Term
How do Loop/High ceiling diuretics such as Furosemide, Bumetandine, Ethacrynic acid, Torsemide work to inhibit sodium reabsorption?
What determines their efficacy? |
|
Definition
Na-K-2Cl symporter inhibitors in the luminal membrane of the TAL
Efficacy
1) 25% of filtered Na is normally reabsorbed by TAL
2) Nephron segments distal to TAL do not possess re-absorptive capacity to rescue flood of rejectate from TAL |
|
|
Term
How does the Na-K-2Cl symporter usually function?
How are K+ and Cl- gotten out of the cell again? |
|
Definition
Remember, Bartter's Syndrome results from mutations in Na-K-2Cl, ROMK or CLC-KB channel.
Re-absorbtion of Na+, K+, and 2Cl- through the apical membrane of the TAL, utilized Na+ gradient crated by Na/K pump in basolateral membrane.
**apical K+ removal by ROMK channels (fuels paracellular movement of cations)**
**basolateral Cl- removal via CLC-Kb channels** |
|
|
Term
| How does the Na-K-2Cl symporter usually function? |
|
Definition
Remember, Bartter's Syndrome results from mutations in Na-K-2Cl, ROMK or CLC-KB channel.
Re-absorbtion of Na+, K+, and 2Cl- through the apical membrane of the TAL, utilized Na+ gradient crated by Na/K pump in basolateral membrane.
**apical K+ removal by ROMK channels (fuels paracellular movement of cations)**
**basolateral Cl- removal via CLC-Kb channels** |
|
|
Term
How do K+ sparing diuretics such as Triamterene and Amiloride work to inhibit sodium reabsorption?
Why are they generally prescribed? |
|
Definition
1) NCC inhibitors in the early distal cnvoluted tubule
2) They cause small increases in NaCl excretion, and are used for antikaliuretic actions to offset others that increase K+ excretion |
|
|
Term
| Why do thiazide and loop diuretics cause potassium and H+ excretion? |
|
Definition
This is why you might use sparing diuretics like Triamterene/Amiloride/Spironolactone.
**Also an issue with RAAS system activation via MR**
**Potassium in principle cells and H+ in type A intercalated cells**
Remember, the luminal membrane of the principle cells of the distal nephron is depolarized relative to the basolateral membrane, creating a lumen-negative transepithelial potential difference.
1) Diuretics increase Na+ delivery to late distal tubule and CD.
2) Increased luminal Na+ augments depolarization and enhances lumen-negative PD, which facilitates K+ excretion
Type A intercalated cells in the distal neprhon that mediate H+ secretion into tubular lumen (driven by H+ ATPase) are aided by a similar partial depolarization of luminal membrane.
1) Increased sodium delivery therefore increases tubular acidification. |
|
|
Term
What congenital disorder presents similarly to each of the following diuretics?
1) Loop diuretics
2) Thiazide diuretics
3) K+ sparing |
|
Definition
1) Na-K-2Cl in TAL- Bartter Syndrome
2) NCC - Gitelman's syndrome
3) ENaC - Liddle's syndrome (low-renin, volume expanded HTN) |
|
|
Term
| How do Thiazides like Chlorothiazide, Hydrocholorthiazide, Metolazone and Chlorthalidone work to inhibit sodium reabsorption? |
|
Definition
**LIke Gitelman's Syndrome**
Na+ Cl- symport inhibitors in early distal convoluted tubule |
|
|
Term
| How do Na+ Cl- symporters function? |
|
Definition
1) Use energy from Na/K ATPase in basolateral membrane to bring Na+ and Cl- into epithelial cells.
2) Na+ exits via Na/K ATPase and Cl- exits via chloride channel |
|
|
Term
| What are the physiological effects of Mineralcorticoid receptor (MR) binding by aldosterone in the distal nephron? |
|
Definition
This is where Spironolactone and Eplenerone (MR antagonists) work.
1) Aldosterone binding to cytosolic MR receptors in late distal tubule and CD leads to nuclear translocation and up-regulation of aldosterone-induced proteins (AIPs)
2) AIPs increase luminal sodium conductance and sodium pump activity in the basolateral membrane.
3) Increased sodium transport increaes the lumen negative transepithelial voltage, causing K+ and H+ excretion |
|
|
Term
| How do Eplenerone and Spironolactone inhibit sodium reabsorption and at the same time spare potassium? |
|
Definition
Inhibit MR activation by aldosterone in the late distal tubule and CD, preventing up-regulation of Aldosterone-induced protein expression.
- Less sodium reabsorption prevents negative-intraluminal gradient that normally drives potassium excretion.
Less sodium reabsorption |
|
|
Term
| Under what clinical conditions are diuretics most useful? |
|
Definition
Remember, edema occurs if lymphatic drainage is overwhelmed by capillary filtration.
Diuretics are best at treating generalized edema due to Cardiac (CHF), Hepatic (Cirrhosis) and Renal causes (Nephrosis). |
|
|
Term
| How can you distinguish between cardiac edema due to LV and RV dysfunction? |
|
Definition
LV dysfunction
1) Increased pulmonary venous pressure
2) Pulmonary edema
RV
1) Hypotension
2) Renal Na Retention (baroreceptor mediated)
3) Systemic edema |
|
|
Term
| Why does Ascites and edema occur in Cirrhosis of the liver? |
|
Definition
1) Chronic damage to hepatocytes results in fibrotic changes, leading to compression of hepatic sinusoids and veins.
**Sinusoidal and Portal HTN results**
2) Increased capillary pressures in sinusoids and veins produces net filtration of fluid into interstitium (ASCITES)
3) As IV fluid volume decreases, so does blood volume, causing decreased renal perfusion (RAAS activation)
4) Aldosterone causes more sodium retention and systemic edema |
|
|
Term
A patient presents with Palmar Erythema, Jaundice, Hypoalbuminemia and Spider angiomata.
Why might this person have systemic edema? |
|
Definition
These are symptoms of chronic liver disease, most likely Cirrhosis.
In cirrhosis, fibrotic compression of hepatic sinusoids and veins leads to portal HTN, which leads to interstitial fluid accumulation, loss of blood volume (RAAS activation and edema). |
|
|
Term
What do enlarged vs. shrunken kidneys on renal imaging indicate about disease?
What would you see in urinalysis of each? |
|
Definition
1) Enlarged is Nephrotic syndrome or AGN (acute glomerulonephritis)
- NS has Hyaline casts, fat bodies and lipid droplets/casts
- AGN has hematuria, erythrocyte casts, leukocyte casts
- CRF has broad, waxy casts.
2) Shrunken is chronic renal failure |
|
|
Term
| What are the two pathophysiological mechanisms generating renal edema? |
|
Definition
1) Nephrotic pathway (albumin loss)
- Urinary loss of albumin
- Hypoalbuminemia
- Lowered capillary oncotic pressure causes fluid to go into interstitium leading to edema
2) Nephritic (Glomerular issue)
- Reduced GFR
- Na+ retention
- Systemic edema |
|
|
Term
What type of edema causes each of the following?
1) Severe edema with absent facial edema or albumin loss
2) Mild edema with severe facial edema and hypoalbuminemia/Proteinuria
3) Moderate edema with ascites and moderate hypoalbuminemia |
|
Definition
1) Cardiac
2) Renal
3) Hepatic |
|
|
Term
What type of edema is an issue in women of childbearing age that presents with abdominal bloating and facial edema?
How does it arise and why is it a concern? |
|
Definition
Idiopathic edema.
- Filtration overwhelms lympathic drainage and capillary permeability increases in interstitial space, leading to increased interstitial oncotic pressure.
-Cosmetic issue rather than medical problem- BUT associated with eating disorders. |
|
|
Term
| What is an aquaretic agent and what are some examples? |
|
Definition
Diuretics that increase diuresis of water, as opposed to water just being pulled along with sodium in Natriuretic agents.
Osmotic agents (pull water into luminal space) such as Manitol and ADH inhibitors are examples of this. |
|
|
Term
| What are the major uses of loop diuretics? |
|
Definition
1) Acute pulmonary edema and CHF
2) Liver Cirrhosis (be careful about volume contraction)
3) Nephrotic syndrome
4) Hypercalcemia (with isotonic saline)
5) Life-threatening Hyponatremia (with hypertonic saline) |
|
|
Term
| What diuretics are best to use in acute pulmonary edema and why? |
|
Definition
Loop diuretics are a good option because they rapidly relive edema by
1) Rapidly increase venous capacitance (decreasing preload)
2) Brisk natriuresis |
|
|
Term
| What are the major side effects of using loop diuretics? |
|
Definition
1) ECFV depletion can be profound
2) Hypokalemia (arrythmias, especially in patients on glycosides)
3) Ototoxicity
4) Hypomagnesemia
5) Hypocalcemia
6) Hyperuricemia (gout)
7) Hyperglycemia |
|
|
Term
| Which diuretics affect the kidney's ability to concentrate urine during hydropenia? |
|
Definition
Which ones interfere with the kidney's ability to form a hypertonic medullary interstitium?
Do
1) Loop diuretics
Don't
1) Thiazide diuretics
2) |
|
|
Term
| What are the common therapeutic uses of thiazide diuretics? |
|
Definition
mild edema (CHF), HTN, NDI, calcium nephrolithiasis.
Not very efficacious, since 90% of urine is already reabsorbed by the time it reaches the DCT.
**Ineffective if GFR< 30-40 ml/min**
1) mild edema associated with CHF, Cirrhosis and Renal (nephrotic syndrome, acute glomerulonephritis and chronic disease) (similar to loop diuretics)
2) HTN- increase slope of renal pressure:natriuresis relationship (BEST INITIAL TREATMENT FOR UNCOMPLICATED HTN)
3) Mainstay for nephrogenic diabetes insipidus (great deal of dilute urine is corrected by increasing proximal tubular water reabsorption and dilution in distal convoluted tubule)
4) Calcium nephrolithiasis (decrease ca excretion) |
|
|
Term
| What are the most serious side effects associated with thiazide diuretics? |
|
Definition
Similar to loop diuretics
1) ECV depletion
2) Hypotension
3) Hypokalemia, **Hyponatremia**, Hypochoremia, Metabolic alkalosis
4) Hyperuricemia
5) Hypercalcemia
6) Hyperglycemia (K+ depletion?)
7) Increase LDL |
|
|
Term
| Which diuretics are a particular concern for induced hyponatremia and how does this occur? |
|
Definition
Thiazide diuretics (NCC in DCT)
1) Decreased ECFV leads to
- increased thirst (more intake)
- ADH secretion (less output)
- INITIATES hyponatremia
2) Blockage of transport in diluting segment of DCT
- Loss of ability to excrete diluted urine
- SUSTAINs hyponatremia |
|
|
Term
| How are Na+ channel inhibitors such as Amiloride and Triamterene utilized clinically for diuresis? |
|
Definition
1) Used in Combination and
- Used in HTN
- Used to offset K+ loss from thiazide and loop diuretics
2) Liddle's syndrome (GOF mutation in ENaC)
3) Amiloride for lithium-induced NDI |
|
|
Term
| Why might you give Amiloride for a patient who has nephrogenic diabetes insipidus? |
|
Definition
This condition is often induced by lithium use over time.
Amiloride actually prevents lithium transport into the collecting tubules. |
|
|
Term
| Why might amiloride be given in combination with a thiazide or loop diuretic? |
|
Definition
Protect you Potassium
1) Blockage hyper-polarizes luminal membrane (reducing the lumen-negative transepithelial voltage.
2) K+, H+, Ca2+ and Mg2+ excretion goes down. |
|
|
Term
| What are the most dangerous side effects of Na+ channel inhibitors used for diuresis? |
|
Definition
Amiloride and Triamtene
1) Hyperkalemia (LIFE THREATENING)*****
2) Megablastosis in Cirrhosis patients because of folic acid deficiency (Triamterene)
3) Renal stones (Triamterene)
4) Interstitial nephritis (Triamterene) |
|
|
Term
| How are MR inhibitors such as Spironolactone and Eplenerone utilized clinically for diuresis? |
|
Definition
Efficacy depends on aldosterone levels (the higher the level, the bigger the effect).
1) Co-administration with thiazide or loop (K+ sparing and improved natriuresis) for HTN or Edema
2) Primary hyperaldosteronism (Spironolactone)
3) Refractory edema with secondary hyperadosteronism (Spironolactone)
4) Spironolactone is drug of choice for hepatic cirrhosis. **
5) Additive in treatment of MI with ventricular arrythmia complications |
|
|
Term
| What are the major adverse effects of MR antagonist use? |
|
Definition
1) Hyperkalemia (life threatening)
2) Gynecomastia, impotence and declebedoreased
3) Gastritis
4) CNS
5) Ulcers. |
|
|
Term
| What are the major determinants of a given diuretic's "Ceiling Dose"? |
|
Definition
1) Potency
- Increased potency will decrease ceiling dose
2) Tubular Transport
- Decreased tubular transport will increase ceiling dose
3) Binding to Urinary Proteins
- Increased binding to urinary proteins will increase the ceiling dose (less can undergo tubular transport). |
|
|
Term
| Why is it difficult to convert Furosimide dosing from IV to PO? |
|
Definition
It has variable (about 50%) bioavailability and must be multiplied by 2, at least, to achieve ceiling dose.
Bumetanide and Torsemide have 100% bioavailability. |
|
|
Term
| Order diuretics in order of decreasing ceiling effect. |
|
Definition
The the lower the ceiling effect, the more the diuretic resistance.
Loops (least resistant) > Thiazide > K-sparing (most resistant) |
|
|
Term
What are the 7 major contributing factors to Diuretic Resistance?
How can you solve the issues? |
|
Definition
Increased resistance means less ceiling effect.
1) Noncompliance
2) NSAIDs
1 & 2 can be solved by patient counseling
3) Decreased tubular transport (push to ceiling dose)
4) Decreased RBF (bed rest)
5) Changes to "volume hormones" (bed rest)
6) Compensation by distal nephron (combination therapy/sequential blockage)
7) Diminished Nephron response (continuous infusion) |
|
|
Term
| How does Diuretic Resistance arise? |
|
Definition
Compensation by more distal epithelial cells when transport is inhibited in more proximal epithelial cells.
Example) You get more ENaC channels when your N/K/2Cl- channels are inhibited.
Deal with this by continuous infusion, more frequent dosing, or sequential blockade (Loop, then Thiazide, ect.) |
|
|
Term
| What is post-diuresis sodium retention? When does it occur? |
|
Definition
After dosing of diuretic, but during the time of sub-maximal inhibition, kidney starts to RETAIN sodium.
This is seen most commonly in high-salt diets, which is why diuretics are most effective when patients are on SALT-RESTRICTED diet. |
|
|
Term
True or False:
Diuretics will be most effective in a patient who is on a high sodium diet. |
|
Definition
False!
Remember post-diuresis sodium retention is WORST in this case and the kidney will keep all the salt in. |
|
|
Term
| What are the 2 basic mechanisms of edema formation? |
|
Definition
1) Alteration in capillary hemodynamics favoring movement of fluid from vascular space to IT
2) Compensatory renal sodium and water retention to expand the decreasing ECF volume in the vascular space. |
|
|
