Diuretics

PHRM 306: Drugs affecting CVS

Diuretics
Diuretics are drugs that act on the kidney to increase the excretion of water and sodium chloride. Most diuretics work by reducing the reabsorption of electrolytes by the kidney tubules. The increased electrolyte excretion is accompanied by an increase in water excretion, necessary to maintain an osmotic balance.

Summary: Sites of Action

Diuretics
Can be used as first-line drug therapy for hypertension unless there are compelling reasons to choose another agent. Low-dose diuretic therapy is safe, inexpensive. Diuretics are effective in lowering blood pressure by 10-15 mm Hg in most patients.

Diuretics
Prevents stroke, myocardial infarction, and congestive heart failure, all of which can cause mortality. Recent data suggest that diuretics are superior to -blockers for treating hypertension in older adults.

A. Thiazide diuretics
All oral diuretic drugs are effective in the treatment of hypertension, but the thiazides have found the most widespread use.

Benzothiadiazine (parent of the class)

Bendroflumethiazide

Hydrochlorothiazide

Chlorothiazide

Actions
Thiazide diuretics, such as hydrochlorothiazide, lower blood pressure initially by increasing sodium and water excretion. This causes a decrease in extracellular volume, resulting in a decrease in cardiac output. Peripheral vascular resistance may increase (due to calcium reabsorption in the tubules)

Actions
They control hypertension in part by inhibiting reabsorption of sodium (Na+) and chloride (Cl) ions from the proximal part of distal convoluted tubules in the kidneys by blocking the thiazide-sensitive Na+-Cl symporter.
(http://en.wikipedia.org/wiki/Diuretic)

Reason unknown

Figure: Actions of thiazide diuretics.

Actions
With long-term treatment (after 6-8 weeks), plasma volume approaches a normal value (cardiac output returns toward normal), but peripheral resistance decreases.

Therapeutic uses
Thiazide diuretics are appropriate for most patients with mild or moderate hypertension and normal renal and cardiac function.

Therapeutic uses
The thiazides and thiazide-like diuretics reduce the risk of death, stroke, heart attack and heart failure due to hypertension. In most countries, the thiazides are the cheapest antihypertensive drugs available.

Therapeutic uses
Thiazide diuretics decrease blood pressure in both the supine (seating) and standing positions Postural hypotension is rarely observed except in elderly, volume-depleted patients.

Therapeutic uses
These agents counteract the sodium and water retention observed with other agents used in the treatment of hypertension (for example, hydralazine).

Therapeutic uses
Thiazides are therefore useful in combination therapy with a variety of other antihypertensive agents, including -blockers, ACE inhibitors, angiotensin-receptor blockers, and potassium-sparing diuretics.

Therapeutic uses
Thiazide diuretics are particularly useful in the treatment of black or elderly patients. They are not effective in patients with inadequate kidney function (creatinine clearance, <50 mL/min). Loop diuretics may be required in these patients.

Pharmacokinetics
Thiazide diuretics are orally active. Absorption and elimination rates vary considerably, although no clear advantage is present for one agent over another. All thiazides are ligands for the organic acid secretory system of the nephron, and as such, they may compete with uric acid for elimination.

Adverse effects
Thiazide diuretics induce
Hypokalemia and hyperuricemia in 70% of patients and Hyperglycemia in 10% of patients. Hypomagnesemia may also occur.
Hyperglycemia Hyperlipidemia Hyperuricemia Hypercalcemia Hypokalemia Hyponatremia

Adverse effects
In the treatment of hypertension, the most common adverse effect of diuretics (except for potassium-sparing diuretics) is potassium depletion.

Adverse effect
Mechanisms of hypokalemia Increased delivery of sodium to the collecting ducts causes increased cellular uptake of Na from the lumen by apical Epithelial Na Channels (ENaCs). This then causes the basolateral Na/K exchanger to more actively exchange Na for K, which is then passively secreted into the lumen through apical channels, resulting in K loss.

Adverse effect
Mechanisms of hypokalemia Activation of renin-angiotensin-aldosterone system by the diuretic hypovolemia: body responds to hypovolemia by opposing diuresis, one effect of which is to produce aldosterone which stimulates the Na/K exchanger, resulting in further loss of potassium.

Adverse effects
Although mild degrees of hypokalemia are tolerated well by many patients, hypokalemia may be hazardous in persons taking digitalis, those who have chronic arrhythmias, or those with acute myocardial infarction or left ventricular dysfunction.

Adverse effect
Hyperuricemia: Uric acid levels in the blood are often increased because thiazides are secreted by the organic acid secretory system in the tubules and compete for uric acid secretion. This may precipitate gout.

Diuretics

LOOP DIURETICS

Loop diuretics
Loop diuretics are diuretics that act on the ascending loop of Henle in the nephron. Loop diuretics act on the Na+-K+-2Clsymporter (cotransporter) in the thick ascending limb of the loop of Henle to inhibit sodium and chloride reabsorption. Example: Furosemide (most common), Bumetanide, Ethacrynic acid, Torsemide.

Loop diuretics
The loop diuretics act promptly, even in patients with poor renal function or who have not responded to thiazides or other diuretics. Loop diuretics cause decreased renal vascular resistance and increased renal blood flow. Loop diuretics increase the Ca2+ content of urine, whereas thiazide diuretics decrease it.

Therapeutic uses
More powerful diuretics (eg, those acting on the loop of Henle) are necessary in severe hypertension, when multiple drugs with sodium-retaining properties are used; in renal insufficiency, when glomerular filtration rate is less than 30 or 40 mL/min; and in cardiac failure or cirrhosis, where sodium retention is marked.

Therapeutic uses
Edema: cardiac, pulmonary or renal Chronic renal failure or nephrosis Hypertension Hypercalcemia Acute and chronic hyperkalemia

Adverse effects
Like the thiazides, the loop agents have hyperglycaemic, hyperuricaemic and hypokalaemic effects. Potassium loss, as with the thiazides, is often clinically unimportant unless there are additional risk factors for arrhythmias (e.g. digoxin treatment).

Adverse effects
Overenthusiastic use of loop diuretics (high doses, IV administration) can cause deafness, which may not be reversible.

Diuretics

POTASSIUM-SPARING DIURETICS

Potassium-Sparing Diuretics
Potassium-sparing diuretics act in the collecting tubule to inhibit Na+ reabsorption and K+ excretion.

Overview
Potassium-sparing diuretics are used alone primarily when aldosterone is present in excess (Conns syndrome). The major use of potassium-sparing agents is in the treatment of hypertension, most often in combination with a thiazide.

Overview
It is extremely important that patients who are treated with any potassium-sparing diuretic be closely monitored for potassium levels. Exogenous potassium supplementation is usually discontinued when potassium-sparing diuretic therapy is instituted.

A. Aldosterone antagonists
Spironolactone: Spironolactone is a synthetic steroid that antagonizes aldosterone at intracellular cytoplasmic receptor sites. The spironolactone-receptor complex is inactive.

Spironolactone
It is a weak diuretic, because only 2% of the total Na+ reabsorption is under aldosterone control.

B. Triamterene and amiloride

Triamterene and amiloride block Na+ transport channels, resulting in a decrease in Na+/K+ exchange. Although they have a K+-sparing diuretic action similar to that of spironolactone, their ability to block the Na+/K+-exchange site in the collecting tubule does not depend on the presence of aldosterone.

B. Triamterene and amiloride

Thus, they have diuretic activity even in individuals with Addison's disease.