CHAPTER 41: Diuretics

The kidney serves three basic functions: The Three Basic Renal Processes

(1) CLEANSING of *extracellular fluid (ECF)* and MAINTEINCE of *ECF volume and composition*; (2) maintenance of *acid-base balance*; and (3) *excretion of metabolic wastes* and foreign substances (eg, drugs, toxins).

Effects of the kidney on ECF are the net result of three basic processes:

(1) filtration (2) reabsorption, and (3) active secretion.

There are four major categories of diuretic drugs:

(1) loop diuretics (also known as high-ceiling diuretics) (eg, furosemide); (2) thiazide diuretics (eg, hydrochlorothiazide); (3) osmotic diuretics (eg, mannitol); and (4) potassium-sparing diuretics. The last group, the potassium-sparing agents, can be subdivided into a. aldosterone antagonists (eg, spironolactone) and b. nonaldosterone antagonists (eg, triamterene).

Hypotension. Furosemide can cause a substantial drop in blood pressure. At least two mechanisms are involved:

(1) loss of volume and (2) relaxation of venous smooth muscle, which reduces venous return to the heart. Signs of hypotension include a. dizziness, b. lightheadedness, and c. fainting. If blood pressure falls precipitously, furosemide should be discontinued. Because of the risk of hypotension, blood pressure should be monitored routinely. Outpatients should be taught to monitor their blood pressure and instructed to notify the prescriber if it drops substantially. Also, patients should be i*nformed about symptoms of postural hypotension (dizziness, lightheadedness)* and advised to sit or lie down if these occur. Patients should be taught that postural hypotension can be minimized by rising slowly.

Of the three basic functions of the kindey, which do diuretics affect most.

(1) maintenance of ECF volume and composition

Conditions that justify use of furosemide include

(1) pulmonary edema associated with congestive heart failure (CHF); (2) edema of hepatic, cardiac, or renal origin that has been unresponsive to less efficacious diuretics; and (3) hypertension that cannot be controlled with other diuretics.

the nephron has four functionally distinct regions

(1) the glomerulus (2) the proximal convoluted tubule 3) the loop of Henle 4) the distal convoluted tubule.

Diuretics - drugs that increase the output of urine. two major applications:

(1) treatment of hypertension and (2) mobilization of edematous fluid associated with heart failure, cirrhosis, or kidney disease. In addition, because of their ability to maintain urine flow, diuretics are used to prevent renal failure.

The ability of thiazides to promote diuresis is dependent on adequate kidney function. These drugs are ineffective when GFR is low

(less than 15 to 20 mL/min).

Distal Convoluted Tubule (Early Segment).

*About 10% of filtered sodium and chloride is reabsorbed* in the early segment of the distal convoluted tubule. Water follows passively.

Prototype Drugs: Diuretics

*Loop Diuretics*: Furosemide *Thiazide Diuretics*: Hydrochlorothiazide *Potassium-Sparing Diuretics*: Spironolactone & Triamterene

Identifying High-Risk Patients: Potassium-sparing diuretics

*contraindicated*: hyperkalemia CAUTION: taking potassium supplements or another potassium-sparing diuretic. CAUTION: 1. ACE inhibitors 2. angiotensin receptor blockers 3. direct renin inhibitors.

If treatment with furosemide alone is insufficient

, a thiazide diuretic may be added to the regimen.

Therapeutic Uses of Thiazides

1. *Essential Hypertension* - 1st choice 2. *Edema* - in pt's w/ mild-mod heartfailure or edma assoc hepatic/renal disease 3. *Diabetes Insipidus* - Diabetes insipidus is a rare condition characterized by excessive production of urine. In patients with this disorder, thiazides reduce urine production by 30% to 50%. The mechanism of this *paradoxical effect* is unclear. 4. *Protection Against Postmenopausal Osteoporosis* - promote tubular reabsorption of calcium

Drug Interactions w/ Feurosemide

1. Digoxin. 2. Ototoxic Drugs. 3. Potassium-Sparing Diuretics. (reduce chance of hypokalemia - beneficial interaction for those taking digoxin or ppl w/ heart dysrhythmias) 4. Lithium - can create Li tox in body (dose of Li should be reduced) 5. Antihypertensive Agents - risk for hypotension 6. Nonsteroidal Antiinflammatory Drugs (NSAIDs). - attenuate the diuretic effects of furosemide.

Distal Nephron: Late Distal Convoluted Tubule and Collecting Duct. The distal nephron is the site of *two important processes*.

1. The first involves *exchange* of sodium *Na+* for potassium *K+* and is under the influence of ALDOSTERONE. 2. The second determines the *final concentration of the urine* and is regulated by antidiuretic hormone *(ADH)*. Although sodium-potassium exchange is discussed in more detail, we will not continue discussion of ADH, as it has little to do with the actions of diuretics.

In addition to being marketed alone, hydrochlorothiazide is available in *fixed-dose combinations* with *potassium-sparing diuretics* and a long list of other drugs:

1. beta blockers, 2. angiotensin-converting enzyme inhibitors, 3. angiotensin receptor blockers, 4. calcium channel blockers, 5. hydralazine, clonidine, and 6. methyldopa

lists three drugs that are not true thiazides. However, these agents are very similar to thiazides both in structure and function, and hence are included in the group.

1. chlorthalidone 2. indapamide 3. metolazone

To promote excretion of water, diuretics must interfere with the normal operation of the kidney. By doing so, diuretics can cause

1. hypovolemia (from excessive fluid loss) 2. acid-base imbalance, and 3. altered electrolyte levels. These adverse effects can be *minimized* by using *short-acting diuretics* and by *timing drug administration* such that the kidney is allowed to operate in a drug-free manner between periods of diuresis. Both measures will give the kidney periodic opportunities to readjust the ECF so as to compensate for any undesired alterations produced under the influence of diuretics.

The risk of dehydration in LOOP can be minimized by

1. initiating therapy with low doses, 2. adjusting the dosage carefully, 3. monitoring weight loss every day, and 4. administering furosemide on an intermittent schedule.

The filtration capacity of the kidney is very large. Each minute the kidney produces.

125 mL of filtrate, which adds up to 180 L/day

Since the total volume of ECF is only *12.5 L*, the kidneys can process the equivalent of all the ECF in the body every *100 minutes*. Hence, the ECF undergoes complete cleansing about

14 times each day.

It is instructive to look at the quantitative relationship between blockade of solute reabsorption and production of diuresis. Recall that the kidneys produce _______ practically all of which is normally reabsorbed.

180 L of filtrate a day, With filtrate production at this volume, a diuretic will increase daily urine output by 1.8 L for each 1% of solute reabsorption that is blocked.

Within the *thick segment* of the *ascending limb of the loop of Henle*, about

20% of filtered sodium and chloride is reabsorbed.

A 3% blockade of solute reabsorption will produce

5.4 L of urine a day—a rate of fluid loss that would reduce body weight by 12 pounds in 24 hours. Clearly, with only a small blockade of reabsorption, diuretics can produce a profound effect on the fluid and electrolyte composition of the body.

The proximal convoluted tubule (PCT) has a high reabsorptive capacity.

A large fraction (about 65%) of filtered sodium and chloride is reabsorbed at the PCT. In addition, essentially **all of the bicarbonate and potassium in the filtrate*** is reabsorbed here.

Since, unlike the descending limb, the ascending limb is not permeable to water, water must remain in the loop as reabsorption of sodium and chloride takes place. This process causes the tonicity of the tubular urine to return to that of the original filtrate (300 mOsm/L).

ASCENDING LOOP OF HENLE = *NOT PERMEABLE TO WATER* Descending loop of Henle = IS permeable to water

*Sodium-Potassium Exchange*. __________the principal mineralocorticoid of the adrenal cortex. stimulates *reabsorption of sodium from the distal nephron*.

Aldosterone

In addition to furosemide, three other loop diuretics are available:

All three are much like furosemide. They all promote diuresis by inhibiting sodium and chloride rea1. ethacrynic acid [Edecrin] 2. torsemide [Demadex] 3. bumetanide [Burinex image, generic only in United States]. bsorption in the thick ascending limb of the loop of Henle. All are approved for edema caused by heart failure, chronic renal disease, and cirrhosis, but only torsemide, like furosemide, is also approved for hypertension.

Potassium-Sparing Diuretics

Amiloride Spironolactone (proto) Triamterene

Potassium is lost through increased secretion in the distal nephron. If serum potassium falls below 3.5 mEq/L, fatal dysrhythmias may result.

As discussed below under Drug Interactions, loss of potassium is of special concern for patients taking digoxin, a drug for heart failure. Hypokalemia can be minimized by consuming potassium-rich foods (eg, dried fruits, nuts, spinach, potatoes, bananas), taking potassium supplements, or using a potassium-sparing diureti

Loop Diuretics

Bumetanide Ethacrynic acid Furosemide (proto) Torsemide

Most diuretics share the *same basic mechanism of action*: blockade of sodium and chloride reabsorption

By blocking the reabsorption of these prominent solutes, diuretics create osmotic pressure within the nephron that prevents the passive reabsorption of water. Hence, diuretics cause water and solutes to be retained within the nephron, and thereby promote the excretion of both.

In addition to the four major categories of diuretics, there is a *fifth group*: the

CARBONIC ANHYDRASE INHIBITORS Although the carbonic anhydrase inhibitors are classified as diuretics, these drugs are *employed primarily to lower intraocular pressure (IOP)* and *not to increase urine production*.

Thiazides and Related Diuretics

Chlorothiazide Chlorthalidone Hydrochlorothiazide (proto) Indapamide Methyclothiazide Metolazone Thiazide diuretics have actions much like those of the loop diuretics. Hence, nursing implications for the thiazides are nearly identical to those of the loop diuretics.

Conversely, since most of the filtered solute has already been reabsorbed by the time the filtrate reaches the distal parts of the nephron, diuretics that act at distal sites have very little reabsorption available to block.

Consequently, such agents produce relatively scant diuresis.

Pregnancy - loop

Contraindicated - unless necessary for maternal life saving measures - may cause fetal death

Reabsorption of solutes 1. electrolytes 2. amino acids 3. glucose takes place by way of *active transport*. *Water* then follows *passively along the osmotic gradient* created by SOLUTE REPUTAKE.

Diuretics work primarily by interfering with REABSORPTION.

Since the amount of solute in the nephron becomes progressively smaller as filtrate flows from the proximal tubule to the collecting duct, drugs that act

EARLY in the nephron have the *opportunity to block the greatest amount of solute reabsorption*. As a result, these agents produce the greatest diuresis.

1. One pump transports ORGANIC ACIDS 2. the other transport ORGANIC BASES Together, these pumps can promote the

EXCRETION of a wide assortment of molecules, including metabolic wastes, drugs, and toxins. The pumps for *active secretion* are located in the *proximal convoluted tubule*.

The kidney has *two major kinds of "pumps"* for ACTIVE SECRETION. These pumps transport compounds

FROM the *plasma* INTO the *lumen* of the nephron. 1. One pump transports ORGANIC ACIDS 2. the other transport ORGANIC BASES

the most widely used thiazide diuretic and will serve as our *prototype* for the group.

Hydrochlorothiazide is

Adverse effects of Furosemide (loop) (aka lasix)

Hyponatremia, Hypochloremia, and Dehydration. Furosemide can produce excessive loss of sodium, chloride, and water. Severe dehydration can result. Signs of evolving dehydration include 1. dry mouth 2. unusual thirst 3. oliguria (scanty urine output). Impending dehydration can also be anticipated from excessive loss of weight. If dehydration occurs, furosemide should be withheld.

Chlorothiazide can be administered

IV as well as PO. (it is the only one)

Parenteral - IV/IM Furosemide is available in solution (10 mg/mL) for IV and IM administration. The usual dosage for adults is 20 to 40 mg, repeated in 1 or 2 hours if needed.

Intravenous administration should be done *slowly* (over 1 to 2 minutes). For high-dose therapy, furosemide can be administered by *continuous infusion at a rate of 4 mg/min or slower*.

Should you combine loop diuretics with aminoglycoside antibiotics?

No, b/c there is a risk for ototoxicity in both

Route of K+ sparing diuretics

ORAL

where are the 2 pumps located that promote active secretion of the nephron of the kidney?

PROXIMAL CONVOLUTED TUBULE (Pump 1) active secretion of organic acids + (pump 2 ) active secretion of organic bases = EXCRETION

Hyperuricemia. Elevation of plasma uric acid is a frequent side effect of treatment. For most patients, furosemide-induced hyperuricemia is asymptomatic. However, for patients predisposed to gout, elevation of uric acid may precipitate a gouty attack.

Patients should be informed about symptoms of gout (tenderness or swelling in joints) and instructed to notify the prescriber if these develop.

Advise patients to take these drugs with or after meals if GI upset occurs.

Potassium-Sparing Diruertics

Drug interactions w/ thiazides

Same as loop except for Ototoxic Drugs.

Baseline Data for Potassium-sparing diuretics

Serum potassium weight blood pressure (sitting and supine) pulse respiratio sodium chloride. For patients with edema, record sites and extent of edema.

Furosemide acts in the thick segment of the ascending limb of Henle's loop to block reabsorption of sodium and chloride. By blocking solute reabsorption, furosemide prevents passive reabsorption of water.

Since a substantial amount (20%) of filtered NaCl is normally reabsorbed in the loop of Henle, interference with reabsorption here can produce profound diuresis.

Before menopause, estrogen from the ovaries acts on renal tubules to promote calcium reabsorption. When menopause occurs, estrogen levels drop, allowing renal excretion of calcium to increase. The resultant decrease in circulating calcium promotes mobilization of calcium from bone, and thereby increases the risk of osteoporosis.

Since thiazides promote renal calcium retention, they may counteract the calcium loss associated with menopause, and may thereby help preserve bone integrity.

Furosemide increases urinary excretion of magnesium, posing a risk of magnesium deficiency

Symptoms include: muscle weakness, tremor, twitching, and dysrhythmias.

Furosemide [Lasix] is available in: TABLETS (20, 40, and 80 mg) and in SOLUTION: (10 mg/mL) for oral use.

The initial dosage for adults is 20 to 80 mg/day as a single dose. The MAX DOSE 600 mg. Twice-daily dosing (8:00 AM and 2:00 PM) is common.

Hyperglycemia. Elevation of plasma glucose is a potential, albeit uncommon, complication of furosemide therapy. Hyperglycemia appears to result from inhibition of insulin release. Increased glycogenolysis and decreased glycogen synthesis may also contribute.

When furosemide is taken by a diabetic patient, he or she should be especially diligent about monitoring blood glucose content.

Ototoxicity. Rarely, loop diuretics cause hearing impairment.

With *furosemide*, deafness is TRANSIENT With *ethacrynic acid* (another loop diuretic), *irreversible hearing loss may occur*. The ability to impair hearing is unique to the loop diuretics. Diuretics in other classes are not ototoxic. Because of the risk of hearing loss, *caution is needed when loop diuretics are used in combination with other ototoxic drugs* (eg, aminoglycoside antibiotics).

There is no benefit to combining furosemide with

another loop diuretic.

Hydrochlorothiazide promotes urine production by

blocking the reabsorption of sodium and chloride in the early segment of the distal convoluted tubule Retention of sodium and chloride in the nephron causes water to be retained as well, thereby producing an increased flow of urine. Since only 10% of filtered sodium and chloride is normally reabsorbed at the site where thiazides act, the maximum urine flow these drugs can produce is lower than with the loop diuretics.

In addition to the nephrons, the collecting ducts (the tubules into which the nephrons pour their contents) play a critical role in kidney function. The *final segment of the distal convoluted tubule* plus the *collecting duct into which it empties*

can be considered a single functional unit: THE DISTAL TUBULE

At the same time, that aldosterone aldosterone stimulates the reasborption of sodium from the distal nephron, it

causes potassium to be secreted Although not directly coupled, these two processes—sodium retention and potassium excretion—can be viewed as an exchange mechanism.

Potassium-sparing diuretics are given primarily to

counterbalance the potassium-losing effects of thiazide diuretics and loop diuretics.

The descending limb of the loop of Henle is freely permeable to water. Hence, as tubular urine moves down the loop and passes through the hypertonic environment of the renal medulla, water is drawn from the loop into the interstitial space. This process

decreases the volume of the tubular urine and causes the urine to become concentrated (tonicity increases to about 1200 mOsm/L).

*Filtration* occurs at the

glomerulus 1st STEP in urine formation.

ADH

has little to do with the actions of diuretics.

Dehydration as seen as an adverse effect in loop can promote *thrombosis and embolism*. Symptoms include

headache and pain in the chest, calves, or pelvis. The prescriber should be notified if these develop.

Furosemide increases urinary excretion of calcium. This action has been exploited to treat

hypercalcemia.

Furosemide is a powerful drug that is generally reserved for situations that require rapid or massive mobilization of fluid. This drug should be avoided when

less efficacious diuretics (thiazides) will suffice.

Furosemide reduces high-density lipoprotein (HDL) cholesterol and raises

low-density lipoprotein (LDL) cholesterol and triglycerides. Although these undesirable effects by themselves can increase the risk of coronary heart disease, they are more than balanced by the beneficial effects of the diuretic therapy on the heart. That is, despite adverse effects on lipids, loop diuretics reduce the risk of coronary mortality by 25%.

When administered to pregnant laboratory animals, loop diuretics have caused

maternal death, abortion, fetal resorption, and other adverse effects. There are no definitive studies on loop diuretics during human pregnancy. However, given the toxicity displayed in animals, prudence dictates that pregnant patients use these drugs only if absolutely required.

Spironolactone (postassium sparing D) may cause Endocrine Effects. -

menstrual irregularities and impotence. Inform patients about these effects, and instruct them to notify the prescriber if they occur.

The basic functional unit of the kidney is the nephron.

nephron

Dosing late in the day produces

nocturia and should be avoided.

Because of its use in *hypertension* a very common disorder, hydrochlorothiazide is

one of our most widely used drugs.

Hydrochlorothiazide is supplied in capsules (12.5 mg) and tablets (12.5, 25, 50, and 100 mg). Like most other thiazides, hydrochlorothiazide is administered

only by mouth. The usual adult dosage is 25 to 50 mg once or twice daily. To minimize nocturia, the drug should not be administered late in the day. To minimize electrolyte imbalance, the drug should be administered on an intermittent basis (eg, every other day).

Thiazides are not helpful in

patients with renal failure or decreased glomular blood flow/filtation

To cleanse the entire ECF, a huge volume of plasma must be filtered. Furthermore, to maintain homeostasis,

practically everything that has been filtered must be reabsorbed—leaving behind only a small volume of urine for excretion.

Be aware that filtration is a *nonselective process*, and therefore cannot regulate the composition of urine. *Reabsorption and secretion*—processes that display a significant degree of selectivity—are the

primary determinants of what the urine ultimately contains. Of the two, *reabsorption is by far the more important*.

Without the Henle's loop orientation, (upper in the renal coretx/lower in the medulla) the kidney could not

produce concentrated urine.

More than 99% of the water, electrolytes, and nutrients that are filtered at the glomerulus undergo .

reabsorption This conserves valuable constituents of the filtrate while allowing wastes to undergo excretion.

Virtually all small molecules (electrolytes, amino acids, glucose, drugs, metabolic wastes) that are present in plasma undergo filtration. In contrast, cells and large molecules (lipids, proteins)

remain behind in the blood.

All nephrons are oriented within the kidney such that the *upper portion of Henle's loop* is located in the

renal cortex

the *lower end of the loop of henle descends toward the

renal medulla.

To min adverse effects in pt's taking potassium sparing antiD

restrict intake of potassium-rich foods. Insulin can be given to (temporarily) decrease potassium levels if exceed 5.0

Adverse Effects of thiazides

same as LOOP except no ottotoxicity

By the time the filtrate leaves the PCT,

sodium and chloride are the only solutes that remain in significant amounts.

The most prevalent constituents of the filtrate are

sodium ions and chloride ions. (NA+ Cl-) Bicarbonate (HCO3-) ions and potassium ions are also present, but in smaller amounts.

Potassium sparing D, triamterene, differs from spironolactone in that

spironolactone, reduces ion transport indirectly through blockade of aldosterone triamterene is a *direct inhibitor* of the exchange mechanism itself. The net effect of inhibition is a decrease in sodium reabsorption and a reduction in potassium secretion. Hence, *sodium excretion is increased, while potassium is conserved*. Because it inhibits ion transport directly, triamterene *acts much more quickly* than spironolactone. Initial responses develop in hours, compared with days for spironolactone. As with spironolactone, diuresis with triamterene is minimal.

Aldosterone promotes sodium-potassium exchange by

stimulating cells of the DISTAL NEPHRON to *synthesize more of the pumps* responsible for sodium and potassium transport.

the maximum diuresis produced by the thiazides is considerably lower

than the maximum diuresis produced by the loop diuretics.

The increase in urine flow that a diuretic produces is directly related to

the amount of sodium and chloride reabsorption that it blocks. Accordingly, drugs that block solute reabsorption to the greatest degree produce the most profound diuresis.

Furosemide is especially useful in patients with severe renal impairment, since, unlike the thiazides,

the drug can promote diuresis even when renal blood flow and glomerular filtration rate (GFR) are low.

The thiazide diuretics (also known as benzothiadiazides) have effects similar to those of the loop diuretics. Like the loop diuretics, thiazides increase renal excretion of 1. sodium, 2. chloride, 3. potassium, and 4. water. In addition, *thiazides elevate plasma levels of uric acid and glucose*. The principal difference between the thiazides and loop diuretics is that

the maximum diuresis produced by the thiazides is considerably lower than the maximum diuresis produced by the loop diuretics. In addition, whereas loop diuretics can be effective even when urine flow is decreased, thiazides cannot.

As sodium, chloride, and other solutes are actively reabsorbed, water follows passively. Since solutes and water are reabsorbed to an equal extent,

the tubular urine remains isotonic (300 mOsm/L).

The *loop agents* are the most *effective diuretics available*. These drugs produce more loss of fluid and electrolytes than any other diuretics. They are known as loop diuretics because

their site of action is in the loop of Henle.