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A Fresh Look at Diuretics
by Arline Kaplan
Geriatric Times March/April 2001 Vol. II Issue 2
Although physicians have relied on diuretics to treat hypertension and edema for more than 50 years, there are still new techniques and fine points to learn, particularly when using diuretics to treat older adults, according to nephrologist Christian W. Mende, M.D.Mende-clinical professor of medicine at the University of California, San Diego, and board certified in internal medicine, nephrology, geriatrics and hypertension-discussed techniques to improve the efficacy and safety of diuretics at the Second Annual U.S. Geriatric & Long-Term Care Congress in Las Vegas.
"Diuretics are actually compounds that increase the urinary salt excretion, and water just happens to come along," he said. "Chemically, diuretics are organic anionic compounds."
Each class of diuretics has a distinct site of action in the nephron (Figure). For example, acetazolamide (Diamox) works in the proximal tubule. Furosemide (Lasix), bumetanide (Bumex), ethacrynic acid (Edecrine) and torsemide (Demadex) work in the loop of Henle. Thiazide diuretics, such as metolazone (Mykrox, Zaroxolyn), chlorthalidone (Hygroton) and hydrochlorothiazide (Hydrodiuril, Microzide), block the reabsorption of sodium in the early distal tubule. Potassium-sparing(K-sparing) diuretics, such as amiloride (Midamor) (in combination with hydrochlorothiazide in Moduretic), triamterene (Dyrenium) (in combination with hydrochlorothiazide in Maxzide, Dyazide) and spironolactone (Aldactone) (in combination with hydrochlorothiazide in Aldactazide), act in the collecting duct, thereby preventing some of the exchange of sodium for potassium that occurs in this portion of the nephron. The K-sparing diuretics, Mende added, are sodium channel blockers.
All diuretics are secreted by the proximal tubule and are effective from the luminal site of tubules, thus blocking the reabsorption of salt and water. As soon as diuresis is induced, the body begins to counteract that process (Mende, 1990).
"Your body very quickly, by the second and third doses, has less of a response to the diuretic," Mende explained. It tries to preserve intravascular volume through renin secretion, increased filtration fraction, a decrease in renal cortical blood flow, activation of the renal tubular sodium/potassium pump and aldosterone secretion.
To help reduce the body's defensive response, physicians may use two or three different types of diuretics at the same time.
"You use a loop diuretic plus a thiazide together, and you could add triamterene or Aldactone to that. Then you have three different diuretics blocking; we call this sequential nephron blocking," said Mende. This sequential blocking process should occur only in the hospital, he added, since patients are likely to lose a lot of potassium, and their electrolytes need to be monitored carefully.
Mannitol and Acetazolamide
Following his introductory remarks, Mende discussed appropriate and inappropriate uses of specific diuretics.
The osmotic diuretic mannitol can only be given intravenously, he said. It is used primarily in trauma when patients are experiencing hypotension and oliguria, during renal artery or aortic aneurysm repair, in reduction of brain edema from trauma, as an antidote for ciguatera poisoning (a gastrointestinal and neurological syndrome that accounts for 25% of all food poisoning from fish), and for rhabdomyolysis, which can occur in cocaine use or result from a crush injury.
Mannitol is not used in an edematous state, however, because it does not promote sodium excretion to a great extent. It is, therefore, of limited use in congestive heart failure (CHF).
Mende next discussed acetazolamide, a carbonic anhydrase inhibitor that inhibits hydrogen ion secretion and lowers serum bicarbonate levels.
"A patient who goes on Diamox has a very alkaline urine, with bicarbonate loss, and the serum bicarbonate drops," Mende said. The diuretic action of acetazolamide stops with serum bicarbonate levels below 22 mEq/L, however.
Clinical uses of the diuretic include alkalization of the urine in myoglobinuria (e.g., crush injuries, cocaine abuse) and in uric acid nephropathy, as well as in aspirin or barbiturate overdose. One of Mende's favorite uses of the drug is as an adjunct in refractory CHF for hospitalized patients receiving large doses of furosemide and thiazides. If they are on metolazone plus furosemide or a thiazide comorbation, they develop contraction alkalosis, and their serum bicarbonate levels can go up to 30 mEq/L or higher, he stated.
"So you add now Diamox, 250 mg every eight hours, to the Lasix and thiazide. You will achieve another liter or two of urine; in addition, you will lower the bicarb [level] from 40 down to 30 down to 25. And after two or three days, you have normal acid-based status and additional diuresis," he said. "And when you do that, you [had] better use 100 [mEq] or 150 mEq of potassium daily."
Acetazolamide, according to Mende, is also useful in high-altitude sickness. It induces a metabolic acidosis which stimulates the respiratory drive and diminishes altitude-induced hypoxemia. Rare side effects of acetazolamide are paresthesias, kidney stones (citrate deficiency) and encephalopathy with coma.
"I have seen two cases and [am aware of] 30 reports of coma on Diamox…So if somebody develops coma, is aged 75 or older and was started on Diamox, think of that as a rare cause of drug-induced coma. When you stop the Diamox, the patient wakes up," he said.
With all diuretics, Mende warned, creatinine levels and electrolytes, including magnesium, should be closely monitored.
"If you use hydrochlorothiazide for hypertension and edema in a patient with creatinine levels above 2 mg/dL, little happens. It just doesn't work anymore if the patient's kidney function is less than 30%," he said. "Metolazone usually costs four times as much as hydrochlorothiazide, but metolazone works all the way to 10% of kidney function. So if you have a creatinine [level] of 2 [mg/dL] or higher, and you need a diuretic, you have two choices, metolazone or all the loop diuretics. Chlorthalidone is much longer acting (up to 36 hours). I have seen the worst hypokalemias ever with it because this drug never quits working," Mende said.
If thiazides are used for hypertension and to reduce urinary calcium excretion by 50% in calcium oxalate stone formers, doses of 12.5 mg qd to 25 mg qd of hydrochlorothiazide are sufficient, according to Mende.
"If you go to the huge doses like we used to do 10 to 15 years ago, all you get is hypokalemia, hypomagnesemia and complications like high uric acid levels. So the way to go is to use low doses," he said.
Eventually, in hypertension, the hydrochlorothiazide dose should be reduced to 6.25 mg qd or 12.5 mg qd, since it is then being used as a vasodilator rather than a diuretic.
The number-one side effect of thiazides is mild hypercalcemia.
"If you see someone with an elevated calcium, look at their drugs, and they are usually on a thiazide. If that is the case, don't do any workup; stop the thiazide; and give them Lasix or Bumex, which reduce calcium. If the calcium comes back to normal [8.4 mg/dL to 10.6 mg/dL], it was the thiazide. If the calcium does not come back to normal within a week, that person deserves a parathyroid test, looking for hyperparathyroidism."
Other side effects of thiazides include photosensitivity and, rarely, leukopenia and pancreatitis.
Loop Diuretics
Although furosemide, bumetanide, ethacrynic acid and torsemide work at different sites, Mende stated, "If you give someone 40 mg per day of Lasix and at the same time 2 mg per day of Bumex, you are wasting one…please decide which one you want to use."
Clinical uses of the loop diuretics include azotemia, acute renal failure with oliguria, acute pulmonary edema, hyponatremia, hypercalcemia (as long as you accompany therapy with a saline infusion) and congestive heart failure.
The loop diuretics "are very potent even in people with terrible kidney function," Mende said.
He explained that the higher the patient's creatinine levels, the higher the dose of loop diuretics needed.
"With Lasix, you can give 140 mg to 160 mg IV, and then go to 200 mg to 300 mg of Lasix IV for 24 hours for patients with reduced renal function," he said.
For patients with acute pulmonary edema, Mende said he uses IV bumetanide, which works within five minutes. It serves as a vasodilator, lowers intrathoracic pressure and stimulates prostaglandin.
For patients with CHF, Mende said he generally uses a loop diuretic instead of a thiazide, because, "you need a powerful diuretic to deal with the edema, low cardiac output and reduced renal function."
Frequently, Mende will combine types of diuretics. While thiazides don't generally work with serum creatinine levels above 2 mg/dL, they do work if they are combined with loop diuretics, he said.
Mende generally uses a twice-daily dose of loop diuretics when treating patients with CHF.
"You are better off to dose bid, because the drug only works for eight hours and the other 16 hours, the kidneys hold onto salt and water," he said.
While loop diuretics can improve hyponatremia, Mende warned that if the patient's sodium falls below 120 mEq/L, do not attempt to correct the levels in one day. If you do it faster than 12 mEq/L per 24 hours, the patient may develop a syndrome called central pontine myelinolysis, which can lead to irreversible degeneration of nerve fibers.
For patients with reduced renal function or renal failure or following open-heart surgery, Mende said it is appropriate to consider continuous infusion of loop diuretics after an IV bolus (e.g., 5 mg of IV Bumex or 100 mg or 200 mg of IV Lasix).
"Once they have a good diuresis, you can then hang up a drip of 1 mg of Bumex per hour, or 20 [mg] of Lasix IV per hour…What is the magic of the continuous drip? The magic is the urine volume is 10% greater and the sodium excretion is 20% greater than intermittent dosing…But you need to start bolusing first," he said. "I see this mistake all the time. If you hang up a drip of 1 mg of Bumex or 20 mg of Lasix per hour right off the bat, without an initial bolus, it will take you four to five hours to start to see diurese."
Specific side effects of loop diuretics, according to Mende, include rare interstitial nephritis (with furosemide) and ototoxicity in high doses, particularly with aminoglycocide cotreatment.
Potassium-Sparing Diuretics
The K-sparing diuretics are weak diuretics alone, Mende explained, because they work in the collecting ducts where only 3% of the filtered load is processed. They are primarily used as adjuncts to thiazides and loop diuretics or for potassium and magnesium spacing. Instead of using thiazides alone for hypertension, Mende suggested combining with triamterene.
Spironolactone is making a tremendous rebirth, Mende said, because it reduces scarring and fibrosis in the heart. By reducing scarring and fibrosis, you are also reducing the arrhythmias seen with CHF.
Amiloride can be used for magnesium deficiency because it increases renal reabsorption. If you have somebody who has hypomagnesemia, and you can't give them enough magnesium orally, because of laxative action, give amiloride, Mende suggested.
Also, amiloride is useful for patients taking lithium who have polyuria and complain of having to get up three or four times at night. At a dose of 5 mg bid, amiloride reduces urine volume by 30%, Mende said, adding that loop or thiazide diuretics are contraindicated in patients taking lithium, because the drugs alter lithium levels.
"Don't use any K-sparing diuretics with angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers [or] nonsteroidals," Mende warned. He also cautioned against using them when serum creatinine levels are above 2 mg/dL.
Specific side effects seen with K-sparing diuretics include hyperchloremic acidosis; hyperkalemia, especially if administered with an ACE inhibitor, angiotensin II receptor blocker or in patients with diabetes; gynecomastia, impotence in men or irregular menstrual cycles in women (only with use of spironolactone); folic acid deficiency (with chronic use of triamterene); or acute renal failure (with triamterene when used with indomethacin [Indocin]).
Throughout his talk, Mende offered some general guidelines to clinicians.
- Tell your patients that they can neutralize every single diuretic by high salt intake, so tell them to take it easy on salt and to drink only when they are thirsty, unless they are exercising.
- Potassium levels should be maintained at 3.5 mEg/L or higher in coronary artery disease with a history of arrhythmias, during anesthesia, and in patients who have diabetes or hypokalemia. Magnesium levels should also be in the high normal range to suppress arrhythmias, particularly in the post myocardial infarction patient.
- Nearly all diuretics are derivatives of sulfa drugs. For patients who have a rare cross-reactivity and who have hypertension or CHF, Mende relies on ethacrynic acid for patients allergic to sulfa-containing diuretics.
- Recognize that nonsteroidal agents reduce diuretic efficiency by up to one-third because they hold on to salt and water and they block prostaglandins.
- For patients with severe CHF who are receiving diuretics, do not forget the value of bed rest, elevation of the legs and the use of compression (elastic bandage, stockings) to mobilize fluids.
Reference
Mende CW (1990), Current issues in diuretic therapy. Hosp Pract (Off Ed) 25(suppl 1):15-21 [see discussion pp30-31].
