Diuretics

Question 1

What is the definition of a diuretic?

Answer 1

Chemical substance which promotes increased urine flow rate and result in a net loss of sodium, chloride, and/or water

Question 2

What is the relative potency of diuretics affecting the proximal tubule, loop of Henle, distal convoluted tubule, and collecting duct? Why?

Answer 2

Loop > proximal > distal > collecting duct

Based on the amount of sodium resorption that happens at all of these segments. The only inconsistency here is that proximal tubule diuretics (i.e. acetazolamide) are less potent than loop of Henle because the sodium and water reabsorption which is blocked there will be compensated for increased activity of sodium transport in the distal nephron.

Question 3

Why is acetazolamide not the most effective diuretic, other than the distal sodium reabsorption issue?

Answer 3

Only 30% of filtered Na is reabsorbed by bicarbonate, most is reabsorbed as NaCl

Fall in serum HCO3 also results in decreased filtered load and thus decreased diuresis

Question 4

What are the metabolic effects of acetazolamide and what type of urine / osmolyte imbalances will it cause?

Answer 4

Normal anion gap hyperchloremic metabolic acidosis -> by blocking bicarbonate reabsorption, NaCl reabsorption is favored, and base is lost.

Urine - becomes alkalinized, due to high concentration of bicarbonate

Electrolytes: causes hypokalemia due to increased distal convoluted tubule ENaC absorption to compensate (think of banana on ground next to red #2 car)

Question 5

What is methazolamide and its clinical indication?

Answer 5

Derivative of acetazolamide with fewer renal side effects
-> better lipid solubiity and aqueous humor penetration

Used for glaucoma to block carbonic anhydrase in ciliary body, decreasing IOP

Question 6

Other than rare use in glaucoma, what are the primary clinical indications of acetazolamide? What will be made worse by this?

Answer 6

Cystinuria and hyperuricemia -> cystine and uric acid are more soluble in alkaline urine

Calcium phosphate stones will be made worse by this -> less soluble in higher pH

Treatment of metabolic alkalosis in edematous states (fluid overload, good to correct this)

Altitude sickness -> corrects respiratory alkalosis caused by hyperventilation

Question 7

What are the important loop diuretics and which one is special / what side effect can it not induce?

Answer 7

Furosemide, Bumetanide, Torsemide

Special: Ethacrynic acid - think Ethics in sketchy -> not a sulfa drug. Can be used in patients with sulfa allergy

Sulfa drugs risk causing acute interstitial nephritis (link of blue kidney bag in sketchy)

Question 8

How do the loop diuretics get to the TALH and what is their potency dependent on?

Answer 8

Secreted into proximal tubule by organic acid pathway. Potency is determined by urinary concentration of diuretic, not plasma concentration

Question 9

What are the ionic disturbances induced by loop diuretics?

Answer 9

Inhibit NKCC - increased sodium, chloride, and potassium excretion

Hypomagnesia, hypocalcemia - loss of K+ positive intraluminal potential

Question 10

What effect do loop diuretics have on gout?

Answer 10

Acutely - increased uric acid excretion due to increased flow rate

Chronically - volume contraction results in increased uric acid reabsorption in proximal tubule -> worsens gout

Question 11

What effect do loop diuretics have on urinary concentration and dilution and why?

Answer 11

Decrease free water clearance -> impaired urinary dilution -> too much solute left in urine for DCT to deal with

Decreased free water absorption -> impaired urinary concentration -> unable to make medullary gradient for concentration of urine in the distal collecting duct

Question 12

What are the edematous states which loop diuretics are useful in treating?

Answer 12

Pulmonary edema, edema in patients with renal failure (also induce increased RBF by inducing COX), nephrotic syndrome, heart failure

Question 13

What are some nonedematous states which loop diuretics are used for?

Answer 13

Hypertension
Hypercalcemia or hyperuricemia -> must give with saline to prevent volume contraction
Acute renal failure -> improves urine production

Question 14

What metabolic acid state do loop diuretics induce?

Answer 14

Metabolic alkalosis - probably due to contraction alkalosis (think of guy squeezing out water from tube in sketchy) -> increased angiotensin II (stimulates Na/H exchanger) and aldosterone (stimulates H+ secretion for K+ reuptake in alpha intercalated cell).

Question 15

What is one scary and possibly irreversible side effect of loop diuretics?

Answer 15

Ototoxicity - deafness. Think of gong in sketchy

-> NKCC2 is present in cochlear stria vascularis, results in edema of ear if blocked

Question 16

What part of the nephron does mannitol affect? How? How does it get into the nephron?

Answer 16

Affects all segments of the nephron. It is freely filtered at the glomerulus and decreases water and solute absorption at various segments, including sodium at the proximal tubule and urea reabsorption in the collecting duct

Ma

Question 17

What is the relative potency of mannitol vs loop diuretics?

Answer 17

Lower sodium excretion, but highest peak urine flow of all diuretics -> greatest risk for dehydration

It increases free water clearance

This relates to its indication

Question 18

What are the three most important indications of mannitol?

Answer 18

1. Cerebral edema
2. Prevention of dialysis disequilibrium syndrome (rapid removal of osmolytes from plasma causes cerebral edema)
3. Intoxications - enhances urinary excretion of toxins / drugs

Question 19

What are the acute and chronic effects of mannitol on plasma osmolality? ECF volume?

Answer 19

Acutely - hyponatremia - pulls water into ECF, diluting sodum
Chronically - Hypernatremia - dehydration due to decreased free water clearance

ECF volume - diuresis of sodium and water leads to hypovolemia (drop in total body Na)

Question 20

What accounts for the majority of the diuretic effect of mannitol?

Answer 20

Increases vasa recta blood flow -> medullary washout, destruction of concentration gradient (lack of countercurrent exchange)

Question 21

What are the clinically relevant distal convoluted tubule diuretics and their mechanism of action?

Answer 21

Hydrochlorothiazide, chlorthalidone, metolazone

Inhibit Na/Cl cotransporter

Question 22

What effect do thiazides have on uric acid and why?

Answer 22

Volume contraction -> stimulates urate absorption

Thiazides also compete with proximal tubule organic acid transporter -> decrease excretion

Can cause hyperuricemia / gout

Question 23

What effect do thiazides have on urinary concentration and dilution?

Answer 23

Concentration - no effect, gradient made in TALH

Dilution - impaired

Question 24

What patients are at greatest risk of having hypokalemia from thiazide diuretic use?

Answer 24

Those also using a loop diuretic -> lots of sodium will reach collecting duct

Question 25

What type of kidney stone do thiazides treat and why?

Answer 25

Calcium stones -> usually calcium phosphate (opposite of acetazolamide usage)
-> increase calcium reabsorption from the DCT

Question 26

What are rarer but important possible side effect of thiazide diuretics?

Answer 26

Hypercalcemia - never give if hypercalcemic, as can worsen problem via volume contraction and increased reabsorption as well

Acute interstitial nephritis (they are sulfa drugs)

Hyperlipidemia and hyperglycemia (think of candy and butter on high platform in sketchy)

Question 27

What transporters does aldosterone normally increase the speed or number of?

Answer 27

Principle cell: Na/K ATPase, ENaC, ROMK

Alpha-intercalated cell: H+ ATPase

Think of all the things with keys in them on the right side of the K+ sparing diuretics sketchy

Question 28

What drugs work as competitive inhibitors of aldosterone?

Answer 28

Think of the lady going to stop the mineral court food services man, while holding an apple in her hand and observed by the inspector with a spiral notebook

Eplerenone (apple)
Spironolactone (spiral notebook)

Question 29

What are the effects of aldosterone antagonists on plasma urine and electrolytes? Why?

Answer 29

Increased Na excretion (block ENaC)
Decreased K+ excretion (Less Na moves out of lumen, intraluminal charge is more positive, less driving force of  K+ out thru ROMK)
Metabolic acidosis (less H+ excretion due to more positive intraluminal potential preventing H+ release by alpha interacalated cells)

Question 30

What are the clinical uses of aldosterone antagonists which aren’t OB/GYN?

Answer 30

Prevent diuretic induced urine K losses
Adjunct with other diuretics
Treatment of hyperaldosteronism

Question 31

What are the adverse effects of aldosterone antagonists?

Answer 31

Hyperkalemia and gynecomastia (particularly spironolactone, which antagonizes androgen receptor as well)

Question 32

What are aldosterone independent potassium sparing diuretics and what is their mechanism of action?

Answer 32

Think of almond guy and tangerine woman toppling the cart of peanuts into the collecting duct

Amiloride (almond) and Triamterene (tangerine)
-> block ENaC an in aldosterone independent mechanism, would be additive to spironolactone or eplerenone

Question 33

What is a unique indication for aldosterone independent K+ sparing diuretics (unlike aldosterone antagonists)?

Answer 33

Treatment of Liddle’s syndrome - autosomal dominant constitutively active ENaC -> blocks this activity

Think of the liddle gnome falling into the collecting duct

Question 34

What is the diuretic braking effect and how can this be prevented?

Answer 34

Prolonged diuretic use results in a plateau in weight loss and return to previous value, due to increased stimulus for Na retention and less natriuretic response to drug.

Prevented by dietary sodium restriction in conjunction with diuretic use, as well as more frequent / prolonged dosing.

Question 35

What are some other causes of diuretic resistance?

Answer 35

Decreased GFR: volume contraction, reduced renal blood flow (i.e. HF, NSAID use, hypoalbuminemia)

Increased reabsorption: Hypertrophy of proximal tubule cells, volume contraction

Inadequate GI absorption: especially in edematous states

Question 36

What type of renal tubular acidosis can K+ sparing diuretics cause and why?

Answer 36

Type IV renal tubular acidosis -> associated with hyperkalemia

• > hypoaldosteronism causes hyperkalemia which decreases NH4 excretion and hence acidosis
• > Aldosterone also directly stimulates H+ secretion by alpha-intercalated cells, blocked in the presence of these drugs
• > lastly, H+ not secreted into lumen by H+-ATPase because of lack of negative charge from hypoaldosteronism