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Understanding diuretics.

INTRODUCTION

Diuretics are drugs which increase the excretion of sodium and water from the body. They are used to help manage a number of disorders, including hypertension, heart failure, pulmonary oedema, renal disease and electrolyte disturbances. Diuretics rely on the principles of osmosis for their actions in the kidneys, and for their therapeutic effects on the body. People taking diuretics have increased risks of dehydration and electrolyte imbalance.

Diuretics are frontline drugs in the management of hypertension. Hydrochlorothiazide (a thiazide diuretic) was the 12th most prescribed drug in the United States in 2018, and furosemide the 15th most prescribed. (1) In Australia in 2015, 46.5 doses of diuretics were taken per day per thousand population, with furosemide the most commonly used. (2) In 2018, an updated Cochrane Review confirmed that low-dose thiazide diuretics were superior to other antihypertensive treatments as first-line therapy, reducing all morbidity and mortality outcomes for people with moderate to severe primary hypertension. (18)

Diuretics reduce blood pressure by depleting the extracellular fluid volume: blood pressure is determined by the cardiac output and the resistance to arterial blood flow. If extracellular fluid (and therefore plasma) volume is reduced, cardiac output also decreases. However, the body responds to depleted extracellular fluid by activating compensatory mechanisms, such as antidiuretic hormone, the renin-angiotensin-aldosterone system

--both of which increase fluid volume

--and the sympathetic nervous system which increases arterial resistance. (3) Commencing antihypertensive treatments with low-dose thiazide diuretics avoids triggering these mechanisms. But for some people, relying only on diuretics for control of hypertension is not effective in the long term, and they are combined with agents that block angiotensin or the sympathetic nervous system. (4)

In heart failure, diuretics reduce oedema but also, by depleting extracellular fluid volume, reduce the workload of the heart. Stronger (loop) diuretics are most commonly used to manage oedematous states. They rely on osmosis to shift sodium and water between body compartments intracellular, extracellular, the plasma and renal tubules.

Osmosis

Osmosis is the movement of water through a semipermeable membrane. Cell membranes are semipermeable, controlling the movement of solutes (substances such as sodium, chloride and larger molecules like glucose and amino acids) and water. All body compartments are separated by semipermeable membranes, including nephrons and the gut, where the cells lining the walls limit the passage of certain substances.

Water will move from a compartment where there are few solutes (therefore more water) to an area with more solutes (less water). See Figure 1, p20. In the body, water generally follows sodium. If sodium ions are moved out of a compartment, the number of solutes decreases, and water moves out as well. Intravenous (IV) fluids and other fluids used in health care (as well as sports replacement fluids) are labelled with their osmolarity. For example, 0.9 per cent sodium chloride (NaCl) intravenous fluid has an osmolarity of 308 mOsmol/L. This number is telling us the number of osmotically active particles in the fluid. The osmolarity of body fluids is 275-295 mOsmol/L, so 0.9 per cent NaCl is regarded as isosmotic, or the same as body fluids.

Tonicity is a relative term, describing what happens to body cells if they are placed in a fluid that generates an osmotic pressure. A fluid that is isotonic has no effect on the volume of the cell. An isotonic fluid is also isosmotic (see Figure 2, below). A hypertonic fluid has more osmotically active particles, so a cell placed in this fluid will shrink, as water flows out to the surrounding fluid. A hypotonic fluid has fewer particles, so water shifts into the cell, causing it to swell. Saline 0.45 per cent is a hypotonic IV solution, used most commonly where there is cellular dehydration, eg with severe hyperglycemia. Because they move freely into body compartments, hypotonic IV solutions can cause swelling in the brain. Dextrose 5 per cent in water, while initially isotonic, becomes hypotonic as the glucose is removed and used by cells.

The concentration and volume of urine varies, depending on the state of the body's water and solutes. The renal tubules have specialised features that allow the reabsorption and secretion of solutes, and osmosis of water, as the urinary filtrate travels from the glomerulus to the collecting ducts and then out of the kidney. The different classes of diuretics act on different regions of the tubules--their impact on diuresis is due to the location of their actions.

THE NEPHRON

The nephron is the functional unit of the kidney. Through filtration, reabsorption and secretion, the nephron regulates water and electrolytes, acid-base balance and urea, and the excretion of other waste products (including drugs).

Sodium and water excretion are regulated by a variety of mechanisms as renal filtrate travels along the tubules of the nephron (5,7) In Figure 3 (below):

A: At the glomerulus, the blood is filtered --about 20 per cent of the plasma volume exits the renal arterioles into the Bowman's capsule. This filtrate has the same composition as plasma, but with no plasma proteins or blood cells.

B: As the filtrate travels along the proximal convoluted tubule, sodium is reabsorbed by the cells lining the tubule walls via carbonic anhydrase--an enzyme that produces hydrogen ions which are then exchanged for sodium. Hydrogen is then pumped into the tubule and sodium is taken out and back into the body. Chloride follows sodium, and water is reabsorbed passively due to osmosis. Up to 70 per cent of filtered sodium is reabsorbed here.

C: The thick ascending limb of the loop of Henle is impervious to water, but actively transports sodium, potassium and chloride out of the tubules via the NaK-2Cl pump. These ions are then carried back deep into the renal medulla, where they create a hypertonic environment in the fluid surrounding the nephron. About 25 per cent of sodium is reabsorbed here --this is the key mechanism by which the body can produce urine that is more concentrated than body fluids.

D: The thin limb of the loop of Henle is highly permeable to water, but impermeable to sodium. The hypertonic environment in the medulla allows water to be reabsorbed from the tubules by osmosis.

E: In the early part of the distal convoluted tubule, a co-transporter molecule reabsorbs sodium and chloride from the tubules.

F: In the latter distal tubule and first part of the collecting duct, sodium is reabsorbed in exchange for potassium and hydrogen. This is controlled by the concentration of sodium in the tubules and by aldosterone. This section of the nephron is largely impermeable to water.

G: As the collecting duct travels down through the medulla of the kidney, it encounters the same hypertonic environment as in the loop of Henle. In the presence of antidiuretic hormone (ADH), the duct becomes permeable to water, which is reabsorbed, creating a more concentrated, reduced volume of urine.

All these mechanisms can be manipulated through the use of diuretic drugs, to increase sodium and water excretion from the body.

ACTIONS OF DIURETICS

A drug's diuretic effect can be mild or strong, depending on where in the nephron it acts. Most diuretics are secreted into the proximal convoluted tubule and act on the surface of the cells lining the tubules. This means they rely on normal secretory function in the proximal tubules to reach their sites of action, and could be affected by poor renal blood flow, uraemia or renal failure. (3)

Carbonic anhydrase inhibitors

Carbonic anhydrase inhibitors act in the proximal convoluted tubule (Figure 3, B), and stop the excretion of hydrogen ions in exchange for sodium. Due to their effect on hydrogen ions, this class of drugs causes renal excretion of bicarbonate to increase. Thus, while carbonic anhydrase inhibitors (eg acetazolamide) are not often used as diuretics, they may be used to induce metabolic acidosis and alkaline urine. (5)

Loop diuretics

Loop diuretics (eg furosemide) act on the loop of Henle, where they inhibit the action of the Na-K-2Cl transporter in the thick ascending limb (Figure 3, C). Less sodium being extracted from the renal filtrate stops the creation of the strongly hypertonic zone in the renal medulla. Therefore, less water is reabsorbed from the loop and the collecting duct. Furosemide also has a completely separate action on blood vessels, causing vasodilation, which contributes to its antihypertensive effects. The mechanisms may include blocking blood vessel responses to angiotensin and noradrenaline, or increasing the secretion of vasodilating prostaglandins. (3)

Loop diuretics are first-line drugs (in combination with beta-blockers and ACE-inhibitors) for hypertension in chronic kidney disease. (4) They are a key therapy for managing oedema arising from congestive heart failure, nephrotic syndrome or liver cirrhosis. (5,7) Furosemide binds strongly to plasma proteins in the blood, and if there is protein in the urinary filtrate (eg nephrotic syndrome) it also binds to this, reducing its effectiveness (5)

Thiazide and thiazide-like diuretics

Thiazide diuretics (eg bendrofluazide, hydrochlorothiazide and chlorothiazide) and non-thiazides with the same pharmacological actions (eg chlorthalidone and indapamide) block the action of the [Na.sup.+]/ [Cl.sup.-] co-transporter in the distal tubules (Figure 3, E). They have a milder action than loop diuretics, because most of the sodium has already been reabsorbed by this stage. While they also increase the loss of potassium and hydrogen ions from the body, this effect is much milder than for loop diuretics, and unlike loop diuretics, they do not increase the loss of calcium from the body. (5)

Thiazide or thiazide-like diuretics are first-line therapy for uncomplicated hypertension, and often given in combination with ACE-inhibitors or angiotensin receptor blocking agents (ARBs). For people with hypertension and coronary artery disease, thiazides are part of first-line dual-therapy strategies, such as thiazide plus beta-blocker, or thiazide plus calcium channel blocker. (4)

The initial antihypertensive effect of this class of diuretics is due to their reduction of blood volume; however they also have a mild vasodilator effect that maintains a lower blood pressure. (5)

Osmotic diuretics

Mannitol is a nonabsorbable solute that, after being filtered in the glomerulus, acts passively in the nephrons by creating an osmotic gradient along the renal tubule, preventing reabsorption of water. It is used in early management of acute kidney injury to support fluid flow along the whole nephron and collecting duct. (5)

Potassium-sparing diuretics

Potassium-sparing diuretics inhibit sodium reabsorption in the latter parts of the distal tubule and the early collecting duct (Figure 3, F). They can be used in combination with the non-potassium-sparing diuretics to preserve potassium in the body. However, they carry a risk of hyperkalaemia, especially for people with renal impairment or those taking drugs that also increase potassium concentration, eg ACE-inhibitors, ARBs and beta-blockers. (5)

Amiloride and triamterene physically block the sodium channels in the membranes of cells lining the collecting ducts. (7) Because sodium cannot enter the cell, it cannot be exchanged for potassium. The increased sodium remaining in the tubules attracts more water so diuresis occurs. Diuretics acting in the collecting duct have very limited effect because most of the sodium has already been reabsorbed from the nephron before reaching this point. (5,7)

Aldosterone receptor antagonists, such as spironolactone, have a similar effect to amiloride, but through blocking the action of aldosterone in the collecting duct. Aldosterone activates sodium exchange mechanisms and increases the number of sodium channels in the cell membrane. Blocking the actions of aldosterone in the cell reduces sodium reabsorption. Spironolactone has a separate antihypertensive effect: it prevents aldosterone-induced vasoconstriction in the arterioles, reducing resistance to blood flow. (8)

ADH receptor antagonists

Also called arginine vasopressin receptor antagonists, these drugs block the actions of antidiuretic hormone (vasopressin) on the collecting ducts (Figure 3, G). Water cannot move out of the collecting ducts as they descend through the hyperosmotic medulla, and the resulting diuresis occurs without affecting plasma sodium or potassium. ADH receptor antagonists are used in congestive heart failure, hyponatraemia, or for patients experiencing syndrome of inappropriate ADH secretion (SIADH).

SIADH can occur with acute psychosis; stroke; alcohol withdrawal; head trauma; carcinomas of the lungs, intestines and brain; or lung disorders including acute respiratory failure. Some drugs also induce SIADH, including ecstasy, antipsychotics, barbiturates and opioids, and anaesthetic drugs. (9)

Lithium and demeclocycline are older ADH antagonists, but their mechanisms of action are not well understood, and lithium especially has numerous serious adverse effects. A newer class of drugs--vaptans --directly block the ADH receptors. Alcohol acts as a diuretic because it suppresses the secretion of ADH from the posterior pituitary gland.

DIURETIC RESISTANCE

Some patients do not respond well to diuretics. This is seen more often in people with generalised oedema associated with nephrotic syndrome, chronic kidney disease, heart failure or liver cirrhosis. While nonadherence to the drug regime (or to concurrent dietary sodium and fluid restrictions) or inadequate dosing may be a cause, there are a number of physiological events that can interfere with diuretic actions. (10)

The drug may be poorly absorbed due to oedema of the gut wall or poor blood flow to the gut. It may not reach its site of action because of poor circulation to the kidneys or impaired secretion into the proximal convoluted tubules. Even where the drug reaches its site of action, the renal response to the diuretic may be abnormal due to: (10,11)

* Low glomerular filtration rate, so limited fluid is entering the tubules for the diuretic to affect.

* Activation of the renin-angiotensin-aldosterone system which counters the action of diuretics by increasing sodium reabsorption in the distal tubules (aldosterone) and in both the proximal and distal tubules (angiotensin II and its by-products). (12)

* Adaptation of the nephron to the presence of diuretics, including hypertrophy of cells in the distal tubules and increased number of sodium reuptake pumps.

* Use of nonsteroidal anti-inflammatory drugs. These block the actions of prostaglandins, which are essential to maintaining renal blood flow. (5)

Increasing the diuretic dose, or combining different classes of diuretics, may be sufficient to overcome resistance in the nephrons.

ADVERSE EFFECTS OF DIURETICS

Most of the adverse effects of diuretics are due to their therapeutic actions.

Potassium: ALL diuretics that inhibit the reabsorption of sodium cause increased Levels of sodium in the urinary filtrate as it arrives at the distal tubule and collecting duct. Here, the excess sodium triggers the Na-K pump. Sodium is taken out of the filtrate, but this requires that potassium be Lost from the body into the urinary filtrate, potentially causing hypokalaemia (Figure 3, F). Up to 50 per cent of people taking diuretics will develop hypokalaemia. (13) Loop and thiazide diuretic therapy should be accompanied by oral potassium supplements and patients encouraged to each potassium-rich food such as bananas, citrus fruit, dried fruits and spinach. Co-prescription of potassium-sparing diuretics may be more effective than the use of potassium supplements. (5)

Plasma potassium levels are strictly regulated by the kidneys to 3.55-mmol/L. Even small changes can disrupt the nerves, the myocardium and other excitable tissues. Signs and symptoms of hypokalaemia are non-specific--weakness, cramping, apathy, palpitations and, if severe, muscle paraysis. (13) Heart rhythm disturbances are common, with S-T segment depression, flattened T-waves and elevated U-waves on ECG. Risk for cardiac dysrhythmias is increased when diuretics are given with digoxin or some antidysrhythmic drugs. (14)

Mild hypokalaemia may be managed with oral potassium supplements, but greater deficits require intravenous replacement. Rapid administration of IV potassium is contraindicated because it can prematurely increase extracellular potassium levels, while intracellular concentration remains Low. This will severely disrupt the electrochemical gradient across cell membranes, causing death. The maximum rate of IV administration of potassium should not exceed 20mmol per hour or 40mmol in a high dependency/intensive care setting with continuous cardiac monitoring. Because it is an extreme irritant, higher doses of potassium must be administered via a central line. Potassium infusions should always be administered through a rate-controlling device.

Hyperkalaemia--a plasma potassium level of 5.5mmol/L or higher--can develop with the use of potassium-sparing diuretics. Again, symptoms are nonspecific and include lethargy, weakness, a flaccid paralysis and palpitations. On ECG, tall, tented T-waves, widening QRS and absent P waves may be seen. (14) People taking potassium-sparing diuretics should be advised to limit potassium-rich foods and over-the-counter NSAIDs or herbal products containing potassium.

Acid-base balance

Because increased sodium in the tubules increases hydrogen ion loss at the same time as potassium, diuretics may also induce a hypokalaemic metabolic alkalosis. Metabolic alkalosis is the most common acid-base disorder in hospitalised patients. (15) Symptoms are similar to hypokalaemia, but accompanied by hypoventilation.

Sodium

Hyponatraemia occurs when the plasma sodium level falls below 135mmol/L (normal 135-145mmol/L). Mild hyponatraemia occurs in about 20 per cent of people taking diuretics, but severe hyponatraemia (Na+ less than 120mmol/L) is more commonly seen with thiazide diuretics. Symptoms range from mild malaise, lethargy, dizziness and nausea to decreased consciousness, seizures and coma. (14,16)

Volume depletion

Effectiveness of diuretics can be monitored by daily weight. A loss of more than 900g per 24 hours indicates excessive diuresis and potential dehydration. Older adults are vulnerable to fluid depletion with diuretic drugs. This increases the risk of dizziness, postural hypotension and fatigue, and therefore falls. They are also more vulnerable to dehydration in hot weather, with gastroenteritis, and following exercise. Maintaining adequate hydration should be encouraged, even where patients worry about the impact of diuretics on social activities (especially Loop diuretics, which, although short acting, have a torrential effect on urine output). Diuretics should be administered in the morning to avoid nocturia. Furosemide absorption is delayed in the presence of food, so for people who time their diuretic therapy around social activities, taking the drug on an empty stomach will improve effectiveness and reduce the duration of its effect.

The 'triple whammy'

Diuretics, ACE-inhibitors (and angiotensin II receptors blockers), and NSAIDs all carry a risk of impairing renal function. When taken in combination, the risk of acute kidney injury is significantly increased. (17) All three classes of drug may reduce glomerular filtration, but by different mechanisms:

* ACE-inhibitors and ARBs, by causing vasodilation of the efferent arteriole.

* Diuretics, through hypovolaemia.

* NSAIDs, by causing vasoconstriction of the afferent arteriole.

In combination, they reduce blood flow to the nephrons and Lower filtration pressure in the glomerulus. The volume of fluid entering and travelling along the renal tubules is not sufficient to support tubular cell survival and an acute kidney injury occurs. Risk is greatest when NSAIDs in the plasma achieve a constant, steady concentration--after about three to seven days of treatment. Risk also increases with age over 75 years, dehydration, chronic kidney disease, diabetes, heart failure, Liver disease and with Maori, Pacific, Asian or Indian ethnicity. (17) It is essential to educate patients prescribed diuretics and ACE-inhibitors or ARBs to avoid or minimise the use of over-the-counter NSAIDs.

LEARNING OUTCOMES

After completing this activity and quiz, you should be able to:

* Outline the renal processing of electrolytes and water.

* Describe the actions of diuretics in the kidneys.

* Explain the effect of diuretics on cardiovascular function.

* Describe adverse drug reactions of diuretics, and their implications.

* References are at www.cpd4nurses.co.nz

Georgina Casey, RN, BSc, PGDipSci, MPhil (nursing), is the director of CPD4nurses.co.nz. She has an extensive background in nursing education and cLinicaL experience in a wide variety of practice settings.

Caption: Figure 1. Osmosis

Caption: Figure 2. Tonicity is the relative strength of a solution compared to body fluids.

Caption: Figure 3. Movement of water and electrolytes across the nephron. (See text for explanation of sections A-G.)
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Title Annotation:CPD + nurses
Author:Casey, Georgina
Publication:Kai Tiaki: Nursing New Zealand
Article Type:Report
Geographic Code:8NEWZ
Date:Jul 1, 2019
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