Pharm: Diuretics Flashcards Preview

MHD/Pharm Block 4 > Pharm: Diuretics > Flashcards

Flashcards in Pharm: Diuretics Deck (90):
1

What is the definition of a diuretic?

a substance/drug that increases the discharge of urine

2

What was the original parent compound for diuretic drugs?

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

3

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

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

4

How does the kidney control ECF volume?

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

5

What happens if NaCl intake > output?

Edema develops
This happens in heart failure, renal failure

6

What does natriuretic mean?

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

7

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

Input: renal artery
Outputs: renal vein and ureter

8

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

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

9

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

Reabsorbed: NaHCO3, NaCl
Secreted: organic acids and bases

10

Is the thin descending limb H2O permeable or impermeable?

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

11

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

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

12

Describe the structure and function of the juxtaglomerular apparatus

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

13

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

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

14

What regulates the H2O permeability of the collecting duct?

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

15

What regulates NaCl permeability of the collecting duct?

Aldosterone

16

What are the ions secreted in the collecting ducts?

K+ and H+ are secreted in the collecting ducts

17

Location of action of acetazolamide

Proximal convoluted tubule

18

Location of action of mannitol

Proximal convoluted tubule

19

Location of action of furosemide

Thick ascending limb

20

Location of action of thiazides

Distal convoluted tubule

21

Location of action of K+ sparing diuretics

Collecting ducts

22

Location of action of ADH antagonists

Collecting ducts

23

Diuretics primarily prevent Na+ ________________

Diuretics primarily prevent Na+ entry into the tubule cells

24

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

They must reach the tubular fluid in order to be effective

25

Describe how diuretics reach the tubular fluid

Mannitol is filtered across the glomerulus
Most others are secreted via organic acid/base transporters in the proximal tubule

26

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

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

27

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

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

28

What is the mechanism of action of acetazolamide?

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

29

Describe the pharmacokinetics of acetazolamide

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

30

What adverse events are associated with acetazolamide?

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

31

What are the contraindications for acetazolamide?

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

32

What is the relationship between ammonia excretion and urine pH?

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

33

What are the CA inhibitors other than acetazolamide?

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

34

What are the indications for acetazolamide treatment?

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

35

What is the mechanism of action for mannitol?

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

36

Describe the pharmacokinetics of mannitol

Not orally absorbed, so given IV to reach kidney
Half life is 1.2 h

37

What condition worsens adverse effects associated with mannitol?

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

38

What are the adverse effects associated with mannitol

Caused by increased plasma osmolarity, water leaves cells, Na follows
-Acute pulmonary edema
-Dehydration
-Headache, nausea, vomiting

39

What are the contraindications for mannitol?

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

40

What are the clinical indications of mannitol?

-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

Describe the ionic movements in the thick ascending limb

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

What is the mechanism of action of the loop diuretics?

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

What is the main loop diuretic?

Furosemide (Lasix)

44

Describe the pharmacokinetics of furosemide

Rapid oral absorption with a short half life, short duration
Renal secretion via OAT

45

What adverse effects are associated with furosemide?

-Hyponatremia, hypokalemia, hypomagnesemia
-Dehydration
-Metabolic alkalosis
-Mild hyperglycemia
-Ototoxicity
-Hypersensitivity

46

What are the clinical indications for furosemide?

-Acute pulmonary edema
-Edema w/ CHF
-Acute hypercalcemia, hyperkalemia
-Hypertension

47

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

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

Describe the ionic movements in the distal convoluted tubule

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

What is the mechanism of action of hydrochlorothiazide?

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

50

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

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

51

Describe the pharmacokinetics of hydrochlorothiazide

Good oral absorption, renal elimination
Short half life (2.5 h)

52

How do thiazide diuretics cause hypercalcemia?

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

What are the adverse effects of hydrochlorothiazide?

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

54

What are the clinical indications for hydrochlorothiazide?

Hypertension
CHF
Prevent kidney stones by reducing Ca2+ excretion

55

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

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

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

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

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

H+ secreted into tubular lumen by proton pump
HCO3- reabsorbed into circulation by HCO3-/Cl- countertransport on basolateral membrane

58

How do CA inhibitors cause hypokalemia?

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

How do loop and thiazide diuretics cause hypokalemia?

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

60

How do loop and thiazide diuretics cause metabolic alkalosis?

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

61

In what situations should K+ sparing diuretics be avoided?

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

62

What is the mechanism of action for spironolactone?

Competitive inhibition of aldosterone receptor
-Also anti-androgenic, decreases testosterone synthesis

63

What affect does spironolactone have on potassium levels and pH?

Sparing of K+ and H+ due to aldosterone inhibition
-The negative lumenal charge is prevented because Na remains in lumen

64

Describe the pharmacokinetics of spironolactone

Slow onset, takes days for effect
Liver metabolism to several active metabolites

65

What adverse events are associated with spironolactone?

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

66

What is the mechanism of action of eplerenone?

Aldosterone antagonist

67

How does eplerenone differ from spironolactone?

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

68

What are the clinical indications for spironolactone?

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

69

What is the mechanism of action of amiloride and triamterene?

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

70

Describe the pharmacokinetics of amiloride

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

71

What are the adverse effects of amiloride?

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

72

What are the clinical indications of amiloride?

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

73

How does triamterene differ from amiloride?

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

74

Which drugs are the ADH antagonists?

Demeclocycline: tetracycline antibiotic
Lithium: psych drug for mania
Vaptans

75

What are the vaptans and how do they differ?

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

76

What adverse effects are associated with ADH antagonists?

hypernatremia, thirst, dry mouth, hypoteension, dizziness

77

What are the indications for ADH antagonists?

SIADH
euvolemic or hypervolemic hyponatremia
CHF

78

Which diuretic drugs most profoundly increase urinary NaCl?

Loop agents + thiazides combo
Loop agent monotherapy

79

Which diuretic drugs most profoundly increase urinary NaHCO3- ?

Carbonic anhydrase inhibitors

80

Which diuretic drugs most profoundly increase urinary K+?

Loop + thiazide combo

81

How does edema form?

If filtration exceeds lymphatic drainage, edema forms
Unbalanced starling forces

82

Describe the mechanism of renal disease causing systemic edema

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

83

How does hepatic cirrhosis cause systemic edema?

Increased pressure in sinusoids leads to exudate, ascites
Decreased albumin production decreases oncotic pressure, RAA system activated, Na retention

84

What diuretic therapies are recommended for CHF?

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

85

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

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

86

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

Hyponatremia
*Corrected with AVP receptor antagonists (vaptans)

87

What are some causes of diuretic resistance?

NSAID use
CHF or chronic renal failure
Nephrotic syndrome
Hepatic cirrhosis

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

88

What drugs interact with K+ sparing diuretics?

ACE inhibitors
NSAIDs

89

What drugs interact with loop diuretics

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

90

What drugs interact with Thiazides?

Anticoagulants (decreased effect)
Beta blockers
Carbamazepine
Digoxin
NSAIDs
Quinidine