(1)
University of Ottawa The Ottawa Hospital, Ottawa, ON, Canada
Diuretics have appropriately maintained a stable place in the management of hypertension and heart failure (HF) because of their proven efficacy and low cost. The aldosterone antagonists spironolactone and its analog eplerenone are diuretics but have added actions that improve myocardial function and are an important part of our armamentarium for the management of patients with HF and hypertension. Loop diuretics are a mainstay for the management of HF; they are powerful agents, however, and serum potassium must not be allowed to fall <3.5 mEq/L (mmol/L). The same caution is needed for thiazide use for the management of hypertension.
Aldosterone antagonists produce salutary effects in selected patients with HF but carry a risk of hyperkalemia that can be avoided by a watchful clinician. Importantly, among inpatients with acute myocardial infarction (MI), the lowest mortality was observed in those with postadmission serum potassium levels between 3.5 and <4.5 mEq/L compared with those who had higher or lower potassium levels. Rates of ventricular fibrillation or cardiac arrest were higher only among patients with potassium levels of less than 3.0 mEq/L and at levels of 5.0 mEq/L or greater (Goyal et al. 2012).
The generic and trade names of available diuretics are listed in Table 7-1.
Table 7-1
Generic and trade names of diuretics
Generic name | Trade name | Tablets | Usual maintenance (mg daily) |
|---|---|---|---|
Group I: thiazides | |||
Chlorothiazide | Diuril, Saluric | 250, 500 | 500–1,000 |
Hydrochlorothiazide | Hydrodiuril, Hydrosaluric, Esidrix, Oretic, Direma | 25, 50, 100 | 12.5–25 |
Bendrofluazide | Aprinox, Berkozide, Centyl, Neo-Naclex | 2.5, 5 | 2.5–5 |
Bendroflumethiazide | Naturetin | 2.5, 5, 10 | 2.5–10 |
Benzthiazide | Aquatag, Exna, Hydrex | 50 | 50–100 |
Cyclothiazide | Anhydron | 2 | 2 |
Hydroflumethiazide | Diurcardin, Hydrenox, Saluron | 50 | 50 |
Chlorthalidone | Hygroton | 25, 50, 100 | 25–50 |
Methyclothiazide | Enduron, Aquatensen, Diutensen-R | 2.5, 5 | 2.5–5 |
Polythiazide | Renese, Nephril | 1, 2, 4 | 0.5–4 |
Trichlormethiazide | Naqua, Metahydrin | 2, 4 | 2–4 |
Cyclopenthiazide | Navidrex, Navidrix | 0.5 | 0.5–1 |
Metolazone | Zaroxolyn, Metenix | 2.5, 5, 10 | 2.5–5 |
Quinethazone | Aquamox, Hydromox | 50 | 50–100 |
Indapamide | Lozol, Natrilix, Lozide (C) | 2.5 | 2.5 |
Group II: loop diuretics | |||
Furosemide | Lasix, Dryptal | 20, 40, 80 | 40–120 |
Frusemide (UK) | Frusetic, Frusid | 500 | |
Ethacrynic acid | Edecrin | 25, 50 | 50–150 |
Bumetanide | Burinex, Bumex | 0.5, 1, 5 | 1–2 |
Piretanide | Arlix | 6 (capsule) | 6–12 |
Torsemide | Demadex | 5, 10, 20, 100 | 5–20 |
Group III: K + -sparing diuretics | |||
Spironolactone | Aldactone | 25, 50 (UK), 100 | 25–100 |
Triamterene | Dyrenium, Dytac | 50, 100 | 50–100 |
Amiloride | Midamor | 5 | 5–10 |
Eplerenone | Inspra | 25 | 50 |
Group IV | |||
Thiazide + K+ sparing | Aldactazide, Dyazide, Moduretic, Moduret | ||
Frusemide + K+ sparing | Frumil, Frusene, Lasoride | ||
Group V | |||
Acetazolamide | Diamox | 250 | – |
Indications
Hypertension
In ALLHAT (2002 ), 33,357 hypertensive patients of mean age 67 were randomized to receive the diuretic, chlorthalidone, 12.5–25 mg/day (n = 15,255); amlodipine, 2.5–10 mg/day (n = 9,048); or lisinopril, 10–40 mg/day (n = 9,054) with a follow-up of 4.9 years. There was good representation for women (47 %) and blacks (35 %); 36 % were diabetics. The primary outcome combined fatal coronary heart disease (CHD) or nonfatal myocardial infarction (MI) occurred in 2,956 participants, with no difference between treatments:
All-cause mortality did not differ between groups. Diuretics proved as effective in controlling blood pressure to goal levels, and outcomes were similar to calcium antagonist or angiotensin-converting enzyme (ACE) inhibitor therapy (ALLHAT 2002).
A diuretic is the drug of choice for the initial treatment in individuals of African origin over age 60, because these agents have been shown to be more effective than the three other agents (calcium antagonists, beta-blockers, and ACE inhibitors or angiotensin receptor blockers) available for the management of hypertension. Diuretics are not as effective in the younger individuals of African origin. A diuretic is necessary for the management of hypertension in patients with HF or edema and in patients who have not responded adequately to one of the three commonly used antihypertensive agents.
Elderly hypertensives.
Diuretics have shown beneficial effects in elderly hypertensive patients beyond age 80.
In HYVET, a double-blind, randomized, placebo-controlled clinical trial involving 3,845 patients 80 years of age or older with hypertension, the effect of stepped-care therapy, beginning with the diuretic indapamide and adding perindopril as needed, was assessed. Active treatment, as compared with placebo, caused a modest reduction in risk.
Treatment was associated with a 21 % reduction in the relative risk of death from any cause, a 64 % reduction in the relative risk of heart failure, and a 30 % reduction in the relative risk of stroke (Beckett et al. 2002).
Heart Failure
Management and relief of symptoms of HF: dyspnea, orthopnea, paroxysmal nocturnal dyspnea, and edema.
Spironolactone and eplerenone have been shown to have an important role in the management of class III and IV HF.
Edema due to renal dysfunction or ascites due to cirrhosis.
Note: edema of the legs presumed to be caused by HF, edema resulting from obstruction of venous return, and dependent edema caused by lack of muscle pump action are some of the most common reasons for diuretic abuse.
Cautions
Cardiac tamponade: when the jugular venous pressure (JVP) is grossly raised (>7 cm) and the patient is not responding to conventional therapy for HF, before giving diuretics to such patients, consideration should be given to a diagnosis of cardiac tamponade or constrictive pericarditis.
Cardiomyopathy: obstructive and restrictive.
Tight mitral stenosis or aortic stenosis.
Ascites with impending hepatic coma.
Edema with acute renal failure.
Pulmonary embolism with shortness of breath: edema caused by cor pulmonale should not be treated aggressively with diuretics. Correct the hypoxemia, and then try to accomplish a very mild diuresis over several weeks.
Monitor intensive diuretic therapy as follows: if any of the following six-point checklist occurs, discontinue diuretics for 24 h and then recommence at approximately half the dose.
1.
Systolic blood pressure is <95 mmHg or orthostatic hypotension is present.
2.
More than 2-kg weight loss per day is associated with symptoms (1 kg of water loss = 140–150 mEq (mmol) of Na+ loss in the presence of normal serum Na+).
3.
Electrolytes:
(a)
Blood urea: >7.0 mmol/L from baseline.
(b)
Serum chloride (Cl–): <94 mEq (mmol)/L.
(c)
Serum sodium (Na+): <128 mEq (mmol)/L.
(d)
Serum potassium (K+): <3.2 mEq (mmol)/L.
(e)
CO2: >32 mEq (mmol)/L.
(f)
Uric acid: >8 mg/dL (464 mmol/L).
(g)
JVP is <1 cm if previously raised. The Frank–Starling compensatory mechanism is lost if diuresis is too excessive and filling pressures fall below a critical point, thereby causing cardiac output and tissue perfusion to fall.
4.
Arrhythmias develop or worsen.
5.
The 24-h urinary Na+ excretion is >150 mEq (mmol).
For the management of moderate-to-severe HF with bilateral edema and pulmonary crepitations, the goal should be
6.
Weight loss, a little more than 1 kg/day for 3 days and then 0.5 kg/day for 7 days, with a minimum of 4 kg to a maximum of 10 kg in 10 days.
Note: a 24-h urinary Na+ excretion < 20 mEq (mmol) indicates inadequate diuretic therapy; 24-h urinary excretion > 100 mEq (mmol), with no weight loss, requires reduction of Na+ intake. This estimation is, however, seldom required.
Thiazides
The thiazide diuretics are shown in Table 7-1. They inhibit sodium reabsorption at the beginning of the distal convoluted tubule (see Fig. 7-1). Thiazides and related diuretics are ineffective if eGFR is less than 30 mL/min/1.73 m2 and should be avoided; metolazone, however, remains effective. Metolazone is effective for resistant edema or heart failure when combined with a loop diuretic, even in renal failure. Profound diuresis can occur, however; thus, the patient should be monitored closely.
Fig. 7-1.
The nephron and the site of action of diuretics. 1, single nephron; 2, the kidney: one million nephrons; 3, distal tubule site of action of aldosterone, spironolactone, and eplerenone; 4, amiloride and triamterene; 5, efferent arteriole; 6, macula densa; 7, glomerular capillaries; 8, afferent arteriole; 9, thiazides; 10, loop diuretics, distal tubule; 11, ascending limb; 12, loop of Henle; 13, collecting tubule; 14, to the renal pelvis; 15, to the ureter; 16, the bladder; asterisk, distal tubule: H2O reabsorption under control of vasopressin. Reproduced with permission from Khan MG, Encyclopedia of Heart Diseases, 2nd edition. New York: Springer Science + Business Media; 2011, p. 417. With kind permission from Springer Science + Business Media.
Chlorthalidone appears to have slightly more antihypertensive effects than hydrochlorothiazide (see chapter 8 discussion of resistant hypertension).
Indapamide and xipamide are chemically related to chlorthalidone. Indapamide is claimed to be effective with less metabolic disturbances.
Thiazides are further discussed in Chap. 8.
Loop Diuretics
The rapid onset of action of loop diuretics, together with their potency in the presence of normal and abnormal renal function and their venodilator effect, renders them more effective than thiazides for the management of acute and chronic HF and life-threatening pulmonary edema.
Mechanism of Action
Loop diuretics inhibit the Na+/K+/C1− transport system of the luminal membrane in the thick ascending loop of Henle, and thus they block Cl− reabsorption at the site where approximately 40 % of filtered Na+ is normally reabsorbed (Fig. 7-1). Loop diuretics, through their action on Na+–Cl− cotransport, inhibit Ca2+, K+, and Mg2+ reabsorption in the loop where some 25 % of filtered K+, 25 % of Ca2+, and 65 % of Mg2+ are normally reabsorbed.
Drug name: | Furosemide; frusemide |
Trade name: | Lasix |
Supplied: | 20, 40, 80, 500 mg |
Dosage: | 20, 40, or 80 mg after food each morning; maintenance 20–40 mg daily or every second day; see text for further advice |
Dosage (Further Advice)
Patients with severe HF may require between 80 and 160 mg furosemide daily, rarely 240 mg daily for a few days, and then a lower maintenance dose. In such patients, it is preferable to give the total dose of furosemide as one dose each morning. If a second dose is necessary, this should be given before 2 PM to avoid bothersome nocturia. Hypokalemia is more common with twice-daily dosage. Also, if the patient was formerly resistant to 80 mg, the renal tubule may be resistant to the 80 mg given later in the day. If a dose of furosemide >60 mg/day is predicted to be necessary for several weeks, then it is advisable to add a K+-sparing diuretic or ACE inhibitor. This will increase diuresis by inhibiting aldosterone and at the same time will conserve K+.
The addition of spironolactone or eplerenone to the HF regimen of beta-blocker, ACE inhibitor, and furosemide has been shown to improve survival.
Intravenous (IV) Dosage
Ampules are available in 10 mg/mL, 20 mg/2 mL, 40 mg/4 mL, and 250 mg/25 mL. The IV dose is given slowly (20 mg/min), and if renal failure is present, it should not exceed 4 mg/min (to prevent ototoxicity).
Action and Pharmacokinetics
Furosemide inhibits Na+ and Cl− reabsorption from the ascending limb of the loop of Henle with, in addition, weak effects in the proximal tubule and the cortical diluting segment. The drug is excreted by the proximal tubule. Because of the site and potency of action, loop diuretics are much more effective than thiazides when the glomerular filtration rate (GFR) is markedly reduced. Loop diuretics remain effective even at GFRs as low as 10 mL/min (Maclean and Tudhope 1983). If a diuretic is required in a patient with a serum creatinine level > 2.3 mg/dL (203 μmol/L), it is reasonable to choose furosemide. Furosemide is also used in preference to thiazide as maintenance therapy in patients with moderate-to-severe or recurrent HF, that is, in patients in whom further episodes may be predicted because of the extent of cardiac disease. IV furosemide has a venodilator effect, and, when it is given to patients with pulmonary edema, relief may appear in 5–10 min.
Intravenous Indications
This route is indicated in emergency, life-threatening situations, such as the following:
Pulmonary edema or interstitial edema resulting from left ventricular failure
Severe HF. with poor oral absorption
Hypertensive crisis
Hypercalcemia and hyperkalemia
In addition to the mechanism of action of loop diuretics outlined earlier, furosemide causes venodilation. This action involves prostaglandins and can be inhibited by nonsteroidal antiinflammatory drugs (NSAIDs). Furosemide has a half-life of 1.5 h and a duration of action of 4–6 h. Diuresis commences some 15–20 min after IV administration, but relief of shortness of breath may be apparent within 10 min because of an increase in systemic venous capacitance, reduced cardiac preload, and a decrease in left atrial pressure. After oral administration, diuresis peaks in 60–90 min.
Contraindications:
Hepatic failure.
Hypokalemia or electrolyte depletion, hyponatremia, or hypotension.
Hypersensitivity to furosemide or sulfonamides.
In women of child-bearing potential, except in life-threatening situations, in which IV furosemide may be absolutely necessary. Furosemide has caused fetal abnormalities in animal studies.
Warnings:
Commence with a minimum dose of 20–40 mg, especially in the elderly.
Monitor electrolytes, blood urea, creatinine, complete blood counts, and uric acid, especially when the dose exceeds 60 mg daily.
Adverse Effects
Hypokalemia, dehydration, anemia, leukopenia, thrombocytopenia, rare agranulocytosis, and thrombophlebitis have been noted, but aplastic anemia seems to be more common with thiazides than with furosemide. Hypotension, hyperuricemia and precipitation of gout, and hypocalcemia and precipitation of nonketotic hyperosmolar diabetic coma may occur. Table 7-2 summarizes the metabolic adverse effects.
Table 7-2
Diuretic-induced metabolic adverse effects
• Hypokalemia |
• Hyponatremia |
• Hypochloremic metabolic alkalosis: |
Cl− < 94 mEq (mmol)/L |
CO2 > 32 mEq (mmol)/L |
• Azotemia |
• Hyperuricemia |
• Hypomagnesemia |
• Dyslipidemia |
• Glucose intolerance |
• Nonketotic hyperosmolar coma |
• Hypocalcemia (loop diuretics) |
• Hypercalcemia (thiazides) |
• Hyperkalemia (K+-sparing diuretics) |
Drug Interactions
1.
Use carefully in the presence of renal dysfunction when combined with cephalosporin or aminoglycoside antibiotics, because increased nephrotoxicity has been noted.
2.
Care should be taken when loop diuretics or thiazides are given to lithium-treated patients. The decreased Na+ reabsorption in the proximal tubules causes an increased reabsorption of lithium and may cause lithium toxicity (Kerry et al. 1980). Patients receiving concomitant chloral hydrate may experience hot flushes, sweating, and tachycardia. Prostaglandin inhibitors indomethacin and other NSAIDs antagonize the actions of loop diuretics as well as thiazides (Yeung Laiwah and Mactier 1981).
3.
The effects of tubocurarine may be increased.
Drug name: | Bumetanide |
Trade names: | Burinex, Bumex |
Supplied: | Tablets: 0.5, 1, and 5 mg Ampules: 2, 4, 10 mL; 500 mg/mL |
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