Glomerular filtration rate diuretics

Another key feature of the thiazide-type diuretics is their limited efficacy in patients whose estimated renal function is reduced, such as the elderly. For example, patients with estimates of reduced renal function, such as those with a glomerular filtration rate (GFR) below 30 mL/minute, should be considered for more potent loop type diuretics such as furosemide. Clinicians often fail to either reconsider the role of thiazide diuretics prescribed to individuals whose renal function has been declining or fail to recognize the likely prevalence of renal compromise in the elderly to begin with. 

The major cause of the diuretic effect is an increase in renal blood flow and glomerular filtration rate. 

Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) are members of a family of so-called natriuretic peptides, synthesized predominantly in the cardiac atrium, ventricle, and vascular endothelial cells, respectively (G13, Y2). ANP is a 28-amino-acid polypeptide hormone released into the circulation in response to atrial stretch (L3). ANP acts (Fig. 8) on the kidney to increase sodium excretion and glomerular filtration rate (GFR), to antagonize renal vasoconstriction, and to inhibit renin secretion (Ml). In the cardiovascular system, ANP antagonizes vasoconstriction and shifts fluid from the intravascular to the interstitial compartment (G14). In the adrenal cortex, ANP is a powerful inhibitor of aldosterone synthesis (E6, N3). At the hypothalamic level, ANP inhibits vasopressin secretion (S3). It has been shown that some of the effects of ANP are mediated via a newly discovered hormone, called adreno-medullin, controlling fluid and electrolyte homeostasis (S8). The diuretic and blood pressure-lowering effect of ANP may be partially due to adrenomedullin (V5). 

Furosemide and ethacrynic acid preserve glomerular filtration rate and are, therefore, the diuretic agents of choice in hypertensive patients with impairment of kidney function(17,18,... 

Rasilez contains aliskiren, which is a renin inhibitor used in hypertension as monotherapy or in combination with other antihypertensives. It is to be used with caution in patients taking concomitant diuretics, on a low-sodium diet or who are dehydrated and in patients with a glomerular filtration rate less than 30 mL/minute. Aliskiren may cause diarrhoea as a side-effect and it should be administered with or after food. It exists in two dosage strengths, 150 mg and 300 mg. 

Only about 10% of the Na-i- filtered by the glomerulus is reabsorbed by the distal convoluted tubule (DCT) and therefore the capacity of the thiazide group of diuretics to influence the elimination of Na-H in the urine is limited compared to the loop agents. Thiazides can prevent the reabsorption of up to 5% of the total filtered Na+, whereas the equivalent figure for loop diuretics is about 20%. Thiazides can still produce a moderate naturesis and diuresis compared to carbonic anhydrase inhibitors and the K+-sparing agents. Most thiazides are ineffective at low glomerular filtration rates. They also hinder the ability of the kidneys to produce a dilute urine. 

The sites of action within the kidney and the pharmacokinetics of various diuretic drugs are discussed in Chapter 15. Thiazide diuretics are appropriate for most patients with mild or moderate hypertension and normal renal and cardiac function. More powerful diuretics (eg, those acting on the loop of Henle) such as furosemide are necessary in severe hypertension, when multiple drugs with sodium-retaining properties are used in renal insufficiency, when glomerular filtration rate is less than 30 or 40 mL/min and in cardiac failure or cirrhosis, in which sodium retention is marked. 

Increased delivery of salt to the TAL leads to activation of the macula densa and a reduction in glomerular filtration rate (GFR) by tubuloglomerular (TG) feedback. The mechanism of this feedback is secretion of adenosine by macula densa cells, which locally causes afferent arteriolar vasoconstriction. This vasoconstriction reduces GFR. Tubuloglomerular feedback-mediated reduction in GFR exacerbates the reduction that was initially caused by decreased cardiac output. Recent work with adenosine receptor antagonists (eg, rolofylline) has shown that it will soon be possible to circumvent this complication of diuretic therapy in heart failure patients. Using rolofylline with a diuretic will make it possible to produce an effective diuresis in patients with heart failure without causing renal decompensation. 

Diuretic activity Dog Oral, parenteral Natriuresis, kaliuresis, water diuresis, renal blood flow, glomerular filtration rate... 

Patients with renal diseases leading to the nephrotic syndrome often present complex problems in volume management. These patients may have reduced plasma volume in conjunction with reduced plasma oncotic pressures, especially those with "minimal change" nephropathy. In these patients, diuretic use may cause further reductions in plasma volume that can impair glomerular filtration rate and may lead to orthostatic hypotension. However, most other causes of nephrotic syndrome are associated with a primary retention of salt and water by the kidney, leading to expanded plasma volume and hypertension despite the low plasma oncotic pressure. In these cases, diuretic therapy may be beneficial in controlling the volume-dependent component of hypertension. In choosing a... 

Pathophysiology Non-potassium-sparing diuretics are the treatment of choice to reduce fluid retention and dyspnea. Acting at specific sites of nephrons, they inhibit sodium and water reabsorption. Loop diuretics act on the loop of Henle, producing a maximal diuretic effect equivalent to 20% to 25% of the filtered sodium load and promoting the free water clearance. Currently available loop diuretics include furosemide, bumetanide, torsemide, and ethacrynic acid. Because of their potency, they are generally effective in patients with advanced renal insufficiency (glomerular filtration rates <25 ml/min) (49). 

Renal plasma flow and glomerular filtration rate are usually unaffected, but free water clearance may increase. Because most sodium is reabsorbed in the proximal renal tubules, spironolactone is relatively ineffective when administered alone. Concomitant administration of a diuretic which blocks re-absorption of sodium proximal to the distal portion of the nephron (such as a thiazide or loop diuretic) is required for maximum diuretic effects. When administered with other diuretics, spironolactone produces an additive or synergistic diuretic response and decreases potassium excretion caused by the other diuretic [65],... 

Prazosin, oxazosin and terazosin (see p. 73) produce a competitive block of oci adrenoceptors. They decrease peripheral vascular resistance and lower arterial blood pressure by causing the relaxation of both arterial and venous smooth muscle. These drugs cause only minimal changes in cardiac output, renal blood flow, and glomerular filtration rate. Therefore, long-term tachycardia and increased renin release do not occur. Postural hypotension may occur in some individuals. Prazosin is used to treat mild to moderate hypertension and is prescribed in combination with propranolol or a diuretic for additive effects. Reflex tachycardia and first dose syncope are almost universal adverse effects. Concomitant use of a p-blocker may be necessary to blunt the short-term effect of reflex tachycardia. 

Ronnhedh C, Jacquenod M, Mather LE (1996) Urineless estimation of the glomerular filtration rate and renal plasma flow in the rat. J Pharm Tox Methods 36 123-129 Sapirstein LG, Vidt DC, Mandell MJ, Hanusek G (1955) Volumes of distribution and clearances of intravenously injected creatinine in the dog. Am J Physiol 181 330-336 Sarkar SK, Holland GA, Lenkinski R et al. (1988) Renal imaging studies at 1.5 and 9.4 T effects of diuretics. Magn Reson. Med 7 117-124... 

Kallikrein-kinin system This system acts in a vasodilatory, diuretic and natriuretic manner. In cirrhotic and ascitic patients, there are lower prekallikrein and bradykinin levels as well as less renal kallikrein activity. The reduction in kallikrein excretion in the urine correlates with (1.) depressed glomerular filtration rate,... 

When problems do arise they usually reflect either interactions, which with caution could have been avoided, or relative overdosage. In the course of time the recommended antihypertensive doses of diuretics have been reduced, and some adverse effects that were noted in the early years are now of less significance these include hypotension, dehydration, reduction of the glomerular filtration rate, and severe hypokalemia. Continued use of thiazides in excessive doses may reflect ignorance of their very flat dose-response curve (1). At currently recommended low doses, diuretics improve overall quality of life, even in asymptomatic patients with mild hypertension (2). The large HANE study (3) provided no evidence of superior efficacy or tolerability of new classes of antihypertensive drugs. 

Acute renal insufficiency with severe hyponatremia has been attributed to vigorous diuretic treatment (metolazone, furosemide, spironolactone) with an ACE inhibitor (27). Because ACE inhibition impairs renal protection against reduced perfusion, the combination of an ACE inhibitor with high-dose furosemide causes a reduction in glomerular filtration rate linearly related to the change in blood pressure. 

A randomized, controlled study has shown an enhanced diuretic response to furosemide in infants taking theophylline during extracorporeal membrane oxygenation (49). The underlying mechanism was uncertain, but may have been an increase in glomerular filtration rate. 

Close laboratory monitoring and judicious use of spironolactone is needed to reduce the risk of hyperkalemia. The excess of hyperkalemia in clinical practice compared with RALES can be explained largely by the use of higher doses of spironolactone and the inclusion of patients with lower glomerular filtration rates and whose aldosterone-mediated compensatory distal tubular potassium excretion is already attenuated (5). Such patients include elderly people, people with diabetes, and those taking beta-blockers, non-steroidal anti-inflammatory drugs, potassium salts, potassium-sparing diuretics, or trimethoprim. 

---