Diuretics and RAAS Drugs

Question 1

Mechanism of Thiazides

Answer 1

Inhibit the Na/Cl symporter on the lumenal side of the DCT to decrease Na reabsorption, thus increasing Na and water excretion

Question 2

Naming of Thiazides

Answer 2

Hydrochlorothiazide (HCTZ), chlorthalidone, metolazone

Question 3

Clinical uses of Thiazides

Answer 3

HTN: first line drug, especially in patients w/edema or hyperkalemia

Question 4

Side effects of Thiazides

Answer 4

Impotence

Hyponatremia (due to Na excretion)

Hypokalemia (kidney tries to compensate loss of Na by exchanging it for K in the Principal Cells of the CD)

Hypercalcemia (low levels of Na in the DCT cells causes increased activity of Na/Ca antiporter on apical side, moving Ca into the bloodstream and Na into the DCT cell)

Hyperglycemia and high cholesterol (unknown mechanism, believed to be due to effects on insulin signaling)

Question 5

Mechanism of Loop Diuretics

Answer 5

Inhibit the Na/K/2Cl symporter on the lumenal side of the TALH to greatly decrease Na absorption, thus promoting Na and water excretion.

Inhibit Na, Ca, and Mg reuptake through intercell junctions in the TALH

Question 6

Naming of Loop Diuretics

Answer 6

Furosemide, torsemide, bumetanide

Question 7

Clinical Uses of Loop Diuretics

Answer 7

Volume overload: induces rapid diuresis

ADHF: Cold/Wet and Warm/Wet (IV administration for rapid diuresis)

HTN: when Thiazides do not work (ex. chronic kidney failure)

Hypercalcemia: when taken in conjunction w/normal saline solution

Question 8

Side Effects

Answer 8

Volume depletion (due to strong effect on TALH), ototoxicity (water depletion messes w/ear receptors)

Hyponatremia (due to Na excretion)

Hypokalemia (kidney tries to compensate loss of Na by exchanging it for K in the Principal Cells of the CD)

Hypocalcemia/hypomagnesemia (due to blockage of Na/Ca/Mg reuptake)

Hyperuricemia (increased concentration of uric acid in renal cells due to increased water excretion)

Hyperglycemia and high cholesterol (unknown mechanism, believed to be due to effects on insulin signaling)

Question 9

Mechanism(s) of K-sparing Diuretics

Answer 9

Inhibit Na/K antiport on the lumenal side of Principal Cells in the CD (triamterene, amiloride)

Inhibit the mineralocorticoid receptor, which normally increases Na/K antiport on the lumenal side of Principal Cells in the CD (spironolactone, eplerenone)

Both mechanisms result in decreased Na reuptake, leading to increased Na and water excretion.

Question 10

Clinical Uses of K-sparing Diuretics

Answer 10

HTN: 2nd line, usually added on top of another diuretic like a thiazide, especially if pt is hypokalemic

CAD/IHD: prevent fibrosis in pt w/heart failure (specifically spironolactone and eplerenone)

HF: spironolactone and eplerenone, “1.5 line drug”

Question 11

Side Effects of K-sparing Diuretics

Answer 11

Hyperkalemia (due to retention of K from the inhibition of Na/K antiport)

Spironolactone only (NOT eplerenone): gynecomastia (swelling of the breasts due to these drugs also mimicing estrogen)

Triamterene and amiloride only: nausea/vomiting

Question 12

Naming of K-sparing Diuretics

Answer 12

Triamterone, amiloride (direct Na channel blocker)

Spironolactone, eplerenone (mineralocorticoid receptor antagonist)

Question 13

Mechanism of ACE-I

Answer 13

Inhibit Angiotensin Converting Enzyme, which normally cleaves Angiotensin I into Angiotensin II. AII action results in SNS stimulation, vasoconstriction, decreased bradykinin (a vasodilator), and decreased Na/water excretion (via stimulation of aldosterone).

The net result of an ACE-I is the opposite of all the above effects. MAJOR EFFECT is to decrease vascular resistance.

Question 14

Naming of ACE-I

Answer 14

-pril suffix (lisinopril, captopril, enalapril)

Question 15

Clinical uses of ACE-I

Answer 15

HTN: first line, especially in diabetics; excellent adjunctive therapy, often prescribed w/thiazides

HF: first line treatment

CAD/IHD: chronic (prevent recurrence, prevent LV remodeling)

Question 16

Side Effects of ACE-I

Answer 16

Cough and angioedemia (due to bradykinin buildup)

Hyperkalemia (due to decreased Na/K antiport)

Renal failure, fetal toxicity

Question 17

Which drugs are contraindicated in pregnant women?

Answer 17

ACE-I, ARB

Question 18

Mechanism of ARB

Answer 18

Antagonist of the Angiotensin II receptor. Results in less SNS stimulation, vasodilation, more Na/water excretion. DOES NOT increase bradykinin. MAJOR EFFECT is to decrease vascular resistance.

Question 19

Naming of ARB

Answer 19

-sartan suffix (valsartan, losartan, candesartan)

Question 20

Clinical uses of ARB

Answer 20

HTN: first line, especially in diabetics; excellent adjunctive therapy, often prescribed w/thiazides

HF: first line treatment

CAD/IHD: chronic (prevent recurrence, prevent LV remodeling), primarily valsartan and candesartan

Question 21

Side effects of ARB

Answer 21

Hyperkalemia (due to decreased Na/K antiport)

Renal failure, fetal toxicity

Unlike ACE-I, cough is not a side effect (angioedema can happen very very rarely)

Question 22

Mechanism of Direct Renin Inhibitor

Answer 22

Directyl inhibit the Renin enzyme, which normally kicks off the RAA system to cause SNS stimulation, vasoconstriction, decreased bradykinin, and increased Na/water retention.

Question 23

Naming of Direct Renin Inhibitor

Answer 23

Aliskiren

Question 24

Clinical Uses of Direct Renin Inhibitor

Answer 24

Currently only for HTN, being evaluated for potential use in HF and renal dysfunction

Question 25

Mechanism of Sacubutril/Valsartan

Answer 25

Sacubutril inhibits the enzyme neprilysin, which normally degrades bradykinin. This results in increased bradykinin levels. Coupled with the ARB Valsartan, you basically get all the effects of an ACE-I

Question 26

Clinical uses of Sacubutril/Valsartan

Answer 26

HF: first line treatment (best drug for HFrEF)

Question 27

Nickname for Sacubutril/Valsartan

Answer 27

Angiotensin Receptor Blocker Neprilysin Inhibitor (ARNI)