Image: Paul Paradis
Once a year we grab a mop, broom, and garbage bag to make our home sparkle. We don’t think twice about rolling up our sleeves in an effort to partake in cleaning emotional clutter. It’s time to do an emotional cleansing. You keep meeting the same performance with practically the same people. Your frame of mind reeks and loved ones comment on having less than upbeat mood. The negative talk we catch ourselves complaining or reprocessing old negative talk from the past. The truth is lately; your job, your friends, and your situation seem to be ill-suited for your life. These are just a few signs that you’re automatically drawing what you don’t want. You may be holding past feeling of resentments, rerunning negative tapes of unworthiness or haven’t let go of an idea or belief that is currently weighing you down. The best way to get back on track is to know that you are in charge of your life.
Take back control by letting go of harmful and poisonous mess that’s been weighing you down so you can make room for what you really want. Be mindful and work on being more mindful of what you say to yourself. If you catch yourself saying things like, “I’m such a loser” or, “I’m not good enough,” right away replace them with more positive, hopeful, yet honest thoughts. For example, you may want to try saying to yourself, “I’m doing the best I can,” rather than, “I’m successful” if that feels true to you. You’re more likely to listen to self-statements if they sound credible. Create a daily gratitude list. Spend some time focusing on what’s working on your life instead of what’s not. This 10-minute activity can change the way you identify your life and draw more good things to come. Move on and purge thoughts, ideas, and people who aren’t aligned with your purpose. Just as you throw away an item of clothing that no longer fits, you may need to reassess the things and people in your life who aren’t serving you. Focus on one goal at a time. It’s just as easy to get snowed under with cleaning up your soul as it is with cleaning up a room. Become conscious that change takes time. Be patient and kind with yourself as you work on loving the whole of who you are, while doing the necessary work to improve your life.
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Renal Handling of Sodium and Water: To understand the action of diuretics, it is first necessary to review how the kidney filters fluid and forms urine. The following discussion and accompanying illustration provide a simple overview of how the kidney handles water and electrolytes. For more detailed explanation, particularly related to ion and fluid movement across the renal tubular cells, the reader should consult a physiology textbook.
As blood flows through the kidney, it passes into glomerular capillaries located within the cortex. These glomerular capillaries are highly permeable to water and electrolytes. Glomerular capillary hydrostatic pressure drives water and electrolytes into Bowman’s space and into the proximal convoluting tubule. About 20% of the plasma that enters the glomerular capillaries is filtered; termed filtration fraction. The proximal convoluting tubule, which lies within the cortex, is the site of sodium, water and bicarbonate transport from the filtrate (urine), across the tubule wall, and into the interstitium of the cortex. About 65-70% of the filtered sodium is removed from the urine found within the proximal convoluting tubule; this is termed sodium reabsorption. This sodium is reabsorbed isosmotically, meaning that every molecule of sodium that is reabsorbed is accompanied by a molecule of water. As the tubule dives into the medulla, or middle zone of the kidney, the tubule becomes narrower and forms Loop of Henle that reenters the cortex as the thick ascending limb that travels back to near the glomerulus. Because the interstitium of the medulla is very hyperosmotic and the Loop of Henle is permeable to water, water is reabsorbed from the Loop of Henle and into the medullary interstitium. This loss of water concentrates the urine within the Loop of Henle.
The thick ascending limb, which is impermeable to water, has a cotransport system that reabsorbs sodium, potassium and chloride at a ratio of 1:1:2. Approximately 25% of the sodium load of the original filtrate is reabsorbed at the thick ascending limb. From the thick ascending limb, the urine flows into the distal convoluting tubule, which is another site of sodium transport (~5% via a sodium-chloride co-transporter) into the cortical interstitium (the distal convoluting tubule is also impermeable to water). Finally, the tubule dives back into the medulla as the collecting duct and then into the renal pelvis where it joins with other collecting ducts to exit the kidney as the ureter. The distal segment of the distal convoluting tubule and the upper collecting duct has a transporter that reabsorbs sodium (about 1-2% of filtered load) in exchange for potassium and hydrogen ion, which are excreted into the urine. It is important to note two things about this transporter. First, its activity is dependent on the tubular concentration of sodium, so that when sodium is high, more sodium is reabsorbed and more potassium and hydrogen ion are excreted. Second, this transporter is regulated by aldosterone, which is a mineralocorticoid hormone secreted by the adrenal cortex. Increased aldosterone stimulates the reabsorption of sodium, which also increases the loss of potassium and hydrogen ion to the urine. Finally, water is reabsorbed in the collected duct through special pores that are regulated by antidiuretic hormone, which is released by the posterior pituitary. Antidiuretic hormone increases the permeability of the collecting duct to water, which leads to increased water reabsorption, a more concentrated urine and reduced urine outflow (antidiuresis). Nearly all of the sodium originally filtered is reabsorbed by the kidney, so that less than 1% of originally filtered sodium remains in the final urine.
Mechanisms of Diuretic Drugs: Diuretic drugs increase urine output by the kidney that is to say promotes diuresis. This is accomplished by altering how the kidney handles sodium. If the kidney excretes more sodium, then water excretion will also increase. Most diuretics produce diuresis by inhibiting the reabsorption of sodium at different segments of the renal tubular system. Sometimes a combination of two diuretics is given because this can be significantly more effective than either compound alone called synergistic effect. The reason for this is that one nephron segment can compensate for altered sodium reabsorption at another nephron segment; therefore, blocking multiple nephron sites significantly enhances efficacy.
Loop diuretics inhibit the sodium-potassium-chloride cotransporter in the thick ascending limb. This transporter normally reabsorbs about 25% of the sodium load; therefore, inhibition of this pump can lead to a significant increase in the distal tubular concentration of sodium, reduced hypertonicity of the surrounding interstitium, and less water reabsorption in the collecting duct. This altered handling of sodium and water leads to both diuresis; to layman, increased water loss and natriuresis meaning increased sodium loss. By acting on the thick ascending limb, which handles a significant fraction of sodium reabsorption, loop diuretics are very powerful diuretics. These drugs also induce renal synthesis of prostaglandins, which contributes to their renal action including the increase in renal blood flow and redistribution of renal cortical blood flow.
Thiazide diuretics, which are the most commonly used diuretic, inhibit the sodium-chloride transporter in the distal tubule. As this transporter normally only reabsorbs about 5% of filtered sodium, these diuretics are less efficacious than loop diuretics in producing diuresis and natriuresis. Nevertheless, they are sufficiently powerful to satisfy most therapeutic needs requiring a diuretic. Their mechanism depends on renal prostaglandin production.
Because loop and thiazide diuretics increase sodium delivery to the distal segment of the distal tubule, this increases potassium loss; potentially causing hypokalemia, because the increase in distal tubular sodium concentration stimulates the aldosterone-sensitive sodium pump to increase sodium reabsorption in exchange for potassium and hydrogen ion, which are lost to the urine. The increased hydrogen ion loss can lead to metabolic alkalosis. In part, the loss of potassium and hydrogen ion by loop and thiazide diuretics results from activation of the renin-angiotensin-aldosterone system that occurs because of reduced blood volume and arterial pressure. Increased aldosterone stimulates sodium reabsorption and increases potassium and hydrogen ion excretion into the urine.
There is a third class of diuretic that is referred to as potassium-sparing diuretics. Unlike loop and thiazide diuretics, some of these drugs do not act directly on sodium transport. Some drugs in this class antagonize the actions of aldosterone called aldosterone receptor antagonists at the distal segment of the distal tubule. This causes more sodium and water to pass into the collecting duct and be excreted in the urine. They are called potassium-sparing diuretics because they do not produce hypokalemia like the loop and thiazide diuretics. The reason for this is that by inhibiting aldosterone-sensitive sodium reabsorption, less potassium and hydrogen ion are exchanged for sodium by this transporter and therefore less potassium and hydrogen are lost to the urine. Other potassium-sparing diuretics directly inhibit sodium channels associated with the aldosterone-sensitive sodium pump, and therefore have similar effects on potassium and hydrogen ion as the aldosterone antagonists. Their mechanism depends on renal prostaglandin production. Because this class of diuretic has relatively weak effects on overall sodium balance, they are often used in conjunction with thiazide or loop diuretics to help prevent hypokalemia.
Carbonic anhydrase inhibitors inhibit the transport of bicarbonate out of the proximal convoluted tubule into the interstitium, which leads to less sodium reabsorption at this site and therefore greater sodium, bicarbonate and water loss in the urine. These are the weakest of the diuretics and seldom used in cardiovascular disease. Their main use is in the treatment of glaucoma.
Cardiovascular effects of diuretics: Through their effects on sodium and water balance, diuretics decrease blood volume and venous pressure. This decreases cardiac filling (preload) and, by the Frank-Starling mechanism, decreases ventricular stroke volume and cardiac output, which leads to a fall in arterial pressure. The decrease in venous pressure reduces capillary hydrostatic pressure, which decreases capillary fluid filtration and promotes capillary fluid reabsorption, thereby reducing edema if present. There is some evidence that loop diuretics cause venodilation, which can contribute to the lowering of venous pressure. Long-term use of diuretics results in a fall in systemic vascular resistance by unknown mechanisms that help to sustain the reduction in arterial pressure.
Therapeutic uses of diuretics:
1. Hypertension: Most patients with hypertension, of which 90-95% have hypertension of unknown origin called primary or essential hypertension, are effectively treated with diuretics. Antihypertensive therapy with diuretics is particularly effective when coupled with reduced dietary sodium intake. The efficacy of these drugs is derived from their ability to reduce blood volume, cardiac output, and with long-term therapy, systemic vascular resistance. The vast majority of hypertensive patients are treated with thiazide diuretics. Potassium-sparing, aldosterone-blocking diuretics, for example, spironolactone are used in secondary hypertension caused by hyperaldosteronism, and sometimes as an adjunct to thiazide treatment in primary hypertension to prevent hypokalemia.
2. Heart failure: Heart failure leads to activation of the renin-angiotensin-aldosterone system, which causes increased sodium and water retention by the kidneys. This in turn increases blood volume and contributes to the elevated venous pressures associated with heart failure, which can lead to pulmonary and systemic edema. The primary use for diuretics in heart failure is to reduce pulmonary and/or systemic congestion and edema, and associated clinical symptoms, for example, shortness of breath – dyspnea). Long-term treatment with diuretics may also reduce the afterload on the heart by promoting systemic vasodilation, which can lead to improved ventricular ejection.
When treating heart failure with diuretics, care must be taken to not unload too much volume because this can depress cardiac output. For example, if pulmonary capillary wedge pressure is 25 mmHg (point A in figure) and pulmonary congestion is present, a diuretic can safely reduce that elevated pressure to a level, for example, 14 mmHg that will reduce pulmonary pressures without compromising ventricular stroke volume. The reason for this is that heart failure caused by systolic dysfunction is associated with a depressed, flattened Frank-Starling curve. However, if the volume is reduced too much, stroke volume will fall because the heart will now be operating on the ascending limb of the Frank-Starling relationship. If the heart failure is caused by diastolic dysfunction, diuretics must be used very carefully so as to not impair ventricular filling. In diastolic dysfunction, ventricular filling requires elevated filling pressures because of the reduced ventricular compliance.
Most patients in heart failure are prescribed a loop diuretic because they are more effective in unloading sodium and water than thiazide diuretics. In mild heart failure, a thiazide diuretic may be used. Potassium-sparing, aldosterone-blocking diuretics, for example, spironolactone are being used increasingly in heart failure.
3. Pulmonary and systemic edema: Capillary hydrostatic pressure and therefore capillary fluid filtration is strongly influenced by venous pressure. Therefore, diuretics, by reducing blood volume and venous pressure, lower capillary hydrostatic pressure, which reduces net capillary fluid filtration and tissue edema.
The Pharmacologic Treatment Of Edema
Edema is the swelling of tissues that occurs when excessive fluid accumulates within the tissue. Fluid comprised of water and electrolytes, with a very small amount of protein and other macromolecules, normally leaves capillaries and small postcapillary venules by a process called filtration. Filtration is primarily driven by the capillary hydrostatic pressure, and the amount filtered per unit time is additionally influenced by the permeability of the endothelium and basement membrane.
The fluid that filters into the tissue flows within the intercellular space or the interstitium and most of it is reabsorbed at the venular end of capillaries where the hydrostatic pressure is lower. Some of the filtered fluid is taken up by lymphatic vessels and returned to the circulation.
Edema may be caused by increased capillary hydrostatic pressure as occurs when venous pressures become elevated by gravitational forces, volume expanded states, in heart failure or with venous obstruction; decreased plasma oncotic pressure as occurs with hypoproteinemia; increased capillary permeability caused by proinflammatory mediators, for example, histamine, bradykinin or by damage to the structural integrity of capillaries so that they become more "leaky" as occurs in tissue trauma, burns, and severe inflammation; lymphatic obstruction as occurs in filariasis.
The most common cause of edema in patients with cardiovascular disorders is heart failure. In left ventricular failure, blood backs up into the pulmonary circuit. This increase in pulmonary blood volume from pulmonary congestion leads to increased pulmonary capillary pressures and fluid filtration into the lungs. This is termed pulmonary edema, and can be life-threatening. As left ventricular failure becomes more severe, or during right ventricular failure, blood backs up into the systemic venous circulation. This elevates venous pressures and capillary hydrostatic pressures, which can lead to edema especially in the feet and legs. Sometimes fluid will accumulate in the abdominal cavity causing ascites. It is important to note that heart failure patients, because of activation of the renin-angiotensin-aldosterone system, retain sodium and water. This increases circulating blood volume and further increases venous and capillary pressures, which enhances edema formation.
Sometimes patients with severe hypertension will also present with systemic edema because of elevated capillary pressures, although it is important to note that capillary pressure is far more sensitive to elevations in venous pressure than to elevations in arterial pressure.
Finally, edema can be a side effect of vasodilator drugs that are used to treat hypertension. Vasodilation of precapillary resistance vessels increases downstream capillary hydrostatic pressure and fluid filtration.
Edema is treated by manipulating the physical factors that are responsible for causing edema. Most commonly, this is done by giving diuretics to stimulate renal excretion of sodium and water, which reduces blood volume and venous and capillary pressures. Improving cardiac function in heart failure patients will also contribute to reducing venous pressures and edema. If other mechanisms are involved in causing the edema, such as lymphatic blockage, varicose veins, venous thrombosis, tissue damage or inflammation, these conditions need to be corrected by other interventions.
The loop diuretics are potent and widely used agents in the therapy of edematous states and congestive heart failure and less commonly as therapy of hypertension. Clinically apparent acute liver injury due to the loop diuretics is exceeding rare, if it occurs at all. The loop diuretics act by inhibition of the sodium-potassium-chloride symporter present in the thick ascending limb of the loop of Henle causing an inhibition of sodium reuptake. The increase in delivery of sodium to the distal convoluted loop overwhelms its capacity for sodium reabsorption and a brisk sodium diuresis ensues. The loop diuretics are grouped together because of shared mechanism of action, but they have distinct chemical structures. The loop diuretics are more potent than the typical thiazide diuretics and usually have a shorter duration of action. As a result, the loop diuretics are used more for the therapy of edema than long term therapy of hypertension. Furosemide was the first loop diuretic to be approved in the United States and is still widely used with more than 37 million prescriptions filled yearly. Furosemide is available in tablets of 20, 40 and 80 mg in generic forms and under the brand name Lasix. Furosemide is also available as an oral solution and in liquid form for injection. The usual adult dose of furosemide is 20 to 320 mg daily, given in one to three divided doses. Bumetanide is a potent loop diuretic that was approved for use in the United States and continues to be used for the treatment of edema. Bumetanide is available as tablets of 0.5, 1 and 2 mg in generic forms and under the trade name of Bumex. The usual oral adult dose is 0.5 to 2 mg in two or three divided doses daily. Torsemide was approved for use in edema in the United States and is still in common use used for both edema and hypertension. Torsemide is available in tablets of 5, 10, 20 and 100 mg in generic forms and under the brand name of Demadex. Solutions are available for intravenous use as well. The usual oral adult dose is 5 to 100 mg daily in one or two divided doses. Side effects of the loop diuretics include dizziness, headache, gastrointestinal upset, hypernatremia, hypokalemia and dehydration.
Use of the loop diuretics has not been associated with an increased rate of serum aminotransferase elevations. There have been only rare reported cases of clinically apparent liver injury associated with loop diuretics and most of these reports have not been very convincing. Interestingly, furosemide causes a direct hepatotoxicity in mice and has been used as an animal model of drug-induced liver injury. This injury does not appear to occur in humans. Thus, clinically apparent liver injury from the loop diuretics must be exceeding rare if it occurs at all. The cause of the rare occurrence of clinically apparent liver injury associated with the loop diuretics is not known. These agents are metabolized minimally by the liver and generally have rapid renal excretion. Cases of clinically apparent liver injury due to the loop diuretics have been too few to characterize their severity and course. There have been no published instances of acute liver failure or chronic liver injury attributed to any of the loop diuretics. Cross reactivity among the four agents is unlikely because of the variability of their chemical structure.