Reabsorption chloride

Two types of diuretics are used for volume management in HF thiazides and loop diuretics. Thiazide diuretics such as hydrochlorothiazide, chlorthalidone, and metolazone block sodium and chloride reabsorption in the distal convoluted tubule. Thiazides are weaker than loop diuretics in terms of effecting an increase in urine output and therefore are not utilized frequently as monotherapy in HF. They are optimally suited for patients with hypertension who have mild congestion. Additionally, the action of thiazides is limited in patients with renal insufficiency (creatinine clearance less than 30 mL/minute) due to reduced secretion into their site of action. An exception is metolazone, which retains its potent action in patients with renal dysfunction. Metolazone is often used in combination with loop diuretics when patients exhibit diuretic resistance, defined as edema unresponsive to loop diuretics alone. 

Chloride reabsorption. Chloride ions are reabsorbed passively according to the electrical gradient established by the active reabsorption of sodium. Chloride ions move from the tubular lumen back into the plasma by two pathways ... 

Although one thiazide diuretic may be 100 times more potent than another weight for weight, all these drugs have essentially the same properties. Their mechanism of action (inhibition of sodium and chloride reabsorption in the distal convoluted tubule of the kidney) is identical and they can therefore be dealt with as a group. Thiazidelike diuretics, structurally different from the thiazides, have similar actions. Thiazide and thiazide-like diuretics are listed in Table 1. 

Edema due to NSAIDs induced sodium and fluid retention usually occurs in susceptible individuals within the first week of therapy. Furthermore, these effects are reversible when the drug is discontinued. Clinically evident peripheral edema occurs in up to 5% of patients [3], likely as a result of decreased renal blood flow, possible redistribution of intrarenal blood flow, and increased reabsorption of sodium chloride in the thick ascending loop of Henle. In elderly patients this increased sodium chloride reabsorption coupled with increased water reabsorption is more likely to result in the edema. 

I Thiazide Diuretics. Thiazide diuretics such as hydrochlorothiazide block sodium and chloride reabsorption in the distal convoluted tubule (approximately 5% to 8% of filtered sodium). The thiazides therefore are relatively weak diuretics and infrequently are used alone in heart failure. However, as is reviewed in detail in the section Treatment Advanced/Decompensated Heart Failure under Diuretic Resistance, thiazides or the thiazide-like diuretic metolazone can be used in combination with loop diuretics to promote a very effective diuresis. 

The renal saluretic response to loop diuretics is partially dependent on intact intrarenal prostaglandin production in the thick ascending loop of Henle. The decrease in the response to loop diuretics is mediated both by removing the inhibition of sodium chloride reabsorption and an increase in renal medullary blood flow causing a reduction in renal concentrating capacity. The net result is that the concurrent use of a NSAID may blunt the diuresis induced by loop diuretics. 

Bumetanide and torsemide both block chloride channels, to varying degrees. This results in a decrease in sodium and chloride reabsorption, and increased diuretic potency, as compared to furosemide, which does not appear to block chloride channels. 

Torsemide decreases the reabsorption of sodium and potassium, but also affects bicarbonate and calcium reabsorption. This effect is variable and may be due to the actions of the drug in the inhibition of chloride reabsorption. 

Zhou, A.P., H.A. Drummond, and R.J. Roman (1996). Role of 20-HETE in elevating loop chloride reabsorption in Dahl SS/Jr. rats. Hypertension 27,631-635. 

Figure 15-5. Mechanism of sodium and chloride reabsorption in the distal convoluted tubule. A separate reabsorptive mechanism, modulated by parathyroid hormone, is present for movement of calcium into the cell from the urine. This calcium must be transported via the sodium-calcium exchanger back into the blood. (Reproduced, with permission, from Katzung BG [editor] Basic Clinical Pharmacology, 8th ed. McGraw-Hill, 2001.)...

The mercurial diuretics essentially contain in an organic molecule. They usually inhibit sodium reabsorption in the proximal tubuler and ascending loop of Henle. There may be slight effect in the distal tubule where inhibition of chloride reabsorption also occurs. The mercurials have been foimd to enhance excretion though potassium loss is less than that produced by many other diuretics. However, the overall action of mercurial diuretics is invariably increased by acidification of urine. The mercurial diuretics are not very much used in clinical practices due to their pronormced and marked side-effects viz., mercurialism, hypersensitivity and excessive diuresis which may lead to electrolyte depletion and vascular complications. Most of the mercurials are administered by intramuscular route and the availability of orally active diru etics has limited their use. 

Thiazide diuretics inhibit sodium and chloride reabsorption in the thick ascending loop, resulting in mild diuresis. Potassium supplements may be necessary because of potassium-wasting effects. 

Furosemide (Lasix) Inhibits chloride reabsorption in thick ascending loop of Henie. High loss of K+ in urine. Preferred diuretic in patients with low GFR and in hypertensive emergencies. Also, edema, pulmonary edema, and to mobilize large volumes of fluid. Sometimes used to reduce serum potassium levels. Hyponatremia, hypokalemia, dehydration, hypotension, hyperglycemia, hyperuricemia, hypocalcemia, ototoxicity, sulfonamide allergy, hypomagnesemia, hypochloremic alkalosis, hypovolemia. 

Figure 4.2 Site of diuretic actions. Thiazide diuretics inhibit sodium and chloride reabsorption in the thick ascending loop of Henle and the early distal tubule. Loop diuretics inhibit chloride reabsorption in the thick ascending loop of Henle. Potassium sparing diuretics inhibit potassium secretion and influence sodium excretion in the distal convoluted tubule. Mannitol osmotically inhibits water and sodium reabsorption throughout the nephron.

Diuretics have an antihypertensive effect by promoting sodium and water loss. They block sodium and chloride reabsorption causing a decrease in fluid volume, a lowering of blood pressure, and a decrease of edema. If sodium is retained, water is also retained in the body and blood pressure increases. 

Gill, J.R. and Bartter, F.C. (1978). Evidence for a prostaglandin-independent defect in chloride reabsorption in the loop of Henle as a proximal cause of Bartter s syndrome. Am. ]. Med., 65, 766-72... 

In kidney, calcitonin increases the secretion of calcium, phosphate, and sodium. The natriuretic effect of calcitonin is associated with water loss, increased urine volume, and weight loss. The effect of calcitonin on sodium excretion is different from that of parathormone. While parathormone appears to favor a sodium for hydrogen exchange, which takes place in the distal tubules, calcitonin acts on the proximal tubule by blocking sodium and chloride reabsorption [37]. 

The mechanism of chloride excretion has not been completely elucidated however, it is known that it is similar to that of sodium excretion in the distal tubules. In the distal tubules, the regulatory mechanism controlling sodium conservation does not affect chloride. Chloride reabsorption is not directly influenced by aldosterone or by carbonic anhydrase. 

The electrometric intracellular [Cl ] of 18.7 .1.3 mM, while it accounts for only 2/3 of the total Cl content of proximal tubule cells, is still significantly greater than that expected from a simple passive distribution of this ion between the intracellular fluid and the two extracellular fluid compartments (luminal and peritubular). Therefore, chloride must be actively transported across the luminal membrane by an anionic pump or a neutral NaCl pump. This constitutes the first or luminal step in transcellular chloride reabsorptive transport. In the second or, peritubular step. Cl could passively accompany the actively and electrogenically extruded Na" as well as be a component of a peritubular electroneutral NaCl active transport process. 

At the luminal cell boundary (Table III, Fig. 4) the measured membrane potential (E ) of 58.5 +. 1.5 mV is significantly (P <0.001) greater than the calculated Cl equilibrium potential (Egi) of 38.0 2.2 mV. For an anion an > E implies active Cl influx. Since the electrochemical PD which drives chloride ions from the cell into the lumen is about 20.5 mV (Table IV), the luminal membrane active chloride reabsorptive mechanism must exceed 20 mV in order to reabsorb Cl" out of the lumen. The net electrochemical force which moves Cl from cell—to-lumen accounts for the observed Cl flux in the stop-flow experiments of Kashgarian et at, (1965). 

---