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Briefly describe the four regulation systems of ECV.

1. Cardiac volume sensors. Cardiac atria and ventricles possess stretch sensors that respond to changes in volume. Volume expansion results in a sharp increase in renal sodium excretion via atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP).

2. Arterial volume sensors. The carotid artery and aortic arch possess an ample content of elastic tissue, rendering this site highly distensible. In addition, the afferent arteriole of the juxtaglomerular apparatus is sensitive to mechanical stretch. The afferent limb of these pathways evokes a change in renal sodium handling. The sympathetic nervous system and renin play a prominent role in mediating this effect.

3. Central nervous system volume sensors. The volume sensing mechanism at this site is poorly understood. However, a decrease in ECV produces several changes in neural and hormonal output that affect renal sodium and water handling.

4. Liver volume sensors. The hepatoportal area detects changes in sodium concentration and volume. An increase in intrahepatic pressure causes renal sodium retention. However, the exact role of this response in regulating extracellular volume is not known. Nonetheless, an increase in hepatic pressure invariably accompanies hepatic cirrhosis and likely participates in sodium retention and volume expansion in this setting. This is referred to as the hepatorenal reflex.


Describe 6 major pathways involved in renal sodium handling.

• Peritubular renal hemodynamics. Changes in the ECV result in parallel, although less severe (due to autoregulation) changes in renal hemodynamics. For example, a fall in ECV reduces glomerular filtration rate (GFR) and correspondingly, the filtered load of sodium. In addition, a decrease in renal perfusion increases filtration fraction, which promotes sodium reabsorption in the proximal tubule (Chap. 6).

• Renin-angiotensin-aldosterone system (RAAS). The RAAS is activated in virtually all conditions associated with a decrease in the ECV. Decreased stretch on the renal afferent arteriole and carotid baroreceptors activate the RAAS. Thereafter, renal sodium conservation occurs via multiple effectors, in particular, an increase in aldosterone and angiotensin II. Angiotensin II has been shown to directly increase sodium reabsorption in the proximal tubule.

• Natriuretic peptides. Increased stretch on atrial and ventricular myocytes in cardiac failure stimulates secretion of ANP and BNP. These natriuretic peptides exert several effects on the kidney, including an increase in renal blood flow, suppression of renin release, and inhibition of sodium reabsorption in the proximal tubule and collecting duct (specifically, the inner medullary collecting duct). ANP is a 28-amino-acid peptide that is produced by cardiac atria. It is a powerful vasodilator and natriuretic agent. BNP is a 32-amino-acid peptide that was originally identified from porcine brain extracts. The majority of BNP in humans is produced in the ventricles. BNP binds to a G-protein receptor that is nearly identical to the ANP receptor. C-type natriuretic peptide (CNP) is a third type of natriuretic peptide that is produced by endothelial cells. CNP is believed to regulate vascular tone, however, its role in volume homeostasis is not known. All of the natriuretic peptides exert their effects through cGMP-dependent protein kinase. Neutral endopeptidase (NEP) metabolizes the natriuretic peptides
to inactive fragments. NEP inhibitors are currently under investigation as potential diuretics.

• Antidiuretic hormone. A significant decline in ECV (usually >10%) stimulates vasopressin release from the posterior pituitary gland. Vasopressin promotes water reabsorption in the collecting duct and increases systemic vascular resistance. The effects on vascular resistance offset a decline in blood pressure when volume is contracted. The water retention contributes to volume expansion.

• Sympathetic nervous system. The sympathetic nervous system stimulates renin release from the afferent arteriole and directly increases sodium reabsorption in the proximal tubule.

• Prostaglandins. Renal prostaglandins may significantly affect the excretion of sodium. For example, PGE2 inhibits sodium reabsorption in the thick ascending limb of Henle. Drugs that interfere with prostaglandin synthesis (nonsteroidal anti-inflammatory drugs [NSAIDs]) can produce clinically important changes in sodium balance. NSAIDs aggravate edema and increase systemic blood pressure. Ideally, they should be avoided in these settings.


Describe the pathophys of two edematous disorders associated with decreased cardiac output.

CHF is the prototypical disease associated with low cardiac output and edema formation (see Fig. 12.6). Nephrotic syndrome is also associated with a fall in cardiac output, as a result of hypoalbuminemia. Hypoalbuminemia is accompanied by a fall in plasma oncotic pressure, which favors movement of fluid from the vascular to the interstitial compartment. Fluid egress engenders a fall in cardiac output and, therefore, ECV.
A decrease in cardiac output activates neurohumoral effectors that promote renal sodium and water retention. In particular, activation of the RAAS, the sympathetic nervous system, and nonosmotic release of vasopressin play a pivotal role in sodium and water retention. The retention of sodium and water optimizes cardiac filling pressures, albeit, at the expense of volume expansion and edema.


List various etiologies of edema associated with low arterial resistance. Explain the pathophys.

Several edema-forming states are characterized by an increase in cardiac output (see Fig. 12.7). These disorders include high-output cardiac failure, cirrhosis, sepsis, pregnancy, arteriovenous fistulas, and use of arterial vasodilator drugs (eg, minoxidil, hydralazine, calcium channel blockers). Although the cardiac output is elevated in these conditions, the ECV is reduced because of arterial underfilling. Arterial underfilling is the result of a relative imbalance in arterial capacitance versus cardiac output. Arterial vasodilatation obligates an increase in cardiac output sufficient to fill the expanded arterial circuit. If the cardiac output is insufficient to compensate for the expanded arterial circuit, a state of relative hypoperfusion exists, analogous to that observed with frank reductions in cardiac output. The neurohumoral response to this state of arterial underfilling is identical to the low cardiac output syndromes.


What are the 3 strategies used to treat edema? When should diuretics be used? What are the four major groups of diuretics?

Three general strategies are employed to manage edema: (1) treat the underlying disease, thereby, correcting the pathophysiology of edema formation, (2) reduce sodium intake (<100 mEq/d), and (3) increase sodium excretion with diuretics. Diuretics should only be employed when successful treatment of the underlying disease is not likely or has failed, or when the edema is severe (pulmonary edema).
Diuretics are classified into four major groups based on their site of action as summarized in Fig. 12.8.

Carbonic Anhydrase Inhibitors
Loop Diuretics
Thiazide Diuretics
Potassium sparing diuretics


Describe the mechanism of CA inhib. What effects do they have on the urine? How strong are they? Why? What aren't they used to treat? Why? What are they used to treat? Side effects?

These agents are derivatives of sulfonamides that inhibit the brush border carbonic anhydrase of the proximal tubule.

Because this enzyme is involved in bicarbonate reabsorption, these agents produce a sodium bicarbonate diuresis. The urine pH increases within 30 minutes and persists for up to 12 hours. Carbonic anhydrase inhibitors are weak diuretics because the distal segments of the nephron are capable of significantly increasing sodium reabsorption in response to an increased sodium load.

The carbonic anhydrase inhibitors are rarely used to treat edema, with one unique exception, that is, volume expansion accompanied by metabolic alkalosis. In otherwise healthy individuals, these drugs invariably produce a hyperchloremic metabolic acidosis. Resistance occurs within 2-3 days as the bicarbonate concentration decreases in plasma.

These agents are used to treat glaucoma, acute mountain sickness, and seizure disorders. Toxicity is relatively uncommon with these drugs, although drowsiness and paresthesias have been reported. Potassium wasting is common with these drugs.


What are loop diuretics like? How powerful? What are their pharmacokinetics? What is their main mechanism? What other mechanisms are there? What are they used to treat? Adverse effects?

Loop diuretics are the most potent diuretics available. Chemically, all except ethacrynic acid contain sulfur and, therefore, may exhibit allergic cross-reactivity with other sulfur-containing compounds (eg, sulfonamide antibiotics). Since ethacrynic acid does not contain a sulfur group it is an alternative in the allergic patient (Fig. 12.9). Nonetheless, ethacrynic acid is rarely used because ototoxicity is significantly greater compared to other diuretics.

The loop diuretics have a rapid onset of action (5-10 minutes after intravenous administration), exert their peak effect in 30 minutes, and persist for 2-12 hours. The pharmacokinetic profile of the loop diuretics is summarized in Table 12.1.

These drugs inhibit NKCC2 in the medullary thick ascending limb of Henle. By blocking NKCC2 the positive transepithelial potential is attenuated (see Fig. 7.3). Therefore, the absorption of the divalent cations, calcium and magnesium, is significantly impaired.

Hypomagnesemia has been reported with sustained use of the loop diuretics. However, hypocalcemia is relatively uncommon, presumably because of compensatory systems that maintain serum calcium such as vitamin D and parathyroid hormone.

The loop diuretics also induce the expression of cyclooxygenase and increase the synthesis of prostaglandins. PGE2 and PGI2 increase sodium excretion and renal perfusion. Agents that interfere with prostaglandin synthesis attenuate the diuresis induced by loop diuretics.

The loop diuretics are primarily used to treat edema, particularly, when severe. They are also effective in the acute management of hypercalcemia and hyperkalemia.
The primary adverse effects include metabolic alkalosis, hypokalemia, hyperuricemia, and hypomagnesemia. They also cause dose-dependent ototoxicity that is usually reversible.


What are thiazide diuretics like? Pharmacokinetics? What is their main mech. of action? Others? What are they used to treat? Describe their adverse effects.

The thiazide diuretics have been available for more than 50 years. They were discovered while pursuing more potent carbonic anhydrase inhibitors. Therefore, they all contain an unsubstituted sulfonamide group (Fig. 12.10). Numerous thiazide diuretics are available for clinical use. They are generally well absorbed orally (chlorothiazide is also available for parenteral use). They have a rapid onset of action (5-10 minutes after intravenous administration, 1 hour after oral administration), with a peak effect in 30-120 minutes and an estimated half-life of 2-24 hours (see Table 12.1).

The thiazide diuretics exert their effect by inhibiting NCC in the distal convoluted tubule. They are less potent than loop diuretics for volume management but have greater efficacy in the treatment of hypertension. These agents facilitate calcium reabsorption in the distal convoluted tubule. The precise mechanism of this effect is unknown. Because these drugs are analogs of carbonic anhydrase, they possess intrinsic (albeit mild) carbonic anhydrase inhibitory effects.

Thiazide diuretics are predominately used in edema-forming states, in particular, CHF and hypertension. They are also used to treat nephrolithiasis due to idiopathic hypercalciuria and nephrogenic diabetes insipidus. They increase the expression of aquaporin 2 as well as decrease the generation of dilute urine in the loop of Henle.

The adverse effects of thiazide diuretics include: hypokalemia, hyperuricemia, hypercalcemia, volume contraction, metabolic alkalosis, hyperlipidemia, hyperglycemia, and hyponatremia. Glucose intolerance and hyperlipidemia tend to abate with prolonged use. Hyponatremia is much more common with these agents than the loop diuretics (particularly in the elderly). Since they do not interfere with sodium transport in the loop of Henle, they are less likely to impair urinary concentration and, accordingly, water conservation.


What is the general mechanism of all potassium sparing diuretics? What are the specific mechanisms of some of the drugs? When are they used? What are their adverse effects?

These weak diuretics all prevent potassium secretion in the cortical collecting duct.

Spironolactone antagonizes the effects of aldosterone on the mineralocorticoid receptor in the collecting duct principal cell. Unlike other diuretics, spironolactone acts on the basolateral aspect of the renal epithelial cell. Eplerenone is a spironolactone analogue, which is much less active on androgen and progesterone receptors. It may supplant spironolactone in the future, since it has fewer adverse effects. However, it is relatively expensive and has been less extensively studied in clinical medicine.

Amiloride and triamterene block ENaC in the cortical collecting duct. Inhibition of sodium transport reduces the negative transepithelial potential, which impairs potassium and hydrogen ion secretion. Not surprisingly, hyperkalemia and metabolic acidosis are common adverse effects with these diuretics.

These agents are commonly added to loop diuretics to achieve a synergistic effect in mobilizing fluid. Moreover, their potassium-sparing actions prove useful in combination with other diuretics. Spironolactone is especially effective in patients with cirrhosis and edema, since the liver normally metabolizes aldosterone. Aldosterone antagonists are also the drugs of choice in primary hyperaldosteronism. Amiloride and triamterene are the drugs of choice in the treatment of Liddle syndrome (see Fig. 8-5). Finally, the aldosterone receptor antagonists prolong survival in patients with CHF and should be administered to all patients with advanced heart failure.

The principal toxicity with the potassium-sparing diuretics is electrolyte and acid-base disturbances. Hyperkalemia is particularly common, especially in patients with preexisting renal disease. Indeed, these agents are contraindicated in this setting. Gynecomastia and impotence occur with spironolactone, however it is less common with eplerenone.


What are 5 major factors that effect diuretic efficacy?

• Drug delivery
• Oral absorption
• Dose-response relationship
• Disease-modifying effects
• Diuretic adaptation


Explain how diuretic drug delivery occurs and how this affects management of diuretic treatment.

With the notable exception of spironolactone, all diuretics exert their effect on luminal membrane sodium transport proteins. Therefore, diuretics must be delivered to the tubular fluid. However, filtration across the glomerular barrier is negligible since the diuretics are highly protein bound (typically >90%). Therefore, diuretics reach the tubular fluid via active secretion by the organic anion transport system in the proximal tubule (Fig. 12.11). In advanced renal disease, accumulation of endogenous organic anions competes with diuretic for transport. At a GFR of <20 mL/min) only 20% of the administered dose of furosemide reaches its site of action. Moreover, since bumetanide is cleared significantly via nonrenal pathways (liver), only 10% of an administered dose reaches its site of action. To compensate for drug delivery, the dose should be increased, while carefully monitoring for adverse effects (hyperglycemia and ototoxicity). Maximally safe doses should be respected regardless of the GFR.


Describe the oral absorption for the different diuretics. How does this affect management of diuretic use?

The oral absorption of the thiazide diuretics is compound specific, but varies from 40% to 100%. In addition, the oral absorption of the loop diuretic, furosemide, is unpredictable, varying from 20% to 90%. Torsemide and bumetanide are well absorbed orally, ranging between 80% and 100%. Clearly, poor oral bioavailability may limit the efficacy of the diuretics. In patients responding poorly to an oral agent, switching to an agent with intrinsically greater bioavailability, such as torsemide, or administering the diuretic intravenously may dramatically improve the diuretic response. There are no intravenous formulations of the potassium-sparing agents.


Explain the dose response relationship for diuretics? How does this affect management of diuretic use?

Diuretics must achieve a threshold concentration in the lumen to elicit a diuresis (Fig. 12.12). Increasing the tubular fluid diuretic concentration above the threshold will elicit an increase in sodium excretion until saturation of the receptor occurs. The sigmoidal dose-response relationship varies among individual patients. Therefore, dose escalation should be considered in patients not responding to the usual or recommended dose. Once the plateau or maximal response is achieved, administering additional diuretic is without benefit.


Explain 3 ways in which CHF affects the efficacy of diuretics. Explain 2 ways in which nephrotic syndrome affects the efficacy of diuretics. How are these things overcome if they are?

Several diseases may significantly alter the dose-response relationship (see Fig. 12.12). For example, the dose-response curve is displaced downward and to the right in patients with CHF (ie, because of sodium retention throughout the nephron). In advanced heart failure the relationship of diuretic dose to response is sufficiently impaired as to preclude an effective diuresis at any dose. In addition, the oral absorption profile in the patient with decompensated CHF is flattened because of delayed absorption (Fig. 12.13). This produces a lower diuretic peak (perhaps below its threshold) but may effectively prolong the diuretic half-life. Because of these uncertainties it is generally advisable to treat decompensated CHF with intravenous diuretics. An additional factor, which commonly accompanies severe CHF, is kidney failure. Thus, the dose of diuretic may require dose escalation to overcome the fall in proximal tubular secretion.

In nephrotic syndrome, hypoalbuminemia decreases the delivery of diuretic to the proximal tubule organic anion secretory pathway. Moreover, proteinuria binds diuretic in the lumen and, therefore, reduces the free (active) diuretic concentration. This displaces the dose-response curve further to the right.


Explain diuretic adaptation. What are some strategies to overcome it?

Resistance to the action of the loop diuretics is relatively common with sustained administration. Loop diuretic resistance is believed to be secondary to compensatory mechanisms in the distal nephron, which collectively are known as diuretic adaptation. Chronic furosemide administration increases the size and the number of cells that transport sodium in the distal convoluted tubule (Fig. 12.14). The extent of adaptation determines the severity of diuretic resistance. To a degree this occurs with all diuretics, that is, adaptation of sodium reabsorption at sites not affected by the diuretic. Strategies that ameliorate diuretic adaptation include: (1) increasing the frequency of the dosing interval, (2) utilizing diuretics with an extended half-life, (3) using diuretic combinations to reduce sodium reabsorption at multiple sites, and (4) continuous infusion of diuretics to maintain the optimal concentration of diuretic. It is foregone conclusion that reducing sodium intake is vital to maximize diuretic efficacy.