Diuretics

Question 1

In the proximal tubule, what is the major ion moved? What does it drive? What drives its movement? What is it countertransported with?

Answer 1

Na+ is driven from the lumen to the blood via a sodium gradient created by the sodium-potassium pump (2/3 of sodium is reabsorbed here). Water, potassium and chloride follow. Sodium reabsorption also drives glucose and amino acid reabsorption. Sodium is countertransported with H+, which combine with bicarbonate to form CO2, which can difuse into the proximal tubule cell to reform bicarbonate, which can then be reabsorbed into the blood. This is driven by the action of carbonic anhydrase.

Question 2

What is the major transporter in the thick ascending limb of the loop of Henle? What is the charge of the lumen, and what results due to this charge?

Answer 2

Na/2Cl/K pump. Some K+ leaks back to the lumen, causing a positive charge, driving Ca & Mg reabsorption.

Question 3

What is the major transporter in the distal tubule? What other channel exists here? What drives this ion’s movement?

Answer 3

Na/Cl cotransproter for reabsorption. A Ca channel for reabsorption also exists, and its diffusion is driven by a gradient created via a 3Na/Ca pump in the basolateral membrane.

Question 4

What ion movements are occurring in the principal cells of the late distal tubule and collecting duct? What controls this? What will an increase in flow (or an increase in sodium delivery) here cause? What is water doing? What regulates this?

Answer 4

Na channels allow sodium reabsorption. This is functionally coupled with K secretion (all driven by the Na/K pump). This is all stimulated by aldosterone – increases Na/K pump and Na channels in the luminal membrane (epithelial Na+ channels). An increase in flow (or an increase in sodium delivery) will increase these movements and cause increased K secretion. H2O is reabsorbed via aquaporins. Water movement is regulated via ADH/AVP (via insertion of aquaporins into the luminal membrane – recall that the gradient for reabsorption has already been created via the counter-current exchange system of the loop of Henle).

Question 5

What ion movements are occurring in the intercalated cells of the late distal tubule and collecting duct? What does potassium have to do with this?

Answer 5

Protons are secreted and titrated against HPO4- and NH3 to form H2PO4 and NH4+. Proton movement is opposite that of potassium, so increased proton secretion (acidosis) allows for more potassium reabsorption (hyperkalemia), and v.v.

Question 6

Carbonic anhydrase inhibitors?

Answer 6

Acetazolamide, Methazolamide, Dichlorphenamide

Question 7

Mxn of action of CA inhibitors? Used for? Side effects? Contraindications? Overall, how good are these drugs for diuresis?

Answer 7

Inhibits luminal carbonic anhydrase at proximal tubule –> less activity of Na/H antiporter, decreased HCO3 and Na+ (and water) reabsorption. Use: Decrease intraocular volume/pressure and the prevention and treatment of altitude sickness. Side effects: Hypokalemia (due to increased K+ excretion), metabolic acidosis (due to loss of HCO3), hepatic encephalopathy (due to formation of ammonia with alkalinization of urine), BM depression, skin toxicity, allergic reactions. Contraindicated in cirrhotic patients (due to hepatic encephalopathy); FeNa = 5%. Overall: limited use as a diuretic.

Question 8

What is aminophylline (theophylline)? MOA? Used for? Side effects? How is this metabolized? What increases blood levels?

Answer 8

(Aminophylline = Theophylline + Ethylenediamine) Bronchodilator (Methylxanthine). MOA: phosphodiesterase inhibition and enhanced signalling via increased cAMP and cGMP; works at proximal tubule; decreased HCO3 and Na+ (and water) reabsorption. Uses: Reduce inflammation and bronchospasm in moderate to severe asthma, night symptoms; NOT as diuretic. FeNa = 5%. Side effects: Larger doses give nausea, vomiting, CNS stimulation or seizures, tachycardia/arrythmias. Metabolized by liver; cimetidine and quinoline increase blood level.

Question 9

Osmotic diuretics? Which is most widely administered?

Answer 9

Mannitol (most widely administered), excess glucose, urea, isosorbide.

Question 10

Mxn of action of osmotic diuretics? Used for? Side effects? How must this be given?

Answer 10

Opposes water and sodium reabsorption at proximal tubule –> increased osmolarity of
tubular fluid. Uses: Increased clearance of drugs, minimize renal failure (shock or surgery), decrease intraocular or intracranial pressures, diagnose oliguria (if there is no increase in urine with administration, a kidney pathology can be presumed). Side effect: Risk of pulmonary edema (due to increased ECF osmotic pressure/volume and a transient increase in ECF intravascular pressure). Must give IV; FeNa = 5%.

Question 11

Most efficacious diuretics?

Answer 11

Loop diuretics (“high ceiling diuretics”) – Furosemide, Bumetanide, Torsemide, Ethacrynic acid.

Question 12

Mxn of action of loop diuretics? Used for? Side effects? Mention how hyponatremia can be corrected. Eventually, what happens in the proximal tubule? What drugs should be avoided? When should this be taken, and what other dietary change should be made? Can these be used in patients with renal insufficiency?

Answer 12

Inhibits Cl portion of Na-K-2Cl cotransporter
in luminal membrane at medullary and
cortical (proximal) talH –> decreased Na, K, Cl, Ca, Mg resorption (increased excretion). Uses: Crisis edema (pulmonary, CHF, cirrhosis – along with diuresis, increase vascular compliance and decrease EDP), hypercalcemia, drug toxicity/OD; severe hypertension in setting of CHF or cirrhosis. Side effects: Hypokalemia/hypocalcemia/hypomagnesemia
(–> arrhythmia), contraction alkalosis (due to ECF contraction in the absence of increased HCO3 elimination…w/ time, the kidney will respond), hyponatremic (though not as great a risk as w/ thiazides – correct with volume restriction), nephrocalcinosis, increased BUN (due to decreased GFR AND/OR increased PT reabsorption) & creatinine (solely due to decreased GFR – NEVER REABSORBED), gout, hyperglycemia (w/ onset of diabetes or destabilization of diabetes), hyperlipidemia; photosensitivity, ototoxicity (esp. w/aminoglycoside), increased concentration of clotting factors drug interactions; erectile dysfunction. Eventually causes increase in PT reabsorption –> increased sodium reabsorption is sufficient to decrease urine sodium to a level equivalent to sodium consumption, although increased water reabsorption is insufficient, SO sodium balance is achieved in the setting of ECF volume contraction. Avoid NSAIDs (may function via prostaglandins), take before salty meals, reduce salt intake; useful in patients with renal insufficiency (GFR

Question 13

Thiazide diuretics? Thiazide-like diuretics?

Answer 13

Chlorothiazide, Hyrochlorothiazide. Chlorthalidone, Quinethazone, Metolazone, Indapamide.

Question 14

Mxn of action of thiazides and thiazide-like diuretics? Used for? Explain the use for diabetes. Explain the use for ADH-resistant polyuria with lithium Can these be used in patients with renal insufficiency? Side effects? Lethal interaction with? What drugs should be avoided? An increased risk of hypokalemia is associated with use of? What happens to positive free water clearance?

Answer 14

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. Uses: HTN, edema,
idiopathic hypercalciuria, nephrogenic diabetes insipidus (by decreasing ECF volume, decreased amts of tubular fluid reach the collecting duct AKA GFR, thereby decreasing urine formation; also, decreased ECF volume reflexively increases PT Na/H2O reabsorption), ADH-resistant polyuria with lithium (same idea, decrease GFR and increase PT response…the concern is that lithium may be increasingly reabsorbed in the PT as well, so care must be taken). Use wanes in patients with renal insufficiency as GFR fib, may be due to hypokalemia). Avoid NSAIDs, bile sequestrants (decrease absorption). Increased risk of hypokalemia w/anti-inflammatory steroids or Amphotericin B. FeNa = 8%.

Question 15

K+ sparing diuretics? Which are the epithelial Na+ channel inhibitors? Which is the aldosterone receptor antagonist?

Answer 15

These are organic bases – filtered and secreted! ENaC inhibitors: Amiloride, Triamterine. Aldosterone receptor antagonist: Spironolactone.

Question 16

Mxn of action of ENaC inhibitors? Used for? Side effects? These are contraindicated in who?

Answer 16

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. Uses: Combination with other diuretics to prevent hypokalemia; edema. Also for amiloride: idiopathic hypercalciuria (stones); lithium-induced polyuria. Side effects: Hyperkalemia in patients with renal failure or on ACE inhibitors. Also for triamterine: Megaloblastic anemia in patients with liver cirrhosis. Contraindicated in patients with renal failure (hyperkalemia), (& for amiloride, ACEi/ARB use). FeNA: 2%.

Question 17

Mxn of action of spironolactone? Used for? Side effects? These are contraindicated in who? The effectiveness of this drug requires? This is the only diuretic that does not require what? How is this given? Why? What is the active metabolite?

Answer 17

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.  Uses: 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.  Side effects: 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.  Contraindicated in patients with
renal failure (hyperkalemia). Requires a salt-restricted diet.  Only drug not requiring tubular lumen access.  Given orally due to water insolubility (and thus not given parenterally or I.V.)  Active metabolite: Canrenoate.  FeNa: 2%.

Question 18

Aquaretics?

Answer 18

Conivaptan, Tolvaptan.

Question 19

Mxn of action of conivaptan & tolvaptan? Used for? What’s the deal with these drugs?

Answer 19

Vasopressin (ADH) receptor antagonist working at collecting duct –> increased free water excretion. Uses: Hyponatremia (SIADH, CHF). New drug class with unproven benefits.

Question 20

What do loop diuretics do to free water clearance in volume expansion? What is the implication? What about in volume contraction?

Answer 20

In volume expansion, there is less positive free water clearance (by increasing Cosm, and recall that CH2O = V - Cosm) – The implication is that there is an increase in the time necessary to return ECF volume to normal. In volume contraction, there is less negative free water clearance (because the kidneys are hindered in their ability to create a gradient in order to conserve water; Cosm is decreased, and recall that CH2O = V - Cosm).

Question 21

Knowing what loop diuretics do to the concentrating abilities of the kidney, do thiazide diuretics have the same effect? Why? What about diluting abilities? What is the implication?

Answer 21

No – Thiazides have NO effect on the concentrating ability of the kidney because they function in the early distal tubule within the cortex, which does not participate in the counter current multiplication system. However, because thiazides block sodium resorption, they increase urine osmolarity and limit the diluting abilities of the kidney. The implication is that in a volume expanded state, thiazides increase Cosm but not CH2O and this increases the time necessary for the kidney to correct ECF volume expansion – this puts the patient at a SERIOUS risk for hyponatremia (a MUCH greater risk than patients on loop diuretics).

Question 22

Why are thiazides used to treat nephrogenic diabetes insipidus and not loop diuretics?

Answer 22

Loop diuretics compromise the concentrating and diluting abilities of the kidney. Thiazides only compromise the diluting ability of the kidneys. Patients with nephrogenic diabetes are chronically volume contracted, so a loop diuretic would be of no help in forming a concentrated urine.

Question 23

Most sulfonamide diuretics are present in the tubular fluid due to?

Answer 23

Proximal tubule secretion.

Question 24

Best drug to increase negative free water clearance in manic-depressive patients who are taking lithium?

Answer 24

Amiloride

Question 25

Best drug to prevent stone formation in the kidney?

Answer 25

Indapamide + other thiazides