Diuretics

Question 1

Proximal Tubule Absorption

Answer 1

• Sodium chloride (active transport), water (passive transport), others (sodium bicarbonate glucose, amino acids, glucose); site of action of acetazolamide (CA inhibitor) and mannitol (osmotic diuretic)

Question 2

Loop of Henle Absorption

Answer 2

• Water is reabsorbed (osmotic forces) in the descending thin segment; site of action of mannitol. NaCl is reabsorbed (35%) in the thick segment and is impermeable to water; site of action of furosemide (loop diuretic), a Na/K/Cl cotransporter inhibitor.

Question 3

Distal Convuluted Tubule Absorption

Answer 3

• Approximately 10% of filtered NaCl is reabsorbed in the distal convoluted tubule and is relatively impermeable to water; site of action of Hydrochlorothiazide (thiazide), a Na/Cl co-transport inhibitor.

Question 4

Collecting Tubule Absorption

Answer 4

• Approx. 2-5% of filtered NaCl is reabsorbed in the collecting tubule; site of action of potassium-sparring diuretics, spironolactone (aldosterone receptor blocker) and amiloride (Na channel blocker). Collecting tubule is also the site of action of conivaptan (AntiDiuretic Hormone receptor antagonist), demeclocycline (AntiDiuretic Hormone cAMP antagonist) and mannitol.

Question 5

Major diuretic drugs which have been found to induce diuresis

Answer 5

• Carbonic anhydrase inhibitors
• Osmotic diuretics
• Loop diuretics
• Thiazides
• Potassium-sparring diuretics
• Antidiuretic hormone (ADH) antagonists

Question 6

Carbonic Anhydrase Inhibitors

Answer 6

• Acetazolamide

Question 7

Acetazolmide MOA

Answer 7

• Carbonic anhydrase inhibitors
• Inhibition of bicarbonic reabsorption

Question 8

Acetazolamide Pharmacodynamics

Answer 8

• Carbonic Anhydrase Inhibitor
• Diuretic efficiency decreases significantly over several days due to enhanced NaCl reabsorption by the remainder of the nephron.

Question 9

Acetazolamide Pharmacokinetics

Answer 9

• Carbonic Anhydrase Inhibitor
• Good oral bioavailability; diuresis is apparent within 30min., persists for 12hrs. after single dose, drug elimination by proximal tubule segment.

Question 10

Acetazolamide Adverse Reactions

Answer 10

• Hyperchloremic metabolic acidosis
• Renal stones
• Renal potassium wasting
• Other toxicities: hypersensitivity reactions

Question 11

Acetazolamide Therapeutic Uses

Answer 11

• Glaucoma- decreases aqueous humor and intraocular pressure
• Urinary alkalinization- enhance excretion of weak acids
• Metabolic alkalosis- diuretic therapy (w/ loop diuretics) during heart failure
• Acute mountain sickness
• Other uses: adjuvants for epilepsy

Question 12

Osmotic Diuretics

Answer 12

• Mannitol

Question 13

Mannitol MOA

Answer 13

• Osmotic Diuretics
• Prevents normal water reabsorption in the proximal tubule, descending limb of the loop of henle and collecting tubule due to osmotic forces. Also opposes the action of ADH in the collecting tubule.

Question 14

Mannitol Pharmacokinetics

Answer 14

• Osmotic Diuretic
• Poorly absorbed, must be given parentarally

Question 15

Mannitol Adverse Reactions

Answer 15

• Osmotic diuretic
• Extracellular volume expansion, may complicate heart failure and produce pulmonary edema
• Dehydration and hypernatremia

Question 16

Mannitol Therapeutic Uses

Answer 16

• Osmotic diuretic
• Reduction of intracranial and intraocular pressure
• To increase urine volume

Question 17

Loop Diuretics

Answer 17

• Furosemide

Question 18

Furosemide MOA

Answer 18

• Loop diuretic
• Inhibit Na/K/Cl transporter in the thick ascending limb of loop of Henle

Question 19

Furosemide Adverse Effects

Answer 19

• Hypokalemic metabolic alkalosis
• Ototoxicity
• Hyperuricemia
• Hypomagnesemia
• Allergic reactions
• Other toxicities: dehydration

Question 20

Furosemide Therapeutic Uses

Answer 20

• Loop diuretic
• Hyperkalemia
• Acute renal failure
• Anion overdose
• Other uses: heart failure; severe hypertension

Question 21

Thiazides

Answer 21

• Hydrochlorothiazide

Question 22

Hydrochlorothiazide MOA

Answer 22

• Thiazide
• Inhibit NaCl reabsorption in the distal convoluted/collecting tubules by blocking the Na+/Cl- transporter
• Enhance Ca2+ reabsorption

Question 23

Hydrochlorothiazide Adverse Effects

Answer 23

• Hypokalemic metabolic alkalosis and hyperuricemia
• Impaired carbohydrate tolerance
• Hyperlipidemia
• Hyponatremia
• Allergic reactions
• Other toxicities: weakness, fatigability

Question 24

Hydrochlorothiazide Therapeutic Uses

Answer 24

• Hypertension
• Heart failure
• Nephrolithiasis due to idiopathic hypercalciuria
• Nephrogenic diabetes insipidus

Question 25

Potassium-sparring diuretics

Answer 25

- Spironolactone - Amiloride - Triamterne

Question 26

Potassium-sparring diuretics MOA

Answer 26

- Competitive antagonist to aldosterone at the late distal tubule and cortical collecting tubule - Spironlactone inhibit mineralocorticoid (aldosterone) receptors - Amiloride inhibit of Na influx

Question 27

Potassium-sparring Diuretics Adverse Effects

Answer 27

- Hyperkalemia - Hyperchloremic metabolic acidosis - Gynecomastia - Acute renal failure - Kidney stones

Question 28

Potassium-sparring Diuretics Therapeutic Uses

Answer 28

- Mineralcorticoid excess due to primary hypersecretion (Conn's syndrome) or to secondary aldosteronism (from heart failure, hepatic cirrhosis, nephrotic syndrome, and other conditions assoc. w/ diminished effective intravascular volume); hypertension

Question 29

Antidiuretic Hormone (ADH) Antagonists

Answer 29

- Conivaptan, IV, PO adm - Demeclocycline, PO adm

Question 30

Antidiuretic Hormone (ADH) Antagonists MOA

Answer 30

- Inhibit the effects of ADH in the collecting tubule - Reduce cyclic AMP production (demeclocycline) - V1A and V2 ADH receptor blocker (conivaptan)

Question 31

Antidiuretic Hormone (ADH) Antagonists Adverse Effects

Answer 31

- Nephrogenic diabetes insipidus (demeclocycline) - Renal failure (demeclocycline) - Other: demeclocycline should be avoided in pts. w/ liver diseases and in children younger than 12 years - Hypokalemia (conivaptan) - Injection site rxns. (conivaptan)

Question 32

Antidiuretic Hormone (ADH) Antagonists Therapeutic Uses

Answer 32

- Syndrome of inappropriate ADH secretion (SIADH) - Other causes of elevated antidiuretic hormone - Conivaptan is currently being evaluated in clinical studies for use in CHF

Question 33

Nephrone Absorption Illustration

Answer 33