Henle, loop diuretics

Distribution Nephrons loop of Henle (loop diuretics) or distal convoluted tubule (thiazides)... 

NKCC is a heavily glycosylated protein with 12 putative membrane-spanning regions. Thirty percent of the sodium that is filtered by renal glomeruli is reabsorbed by Na-K-2C1 cotransport in the ascending limb of Henle in the nephron. Na-K-2C1 cotransport is a target of all loop diuretics. 

Figure 46-1. The nephron is the functional unit of the kidney. Note the various tubules, the site of most diuretic activity. The loop of Henle is the site of action for the loop diuretics. Thiazide diuretics ad at the ascending portion of the loop of Henle and the distal tube of the nephron.

Several adaptive mechanisms by the kidney limit effectiveness of loop diuretic therapy. Postdiuretic sodium retention occurs as the concentration of diuretic in the loop of Henle decreases. This effect can be minimized by decreasing the dosage interval (i.e., dosing more frequently) or by administering a continuous infusion. Continuous infusion loop diuretics may be easier to titrate than bolus dosing, requires less nursing administration time, and may lead to fewer adverse reactions. 

Prolonged administration of loop diuretics can lead to a second type of diuretic resistance. Enhanced delivery of sodium to the distal tubule can result in hypertrophy of distal convoluted cells.17 Subsequently, increased sodium chloride absorption occurs in the distal tubule which diminishes the effect of the loop diuretic on sodium excretion. Addition of a distal convoluted tubule diuretic, such as metolazone or hydrochlorothiazide, to a loop diuretic can result in a synergistic increase in urine output. There are no data to support the efficacy of one distal convoluted tubule diuretic over another. The common practice of administering the distal convoluted tubule diuretic 30 to 60 minutes prior to the loop diuretic has not been studied, although this practice may first inhibit sodium reabsorption at the distal convoluted tubule before it is inundated with sodium from the loop of Henle. 

Loop diuretics ascending limb of the Loop of Henle... 

The answers are 370-c, 371-d, 372-c. (Hardman, pp 697, 701, 705.) The loop diuretic ethacrynic acid has its site of action in the ascending limb of the loop of Henle. This drug inhibits the reabsorption of Na and Cl" by interfering with the Na+, K+, 2CL co-transport system. In addition, loop diuretics block the reabsorption of Mg and Ca from the renal tubular fluid into the blood in this segment of the nephron unit. 

Lasilix containing furosemide is classified as a loop diuretic and acts by inhibiting re-absorption from the ascending part of the loop of Henle. Thiazide diuretics, such as bendroflumethiazide, act by inhibiting re-absorption at the beginning of the distal convoluted tubule. 

Furosemide is a highly effective and quick-acting diuretic whose action, hke all of the examined loop diuretics, is associated with blocking reabsorption of ions in the ascending bend of Henle s loop. It is used for edema syndrome of various origins, edema of the lungs and brain, chronic renal insufficiency, some forms of hypertonic crises, and poisoning by barbiturates and other compounds excreted mainly with urine. 

Uses Edema, HTN, CHF, h atic cirrhosis Action Loop diuretic -1- reabsorption of Na Cr in ascending loop of Henle distal tubule Dose 5-20 mg/d PO or IV 200 mg/d max Caution [B, ] Contra Sulfonylurea sensitivity Disp Tabs, inj SE Orthostatic -1- BP, HA, dizziness, photosens, electrolyte imbalance, blurred vision, renal impair Notes 20 mg torsemide = 40 mg furosemide Interactions t Risk of ototox W/ aminoglycosides, cisplatin t effects W/ thiazides t effects OF anticoagulants, antih5rpCTtensives, Li, salicylates X effects IT/barbiturates, carbamaz ine, cholestyramine, NSAIDs, phenytoin, phenobarbital, probenecid, dandehon EMS t Effects of anticoagulants monitor for S/Sxs tinnitus, monitor ECG for hypokalemia (flattened T waves) OD May cause HA, hypotension, hypovolemia, and hypokalemia give IV fluids symptomatic and supportive... 

These potent diuretic agents interact with almost the entire nephron, including Henle s loop (Fig. 7). Their primary effect is probably the inhibition of the active reabsorption of chloride ions, which then leads to the enhanced excretion of sodium ions and water. Plasma volume is reduced as a result of these effects, whereas in the long-term both cardiac preload and afterload will diminish. The metabolic side-effects of the loop diuretics are globally the same as those of the thiazides, with some incidental differences. Plasma renin activity increases by loop diuretic treatment and it can be well imagined that this effect is noxious in the long-term management of heart failure. The loop diuretics provoke a clearly... 

Diuretics and their mechanisms of action will be discussed in detail in Chapter 21. Loop diuretics, such as furosemide (Lasix), block the Na" -K" -2CLsymporter in the ascending limb of the loop of Henle.The resultant effect is delivery of more Na" to the distal tubule and enhanced urinary loss of Na" and water. Unfortunately, the resultant increase in urinary excretion of and K+ can lead to arrhythmias. The potential for arrhythmias is exacerbated by the loss of Mg++ and Ca++ and an underlying vulnerability of the myocardium in CHF. However, loop diuretics are still part of the mainstay of therapy for CHF despite these potential problems and the absence of well-controlled multicenter clinical trials. The rationale for their use is so compelling that placebo-controlled studies appear unethical. Moreover, furosemide was accepted as the standard of care in all of the clinical trials that form the basis for recommended therapy for CHF. The use of the potassiumsparing diuretic spironolactone has been shown to improve survival and is discussed below. 

The site of action of loop diuretics is the thick ascending limb of the loop of Henle, and diuresis is brought about by inhibition of the Na -K -2CE transporter. This seg-... 

Mechanism of Action A loop diuretic that enhances excretion of sodium, chloride, and fo lesser degree, potassium, by direct action at the ascending limb of the loop of Henle and in fhe proximal tubule. Therapeutic Effect Produces diuresis. Pharmacokinetics ... 

These are the most efficacious agents available for inducing marked water and electrolyte excretion. The peak diuresis is far greater than that observed maximally with other diuretics. The drugs in this group include furosemide, bumetanide and ethacrynic acid and the main site of action is the thick ascending limb of loop of Henle, thus they are often called loop diuretics. ... 

Loop diuretics Furosemide Block Na/K/2CI transporter in renal loop of Henle Like thiazides t greater efficacy Severe hypertension, heart failure See Chapter 15... 

Furosemide Loop diuretic Decreases NaCI and KCI reabsorption in thick ascending limb of the loop of Henle in the nephron (see Chapter 15) Increased excretion of salt and water reduces cardiac preload and afterload reduces pulmonary and peripheral edema Acute and chronic heart failure severe hypertension edematous conditions Oral and IV duration 2-4 h Toxicity Hypovolemia, hypokalemia, orthostatic hypotension, ototoxicity, sulfonamide allergy... 

Thick ascending limb of Henle s loop (TAL) Active reabsorption of 15-25% of filtered Na+/ K+/ Cl secondary reabsorption of Ca2+ and Mg2+ Very low Na/K/2CI (NKCC2) Loop diuretics... 

Because Henle s loop is indirectly responsible for water reabsorption by the downstream collecting duct, loop diuretics can cause severe dehydration. Hyponatremia is less common than with the thiazides (see below), but patients who increase water intake in response to hypovolemia-induced thirst can become severely hyponatremic with loop agents. Loop agents are sometimes used for their calciuric effect, but hypercalcemia can occur in volume-depleted patients who have another—previously occult—cause for... 

---