Week 1: PHM-Diuretics

Question 1

Which 2 classes of diuretics combine at the thick descending & ascending limbs acting synergistically?

Answer 1

Loop and Thiazine; ex of how adding 2+ diuretics from different classes have synergistic action as long as sites of action differ

Question 2

What is the site and MOA of carbonic anhydrase inhibitors?

Answer 2

Site: PCT MOA: Inhibit CA in lumen and in tubular cells. Decrease sodium bicarbonate reabsorption and causes HCO3 diuresis (may even lead to metabolic acidosis) *Normally, intraluminal/cellular mechanisms turn HCO3 into carbonic acid, which will dissociate into H2O and CO2 to be reabsorbed intracellularly by CA to regulate Na and H2O

Question 3

How can CA inhibitors lead to Ca stones?

Answer 3

CA inhibitors alkalinize the urine; uric acid and cysteine and relatively insoluble in acidic urine and stones may form but their solubility can be enhanced by pH increase *excessive alkalization can lead to Ca stones*

Question 4

Why are CA inhibitors used to treat alkalosis induced by excessive use of other diuretics?

Answer 4

CA inhibitors induce hyperchloremic metabolic acidosis

Question 5

What diuretic class is used as prophylaxis/Tx of acute mountain sickness?

Answer 5

CA Inhibitors

In severe cases, rapidly progressive pulmonary and cerebral edema can occur.
But CSF formation and pH decrease so drugs like acetazolomide can ↑ ventilation and ↓ Sx

Question 6

When are CA inhibitors contraindicated?

Answer 6

Liver Disease!

Urinary alkalinization->ammonia diversion in urine into systemic circulating, inducing worsening hepatic encephalopathy

Question 7

What are 3 side effects/toxicities of CA Inhibitors?

Answer 7

1) Phosphaturia and Hypercalciuria
2) K Wasting: ↑ Na presented to CT (w/ HCO3) partially reabsorbed; lumen’s (-) electrical potential ↑ enhanced K secretion
3) Drowsiness and paresthesia: w/ higher doses from potential inhibition of CA in CNS

Question 8

What are 3 ex’s of CA Inhibitors?
Which 2 are used for glaucoma Tx?*

Answer 8

1) Acetazolomide
2) Dichlorphenamide*
3) Methazolamide*

Question 9

What is a PK consideration for CA Inhibitors?

Answer 9

efficacy ↓ after several days use

↓ HCO3 in glomerular filtrate; HCO3 depletion
->enhanced NaCl reabsorption by remainder of nephron

Question 10

What is the site and MOA of loop diuretics?

Answer 10

Site: cortical and medullary thick ascending limb

MOA: inhibits NKCC2
↓ reabsorption of NaCl and ↓ lumen (+) potential that comes from K recycling
↓ in (+) potential also causes ↑ Mg and Ca excretion

Question 11

What 2 things can loop diuretics stimulate?

Answer 11

1) Briefly stimulates RBP and ↓ peripheral venous compliance
2) Stimulates PGN synthesis in lung and kidney
*PG2 can enhance diuretic effect*

Question 12

What drug class can interfere w/ loop activity especially in 2 comorbid conditions*?

Answer 12

NSAIDs ↓ PG synthesis in kidney

Interferes w/ loop activity’s diuretic effects for pts w/ nephrotic syndrome* and hepatic cirrhosis*

Question 13

What are the 1st and 2nd line indications for loop diuretics?

Answer 13

1st: acute pulmonary edema; Tx for CHF to ↓ venous and pulmonary congestion
K, Mg, Ca excretion ↑ bc NKCC inhibited

2nd (or in combo w/ thiazide diuretics): HTN or severe HF in pts who are diuretic resistant

Question 14

What class can help in acute and chronic renal failure patients but can’t prevent or shorten duration?

Answer 14

Loop Diuretics

Question 15

What are 4 side effects of Loop Diuretics?

Answer 15

1) Hypochloremic metabolic alkalosis: ↑ Na delivery to distal tubule-> ↑ urinary excretion of K and H
2) Hypokalemia
3) Hypomagnesemia
4) Hyperuricemia: may precipitate gout attacks
*shouldn’t be used in pts w/ hx*

Question 16

What is a possible dose related side effect of Loop Diuretics?

Answer 16

Hearing loss

From alts in electrolyte composition in inner ear fluid; usually reversible

Question 17

What is a cross-reactivity risk w/ Loop Diuretics?

Answer 17

Pts w/ sulfonamide allergy

Question 18

What are 4 ex’s of Loop Diuretics?
Which one can be used for sulfa allergic?*

Answer 18

1) Furosemide
2) Bumetanide
3) Torsemide
4) Ethacrynic Acid*

Question 19

Why is the hypocalcemia generated w/ Loop Diuretics not a concern?

Answer 19

Bc Ca actively reabsorbed in DCT

Question 20

What might loop diuretics enhance in hypercalcemic disorders? Does this offer Tx potential?

Answer 20

↑ Ca excretion

May be used to Tx mild hyperkalemia

Question 21

What is the site and MOA of Thiazide diuretics?

Answer 21

Site: DCT

MOA: Inhibits NaCl reabsorption from luminal side of epithelial cells in DCT by blocking NaCl transporter

Question 22

Which class is a “ceiling diuretic?”

Answer 22

Thiazide Diuretics

↑ dose above normal doesn’t further diurese

Question 23

How do Thiazide Diuretics affect Ca levels?

Answer 23

↓ renal excretion of Ca
(+) in treating Ca containing urinary stones

Question 24

In what clinical condition are Thiazide diuretics indicated?

Answer 24

Diabetes Insipidus

Question 25

What are the primary indications and uses of Thiazide Diuretics?

Answer 25

Primarily results in contraction of ECF volume - (+) in HTN and mild CHF Tx - Edema assoc w/ liver and renal diseases Adjunct to loop diuretics

Question 26

``` Which class is 1st line Tx for Nephrogenic Diabetes Insipidus? 3 effects and clinical manifestations ```

Answer 26

**Thiazide Diuretics** 1) Paradoxically reduce polyuria 2) Plasma vol ↓, leading to enhanced proximal reabsorption of NaCl and H2O; ↓ fluid delivery to distal segments 3) ↑ expression of Na transporters in DCT and collecting tubules Clinical: Excretion of large vols of dilute urine; hyponatremia, lethargy, anorexia, N/V, muscle cramps

Question 27

What are 2 rare side effects of Thiazide Diuretics?

Answer 27

Photosensitivity and generalized dermatitis

Question 28

What are 8 metabolic consequences of Thiazide Diuretics?

Answer 28

1) Metabolic alkalosis 2) Hyponatremia (from ↑ ADH and thirst) 3) Hypokalemia 4) Hypomagnesemia 5) Hypochloremia 6) Uric acid and Ca retention 7) Hyperglycemia 8) Hyperlipidemia

Question 29

What are 3 possible causes of hyperglycemia from Thiazide Diuretics?

Answer 29

1) Impaired pancreatic rel of insulin 2) ↓ tissue use of glucose 3) ↓ glucose tolerance, even unmasking DM \*Seen in doses \> 50 mg, not in doses 12.5 mg

Question 30

What are 4 ex's of Thiazide Diuretics? What are 2 special indications?

Answer 30

1) Hydrochlorothiazide 2) Chlorothiazide 3) Chlorothalidone\* 4) Metolazone\* \*Chlorothalidone: ↓ stroke and heart attacks in HTN (over HCTZ) \*Metolazone: CHF pts resistant to loop diuretics, add-on to loop

Question 31

What is the site and MOA of ADH Antagonists?

Answer 31

Site: Collecting Duct MOA: Inhibits ADH effects can ↓ peripheral vascular resistance and ↑ CO

Question 32

When are ADH Antagonists not inidicated?

Answer 32

HTN or HF settings

Question 33

What are 2 ex's of ADH Antagonists? What is a special consideration for 1?

Answer 33

1) Conivaptan \*must be infused IV 2) Tolvaptan

Question 34

What are 2 indications for ADH Antagonists?

Answer 34

1) Hypervolemic and euvolemic hyponatremia (not corrected w/ fluid resuscitation) 2) SIADH mgmt when H2O restriction has failed

Question 35

What is a side effect and consideration for ADH Antagonists?

Answer 35

1) Severe hypernatremia \*Too rapid correction of Na can cause osmotic demyelination-\> dysphagia, lethargy, seizures, even death

Question 36

What is an ex of an osmotic diuretic?

Answer 36

Mannitol

Question 37

What are 2 considerations for the osmotic diuretic Mannitol?

Answer 37

Rapid distribution in ECF and H2O extraction from cells 1) prior to diuresis, acute ↑ in ECF vol and hyponatremia can complicate HF and produce pulmonary edema 2) excessive use w/o adeq H2O replacement can lead to severe dehydration and hypernatremia

Question 38

What are 2 side effects of osmotic diuretics?

Answer 38

1) N/V, headache from initial hyponatremia 2) Hyperkalemia: H2O extracted from cells, intracellular K ↑ leading to cellular losses and ↑ in extracellular compartments

Question 39

What are 5 indications and responses for osmotic diuretics?

Answer 39

1) ↓ extracellular vol and pressure 2) ↑ H2O excretion rather than Na, compared to other classes 3) ↓ intraocular pressure 4) prevents acute renal failure after severe trauma or complicated surgical procedures, resulting in large pigment load on kidneys (from hemolysis/rhabdomyolysis) 5) promotes renal excretion of toxins

Question 40

When are osmotic diuretics not useful?

Answer 40

Conditions w/ Na retention

Question 41

What are 4 ex's of K sparing Diuretics?

Answer 41

1) Spironolactone 2) Eplerenone 3) Triamterene 4) Amiloride

Question 42

What are 2 side effects of K Sparing Diuretics?

Answer 42

1) Hyperkalemia: esp in aldo receptor antagonists, risk ↑ w/ renal disease 2) Hyperchloremic metabolic acidosis by inhibiting H and K secretion

Question 43

What are side effects specific to the K sparing diuretic spironolactone (not eplerenone!)?

Answer 43

Endocrine abnormalities on steroid receptors: androgen and progesterone 1) Gynecomastia 2) Hirsutism 3) Impotence 4) Benign prostatic hyperplasia 5) Menstrual irregularities

Question 44

What is the site of action and 2 MOA's for K sparing diuretics?

Answer 44

Site: Cortical collecting tubule MOA 1: competitive aldosterone antagonist (↓ EF): *Spironolactone and Eplerenone* MOA 2: interferes w/ Na influx through epithelial Na ion channels in luminal membrane of collecting ducts *Triamterene and Amiloride*

Question 45

What are 2 general PD effects of K sparing diuretics? What about for spironolactone and amiloride?

Answer 45

1) Na/K exchange sites are not stimulated 2) Prevents Na reabsorption and K/H secretion Spironolactone: prevents protein synthesis that normally responds to aldo Amiloride: directly blocks ENac

Question 46

When is the K sparing diuretic Spironolactone indicated?

Answer 46

Most effective in primary and secondary hyperaldosteronism \*Prevents aldosterone binding to its receptor\* Also cirrhotic edema (ascites) Tx Vs. hypokalemia (in combo w/ Loop or Thiazide)

Question 47

What might evoke secondary hyperaldosteronism?

Answer 47

HF, Hepatic Cirrhosis, Nephrotic Syndrome

Question 48

What is the K sparing diuretic Eplerenone and its effects?

Answer 48

Spironolactone analogue w/ greater SP for aldo receptors and fewer AE Interferes w/ fibrotic and inflammatory effects of aldosterone, slows progression of albumineria in diabetes

Question 49

How do Triamterene and Amiloride work and when are they indicated?

Answer 49

Directly interfere w/ Na entry Can counteract K wasting of Thiazide (all K sparing diuretics) Used in combo w/ Thiazide for HTN Tx

Question 50

What are the 3 sites of action for osmotic diuretics?

Answer 50

1) **Proximal Tubule:** ↓ Na reabsorption by osmotic gradient, ↑ urine vol 2) **Descending LOH:** ↑ medullary blood flow, inhibits passive reabsorption of H2O 3) **Collecting Duct:** via osmotic effects, opposes ADH action

Question 51

``` Which class of diuretics is indicated for Diabetes Insipidus? How do the two types of DI compare? In which one is administration of ADH or an analogue uniquely effective?\* ```

Answer 51

**Thiazide Diuretics** * Central DI*: deficient production of ADH (adjunct Tx)\* * Nephrogenic DI*: inadequate responsiveness to ADH (1st line)