Diuretics

Question 1

What is a diuretic?

Answer 1

A diuretic is any compound that causes the excretion of an increased volume of urine from the body. More accurately, it is a drug that increases the excretion of both fluids (water) and solutes (e.g., Na+).

Question 2

How do diuretics act?

Answer 2

Most diuretics increase the excretion of Na+ and water by the kidneys. They either have a direct action on the cells of the nephron or modify the content of the filtrate. The reabsorption of Na+ from the filtrate is inhibited, leading to increased Na+ excretion. Water loss is secondary to Na+ excretion.

Question 3

When do we use diuretics?

Answer 3

Diuretics are used in various conditions associated with fluid retention. Some of these conditions include chronic heart failure, chronic liver disease (cirrhosis), chronic kidney disease, nephrotic syndrome, pre-menstrual edema, leg venous insufficiency, hypertension, glaucoma, raised intra-cranial pressure, and to increase excretion of drugs or Ca2+.

Question 4

How does water act as a diuretic?

Answer 4

Under normal conditions, increased water intake leads to an increase in the volume of urine excreted. This process is controlled by antidiuretic hormone (ADH), the most important hormone regulating water balance. ADH is secreted from the posterior pituitary in response to changes in serum osmolality. Normally, some ADH is present in the circulation, maintaining urine volume at approximately 1.5 L/day. However, this can be adjusted in various ways, such as the effects of alcohol or nicotine.

Question 5

What happens when there is reduced expression of AQP2 channels in the DCT and Collecting Duct cells?

Answer 5

Reduced expression of AQP2 channels on the apical surface of DCT (Distal Convoluted Tubule) and Collecting Duct cells leads to more water excretion. As a result, urine production increases, and less water is reabsorbed back into the bloodstream. This results in reduced levels of ADH in the blood.

Question 6

How do alcohol and nicotine affect ADH release and urine volume?

Answer 6

Alcohol inhibits ADH release, leading to an increase in urine volume. On the other hand, nicotine and morphine increase ADH release, which reduces urine volume.

Question 7

What is the role of demeclocycline in treating SIADH?

Answer 7

Demeclocycline acts as an ADH antagonist in the collecting ducts. It is used for the treatment of the syndrome of inappropriate ADH (SIADH), a condition characterized by excessive ADH secretion. By blocking ADH action, demeclocycline helps to reduce water reabsorption in the collecting ducts.

Question 8

What is the function of tolvaptan?

Answer 8

Tolvaptan is an ADH V2 receptor antagonist. It is used as a second-line treatment for SIADH. By blocking the V2 receptors, tolvaptan inhibits the effects of ADH and helps to increase urine volume.

Question 9

What is the role of caffeine as a diuretic?

Answer 9

Caffeine, found in coffee, tea, and cola, is a weak diuretic. It increases cardiac output and dilates the afferent renal arteriole, leading to an increase in glomerular filtration rate (GFR) and subsequent urine production.

Question 10

What are the different parts of the nephron involved in fluid reabsorption?

Answer 10

The nephron consists of the glomerulus, Bowman’s capsule, proximal tubule (70% reabsorption), loop of Henle (20% reabsorption), distal tubule (5% reabsorption), and collecting duct (4% reabsorption). The glomerular filtration rate (GFR) is approximately 180 L/day, but only 1% of the filtrate becomes urine.

Question 11

What are examples of carbonic anhydrase inhibitors?

Answer 11

Acetazolamide is an example of a carbonic anhydrase inhibitor

Question 12

What are examples of osmotic diuretics?

Answer 12

Mannitol is an example of an osmotic diuretic.

Question 13

What are examples of loop diuretics?

Answer 13

Furosemide and Bumetanide are examples of loop diuretics.

Question 14

What are examples of thiazide diuretics?

Answer 14

Bendroflumethiazide, Indapamide, Hydrochlorothiazide, and Chlortalidone are examples of thiazide diuretics.

Question 15

What are examples of potassium-sparing diuretics?

Answer 15

Spironolactone, Eplerenone, and Amiloride are examples of potassium-sparing diuretics.

Question 16

Where do most diuretics act?

Answer 16

Most diuretics (but not all) are secreted into the proximal tubule and act from the luminal (urine) side of the tubule.

Question 17

What are the different segments of the nephron where diuretics act?

Answer 17

Diuretics can act on various segments of the nephron, including the proximal tubule, descending and ascending limbs of the loop of Henle, distal tubule, and collecting ducts.

Question 18

How do loop diuretics work at a molecular level?

Answer 18

Loop diuretics act on the Na/K/2Cl cotransporter (NKCC2) in the thick ascending limb of the Loop of Henle. They block the Cl- channel of the cotransporter, resulting in increased loss of Na+, K+, Cl-, and water.

Question 19

What are the main uses of loop diuretics?

Answer 19

Loop diuretics are much more powerful than other diuretics and are used to clear peripheral edema. They are also administered intravenously for acute pulmonary edema. Furosemide, also known as ‘Lasix,’ is a commonly used loop diuretic with an effect that lasts for approximately 6 hours.

Question 20

What are some side effects associated with loop diuretics?

Answer 20

Side effects of loop diuretics include dehydration, renal impairment, hypokalemia (low levels of K+), hyponatremia (low levels of Na+), hypocalcemia (low levels of Ca2+), hypomagnesemia (low levels of Mg2+), hyperuricemia (elevated uric acid levels causing gout), and auditory nerve damage (especially with high doses and renal impairment), also known as ‘ototoxicity.’ The loss of Na+/K+ and Ca2+/Mg2+/Cl- is associated with these side effects.

Question 21

What is the main cause of hypokalemia associated with loop diuretics?

Answer 21

Loop diuretics increase Na+ delivery to the distal tubule, where it is exchanged for K+. This exchange of Na+ for K+ leads to increased excretion of K+ in the urine, which is the main cause of hypokalemia associated with loop diuretics.

Question 22

How do loop diuretics and thiazide diuretics differ in terms of molecular action?

Answer 22

Loop diuretics act by blocking the Na/K/2Cl cotransporter in the thick ascending limb of the Loop of Henle, while thiazide diuretics act by blocking the Na/Cl cotransporter in the distal convoluted tubule.

Question 23

What are the main effects of thiazide diuretics?

Answer 23

Thiazide diuretics inhibit the apical Na/Cl co-transporter in the distal tubule, leading to increased loss of Na+, K+, Cl-, and water. However, thiazide diuretics are much less powerful than loop diuretics. They are commonly used for the treatment of mild edema or hypertension. Thiazide diuretics have a longer duration of action, up to 24 hours. Bendroflumethiazide is an example of a thiazide diuretic, which is available in generic form and is relatively inexpensive.

Question 24

How does Na+/K+ exchange occur in the distal tubule?

Answer 24

In the distal tubule, Na+ and Cl- are reabsorbed via the apical Na+/Cl- co-transporter. This increases the Na+ concentration in the tubular cells. Na+ is then exchanged for K+ on the basolateral side of the tubular cells. The K+ is subsequently excreted in the urine, contributing to the hypokalemia observed with loop diuretics.

Question 25

How does Indapamide affect the K+ATP-sensitive Potassium channel?

Answer 25

Indapamide activates the K+ATP-sensitive Potassium channel in the smooth muscle of blood vessels, which leads to the dilation of arterioles.

Question 26

What are the effects of thiazide-like drugs, such as Indapamide?

Answer 26

Thiazide-like drugs exert several effects, including increased Na+ and water loss in the kidneys through the inhibition of the Na/Cl co-transporter. This results in a decrease in blood pressure (BP). Additionally, thiazide-like drugs activate the K-ATP channel in arterioles, further contributing to BP reduction.

Question 27

What are the effects of thiazide-like drugs, such as Indapamide?

Answer 27

Thiazide-like drugs exert several effects, including increased Na+ and water loss in the kidneys through the inhibition of the Na/Cl co-transporter. This results in a decrease in blood pressure (BP). Additionally, thiazide-like drugs activate the K-ATP channel in arterioles, further contributing to BP reduction.

Question 28

What are the effects of thiazide-like drugs, such as Indapamide?

Answer 28

Thiazide-like drugs exert several effects, including increased Na+ and water loss in the kidneys through the inhibition of the Na/Cl co-transporter. This results in a decrease in blood pressure (BP). Additionally, thiazide-like drugs activate the K-ATP channel in arterioles, further contributing to BP reduction.

Question 29

What are the potential side effects of thiazide-like drugs?

Answer 29

Thiazide-like drugs can have various side effects, including hyponatremia (decreased Na+ levels), hypokalemia (decreased K+ levels), alkalosis (decreased H+ levels), hypercalcemia (increased Ca2+ levels), hypomagnesemia (decreased Mg2+ levels), increased urate levels (contributing to gout), insulin resistance, increased glucose levels (potentially leading to diabetes), and a potential increase in lipids (related to arterial disease).

Question 30

What are some other uses of thiazide-like drugs?

Answer 30

Thiazide-like drugs, including Indapamide, can be used for the treatment of urinary tract stones and nephrogenic diabetes insipidus.

Question 31

What is the molecular action of aldosterone antagonists?

Answer 31

Aldosterone antagonists block the upregulation of Na+ channels in the distal convoluted tubule (DCT) by aldosterone.

Question 32

What are examples of aldosterone antagonists?

Answer 32

Spironolactone and Eplerenone are examples of aldosterone antagonists. Eplerenone is associated with fewer side effects compared to spironolactone.

Question 33

In which conditions are aldosterone antagonists beneficial?

Answer 33

Aldosterone antagonists, such as spironolactone and eplerenone, have a prognostic benefit in conditions with very poor left ventricular (LV) function and post myocardial infarction (MI), especially in cases with acute heart failure.

Question 34

What is the mechanism of action of aldosterone antagonists in blocking sodium channels in the DCT?

Answer 34

Aldosterone antagonists prevent the upregulation of sodium channels (ENaC) in the DCT, thereby inhibiting sodium reabsorption.

Question 35

What are some side effects associated with spironolactone?

Answer 35

Spironolactone can cause impaired renal function, hyperkalemia (elevated K+ levels), metabolic acidosis, gynecomastia (enlargement of breast tissue in males), and testicular atrophy. Eplerenone, on the other hand, has fewer estrogenic side effects compared to spironolactone due to its structural similarity to estrogen.

Question 36

What are the clinical uses of aldosterone antagonists?

Answer 36

Aldosterone antagonists are used as an add-on treatment in resistant hypertension, first-line treatment in hyperaldosteronism, and first-line treatment in cirrhosis.

Question 37

How does amiloride work as a diuretic?

Answer 37

Amiloride is a direct inhibitor of epithelial Na+ channels (ENaC) in the distal convoluted tubule (DCT). It reduces Na+/K+ exchange in the DCT, resulting in decreased sodium reabsorption.

Question 38

What is the role of amiloride in combination with loop diuretics?

Answer 38

Amiloride is often used in fixed-dose combination with loop diuretics, such as furosemide, in medications like ‘Co-amilfruse.’ This combination helps to balance the potassium-sparing effects of amiloride with the potent diuretic action of loop diuretics.

Question 39

What are osmotic diuretics and their mechanism of action?

Answer 39

Osmotic diuretics, such as mannitol, are non-reabsorbable solutes given intravenously. They undergo glomerular filtration but are not reabsorbed. By increasing the osmolarity of the circulating plasma and urine, they promote the movement of water into the urine by osmosis, leading to diuresis.

Question 40

What is the clinical use of osmotic diuretics like mannitol?

Answer 40

Osmotic diuretics are no longer used for hypertension due to their effect on increasing blood volume. However, they are now primarily used for the treatment of cerebral edema, which refers to brain swelling following conditions like head injury. Mannitol, as an osmotic diuretic, helps draw fluid out of the brain tissue and into the blood, thereby reducing intracranial pressure.