PHA 824

The Pharmacology of Diuretic Drugs

Dr. M.T. Piascik


 

Objectives

The student should be able to explain or describe;

1) The physiology of the kidney as it relates to the mechanisms of action and therapeutic uses of diuretic drugs.

2) The prototypes of the major diuretic classes.

3) The mechanisms of action and major side effects of the prototype diuretic drugs.

4) The therapeutic uses for diuretic drugs.

 

Diuretics are drugs that increase the rate of urine flow. There are several classes of diuretic drugs. These agents are used in the management of edema and hypertension.

A good review of the basic science and clinical applications of diuretics can be found in Chapter 15 of Katzung’s Basic and Clinical Pharmacology.

  • Na channel inhibitors: amiloride, triamterene
  • Aldosterone receptor antagonists: spironolactone, eplerenone

             

REGULATION OF RENAL FUNCTION BY SELECTED HORMONES

The Renin-Angiotensin System

            

AT1 and AT2 receptors are typical GPCRs. They couple through G-proteins to activate a variety of cell signaling events that alter myocardial, vascular, renal and CNS activity. It is much too simplistic to envision that any GPCR couples to only one G-protein. AT1 mediated-signaling is a result of interacting with multiple G-proteins.

Aldosterone acts as a typical steroid hormone. Aldosterone binds to a cytoplasmic receptor that is transported to the nucleus. The [AR] complex binds to DNA elements to enhance the synthesis of a Na+, K+-ATPase and a Na+ channel involved in a Na+and K+ transport in the distal tubule and collecting ducts.

 

CARBONIC ANHYDRASE INHIBITORS

These agents are sulfonamide in structure. The diuretic action was found as a side effect of sulfanilamide, one of the first antibiotics. Acetazolamide, dichlorphenamide and methazolamide are the clinically used carbonic anhydrase inhibitors. Acetazolamide is the prototype for this class of drugs.

a) Mechanism of Action

These agents interfere with the reabsorption of HCO3- . HCO3- is reabsorbed in the proximal tubule and requires the activity of carbonic anhydrase. HCO3- reabsorption takes place in a circuitous way. Intracellularly carbonic anhydrase (CA in the diagram) converts H2O and CO2 to carbonic acid (H2CO3). H2CO3 dissociates into H+ and HCO3-.

The HCO3- is transported across the basolateral membrane. H+ is secreted into the tubular lumen in exchange for Na+. The H+ combines with a filtered HCO3- (using CA) to form H2CO3 which immediately dissociates into H2O and CO2 that is reabsorbed. Therefore, a filtered bicarbonate is reabsorbed for every H+ secreted. Carbonic anhydrase inhibitors, by blocking the enzyme, prevent the reabsorption of NaHCO3- and hence diuresis occurs.

 

b) Effects on Electrolytes and Renal Hemodynamics

Metabolic acidosis results as a result of HCO3- loss. There is an increase in Na+ and K- excretion. However, the naturesis is modest due to the large Na+ capacity of the ascending loop of Henle and the distal tubule. By inhibiting proximal tubule reabsorption, the increase in solute delivery to the distal tubule increases afferent arteriolar resistance thus decreasing renal blood flow and GFR (tubuloglomerular feedback regulation).

c) Toxicity and Adverse Effects

Metabolic acidosis, sedation and paresthesia. Also, because of the structural similarity to sulfonamides, carbonic anhydrase inhibitors can cause bone marrow depression and allergic reactions.

                d) Therapeutic Uses

Carbonic anhydrase inhibitors are not used for their diuretic properties. Rather these agents are used to reduce intraocular pressure in the treatment of glaucoma. This is because these agents inhibit intraocular carbonic anhydrase and thus the formation of aqueous humor. Carbonic anhydrase inhibitors are also used to treat epilepsy, altitude and motion sickness.

THIAZIDE DIURETICS

These were originally synthesized as carbonic anhydrase inhibitors. While some thiazides have carbonic anhydrase inhibitory activity, the major site of action is in the distal tubule. Hydrochlorothiazide is the prototype for this class of drug. Chlorthalidone, indapamide and metolazone are long acting diuretics. These drugs do not have the thiazide structure but are referred to as thiazide-like. The clinically available thiazides and thiazide-like agents have the same mechanism of action. They differ only in pharmacokinetic properties such as the plasma half-life.

a) Mechanism of Action

 

 

Thiazide diuretics are secreted into the tubular fluid by proximal tubule cells. These agents act in the distal convoluted tubule and block a Na+, Cl- symporter that is associated with the luminal membrane. This transport system moves both Na+ and Cl- into the cell using the free energy produced by the Na+, K+, ATPase. The Na+ is pumped out of the epithelial cell via this transport system in the basolateral membrane. The Cl- exits the cell via a Cl- channel. Because thiazides are related in structure to carbonic anhydrase inhibitors, some of these agents have weak carbonic anhydrase activity.

b) Effects on Electrolytes and Renal Hemodynamics

1) Na+, Cl- excretion is enhanced. However, the effect on Na+ is small because most of the Na+ has already been absorbed prior to reaching the distal tubule.

2) K+ excretion is enhanced due to the increase in Na+ delivered to the distal tubule.

3) In the long term, uric acid excretion is reduced.

4) Ca2+ excretion is decreased via a poorly understood mechanism.

5) The excretion of Mg2+ is enhanced.

6) Thiazides have little effect on renal blood flow or total glomerular filtration rate.

c) Side Effects, Drug Interactions and Toxicity

The likelihood of side effects with the thiazides increases with the plasma concentration of the drug. These drugs were introduced in the 1950s and early clinical trials were carried out with high drug concentrations (200 mg/day) designed to produce significant diuresis. As a consequence many side effects were reported. However, more recently, clinical trials have shown that low doses of thiazide diuretics (12-25 mg/day) are actually MORE effective than higher doses in reducing cardiovascular events. The reported side effects are provided below. In many instances the likelihood of observing a particular side effect and the severity is dependent on the dose of diuretic. Potential side effects of diuretic drugs include;

1) Electrolyte abnormalities include volume depletion, hypokalemia, hyponatremia, hypochloremia, hypercalcemia, hyperuricemia and hypomagnesemia.

2) Hyperglycemia and a reduction in the efficacy of hypoglycemic drugs.

3) Increases plasma levels of LDL cholesterol, and triglycerides. While the effects on glucose levels and cholesterol and triglycerides have been observed, it is not clear that these result in an increase of risk for diuretic usage.

4) Sexual dysfunction (impotence)

5) The hypokalemia resulting from thiazides increases the likelihood of ventricular rhythm disturbances. This is a potentially serious consequence.

6) A variety of drug-drug interactions have also been reported;

6 i) A decrease in the efficacy of a variety of drugs including anticoagulants and uricosorics (drugs used to treat gout).

6 ii)Thiazides increase the risk of toxicity (i.e. increase the likelihood of rhythm disturbances) of cardiac glycosides, quinidine and antiarrhythmic drugs.

6 iii) Nonsteroidal anti-inflammatory agents reduce the efficacy of thiazide diuretics.

                6 iv) Thiazides can increase the blood levels of lithium.

e) Clinical Uses

Thiazides can be used to treat edema associated with a variety of pathophysiologic conditions including congestive heart, cirrhosis, renal insufficiency and the nephrotic syndrome.

However, their major use is in the therapy of hypertension. They can be used alone or in combination with numerous other antihypertensives. Initially, thiazides reduce plasma volume which contributes to the hypotensive effect. Long term use is associated with a decrease in peripheral vascular resistance. The effects on vascular resistance are due to direct effects on vascular smooth muscle. However, the mechanisms underlying these effects are not well understood.

Loop or High Ceiling Diuretics

 

Furosemide

Ethacrynic acid

Bumetanide

Torsemide

a) Mechanism of Action

Like thiazides these agents must be secreted into the tubular fluid by proximal tubule cells. In the thick ascending loop Na+ and Cl- reabsorption is accomplished by a Na+, K+, Cl- symporter. The thick ascending limb has a high reabsorptive capacity and is responsible for reabsorbing 25% of the filtered load of Na+. The loop diuretics act by blocking this symporter. Because of the large absorptive capacity and the amount of Na+ delivered to the ascending limb, loop diuretics have a profound diuretic action. In addition, more distal nephron segments do not have the reabsorptive capacity to compensate for this increased load. The osmotic gradient for water reabsorption is also reduced resulting in an increase in the amount of water excreted. The reduction in cellular K+ also results in a loss of Ca2+ and Mg2+.

b) Effects on Electrolytes and Renal Blood Flow

Loop diuretics cause a significant increase in Na+,K+ and Cl- excretion. Ca2+ and Mg2+ excretion are also enhanced. Loop diuretics block the Na+, K+, Cl- symporter in the macula densa. As a result the tubuloglomerular feedback mechanism is blocked. Because of this loop diuretics maintain renal blood flow.

c) Side Effects, Drug Interactions and Toxicity

1) Many side effects occur as a result of abnormalities in fluid or electrolytes. This would include volume depletion, hyponatremia, hypokalemia, hypochloremia, hypocalcemia and hypomagnesemia.

2) Ototoxcity, especially with ethacrynic acid

3) Hypotension

4) Metabolic effects-hyperuricemia, hyperglycemia, increase triglyceride and cholesterol levels, increase LDL cholesterol and decrease HDL cholesterol.

5) As with thiazides the hypokalemia produced by high ceiling diuretics can increase the likelihood of ventricular arrhythmias.

6) There are numerous potential drug interactions that can occur with loop diuretics including;

6 i) Loop diuretic can increase the likelihood of ventricular rhythm disturbances seen with certain antiarrhythmic drugs and cardiac glycosides

6 ii) Co-administration of drugs which are themselves ototoxic. This would include aminoglycoside antibiotics or the anticancer drug cisplatin.

6 iii) Nonsteroidal antiinflammatory drugs blunt the actions of loop diuretics.

6 iv) Loop diuretics can increase the blood levels of lithium.

                6 v) Agents, such as probenecid, that block secretion into the distal tubule will decrease the response to high ceiling diurectis.

e) Clinical Uses

The vigorous diuresis produced by loop diuretics makes these especially useful for rapid reduction of edematous fluid. Indications include renal insufficiency, ascites, the nephrotic syndrome, pulmonary edema and congestive heart failure. While not drugs of first choice in the treatment of hypertension, loop diuretics may be used to treat hypertension. The increase in Ca2+ excretion caused by these agents makes them useful in the treatment of hypercalcemia.

POTASSIUM SPARING DIURETICS

Hypokalemia is a problem associated with the use of thiazide or loop diuretics. Signs and symptoms of hypokalemia include muscle weakness, drowsiness (and a variety of other CNS manifestations and cardiac rhythm disturbances). The potassium loss can be managed with K+ supplementation (K+ salts or foods rich in K+) or the use of K+ sparing diuretics. There are two types of potassium sparing diuretics. They are;

1) Renal epithelial Na+ channel inhibitors - amiloride, triamterene

2) Aldosterone Antagonists - spironolactone, eplerenone

a) Na+ Channel Inhibitors

Mechanism of Action - amiloride and triamterene

In the distal tubule a Na channel is expressed and conducts Na down the concentration gradient established by the Na+, K+ ATPase. The elevation of intracellular Na+ depolarizes the luminal side of the cell . This relative depolarization results in K+ secretion into the tubular lumen. Diuretics that work at a site proximal to the distal convoluted tubule increase the Na+ load and thus increase the amount of K+ that is secreted. This is why most diuretics produce hypokalemia. Amiloride and triamterene block the epithelial Na+ channel. As a result the driving force for K+ secretion is eliminated, hence K+secretion ceases. The diuretic effect is modest.

b) Toxicity and Side Effects

The most obvious side effect is an extension of the therapeutic action of these drugs, that is hyperkalemia. These drugs are contraindicated in situations in which hyperkalemia occurs as well as patients predisposed to hyperkalemia (renal failure, treatment with ACE inhibitors).

c) Aldosterone antagonists

Mechanism of action -spironolactone and eplerenone

Recall that aldosterone interacts with a cytoplasmic mineralocorticoid receptor to enhance the expression of the Na+, K+-ATPase and the Na+ channel involved in Na+ transport in the distal tubule . Spironolactone and eplerenone bind to the intracellular receptor blocking the actions of aldosterone on gene expression.

Spironolactone: Like the Na+ channel blockers spironolactone has limited efficacy alone but is often given with other diuretics. Spironolactone is metabolized to canrenone which is the active drug molecule. The diuretic and naturetic effects of spironolactone are modest. Therefore, these agents are not usually used alone to treat edema or hypertension but rather in combination with thiazides or loop diuretics. This enhances the effects of the more potent diuretics and counteracts the K+ loss seen with these diuretics. Recent studies indicate that aldosterone contributes to cardiac hypertrophy. The Randomized Aldactone Evaluation Study (RALES) showed that spironolactone, when added to a standard treatment regimen, decreased the risk of morbidity and mortality in patients with severe congestive heart failure.

Toxicities and cautions are similar to Na+ channel inhibitors. Due to its steroid structure, spironolactone can cause antiandrogen effects such as gynecomastia, decreased libido and impotence in men as well as menstrual irregularities and hair growth in women.

Eplerenone: Is an analog of spironolactone introduced in 2003. Eplerenone has lower affinity compared to spironolactone for the mineralocorticoid receptor. Nonetheless, it blocks aldosterone-induced gene expression. However, eplerenone has little affinity for androgen or progesterone receptors. Therefore it is void of the unpleasant steroid hormone-like effects (gynecomastia, hair growth, etc). Clinical trials have shown that eplerenone can be used to effectively treat hypertension. In addition, eplerenone has been shown to improve outcomes in patients with heart failure.

Osmotic Diuretics

Glycerin

Isosorbide

Mannitol

Urea

a) Mechanism of Action

Osmotic diuretics are freely filterable but not reabsorbed and prevent H2O reabsorption in the proximal tubule. Osmotic diuretics also extract H2O from systemic body compartments. This expands extracellular fluid volume and increases renal blood flow. This increase in blood flow removes NaCl and urea from the renal medulla. The loss of these solutes decreases the medullary toxicity and hence the ability to generate a concentrated urine.

b) Toxicity and Adverse Effects

Osmotic diuretics increase the excretion of all electrolytes. The increase in extracellular fluid volume could exacerbate congestive heart failure or pulmonary congestion.

c) Clinical Uses

Osmotic diuretics maintain renal blood flow in patients with acute renal failure. These agents can also be used to treat increases in intraocular pressure in glaucoma as well as reduce cerebral edema.