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MHD/Pharm Block 4 > Pharm: Diuretics > Flashcards

Pharm: Diuretics Flashcards

1
Q

What is the definition of a diuretic?

A

a substance/drug that increases the discharge of urine

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2
Q

What was the original parent compound for diuretic drugs?

A

Sulfanilamide (an antibiotic) that causes metabolic acidosis and alkaline urine (NaHCO3 diuresis)

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3
Q

What are the diuretics empirically derived from sulfanilamide and how do they work?

A

Acetazolamide (CA inhibitor)
Dichlorphenamide (CA inhibitor)
Disulfamoylchloraniline (most commonly used diuretic today)

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4
Q

How does the kidney control ECF volume?

A

Adjusting NaCl and H2O excretion by altering nephron permeability, regulating ion channels

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5
Q

What happens if NaCl intake > output?

A

Edema develops

This happens in heart failure, renal failure

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6
Q

What does natriuretic mean?

A

Increased Na+ excretion

-In addition to diuretics increasing urine output, many also increase Na+ excretion (natriuretic)

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7
Q

What are the anatomical input(s) and output(s) to the kidney?

A

Input: renal artery
Outputs: renal vein and ureter

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8
Q

List the components of the nephron in order that filtered fluid traverses the nephron

A 
Glomerulus
Proximal convoluted tubule
Loop of henle (thin descending and ascending, thick ascending)
Distal convoluted tubule
Collecting ducts
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9
Q

What are the major substances reabsorbed and secreted in the proximal convoluted tubule?

A

Reabsorbed: NaHCO3, NaCl
Secreted: organic acids and bases

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10
Q

Is the thin descending limb H2O permeable or impermeable?

A

Permeable

Water is reabsorbed from the lumen leading to concentration of the tubular fluid

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11
Q

What is the major ion transporter in the thick ascending limb?

A

Na+/K+/2Cl- cotransporter pumps these cations out of the lumen

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12
Q

Describe the structure and function of the juxtaglomerular apparatus

A

Cells from distal convoluted tubule and glomerular afferent arteriole containing osmoreceptors (macula densa) and mechanoreceptors (JG cells) that regulate the RAA system via renin release

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13
Q

What ion is reabsorbed in the distal convoluted tubule and what regulates this reabsorption?

A

Ca2+ is reabsorbed in the DCT in the presence of PTH

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14
Q

What regulates the H2O permeability of the collecting duct?

A

In the presence of ADH, the collecting ducts are permeable to H2O due to aquaporin insertion

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15
Q

What regulates NaCl permeability of the collecting duct?

A

Aldosterone

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16
Q

What are the ions secreted in the collecting ducts?

A

K+ and H+ are secreted in the collecting ducts

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17
Q

Location of action of acetazolamide

A

Proximal convoluted tubule

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18
Q

Location of action of mannitol

A

Proximal convoluted tubule

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19
Q

Location of action of furosemide

A

Thick ascending limb

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20
Q

Location of action of thiazides

A

Distal convoluted tubule

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21
Q

Location of action of K+ sparing diuretics

A

Collecting ducts

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22
Q

Location of action of ADH antagonists

A

Collecting ducts

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23
Q

Diuretics primarily prevent Na+ ________________

A

Diuretics primarily prevent Na+ entry into the tubule cells

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24
Q

Where do diuretics have to get to in order to be effective?

A

They must reach the tubular fluid in order to be effective

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25
Q

Describe how diuretics reach the tubular fluid

A

Mannitol is filtered across the glomerulus

Most others are secreted via organic acid/base transporters in the proximal tubule

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26
Q

What primarily drives Na+ reabsorption throughout the tubule epithelial cells?

A

The Na/K ATPase pump on the basolateral membrane keeps a low [Na+] and a high [K+] inside the cells

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27
Q

Describe the pathway for Na+ and HCO3- absorption in the proximal convoluted tubule

A

Transporters: Na/H antiport on lumenal side, Na/HCO3- on basolateral side

1) Na enters cells via antiporter down gradient and is pumped out via Na/K pump
2) HCO3- is converted to CO2 and H2O in the tubules by CA, which then can diffuse into the cell
3) CO2 and H2O combine to form H+ and HCO3- via intracellular CA
4) HCO3- pumped out of cell into blood

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28
Q

What is the mechanism of action of acetazolamide?

A

Reversibly inhibits carbonic anhydrase, thus inhibiting the reabsorption of HCO3- in the proximal tubule

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29
Q

Describe the pharmacokinetics of acetazolamide

A

Good oral absorption
Effect begins ~30 minutes, lasts 12 hours
Renal secretion via OAT

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30
Q

What adverse events are associated with acetazolamide?

A

Metabolic acidosis (due to chronic excretion of HCO3-)
Hypokalemia (acute effect)
Calcium phosphate stones (due to high pH in tubule)
Drowsiness, paresthesias and hypersensitivity

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31
Q

What are the contraindications for acetazolamide?

A

Cirrhosis because serum NH3 is elevated by both liver failure and increased tubule pH

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32
Q

What is the relationship between ammonia excretion and urine pH?

A

Inversely related

Increased urine pH (like due to acetazolamide treatments) will decrease ammonia excretion, thus increasing serum ammonia

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33
Q

What are the CA inhibitors other than acetazolamide?

A

Dichlorphenamide: 30x potency
Methazolamide: 5x potency
Dozolamide: topical ocular use

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34
Q

What are the indications for acetazolamide treatment?

A 
Diuretic therapy (used in combination)
Glaucoma (reduce intraocular pressure)
Urinary alkalinization (treat overdose, stones)
Acute mountain sickness
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35
Q

What is the mechanism of action for mannitol?

A

Osmotic diuretic (holds water in tubule) that acts in the water permeable segments of the nephron (proximal tubule, descending loop, collecting ducts +ADH)

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36
Q

Describe the pharmacokinetics of mannitol

A

Not orally absorbed, so given IV to reach kidney

Half life is 1.2 h

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37
Q

What condition worsens adverse effects associated with mannitol?

A

AEs predominate if filtration is impaired because mannitol cannot reach the tubule without filtration

38
Q

What are the adverse effects associated with mannitol

A

Caused by increased plasma osmolarity, water leaves cells, Na follows

  • Acute pulmonary edema
  • Dehydration
  • Headache, nausea, vomiting
39
Q

What are the contraindications for mannitol?

A

CHF, renal failure, pulmonary edema

*CHF and RF reduce glomerular filtration, pulmonary edema would be exacerbated

40
Q

What are the clinical indications of mannitol?

A
  • Maintenance/Increase of urine volume (Renal failure, drug overdose)
  • Reduce intracranial/intraocular pressure (doesn’t cross BBB or enter eye, so it pulls fluid out)
41
Q

Describe the ionic movements in the thick ascending limb

A

Transporters: Na/K/2Cl cotransporter moves cations in from lumen, Na/K ATPase basolateral, K+/Cl- cotransport basolateral

1) ATPase maintains Na gradient to drive NaKCl cotransporter
2) K+ enters from both sides and diffuses back into lumen through channel creating a positive lumenal charge
3) Positive lumenal charge repels Mg and Ca promoting paracellular diffusion

42
Q

What is the mechanism of action of the loop diuretics?

A

Block the Na/K/2Cl cotransporter which increases urinary water, Na, K, Ca, and Mg excretion
- Also dilates venous system and renal vasodilation mediated by PGs

43
Q

What is the main loop diuretic?

A

Furosemide (Lasix)

44
Q

Describe the pharmacokinetics of furosemide

A

Rapid oral absorption with a short half life, short duration

Renal secretion via OAT

45
Q

What adverse effects are associated with furosemide?

A
  • Hyponatremia, hypokalemia, hypomagnesemia
  • Dehydration
  • Metabolic alkalosis
  • Mild hyperglycemia
  • Ototoxicity
  • Hypersensitivity
46
Q

What are the clinical indications for furosemide?

A
  • Acute pulmonary edema
  • Edema w/ CHF
  • Acute hypercalcemia, hyperkalemia
  • Hypertension
47
Q

What are the loop diuretics other than furosemide and how do they differ?

A 
Bumetanide (40x potency, shorter half life, liver metabolism)
Torsemide (longer half life, duration, better oral absorption, liver metabolism)
Ethacrynic acid (different structure, used w/ hypersensitivity, BAD AEs)
48
Q

Describe the ionic movements in the distal convoluted tubule

A

Transporters: lumenal Na/Cl symporter, basolateral Na/K ATPase and Na/Ca antiporter

  • Na gradient drives Na/Cl symporter
  • Ca absorption regulated by PTH
49
Q

What is the mechanism of action of hydrochlorothiazide?

A

Inhibition of the Na/Cl cotransporter on the lumenal side of the distal tubule

50
Q

How does the Ca2+ reabsorption differ between loop diuretics and hydrochlorothiazide?

A

Loop diuretics decrease Ca2+ reabsorption whereas hydrochlorothiazide increases Ca2+ reabsorption

51
Q

Describe the pharmacokinetics of hydrochlorothiazide

A

Good oral absorption, renal elimination

Short half life (2.5 h)

52
Q

How do thiazide diuretics cause hypercalcemia?

A

Inhibition of Na/Cl cotransporter decreases intracellular [Na+], producing a bigger gradient for the Na/Ca antiporter on the basolateral membrane. More Ca gets pumped out of the cells (reabsorption), leading to hypercalcemia

53
Q

What are the adverse effects of hydrochlorothiazide?

A 
Hyponatremia, hypokalemia
Dehydration
Metabolic alkalosis
Hyperuricemia
Hyperglycemia
Hyperlipidemia (LDL)
Weakness, fatigue, paresthesia, hypersensitivity
54
Q

What are the clinical indications for hydrochlorothiazide?

A

Hypertension
CHF
Prevent kidney stones by reducing Ca2+ excretion

55
Q

What are the thiazide drugs other than hydrochlorothiazide and how to the differ?

A

Chlorothiazide: 1/10 potency, short half life
Metolazone: 10x potency, long half life
Indapamide: 20x potency, longer half life, liver metabolism
Chlorthalidone: same potency, Longest half life

56
Q

Describe the ionic movements in the principal cell of the collecting tubule

A

Na and water reabsorbed with ADH present
K secreted via K+ channels
Basolateral Na/K ATPase
*Aldosterone regulates Na/K ATPase and channel expression

57
Q

Describe the ionic movements in the intercalated cells of the collecting tubule

A

H+ secreted into tubular lumen by proton pump

HCO3- reabsorbed into circulation by HCO3-/Cl- countertransport on basolateral membrane

58
Q

How do CA inhibitors cause hypokalemia?

A

Increased tubular HCO3- makes lumen potential more negative. This electrogradient increases K+ efflux from principal cells into the tubule and thus increased K+ excretion, hypokalemia

59
Q

How do loop and thiazide diuretics cause hypokalemia?

A

Increased tubular Na+ and Cl- creates a more negative lumen potential, which promotes K+ efflux from principal cells

60
Q

How do loop and thiazide diuretics cause metabolic alkalosis?

A

Lumen negative potential (increased Na and Cl-) enhances H+ efflux from the intercalated cells. More HCO3- is therefore reabsorbed, leading to alkalosis

61
Q

In what situations should K+ sparing diuretics be avoided?

A

Hyperkalemia

Patients on drugs (ACEi’s) or with diseases (DM, renal insufficiency) that could cause hyperkalemia

62
Q

What is the mechanism of action for spironolactone?

A

Competitive inhibition of aldosterone receptor

-Also anti-androgenic, decreases testosterone synthesis

63
Q

What affect does spironolactone have on potassium levels and pH?

A

Sparing of K+ and H+ due to aldosterone inhibition

-The negative lumenal charge is prevented because Na remains in lumen

64
Q

Describe the pharmacokinetics of spironolactone

A

Slow onset, takes days for effect

Liver metabolism to several active metabolites

65
Q

What adverse events are associated with spironolactone?

A 
Hyperkalemia (K+ sparing)
Metabolic acidosis (H+ sparing)
Gynecomastia, amenorrhea, impotence, decreased libido 
GI upset, ulcers
CNS: headache, confusion, fatigue
66
Q

What is the mechanism of action of eplerenone?

A

Aldosterone antagonist

67
Q

How does eplerenone differ from spironolactone?

A

Same MOA, but does not inhibit testosterone binding, so it has decreased side effects
Much more expensive

68
Q

What are the clinical indications for spironolactone?

A 
Primary and secondary hyperaldosteronism
Liver cirrhosis (drug of choice)
Hypertension
69
Q

What is the mechanism of action of amiloride and triamterene?

A

Blocks Na+ channels in the principal cells, thus decreasing the driving force for K+ efflux
K+ sparing

70
Q

Describe the pharmacokinetics of amiloride

A

Long half life (21h)
Secreted into tubule via OBT
Excreted unchanged by kidney

71
Q

What are the adverse effects of amiloride?

A

Hyperkalemia (exacerbated by NSAIDs)
GI upset: NVD
Muscle cramps
CNS: headache, dizziness

72
Q

What are the clinical indications of amiloride?

A

Edema
Hypertension
Used in combo with other diuretics to minimize K+ loss

73
Q

How does triamterene differ from amiloride?

A

10x less potent than amiloride with a much shorter half life

74
Q

Which drugs are the ADH antagonists?

A

Demeclocycline: tetracycline antibiotic
Lithium: psych drug for mania
Vaptans

75
Q

What are the vaptans and how do they differ?

A

V2 (kidney) receptor antagonists: tolvaptan, mozavaptan, lixivaptan
V1a (vascular smooth muscle) and V2 antagonist: conivaptan

76
Q

What adverse effects are associated with ADH antagonists?

A

hypernatremia, thirst, dry mouth, hypoteension, dizziness

77
Q

What are the indications for ADH antagonists?

A

SIADH
euvolemic or hypervolemic hyponatremia
CHF

78
Q

Which diuretic drugs most profoundly increase urinary NaCl?

A

Loop agents + thiazides combo

Loop agent monotherapy

79
Q

Which diuretic drugs most profoundly increase urinary NaHCO3- ?

A

Carbonic anhydrase inhibitors

80
Q

Which diuretic drugs most profoundly increase urinary K+?

A

Loop + thiazide combo

81
Q

How does edema form?

A

If filtration exceeds lymphatic drainage, edema forms

Unbalanced starling forces

82
Q

Describe the mechanism of renal disease causing systemic edema

A

2 Pathways:

1) Urinary loss of albumin decreases plasma oncotic pressure
2) reduced GFR leads to renal Na retention, water retention

83
Q

How does hepatic cirrhosis cause systemic edema?

A

Increased pressure in sinusoids leads to exudate, ascites

Decreased albumin production decreases oncotic pressure, RAA system activated, Na retention

84
Q

What diuretic therapies are recommended for CHF?

A 
Spironolactone to prevent hypokalmeia induced heart problems
ACE inhibitors (increase K) may be used with thiazide or loop diuretics
85
Q

How does diuretic treatment differ between chronic right heart failure and acute left heart failure?

A

Right: oral loop diuretics
Left: IV loop diuretics (Emergent situation)

86
Q

What is the most common electrolyte disorder in hospitalized patients? How is this treated?

A

Hyponatremia

*Corrected with AVP receptor antagonists (vaptans)

87
Q

What are some causes of diuretic resistance?

A

NSAID use
CHF or chronic renal failure
Nephrotic syndrome
Hepatic cirrhosis

*Overcome via increased dose, decreased interval, add another drug

88
Q

What drugs interact with K+ sparing diuretics?

A

ACE inhibitors

NSAIDs

89
Q

What drugs interact with loop diuretics

A 
Aminoglycosides
Anticoagulants (increased effect)
Beta blockers
Digoxin
NSAIDs
Quinidine
Sulfonureas
Steroids
90
Q

What drugs interact with Thiazides?

A 
Anticoagulants (decreased effect)
Beta blockers
Carbamazepine
Digoxin
NSAIDs
Quinidine

MHD/Pharm Block 4 (25 decks)

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