Diuretics and RAAS

Filter blood to remove waste while retaining essential solutes (glucose, protein, electrolytes) and reabsorbing water

Kidney

Fluid in the peritoneal (abdominal) cavity

Ascites

Swelling in the lower extremities (feet/ankles)

Peripheral edema

Fluid in the lungs (alveoli)

Pulmonary edema

Sustained abnormal elevation of arterial blood pressure

Hypertension

Released by JG (granular) cells in response to low pressure

Renin

Causes potent vasoconstriction

Angiotensin II

Released by the adrenal cortex; causes salt and water retention

Aldosterone

The initial “dumping” of fluid from the blood into the nephron

Filtration

Taking back what the body needs (water, Na+, etc.) from the tubule back into the blood

Reabsorption

Actively moving waste from the blood into the tubule for excretion

Secretion

Movement of water is always linked to the movement of _________

Sodium

Work by blocking Na+ reabsorption, forcing salt and water to stay in the urine for excretion

Diuretics

Site of action is PCT; work early in nephron

Carbonic anhydrase inhibitors

Site of action is ascending loop; most potent, targets the NKCC2 transporter

Loop diuretics

Site of action is DCT; targets the NCC transporter; standard for hypertension

Thiazide diuretics

Site of action is collecting duct; targets ENaC; prevents potassium loss

K+-sparing diuretics

Primarily used for edema (fluid retention) and hypertension

Diuretics

If two diuretics work at different sites, their effects are additive or _______

Synergistic

Adverse effects include hypotension and dizziness, electrolyte imbalance, ototoxicity, photosensitivity, and flushing

Diuretics

What are the two classes of diuretics that work on the PCT?

Carbonic anhydrase inhibitors and SGLT2 inhibitors

These drugs hit the very beginning of the tubule. Because the rest of the nephron can “catch” much of the sodium left behind, they are relatively weak diuretics but have specialized uses

Carbonic anhydrase inhibitors

What are the three examples of carbonic anhydrase inhibitors?

Acetazolamide, methazolamide, and dichlorphenamide

These drugs inhibit the carbonic anhydrase enzyme in the PCT lumen and cell; prevent the breakdown of H2CO3 into H2O and CO2

Carbonic anhydrase inhibitors

Decreases [H+] in the filtrate, increases [HCO3-] and [Na+] in the filtrate

Carbonic anhydrase inhibitors

Used for glaucoma, altitude sickness, metabolic alkalosis, and gout

Carbonic anhydrase inhibitors

At high altitudes, you hyperventilate, which causes respiratory ______

Alkalosis

Acetazolamide forces the kidneys to excrete ________, creating a compensatory metabolic acidosis, lowering the blood pH back toward normal

Bicarbonate

PCT: primarily used for diabetes, but their diuretic effect is crucial for kidney protection

SGLT2 inhibitors

These diuretics cause glucosuria (glucose in urine) and block sodium reabsorption

SGLT2 inhibitors

In diabetes, the kidney over-absorbs sodium and glucose, so the macula densa thinks the body is depleted; this causes the afferent arteriole to dilate, leading to _________

Hyperfiltration

These drugs restore sodium delivery to macula densa, triggering afferent vasoconstriction, normalizing GFR and protecting the kidney from long-term damage

SGLT2 inhibitors

Acts as an osmotic diuretic

Mannitol

A sugar that is filtered but not reabsorbed; it stays in the tubule and pulls water with it via osmosis

Mannitol

Used for acute edema, specifically for cranial (brain swelling) and ocular (eye) pressure

Mannitol

Route is IV only (not absorbed well orally); onset is fast (1-3 hours)

Mannitol

Can cause hypernatremia and hyperkalemia as well as volume depletion leading to dehydration

Mannitol

What transporter do loop diuretics target?

NKCC2

Loop diuretics compete for the ________ binding site in NKCC, blocking the reabsorption of Na+, K+, and 2 Cl-

Chloride

Inhibiting the NKCC2 pump disrupts the ________ gradient, also preventing the reabsorption of magnesium and calcium

Electrical

General indications are edema (associated with heart failure, hepatic cirrhosis, or renal disease) and hypertension

Loop diuretics

These diuretics can cause electrolyte imbalance, ototoxicity, drug interactions, and hypotension

Loop diuretics

Hearing impairment or dizziness (highest risk with IV/IM boluses or when used with Aminoglycosides) seen with loop diuretics

Ototoxicity

Loop diuretics can cause ________ toxicity

Lithium

What are the four examples for loop diuretics?

Furosemide, Torsemide, Bumetanide, and Ethacrynic acid

Contains a chloride moiety and a Furan ring; bioavailability is highly variable; GI absorption is impaired by food and edema; excreted mostly unchanged in urine

Furosemide

This loop diuretic has GI absorption impaired by food

Furosemide

Pregnancy Category B (safer); longer duration of action and less ototoxicity; metabolized by CYP2C9

Torsemide

The most potent loop diuretic; onset is very fast (2-3 minutes via IV)

Bumetanide

Loop diuretic with no sulfonamide group; go-to for patients with a sulfa allergy; increases urea excretion

Ethacrynic acid

What is the transporter targeted by thiazide diuretics?

NCC1

These diuretics increase excretion of Na+ and Cl- (and water follows)

Thiazide diuretics

Thiazides decrease _______ excretion (meaning they help the body keep calcium)

Calcium

Thiazide diuretics ______ Na+/Cl- entry, decreasing intracellular Cl-

Inhibit

Thiazide diuretics cause membrane hyperpolarization, which opens the _______ channel, allowing more Ca+2 to be reabsorbed from the urine into the blood

TRPV5

Thiazides are useful for patients with ______ ______ caused by high urine calcium

Kidney stones

Preferred thiazide diuretic; very long-acting; has a half-life of 40-60 hours so dosed only 2-3 times per week

Chlorthalidone

What are the four examples for thiazide diuretics?

Chlorthalidone, hydrochlorothiazide, indapamide, and metolazone

Most commonly prescribed thiazide diuretic often found in combination pills; half-life is 6-15 hours; excreted unchanged in urine

Hydrochlorothiazide

Thiazide with high bioavailability (3%); biphasic half-life (14 and 25 hours); hepatic metabolism

Indapamide

Thiazide-like diuretic; must be taken with food/milk; onset is 60 min; side effects are chest/abdominal pain

Metolazone

Unlike loops, _______ do not typically cause hearing issues

Thiazides

_______ increase serum calcium (Loops decrease it)

Thiazides

Typically contain a chloride moiety and a sulfonamide group

Thiazides

What is the transporter for loop diuretics?

NKCC2

What is the transporter for thiazide diuretics?

NCC1

These drugs act on the Cortical Collecting Tubule (CCT); they are weak because they only affect <3% of filtered sodium, but they are crucial for maintaining potassium balance

Potassium-sparing diuretics

Stimulated by low blood volume/pressure, low blood Na+, or high blood K+

Aldosterone

This hormone inserts ENaC on the apical side of the collecting duct and Na+/K+ ATPase on the basolateral side to increase Na+ and water reabsorbtion and K+ secretion

Aldosterone

Aldosterone triggers K+ _________

Secretion

What are the two types of potassium-sparing diuretics?

Aldosterone antagonists and Na+ channel blockers

These drugs competitive inhibit the mineralocorticoid receptor, preventing the actions of aldosterone

Aldosterone antagonists

What are the two examples of aldosterone antagonists?

Spironolactone and Eplerenone

First-line potassium-sparing diuretic for reducing cardiac workload; primary drug for ascites (cirrhosis), usually paired with Furosemide

Spironolactone

Can cause gynecomastia (breast tissue development in men) because it is non-specific and hits androgen receptors

Spironolactone

Has same uses as spironolactone but more specific; must lower risk of gynecomastia; metabolism by CYP3A4

Eplerenone

Major side effect of potassium-sparing diuretics

Hyperkalemia

These block apical sodium channels (ENaC) directly. By blocking Na+ entry, the cell loses the electrical gradient that usually pulls K+ into the urine

Na+ channel blockers

What are the two examples for Na+ channel blockers?

Amiloride and Triamterene

Often combined with Thiazides to counteract hypokalemia; side effects are headache, nausea, and impotence; excreted unchanged in urine

Amiloride

Na+ channel blocker; use with caution in patients with kidney stones; excreted unchanged in urine

Triamterene

Site of massive reabsorption of solutes (glucose, amino acids) and Na and HCO3

PCT

Key enzyme acting at the PCT

Carbonic anhydrase

Inhibits carbonic anhydrase; results in decreased HCO3- reabsorption; used for glaucoma and altitude sickness

Acetazolamide

Concentrates urine; it is highly permeable to water but impermeable to solutes

Descending limb

What drug class acts at the descending limb?

Osmotic diuretics

Dilutes urine; impermeable to water but actively reabsorbs solutes

Ascending limb

What is the key transporter at the ascending limb?

NKCC2

What class of drugs act at the ascending limb?

Loop diuretics

Fine-tuning of electrolytes

DCT

What is the key transporter at the DCT?

NCC

What class of drugs act at the DCT?

Thiazide diuretics

Final water and salt adjustment; site of aldosterone and ADH action

Collecting duct

What is the key transporter at the collecting duct?

ENaC

What class of drugs act at the collecting duct?

Potassium-sparing diuretics

A neurohormonal pathway designed for volume regulation and blood pressure maintenance; it is primarily activated by low arterial blood pressure

RAAS

An enzyme secreted by granular cells of the kidney

Renin

This is released due to direct SNS stimulation, macula densa sensing low Na+ in distal tubule, or reduced stretch in afferent arteriole

Renin

A prohormone (glycoprotein) produced by the liver; it is always circulating in the blood; production increases with pregnancy, estrogen, and corticosteroids

Angiotensinogen

Formed when renin cleaves Angiotensin. It is physiologically inactive

Angiotensin I