Diuretics



Diuretics



Classification of Diuretics








aAlso chlorthalidone, metolazone.


bAlso bumetanide, torsemide (DEMADEX).


cAlso tolvaptan (SAMSCA).




Overview


Diuretics are used in the management of edema associated with cardiovascular, renal, and endocrine abnormalities, as well as in the treatment of hypertension, glaucoma, and several other clinical disorders (Table 13-1). The drugs act at various sites in the nephron to cause diuresis (an increase in urine production). Most diuretics inhibit the reabsorption of sodium from the nephron into the circulation and thereby increase natriuresis (the excretion of sodium in the urine). Several types of diuretics also increase kaliuresis (the excretion of potassium in the urine) and affect the excretion of magnesium, calcium, chloride, and bicarbonate ions.



TABLE 13-1


Usefulness of Diuretics in the Management of Various Clinical Disorders*





















































































































DISORDER THIAZIDE AND RELATED DIURETICS LOOP DIURETICS POTASSIUM- SPARING DIURETICS OSMOTIC DIURETICS CARBONIC ANHYDRASE INHIBITORS
Cerebral edema 0 0 0 + 0
Cirrhosis + ++ + 0 0
Congestive heart failure + ++ + 0 0
Diabetes insipidus ++ 0 0 0 0
Epilepsy 0 0 0 0 +
Glaucoma 0 0 0 + ++
High-altitude sickness 0 0 0 0 ++
Hyperaldosteronism 0 0 + 0 0
Hypercalcemia 0 ++ 0 0 0
Hypertension ++ + + 0 0
Hypokalemia 0 0 ++ 0 0
Nephrolithiasis ++ 0 0 0 0
Nephrotic syndrome + ++ + 0 0
Pulmonary edema + ++ + 0 0
Renal impairment + ++ 0 + 0


image


*Ratings range from 0 (not useful) to ++ (highly useful).



Nephron Function and Sites of Drug Action


Sodium and other electrolytes are reabsorbed into the circulation at various sites throughout the nephron by active and passive processes that involve ion channels, transport proteins, and the sodium pump (Na+,K+-ATPase). Ion channels are unique membrane proteins through which a specific ion moves across the cell membrane in the direction determined by the electrochemical gradient for the ion. The transport proteins include symporters, which transport two or more ions in the same direction, and antiporters, which transport ions in opposite directions across cell membranes. Most diuretics block a specific ion channel or transporter in the tubular epithelial cells. The sites and mechanisms by which diuretics affect ion reabsorption and secretion in the nephron are illustrated in Box 13-1.



Box 13-1   Sites and Mechanisms of Action of Diuretics


In the proximal tubule (A), carbonic anhydrase catalyzes the reversible conversion of hydrogen ion and bicarbonate to carbon dioxide and water, thereby enabling the reabsorption of sodium bicarbonate. This process is inhibited by carbonic anhydrase inhibitors such as acetazolamide.


In the thick ascending limb of the loop of Henle (B), the Na+,K+,2Cl− symporter transports sodium, potassium, and chloride ions into the tubular cells, and then sodium is transferred to the interstitial fluid by the sodium pump. Potassium back-diffuses into the lumen and contributes to the positive transepithelial potential that drives paracellular calcium and magnesium reabsorption. By inhibiting the symporter, the loop diuretics reduce the back-diffusion of potassium and increase the excretion of calcium and magnesium.


In the distal tubule (C), sodium is transported into tubular epithelial cells by the Na+,Cl− symporter and then is transferred to interstitial fluid by the sodium pump. The Na+,Cl− symporter is inhibited by thiazide and related diuretics.


In the collecting duct (D), sodium enters the principal cells through sodium channels. Sodium is then transferred into the interstitial fluid by the sodium pump, while potassium is pumped in the opposite direction and then moves through potassium channels into the tubular fluid. Aldosterone stimulates these processes by increasing the synthesis of messenger RNA that encodes for sodium channel and sodium pump proteins. The potassium-sparing diuretics exert their effects via two mechanisms: amiloride and triamterene inhibit the entrance of sodium into the principal cells, whereas spironolactone blocks the mineralocorticoid receptor and thereby inhibits sodium reabsorption and potassium secretion.


image

A, Antiporter; ALDO, aldosterone; CA, carbonic anhydrase; MR, mineralocorticoid receptor; mRNA, messenger RNA; S, symporter.




Proximal Tubule


The proximal tubule is an important site of tubular reabsorption and secretion. Essentially all of the filtered glucose, amino acids, and other organic solutes are reabsorbed in the early portion of the proximal tubule. About 85% of filtered sodium bicarbonate is reabsorbed in the proximal tubule, and this reabsorption is inhibited by a class of diuretics known as carbonic anhydrase (CA) inhibitors. For reasons described later in this chapter, these drugs are relatively weak diuretics and are seldom used for this purpose, although their actions are useful in the treatment of glaucoma and other conditions.


About 40% of filtered sodium chloride is reabsorbed in the proximal tubule. This is a relatively unimportant site of diuretic action, however, because inhibition of sodium chloride reabsorption in the proximal tubule leads to greater sodium chloride reabsorption in more distal segments of the nephron.


The proximal tubule is the major site of the active tubular secretion of organic acids and bases into the nephron lumen, including both endogenous compounds (e.g., uric acid) and drugs (e.g., penicillins). The loop diuretics and thiazide diuretics are also secreted by proximal tubular cells into the tubular lumen.





Collecting Duct


The collecting duct serves to adjust the final composition and volume of urine to regulate extracellular fluid composition and pH and thereby maintain physiologic homeostasis. The collecting duct is the site of action of aldosterone and antidiuretic hormone. Aldosterone is a mineralocorticoid that increases sodium reabsorption, thereby promoting sodium retention by the body. Antidiuretic hormone increases the reabsorption of water from the collecting duct, which conserves body water and concentrates the urine. The actions of these hormones are partly responsible for maintaining plasma volume and osmolality in the normal range.


The collecting duct is responsible for the reabsorption of about 3% of the filtered sodium chloride. This reabsorption is coupled with potassium and hydrogen excretion. The potassium-sparing diuretics inhibit these processes and are primarily used to reduce potassium excretion and prevent hypokalemia.



Diuretic Agents


Thiazide and Related Diuretics


The thiazides and related diuretics are the most commonly used diuretics. They are orally efficacious, have a moderate natriuretic effect, and have few adverse effects in most patients.



Drug Properties



Chemistry and Pharmacokinetics

Thiazides are sulfonamide compounds and were the first orally administered diuretics to be widely used for the treatment of hypertension and edema. Thiazides exhibit good oral bioavailability and are actively secreted into the nephron by proximal tubular cells, and they travel through the nephron lumen to reach their site of action in the distal tubule. Some of the thiazides are partially metabolized before excretion in the urine (Table 13-2).



TABLE 13-2


Pharmacokinetic Properties of Diuretics*
























































































































DRUG ORAL BIOAVAILABILITY ELIMINATION HALF-LIFE (HOURS) ROUTE OF ELIMINATION DURATION OF ACTION (HOURS)
Thiazide and Related Diuretics      
Hydrochlorothiazide 70% 5 60% R and 40% M 12 for oral
Indapamide 90% 16 70% R and 30% M 30 for oral
Metolazone 65% 8 80% R and 20% M 18 for oral
Loop Diuretics        
Bumetanide 85% 1.25 65% R and 35% M 5 for oral
1 for IV
Ethacrynic acid 100% 1 65% R and 35% M 7 for oral
2 for IV
Furosemide 60% 2 60% R and 40% M 7 for oral
2 for IV
Torsemide 80% 3.5 30% R and 70% M 7 for oral
7 for IV
Potassium-Sparing Diuretics    
Amiloride 20% 8 R 24 for oral
Spironolactone 65% 1.5 M 60 for oral
Triamterene 50% 4 M 14 for oral
Osmotic Diuretics        
Glycerol 95% 0.07 M 1 for oral
Mannitol NA 1 R 7 for IV
Carbonic Anhydrase Inhibitors    
Acetazolamide 70% 7.5 R 10 for oral
Dorzolamide NA Biphasic† R and M 8 for topical
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Jul 23, 2016 | Posted by in PHARMACY | Comments Off on Diuretics

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