Renal physio and diuretics 3 and 4

Question 1

Three types of diuretics and what their mechanism is; what is a diuretic?

Answer 1

1. Aquaretics (decrease ability of ADH to increase water perm of late distal tubule and CD; response similar to nephrogenic or central diabetes insipidus)
2. Saluretics (decrease SOLUTE reabsorption in one or more segments of the nephron; think loop diuretics, thiazides, K-sparing diuretics)
3. Osmotic diuretics (enter tubular fluid by glomerular filtration and are neither reabsorbed nor secreted along nephron; mannitol, excess glucose, urea);
   increase volume and rate of urine output by decreasing active reabsorption of solutes (saluretics) and/or water (aquaretics)

Question 2

Therapeutic uses of Diuretics:

Answer 2

1. HTN
2. Treat edema (generalized or focal imbalance in ECF distribution)
3. Treat hypo/hypercalcemia and hypo/hyperkalemia
4. Decreasing CSF volme and pressure
5. Decreasing intraocular fluid volume and pressure

Question 3

In each of the four main segments, what is the FENa? What goes on at each level of the nephron?

Answer 3

1. PT: carbonic anhydrase inhibitors decrease Na and bicarb reabsorption, but you only excrete maximally 5% of filtered Na because of compensatory increases in Na reabsorption occurring downstream of prox tubule; some K in urine because of what happens downstream
2. ThAL: high-ceiling or loop diuretics decrease Na, K, and Cl reabsorption, increasing FENa to 25% if increased amount of Na delivered from PT; largest diuresis
3. Cortical ThAL and early distal tubule: thiazides decrease Na and Cl reabsorption from tubular fluid; FENa goes up to 8%, and some carbonic anhydrase activity is inhibited also; K increases because of Na going to late distal tubule and early CD
4. Late distal tubule and CD: K-sparing diuretics decrease Na and tubular fluid reabsorption and K secretion; induce smallest diuresis (FENa up to 2%) and they are best if used with loop or thiazide diuretics

Question 4

Loop diuretics ____ capacity of kidney to

Answer 4

decrease; concentrate and dilute urine in response to decreased and increased water consumption:

1. decrease solute reabsorption and dilution of tubular fluid in cortical ThAL (less positive free water clearance when patient is volume expanded and increased osmolar clearance)
2. Decrease solute reabsorption and countercurrent multiplication of ion concentrations in the medullary ThAL (tough to make more concentrated urine; make less negative free water clearance with patient volume contracted and can’t defend against dehydration and ECF volume contraction)

Question 5

Thiazide diuretics ____ capacity of urine to

Answer 5

dilute the urine in response to increased water consumption:
1. decrease solute reabsorption and dilution of tubular fluid in the early distal tubule (increases urine osmolarity and osmolar clearance and limits ability of kidney to make dilute urine; if someone is volume expanded, thiazide diuretics decrease magnitude of positive free water clearance by causing increase in osmotic clearance);
at greater risk of HYPONATREMIA than with loop diuretic because these guys limit kidney ability to take water in excess of solute from ECF and add to urine, but don’t limit ability of kidney to take water in excess of solute from tubular fluid and add to ECF

Question 6

Acetazolamide (Diamox), Methazolamide (Neptazane), Dichlorphenamide (Daranide)

Answer 6

Class: Carbonic anhydrase inhibitors (PT)
Mech: Inhibits luminal carbonic anhydrase at proximal tubule –> less activity of Na/H antiporter, decreased HCO3 and Na+ (and water) reabsorption, with less K taken up as well in late distal and CD
Thera: Decrease intraocular volume/pressure and the prevention and treatment of mountain sickness
Important SE’s: Increased K+ excretion (hypokalemia) and metabolic acidosis (loss of bicarb)
Other SE’s: Hepatic encephalopathy (accumulation of NH3 in ECF), BM depression, skin toxicity, allergic reactions
Misc: Contraindicated in cirrhotic patients; FeNa = 5%

Question 7

Osmotic diuresis is

Answer 7

an increase in rate and volume of urine elimination due to filtration and presence of a nonreabsorbable solute in the tubular fluid; increases osmolarity of the proximal tubular fluid which opposes isotonic reabsorption of Na and water

Question 8

Mannitol (Osmitrol)

Answer 8

Class: Osmotic diuretic
Mech: Opposes water and sodium reabsorption at proximal tubule –> increased osmolarity of tubular fluid
Thera: Increased clearance of drugs, minimize renal failure (shock or surgery), decrease intraocular or intracranial pressures, diagnose oliguria
Important SE’s: Risk of pulmonary edema
Misc: FeNa = 5%; must give IV; other osmotic diuretics include glucose (could induce osmotic diuresis in poorly controlled diabetes mellitus), urea, isorbide

Question 9

Furosemide (Lasix), Bumetanide (Bumex), Torsemide (Demadex), Ethacrynic acid (Edecrin)

Answer 9

Class: Loop diuretic (- charge); ethacrynic acid with NO H2NSO2 group!!!
Mech: Inhibits Cl portion of Na-K-2Cl cotransporter in luminal membrane at medullary and cortical (proximal) talH –> decreased K+, Ca++ and Na+ reabsorption, resultant K+ loss
Thera: Crisis edema (pulmonary, CHF, cirrhosis), hypercalcemia, drug toxicity/OD; severe hypertension in setting of CHF or cirrhosis
Important SE’s: Hypokalemia/hypocalcemia/hypomagnesemia (–> arrhythmia), contraction alkalosis, increased BUN & creatinine, ototoxicity (esp. w/aminoglycoside)
Other SE’s: Hyper -glycemia, -lipidemia, -uricemia; hypo -magnesia, -natremia; gout, photosensitivity, nephrocalcinosis, drug interactions; erectile dysfunction;
Misc: FeNa = 25%; eventually causes increase in PT reabsorption,decreases positive & negative free water clearance; decreases cortex-medulla molarity gradient; avoid NSAIDs, take before salty meals, reduce salt intake; useful in patients with renal insufficiency (GFR < 30-40)

Question 10

Chlorothiazide (Chlotride), Hydrochlorothiazide (Microzide)

Answer 10

Class: Thiazide diuretic (- charge)
Mech: Inhibits the Cl portion of the Na-Cl cotransporter in the luminal membrane at the early distal tubule –> decreased Na+ (and water) reabsorption, increased Ca++ reabsorption, resultant K+ loss
Thera: HTN (intravascular contraction), chronic edema (cardiac insufficiency), idiopathic hypercalciuria (stones), nephrogenic diabetes insipidus, avoid polyuria if on Li therapy (contract ECF volume and compensatory increase in prox tubular Na and H2O reabsorption)
Important SE’s: Hypokalemia/hypercalcemia, contraction alkalosis, increased BUN & creatinine
Other SE’s: Hyper -glycemia, -lipidemia, -uricemia, -calcemia; hypo -magnesia, -natremia; gout, photosensitivity, impotence, drug interactions
Misc; FeNa = 8%; lethal interaction w/quinidine (v. tach –> fib, may be due to hyperkalemia); avoid NSAIDs, bile sequestrants; increased risk of hypokalemia w/anti-inflammatory steroids or Amphotericin B; decreases positive free water clearance (we DECREASE rather than INCREASE urine volume)

Question 11

Chlorthalidone (Thalitone), Quinethazone (Hydromox), Metolazone (Zaroxolyn), Indapamide (Lozol)

Answer 11

Class: Thiazide-like diuretic

Otherwise, same as thiazides!!!!!

Question 12

Spironolactone (Aldactone)

Answer 12

Class: K+-sparing diuretic; aldosterone receptor antagonist
Mech: Competes for aldosterone receptor, inhibiting mRNA transcription and translation --> decreased Na and K channels, decreased number and activity of Na-K-ATPase pumps in the late distal tubule and collecting duct --> decreased K+ secretion, distal tubule acid secretion
Thera: Reduction in CHF mortality (30% in NYHA class III and IV); combination with other diuretics to prevent hypokalemia; edema; primary and secondary aldosteronism; hypertension; anti-testosterone agent
Important SE's: Hyperkalemia in patients with renal failure or on ACE inhibitors; male patients may have gynecomastia, erectile dysfunction, and loss of libido; female patients may have amenorrhea, breast soreness, and oligomenorrhea
Misc: Contraindicated in patients with renal failure (hyperkalemia); FeNa = 2%; requires a salt-restricted diet; only drug not requiring tubular lumen access

Question 13

Amiloride (Midamor), Triamterene (Dyrenium)

Answer 13

Class: K+-sparing diuretic; renal ENaC inhibitor (+ charge)
Mech: Blocks Na channel and Na/H antiporter in lumenal membrane at the late distal tubule and collecting duct –> decreased K+ secretion and distal tubule acid secretion, increased Ca++ absorption
Thera: Combination with other diuretics to prevent hypokalemia; edema, idiopathic hypercalciuria (stones); lithium-induced polyuria & toxicity, Liddle syndrome, mucocilliary clearance (HEH LIDDLE PM)
Important SE’s: Hyperkalemia in patients with renal failure or on ACE inhibitors
Other SE’s: triamterene with megaloblastic anemia in patients with liver cirrhosis
Misc: Amiloride contraindicated in patients with renal failure (hyperkalemia), ACEi/ARB use; FeNa = 2%;

Question 14

Factors determining quantity of diuretic present at its site of action include:

Answer 14

1. plasma concentration
2. RBF
3. Glomerular filtration
4. Tubular secretion
5. Tubular fluid concentration;
   something like spironolactone only dependent on first 2, other guys dependent on all five

Question 15

Transcellular organic cation secretion occurs by; organic anion secretion occurs by

Answer 15

passive at basolateral membrane at PT with faciliated diffusion, active with coupling with proton influx at luminal;
active at basolateral membrane with coupling of efflux of IC ketoglutarate with influx of organic anion, passive at luminal membrane with faciliated diffusion;

watch out for low GFR, have to give higher dose of diuretic because of competition b/w e.g. organic anions and diuretics!!