DIURETICS+SUMMARY

Diuretics
 * History:** Diuretics can be divided into thiazide diuretics, loop or high-ceiling diuretics, distal tubule or potassium-sparing diuretics, osmotic diuretics, and carbonic anhydrase inhibitors. Before the release of the first thiazide (e.g., chlorothiazide) in 1957, carbonic anhydrase inhibitors and mercurial diuretics were the only diuretics used in clinical practice. Today, mercurial diuretics are no longer used because of their toxicity and due to the availability of other agents.

Shortly after sulfanilamide was introduced in 1939, metabolic acidosis was recognized as a side effect. It was later determined that sulfanilamide inhibited carbonic anhydrase. Carbonic anhydrase inhibitors and thiazide diuretics, both of which possess diuretic activity, are chemical derivatives sulfonamides. Acetazolamide, the most commonly-used carbonic anhydrase inhibitor today, was originally introduced in 1953. While it produces diuresis immediately, its effects are short-lived due to rapid adaptation by the nephron. As a result, carbonic anhydrase inhibitors are impractical diuretics and are used more frequently in ophthalmology because of their effects on intraocular pressure.

Thiazide diuretics were synthesized in an attempt to create more potent carbonic anhydrase inhibitors. While thiazide diuretics do not inhibit carbonic anhydrase, they nevertheless replaced mercurial diuretics since thiazides were much less toxic. Although thiazide diuretics are chemically similar to sulfonamides, thiazides possess no antimicrobial activity. After chlorothiazide was marketed in 1957, no fewer than 7 additional thiazides were released in the next several years. Today, hydrochlorothiazide is the predominant thiazide diuretic used in clinical practice.

During the 1980s, the popularity of thiazides as antihypertensive agents declined somewhat, due in part to the availability of many, new antihypertensive agents, and to the discovery that thiazides could increase serum lipids. It has since been determined that thiazides affect serum lipids only modestly and, because of their extremely low cost, they have reaffirmed their role as important agents in the treatment of hypertension.

Two distal tubule diuretics, spironolactone and triamterene, were made available in the early 1960s, followed, in the late 1960s, by 2 loop diuretics, furosemide and ethacrynic acid. Amiloride, another potassium-sparing distal tubule diuretic, was released in 1981. Additional loop diuretics were released in 1983 (bumetanide) and 1994 (torsemide). Finally, several additional sulfonamide/thiazide derivative diuretics have also been marketed: chlorthalidone, metolazone, and indapamide.

Osmotic diuretics have been available for decades. Hypertonic solutions of dextrose, glycerin, mannitol, sucrose, and urea have all been employed as osmotic diuretics. Today, mannitol is most commonly chosen when there is a need for a systemic osmotic agent. Glycerin is too rapidly metabolized to be an effective diuretic.


 * Mechanism of Action:** With the exception of mannitol and other osmotic agents, all diuretics affect electrolyte transport at the nephron epithelium. Thiazides inhibit sodium reabsorption at the cortex level, specifically, the section of the nephron just distal to the loop of Henle. Thiazides exert their actions from the luminal side of the nephron membrane, thus, they first must be filtered to reach the site of action. Metolazone, a highly-potent, long-acting thiazide, may act in the proximal tubule in addition to the distal tubule. Unlike the rest of the thiazides, metolazone maintains its effectiveness when GFR is poor, and this may be explained by its proximal site of action or, more likely, its superior potency demonstrated by the ability of metolazone to penentrate to the site of action when GFR is impaired.

Carbonic anhydrase inhibitors interfere with the actions of carbonic anhydrase in not only the renal cortex, but also in the eye, resulting in decreased aqueous humor production; and in the CNS, to control seizures and decrease the rate of formation of CSF. In the kidney, drugs such as acetazolamide enhance the clearance of sodium and bicarbonate. In the distal tubule, potassium is lost in an effort to reclaim filtered sodium.

The actions of loop diuretics can be mediated by several mechanisms operating within the thick, medullary segment of the ascending loop. These include (a) interference with Na-K-2Cl ion cotransport at the luminal surface, (b) interference with the Na-K pump, and (c) anion exchange. While furosemide appears to exert actions at all 3 sites, bumetanide and torsemide are specific for the Na-K-2Cl cotransport system. Ethacrynic acid also works at Na-K-2Cl cotransport site but by possibly a mechanism unique from the other 3 loop diuretics.

Various drug combinations can produce a powerful diuretic effect. Perhaps the most well-known diuretic combination is metolazone with a loop diuretic. Simultaneous use of metolazone with a loop-active diuretic produces extensive fluid and electrolyte loss due to the inhibition of two sequential sites within the nephron. This drug combination is often used when the response to a loop diuretic is less than desired. A similar response may be obtained when other thiazides are combined with a loop diuretic if creatinine clearance is not impaired to prevent penetration of the thiazide to the site of action. When renal plasma flow is poor, some clinicians use mannitol, an osmotic diuretic, in combination with loop diuretics in an effort to increase delivery of the loop diuretic to the site of action.


 * Distinguishing Features:** Hydrochlorothiazide is the most commonly used agent of the thiazide group. Its oral bioavailability is much better than chlorothiazide. Many other thiazides are marketed but none differs substantially from hydrochlorothiazide. In general, thiazide diuretics are ineffective in patients with creatinine clearance values less than 30 ml/min.

Several agents are often grouped with the thiazides, although they differ somewhat. Chlorthalidone is much longer acting than hydrochlorothiazide butchlorthalidone is significantly more expensive. Metolazone, another thiazide-like agent, is much more potent than hydrochlorothiazide and maintains its effectiveness when GFR is less than 30 ml/min. Metolazone is often used in combination with a loop diuretic in cases of edema refractory to other diuretics. Indapamide, a thiazide-like agent, with calcium channel blocking action, is also effective in patients with creatinine clearance values less tha 30 ml/min.

Despite several differences, the 4 loop diuretics are very similar. Aside from subtle differences in their specific sites of action, furosemide, bumetanide, and torsemide are essentially interchangeable, however, torsemide, due a longer duration of action, can be dosed once daily. Ethacrynic acid is both chemically and pharmacologically distinct from the other 3 loop-acting diuretics and some clinicians feel this drug may be effective in acute renal failure when the other three are inactive. Due to adverse reactions, ethacrynic acid has fallen out of routine use.


 * Adverse Reactions:** Aside from electrolyte imbalances, most diuretics are relatively free from adverse reactions if used appropriately. Although some clinicians believe that modest hypokalemia represents a significant loss of total body potassium, a review of numerous studies indicates that this is not significant with thiazide diuretics; only 5% of total body potassium is lost.[996] Electrolyte loss, however, can be more profound with loop diuretics. The major site of magnesium reabsorption is the loop of Henle. Since thiazide diuretics do not exert effects at this site, hypomagnesemia is less of a problem with thiazides than with loop diuretics.[996] Hypersensitivity reactions are possible if thiazides or carbonic anhydrase inhibitors are administered to sulfonamide-sensitive patients. Furosemide is sometimes considered as having cross-reactivity with sulfonamides, however, in clinical practice, this almost never occurs.[53] [178]

Thiazides are known to cause hyperlipidemia but the magnitude is slight and these changes may revert to baseline after several months of use. In a comprehensive meta-analysis, diuretics were associated with increased total and LDL cholesterol, especially among blacks, and HDL cholesterol were decreased in patients with diabetes.[995] Diuretics also increase serum triglycerides and VLDL cholesterol.[995] Long-term trials indicate that serum cholesterol levels are elevated only for the first 6—12 months of therapy and then decrease to pretreatment levels.[996] Pancreatitis has been associated with thiazide diuretic use, but this may be secondary to hypertriglyceridemia.

It has been suspected that thiazides increase plasma glucose however major studies have refuted this. Further, the consensus of clinical trials indicates that long-term therapy with thiazides does not increase the incidence of diabetes.[996] It is well-known that obesity and hypertension can contribute to insulin resistance.

Regarding loop diuretics, ototoxicity is a well-known adverse effect of ethacrynic acid. However, while ethacrynic acid is the most ototoxic of the 4, furosemide can also be ototoxic, especially if large IV doses are administered too rapidly.[51] While loop diuretics, because of their potency, are often associated with hypokalemia, it is important to note that these diuretics can also cause hypomagnesemia, hyponatremia, and hypochloremia. Patients with hypokalemia often demonstrate hypomagnesemia concomitantly. Hypochloremic metabolic alkalosis is a common adverse reaction of aggressive diuresis without proper potassium chloride supplementation.