide diuretics
1) chlorothiazide
2) hydrochlorothaizide
3) chlorthalidone
4) indapamide
5) metolazone
(3-5 are not true thiazides, but have similar mechanism of action and are therefore "thiazide-like" diuretics)
Name the 2 most commonly used thiazide diuretics
1) hydrochlorothiazide (most potent, doesn't inhibit carbonic anyhdrase as much)
2) chlorthalidone
What is Thiazides' mechanism of action?
It acts on distal convoluted tubule (DCT) to decrease the reabsorption of Na+ (inhibits the Na+/Cl- cotransporter on the luminal membrane of the DCT). The result is increased tubular osmolarity - hyperosmolar urine is unique to the thiazide diuretics
How do thiazide diuretics work in the setting of decreased renal function?
They don't...because the site of action is on the luminal membrane, they have to excreted into the lumen to be effective. In the setting of decreased renal function, thiazides lose their efficacy
What are the 5 actions of thiazide diuretics?
1) increased excretion of Na & Cl
2) Loss of K
3) Loss of Mg
4) Decreased urinary Ca excretion
5) reduced peripheral vascular resistance
T/F Thaiazides promote Ca++ reabsorption, and have been shown to actually preserve bone mineral density, reducing hip fracture risk by 30%
What are the 4 therapeutic uses of thiazide diuretics?
1) Hypertension (mild-moderate essential HTN) - effective in 3-7 days; they have synergistic effects when used with ACE inhibitors
2)Heart failure (diuretic of choice)
3) Hypercalciuria - helps treat hypocalcemia, and is also helpful for patients with calcium stones
4) Diabetes insipidus (nephrogenic) - produces hyperosmolar urine reducing urine volume
What are the pharmacokinetics of thiazide diuretics?
Effective 1-3 weeks after oral ingestion. They exhibit a prolonged half-life (40 hours). They are secreted by the organic acid secretory system in the proximal tubule of the kidney
What are the 8 adverse side effects of thiazides
1) hypokalemia
2) hyponatremia
3) hypercalcemia
4) dehydration
5) hyperuricemia
6) hyperglycemia
7) hyperlipidemia
8) hypersensitivity
How are thiazides and gout related?
Thiazides decrease the amount of uric acid excreted by the organic acid secretory system located in the proximal tubuel. Since uric acid is insoluable, it builds up in the joints, which may result in gouty attacks in those who are predisposed. Probenecid (a drug used in gout treatment) interferes in the excretion of thiazides and increases serum uric acid levels.
Which thiazide-like diuretic can be used in advanced renal failure?
Metolazone will cause Na+ excretion in this setting
Which thiazide-like diuretic is lipid soluble?
Indapamide - low doses show significant anti-HTN actions with minimal diuretic effects. Metabolized and excreted by the GI tract and the kidneys - less likely to accumulate in patients with renal failure
On which area of the nephron do Potassium-sparing diuretics work?
Collecting duct
spironolactone - aldosterone antagonist
amiloride & triamterene - block Na+ channels
They all prevent the loss of K+ that occurs with thiazide or loop diuretics
Where is the organic acid base secretory system located?
in the lumen of the proximal tubule
What organic substances does the proximal tubule secrete?
organic acids: creatinine, dopamine, epinephrine, norepinephrine,
Organic bases: bile salts, hippurates, oxalate, prostaglandins, and urate
What inorganic substances does the proximal tubule secrete?
amiloride, atropine, cimetidine, isoproterenol, morphine, procainamide, quinine, acetazolamide, bumetanide, chlorothiazide, penicillin, probenecid, salicylate
T/F The organic acid/base secretory system can secrete all of the substances filtered thru it at any given time
false - the system is saturable, and diuretic drugs compete for transfer with endogenous substances. A number of interactions can occur (i.e. probenicid interferes with penicillin secretion)
Where in the nephron can the major site of Na+ reabsorption be found?
40% in the proximal tubule
35% in ascending limb of loop of Henle
10% in the distal convoluted tubule
2-5% in the collecting tubule
How does spironolactone work?
It antagonizes aldosterone at intercellular cytoplasmic receptor sites, preventing translocation of the receptor complex into the nucleus of the target cell, preventing the production of proteins that stimulate the Na/K-exchange sites of the collecting tubule - ultimately prevents Na+ reabsorption as well as K+ and H+ secretion
What does spironolactone do?
At high levels of aldosterone (which most edamatous patients have), it blocks the actions of aldosterone. When the aldosterone levels are not elevated, there is no diuretic effect...all of this depends on renal prostaglandin synthesis
Name spironolactone's 3 therapeutic uses
1) diuretic - most useful property is K+ retention when used in conjunction w/ other diuretics
2) secondary hyperaldosteronism - only stand-alone drug that induces a net negative salt balance
3) Heart Failure - prevents remodeling that occurs in progressive heart failure
What are spironolactone's pharmacokinetics?
completely absorbed orally and is strongly bound to proteins. Rapidly converted to its active motabolite - canrenone - which is responsible for much of spironlactone's actions and has mineralcorticoid blocking actions.
spironolactone induces hepatic cytochrome P450
What are spironolactone's adverse effects?
1) gastric upset
2) peptic ulcers
3) gynecomastia in males & menstrual irregularities in females (due to it's chemical resemblance to sex steroids).
4) Hyperkalemia (chronic use)
5) nausea (chronic use)
6) lethargy (chronic use)
7) mental confusion (chronic use)
This drug shouldn't be given at high doses for long periods - it's more effect when given for a few days at a time.
At low doses, the drug can be used chronically with few sides affects (as noted above)
Will Triamterene and amiloride work without high levels of aldosterone?
Yes, so they can be used in individuals with Addison's disease.
However, they are not efficatious stand-alone diuretics. They are typically used in conjunction with other diuretics and are valued for their K+ sparing abilities
How do Triamterene and Amiloride work?
They block Na+ transport channels, resulting in a decrease in Na+/K+-exchange
What are some side effects of Triamterene and Amiloride?
leg cramps
possibly increased blood urea nitrogen
uric acid retention
What happens in a nephron's descending loop of Henle?
Isotonic filtrate coming from the proximal convoluted tubule enters the descending loop of Henle which passes into the Medulla of the kidney.
Due to the medulla's counter-current mechanism, water leaves the tubule and is reabsorbed - resulting in a 3-fold increase of salt concentraton
What happens in a nephron's ascending loop of Henle?
The cells lining the tubules at this point in the nephron are impermeable to water.
Active reabsorption of Na+ (25-30% NaCl is reabsorbed here), K+, and 2Cl-, as well as paracellular reabsorption of Ca++ and Mg++ cause dilution of the tubular fluid. Loop Diuretics block these actions by disabling the Na/K/2CL cotransporter pump.
What happens in a nephron's Distal Convoluted tubule
Cells are impermeable to water, 10% NaCl is reabsorbed via a Na/Cl transporter that is sensitive to Thaizide diuretics.
Ca++ is monitored and then reabsorbed by a Na+/Ca++ exchanger into the interstitial fluid; Excretion is also regulated by the parathyroid hormone at this point in the tubule.
What happens in a nephron's collecting tubule and duct?
ADH promotes the reabsorption of water by rendering this section permeable to water.
Na+ and water enters the principle cells lining the tubule and is subsequently pumped out into the interstitial fluid in exchange for K+. The K+ then leaves the cell and enters the tubular fluid. Aldosterone receptors influence this transaction.
H+ is secreted via the intercalated cells.
Name 4 common kidney-related reasons for edema
1) heart failure
2) Hepatic Ascites - either portal HTN, or secondary hyperaldosteronism
3) Nephrotic syndrome
4) premenstrual edema
Name 3 uses of diuretics in non-edematous states
1) hypertension
2) hypercalcemia
3) diabetes insipidus (reduced plasma volume leads to a reduction in GFR which promotes Na+ and water reabsorption).

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