Absorption in Proximal Tubule
Sodium reabsorbed with chloride isosmotically (50-75% of filtered load)
Potassium reabsorbed
Bicarbonate reabsorbed (80-90%)
Absorption in Ascending Limb of Loop of Henle
Sodium and Chloride reabsorbed (20-30%) - Active chloride reabsorption
Impermeable to water
May compensate for increased delivery of sodium from proximal tubule by increasing reabsorption
Cortical and medullary segments differ in response to diuretics
Absorption in Distal Tubule and Collecting Duct
Sodium Reabsorbed (8-9%)
Potassium Secreted
Regulation of sodium and potassium exchange by aldosterone
Permeability to water regulated by ADH
Vasodilators (Glomerulus)
Fenoldopam, dopamine, atriopeptins
6 Characteristics of vasodilators
- Increase RBF without increasing GFR
- Filtration fraction (GFR/RBF) decreases which reduces protein concentration and hydroosmotic forces
- Decrease in osmotic forces in peritubular capillaries allows water to leak back into tubule
- Greater back-leak reduces net reabsorption so sodium excretion increases
- Weak as diuretics due to compensatory sodium reabsorption in more distal segments
- Uses limited - Dopamine agonist may be used to increase RBF in shock
Osmotic Diuretics (MANNITOL) properties
Freely filtered
Not reabsorbed
Metabolically inert
Osmotic Diuretics mechanism of action
- Non-reabsorbed solute limits the reabsorption of water from the tubule
- Sodium is reabsorbed without water. Sodium concentration in tubule falls
- Reduced sodium concentration diminishes sodium reabsorption due to unfavorable concentration gradient
- Action continues in ascending limb and distal tubule to limite sodium reabsorption
- Enhanced potassium excretion occurs in distal tubule due to increased sodium
- Urine flow increases as does excretion of sodium, potassium and chloride
Osmotic Diuretics Therapeutic Use
- Must be given intravenously - limited to inpatients
- Acute renal failure
- Edematous conditions in which volume load is not detrimental
- Glaucoma
Toxicity or Side Effects of Osmotic Diuretics
Related to volume overload and expansion of intravascular fluid volume
Rare hypersensitivity
Drug that inhibits Carbonic Anhydrase
Acetazolamide
Mechanism of Acetazolamide
- Secreted into proximal tubule by Organic Anion Transporter
- Carbonic anhydrase catalyzes formation of carbonic acid from CO2 and H2O - this process H+ needed for bicarbonate reabsorption
- Blockade of enzyme decreases bicarbonate reabsorption and thereby sodium reabsorption in proximal tubule - Urine pH increases
- Loop of Henle is not permeable to bicarbonate so cannot compensate for increased sodium load
- Potassium secretion in distal tubule increases
- Urine volume increases as does excretion of sodium, potassium and bicarbonate
Therapeutic uses of Carbonic Anhydrase inhibitors
Glaucoma - reduce aqueous humor formation
Alkalinzine urine to decrease drug toxicity
Treat symptoms of acute altitude sickness
Acetazolamide Toxicity
Metabolic acidosis occurs which reduces renal response to the drug
Generally safe
Loop Diuretics
Furosemide
Bumetanide
Ethacrynic acid
Loop Diuretics Mechanism of Action (it does a lot)
- Secreted into proximal tubule by OAT
- Act on cortical and medullary segments of the ascending limb to inhibit active chloride reabsorption - results in reduced reabsorption of both sodium and chloride (NA+, K+, 2Cl- symporter)
- In high doses may inhibit carbonic anhydrase
- Potent diuretics, 20-30% of filtered load of sodium is excreted
- Increases RBF and sometimes GFR
- K+ excretion increases due to increased sodium delivery to distal tubule
- Impairs the kidney’s ability to make a concentrated or diluted urine
- Enhance urate reabsorption in proximal tubule
- Enhance excretion of calcium
- Urine volume increases as does the excretion of sodium, chloride and potassium
Therapeutic uses of Loop Diuretics
- Diuresis is rapid in onset and short in duration
Management of edema due to cardiac, hepatic or renal disease - Since loop diuretics tend to increase RBF and GFR, they are of value in treating edema associated with nephrotic syndrome and chronic renal failure
- Acute pulmonary edema
- Hypertension
Loop Diuretics Toxicity
- Hypokalemia
- Hyperuricemia
- Hyperglycemia (Furosemide)
- Ototoxicity - deafness with high doses
- Volume depletion
Thiazide and Related Diuretics
Chlorothiazide
Hydrochlorothiazide
Metolazone
Thiazide Diuretics Mechanism of Action
- Secreted in proximal tubule by OAT
- Act on the cortical diluting segment of ascending limb to inhibit sodium chloride reabsorption (co-transporter)
- In higher doses, some thiazides inhibit carbonic anhydrase and have a proximal tubular effect
- Intermediate activity - 8-10% of the filtered load of sodium excreted
- Reduce GFR
- Potassium secretion increases due to increased sodium delivery to distal tubule
- Impairs the kidney’s ability to produce a dilute urine
- Enhance urate reabsorption in proximal tubule
- Decrease renal excretion of calcium
- Urine volume increases as does the excretion of sodium, chloride, and potassium - hypertonic urine
Thiazide diuretics - Therapeutic Uses
- Diuresis is rapid in onset (w/in 1 hour) and long in duration
- Management of edema due to congestive cardiac failure
- Hypertension
- Management of hypercalciuria in patients with renal calculi (kidney stones) composed of calcium salts
Thiazide diuretics Toxicity
Hypokalemia
Hyperuricemia
Hyperglycemia - decreased insulin secretion
Should not be used when GFR < 25 ml/min
Potassium Sparing diuretics
Spironolactone; Eplerenone
K+ sparing diuretics - mechanism of action
- Acts on distal tubule as a competitive antagonist of aldosterone
- Requires endogenous aldosterone for activity
- Urine volume increases - excretion of sodium increases; potassium excretion decreases
- Weak as diuretics - 2-3% of filtered sodium is excreted
K+ sparing diuretics - therapeutic uses
- Hypertension
- Refractory edema
- Primary aldosteronism
- Used with a thiazide or loop diuretic to enhance diuretic effect and reduce potassium loss
- Long duration of action
