Diuretics

Question 1

Carbonic anhydrase inhibitors

Answer 1

acetazolamide

Question 2

osmotics

Answer 2

mannitol
glycerin
isosorbide
urea

Question 3

Na+/K+/2Cl- Blockers (Loop Diuretics)

Answer 3

furosemide
ethacrynic acid
bumetanide

Question 4

Na+/Cl- blockers

Answer 4

hydrochlorothiazide
chlorthalidone
indapamide

Question 5

inhibitors of ENaC

Answer 5

Amiloride

triameterene

Question 6

Aldosterone antagonists

Answer 6

sprionolactone

epelereone

Question 7

vasopressin (ADH) antagonists

Answer 7

tolvaptan

conivaptan

Question 8

What are the two major clinical indications for diuretic therapy

Answer 8

1. edematous states

2. hypertension

Question 9

What are the major edema-causing conditions where diuretics are used

Answer 9

heart failure
pulmonary edema
nephrotic syndrome
hepatic cirrhosis

Question 10

How is the steady state of the kidney defined?

Answer 10

intake = excretion

Question 11

How do diuretics change steady state?

Answer 11

They create a new steady state where excretion is increased, to a point, over intake so homeostasis is less body fluid

Question 12

What is diuretic “braking”

Answer 12

The adaptational effects of diuretic use that prevent endless excretion and volume depletion. Usually through modification of the Renin-Ang and ADH pathways

Question 13

What is the most effective medication for edematous states?

Answer 13

Loop diuretics

Question 14

What is the most effective medication for hypertension?

Answer 14

Thiazides (hydrochlorothiazide)

Decrease BP by decreasing cardiac output and decreasing total peripheral resistance (TPR)

Question 15

What is the main determinant of extracellular fluid volume ECFV?

Answer 15

Na+

Therefore most diuretics aim to decrease EDFV by increasing Na+ excretion

Question 16

Why prescribe a loop and thiazide combo?

Answer 16

Loop diuretics can be refractory due to compensatory Na+ reabsorption. Thiazides counteract this. However, this combo requires careful hemodynamic monitoring!

Question 17

What can you do to counteract the K+ wasting of loops and thiazides?

Answer 17

Advise patient to restrict sodium and to take K+ supplements.
If this is not enough, add K+ sparing diuretics

Question 18

List the major classes of diuretics in order based on their site of action on the nephron: PCT through CD

Answer 18

Carbonic Anhydrase inhibitors: PCT (plus CD)
Osmotic Diuretics: tDLH (plus PT, CD)
Loops (Na+K+2Cl- blockers): TALH
Thiazides (Na+Cl- blockers): DCT
ENaC inhibitors: late DCT, CD
Aldosterone (Mineralocorticoid)Antagonists: late DCT, CD
Vasopressin (ADH) Antagonists: CD

Question 19

Which diuretics are K+ wasting?

Answer 19

Loops: Furosemide, ethacrynic acid, bumetanide
Thiazides: Hydrocholorothiazide, chlorthalidone (indapamide)

Question 20

Why doesn’t a patient on diuretics end up looking like a raisin?

Answer 20

Diuretic Braking

Question 21

What is the MOA of Carbonic anhydrase inhibitors? (Acetazolamide)

Answer 21

They interfere with bicarbonate reabsorption and H+ secretion, thereby decreasing Na+ absorption

Question 22

Why are carbonic anhydrase inhibitors weak diuretics?

Answer 22

Increased tubular Na+ activates tubuloglomerular feedback (TGF) causing decreased GFR (adenosine causes afferent restriction and renin causes EA relaxation)

Question 23

What is the effect of carbonic acid inhibitors on Urine and Plasma?

Answer 23

Urine: increased bicarb (alkalinuria), Na+, K+
Plasma: decreased bicarb and H+ (acidemia) and K+, increased Cl- (chloremia)

Question 24

What are the indications for carbonic acid inhibitors?

Answer 24

Metabolic alkalosis, prophylaxis re respiratory alkalosis from Acute Mountain Sickness, intraoccular pressure, urinary alkalization to excrete acids

Question 25

What are the adverse effects of carbonic acid inhibitors?

Answer 25

Generally well-tolerated; renal stones due to alkaline pH of urine (Ca++ salts less soluble)

Question 26

What is the mechanism of action of osmotic diuretics (Mannitol)?

Answer 26

They change the osmotic gradient so less water is reabsorbed. They act like albumin, attracting water, pulling water from the ICF to ECF, from tissues into blood, and then into the tubular lumen.

Question 27

Does mannitol come in pill form?

Answer 27

No. It is not absorbable in the GI tract so it must be IV

Question 28

What is the effect of osmotic diuretics in the urine and plasma?

Answer 28

Urine: increased Mg++ (reason not understood) Plasma: acute: draws fluid into blood causing relative hyponatremia which can cause pulmonary edema, CHF, HA, N/V Later: draws fluid into lumen causing relative hypernatremia -> hyperkalemia because as cells shrink, relative K+ concentration in cells which exits into plasma

Question 29

What are the indications for osmotic diuretics?

Answer 29

Intracranial or intra-ocular pressure pre- and post- surgery acute glaucoma dialysis disequilibrium

Question 30

What is the mechanism of action of loop diuretics? (Furosemide, ethacrynic acid)

Answer 30

Inhibit the Na/K/2Cl symporter in the TALH

Question 31

What are the adverse effects of loop diuretics?

Answer 31

``` Hypokalemia, hypomagnesia --> arrhythmia Hypocalcemia, hypochloremia Alkalemia Hypotension -> falls re elderly Ototoxicity Hyperuricemia -> gout ``` Decreased Na/K/2Cl symporter leads to decreased K+ backleak leads to decreased Ca++ and Mg++ reabsorption. Excess Na+ in lumen -> excess K+ secretion Excess Cl- in lumen -> excess K+ and H+ excretion

Question 32

What are the indications for loops?

Answer 32

Decrease morbidity and mortality in HF Hypertension: first choice re HT with CHF Edema (pulmonary, cardiac, hepatic) Acute hypercalcemia, mild hyperkalemia Acute renal failure (to increase urine flow)

Question 33

What is the effect of loop diuretics on the urine and plasma?

Answer 33

Urine: increased excreation of ALL IONS: Na+, Cl-, K+, Mg++, CA++ (and HCO3- re furosemide) Plasma: hypochloremic alkalosis and hypokalemia

Question 34

Why do loop diuretics cause PROFOUND diuresis?

Answer 34

They also block the Na/K/2Cl channels in the macula densa so they do not sense the increased Na+. They release prostaglandins causing AA dilation causing increased renal blood flow

Question 35

What is the MOA of the Thiazides?

Answer 35

Inhibition of Na/Cl symport in the DCT

Question 36

What is the effect of thiazides on the urine and plasma?

Answer 36

Urine: decreased Ca++ excretion, increased K+ and H+ excretion (aciduria) Plasma: hypokalemia, metabolic alkalosis.

Question 37

What are the adverse effects of thiazides (and why)?

Answer 37

Hypokalemia --> cardiac arrhythmia Hypercalcemia, Hyperuricemia Hypotension Hyperglycemia (not understood why) -> hyperlipidemia so C/I re DM patients Less Na+ is reabsorbed to less Ca++ is excreted; more Na+ in lumen causes more K+ excretion -> more H+ excretion -> aciduria and alkalemia

Question 38

What are the indications of thiazides?

Answer 38

Decreased morbidity and mortality re HF and HTN First choice for simple essential HTN CHF, hypercalciuria (to prevent kidney stones) Nephrogenic diabetes insipidus

Question 39

What is the MOA of ENaC inhibitors?

Answer 39

Epithelial Na+ Channels (ENaC) in the principal cells in the late distal tubule and CD reabsorb less Na+

Question 40

What are the side effects of ENaC inhibitors and why?

Answer 40

hyperkalemia (esp re renal failure), kidney stones, acute renal failure (esp with Triamterene with indomethacin) Less Na+ reabsorption -> less K+ secretion/excretion therefore hyperkalemia

Question 41

What are the effects of ENaC inhibitors on the urine and plasma?

Answer 41

Urine: decreased K+ and H+ excretion Plasma: increased K+

Question 42

What are the indications of ENaC inhibitors?

Answer 42

Amiloride + HCTZ decrease morbidity (strokes) in elderly with HTN (Decreased stroke risk when added to thaizides and loops due to K+ sparing.)

Question 43

What is the MOA of aldosterone antagonists? (Spironolactone)

Answer 43

Metabolite is competitive inhibitor for the mineralocorticoid receptor (MR) for aldosterone, so most effective when aldosterone is high. NOTE: aldosterone in CD and DCT stimulates luminal Na+ (and K+) channels and increases Na/K/ATPas channel expression on the interstitial side, both to absorb Na+

Question 44

What is the effect of aldosterone antagonists on the urine and plasma?

Answer 44

Urine: decreased K+, mildly increased Na+, Cl- and water excretion Plasma: hyperkalemia (serum K+ should be monitored even if using K+ wasting diuretics!)

Question 45

What are the side effects of aldosterone antagonists and why?

Answer 45

Hyperkalemia (especially with ACEIs) | Gynecomastia and menstrual irregularities (antiadrenergic effect)(Spironolactone only - not eplerenone)

Question 46

What are the indications of aldosterone antagonists ?

Answer 46

Decrease morbidity and mortality in HF in combo with loops or thaizides (due to K+ sparing) Primary and secondary hyperaldosteronism Secondary hypertension

Question 47

What is the MOA of Vasopressin Antagonists? (Tolvaptan, conivaptan, "-vaptans")

Answer 47

V2 ADH receptor antagonists thereby decreasing aquaporin (AQP2) insertion in the basolateral (not luminal) side of the CD thereby decreasing water reabsorption

Question 48

What is the effect of vasopressin antagonists on urine and plasma?

Answer 48

Urine: increased volume and decreased osmolarity Plasma: increased sodium

Question 49

What are the side effects of vasopressin antagonists and why?

Answer 49

Hypernatremia: less water is reabsorbed so more water excreted without Na+

Question 50

What are the indications for vasopressin antagonists?

Answer 50

Syndrome of Inappropriate ADH (SIADH) | hyponatremia