L7 - Pharmacology of Diuretics

What are the main clinical reasons to use diuretics?

Fluid overload/edema and hypertension (when blood volume is the problem).

Why are diuretics useful for treating edema?

They increase urine output, removing excess fluid from the body → ↓ swelling.

When are diuretics especially helpful for hypertension?

When elevated blood pressure is driven by excess blood volume.

What is a diuretic?

A drug that increases urine volume.

What does "natriuretic" mean?

Increases renal sodium (Na⁺) excretion.

Why are natriuretics usually considered diuretics too?

Because increased Na⁺ excretion almost always increases water excretion.

What does "aquaretic" mean?

Increases excretion of solute-free water (water without sodium), such as osmotic and ADH antagonists

What is the main function of the proximal convoluted tubule (PCT)?

Reabsorption of Na⁺, K⁺, Ca²⁺, Mg²⁺, glucose, amino acids, and water.

Which ions are actively reabsorbed in the thick ascending limb of Henle's loop?

Na⁺, K⁺, and Cl⁻.

Which ions are secondarily reabsorbed in the thick ascending limb?

Ca²⁺ and Mg²⁺.

What is special about water permeability in the thick ascending limb?

Very low water permeability. Water does NOT follow salt, making the tubular lumen HYPOosmotic

What is actively reabsorbed in the distal convoluted tubule (DCT)?

Na⁺ and Cl⁻.

What hormone regulates calcium reabsorption in the distal convoluted tubule?

Parathyroid hormone (PTH).

What is the water permeability of the distal convoluted tubule?

Very low water permeability. Water does NOT follow salt, making the tubular lumen even more HYPOosmotic

What happens in the cortical collecting tubule?

Na⁺ reabsorption coupled to K⁺ and H⁺ secretion.

How does the body respond to chronic diuretic use in terms of salt intake and thirst?

Increased drive to eat salt and increased thirst. (compensation)

What happens to the sympathetic nervous system with chronic diuretic use?

Sympathetic activation increases due to decreased BP and volume (compensation)

What hormonal system is activated with chronic diuretic use?

Renin-angiotensin-aldosterone system (RAAS) due to perceived volume depletion from sodium and water loss. (compensation)

Why is it common for diuretics to be prescribed with antihypertensives?

Antihypertensives block the compensatory effects of the body, such as RAAS

What may happen if a diuretic is suddenly discontinued after chronic use?

Rebound sodium and water retention (can worsen edema or BP).

Where do loop diuretics act in the nephron?

Thick ascending limb of the Loop of Henle.

What transporter do loop diuretics inhibit?

Na⁺/K⁺/2Cl⁻ cotransporter (NKCC2).

What is the primary effect of inhibiting NKCC2?

Decreased reabsoprtion of Na+, K+, Cl-, and indirectly Mg2+/Ca2+

Name two common loop diuretics

Furosemide and torsemide

What electrical gradient is normally created by NKCC2 activity?

A lumen-positive potential driven by K⁺ recycling.

This means that K+ is leaked back into the tubular fluid, creating a positive gradient compared to the blood

How do loop diuretics affect the lumen-positive potential?

They decrease the lumen-positive potential.

What normally drives Mg²⁺ and Ca²⁺ reabsorption in the thick ascending limb?

The lumen-positive potential created by NKCC2 activity and K⁺ recycling.

This means that excess positive charge in the fluid from K+ pushes Mg²⁺ and Ca²⁺ into the blood

How do loop diuretics affect Mg²⁺ and Ca²⁺ handling?

They increase excretion of Mg²⁺ and Ca²⁺ by eliminating the lumen-positive potential.

There is no longer a positive gradient compared to the blood, so they stay in the tubular fluid

What electrolyte abnormality can prolonged loop diuretic use cause?

Hypomagnesemia.

Do loop diuretics commonly cause hypocalcemia?

Rarely, due to compensatory mechanisms, but can be used to help decrease levels in hypercalcemia

What acid-base disturbance can loop diuretics cause?

Hypokalemic metabolic alkalosis.

Why do loop diuretics cause hypokalemic metabolic alkalosis?

↑ Na⁺ delivery to the collecting tubule → ↑ K⁺ and H⁺ secretion.

Less K+ in the blood, more K+ leaves cells, causing H+ to enter cells, leading to alkalosis

Why doesn't water also follow Na⁺ if its absorption is increased later in the kidney when using loop diuretics? (at the collecting duct)

Loop diuretics prevent the medulla from becoming hyperosmotic with ions. Even if the collecting duct allows water flow, the tubular fluid has a similar ion concentration, and water doesn't reabsorb as efficiently.

What uric acid abnormality is caused by loop diuretics?

Hyperuricemia, leading to gout

Why can loop diuretics worsen gout?

Reduced blood volume → higher concentration of uric acid

What magnesium abnormality is associated with loop diuretics, and how is it managed?

Hypomagnesemia, manage by giving magnesium supplementation if problematic.

What calcium abnormality can loop diuretics cause?

Hypocalcemia (rare).

What type of drug allergy can occur with loop diuretics?

Sulfonamide allergy.

What volume-related adverse effect can loop diuretics cause and how is it managed?

Dehydration, managed by lowering the dose.

What enzyme do loop diuretics induce in the kidney?

COX-2 (cyclooxygenase-2), which produces PGE₂. (important prostaglandin for loop effects)

What is the role of PGE₂?

Inhibits salt reabsorption.

Inhibits NaCl detection by the macula densa.

Increase renal blood flow (via vasodilation).

How do NSAIDs interfere with loop diuretics?

They inhibit COX, decreasing prostaglandin production and reducing renal blood flow and diuretic effect.

How quickly are loop diuretics absorbed?

Rapidly absorbed

Which loop diuretic is absorbed faster: torsemide or furosemide?

Torsemide (≈ 1 hour) is absorbed faster than furosemide (≈ 2-3 hours)

How are loop diuretics eliminated from the body?

By the kidney via glomerular filtration and tubular secretion

What determines the half-life of loop diuretics?

Renal function

What happens to loop diuretic clearance in renal impairment?

Clearance decreases and half-life is prolonged

Which drugs can block tubular secretion of loop diuretics, decreasing their elimination?

NSAIDs and probenecid

Does furosemide have active metabolites?

Presence of active metabolites is unclear

What is the half-life of furosemide?

2-3 hours

Which loop diuretic has at least one active metabolite with a longer half-life?

Torsemide

What is the half-life of torsemide?

4-6 hours

Where do thiazide diuretics act in the nephron?

The distal convoluted tubule

What transporter do thiazide diuretics inhibit?

Na⁺/Cl⁻ cotransporter (NCC)

What is the prototype thiazide diuretic?

Hydrochlorothiazide (HCTZ)

What class of chemical structure do thiazides belong to?

Sulfonamides

What normally happens to Na⁺ and Cl⁻ in the DCT?

Na⁺ and Cl⁻ are reabsorbed along the tubule.

What happens to Ca²⁺ in the DCT?

Ca²⁺ can be reabsorbed under the influence of the parathyroid hormone (PTH)

OR

It can be excreted under the influence of the Na⁺/Ca²⁺ exchange due to sodium reabsorption

What happens to Na⁺ and Cl⁻ when thiazides are acting?

Na⁺ and Cl⁻ are NOT reabsorbed and remain in the tubular fluid, increasing the osmolarity

What happens to Ca²⁺ levels with thiazides?

Slight ↑ in blood Ca²⁺ (decreased Ca²⁺ excretion) because decreased Na⁺ reabsorption decreases Na+/Ca2+ exchange, increasing calcium that remains in the blood

Is thiazide-induced hypercalcemia usually clinically significant?

Nope, usually mild

When can thiazides cause problematic hypercalcemia?

In patients with inappropriate PTH-mediated Ca²⁺ reabsorption (e.g., hyperparathyroidism)

How does the body normally prevent hypercalcemia with thiazides?

PTH decreases to limit Ca²⁺ reabsorption

What enzyme do thiazides induce expression of that affects their efficacy?

COX-2

Why does COX-2 induction matter for thiazide diuretics?

COX-2 → renal prostaglandin production → helps thiazide efficacy

How do NSAIDs affect thiazide diuretics?

NSAIDs ↓ prostaglandin production → slightly ↓ thiazide efficacy

Which thiazide is absorbed orally?

Hydrochlorothiazide (HCTZ)

How are thiazides eliminated from the body?

By the kidney via the organic acid secretory system in the proximal tubule

What important substance do thiazides compete with for tubular secretion?

Uric acid

What electrolyte/metabolic effect results from thiazides competing with uric acid?

Hyperuricemia

Why can thiazides precipitate gout attacks?

1. They decrease uric acid secretion → increased serum uric acid → gout flare

2. The decrease volume of blood and increase urea concentration

What acid-base disturbance can thiazide diuretics cause?

Hypokalemic metabolic alkalosis.

Why do thiazide diuretics cause hypokalemic metabolic alkalosis?

↑ Na⁺ delivery to the collecting tubule → ↑ K⁺ and H⁺ secretion.

Less K+ in the blood, more K+ leaves cells, causing H+ to enter cells, leading to alkalosis

Why doesn't water also follow Na⁺ if its absorption is increased later in the kidney when using thiazide diuretics? (at the collecting duct)

Although the medullary gradient is intact and some Na⁺ and water are reabsorbed in the collecting duct, not all of it can be reclaimed, resulting in net Na⁺ and water loss (diuresis).

Why are loop diuretics more potent than thiazides?

Loop diuretics block NKCC2 in the thick ascending limb and abolish the medullary osmotic gradient, preventing water reabsorption and causing strong diuresis, whereas thiazides block NaCl reabsorption in the distal tubule but preserve the gradient, so diuresis is weaker.

How can loop and thiazides alter water balance if their site of action is impermeable to water?

Even though loops and thiazides act in water-impermeable segments, they cause diuresis mainly by altering how much water can be reabsorbed downstream in the collecting duct.

What effect do thiazides have on glucose tolerance?

Decrease glucose tolerance → may cause hyperglycemia (especially at higher HCTZ doses)

What is the mechanism for thiazide-induced hyperglycemia?

Off-target stimulation of pancreatic β-cells induces K+ efflux, hyperpolarizing the cell, decreasing insulin release

What electrolyte abnormality commonly occurs with thiazide diuretics?

Hyponatremia

Why do thiazides cause hyponatremia?

Thiazides block NaCl reabsorption in the distal tubule (the kidney's diluting segment), so sodium is lost (not all can be reclaimed) while water can still be reabsorbed in the collecting duct (ADH/medulla gradient), leading to dilution of serum sodium (hyponatremia).

Compare the hyponatremia risk between loop and thiazide diuretics

Thiazides cause more hyponatremia because they impair urine dilution in the distal tubule while preserving water reabsorption in the collecting duct, whereas loop diuretics impair urine concentration in the collecting duct and promote water loss.

What effect do thiazides have on uric acid?

Cause hyperuricemia

Mechanism of thiazide-induced hyperuricemia?

Volume depletion and competition with uric acid for the same renal transporter

What dermatologic risk is associated with thiazides?

Increased risk of non-melanoma skin cancer (photosensitization)

What type of allergy is associated with thiazides?

Sulfa allergy

Where do potassium-sparing diuretics act in the nephron?

The collecting duct

What is the main effect of potassium-sparing diuretics on sodium?

Prevent Na⁺ absorption

What happens to potassium secretion when Na⁺ absorption is blocked in the collecting duct?

K⁺ secretion decreases

Why are these drugs called "potassium-sparing" diuretics?

They block K⁺ excretion, so potassium is retained

What are the two mechanisms by which potassium-sparing diuretics can act?

1. Inhibit ENaC channels

2. Block aldosterone receptors

Name three common potassium-sparing diuretics

Triamterene, Spironolactone, and Eplerenone

What channel does triamterene inhibit?

Epithelial sodium channel (ENaC)

What is the effect of triamterene in the collecting duct?

↓ Na⁺ reabsorption and ↓ K⁺ secretion

What receptor do spironolactone and eplerenone block?

Aldosterone (mineralocorticoid) receptor

What is the effect of blocking the aldosterone receptor?

↓ Na⁺ reabsorption and ↓ K⁺ secretion by disrupting the upregulation of ENaC and the Na⁺/K⁺ ATPase

Why does spironolactone have a long half-life?

It is converted by the liver into active metabolites (>12 hours)

What extra receptor does spironolactone block besides aldosterone receptors?

Androgen receptor

What clinical issue can occur due to spironolactone's androgen receptor blockade?

Undesired endocrine effects (especially in men) such as feminization

How is eplerenone different from spironolactone in receptor selectivity?

More selective for mineralocorticoid (aldosterone) receptors and much less antagonism of androgen receptors

How is triamterene metabolized and eliminated?

Metabolized by the liver to an active metabolite and excreted by the kidney