Renal and Genitourinary Systems

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Chapter 25 Renal and Genitourinary Systems

Thiazide Diuretics

Description

Diuretics result in increased urine production and also lower blood pressure.

Prototype and Common Drugs

Prototype: hydrochlorothiazide

Others: chlorothiazide, chlorthalidone

MOA (Mechanism of Action)

Generally speaking, diuretics manipulate a solute (usually Na⁺), and water passively follows.

↓ Na⁺ reabsorbed in kidney → ↑ Na⁺ lost in urine → ↑ water lost in urine

Specifically, thiazide diuretics inhibit the Na⁺/Cl⁻ co-transporter channel in the distal tubule of the nephron (Figure 25-1).

Therefore Na⁺, Cl⁻ (and water) remain in the lumen of the tubule: natriuresis and diuresis. In addition, the actions of the thiazides impact other ions.

A passive Na⁺/H⁺ exchange occurs at a distal site in the tubule. Na⁺ gradients drive this exchange. When the Na⁺/Cl⁻ cotransporter is blocked, the Na⁺ concentration in the lumen of the tubule is high, which facilitates Na⁺ reabsorption in exchange for excretion of H⁺ ions at this distal site. Therefore thiazides create alkalosis by H⁺ ion loss through a secondary, passive exchange.

Similarly, Na⁺ is exchanged for K⁺ at a distal site in the tubule. By enhancing delivery of Na⁺ to distal sites of the nephron, Na⁺ is exchanged for K⁺, leading to enhanced K⁺ excretion, in a similar manner to the K⁺ depletion that occurs with loop diuretics.

Thiazides also promote Ca⁺² reabsorption through a poorly understood mechanism.

Owing to the fact they act so distally in the nephron, after much of the Na⁺ reabsorption has already occurred, thiazides are relatively weak diuretics when compared with loop diuretics.

Thiazides are also vasodilators, an effect independent of their diuretic actions. Their antihypertensive effect is probably related mainly to this mechanism and not the diuretic mechanism.

Effect on plasma ion concentrations:

Decreased Na⁺, Cl⁻, K⁺, Mg⁺²

Increased Ca⁺²

Increased HCO₃⁻. (This creates a metabolic alkalosis.) This is a result of H⁺ ion loss. Remember that the equation will shift left with a loss of H⁺:

Figure 25-1

Pharmacokinetics

Thiazide diuretics exert their pharmacologic actions from the luminal side; therefore they must be in the lumen of the tubule to achieve their effect.

Thiazides primarily enter the renal tubule through secretion in the proximal tubule (PT) via the organic acid co-transporter. In patients with renal impairment, higher doses of thiazides may be required to overcome impaired tubular secretion and maintain sufficient tubular concentrations to achieve a pharmacologic effect.

Most thiazides become ineffective once creatinine clearance gets too low (typically <30 to 50 mL/min).

Indications

First-line treatment for hypertension

Nephrogenic diabetes insipidus (DI) (rare)

Contraindication

Sulfa allergy: Thiazide diuretics should be used with extreme caution (or not at all) in patients reporting hypersensitivity reactions to sulfa-containing drugs.

Side Effects

Dehydration and decreased Na⁺ occur.

Hypokalemia or hypokalemic metabolic alkalosis: Thiazide diuretics enhance excretion of both K⁺ and H⁺ because of increased distal tubule delivery of Na⁺, and hence Na⁺ reabsorption, in the distal nephron.

Impaired glucose tolerance is caused by impaired insulin release and diminished use of glucose.

Hyperlipidemia: Thiazide diuretics increase cholesterol and low-density lipoprotein (LDL); the mechanism has not been established.

Hyperuricemia: Thiazides compete with uric acid for secretion into the PT, reducing the excretion of uric acid. This can lead to attacks of gout.

Impotency (rare) is likely a result of reduced volume.

Renal dysfunction (increased serum creatinine) may occur secondary to hypovolemia and reduced blood pressure. This is typically only seen in patients with already reduced GFR.

Important Notes

Diuretics that act on the renal tubules require functioning kidneys to exert their effects. Patients with advanced renal dysfunction will not respond to these diuretics.

As noted, thiazides are weaker diuretics than loop diuretics (such as furosemide). This is because they act at a site distal to where loop diuretics act. The loop of Henle is positioned before the distal convoluted tubule, and 90% of Na⁺ will have already been reabsorbed before the ultrafiltrate reaches the distal tubule.

Thiazides have what would appear to be a paradoxical role in the treatment of nephrogenic DI. Although the mechanism has not been confirmed, their efficacy likely stems from their ability to reduce intravascular volume, in turn stimulating Na⁺ reabsorption and reducing the amount of fluid presented to the distal segments of the nephron.

By enhancing reabsorption of calcium and subsequent reduction in urinary calcium concentration, thiazides can be used to reduce formation of calcium-containing renal stones.

Hydrochlorothiazide has a relatively flat dose-response curve, and the effective dose range is 12.5 mg to 50 mg. Doses above 50 mg will only increase the incidence of side effects, without contributing to efficacy.

Advanced

Concomitant administration of thiazides with antiarrhythmic agents that prolong the QT interval (e.g., quinidine, sotalol) may predispose to torsades de pointes. The mechanism is unknown but may be related to hypokalemia induced by the thiazide.

Evidence

As First-Line Agents in Hypertension

A 2009 Cochrane review (24 trials, N = 58,040 participants) compared benefits and harms of first-line antihypertensives with those of placebo or no treatment over a minimum of 1 year. Thiazides (19 trials) reduced mortality (relative risk [RR] 0.89), stroke (RR 0.63), and coronary heart disease (RR 0.84) versus placebo.

FYI

It is believed that thiazides also exert weak diuretic effects at the PT. Some thiazides inhibit carbonic anhydrase (CA) at this site, perhaps accounting for their diuretic effect at the PT.

Thiazides were derived from the CA inhibitor acetazolamide. It is therefore not surprising that some thiazides inhibit Na⁺ reabsorption at the PT.

Diuretics result in increased urine production and also lower blood pressure.

Prototype and Common Drugs

Prototype: furosemide

Others: ethacrynic acid, torsemide, bumetanide

MOA (Mechanism of Action)

Generally speaking, diuretics manipulate a solute (usually Na⁺), and water passively follows:

↓ Na⁺ reabsorbed in kidney → ↑ Na⁺ lost in urine → ↑ water lost in urine

Loop diuretics inhibit the Na⁺/K⁺/2Cl⁻ co-transporter channel in the thick ascending limb (Henle’s loop) of the renal tubule. This results in less Na⁺ being reabsorbed back into the body. Cl⁻ and K⁺ also move in the same direction through this ion channel, as does Na⁺ (Figure 25-2).

Therefore Na⁺, Cl⁻, and K⁺ are lost in the urine: Natriuresis and diuresis. Blockade of the Na⁺/K⁺/2Cl⁻ cotransporter has effects on other ions as well.

Normally, the K⁺ channel on the luminal membrane (cell membrane adjacent to the tubular lumen) and the Cl⁻ channel on the basolateral membrane (cell membrane opposite the tubular lumen) creates a potential difference between the tubular lumen (positive) and the interstitium (negative). Blockade of the Na⁺/K⁺/2Cl⁻ cotransporter interferes with the ability of these channels to create this positive to negative gradient.

Disruption of this electrochemical gradient facilitates excretion of Ca⁺² and Mg⁺². Normally these divalent cations undergo paracellular reabsorption, repelled by the positively charged tubular lumen and attracted to the negatively charged interstitium. Attenuation of the positive to negative gradient reduces paracellular reabsorption of Ca⁺² and Mg⁺², and they are excreted.

A passive Na⁺/H⁺ exchanger is present at a distal site in the tubule. Na⁺ gradients drive this exchange. When the Na⁺/K⁺/2Cl⁻ channel is blocked, the Na⁺ concentration in the lumen of the tubule is high, which facilitates the reabsorption of Na⁺ and excretion of H⁺ at this distal site. Therefore furosemide creates alkalosis by H⁺ ion loss through a secondary, passive exchange.

Similarly, by enhancing delivery of Na⁺ to distal sites of the nephron, Na⁺ is exchanged for K⁺, leading to enhanced K⁺ excretion, and this further depletes K⁺.

Like the thiazides, the loop diuretics are also believed to act as vasodilators, an effect independent of their diuretic actions. This may contribute to the anti-hypertensive effects of the loop diuretics.

Figure 25-2

Effect on Ions

Decreased Na⁺, K⁺, Cl⁻, Ca⁺², Mg⁺². Note the large number of cations excreted.

Increased HCO₃⁻. (This creates a metabolic alkalosis.) This is a result of H⁺ ion loss. Remember that the equation will shift left with a loss of H⁺:

Pharmacokinetics

Loop diuretics act on the apical (lumen) side of the tubule and therefore must be in the tubule in order to exert their effects.

Most loop diuretics are bound extensively to plasma proteins, limiting delivery of these agents to the tubules by filtration. Therefore they rely on secretion by the organic acid transport system in the PT.

The secretion of loop diuretics into the PT may be inhibited by agents that compete for weak acid secretion, such as nonsteroidal antiinflammatory drugs (NSAIDs) or probenecid.

Nephrotic syndrome

Acute hypercalcemia

Contraindications

Hypovolemia is a contraindication.

Severe K⁺ abnormalities are contraindications.

Sulfa allergy: Furosemide, bumetanide, and torsemide may be cross-reactive in those who have an allergy to sulfonamides.

Dehydration may occur.

Hypokalemia is caused by Na⁺ reabsorption in exchange for K⁺ excretion at the distal tubule.

Metabolic alkalosis (increased HCO₃⁻)

Increased exchange of Na⁺ in the lumen for H⁺ in the cell, resulting in H⁺ loss.

and that decreased H⁺ will drive the equation to the right and cause increased HCO₃⁻.

Other electrolytes disturbances: Given the large number of ions (Na⁺, Cl⁻, and so on) that are affected by these agents, electrolytes should be monitored.

Ototoxicity: Reversible hearing loss occurs most often in those with reduced renal function or who are receiving other ototoxic agents such as aminoglycoside antibiotics. The mechanism has not been established, although the Na⁺/K⁺/2Cl⁻ transporter is also found in the inner ear. High-dose furosemide can cause permanent deafness.

Hyperuricemia: The reduction in volume induced by the potent actions of loops elicits a compensatory increase in uric acid reabsorption in the PT. Loop diuretics also compete with uric acid for secretion into the PT. Increased levels of uric acid may precipitate attacks of gout.

Renal dysfunction (increased serum creatinine) may occur secondary to hypovolemia and reduced blood pressure. This is typically only seen when high doses are used in patients with already reduced GFR.

Diuretics versus Placebo or Other Interventions for Treatment of Heart Failure

A 2006 Cochrane review (14 trials, N = 525 participants) compared diuretics with placebo (seven trials) and other interventions (seven trials) for treatment of heart failure. The diuretics included were a mixture of loop diuretics, potassium-sparing diuretics, and thiazides. Based on three trials (N = 202 participants), diuretic treatment reduced the odds of death versus placebo (OR 0.24), and in two trials (N = 169 participants) it reduced the odds of admission because of worsening heart failure (OR 0.07). Diuretics improved exercise capacity in four trials (N = 91 participants) versus active controls.

Blood-Pressure–Lowering Effect versus Placebo or No Treatment

A 2009 Cochrane review (nine trials, N = 460 participants) compared the blood-pressure–lowering efficacy, tolerability, and biochemical effects of a variety of loop diuretics versus placebo or no treatment. The authors found a mean reduction (systolic/diastolic blood pressure) of −7.9/−4.4 mmHg and no differences between drugs in this class with respect to blood-pressure–lowering efficacy. This is considered to be a modest antihypertensive effect. Withdrawals because of adverse effects and biochemical changes were not significantly different from control.

Important Notes

Diuretics that exert their effects by acting on the renal tubules require functioning kidneys to induce diuresis. Patients with advanced renal dysfunction will not respond to these diuretics.

Loop diuretics are much stronger diuretics than thiazides. This is because they work in the loop of Henle, which is positioned before (proximal to) the distal convoluted tubule where the thiazides work.

Potassium-Sparing Diuretics

Potassium-sparing diuretics are diuretics that result in increased urine production and also lower blood pressure while increasing serum levels of potassium.

Prototypes and Common Drugs

Aldosterone Antagonist

Prototypes: spironolactone

Others: eplerenone

Epithelial Na Channel (ENaC) Blockers

Prototypes: Triamterene, amiloride

MOA (Mechanism of Action)

Diuretics manipulate a solute (usually Na⁺), and water passively follows:

↓ Na⁺ reabsorbed in kidney → ↑ Na⁺ lost in urine → ↑ water lost in urine

Thus most diuretics lead to enhanced Na⁺ in the lumen of the tubule (i.e., the urine). High Na⁺ concentrations in the tubule lead to a compensatory reabsorption of Na⁺ in exchange for K⁺ excretion in the distal nephron, leading to the hypokalemia associated with many diuretics.

The goal of potassium-sparing diuretics is to prevent this reabsorption of Na⁺ and subsequent loss of K⁺ in the late distal tubule or collecting duct of the nephron.

The exchange of Na⁺ for K⁺ in the distal nephron is mediated by the actions of the epithelial Na⁺ channel (ENaC) on the luminal side of the membrane and the Na⁺/K⁺-ATPase pump on the basolateral membrane (side opposite the lumen of the tubule).

The basolateral Na⁺/K⁺-ATPase pump creates a gradient for the entry of Na⁺ into the cell from the ENaC on the luminal side of the membrane.

The Na⁺/K⁺-ATPase pump actively pumps Na⁺ out of the cell into the interstitium, in exchange for a K⁺ ion.

The Na⁺ that is lost from the cell is replaced by another Na⁺ ion, which enters passively through ENaC.

The K⁺ that entered the cell exits into the lumen of the tubule through a K⁺ channel.

The potassium-sparing diuretics inhibit this exchange of Na⁺ for K⁺ by inhibiting ENaC alone or both ENaC and the Na⁺/K⁺-ATPase pump.

Triamterene and Amiloride

Amiloride and triamterene inhibit ENaC on the luminal membrane, preventing Na⁺ from moving from the tubular lumen into the cell. This keeps Na⁺ in the lumen of the tubule, therefore facilitating natriuresis.

Reduced entry of Na⁺ into the cell also reduces the amount of Na⁺ that can be exchanged for K⁺ at the ATPase pump. With the Na⁺/ K⁺-ATPase pump unable to exchange Na⁺ for K⁺, the K⁺ stays in the bloodstream.

Spironolactone and Eplerenone (Figure 25-3)

Spironolactone and eplerenone

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