Diuretics - Dr. DeLander

Question 1

What do diuretics require in order to work?

Answer 1

They need to be actively secreted into the area that they need to work in order to have an effect.

Question 2

What sizes of molecules do the diuretics interrupt?

Answer 2

Most are small (like Na) except the osmotics.

Question 3

What is important in diuretics?

Answer 3

Not only the mechanism of action, but also the SITE of action.

Question 4

Osmotic diuretics:
Drugs
Site of action
MOA

Answer 4

Mannitol
Isosorbide
SITE of action is the proximal tubule and
MOA - counter-current exchange system (availability of ions in the interstitial spaces)
The blood flow is fast, and the capillaries are leaky. Ions leak back out, get reabsorbed, and get pushed back down again to the bottom. If the flow is fast, then the system is not very efficient. If it is slow, then the system is very efficient.
RATE OF FLOW THROUGH THE VASA RECTA IS IMPORTANT
Mannitol brings more fluid into the vasa recta in general. Greater perfusion of the kidneys. Get decreased release of renin, less angiotensin, LESS SODIUM reabsorption. Also means rate of flow through vasa recta is faster. Increasing renal blood flow through osmotic use. More of a systemic change in volume rather than drawing more water back into the filtrate. Changes in interstitial osmolality. Diminished interstitial osmolality.

Question 5

Where can you reabsorb ions without water being able to follow?

Answer 5

The thick ascending limb

Question 6

What perfuses the kidney?

Answer 6

The efferent artery leaving the glomerulus.

Question 7

How good are osmotic diuretics?

Answer 7

Not very good. Not enough "umpf"
Used to maintain GFR
Used to dehydrate compartments. (If you load up the system with solutes, it will pull water).
Used for cerebral edema
Used for glaucoma

Question 8

How does increasing renal blood flow create a diuretic effect?

Answer 8

The increased blood flow and volume of the vasa recta “washes away” the medullary gradient that has built up in the kidney, which prevents the loop of Henle from concentrating urine. Urine volume increases, but the loss of water is greater than sodium which can lead to hypernatremia.

Question 9

What do you have to be concerned about for osmotic diuretics?

Answer 9

Renal disease: Mannitol leaves through the kidney, and can’t leave if the kidney is compromised
Pulmonary edema - heart has to work harder
Severe dehydration - Encouraging fluids to leave can cause more dehydration.

Question 10

Carbonic anhydrase inhibitors:
prototype
SOA
MOA

Answer 10

Prototype: Acetazolamide
SOA - proximal tubule (Na reabsorption)
Carbonic anhydrase: Responsible for reabsorbing Co2 back into the body through (in part) an exchange of generated hydrogen ions and sodium comes back in.
MOA - An inhibitor would block both sides of that. Going to inhibit the generation of hydrogen ions, which will not be secreted. Will not get a reabsorption of sodium. Will see an increase in the concentration of sodium showing up in the tubular filtrate. This would draw water and cause diuresis.

See increase in secretion of several ions
(Na, K, HCO3, PO4)
See decreased Cl and H (H isn’t produced, and Cl stays to balance the HCo3 leaving)

Question 11

How efficient are CA I’s at diuresis?

Answer 11

They are not very effective, because there are other places to reabsorb Na besides the proximal tubule.
Also, the diuresis is self-limiting after 1 week. Na staying inside the tubule, but H ions back up and cause mild acidosis. H ions find other ways into the filtrate and Na can find other ways back out. Acidosis gets to be enough to overwhelm diuretic effects, and body self-corrects. Have to use drug holiday in order to use again after 1 week.

Question 12

What indications are for CA I’s

Answer 12

• Open angle glaucoma (these decrease production of aqueous humor)
• Mountain sickness (have alkaline system from blowing off CO2 - can balance with acidosis)

Question 13

What concerns are there for CA I’s?

Answer 13

Existing electrolyte imbalances
Predisposition to kidney stones (harder to get crystals out if acidic)
Acute renal failure (decreases renal blood flow, don’t want to make worse)
Sulfonamide sensitivity (some are sulfonamides)
Pre-existing acidosis (will make worse)
Hepatic dysfunction (tend to retain ammonia, a positive ion that can be disruptive)

Question 14

Loop diuretics:
Prototype
SOA
MOA

Answer 14

Prototype: furosemide, (bumetamide used. Ethacrynic acid not as much because of GI SE’s)
SOA - thick ascending limb on the luminal side (the filtrate side of the cells lining the thick ascending limb)
MOA - Blockade of Na/K/2Cl symporter
Brings everything back into the cell. On the basal membrane have Na/K ATPase to keep low Na concentrations inside the cell. Driving force. Ca and Mg are there to remind us of small paracellular movement (some reabsorption). If we block Na/K/Cl transporter, will see increased excretion of about every ion that is going past there (Na, Cl, K, Mg, Ca). Increased tubular concentrations and increased loss out of the body. Other sites that can help us reabsorb sodium. But this spot is responsible for setting up the medullary interstitial gradient. (inhibit the amount of ions that are contributing to the gradient). So we see significant diuresis because of keeping the ions in the tubule, but mainly because of messing up the gradient. The efficacy of these agents is about 8x of any other types that we have.

Question 15

Loop diuretic SE’s

Answer 15

k levels - change Na concentrations in the body. Has a last stop. Na/K exchange there. Renin formation, angiotensin II, aldosterone stimulated. Get a bump in the amount of potassium that is excreted into the tubules. If we boost Na concentrations, the passive reabsorption will be increased to move into the cell and back into the body. Does that while it exchanges potassium. At first glance you would think that we would lose a lot of sodium, but you actually get a large loss of potassium as our greatest concern.

Modest increase in renal blood flow. (Maybe loop diuretics in the way of macula densa flow rate)

Persistent decrease in TPR (both for loop and thiazide diuretics). Similar effects. Short term effects are big increase of fluid loss. Hormones are used by the body to adjust. Long term, total peripheral resistance decreases by the general vasodilation of vascular system. EETs help to cause opening of Ca-regulated K-channels. Best evidence for involvement of potassium channels. K channels tend to stay open longer. K leaves, hyper polarizes cell. Get less vasoconstriction and get vasodilation.

Question 16

Indications for loop diuretics

Answer 16

Edema
Hypertension
CHF
Hypercalcemia (one of the only drugs that cause excretion of Ca)
Acute renal failure (they increase renal blood flow, so can attempt to re-establish)
(Need aggressive diuresis in a short time, for resistant hypertension)

Question 17

What are the cautions and side effects of loop diuretics?

Answer 17

Preexisting electrolyte imbalance
Ototoxicity (don’t take with glycosides, only usually causes this in combo or at high doses)
Hyperuricemia - Same transporter as uric acid. Can trigger an acute flare, rather than cause.
Aggravate pre-existing diabetes? (Possibly hyper polarizes B cells, making it harder for insulin to be released
Increased plasma lipids
Sulfonamide sensitivity

Severe electrolyte imbalance and established anuria (no urine output) are contraindications.

Question 18

What are drug interactions with loop diuretics?

Answer 18

Synergistic with other diuretics
Synergistic with other antihypertensives
Decreases Li excretion
Low K sensitizes heart to digitalis
NSAIDS decrease efficacy
Organic acids may decrease efficacy
Avoid other ototoxic agents

Question 19

Thiazide (like) diuretics
Prototype
SOA
MOA

Answer 19

HCTZ, Chlorthalidone
SOA - Early DCT (site of action of parathyroid hormone) and late TAL, luminal membrane
MOA - blockade of the Na/Cl transporter. Get increased tubular concentrations of Na, Cl, K, and Mg, which result in diuresis.
Decreased Ca excretion, persistence decrease in TPR (like loop) even after we lose the diuretic effect . (Different paracellular transport is different between loop and this, Hormonal difference - parathyroid hormone, which causes increased reabsorption of Ca)

Question 20

What is the “ratio of efficacy” of loop diuretics, thiazides, and K sparing diuretics in their diuretics effects?

Answer 20

Loop diuretics = 8
Thiazide diuretics = 1
K-sparing = 0.5

Question 21

What are the indications for thiazide diuretics?

Answer 21

Edema
Hypertension
CHF
Hypercalciuria (this stimulates Ca reabsorption, so maybe will be helpful)
Meziere’s Disease (vertigo). Sometime associated with menstrual cycle. Thought is that it decreases the amount of fluid in the ear.

Question 22

What are the side effects associated with thiazide diuretics?

Answer 22

Preexisting electrolyte imbalance
Sulfonamide sensitivity
Metabolic SE’s
CI - Severe electrolyte imbalance, established anuria

Question 23

Which diuretic class has a greater chance of causing “metabolic side effects”

Answer 23

Thiazide diuretics have a higher risk of causing metabolic side effects such as hyperuricemia, aggravation of preexisting diabetes, and increased plasma lipids.

Question 24

What is the main difference between loop diuretics and thiazide diuretics?

Answer 24

Efficacy as a diuretic is greater for loop diuretics, effect on calcium is different (excreted with loop, retained with thiazides). K loss is greater with loop diuretics than thiazide diuretics, but significant with both.

Question 25

K sparing diuretic types

Answer 25

Two types:

• block channels
• aldosterone antagonists

Question 26

SOA of k-sparing diuretics

Answer 26

• Late distal convoluted tubule or collecting duct

- 90% of Na reabsorption has already occurred by this point

Question 27

What are the actions of K-sparing diuretics?

Answer 27

Diuresis (modest)

Excretion of Na, Cl

Question 28

K sparing prototypes of Na blocking channel?

Prototypes of aldosterone antagonist?

Answer 28

Triamterene, amiloride

Spironolactone, eplerenone

Question 29

Indications of k sparing diuretics

Answer 29

Hypokalemia, or prevention of
Edema
Hypertension

Question 30

Side effects of K sparing diuretics - Na channel blockers

Answer 30

Hyperkalemia w/ metabolic acidosis
CI - preexisting acidosis, renal disease (have to able to get these drugs to the site of action
Interactions are straightforward. Different ones include desensitizing the heart to digitalis. RAS inhibition may increase hyperkalemia. (If we stop making angiotensin II and don’t stimulate aldosterone release, cause further retention of potassium). Generally don’t want to give this agent at the same time you are blocking the RAS. Don’t use ARBs/ACEs. Don’t take potassium supplements while on these medications.

Question 31

Aldosterone antagonists

MOA

Answer 31

Blockade of aldosterone receptors (rather than channel blockers). There are multiple mechanisms by which Na/K exchange is facilitated.
Actions are increased tubular Na, Cl, which result in increased excretion of Na, Cl. K and H are retained.

Question 32

Indications for aldosterone antagonists:

Answer 32

Edema
CHF
Hypertension
Hypokalemia
Aldosteronism (tumor in adrenal gland stimulating release of aldosterone)

Question 33

What are some SEs of aldosterone receptor antagonists?

Answer 33

Hyperkalemia or acidosis
Endocrine actions (especially spironolactone) including gynecomastia and impotence
Same drug interactions.

Question 34

Complications associated with diuretic therapy:

Answer 34

1. Hypokalemia - thiazide, loop diuretics. Can give K supplement (KCl) once you see depletion symptoms OR add potassium-sparing agent.
2. Vascular depletion (not enough blood) - primarily because of loop diuretics because they are aggressive
3. Hyperkalemia - Flip side, usually because someone messed up and forgot to pull a drug when switching therapy or overdosed on K in an IV. Kayexelate (exchange resin Na for K). Patiromer (binds and prevents absorption of K). Facilitates excretion of potassium.