Complete Guide to Diuretics

Diuretics work using various mechanisms

Ever since antiquity, we've used diuretics to pee more.  Some diuretics like caffeine are ubiquitous (think tea or soft drinks).  However, it wasn't until the twentieth century that mankind realized the pharmacological potential of diuretics.  In 1937, researchers discovered carbonic anhydrase diuretics.  By 1957,  researchers had discovered much more potent chlorothiazide diuretics.

Diuretics work by increasing the volume of urine that you produce and altering your body's electrolyte or body salt compositions.

  Pretty simple concepts, huh?  Nevertheless. the various biochemical mechanisms by which diuretics work are inimically difficult to understand.  For example, the formation of urine involves concentration gradients, osmosis, transporters and so forth.  

In a general sense, diuretics work by ridding our body of excess fluid volume or "water."  There are plenty of diseases which are assuaged by the release of fluid including hypertension, heart failure, brain swelling (edema), eye swelling (eye swelling) and swelling secondary to liver or kidney disease,

Before I do my best to explain how diuretics work, I should briefly go over the nephron and the anatomy of the renal tubules.  After all, diuretics work by action on the various parts of the nephron, the basic structural unit of the kidney which is responsible for filtering urine.

A look at the nephron

Here is a rundown of nephron anatomy:

  1. Blood is brought from the body into the renal corpuscle which is composed of the glomerulus, a tuft of capillaries, and the Bowman's capsule.  The renal corpuscle is the first step in urine filtration. 
  1. The glomerulus hooks up into the renal tubules, a system of microscopic tubes responsible for making urine.  The first part of the renal tubule is the proximal convoluted tubule.
  2. The proximal convoluted tubule feeds into the loop of Henle.  The first part of the loop is descending limb and the second is the thick ascending limb. 
  1. The ascending limb feeds into the distal convoluted tubule.
  2. The distal convoluted tubule hooks up to the collecting duct.

Although the parts of the nephron are unlabelled, you can get a better idea of what I'm talking about by checking out the picture accompanying this article.

As previously mentioned, different diuretics work on different parts of the renal tubule.  Overall, the nephron is responsible for secreting waste into an ultrafiltrate which eventually becomes urine and reabsorbing nutrients and other good stuff that our body needs like sodium ions (Na+), sodium bicarbonate (NaHCO3), potassium ions (K+), water and nearly all filtered glucose and amino acids.  (Technically, most of this nutrient reabsorption takes place in the proximal convoluted tubule.)

Carbonic anhydrase inhibitors

Carbonic anhydrase inhibitors like acetazolamide work by inhibiting the enzyme carbonic anhydrase located in the proximal convoluted tubule.  Typically, carbonic anhydrase is responsible for sucking sodium (NHE3 antiporter), potassium, water, amino acids and sugars back into your blood.

  By inhibiting this enzyme, drugs like acetazolamide increase the amount of water in the renal tubule system.  Carbonic anhydrase inhibitors are mostly used to treat glaucoma.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are phosphorylated ribonucleotides which take action on the sodium glucose cotransporter located in the proximal convoluted tubule.  They inhibit this transporter's actions and diminish the reabsorption of glucose and sodium ions back into your blood.  With fewer sodium ions reabsorbed less water follows ( osmosis), and a mild diuresis results.  Although SGLT2 drugs like canagliflozin and dapagliflozin are technically mild diuretics, because of their sugar actions, they're mostly used to treat diabetes.acetazolimide

Loop diuretics

Loop diuretics like furosemide inhibit the Na/K/2Cl transporter in the thick ascending loop of Henle; thus, decreasing sodium and water reabsorption into your blood.  Because loop diuretics also mess with potassium reabsorption, potassium wasting can occur.  If potassium wasting is severe enough, hypokalemia can result.  Most notably, hypokalemia can screw up the way your heart works.  Furosemide is used to treat hypertension (high blood pressure), fluid in the lungs (pulmonary edema), generalized swelling, hyperkalemia (dangerously high potassium levels) and hypercalcemia or high calcium levels (off-label use).

Thiazides

Thiazides work by screwing with the Na/Cl transporter in the distal convoluted tubule.  In addition to blocking the reuptake of sodium ions and water, thiazides also result in some potassium wasting.  Thiazides are used as first-line treatment of hypertension--in fact, a famous study found that thiazides are more effective as first-line treatment of hypertension than ACE inhibitors

When glomerular filtration rate (a measure of kidney function) is very low, thiazides don't work that well.  Of note, thiazides are often combined with loop diuretics for the synergistic effect. 

In addition to hypertension, thiazides are also used to treat calcium-containing kidney stones and diabetes insipidus (different from the much more common type 1 and type 2 diabetes mellitus).

Potassium-sparing diuretics

As their names suggest, potassium-sparing diuretics work by increasing urine volume without wasting potassium.  Potassium-sparing like spironolactone or amiloride both act on the collecting tubules but employ different mechanisms of action. 

Spironolactone antagonizes aldosterone in a poorly understood fashion.  Aldosterone is a steroid hormone produced by the adrenal cortex.  By antagonizing the effects of aldosterone, potassium, sodium and water retention is reduced.  Spironolactone is often used to counteract potassium-wasting caused by thiazide and loop diuretics.  This drug is also administered after the heart attack or used to treat aldosteronism from any cause.

Amiloride blocks sodium channels in the collecting tubule and thus blocks the reabsorption of water into your body.  Like spironolactone, amiloride is often used to counteract potassium-wasting caused by other diuretics.

Osmotic diuretics

Osmotic diuretics pass through your body intact.  When an osmotic diuretic like mannitol gets into your renal tubules, they draw in water by means of osmosis.  (Remember with osmosis, water follows high concentration solutes.  Furthermore, osmotic diuretics in vasculature outside the kidney (think brain or eye)  can also draw off water and reduce swelling. 

In addition to treating both eye swelling (glaucoma) and brain swelling (increased intracranial pressure), osmotic diuretics are also used to renal failure secondary to increased solute load resulting from chemotherapy or rhabdomyolysis (muscle breakdown).  In other words, by diluting drugs and bits of muscle in the nephron, less stress is placed on the kidneys.

Vaptans

Vasoreceptor antagonists or vaptans (conivaptan and tolvaptan) are a new class of drug.  They work via antagonism of vasopressin or antidiuretic hormone and enable your body to secrete electrolyte-free water.  As such, vaptans help with hyponatremic conditions defined by low sodium concentration in the blood like SIADH

Most of the diuretics discussed in this article are available by prescription.  Nevertheless, you can buy some diuretics without a prescription. Even though merely increasing your urine volume and fiddling with your electrolyte levels may sound benign, when taken improperly, diuretics can cause dehydration and potentially lethal electrolyte imbalance (mess with your body salts).  Diuretics can also exacerbate cirrhosis, heart failure or renal failure.  Please take diuretics only after consulting with your physician especially if you fluid balance issues.

On a final note, if you're wondering about caffeine, a diuretic that I briefly mentioned in the lede, research shows that when a healthy person drinks caffeinated beverages, loss of fluid is no more than the volume of the beverage consumed and hydration status isn't compromised.  In other words, if you're healthy then caffeine is safe.

Selected Sources

Eaton DC, Pooler JP. Chapter 8. Regulation of Potassium Balance. In: Eaton DC, Pooler JP. eds. Vander's Renal Physiology, 8e. New York, NY: McGraw-Hill; 2013. Accessed June 18, 2015.

Sam R, Pearce D, Ives HE. Diuretic Agents. In: Katzung BG, Trevor AJ. eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill; 2015. Accessed June 18, 2015.

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