Diuretics

Question 1

Net excretion of sodium in the urine

Answer 1

Natiuresis

Question 2

Net excretion of water in the urine

Answer 2

Diuresis

Question 3

3 processes in the nephron in urine production

Answer 3

1. glomerular filtration
2. tubular secretion
3. tubular reabsorption

Question 4

What types of particles cannot be filtered by the glomerulus?

Answer 4

Large particles, charged particles (anions and cations)

Question 5

How do particles which bypass the glomerulus get into the urine?

Answer 5

They bypass the glomerulus, remain in efferent arterial circulation (peritubular capillaries), leak through fenestrae in the peritubular capillaries, move into the interstitial space around the proximal convoluted tubule, bind to the receptors on the basolateral membrane, move into and through the cell, bind to receptors on the luminal aspect of the cell and finally move into the lumen/luminal fluid (urine)

Question 6

What diuretics are secreted by the proximal convoluted tubule into the urine?

Answer 6

Acetazolamide, Chlorothiazide, Hydrochlorothiazide, Furosemide, Bumetanide (all anions)

Question 7

Where in general is the site of action for diuretics?

Answer 7

Receptors on the LUMINAL (or “apical”) membrane in the nephron only. Diuretics have no effect beyond the collecting ducts

Question 8

Where in the nephron is most sodium reabsorbed?

Answer 8

Proximal convoluted tubule (67%)
Thick Ascending Loop of Henle (25%)
Distal convoluted tubule (5%)

Question 9

What % of Na is reabsorbed?

Answer 9

99.5%

Question 10

What % of water is reabsorbed?

Answer 10

99%

Question 11

Mannitol

Answer 11

Osmotic diuretic
MOA: “high-efficacy” diuretic freely filtered at the glomerulus, creates osmotic gradient (increased osmolarity of urine), favors retention of water. Does NOT CROSS placenta, GI tract, BBB. Effect is highly dose-dependent.

site of action: throughout the nephron

therapeutic uses: sudden increase in ICP, help flush out toxic substances, maintain urine flow in acute renal failure, glaucoma (given as eye drops)

adverse effects: precipitate pulmonary edema (caution for pts with CHF or pre-existing pulmonary edema)

Question 12

Acetazolamide

Answer 12

Carbonic Anhydrase Inhibitor

MOA: “low-efficacy” diuretic secreted into PCT, produces small ant of urine that is rich in bicarb. Blocks carbonic anhydrase in the cell and on luminal membrane of PCT. Results in urine with higher pH, very high bicarb, small increase in Na and water.

site of action: luminal membrane of proximal convoluted tubule

therapeutic effect: forced alkaline diuresis of drugs with acidic pKa **, glaucoma, metabolic alkalosis, high altitude sickness

adverse effect: metabolic acidosis

Question 13

Loop Diuretics

Answer 13

• Furosemide
• Bumetanide
• Torsemide
• Ethacrynic acid

Question 14

Furosemide

Answer 14

Loop Diuretic

MOA: “high efficacy” diuretic secreted into PCT, blocks Na/K/2CL transporter (symporter), thus blocks reabsorption of Na, K, Cl (short term) as well as Mg, Ca (over the longer term)

site of action: luminal side of thick ascending loop of Henle

therapeutic use: first line drug for pulmonary edema, given for peripheral edema only refractory to other drugs, systemic hypercalcemia, hypertension (not first line drug), no effect on urea (vs thiazides)

adverse effects: HYPOKALEMIA, OTOTOXICITY, volume depletion, hyponatremia, metabolic alkalosis, activation of RAS due to big vol depletion, multiple drug interactions [more ototoxicity with aminoglycosides, increases toxicity of cardiac glycosides, competitive antagonist for other drugs secreted by PCT (probenecid, pcn, salicylates)]

Question 15

Thiazide / Thiazide-like Diuretics

Answer 15

• Hydrochlorothiazide
• Chlorothiazide
• Chlorothalidone
• Metolazone

Question 16

Hydrochlorothiazide

Answer 16

Thiazide/Thiazide-like diuretics

site of action: early distal convoluted tubule

MOA: fairly “low-efficacy” diuretic secreted into PCT, blocks Na-Cl symporter (blocks reabsorption from tubule back to blood); promotes excretion of Na, Cl, K (short term); (longer term) inhibits Ca secretion into tubule (retain Ca), promotes Mg secretion into tubule (lose Mg)

therapeutic use: htn (first line drug), hypocalcemia, peripheral edema

adverse effects: NO OTOTOXICITY, hypokalemia, volume depletion and activation RAS, aggravate hyperglycemia, increases toxicity cardiac glycosides due to low K, competitive antagonist for other drugs secreted at PCT, incr plasma uric acid (worsening gout sx)

Question 17

Epithelial Na Channel (ENaC) Antagonists

Answer 17

• Amiloride

- Triamterene

Question 18

Amiloride

Answer 18

ENaC Antagonist / K-sparing diuretic

site of action: late distal tubule & collecting ducts

MOA: filtered into tubular fluid by glomerulus, binds to/blocks Na-only channel (not transporter) on epithelial/luminal/apical side of late DCT. prevents reabsorption of Na and subsequent secretion of K (via separate channel)

therapeutic use: htn (given with a loop diuretic to prevent hypokalemia assoc with loops), hypokalemia (assoc with anything else), refractory edema

adverse effects: hyperkalemia

Question 19

Spironolactone

Answer 19

Aldosterone receptor blocker / K-sparing diuretics

site of action: late distal tubule & collecting ducts

MOA: drug and aldosterone enter nephron cell from blood side. competitively blocks intracellular aldosterone receptors. aldosterone in the cell upregulates ENaC (directs creation of more ENaC). blocking aldosterone prevents its effect on Na reabsorption. will ONLY have an effect in the presence of elevated aldosterone levels

therapeutic use: htn associated with elevated aldosterone, hypokalemia, primary aldosteronism, refractory edema

adverse effect: hyperkalemia

Question 20

Conivaptan

Answer 20

Vasopressin (ADH) antagonist (aquaretics)

site of action: collecting ducts

MOA: blocks vasopressin receptors on basolateral aspect of cell, has NO effect on Na, results in water diuresis only

therapeutic use: hypoosmolality/ hyponatremia (SIADH)

adverse effects: increased thirst, [volume depletion and activation RAS??]

Question 21

Side effect profile differences between loop diuretics and thiazides?

Answer 21

loops: OTOTOXICITY, no effect on urea
thiazides: NO ototoxicity, INCREASES plasma urea concentration/ worsens GOUT (promotes reabsorption of urea at PCT)