Diuretics

Question 1

1. What is the general function of diuretics?

Answer 1

Diuretics act by blocking specific transport functions of the renal tubules leading to an increased excretion of urinary sodium chloride and water. By increasing the amt of NaCl and water there is a decrease in both blood volume and venous pressure leading to a decreased preload, fall in CO and fall in arterial pressure. Diuretics decrease blood pressure or eliminate edema.

Question 2

2. Discuss the role of the proximal tubule of the kidney.

Answer 2

Proximal tubule → reabsorbs 65% filtered Na, 85% NAHCO3, 65% K+, 60% water, all glucose and AA. The most important ions in regards to diuretic actions are NaHCO3 (sodium bicarb) and NaCl (sodium choride). The Na+-H+ antiporter movement from lumen then into blood via Na+-K+ transporter is the main driving force for water reabsorption. HCO3- wants to be reabsorbed as well but has poor permeability so via the carbonic anhydrase enzyme it is converted to H2CO3 → OH- + CO2. CO2 quickly diffuses into cell and OH- turns to water with the addition of a proton. CO2 in the cell quickly turns back to H2CO3 then intracellular carbonic anhydrase dissociates it to H+ (for the antiporter) and HCO3-.

Question 3

3. Discuss the role of thick ascending limb of the loop of henle in the kidney.

Answer 3

The thick ascending loop of henle receives hypertonic filtrate and allows for reabsorption of NaCl without water. Na+ is reabsorbed via Na+/K+/2Cl- cotransporter (NKCC2). Cl- exits basolateral side of cell, Na+ exits via Na+/K+ ATPase on basolateral side and K+ is recycled back to the lumen for the NKCC2 function. There is also additional reabsorption of Na+, Ca2+ and Mg2+ from lumen to the interstitium driven by K+ recycling.

Question 4

4. Discuss the role of the distal convoluted tubule in the kidney.

Answer 4

Distal convoluted tubule activity reabsorbs4-8% of filtered NaCl. Na+ enters via Na+/Cl- cotransporter (NCCT) and Na+ exits on basolateral side via Na+/K+ ATPase. Ca2+ is reabsorbed via Na+/Ca2+ exhcnagers.

Question 5

5. Discuss the role of the cortical collecting duct in the kidney.

Answer 5

The collecting duct is the final site of NaCl reabsorption and this determines the final Na+ concentration in the urine. Luminal Na+ enters cell via ENaC and exits basolateral side via Na+/K+ ATPase. K+ is secreted into the lumen. ENaC and K+ movement is under the control of aldosterone. Collecting duct also expresses vasopressin (ADH) channels that controls the permeability of the collecting tubule to water. (without ADH the urine is dilute)

Question 6

8. What is the action of Furosemide?

Answer 6

Furosemide is a loop diuretic that selectively inhibits NaCl reabsorption in the thick ascending loop of henle by inhibiting the luminal Na+/K+/Cl- cotransporter (NKCC2). This is called a high-ceiling diuretic b/c water is unable to be reabsorbed therefore it is extremely effective. By inhibiting the reabsorption of NaCl, there is a lowered lumen-positive (K+) potential that would usually come from K+ recycling. The positive potential usually drives divalent cation reabsorption in the loop and therefore by reducing potential, loop diuretics Mg2+ and Ca2+ are unable to be reabsorbed and remain in the filtrate to be excreted. Loop diuretics increase urinary excretion of K+ and titratable acid due to increased delivery of Na+ to the distal tubule and therefore increased action of Na+/K+ exchanger. This predisposes the pt to hypokalemia and metabolic acidosis. All together by decreasing sodium and water reabsorption there is a decrease in renal vascsular resistance and an increase in renal blood flow.

Question 7

9. What is the interaction of loop diuretics (furosemide) with Eicosanoids?

Answer 7

Loop diuretics induce expression of COX-2 which synthesizes prostaglandins from arachidonic acid. The prostaglands appear to mediate the diuretic/natriuretic actions to help increase the electrolyte and fluid excretion. It also has an effect on increased renal blood flow.

Question 8

10. What are the clinical uses of Furosemide?

Answer 8

1. edema associated with heart failure and hepatic/renal disease
2. acute pulmonary edema
   * NOT a first like drug in the tx of HTN, only indicated when thiazide is not sufficient
   * IV and oral administration with half life of 2-4hrs

Question 9

11. What are the adverse side effects of Furosemides?

Answer 9

1. Ototoxicity → manifesting as tinnitus and hearing impairment
2. Hyperuricemia → precipitating gout
3. Acute hypovolemia → depletion of Na+ leading to hyponatremia and hypotension
4. K+ depletion → leading to cardiac arrhythmias
5. Hypomagnesemia and hypocalcemia
6. Hypersensitivity, hyperglycemia, hyperlipidemia, photosensitivity, parasthesias, bone marrow depression, GI disturbances

Question 10

12. What is the mechanism of Thiazide diuretics?

Answer 10

Thiazides inhibit NaCl reabsorption in the distal convoluted tubule by blocking the Na+/Cl- cotransporter (NCCT). By allowing more Na+ to make it to the collecting duct, there is the same effect as what happens with loop diuretics where increased action of Na/K ATPase and therefore increased excretion of K+ and acid. By increasing the sodium and water excretion there is a decrease in extracellular volume and a decrease in CO and renal blood flow. Unlike loop diuretics, thiazides are able to increase the reabsorption of calcium preventing kidney stones.
Taken orally with half life of 40hrs – takes 1-3 weeks to produce stable effect. Long term treatment with thiazides will allow for normal plasma volume, but a sustained decrease in peripheral resistance therefore lowering blood pressure.

Question 11

13. What are examples of Thiazide diuretics?

Answer 11

1. Hydrochlorothiazide
2. Chlorthialidone – long duration of action (half life = 40-60hrs), used to treat HTN once daily
3. Metolazone – most potent, causes Na+ excretion in advance kidney failure

Question 12

14. What are Thiazides used for clinically?

Answer 12

1. mild to moderate HTN – first-line anti-hypertensive in black/elderly pts who do not respond well to treatment with ACEIs or ARBs.
2. treatment of edema due to heart failure
3. used off label for tx of diabetes insipidus – thinking is that the antidiuretic effect of thiazides is a result of induced sodium deficit causing reduced serum osmolality and decreased thirst
4. HypercalciURIA → inhibits Ca2+ excretion therefore decreases amt of calcium being excreted that can precipitate in the tubules therefore particularly useful for kidney stones
5. Premenstrual edema
6. Counteract sodium and water retention drugs – therefore are useful in combination therapy

Question 13

15. What is hydrochlorothiazide?

Answer 13

Hydrochlorothiazide is a thiazide diuretic that used to be the treatment of edema for hepatic cirrhosis, but has since been replaced by spironolactone. Hydrochlorothiazide also used to be used in the management of edema in patients with renal dysfunction, but has since been replaced with loop diuretics (ex. furosemide).

Question 14

16. What are the adverse side effects of thiazide diuretics?

Answer 14

1. Hypokalemia
2. Hyponatremia
3. Hyperuricemia → due to competition for organic secretory pathway in proximal tubule by thiazides and uric acid
4. Hypercalcemia
5. Hyperglycemia → thiazides decrease glucose tolerance
6. Hyperlipidemia → b/c they increase plasma levels of LDL cholesterol, total cholesterol and total triglycerides
7. Hypersensitivity

Question 15

17. What are K+ sparing diuretics?

Answer 15

Potassium sparing diuretics are competitive aldosterone antagonists (inhibitors). Therefore these diuretics act on the aldosterone receptors [that activate ENaC (Na+ reabsorber) and ROMK (K+ excreter)] at the late distal and cortical collecting ducts causing salt and water retention. These drug antagonize aldosterone at intracellular cytoplasmic receptor sites preventing the translocation of receptor complex into the nucleus. The levels of aldosterone determine effect of diuretics. The higher the amt of aldosterone the greater the effect of the antagonist/diuretic.

Question 16

18. What are examples of K+ sparing diuretics aldosterone antagonists?

Answer 16

1. Spironolactone (active metabolite = canrenone) – part of 1st line therapy in pts with HTN and severe LV dysfunction
2. Eplerenone
   * both given orally and strongly bound to proteins with half life of 2-3 days

Question 17

19. What is the clinical use of Spirnolactone?

Answer 17

1. management of edema associated with excessive aldosterone excretion or in CHF that is non-responsive to other drugs
2. HTN
3. Primary hyperaldosteronism diagnosis
4. Hypokalemia
5. Cirrhosis of liver accompanied by edema or ascites
6. Nephrotic syndrome
7. Severe heart failure → increases survival and reduce hospitalization when added to standard therapy b/c it prevents cardiac remodeling (esp. with spironolactone)
8. Off label tx of female acne and hirsuitism

Question 18

20. What is a major side effect of Spironolactone?

Answer 18

Spironolactone has affinity toward progesterone and androgen receptors where it acts as an antagonist and thereby induces side effects such as gynecomastia, impotence, and menstrual irregulatories. Eplerenone (different K+ sparing diuretic) has low affinity for these receptors therefore is less likely to produce these effects.

Question 19

21. What are the adverse side effects of K+ sparing aldosterone antagonist diuretics?

Answer 19

1. gastric upset and peptic ulcers → spirnolactone
2. endocrine effects
3. hyperkalemia – due to reduced potassium excretion
4. hyperchloremic metabolic acidosis → by inhibiting H+ secretion in parallel with K+ secretion
5. drowsiness, lethargy, ataxia, confusion, headache
   * Eplerenone - lack of adverse side effects

Question 20

22. What are examples of K+ sparing inhibtors of renal epithelial Na+ channel diuretics?

Answer 20

1. Amiloride

2. Triamterene

Question 21

23. What is the mechanism of action of Amiloride and Triamterene?

Answer 21

Both of these drugs cause a small increase in NaCl excretion and are usually initiated due to their antikaliuretic actions to offset the hypokalemia seen with other diuretics (furosemide and thiazides). Both drugs competitively inhibit ENaC at the collecting duct. K+ secretion is inhibited b/c o the loss of Na+ driving force. These drugs DO NOT rely on the presence of aldosterone to function.

Question 22

24. Discuss the metabolism of Amiloride and Triamterene.

Answer 22

Triamterene → metabolized in liver, renal excretion of active form and metabolites
Amiloride → urinary excretion of intact drug

Question 23

25. What are the adverse side effects of Amiloride and Triamterene?

Answer 23

1. hyperkalemia
2. hyponatremia
3. leg crampsGI upset
4. dizziness, pruritus, headache, minor visual changes
5. Reduced glucose tolerance → Triamterene
6. Photosensitization → Triamterene
7. Interstitial nephritis → Triamterene
8. Renal stones → Triamterene

Question 24

26. What are carbonic anhydrase inhibitors?

Answer 24

Carbonic anhydrase inhibitors [ACETAZOLAMIDE] inhibit intracellular and extracellular forms of carbonic anhydrase resulting in a reduction of bicarb reabsorption in the proximal convoluted tubules and decrease production of H+ inside the cell therefore decreasing Na+/H+ antiporter activity. This decreases Na+ reabsorption. This drug only has a mild diuretic action b/t bicarb depletion enhances NaCl reabsorption by remainder of nephron.

Question 25

27. What are the clinical uses of Acetazolamide?

Answer 25

1. Glaucoma → decreases formation of aqueous humor and thereby decrease intraocular pressure, pre-op management of angle-closure glaucoma and tx for open-angle glaucoma 2. Mountain sickness → excrete bicarb, acidify blood, increase ventilation, increase amt of O2 in blood 3. Metabolic alkalosis → increased H+ in blood 4. Epilepsy * medication is given orally and is excreted unchanged in proximal renal tubule – therefore, dose must be reduced if there is renal insufficiency

Question 26

28. What are the adverse effects of Acetazolamide?

Answer 26

1. metabolic acidosis → reduction in bicarb stores 2. hyponatremia 3. hypokalemia 4. renal stones (Crystalluria) → phosphaturia and hypercalciuria during bicarbonaturic response 5. malaise, fatigue, depression, drowsiness, paresthesias (with large doses) 6. hypersensitivity allergic reactions

Question 27

29. What is the mechanism of osmotic diuretics?

Answer 27

Osmotic diuretics increase osmotic pressure of the plasma thus draws water out of the body tissue and produces osmotic diuresis. Osmotic diuresis expands the extracellular fluid volume, decreases blood viscosity and inhibits renin release. There is an increased urine excretion of nearly all ions/electrolytes: Na+, K+, Ca2+, Mg2+, Cl-, bicarb, phosphate. There is no effect on sodium excretion directly only that it increases urine volume.

Question 28

30. What is an example of drug that acts as an osmotic diuretic?

Answer 28

Mannitol | *delivered via IV b/c only a small amt can be absorbed through GI tract

Question 29

31. What are the clinical uses of Mannitol?

Answer 29

1. reduction of increased intracranial pressure associated with cerebral edema 2. reduction of increased intraocular pressure 3. promotion of urinary excretion of toxic substances 4. genitourinary irrigant in transurethral prostatic resection 5. other transurethral surgical procedures

Question 30

32. What are the adverse side effects of Mannitol?

Answer 30

1. extracellular volume expansion and hyponatremia | 2. tissue dehydration

Question 31

33. What are the contraindications for Mannitol?

Answer 31

Active cranial bleeding, CHF, pulmonary edema

Question 32

34. What are ADH antagonists?

Answer 32

Ex. Conivaptan – ADH antagonists inhibit the effect of ADH in the collecting tubule byt acting on V1 and V2 receptors. Therefore, if the collecting duct cannot reabsorb water, then the urine will end up diluted. Conivaptan is administered by IV and is metabolized by CYP3A4. It also acts as an inhibitor of CYP3A4.

Question 33

35. What is the clinical use of Conivaptan?

Answer 33

1. euvolemic and hypervolemic hyponatremia in hospitalized pts 2. treatment of SIADH 3. heart failure – only when benefits outweigh risks

Question 34

36. What are the adverse side effects of Conivaptan?

Answer 34

1. nephrogenic diabetes insipidus 2. infusion site reactions 3. atrial fibrillation, GI and electrolyte disturbances

Question 35

37. What are the contraindications of Conivaptan?

Answer 35

1. hypovolemic hyponatremia | 2. renal failure