Diuretic Drugs

Question 1

Where do Carbonic Anhydrase Inhibiters exert their effects?

Answer 1

Proximal tubule

Question 2

Where do Osmotic Diuretics exert their effects?

Answer 2

Proximal tubule and Thin descending limb of Henle

Question 3

Where do Loop Diuretics exert their effects?

Answer 3

Thick Ascending limb of Henle

Question 4

Where do Thiazide Diuretics exert their effects?

Answer 4

Distal Convoluted Tubule

Question 5

Where do Na+ channel blockers and Spironolactone exert their effects?

Answer 5

Cortical collecting duct

Question 6

Where do Vaptans exert their effect?

Answer 6

Collecting Duct

Question 7

Furosemide: MOA

Answer 7

• In the TAL, it blocks the Na+-K+-2Cl- cotransporter

- Indirectly inhibits reabsorption of Ca2+ and Mg2+

Question 8

Furosemide: Effects

None emphasized

Answer 8

Causes increased excretion of water, sodium, potassium, chloride, magnesium, and calcium

Question 9

Furosemide: Clinical Applications

Answer 9

• Management of edema
• Acute pulmonary edema by decreasing preload
  • Decreases EC volume
  • Rapid dyspnea
• Treatment of hypertension (that is unresponsive to other diuretics)
• Also works in patients with low GFR and low RBF

Question 10

Furosemide: Toxicities

Answer 10

• hypokalemia
• hyponatremia
• hypocalcemia (increases kidney stone risk)… Opposite of thiazides
• hypomagnesemia
• hypochloremic metabolic alkalosis
• hyperglycemia
• hyperuricemia (increases risk of gout)
• increased cholesterol and triglycerides (increases atherosclerosis risk)
• ototoxicity: vertigo, hearing impairment, tinnitus
- Dangerous to use during pregnancy (crosses placenta)
• sulfonamide, so risk of hypersensitivity

Question 11

sulfonamide similar to furosemide with longer t1/2, better oral absorption and some evidence that it works better in heart failure

Answer 11

torsemide

Question 12

sulfonamide similar to furosemide, but more predictable oral absorption

Answer 12

bumetanide

Question 13

non-sulfonamide loop diuretic reserved for those with sulfa allergy

Answer 13

ethacrynic acid ****

Question 14

Furosemide: Drug Interactions

Answer 14

• Digoxin
• Ototoxic drugs
• Potassium-sparing diuretics - can counterbalance potassium-wasting effects
• Can also increase lithium toxicity, potentiate effects of other antihypertensive agents and have diuretic effects antagonized by NSAIDs

Question 15

Hydrochlorothiazide: MOA

Answer 15

Blockade of Na+-Cl- cotransporter in the distal tubule

Question 16

Hydrochlorothiazide: Effects

Answer 16

K+ losing

Question 17

Hydrochlorothiazide: Clinical Applications

Answer 17

• Management of mild-to-moderate hypertension, alone or in combination with other antihypertensive agents
- Not effective in patients with low GFR or low RBF

• Off-Label: Calcium nephrolithiasis (decreases calcium excretion which decreases risk of kidney stones); treats nephrogenic diabetes insipidus

Question 18

Hydrochlorothiazide: Toxicities

Answer 18

• hypovolemia
• K+ losing
• hypokalemia
• hypomagnesemia ** (may be severe)
• hyponatremia
• hypochloremic metabolic alkalosis **
• sulfonamide drug, so hypersensitivity reactions possible
• increase plasma glucose, urate (risk of gout), and lipid levels
• Avoid starting during pregnancy

Question 19

Hydrochlorothiazide: Pharmacokinetics (None emphasized)

Answer 19

Well absorbed via oral administration

Question 20

Similar to HCTZ, but poor oral absorption

Answer 20

chlorothiazide

Question 21

similar to HCTZ, but half-life of 40-60 hrs… prolonged/stable response with proven benefits, often preferred by hypertension specialists

Answer 21

chlorthalidone

Question 22

Another long-acting thiazide diuretic, this is a favorite of cardiologists for use as an adjunct diuretic in the treatment of congestive heart failure

Answer 22

metolazone

Question 23

Hydrochlorothiazide: Drug Interactions

Answer 23

• often combined with antihypertensive medications from other drug classes to potentiate the blood pressure lowering effects
• K+ loss can be offset by combining with K+-sparing diuretics
• Increases risk of digoxin and lithium toxicity

Question 24

Amiloride: MOA

Answer 24

Blocks epithelial sodium channels (E Na C) in the collecting ducts (and adjacent upstream nephron region known as the “connecting tubule”) responsible for Na+-K+ exchange

• so it increases urinary Na+ excretion and decreases urinary K+ excretion

Question 25

Amiloride: Clinical Applications

Answer 25

* Counteracts K+ loss | * Used to treat hypertension and edema, often in combination with a loop or thiazide diuretic

Question 26

Amiloride: Pharmacokinetics

Answer 26

since channel is blocked directly, effects are seen more rapidly than with spironolactone (e.g., <2 hrs) but smaller and therefore harder to detect, last 12- 16 hrs

Question 27

Amiloride: Toxicities

Answer 27

* hyperkalemia | * nausea, vomiting, leg cramps, and dizziness are common; blood dyscrasias are rare

Question 28

used similar to amiloride for edema and off-label for hypertension, rapidly absorbed, duration of action 6-9 hrs, eliminated as drug metabolites

Answer 28

triamterene

Question 29

Spironolactone: MOA

Answer 29

* competitive antagonist of aldosterone receptors * leads to increased sodium excretion and decreased potassium excretion * side effects due in part to it being a partial agonist at androgen receptors

Question 30

Spironolactone: Effects

Answer 30

K+ sparing diuretic

Question 31

Spironolactone: Clinical Applications

Answer 31

• Off-label: - reduce fibrosis post-MI heart failure • used to treat hypertension and edema, often in combination with a loop or thiazide diuretic * primary hyperaldosteronism * greatly reduces mortality rate in patients with severe heart failure... e.g., decreases myocardial fibrosis, reduces early morning rise in HR

Question 32

Spironolactone: Pharmacokinetics

Answer 32

* can take 48 hours to work * steroid hormones produce effects with a slow onset (i.e., takes time for protein synthesis) and slow offset (proteins last for awhile)

Question 33

Spironolactone: Toxicities

Answer 33

* hyperkalemia | * amenorrhea, hirsutism, gynecomastia, impotence, menstrual irregularities, and deepening voice

Question 34

Spironolactone: Drug Interactions

Answer 34

• often combined with thiazide and loop diuretics to counteract their potassium loss ** • should “never” be given with drugs that increase plasma potassium levels... but still used cautiously with ACE inhibitors in heart failure

Question 35

Vapatans: MOA

Answer 35

vaptans | block the antidiuretic hormone receptor in the collecting duct

Question 36

more selective aldosterone antagonist (also lacks sulfur), approved for use in post-MI heart failure and alone or in combination for treatment of hypertension; less gynecomastia, etc. ... but ~10x more expensive than generic spironolactone

Answer 36

eplerenone

Question 37

Conivaptan: MOA

Answer 37

- non-peptide arginine vasopressin receptor antagonist - prevents ADH-mediated insertion of the aquaporin water channels into luminal membrane of principal cells in collecting duct - Prevents the reabsorption of water, therefore increases water excretion - Decreased plasma volume and increased plasma osmolality, primarily due to an increase in plasma sodium concentration

Question 38

Conivaptan: Effects

Answer 38

promotes the | excretion of free water

Question 39

Conivaptan: Clinical Applications

Answer 39

• Treatment of euvolemic and hypervolemic hyponatremia in patients who are... - hospitalized - symptomatic - not responsive to fluid restriction • Monitor closely plasma sodium and neurological status - too rapid serum sodium correction (>12 mEq/L/24 hours) can lead to seizures, osmotic demyelination, coma, or death • autosomal dominant polycystic kidney disease (slow progression)

Question 40

Conivaptan: Pharmacokinetics

Answer 40

* Administered IV | * conivaptan not available, t1/2 of 5.3 – 8.1 hrs

Question 41

Conivaptan: Toxicities

Answer 41

– orthostatic hypotension – fatigue – thirst – polyuria, bedwetting

Question 42

Conivaptan: Drug Interactions

Answer 42

* metabolized by CYP3A4, so inhibitors and inducers of this enzyme can alter its half-life and potential for toxicity * selective water loss means: - possibility of hypovolemia - other electrolytes and drugs can become concentrated... e.g., hypernatremia, hyperkalemia, hyperuricemia - toxic levels of drugs

Question 43

selective V2 receptor antagonist administered orally... • initiate and reinitiate tolvaptan in patients only in a hospital where plasma sodium can be closely monitored •must use < 30 days for hyponatremia, longer use can lead to potentially fatal hepatotoxicity - used to slow progression of adult polycystic kidney disease (must monitor liver)

Answer 43

tolvaptan

Question 44

Carbonic Anhydrase Inhibitors (Acetazolamide): MOA

Answer 44

* bicarbonate ion remains in early proximal tubule * H+ cycling lost, inhibiting Na+ /H+ exchange • pharmacological effect - sodium bicarbonate diuresis - hyperchloremic acidosis

Question 45

Carbonic Anhydrase Inhibitors (Acetazolamide): Therapeutic Uses

Answer 45

``` These are now quite limited • urinary alkalinization • metabolic alkalosis • glaucoma: acetazolamide, dorzalamide • acute mountain sickness ```

Question 46

Carbonic Anhydrase Inhibitors (Acetazolamide): Adverse Effects

Answer 46

* hyperchloremic metabolic acidosis * nephrolithiasis: renal stones * potassium wasting

Question 47

Mannitol: MOA

Answer 47

– the inability to reabsorb this solute keeps water in the proximal tubule lumen; this water is delivered to the distal portions of the nephron where much of it is ultimately excreted – mannitol acts throughout the body to PULL WATER OUT OF THE CELLS – the net effect after administering mannitol is to EXCRETE TOTAL BODY WATER IN EXCESS OF PLASMA ELECTROLYTES

Question 48

Mannitol: Pharmacokinetics

Answer 48

– distributes in extracellular fluid, must give IV in large amounts sufficient to raise its osmolality (e.g., **50-200** grams over 24 hours) – effects are noticeable within 30–60 minutes, and mannitol is eliminated unchanged in the urine over a period of 6-8 hours

Question 49

Mannitol: Adverse Effects

Answer 49

– extracellular volume is acutely increased because mannitol sucks water out of the cells, which can exacerbate heart failure – headache, nausea, vomiting, and fluid and electrolyte imbalances also occur

Question 50

Mannitol: Therapeutic Uses

Answer 50

– PROPHYLAXIS OF RENAL FAILURE, keeps some fluid volume in the tubules to prevent them from collapsing when the glomerular filtration rate is very low – REDUCTION OF INTRACRANIAL PRESSURE – REDUCTION OF INTRAOCULAR PRESSURE (treating glaucoma) when patients haven’t responded to other therapy

Question 51

Alternative Medicine?

Answer 51

• herbal diuretics • licorice (contains GLYCYRRHIZIC ACID) - potentiates aldosterone effects in kidney and dose-dependently increases systolic blood pressure (~3-14 mm Hg)