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Renal Pharm > Diuretics and Aquaretics > Flashcards

Diuretics and Aquaretics Flashcards

1
Q

What is the main goal/purpose of diuretic use?

A

to moblilze or get rid of Na+

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2
Q

What does potency of a diuretic refer to?

A

The extent to which they moblize Na+ (more potent=more Na+ loss in urine)

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3
Q

Which diuretic classes act predominantly in the PCT? (2)

A
  1. CA Inhibitors 2. Osmotic Diuretics
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4
Q

Which diuretics act along the L of H?

A

Loop Diuretics

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5
Q

Which diuretic classes act predominantly in the DCT? (3)

A

Thiazide Diuretics, Aldosterone Antagonists, K-Sparing Diuretics

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6
Q

What are the two major areas of the nephron where CA is present and in what relative amounts?

A
  1. 90% in PCT

2. 10% in DCT

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7
Q

What is a specific CA Inhibitor?

A

Acetazolamide

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8
Q

What is the mechanism of action of CA inhibitors?

A

They are potent competitive inhibitors of CA, acting in PT (90%) and DT (10%), resulting in bicarbonate loss in the urine (as H+ needed for HCO3- reabsorption is not produced)

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9
Q

What is the net effect of CA inhibitor use? (2)

A
  1. Alkaline urine

2. Enhanced chloride reabsportion (leading to hyperchloremic systemic acidosis)

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10
Q

Clinical uses of CA Inhibitors? (4)

A
  1. In Glaucoma to reduce intraocular pressure
  2. To alkalinize tubular urine in patients with Cystinuria
  3. Management of seizures
  4. Prophylaxis for mountain sickness
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11
Q

Side effects of CA inhibitors? (2)

A
  1. Metabolic Acidosis

2. Markedly increases K+ loss in urine for one day (acute hypokalemia bc MD goes crazy)

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12
Q

What are the characteristics of Osmotic Diuretics (4)? One example?

A

Small (1) molecules that are filtered (2) but not reabsorbed (3) by the kidney; they are inert (4) (have no other pharmacologic effect; Example→Mannitol

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13
Q

What is the mechanism of action of Osmotic Diuretics? What two places do they effect?

A
  1. PCT (minor)→They osmotically inhibit Na+/H20 reabsorption in the PCT.
  2. Loop (major)→They expand ECFV by increasing plasma osmolarity (decreased blood viscosity as water is drawn out of peripheral tissues)→ increase renal medullary blood flow→ reduces the medullary tonicity→impairs the ability of thin segments of L of H to extract H2O and reabsorb NaCl
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14
Q

Net effect of Osmotic Diuesis use?

A
  1. Significantly increase urine flow and volume with small increments of Na+, K+, and Cl-
  2. Initially increases plasma volume and BP
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15
Q

Clinical uses of Osmotic Diuretics? (3)

A
  1. Treatment of Dialysis Disequilibrium Syndrome
  2. Reduce Intracranial Pressure
  3. Reduce Intraocular Pressure
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16
Q

Side effects of OD’s? (2)

A
  1. Volume Overload

2. Contraindicated in patients with heart failure (may not be able to tolerate the volume expansion)

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17
Q

What is the mechanism of action and effect of Loop Diuretics?

A

Inhibit Na-K-2Cl symporter in TALH and the ability of MD to sense NaCl.
Increase RBF
Increase Prostaglandin biosynthesis
Stimulate renin release and maintain GFR

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18
Q

What are the three ways that LD’s increase renin release inside the kidney?

A
  1. Inhibiting the MD
  2. Reflexively activating the sympathetic NS
  3. Stimulating intrarenal baroreceptor mechanisms
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19
Q

Net effects of LD use? (3)

A
  1. Copious diuresis with significant Na loss
  2. Increase K+, Ca2+, and Mg2+ excretion
  3. Increased excretion of H+ resulting in mild metabolic alkalosis

STAR: Impairs ability of kidney to concentrate urine, resulting in copious diuresis while maintaining GFR

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20
Q

What are three examples of LD’s?

A

Furosemide (Lasix), Bumetanide, Torsemide

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21
Q

Therapeutic uses of LD’s? (6)

A
  1. Moderate to severe Edema or HTN due to cardiac, hepatic, and/or renal failure (GFR<30ml/min)
  2. Acute pulmonary edema→rapid mobilization of edema fluid
  3. Mobilization of Ca2+ in hypercalcemia
  4. Maintenance of renal PGs, renin, and GFR to prevent renal failure
  5. Wash out toxins by increasing urine flow
  6. Antihypertensive particularly when GFR is very low (often in combo with other drugs)
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22
Q

What effects allow LD’s to aid in the treatment of Acute pulmonary edema? (4)

A

Decrease Pulmonary wedge pressure, Venodilation resulting in reduced LV filling pressure, Increased compliance of pulmonary vasculature that facilitates mobilization of fluids, Brisk copious diuresis

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23
Q

What is the most potent class of diuretics?

A

Loop Diuretics

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24
Q

What is required for Furosemide to be able to inhibit the luminal NK2C symporter?

A

It must first be secreted into the lumen by organic acid transporters in the PCT into the lumen.

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25
Q

Dose-response curve of Furosemide is shifted to the right by what?

A

Renal disease (impaired secretion); in patients with renal disease and reduced GFR, the dose has to be increased from 20 (normal) to 200 mg/day.

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26
Q

Is it ok to dramatically increase the amount of Furosemide given to patients with Renal disease and low GFR? Why?

A

Yes; because it has a wide margin of safety (TI; the minimum beneficial concentration is much lower than the MTC)

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27
Q

What are the side effects of Furosemide?

A
  1. Fluid and electrolyte imbalance (hypokalemia and pH disorders, mostly alkalosis)
  2. Ototoxicity (dont give with streptomycins which have this same effect)
  3. Elevated BUN, Hyperglycemia, Hyperuricemia
  4. Drug interactions
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28
Q

What are some drug interactions of furosemide?

A
  1. Li+ 2. Indomethacin (NSAIDs which reduce effectiveness by inhibiting PG synthesis) 3. Probenecid (impairs secretion)
  2. Warfarin
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29
Q

Why is furosemide contraindicated in patients taking warfarin?

A

Warfarin is 99% protein bound, while Furosemide is 80% protein bound. Furosemide could displace warfarin, drastically increasing its therapeutic levels, resulting in bleeding.

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30
Q

Which LD is taken instead of furosemide in patients taking warfarin?

A

Bumetanide (40x more potent than furosemide)

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31
Q

What does torsemide do? How is it different than other LD’s (2)?

A

It’s a vasodilator:

  1. It’s a long-lasting LD (given once daily; longer half-life)
  2. In addition to diuretic effect, it also lowers blood pressure
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32
Q

How much of the GFR is handled in the DCT? What happens to the tubular fluidin the DCT?

A

Only 10% of GFR is handled in DCT, where fine-tuning of urinary volume and composition takes place.

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33
Q

What are the three different segments in the DCT?

A
  1. Na-K Aldosterone-Independent segment (has Na-Cl symporter; Na reabs without H2O reabs)
  2. Aldosterone-Sensitive segment (Na exch’d for H+ and K+)
  3. Sodium Load Segment (Na reabs is proportional to amt of Na that reaches this segment in exch for H+ and K+)
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34
Q

How much of the Na+ filtered is absorbed in the inner medullary CD and what two types of Na+ channels are expressed in IMCD?

A

Up to 5%; 1. Amiloride-sensitive cyclic nucleotide gated (CNG) cation channel 2. Low-conductance highly selective ENaC channel

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35
Q

What is the other name for Thiazide Diuretics (TDs) and what are some specific examples?

A

Benzothiadiazides;

1. Hydrochlorothiazide (HCTZ) 2. Chlorthalidone 3. Metolazone (4. Quinethazone 5. Indapamide)

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36
Q

What is the mechanism of action of TD’s?

A

They inhibit Na-Cl symporter in the aldosterone-independent segment of the early DCT.

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37
Q

What is the net effect of TD use? (4)

A
  1. Mild loss of Na+ and water
  2. Na+ loss leads to reduced GFR (w/ chronic use)
  3. Elevated K+ excretion→Hypokalemia
  4. Increased H+ excretion (as titratable acid HCl)→Hypochloremic Alkalosis
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38
Q

How do TD’s compare to LD’s in excretion of Mg2+ and Ca2+

A

LD’s increase urinary excretion of both, while TD’s increase urinary excretion of Mg2+ but decrease urinary excretion of Ca2+

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39
Q

Therapeutic uses of TD’s?

A
  1. Treatment of mild to moderate edema
  2. Alone in Essential Hypertension (as arterial vasodilators) and to augment other antihypertensives
  3. Hypercalciurea (to aid with kidney stones) and Osteoporosis→related to reduced Ca2+ excretion
  4. Management of NDI
40
Q

Side effects of TD’s?

A
  1. Depletion: Hypokalemia, Hypomagnesemia
  2. Retention: Hyperuricemia, Hypercalcemia, Hyperglycemia
  3. Lipid Disorders
41
Q

What are the two classes of TD’s? When are they used?

A

A. Class 1→ preferred choice when GFR>50ml/min: HCTS, Chlorthalidone, Quinethazone
B. Class 2→more potent; might be effective when 30<50ml/min: Metolazone, Indapamide

42
Q

What is the diuretic of choice when GFR<30ml/min?

A

LD

43
Q

Which requires monitoring LD or TD? Which require(s) secretion to exert their effect? Which is more potent? Why?

A

LD’s; both; LD’s; because of how much Na+ is available to prevent reabs of at their sites of action

44
Q

What are the two types of cells composing the late DCT and CD?

A
  1. Principal cells

2. Intercalated cells

45
Q

What are the two types of principal cells?

A 
Type A (hormonally responsive)
Type B (load responsive)
46
Q

What do Type A principal cells do? How are they regulated?

A

They are involved in Na+ reabsorption and K+ secretion. They are hormonally regulated by ALDOSTERONE.

47
Q

What do Type B principal cells do? How are they regulated?

A

They too are involved in Na+ reabsorption and K+ secretion (but K+ secretion to a lesser extent than Type A cells). They are LOAD-DEPENDENT; the more Na+ that is delivered, the more is reabsorbed in exchange for K+ secretion.

48
Q

Describe the physiological action aldosterone in Type A principal cells in DCT:

A

Ald binds MR in DCT cells, the complex translocates to the nucleus (transcr factor) and increases the expression of ENaC channels and K+ channels in the luminal membrane. So, transepithelial Na+ transport is increased, increasing lumen-negative transepithelial voltage, which increases secretion of K+ and H+.

49
Q

What are specific examples of aldosterone antagonists? (2)

A

Spironolactone and Eplenorone

50
Q

What is the mechanism of action of aldosterone antagonists?

A

Competitively inhibit aldosterone by binding to aldosterone receptor in the late DT and CD.

51
Q

What is the net effect of aldosterone antagonists? (2)

A
  1. Increased urinary excretion of Na+ (natriuretic effect)

2. REDUCED EXCRETION OF K+ (K-SPARING)

52
Q

What is unique about the PK’s of spironolactone?

A

It is a prodrug that is extensively metabolized to its active form.

53
Q

What is the active form of spironolactone?

A

Canrenone

54
Q

What are the clinical uses of aldosterone antagonists?

A
  1. Spironolactone is used as a mild diuretic in combination with HCTZ
  2. Diuretic of choice for Cirrhosis
55
Q

What are the side effects of aldosterone antagonists?

A
  1. Hyperkalemia
  2. Gynecomastia (in males)
  3. HIrsutism and uterine bleeding (in females)
    2 and 3 are the result of its structural similarity to sex steroids
56
Q

What is useful about Eplenerone? Why?

A

It is safer, causing less side effects because it has a lower affinity for androgen receptors

57
Q

What is the drug that combines both Spironolactone and HCTZ called? Why combine them?

A

Aldactazide; get the effect of HCTZ without the hypokalemia

58
Q

What are the 2 K-Sparing Diuretics?

A

Triamterene and Amiloride

59
Q

What is the mechanism of action of K-sparing diuretics?

A

They inhibit Na+ reabsorption and K+ secretion in the late DT and CD (sodium load segment).

60
Q

Why do they not cause hirsutism and gynecomastia like aldosterone antagonists?

A

They are organic bases and are not structurally related to aldosterone.

61
Q

What are the pharmacological effects of K-sparing diuretics?

A
  1. Increase urinary excretion of Na+ (weak effect)

2. Inhibit the secretion of K+ and H+ (K-sparing)

62
Q

How are K-sparing diuretics used?

A

Diuretics combined with HCZT to increase their effectiveness and reduce K+ excretion.

63
Q

What is the combination of a K-sparing diuretic and HCZT called?

A

Dyazide

64
Q

What are the side effects of K-sparing diuretics?

A

Hyperkalemia, megaloblastic anemia in patients with cirrhosis

65
Q

What is the mechanism of ANP (& BNP)

A

They are produced in response to stretch. They bind to NPR(A) which activates GC which increases cGMP which inhibits the nonspecific CNG cation channel in the IMCD. This increases Na+ urinary excretion.

66
Q

What is recombinant BNP?

A

Nesiritide

67
Q

What does Nesiritide do? What are its side effects? In what patients is it used in?

A

It increases Na+ excretion;
Numerous side effects related to its low TI;
Mostly used in patients with low CHF (it vasodilates via cGMP→NO, reducing pressure and inreasing CO)

68
Q

How are diuretics in general used?

A

as monotherapy or as adjuncts

69
Q

What are the clinical uses of diuretics? (2)

A
  1. Hypertension (alone or in combo with ACEI’s or B-blockers)
  2. Patients with Edematous conditions (heart or renal failure) require diuretic for BP control
70
Q

Why are diuretics good drugs?

A

The induce therapeutic responses at lower doses and are cheap. USE AT LOW DOSES

71
Q

Patients with volume dependent hypertension (low renin levels) respond best to which diuretic class?

A

Thiazides

72
Q

When should you take thiazides? Why?

A

Once in the morning to reduce K+ wasting during nightime sleep

73
Q

Which diuretics require montioring?

A

Loop diuretics

74
Q

K-sparing diuretics are useful in patients with what?

A

risk of K+ depletion

Hyperuricemia (gout)

75
Q

What is the drug of choice in cirrhosis?

A

Spironolactone

76
Q

When is ADH (AVP) released? (3 triggers)

A
  1. Elevation in plasma osmolarity> 280mOsm/kg
  2. Depletion of ECFV (dehydration, bleeding)
  3. Other: pain, nausea hypoxia
77
Q

What is the result of AVP activation of its V1 receptor (in vascular smooth muscle)?

A

Activation of Gq-PLC-IP3 pathway, mobilizing Ca2+ causing vasoconstriction of precapillary arterioles.

78
Q

Where is the V2 AVP Receptor located?

A

in principal cells in the renal CDs

79
Q

What happens when AVP binds V2 Receptor in principal cells?

A

Activates Gs→cAMP→PKA, which phosphorylates AQP-2 increasing the insertion of water channel containing vesicles into the apical membrane of CD.

80
Q

How are AQP-2’s inserted into the membrane to form a water channel?

A

after being phosphorylated by PKA, they are inserted into the apical membrane as tetramers forming water channels.

81
Q

What is the result of AQP-2 channels?

A

Increased permeability of CD to water, ultimately allowing the CD to concentrate urine.

82
Q

What else does PKA do?

A

Increases the permeability of the CD to urea

83
Q

What is the net result of V1 rec agonists? V2 rec agonists?

A

vasopresser (vasoconstrictor);

increased water permeability in the CD

84
Q

What do aquaretics do?

A

they interfere with the handling of water in the kidney

85
Q

When are V1R agonists used? Why are they rarely used?

A

to reduce bleeding in esophageal varices or bleeding ulcers;

numerous side effects

86
Q

What is DI? Symptoms of Diabetes Insipidus (DI)?

A

Impaired water conservation caused by defects in ADH system;

Excrete large volumes of dilute urine, polydipsia (drink lots of water)

87
Q

How is CDI distinguished from NDI?

A

CDI is sensitive to ADH, so urine osmolarity will increase when administered a V2R agonist; while NDI will not respond to the V2R agonist

88
Q

Causes of CDI? NDI?

A

Head injury, trauma, radiation, etc affecting pituitary (ADH synthesis and release);
V2R mutations, drugs, obstructive renal disease

89
Q

What agent is used to treat CDI?

A

Desmopressin (selective V2R agonist)

90
Q

Why does Desmopressin (DDAVP) not have the side effects of AVP?

A

It is highly selective for the V2R (doesn’t really bind to V1R)

91
Q

Why is DDAVP used to treat bleeding disorders? Other use?

A

It increases factor VIII and vWF levels via extrarenal V2R’s; it also is used to treat nocturnal enurisis

92
Q

How is NDI treated?

A

maintain adequate water intake and give a Thiazide Diuretic

93
Q

What is SIADH? How is it diagnosed? How is it treated?

A

Excessive production of ADH resulting in impaired water secretion and plasma hypo-osmolarity (hyponatremia);
Hypo-osmolarity;
Demeclocycline and Vaptans

94
Q

What are the two vaptans? How do they work?

A

Tolvaptan and Conivaptan; they are V2R antagonists

95
Q

What do they treat? Where are they used?

A

Hypervolemic and Euvolemic (dilutional) Hyponatremia (SIADH); used only in a hospital setting

Renal Pharm (4 decks)

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