Diuretic Drugs



Diuretic Drugs


Objectives


When you reach the end of this chapter, you will be able to do the following:



Drug Profiles



Key Terms


Afferent arterioles The small blood vessels approaching the glomerulus (proximal part of the nephron). (p. 460)


Aldosterone A mineralocorticoid steroid hormone produced by the adrenal cortex that regulates sodium and water balance. (p. 461)


Ascites Intraperitoneal accumulation of fluid (defined as a volume of 500 mL or more) containing large amounts of protein and electrolytes. (p. 464)


Collecting duct The most distal part of the nephron between the distal convoluted tubule and the ureters, which lead to the urinary bladder. (p. 461)


Distal convoluted tubule The part of the nephron immediately distal to the ascending loop of Henle and proximal to the collecting duct. (p. 460)


Diuretics Drugs or other substances that tend to promote the formation and excretion of urine. (p. 460)


Efferent arterioles The small blood vessels exiting the glomerulus. At this point blood has completed its filtration in the glomerulus. (p. 460)


Filtrate The material that passes through a filter. In the case of the kidney, the filter is the glomerulus and the filtrate is the material extracted from the blood (normally liquid) that becomes urine. (p. 461)


Glomerular capsule The open, rounded, and most proximal part of the proximal convoluted tubule that surrounds the glomerulus and receives the filtrate from the blood. (p. 460)


Glomerular filtration rate (GFR) An estimate of the volume of blood that passes through the glomeruli of the kidney per minute. (p. 460)


Glomerulus The cluster of kidney capillaries that marks the beginning of the nephron and is immediately proximal to the proximal convoluted tubule. (p. 460)


Loop of Henle The part of the nephron between the proximal and distal convoluted tubules. (p. 460)


Nephron The functional filtration unit of the kidney, consisting of (in anatomic order from proximal to distal) the glomerulus, proximal convoluted tubule, loop of Henle, distal convoluted tubule, and collecting duct, which empties urine into the ureters. There are approximately 1 million nephrons in each kidney. (p. 460)


Open-angle glaucoma A condition in which pressure is elevated in the eye because of obstruction of the outflow of aqueous humor. (p. 461)


Proximal convoluted (twisted) tubule The part of the nephron that is immediately distal to the glomerulus and proximal to the loop of Henle. (p. 460)


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Anatomy, Physiology, and Pathophysiology Overview


Diuretics are drugs that accelerate the rate of urine formation via a variety of mechanisms. The result is the removal of sodium and water from the body. Diuretics were discovered by accident when it was noticed that a mercury-based antibiotic had a very potent diuretic effect. All the major classes of diuretic drugs in use today were developed between 1950 and 1970, and they remain among the most commonly prescribed drugs in the world.


The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure reaffirmed the role of diuretics, especially the thiazides, as first-line drugs in the treatment of hypertension. The hypotensive activity of diuretics is due to many different mechanisms. They cause direct arteriolar dilation, which decreases peripheral vascular resistance. They also reduce extracellular fluid volume, plasma volume, and cardiac output, which may account for the decrease in blood pressure. They have long been the mainstay of therapy not only for hypertension but also for heart failure. Two of their advantages are their relatively low cost and their favorable safety profile. The main problem with their use is the metabolic adverse effects that can result from excessive fluid and electrolyte loss. These effects are usually dose related and are controllable with dosage titration (careful adjustment).


This chapter reviews the essential properties and actions of the following important classes of diuretic drugs: carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide and thiazide-like diuretics. All diuretics work primarily in the kidney.


The kidney plays a very important role in the day-to-day functioning of the body. It filters out toxic waste products from the blood while simultaneously conserving essential substances. This delicate balance between elimination of toxins and retention of essential chemicals is maintained by the nephron. The nephron is the main structural unit of the kidney, and each kidney contains approximately 1 million nephrons. Diuretics exert their effect in the nephron. The initial filtering of the blood takes place in the glomerulus, a cluster of capillaries surrounded by the glomerular capsule. The rate at which this filtering occurs is referred to as the glomerular filtration rate (GFR), and it is used as a gauge of how well the kidneys are functioning as filters. The GFR can be estimated mathematically by calculating creatinine clearance. This is typically calculated by hospital pharmacists and is used to adjust drugs based on the patient’s renal function. Normally about 180 L of blood are filtered through the nephrons every day.


The GFR, which can also be thought of as the rate at which blood flows into and out of the glomerulus, is regulated by the small blood vessels approaching the glomerulus (afferent arterioles) and the small blood vessels exiting the glomerulus (efferent arterioles). A mnemonic (memory aid) for remembering which arteriole is which is “A for approach and afferent” and “E for exit and efferent.” Alterations in blood flow such as those that occur in a patient in shock can therefore have a dramatic effect on kidney (renal) function. Diuretics may have diminished effects in situations of low blood flow, because the kidney receives less blood, and therefore less diuretic reaches the site of action.


The proximal convoluted (twisted) tubule or, more simply, the proximal tubule, follows the glomerulus anatomically and returns 60% to 70% of the sodium and water from the filtered fluid back into the bloodstream. Blood vessels surround the nephrons and allow substances to be directly resorbed from or secreted into the bloodstream. This process is one of active transport that requires energy in the form of adenosine triphosphate (ATP) molecules. The active transport of sodium and potassium ions back into the blood causes the passive resorption of chloride and water. The chloride ions (Cl–) and water passively follow the sodium ions (Na+) and, to a lesser extent, potassium ions (K+) by osmosis. Another 20% to 25% of sodium is resorbed back into the bloodstream in the ascending loop of Henle. Chloride is actively resorbed in the loop of Henle, and sodium passively follows it.


The remaining 5% to 10% of sodium resorption takes place in the distal convoluted tubule, often called the distal tubule, which anatomically follows the ascending loop of Henle. In the distal tubule, sodium is actively filtered in exchange for potassium or hydrogen ions, a process regulated by the hormone aldosterone. The collecting duct is the final common pathway for the filtrate that started in the glomerulus. It is here that antidiuretic hormone acts to increase the absorption of water back into the bloodstream, thereby preventing it from being lost in the urine. The entire nephron, along with the sites of action of the different classes of diuretics, is shown in Figure 28-1.



Pharmacology Overview


The various diuretics are classified according to their sites of action within the nephron, their chemical structure, and their diuretic potency. The sites of action of the various diuretics are determined by the way in which they affect the various solute (electrolyte) and water transport systems located along the nephron (see Figure 28-1). The commonly used classes of drugs and the individual drugs in these classes are listed in Table 28-1. The most potent diuretics are the loop diuretics, followed by mannitol, metolazone (a thiazide-like diuretic), the thiazides, and the potassium-sparing diuretics. The potency of these diuretics is a function of where they work in the nephron to inhibit sodium and water resorption. The more sodium and water they inhibit from resorption, the greater the amount of diuresis and therefore the greater the potency.



Carbonic Anhydrase Inhibitors


Carbonic anhydrase inhibitors (CAIs) are chemical derivatives of sulfonamide antibiotics. As their name implies, CAIs inhibit the activity of the enzyme carbonic anhydrase, which is found in the kidneys, eyes, and other parts of the body. The CAIs work at the location of the carbonic anhydrase enzyme system along the nephron, primarily in the proximal tubule. Acetazolamide is the CAI most commonly used today.


Mechanism of Action and Drug Effects


The carbonic anhydrase system in the kidney is located just distal to the glomerulus in the proximal tubules, where roughly two thirds of all sodium and water is resorbed into the blood. In the proximal tubules, there is an active transport system that exchanges sodium for hydrogen ions. For sodium and water to be resorbed back into the blood, hydrogen must be exchanged for it. Without hydrogen, this cannot occur, and the sodium and water will be eliminated with the urine. Carbonic anhydrase makes hydrogen ions available for this exchange. When its actions are inhibited by a CAI such as acetazolamide, little sodium and water can be resorbed into the blood and they are eliminated with the urine. The CAIs reduce the formation of hydrogen (H+) and bicarbonate (HCO3–) ions from carbon dioxide and water through the noncompetitive, reversible inhibition of carbonic anhydrase activity. This results in a reduction in the availability of the ions, mainly hydrogen, for use by active transport systems.


The reduction in the formation of bicarbonate and hydrogen ions can have effects on other parts of the body. CAIs can induce respiratory and metabolic acidosis. Both respiratory and metabolic acidosis can increase oxygenation during hypoxia by increasing ventilation, cerebral blood flow, and the dissociation of oxygen from oxyhemoglobin. These actions are usually beneficial to the patient. An undesirable effect of CAIs is elevation of the blood glucose level and glycosuria in diabetic patients. This may be due in part to CAI-enhanced potassium loss through the urine.


Indications


Therapeutic applications of CAIs include the treatment of glaucoma, edema, and high-altitude sickness.


CAIs are used as adjunct drugs in the long-term management of open-angle glaucoma that cannot be controlled by topical miotic drugs or epinephrine derivatives alone (see Chapter 57). Glaucoma is caused by the obstruction of the outflow of aqueous humor. When CAIs are given, an increase in the outflow of aqueous humor results. They are also used short term in conjunction with miotics to lower intraocular pressure in preparation for ocular surgery and as an adjunct in the treatment of secondary glaucoma.


Acetazolamide is also used to manage edema secondary to heart failure that has become resistant to other diuretics. However, as a class, CAIs are much less potent diuretics than loop diuretics or thiazides, and the metabolic acidosis they induce diminishes their diuretic effect in 2 to 4 days.


Acetazolamide is also effective in both the prevention and treatment of the symptoms of high-altitude sickness. These symptoms include headache, nausea, shortness of breath, dizziness, drowsiness, and fatigue.


Contraindications


Contraindications to the use of CAIs include known drug allergy, hyponatremia, hypokalemia, severe renal or hepatic dysfunction, adrenal gland insufficiency, and cirrhosis.


Adverse Effects


Common undesirable effects of CAIs are metabolic abnormalities such as acidosis and hypokalemia. Drowsiness, anorexia, paresthesias, hematuria, urticaria, photosensitivity, and melena (blood in the stool) can also occur.


Interactions


Because CAIs can cause hypokalemia, an increase in digoxin toxicity may occur when they are combined with digoxin. Use with corticosteroids may also cause hypokalemia. The effects of amphetamines, carbamazepine, cyclosporine, phenytoin, and quinidine may be increased when these drugs are taken concurrently with CAIs.


Dosages


The usual dose of acetazolamide is 250 to 500 mg per day, which may be given orally or IV.


Drug Profile


acetazolamide


Use of acetazolamide (Diamox) is contraindicated in patients who have shown a hypersensitivity to it as well as in those with significant liver or kidney dysfunction, low serum potassium or sodium levels, acidosis, or adrenal gland failure. Acetazolamide is available in both oral and parenteral forms. It is classified as a pregnancy category C drug.



Loop Diuretics


Loop diuretics (bumetanide, ethacrynic acid, furosemide, and torsemide) are very potent diuretics. Bumetanide, furosemide, and torsemide are chemically related to the sulfonamide antibiotics. Because they are structurally related to the sulfonamides, they are often listed as contraindicated in sulfa-allergic patients. However, analysis of the literature indicates that cross-reaction is unlikely to occur. Loop diuretics are commonly given to patients with sulfa allergy with no problems; however, always be aware of the potential of allergy.


Mechanism of Action and Drug Effects


Loop diuretics have renal, cardiovascular, and metabolic effects. These drugs act primarily along the thick ascending limb of the loop of Henle, blocking chloride and, secondarily, sodium resorption. They are also thought to activate renal prostaglandins, which results in dilatation of the blood vessels of the kidneys, the lungs, and the rest of the body (i.e., reduction in renal, pulmonary, and systemic vascular resistance). The hemodynamic effects of loop diuretics are a reduction in both the preload and central venous pressures (which are the filling pressures of the ventricles). These actions make them useful in the treatment of the edema associated with heart failure, hepatic cirrhosis, and renal disease.


Loop diuretics are particularly useful when rapid diuresis is needed, because of their rapid onset of action. The diuretic effect lasts at least 2 hours. Loop diuretics have a distinct advantage over thiazide diuretics in that their diuretic action continues even when creatinine clearance decreases below 25 mL/min. This means that even when kidney function diminishes, loop diuretics can still work. Because of their potent diuretic effect and the duration of action, loop diuretics are usually effective when given in a single daily dose. This allows the renal tubule time to partially compensate for the potassium depletion and other electrolyte derangements that often accompany around-the-clock diuretic therapy. Despite this, the major adverse effect of loop diuretics is electrolyte disturbances. Prolonged administration of high dosages can also result in hearing loss stemming from ototoxicity, although this is rare.


Summary of Major Drug Effects of Loop Diuretics


Loop diuretics produce a potent diuresis and subsequent loss of fluid. The resulting decreased fluid volume leads to a decreased return of blood to the heart, or decreased filling pressures. This has the following cardiovascular effects:



The metabolic effects of the loop diuretics are secondary to the electrolyte losses resulting from the potent diuresis. Major electrolyte losses include loss of sodium and potassium and, to a lesser extent, calcium. Changes in the plasma levels of insulin, glucagon, and growth hormone have also been observed in association with loop diuretic therapy.


Indications


Loop diuretics are used to manage the edema associated with heart failure and hepatic or renal disease, to control hypertension, and to increase the renal excretion of calcium in patients with hypercalcemia. As with certain other classes of diuretics, they may also be indicated in cases of heart failure resulting from diastolic dysfunction.


Contraindications


Contraindications to the use of loop diuretics include known drug allergy, hepatic coma, and severe electrolyte loss. Although allergy to sulfonamide antibiotics is listed as a contraindication, analysis of the literature indicates that cross-reaction with the loop diuretics is unlikely to occur. Loop diuretics are commonly given to such patients in clinical practice.


Adverse Effects


Common undesirable effects of the loop diuretics are listed in Table 28-2. Hypokalemia is of serious clinical importance. To prevent hypokalemia, patients often receive potassium supplements along with furosemide. Furosemide can produce erythema multiforme, exfoliative dermatitis, photosensitivity, and in rare cases aplastic anemia. Torsemide may rarely cause blood disorders, including thrombocytopenia, agranulocytosis, leukopenia, and neutropenia. It may also cause a severe skin disorder called Stevens-Johnson syndrome.



Toxicity and Management of Overdose


Electrolyte loss and dehydration, which can result in circulatory failure, are the main toxic effects of loop diuretics that require attention. Treatment involves electrolyte and fluid replacement.


Interactions


Loop diuretics exhibit both neurotoxic and nephrotoxic properties, and they produce additive effects when given in combination with drugs that have similar toxicities. The drug interactions are summarized in Table 28-3.



Loop diuretics also affect certain laboratory results. They cause increases in the serum levels of uric acid, glucose, alanine aminotransferase, and aspartate aminotransferase. Their combined use with a thiazide (especially metolazone) results in the blockade of sodium and water resorption at multiple sites in the nephron, a property referred to as sequential nephron blockade, which increases their effects. Nonsteroidal antiinflammatory drugs (NSAIDs) may diminish the reduction in vascular resistance induced by loop diuretics because these two drug classes have opposite effects on prostaglandin activity.


Dosages


For dosage information on loop diuretics, see the table on this page.


Drug Profile


The currently available loop diuretics are bumetanide, ethacrynic acid, furosemide, and torsemide. Ethacrynic acid is rarely used clinically. As a class they are very potent diuretics, but


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May 9, 2017 | Posted by in NURSING | Comments Off on Diuretic Drugs

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