Pharmacology: Diuretics

Front 1

Define diuretics:

Back 1

*Drugs that increase the rate of urine flow.

*Clinically useful diuretics also increase the rate of Na+ excretion (natriuresis) and of an accompanying anion, usually Cl.

*NaCl in the body is the major determinant of extracellular fluid volume, and most clinical applications of diuretics are directed toward reducing extracellular fluid volume by decreasing total-body NaCl content.

Front 2

What are the many Potential Therapeutic Uses for Diuretics?

Back 2

•Hypertension
•Heart failure
•Other edematous conditions:
–Nephrotic syndrome
–Liver disease (cirrhosis)
•Management of electrolyte abnormalities:
–Hyponatremia
–Hypernatremia/nephrogenic diabetes insipidus
–Hyperkalemia
–Hypokalemia
–Hypercalcemia
•Hypercalciuria and calcium-containing nephrolithiasis

Front 3

What are the sites of action of diuretics?

Back 3

Front 4

What is Osmotic Diuresis?

Back 4

*An “osmotic diuresis” constitutes an increase in urine flow produced by a non-reabsorbed solute (such as glucose or mannitol which traps fluid within the tubule).

*The resultant urine is usually isosmotic with plasma and, at high flow rates is not influenced by the presence or absence of ADH.

Front 5

At a given load of solute, what will urine flow look like for someone given high dose DDAVP, someone with diabetes insipidus, and someone taking an isosmotic diuretic?

Back 5

*DI: no ADH!

Front 6

How do carbonic anhydrase inhibitors work?

Back 6

*In the PCT.
*Blocks conversion of CO2 + H2O to H2CO3, and conversion of H2CO3 back to CO2 + H2O.

Front 7

Which of the following laboratory results would you expect in a subject taking acetazolamide (CA inhibitor)?

a.Na 140, K 3.5, Cl 112, HCO3 18 Urine pH 4.5
b.Na 140, K 3.5, Cl 112, HCO3 18, Urine pH 7
c.Na 140, K 3.5, Cl 98, HCO3 18, Urine pH 7
d.Na 140, K 3.5, Cl 98, HCO3 18, Urine pH 4.5
e.Na 140, K 3.5, Cl 98, HCO3 24, Urine pH 7

Back 7

b.Na 140, K 3.5, Cl 112, HCO3 18, Urine pH 7

*More bicarb in the urine increases the pH (you're also not excreting H+ as much).
*Chloride goes up!
*This is called a hyperchloremic, non anion gap, metabolic acidosis.

*Carbonic anhydrase inhibitors cause bicarbonate loss by inhibiting bicarbonate conversion and leading to bicarbonaturia which alkalinizes the urine. Augmented chloride reabsorption raises the serum chloride, leading to a “hyperchloremic” metabolic acidosis with a normal anion gap.

Front 8

How do loop diuretics work?

Back 8

*Block the NKCC2 channel in the thick ascending limb.
*Increased excretion of Na/Cl/K.
*This is a very strong diuretic!

Front 9

How do Thiazide Diuretics work?

Back 9

*DCT.
*Block the Na/Cl channel.
*Less effective than loops!

Front 10

Which of the following diuretic classes would most likely cause hyponatremia?

a. Loop diuretics
b. Thiazides

Back 10

*B: thiazide diuretics.

*Thiazide diuretics impair only urinary dilution because of their selective effect on the distal tubule. By contrast, loop diuretics impair both dilution and concentration.

*Remember the DCT is known as the "diluting segment." Thiazides impair this, so urine can get really concentrated, ADH gets stimulated--> Na loss.

*Think of it as thiazides making you hold onto water--> hyponatremia.

Front 11

What's the effect of thiazides on free water clearance?

Back 11

*Look at older people on thiazides. This can lead to hyponatremia in elderly people on thiazides.

Front 12

How do the K-Sparing Diuretics (the direct ENAC ones) work?

Back 12

*They are Direct ENaC inhibitors.
*Not a significant natriuresis; DOES limit K excretion.
*Also inhibits H+ excretion in the intercalated cells.
*Used to counteract loop diuretics, which may cause hypokalemia.

*Adverse: may cause hyperkalemia and metabolic acidosis.

Front 13

Where do the other K-Sparing Diuretics (Aldosterone Antagonists) work?

Back 13

*Net effect is the SAME as direct ENAC inhibitors.
*They block the mineralocorticoid receptor, which has the same end result as blocking the ENAC.

Front 14

Sites of action of ALL the major diuretics:

Back 14

*CA inhibitors act on PCT (65% of solute reabsorption).
*Loops act at thick ascending limb (25%).
*Thiazides act at early DCT (6%).
*K sparing at CD and late DCT.

Front 15

What is the “braking phenomenon”?

Back 15

*A sustained imbalance between dietary Na intake and Na loss is incompatible with life.

*Although continued diuretic administration causes a sustained net deficit in total-body Na, the time course of natriuresis is finite because renal compensatory mechanisms bring Na excretion in line with Na intake, a phenomenon known as diuretic braking.

Front 16

Time course of a diuretic's effect on body weight and Na excretion:

Back 16

*This is the image of the braking phenomenon. Also shows that diuretic weight loss is transient.

Front 17

What does this mean?

Back 17

*This shows the braking phenomenon. Blue line is delivery of furosemide. Not compensatory drop in Na excretion. Also note that at the next drug dose, the excretion is even less.
*The point: someone on a high Na diet will not see great effect from a loop diuretic, and they're the strongest we've got.

Front 18

What are some Strategies to Overcome Diuretic Braking?

Back 18

*Restrict dietary salt to prevent postdiuretic salt retention.  

*Consider adding another class of diuretic.  

*Consider multiple daily dosing or a diuretic with prolonged action.  

*Do not stop diuretic therapy abruptly.  

*Prevent or reverse diuretic-induced metabolic alkalosis.

Front 19

What is the effect of NSAIDs on diuretics?

Back 19

*Action of diuretics is potentiated by PGs. NSAIDs inhibit PGs. Therefore, NSAIDs reduce efficacy of all diuretics.

Front 20

Table of diuretics, uses, effects:

Back 20

*Acetazolamide used for glaucoma. Not very potent. Alkalinizes the urine.

Front 21

Segmental Diuretic Actions and Genetic Syndromes Associated with Changes in Tubular Function:

Back 21

*Loops = Bartter syndrome
*Thiazides = Gitelman
*Gordon syndrome (pseudohypoaldosteronism type 2) is like the opposite of a thiazide--> causes HTN and hyperkalemia.
*Liddle syndrome = the opposite of action of the K sparing diuretics.

Front 22

Fluid, electrolyte and acid-base problems associated with diuretic use:

Back 22

•Sodium depletion, hypovolemia, azotemia.
•Serum sodium:
–Hyponatremia (thiazides in particular).
–Hypernatremia (mannitol increases free water excretion).
•Potassium:
–Hypokalemia.
–Hyperkalemia (K-sparing agents).
•Hypomagnesemia.
•Acid-base:
–Metabolic alkalosis.
–Metabolic acidosis (K-sparing agents, CAIs).
•Calcium:
–Hypercalciuria (loop diuretics).
–Hypercalcemia (thiazide diuretics).
•Lipid abnormalities, hyperglycemia, hyperuricemia.

Front 23

Diuretic actions and impact on serum potassium:

Back 23

*Diuretics shift K from extracellular to intracellular space.
*End result is loss of K.
*Note drugs that cause hyperkalemia by blocking these steps.

Front 24

Take home points from this lecture:

Back 24

•Diuretics are commonly used agents which can treat a host of disorders.

•Diuretic actions can be predicted by which segment of the nephron they target.

•The complications of diuretic usage are similarly based on the characteristics of the urine they produce.

•An innate “braking phenomenon” takes place when, by augmenting sodium reabsorption in unaffected nephron segments, the kidney reduces the natriuretic response to repeated diuretic exposure.