Diuretics

Question 1

What is the functional unit of the kidney?

Answer 1

the nephron

Question 2

What is the role of the kidney?

Answer 2

to regulate fluid, electrolyte, and acid/base balance, while eliminating metabolic/nitrogenous waste products.

Question 3

What % of the blood is filtered through the glomerulus every minute (GFR)?

Answer 3

20% forming ultra filtrate

Question 4

What is tubular reabsorption?

Answer 4

when solutes and water inside the tubular lumen are transported back to the blood. Diuretics mainly block Na+ reabsorption (and therefore water).

Question 5

What is tubular secretion?

Answer 5

when organic acids (diuretics, penicillins, uric acid) and bases and K+ ions are actively secreted into the tubular lumen.

Question 6

What are the macula densa cells?

Answer 6

found at the junction of the ascending limb/distal tubule and sense increased Na+ loss. They will cause the juxtaglomerular cells to secrete renin, which is sent to afferent arteriole to vasoconstrict, which decreases RBF/GFR to protect from salt/water wasting.

Question 7

What happens when decreased renal blood flow (RBF) stimulates the RAAS?

Answer 7

RAAS will generate angiotensin II to release aldosterone/ADH to increase Na+/water retention in distal portion of distal tubule and collecting ducts.

Question 8

**What are carbonic anhydrase (CA) inhibitors?

Answer 8

On the intraluminal side of the PCT, luminal Na+ is exchanged for cellular H+. CA inhibitors are diuretics that work to inhibit the enzyme carbonic anhydrase on the luminal side of the tubular cells in the proximal convoluted tubule, which normally rapidly converts carbonic acid (H2CO3; formed from combining secreted H+ into the lumen with bicarb (HCO3)) to carbon dioxide and water, which then diffuses naturally into the tubular cells. As the Na+/K+ pump works to pump Na+ out on the basal side of the tubular cells into the interstitium, water follows. Thus, if CA is inhibited, less Na+ (due to H+ being stuck with bicarb, since it can’t dissociate without CA, and thus Na+ will not be exchanged) and H2O will enter the tubular cells, and therefore be urinated out.

Question 9

What carbonic anhydrase inhibitors must we know?

Answer 9

acetazolamide and mannitol

Question 10

**What do we have to know about acetazolamide?

Answer 10

• sulfonamide (beware of sulfa allergy) CA inhibitor, increasing loss of bicarb, Na+ and thus water at the PCT. This means you are also ALKYLATING the urine, thus increasing blood acidity, encouraging a non-anion gap (hyperchloremic) metabolic acidosis.
• However, it is used to treat metabolic alkalosis by acidifying the blood! It is also used for glaucoma to decrease intraocular pressure.

Question 11

**What do we have to know about mannitol?

Answer 11

It is an osmotic diuretic in the PCT that holds water in the lumen, but does NOT help eliminate edematous fluid, and thus would not help CHF. Rather it extracts intracellular fluid, shrinking the size of the cells, and for this reason it is helpful in reducing intracranial pressure of cerebral edema.

Question 12

What happens if you overdose on mannitol?

Answer 12

you cause a HYPERNATREMIA, HYPERKALEMIA, and volume depletion. So keep these pts well hydrated.

Question 13

**What are loop diuretics?

Answer 13

function at the ascending limp of the loop of henle by blocking the Na+/K+/2Cl- co-transporter on the luminal side of the cell. Because this part of the nephron is impermeable to water, the increased solute concentration that remains in the lumen will prevent water from leaving in the collecting duct, since the interstitial solute gradient is now altered. Because K+ normally diffuses back into the tubular lumen driving Mg++ and Ca++ into the cells, blocking of the Na+/K+/2Cl- channel will also reduce the lumen positive potential thus preventing Mg++ and Ca++ resorption. So you will get HYPOMAGNESEMIA and HYPOCALCEMIA (to a lesser degree due to compensatory mechanisms). 
Also you well get HYPOKALEMIA due to exchange of intraluminal Na+ for cellular K+ once the fluid gets to the collecting duct. These will also cause a metabolic alkylosis, due to the reduction in blood volume caused by these drugs, you will stimulate the RAAS system which exchanges Na+ for H+ ions at the PCT, thus ACIDIFYING the urine!
You will also get HYPERURICEMIA (due to hypovolemia associated enhancement of uric acid reabsorption in the proximal tubule= gout) and HYPERGLYCEMIA (related to hypokalemia interferences with release of insulin).

Question 14

What is furosemide?

Answer 14

potent sulfonamide loop diuretic (inhibits Na+/K+/2Cl-) that is used to treat CHF, pulmonary edema, acute/chronic renal failure, and hypercalcemia.

Question 15

What is the main side effect of furosemide?

Answer 15

ototoxicity

Question 16

What are thiazides?

Answer 16

sulfonamide drugs that function at the distal convoluted tubule by blocking the Na+/Cl- co-transporter at the apical membrane (aka luminal side). This will not remove as much fluid as the loop diuretics however bc only 10% of the volume is reabsorbed after the distal convoluted tubule (because the distal convoluted tubule is impermeable to water, so it is absorbed after in the collecting duct). Instead they increase Na+ excretion and are therefore more helpful in reducing blood pressure. Because there is no back leak of K+ into the lumen here like there is in the ascending loop of henle, there is no lumen positive potential. Instead Ca++ is actively reabsorbed by the epithelial cells (regulated by PTH) and then exchanged into the interstitium for Na+ ions via the Na+/Ca++ exchanger (due to the lowered Na+ gradient). Thus, calcium increases with thiazides :)
You will also get HYPERURICEMIA (due to hypovolemia associated enhancement of uric acid reabsorption in the proximal tubule= gout) and HYPERGLYCEMIA (impaired pancreatic release of insulin).
Thiazides will also cause metabolic alkalosis just like loop diureteics, due to the reduction in blood volume caused by these drugs, stimulating the RAAS system which exchanges Na+ for H+ ions at the PCT, thus ACIDIFYING the urine!

Question 17

What is hydrochlorothiazide?

Answer 17

thiazide diuretic that is less potent than the loop diuretics, acts on the distal convoluted tubule, and is used to treat hypertension, CHF, renal failure, diabetes insipidus (insensitivity to ADH; has paradoxical action), and hypercalcEMIA/kidney stones (to decrease the amount of calcium in the luminal fluid).

Question 18

Will thiazides cause hypocalciURIA?

Answer 18

YES! (pay attention to the name, because this refers to decreased calcium in the URINE, which makes sense because thiazides increase calcium reabsorption into the body, lowering the amount of calcium in the urine).

Question 19

What are the K+ sparing diuretics?

Answer 19

competitive antagonists of aldosterone (produced in the adrenal cortex and acts intracellularly) at the principle cells of collecting duct (major site of Na+, K+, and H2O transport). Here, Na+ travels into the tubular cells alone (through ENaC), causing an intraluminal negative charge. Thus K+, will exit the tubular cells into the tubular filtrate in order to balance this charge. Aldosterone causes the upregulation of these apical membrane channels (as well as the basolateral Na+/K+ ATPase) normally increasing fluid retention. It also upregulates a H+ ATPase on the apical membrane that pumps H+ ions into the lumen. However, if this is blocked, then fluid will not be able to be retained and be excreted, K+ will not need to balance the charge and thus not be excreted, and H+ ions will be prevented from leaving, thus ALKALIZING the urine and causing a normal anion gap (meaning nongapped) acidosis.
So this will cause NATRIURESIS= increased Na+ in the URINE! Duh

Question 20

What is likely occurring if you have high BP with low K+?

Answer 20

Could be hyperaldosteronism (too much aldosterone) and therefore K+ sparing diuretics would be perfect to treat!

Question 21

What is sporinolactone?

Answer 21

K+ sparing diuretic inhibiting intracellular aldosterone receptors with a long half-life that is used to treat mineralocorticoid excess, Conn’s syndrome, secondary aldosteronism from CHF, cirrhosis, and nephrotic syndrome.

Question 22

What are the ADRs of sporinolactone?

Answer 22

HYPERKALEMIA (duh bc it is a K+ sparing diuretic) and antiandrogenic effects (TREATS hirtuism in girls :) and CAUSES gynecomastia and impotence in boys :( ).

Question 23

What are amiloride and triampterene?

Answer 23

similar potency as spironolactone, not dependent on aldosterone levels (because it inhibits ENaC; Na+ channels), and used in combination with other diuretics to prevent hypokalemia.

Question 24

What is an ADR of amiloride and triampterene?

Answer 24

HYPERKALEMIA (duh bc it is a K+ sparing diuretic) esp. with ACE inhibitors.

Question 25

What is Conivaptan?

Answer 25

ADH receptor inhibitor that decreases water reabsorption by inhibiting V2 receptor. It is used for syndrome of inappropriate ADH secretion (SIADH), hypothyroidism, and adrenal insufficiency.

Question 26

What is Demeclocycline?

Answer 26

a tetracycline that antagonizes ADH by inhibiting cAMP in the collecting tubules. It is indicated for SIADH. Remember not to use this in kids because it is a tetracycline and thus will cause photosensitivity and yellow teeth.