Basics of Diuretics

You might recognize this image from one of our videos highlighting the physiology of the different segments of the nephron. This video can be found here. Using the information from that video, I want to summarize the mechanism of action and common side effects of various diuretics. Having a good understanding of diuretics demonstrates a deeper knowledge of kidney physiology as these drugs target different parts of the nephron leading to both their intended and unintended effects. I’ve highlighted and labeled four sections of the nephron that correspond to the sites of action of the various types of diuretics.

1.   Carbonic Anhydrase Inhibitors (Acetazolamide)1These diuretics, or drugs that to promote urine production,  act by inhibiting the enzyme for which they are named, carbonic anhydrase (CA). This enzyme assumes two forms in the proximal tubule: one form within the brush border that converts bicarbonate to carbon dioxide and water, and the other intracellular form that converts water and carbon dioxide to carbonic acid which spontaneously dissociates to bicarbonate and a free hydrogen ion. Inhibition of CA prevents tubular absorption of bicarbonate leading to a disruption in sodium gradients and eventual natriuresis, the excretion of sodium in the urine.It is important to note that CA inhibitors are not first line for hypertension. These drugs are more commonly used for altitude sickness, by offsetting altitude induced respiratory alkalosis and speeding up the process of acclimatization2, and cerebral edema via inhibition of carbonic anhydrase in the central nervous system and decreased neuronal discharge3.Since there is urinary loss of bicarbonate as well as sodium, a common side effect for these drugs is the development of a proximal (type 2) renal tubular acidosis and thus a metabolic acidosis.

2. Loop Diuretics (Furosemide, Torsemide, Bumetanide, Ethacrynic Acid)

These diuretics lead to natriuresis via inhibition of the Na-K-2Cl cotransporter on the luminal side of ascending loop of Henle cells. Inhibition of sodium reabsorption leads to the profound diuretic response.

These powerful diuretics are useful for management of acute fluid overload and can restore volume balance in patients with heart failure, liver failure, and pulmonary edema. While not first line, they can also be used to manage hypertension especially when associated with diminished kidney function.

Patients using loop diuretics should be monitored for excessive fluid and electrolyte loss as hypokalemia can be an adverse side effect.

3. Thiazide Diuretics (Hydrochlorothiazide, Chlorthalidone)

Thiazides produce natriuresis via inhibition of the NaCl symporter in the distal tubule. By lowering intraepithelial Na concentration, activity of the basolateral Na/Ca antiporter is increased facilitating increased Ca reabsorption from the tubular lumen.

These agents are excellent first line agents in managing hypertension in an outpatient setting.

Thiazides, much like loop diuretics, can also cause hypokalemia. Additionally, thiazides can cause an array of metabolic and electrolyte abnormalities such as hyperglycemia, hyperuricemia, hyperlipidemia, hypercalcemia, and hyponatremia.

4. Potassium Sparing Diuretics (Amiloride, Triamterene, Spironolactone, Eplerenone)1

Potassium sparing diuretics can largely be divided into two categories based on mechanism of action

-Competitive antagonism of intracellular mineralocorticoid receptors (spironolactone, eplerenone)

Epithelial sodium channel (ENaC) blockers (amiloride, triamterene)

These diuretics have earned their name due to their lack of excretion, or “sparing”, of potassium contrary to their thiazide and loop counterparts. For this reason, these drugs are often paired with the potassium wasting diuretics especially if a patient has had hypokalemia in the past.

The most adverse effect to be aware of is hyperkalemia as this increases the risk for potentially fatal arrhythmias.

Ed Diaz, Medical Student, UNC Chapel Hill

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