8-4. TYPES OF DIURETICS
There are several types of diuretics. The categories are defined based upon their mechanism of action.
a. Osmotic Diuretics. Osmostic diuretics produce a diuresis of water rather than a diuresis of sodium. The body does not metabolize osmotic diuretics. Instead, the drug molecules are not reabsorbed in the kidney tubules. This greatly affects the tonicity of every part of the kidney tubules through which the glomerular filtrates pass. By the process of osmosis, the drug molecules draw an increased amount of water from the interstitial fluid compartment. The result is that a great volume of urine is produced (water diuresis). It just so happens that sodium is contained in that urine and is subsequently removed from the body. Thus, the osmotic diuretics indirectly produce a removal of sodium from the body. Following is one example of an osmotic diuretic: Mannitol. Mannitol is used to prevent acute renal (kidney) failure, evaluate kidney functioning, treat glaucoma (by the reduction of intraocular pressure), promote the urinary excretion of toxic substances (diuresis in certain drug intoxications) and reduce intracranial pressure (pressure in the head). The usual dosage of mannitol is from 50 to 200 grams in a 24-hour period by intravenous infusion. Side effects associated with the use of mannitol include pulmonary congestion, fluid and electrolyte imbalance, acidosis, electrolyte loss, and dryness of mouth and dehydration. Since mannitol may crystallize on exposure to low temperatures, you should observe mannitol vials and premixed bags for such crystals. When you observe these crystals, you should warm the vials or bags in a 500° C water bath in order to dissolve the crystals. The product should be cooled to body temperature before the mannitol solution is administered. Mannitol is available in a 5, 10, 15, 20, and 25 percent injection.
b. Thiazide Diuretics. Thiazide diuretics work by the inhibition of sodium reabsorption in the first portion of the distal tubule. The passive diffusion of the accompanying water and chloride is correspondingly reduced. Thus, the result is an increased excretion of sodium, water, and chloride from the body. When the thiazide acts on the proximal tubule, the carbonic anhydrase activity in the distal tubule is also decreased. This causes increased secretion of potassium. Consequently, the water lost contains sodium, potassium, and chloride. This loss of potassium can present problems to the patient.
(1) Hydrochlorothiazide (Hydrodiuril®). Hydrochlorothiazide is used in the treatment of essential hypertension and edema found in congestive heart failure. The usual dose of this drug is from 12.5 to 100 milligrams per day. Side effects commonly associated with hydrochlorothiazide include hypokalemia, hyperglycemia, and hyperuricemia. This drug should be used in caution in patients suffering from diabetes or gout and in patients who take digitalis.
(2) Chlorothiazide (Diuril®). This drug is used as a diuretic and as an antihypertensive. It is available in both parenteral and oral dosage forms. For side effects, refer to hydrochlorothiazide.
(3) Chlorthalidone (Hygroton®). Although chlorthalidone is not the same chemically as the thiazide diuretics, it has the same effects as these agents. For indications and side effects, you should refer to hydrochlorothiazide.
c. Potassium-Sparing Diuretics. This type of diuretic is used when there is a need to maintain normal levels of potassium in the patient along with the diuresis. The specific mechanisms of actions of selected drugs in this category.
(1) Spironolactone (Aldactone®). Spironolactone causes sodium diuresis and potassium retention by acting as an aldosterone competitive antagonist. That is, this drug acts on the distal tubule to block the sodium-potassium exchange mechanism. The net result is sodium loss and potassium retention. Consequently, by antagonizing aldosterone, sodium as well as water diuresis and potassium retention are affected. Spironolactone is used for primary hyperaldosteronism, edema associated with congestive heart failure, cirrhosis of the liver or ascites, essential hypertension, and in hypokalemia when other means are considered inappropriate or inadequate. The usual dose of this drug is from 25 to 400 milligrams per day depending upon the condition of the patient. Although spironolactone is a mild diuretic, it can hasten major side effects such as gastrointestinal symptoms (for example: cramping and diarrhea), lethargy, hyperkalemia, and hyponatremia. Hyperkalemia is a major side effect that occurs in patients who have impaired renal function. Hyperkalemia can cause irregularities that may be fatal. Spirolactone also causes estrogen-like side effects because of its hormone-like structure.
(2) Triamterene (Dyrenium®). While triamterene produces effects similar to those of spironolactone, the effects produced by triamterene are not dependent on the presence of aldosterone. This agent acts directly on the distal tubule where it prevents the passage of sodium across the membrane of the tubule. Thus, by blocking sodium reabsorption, potassium loss is reduced. Triamterene is used for edema associated with congestive heart failure and cirrhosis of the liver. The usual dosage of this drug is from 25 to 200 milligrams per day. The daily dose should not exceed 300 milligrams. Side effects associated with this agent include electrolyte imbalances, hyperkalemia, weakness, and dry mouth. Like spironolactone, hyperkalemia is a major side effect which can occur in patients who have impaired renal function or when the drug is administered alone.
d. Carbonic Anhydrase Inhibitor Diuretics. Carbonic anhydrase inhibitors produce diuresis by inhibiting carbonic anhydrase in the renal tubules. Carbonic anhydrase is an enzyme that catalyzes the following reaction: From the reaction above, it can be deduced that removal of or blocking the enzyme carbonic anhydrase would result in a much slower reaction. Consequently, there would be a greatly reduced production of hydrogen ions and bicarbonate ions. This interferes with the ion exchange mechanism at the distal tubule, where the sodium ion that accompanies the bicarbonate ion is reabsorbed only by exchange for hydrogen or potassium ions secreted into the tubule. Normally the bicarbonate ion that accompanies the sodium ion (provided by the glomerular filtrate) is reabsorbed almost complete at the distal tubule. With reduced production of hydrogen ion due to inhibition of the carbonic anhydrase, the bicarbonate ion, together with the sodium ion will not be reabsorbed. Thus, the sodium will be excreted in an unusually large amount--with a corresponding loss of water (remember, where sodium goes, water goes).
Acetazolamide (Diamox®). Acetazolamide is one example of a carbonic anhydrase inhibitor. Although rarely used today, it may be used in the treatment of edema because of congestive heart failure; drug-induced edema; petit mal and unlocalized seizures; and open-angle and secondary glaucoma. The usual dosage of this drug ranges from 250 milligrams to 2 grams--depending on the type of condition being treated. Actually, the dosage recommendations for glaucoma and epilepsy differ considerably from those of congestive heart failure, since the first two conditions are not dependent on carbonic anhydrase inhibition in the kidney which requires intermittent dosage if it is to recover from the inhibitory effect of the therapeutic agent. The side effects of this agent include loss of appetite, transient myopia (nearsightedness), drowsiness, and acidosis. Acetazolamide is available in the injectable form.
e. Inhibition of Sodium Transport in the Ascending Limb of the Loop of Henle, the Distal Tubule, and the Proximal Sites Diuretics. Diuretics of this type are extremely potent and rapidly acting. In fact, they are used only after less potent--but safer--diuretics have failed. As the category type states, this type of diuretic acts by inhibiting sodium transport in the ascending limb of the loop of Henle, the distal tubule, and in the proximal sites. Thus, a greater fraction of filtered sodium can escape reabsorption. Thereby, increased sodium and water excretions occur. Diuretics of this type are called "loop diuretics".
(1) Furosemide (Lasix®). Furosemide is used in the treatment of edema associated with congestive heart failure, cirrhosis of the liver and renal disease, pulmonary edema, and hypertension. It is particularly useful when an agent with a greater diuretic potential than that of those commonly used is desired. This agent is also a rapidly acting diuretic. When administered orally it acts within one hour. When administered by injection it acts within 5-10 minutes. However, the agent does produce massive changes in electrolyte and water balance in the body. The usual dosage of furosemide is 20 to 80 milligrams given in a single dose--preferably in the morning. Depending on the patients response, this dose can be repeated, maintained, or reduced. There are numerous adverse effects associated with the use of furosemide.
These adverse effects include hypokalemia, hyponatremia, hyperglycemia, electrolyte depletion, and hypovolemia. Reservsible and irreversible hearing impairment and loss may occur with any of the loop diuretics. It is often associated with rapid infusion and the use of extremely high doses. The injectable form of the drug must be stored at controlled room temperature and should not be used if the solution is yellow. The oral solution and tablet preparations should be dispensed in light--resistant containers.
(2) Other loop diuretics include bumetanide (Bumex®), ethacrynic acid (Edecrin®), and torsemide (Demadex®).
f. Inhibition of Sodium and Chloride Reabsorption Diuretics. The mechanism of action of this type is very similar to the thiazide diuretics. That is, drugs of this category inhibit sodium and chloride reabsorption that results in the increased excretion of sodium, chloride, and water. Chlorthalidone (Hygroton®). This agent differs from the thiazide diuretics only in chemical structure. Chlorthalidones pharmacological action is indistinguishable from the thiazide diuretics. Chlorthalidone is used in the management of hypertension--either as the sole therapeutic agent or to enhance the effect of other antihypertensive drugs in patients who have the more severe forms of hypertension. It is also used as adjunctive therapy in the treatment of edema associated with congestive heart failure, hepatic cirrhosis, and various forms of renal dysfunctions. Refer to the information on hydrochlorothiazide for side effect information.
g. Combination Diuretics (Potassium-Sparing and Thiazide Diuretic Combination). The potassium-sparing and thiazide diuretics have different but complementary mechanisms and sites of action. Therefore, when given together they produce additive diuretic and antihypertensive effects. The thiazide component blocks the reabsorption of sodium and chloride ions and thus increases the quantity of sodium traversing the distal tubule and the volume of water excreted in the urine. This characteristically induces potassium loss. The potassium-sparing component inhibits the reabsorption of sodium in exchange for potassium and hydrogen ions at the distal tubule, so that sodium excretion is greatly favored and the excess loss of potassium, as well as hydrogen and chloride ions induced by the thiazide, is reduced.
(1) Aldactazide® (combination of spironolactone and hydrochlorothiazide). This drug is used for the treatment of edema associated with congestive heart failure, cirrhosis of the liver and ascites and for essential hypertension.
(2) Dyazide® (combination of triamterene and hydrochlorothiazide). This agent is used in the treatment of edema associated with congestive heart failure, cirrhosis of the liver, and hypertension. The usual dosage of this product from 1 to 2 capsules taken twice daily after meals. The patient should take no more than four capsules per day. The side effects associated with this agent include hyperglycemia, hyperuricemia, and gastrointestinal disturbances. Each Dyazide® capsule contains 37.5 milligrams of triamterene and 25 milligrams of hydrochlorothiazide. There are other combinations of these diuretics available as generics or as Maxide® (75/50; 50/25). One must be very careful and doublecheck the active ingredients to ensure that the correct product is dispensed.
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Ancillary Content and Online Version: David L. Heiserman
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