Diuretics Flashcards
Diuretics alter physiologic renal mechanisms to increase the flow of urine with greater excretion of sodium (natriuresis, Fig. 4-1).
Diuretics alter physiologic renal mechanisms to increase the flow of urine with greater excretion of sodium (natriuresis, Fig. 4-1).
Diuretics have traditionally been used in the treatment of symptomatic heart failure with fluid retention, added to standard therapy such as angiotensin-converting enzyme (ACE) inhibition.
Diuretics have traditionally been used in the treatment of symptomatic heart failure with fluid retention, added to standard therapy such as angiotensin-converting enzyme (ACE) inhibition.
In hypertension, diuretics are recommended as first-line therapy, especially because a network metaanalysis found low-dose diuretics the most effective first-line treatment for prevention of cardiovascular complications. However, increased awareness of diuretic-associated diabetes has dampened but not extinguished enthusiasm for first-line diuretics. New diabetes is an even greater risk of diuretic–β-blocker combinations for hypertension (see Chapter 7, p. 257). Thus current emphasis is toward diuretic combinations with ACE inhibitors or angiotensin receptor blockers (ARBs) to allow lower diuretic doses, to reduce the blood pressure (BP) quicker, and to offset adverse renin-angiotensin activation.
In hypertension, diuretics are recommended as first-line therapy, especially because a network metaanalysis found low-dose diuretics the most effective first-line treatment for prevention of cardiovascular complications. However, increased awareness of diuretic-associated diabetes has dampened but not extinguished enthusiasm for first-line diuretics. New diabetes is an even greater risk of diuretic–β-blocker combinations for hypertension (see Chapter 7, p. 257). Thus current emphasis is toward diuretic combinations with ACE inhibitors or angiotensin receptor blockers (ARBs) to allow lower diuretic doses, to reduce the blood pressure (BP) quicker, and to offset adverse renin-angiotensin activation.
Fig 4-1. s 94
Fig 4-1
Differing effects of diuretics in congestive heart failure and hypertension:
In heart failure with fluid retention, diuretics are given to control pulmonary and peripheral symptoms and signs of congestion. In noncongested heart failure, diuretic-induced ………… activation may outweigh advantages.
In heart failure with fluid retention, diuretics are given to control pulmonary and peripheral symptoms and signs of congestion. In noncongested heart failure, diuretic-induced renin activation may outweigh advantages.
Diuretics should rarely be used as monotherapy, but rather should be combined with ACE inhibitors and generally a β-blocker.
Diuretics should rarely be used as monotherapy, but rather should be combined with ACE inhibitors and generally a β-blocker.
Often the loop diuretics (Fig. 4-2) are used preferentially, for three reasons: Which ones?
Often the loop diuretics (Fig. 4-2) are used preferentially, for three reasons:
(1) the superior fluid clearance for the same degree of natriuresis;
(2) loop diuretics work despite renal impairment that often accompanies severe heart failure; and
(3) increasing doses increase diuretic responses, so that they are “high ceiling” diuretics.
Yet in mild fluid retention thiazides may initially be preferred, especially when there is a background of hypertension.
In general, diuretic doses for congestive heart failure (CHF) are higher than in hypertension.
Yet in mild fluid retention thiazides may initially be preferred, especially when there is a background of hypertension.
In general, diuretic doses for congestive heart failure (CHF) are higher than in hypertension.
Yet in mild fluid retention thiazides may initially be preferred, especially when there is a background of hypertension.
In general, diuretic doses for congestive heart failure (CHF) are higher than in hypertension.
Se Fig 4-2:
The multiple sites of action of diuretic agents
Se Fig 4-2:
The multiple sites of action of diuretic agents
In hypertension, to exert an effect, the diuretic must provide enough ……… to achieve some persistent volume ………
In hypertension, to exert an effect, the diuretic must provide enough natriuresis to achieve some persistent volume depletion.
Diuretics may also work as ………….. and in other ways. Therefore, once-daily furosemide is usually inadequate because the initial ………… loss is quickly reconstituted throughout the remainder of the day. Thus a longer-acting ………..-type diuretic is usually chosen for hypertension.
Diuretics may also work as vasodilators and in other ways. Therefore, once-daily furosemide is usually inadequate because the initial sodium loss is quickly reconstituted throughout the remainder of the day. Thus a longer-acting thiazide-type diuretic is usually chosen for hypertension.
The three major groups of diuretics are?
The loop diuretics, the thiazides, and the potassium-sparing agents. Aquaretics constitute a recent fourth.
Each type of diuretic acts at a different site of the nephron (see Fig. 4-2), leading to the concept of sequential nephron blockade. All but the ………. must be transported to the luminal side; this process is blocked by the buildup of ………….in renal insufficiency so that progressively larger doses are needed. Especially thiazides lose their potency as renal function falls.
Each type of diuretic acts at a different site of the nephron (see Fig. 4-2), leading to the concept of sequential nephron blockade. All but the potassium sparers must be transported to the luminal side; this process is blocked by the buildup of organic acids in renal insufficiency so that progressively larger doses are needed. Especially thiazides lose their potency as renal function falls.
Loop diuretics
Furosemide:
Furosemide (Lasix, Dryptal, Frusetic, Frusid), one of the standard loop diuretics for severe CHF, is a ……..derivative. Furosemide is initial therapy in acute pulmonary edema and in the pulmonary congestion of left-sided failure of acute myocardial infarction (AMI).
Furosemide (Lasix, Dryptal, Frusetic, Frusid), one of the standard loop diuretics for severe CHF, is a sulfonamide derivative. Furosemide is initial therapy in acute pulmonary edema and in the pulmonary congestion of left-sided failure of acute myocardial infarction (AMI).
Relief of dyspnea even before diuresis results from ……… and ………. reduction.
Relief of dyspnea even before diuresis results from venodilation and preload reduction.
Pharmacologic effects and pharmacokinetics:
Loop diuretics including furosemide inhibit the ………– cotransporter concerned with the transport of chloride across the lining cells of the ………..limb of the loop of Henle (see Fig. 4-2). This site of action is reached …………….., after the drug has been excreted by the ……… tubule.
Loop diuretics including furosemide inhibit the Na+/K+/2Cl– cotransporter concerned with the transport of chloride across the lining cells of the ascending limb of the loop of Henle (see Fig. 4-2). This site of action is reached intraluminally, after the drug has been excreted by the proximal tubule.
The effect of the cotransport inhibition is that …………………… all remain intraluminally and are lost in the ………. with the possible side effects of hypo……. hypo…….., hypo………, and ……..
The effect of the cotransport inhibition is that chloride, sodium, potassium, and hydrogen ions all remain intraluminally and are lost in the urine with the possible side effects of hyponatremia, hypochloremia, hypokalemia, and alkalosis.
Loop-diuretics: However, in comparison with thiazides, there is a relatively greater ….. volume and relatively less loss of ……..
However, in comparison with thiazides, there is a relatively greater urine volume and relatively less loss of sodium.
Loop-diuretics: Venodilation reduces the …….. in acute left ventricular (LV) failure within 5-15 min; the mechanism is not well understood. Conversely, there may follow a reactive vaso……….
Venodilation reduces the preload in acute left ventricular (LV) failure within 5-15 min; the mechanism is not well understood. Conversely, there may follow a reactive vasoconstriction.
Dose.
Intravenous furosemide is usually started as a slow 40-mg injection (no more than 4 mg/min to reduce ototoxicity; give 80 mg over 20 min intravenously 1 hour later if needed). When renal function is impaired, as in older adult patients, higher doses are required, with much higher doses for renal failure and severe CHF. Oral furosemide has a wide dose range (20 to 240 mg/day or even more; 20, 40, and 80 mg tablets in the United States; in Europe, also scored 500 mg tablets) because of absorption varying from 10% to 100%, averaging 50%.11 In contrast, absorption of bemetanide and torsemide is nearly complete. Furosemide’s short duration of action (4 to 5 hours) means that frequent doses are needed when sustained diuresis is required. Twice-daily doses should be given in the early morning and midafternoon to obviate nocturia and to protect against volume depletion. For hypertension, furosemide 20 mg twice daily may be the approximate equivalent of hydrochlorothiazide (HCTZ) 25 mg. Furosemide causes a greater earlier (0 to 6 hours) absolute loss of sodium than does HCTZ but, because of its short duration of action, the total 24-hour sodium loss may be insufficient to maintain the slight volume contraction needed for sustained antihypertensive action, thus requiring furosemide twice daily. In oliguria (not induced by volume depletion), as the glomerular filtration rate (GFR) drops to less than 20 mL/min, from 240 mg up to 2000 mg of furosemide may be required because of decreasing luminal excretion. Similar arguments lead to increasing doses of furosemide in severe refractory heart failure.
Dose.
Intravenous furosemide is usually started as a slow 40-mg injection (no more than 4 mg/min to reduce ototoxicity; give 80 mg over 20 min intravenously 1 hour later if needed). When renal function is impaired, as in older adult patients, higher doses are required, with much higher doses for renal failure and severe CHF. Oral furosemide has a wide dose range (20 to 240 mg/day or even more; 20, 40, and 80 mg tablets in the United States; in Europe, also scored 500 mg tablets) because of absorption varying from 10% to 100%, averaging 50%.11 In contrast, absorption of bemetanide and torsemide is nearly complete. Furosemide’s short duration of action (4 to 5 hours) means that frequent doses are needed when sustained diuresis is required. Twice-daily doses should be given in the early morning and midafternoon to obviate nocturia and to protect against volume depletion. For hypertension, furosemide 20 mg twice daily may be the approximate equivalent of hydrochlorothiazide (HCTZ) 25 mg. Furosemide causes a greater earlier (0 to 6 hours) absolute loss of sodium than does HCTZ but, because of its short duration of action, the total 24-hour sodium loss may be insufficient to maintain the slight volume contraction needed for sustained antihypertensive action, thus requiring furosemide twice daily. In oliguria (not induced by volume depletion), as the glomerular filtration rate (GFR) drops to less than 20 mL/min, from 240 mg up to 2000 mg of furosemide may be required because of decreasing luminal excretion. Similar arguments lead to increasing doses of furosemide in severe refractory heart failure.
Indications.
Furosemide is frequently the diuretic of choice for severe heart failure and acute pulmonary edema for reasons already discussed. After initial intravenous use, oral furosemide is usually continued as standard diuretic therapy, sometimes to be replaced by ……… as the heart failure ameliorates.
Furosemide is frequently the diuretic of choice for severe heart failure and acute pulmonary edema for reasons already discussed. After initial intravenous use, oral furosemide is usually continued as standard diuretic therapy, sometimes to be replaced by thiazides as the heart failure ameliorates.
In AMI with clinical failure, intravenous furosemide has rapid beneficial hemodynamic effects and is often combined with ACE inhibition. In hypertension, twice-daily low-dose furosemide can be effective even as monotherapy or combined with other agents and is increasingly needed as renal function deteriorates. In hypertensive crisis, intravenous furosemide is used if fluid overload is present. In a placebo-controlled study, high-dose furosemide given for acute renal failure increased the urine output but failed to alter the number of dialysis sessions or the time on dialysis.
In AMI with clinical failure, intravenous furosemide has rapid beneficial hemodynamic effects and is often combined with ACE inhibition. In hypertension, twice-daily low-dose furosemide can be effective even as monotherapy or combined with other agents and is increasingly needed as renal function deteriorates. In hypertensive crisis, intravenous furosemide is used if fluid overload is present. In a placebo-controlled study, high-dose furosemide given for acute renal failure increased the urine output but failed to alter the number of dialysis sessions or the time on dialysis
Contraindications?
In heart failure without fluid retention, furosemide can increase aldosterone levels with deterioration of LV function. Anuria, although listed as a contraindication to the use of furosemide, is sometimes treated (as is oliguria) by furosemide in the hope for diuresis; first exclude dehydration and a history of hypersensitivity to furosemide or sulfonamides.
Hypokalemia with furosemide.
Clearly, much depends on the doses chosen and the degree of diuresis achieved. Furosemide should not be used intravenously when electrolytes cannot be monitored. The risk of hypo…… is greatest with high-dose furosemide, especially when given intravenously, and at the start of myocardial infarction when hypo…… with risk of arrhythmias is common even in the absence of diuretic therapy.
Clearly, much depends on the doses chosen and the degree of diuresis achieved. Furosemide should not be used intravenously when electrolytes cannot be monitored. The risk of hypokalemia is greatest with high-dose furosemide, especially when given intravenously, and at the start of myocardial infarction when hypokalemia with risk of arrhythmias is common even in the absence of diuretic therapy. Carefully regulated intravenous potassium supplements may be required in these circumstances.
Loop diuretics: In heart failure, digitalis toxicity may be precipitated by ……….
In heart failure, digitalis toxicity may be precipitated by overdiuresis and hypokalemia.
Loop diuretics: Other side effects.
The chief side effects, in addition to hypokalemia, are ……… and…….
hypovolemia and hyperuricemia.
Loop diuretics. Hypovolemia, with risk of pre renal ………., can be lessened by a low starting initial dose (20 to 40 mg, monitoring blood urea). A few patients on high-dose furosemide have developed severe hyperosmolar nonketotic hyperglycemic states. Atherogenic blood lipid changes, similar to those found with thiazides, may also be found with loop diuretics. Occasionally diabetes may be precipitated.
Minimizing …………….. should lessen the risk of glucose intolerance.
Hypovolemia, with risk of prerenal azotemia, can be lessened by a low starting initial dose (20 to 40 mg, monitoring blood urea). A few patients on high-dose furosemide have developed severe hyperosmolar nonketotic hyperglycemic states. Atherogenic blood lipid changes, similar to those found with thiazides, may also be found with loop diuretics. Occasionally diabetes may be precipitated.
Minimizing hypokalemia should lessen the risk of glucose intolerance.
Furosemide (like other sulfonamides) may precipitate …………. or may cause blood dyscrasias. Reversible dose-related ……….. (electrolyte disturbances of the endolymphatic system) can be avoided by infusing furosemide at rates not greater than 4 mg/min and keeping the oral dose less than 1000 mg daily. Urinary retention may by noted from vigorous diuresis in older adults. In pregnancy, furosemide is classified as Category C. In nursing mothers, furosemide is excreted in the milk.
Furosemide (like other sulfonamides) may precipitate photosensitive skin eruptions or may cause blood dyscrasias. Reversible dose-related ototoxicity (electrolyte disturbances of the endolymphatic system) can be avoided by infusing furosemide at rates not greater than 4 mg/min and keeping the oral dose less than 1000 mg daily. Urinary retention may by noted from vigorous diuresis in older adults. In pregnancy, furosemide is classified as Category C. In nursing mothers, furosemide is excreted in the milk.
Loss of diuretic potency.
……….. is the phenomenon whereby after the first dose, there is a decrease in the diuretic response caused by ……………. activation and prevented by restoring the diuretic-induced loss of ………………
Long-term tolerance refers to increased reabsorption of ………. associated with ……….. of the distal nephron segments (see “Diuretic Resistance” later in this chapter). The mechanism may be increased growth of the nephron cells induced by increased ……………….
Loss of diuretic potency.
Braking is the phenomenon whereby after the first dose, there is a decrease in the diuretic response caused by renin-angiotensin activation and prevented by restoring the diuretic-induced loss of blood volume.
Long-term tolerance refers to increased reabsorption of sodium associated with hypertrophy of the distal nephron segments (see “Diuretic Resistance” later in this chapter). The mechanism may be increased growth of the nephron cells induced by increased aldosterone.12
Drug interactions with furosemide.
Co-therapy with certain …………. can precipitate ototoxicity. …………. may interfere with the effects of thiazides or loop diuretics by blocking their secretion into the urine of the proximal tubule.
.
Drug interactions with furosemide.
Co-therapy with certain aminoglycosides can precipitate ototoxicity. Probenecid may interfere with the effects of thiazides or loop diuretics by blocking their secretion into the urine of the proximal tubule.
………………lessen the renal response to loop diuretics, presumably by interfering with formation of vaso…………
Indomethacin and other nonsteroidal antiinflammatory drugs (NSAIDs) lessen the renal response to loop diuretics, presumably by interfering with formation of vasodilatory prostaglandins.
High doses of furosemide may competitively inhibit the excretion of ……….. to predispose to salicylate poisoning with tinnitus. Steroid or adrenocorticotropic hormone therapy may predispose to hypo…….
High doses of furosemide may competitively inhibit the excretion of salicylates to predispose to salicylate poisoning with tinnitus. Steroid or adrenocorticotropic hormone therapy may predispose to hypokalemia.
Furosemide, unlike thiazides, does not decrease renal excretion of lithium, so that lithium toxicity is not a risk. Do loop diuretics alter blood digoxin levels or interact with warfarin?
Furosemide, unlike thiazides, does not decrease renal excretion of lithium, so that lithium toxicity is not a risk. Loop diuretics do not alter blood digoxin levels, nor do they interact with warfarin.
Bumetanide
The site of action of bumetanide (Bumex, Burinex) and its effects (and side effects) are very similar to that of ……………. (Table 4-1). As with …………., higher doses can cause considerable electrolyte disturbances, including hypokalemia. As in the case of furosemide, a combined diuretic effect is obtained by addition of a thiazide diuretic. In contrast to furosemide, oral absorption is predictable at 80% or more.
Bumetanide
The site of action of bumetanide (Bumex, Burinex) and its effects (and side effects) are very similar to that of furosemide (Table 4-1). As with furosemide, higher doses can cause considerable electrolyte disturbances, including hypokalemia. As in the case of furosemide, a combined diuretic effect is obtained by addition of a thiazide diuretic. In contrast to furosemide, oral absorption is predictable at 80% or more.
Bumetanide: Dosage and clinical uses.
In CHF, the usual oral dose is 0.5 to 2 mg, with 1 mg bumetanide being approximately equal to 40 mg furosemide. In acute pulmonary edema, a single intravenous dose of 1 to 3 mg over 1 to 2 minutes can be effective; repeat if needed at 2- to 3-hour intervals to a maximum of 10 mg daily. In renal edema, the effects of bumetanide are similar to those of furosemide.
Dosage and clinical uses.
In CHF, the usual oral dose is 0.5 to 2 mg, with 1 mg bumetanide being approximately equal to 40 mg furosemide. In acute pulmonary edema, a single intravenous dose of 1 to 3 mg over 1 to 2 minutes can be effective; repeat if needed at 2- to 3-hour intervals to a maximum of 10 mg daily. In renal edema, the effects of bumetanide are similar to those of furosemide.
Side effects and cautions.
Side effects associated with bumetanide are similar to those of furosemide; ototoxicity may be less and renal toxicity more. The combination with other potentially nephrotoxic drugs, such as aminoglycosides, must be avoided. In patients with renal failure, high doses have caused myalgia, so that the dose should not exceed 4 mg/day when the GFR is less than 5 mL/min. Patients allergic to sulfonamides may also be hypersensitive to bumetanide. In pregnancy, the risk is similar to furosemide (Category C).
Side effects and cautions.
Side effects associated with bumetanide are similar to those of furosemide; ototoxicity may be less and renal toxicity more. The combination with other potentially nephrotoxic drugs, such as aminoglycosides, must be avoided. In patients with renal failure, high doses have caused myalgia, so that the dose should not exceed 4 mg/day when the GFR is less than 5 mL/min. Patients allergic to sulfonamides may also be hypersensitive to bumetanide. In pregnancy, the risk is similar to furosemide (Category C).
Conclusion.
Most clinicians will continue to use the agent they know best (i.e., furosemide). Because furosemide is widely available in generic form, its cost is likely to be less than that of torsemide or bumetanide.
Torsemide
Torsemide (Demadex) is a …… diuretic with a …………. duration of action than furosemide (see Table 4-1).
A subdiuretic daily dose of 2.5 mg may be antihypertensive and free of changes in plasma potassium or glucose, yet in the United States the only doses registered for antihypertensive efficacy are 5 to 10 mg daily. It remains uncertain whether torsemide or other loop diuretics cause less ………….. disturbances than do thiazides in equipotent doses.
Torsemide
Torsemide (Demadex) is a loop diuretic with a longer duration of action than furosemide (see Table 4-1).
A subdiuretic daily dose of 2.5 mg may be antihypertensive and free of changes in plasma potassium or glucose, yet in the United States the only doses registered for antihypertensive efficacy are 5 to 10 mg daily. It remains uncertain whether torsemide or other loop diuretics cause less metabolic disturbances than do thiazides in equipotent doses.
In heart failure, an intravenous dose of torsemide 10 to 20 mg initiates a diuresis within …….. minutes that peaks within the first hour. Similar oral doses (note high availability) give an onset of diuresis within …. hour and a peak effect within 1 to 2 hours, and a total duration of action of ………. hours.
In heart failure, an intravenous dose of torsemide 10 to 20 mg initiates a diuresis within 10 minutes that peaks within the first hour. Similar oral doses (note high availability) give an onset of diuresis within 1 hour and a peak effect within 1 to 2 hours, and a total duration of action of 6 to 8 hours.
Torsemide 20 mg gives approximately the same degree of natriuresis as does furosemide …… mg but absorption is much ………… In hypertension, an oral dose of 5-10 mg once daily may take 4-6 weeks for maximal effect. There are no long-term outcome studies available for either of these indications.
Torsemide 20 mg gives approximately the same degree of natriuresis as does furosemide 80 mg but absorption is much higher and constant. In hypertension, an oral dose of 5-10 mg once daily may take 4-6 weeks for maximal effect. There are no long-term outcome studies available for either of these indications.
In renal failure, as in the case of other loop diuretics, the ………….. of the drug falls as does the renal function. Yet the plasma half-life of torsemide is unaltered, probably because ……… clearance increases.
In renal failure, as in the case of other loop diuretics, the renal excretion of the drug falls as does the renal function. Yet the plasma half-life of torsemide is unaltered, probably because hepatic clearance increases.
In edema of hepatic cirrhosis, the dose is 5 to 10 mg daily, titrated to maximum 200 mg daily, given with aldosterone antagonist. In pregnancy, torsemide may be relatively safe (Category B versus Category C for furosemide).
In edema of hepatic cirrhosis, the dose is 5 to 10 mg daily, titrated to maximum 200 mg daily, given with aldosterone antagonist. In pregnancy, torsemide may be relatively safe (Category B versus Category C for furosemide).
Torsemide: Metabolic and other side effects, cautions, and contraindications are similar to those of ………………..
Metabolic and other side effects, cautions, and contraindications are similar to those of furosemide.
