Diuretics and RAAS drugs Flashcards Preview

CVPR Exam 1 > Diuretics and RAAS drugs > Flashcards

Flashcards in Diuretics and RAAS drugs Deck (80):
1

What are the drug targets at the level of decreased cardiac output?



• Na/K ATPase
• Beta adrenergic receptor

2

What are the drug targets at the level of increased sympathetic discharge?

• Components in the baroreceptor response

3

What are the drug targets at the level of increased venous return?

• Alpha 1 adrenergic receptor
• Angiotensin receptor - AT-1

4

What are the drug targets at the level of cardiac remodeling?

• Angiotensin receptor - AT-1
• Berta adrenergic receptor (Beta1)
• Aldosterone receptor

5

What are the drug targets at the level of increased afterload?

• Alpha 1 adrenergic receptor
• Angiotensin receptor - AT-1

6

What are the drug targets at the level of fluid retention?

• Na reabsorption components

7

What are the drug targets at the level of increased Renal Release?

• RAAS response components

8

What are the signs and symptoms that suggest a need for Furosemide use?

• Furosemide = diuretic
• Dyspnea and peripheral edema

9

Do ARBs and ACEI together work synergistically?

• No added benefit with dual use

10

What does Lisinopril do?

• Vasodilation and decreased aldosterone activatoin PLUS antiremodeling effect

11

What are two alternatives to furosemide?

• Torsemide and bumetanide are preffered by some patients
• More reliable absorption
Lisinopril is a classic example of what type of drug?
• ACEI, ACE inhibitor
• Started during or after the optimization of diuretic therapy
• Start low then titrate to goal

12

When is furosemide used?

• Diuretic, often used first in the reversing of sodium and fluid retention
• Relieves volume overload symptoms (dyspnea and peripheral edema)
• Can be used chronically and acutely

13

What controls Na movement mostly and where are these things?


• Active transport via Na/K ATPase controls sodium movement
• Activity is at the interstitial surface (blood surface, as opposed to luminal or urine surface)

14

Nearly all diuretic agents exert their effects where on what?

• At the luminal surface of renal tubule cells (urine surface, not blood surface or interstitial surface)
• Membrane transport proteins
○ Thiazides
○ Furosemide
○ triamterene
• Enzymes
○ acetazolamine
• Hormone receptors
○ spironolactone

15

Glucose, amino acids, metabolites and NaHCO3 are nearly all reabsorbed where in the kidney?



• Proximal convoluted tubule
• 60-70% of sodium is reabsorbed here too

16

What are the parmacokinetic properties of Acetazolamide?

• Well absorbed orally
• Effects within 30min that persist for 12 hours
• Secreted into proximal tubule (RENALLY eliminated)!

17

Acetazolamide is what type of drug and what does it do?

• Carbonic Anhydrase Inhibitor
• Depresses NaHCO3 reabsorption in proximal tubule
• Inhibits formation of aqueous humor and CSF that is dependent on HCO3 transport
• Used for Glaucoma, acute mountain sickness (slows progression of pulmonary edema)

18

Where in the kidney are potential drug-drug interactions likely to take place?

• Proximal convoluted tubule of the kidney
• This is where orgainic acids (including diuretics) are secreted

19

Where in the kidney does acetazolamide work and what does it do?

• Works in proximal convoluted tuble of kidney
• Inhibits carbonic anhydrase (CA)
• CA is on luminal surface and allows for reabsorption of HCO3 and exchange of H for Na
• Inhibition of CA results in retentio nof HCO3 in the urine
• Results in mild alkaline diuresis

20

What are the uses of Acetazolamide?



• Note, the major use of this drug is not as a diuretic agent nor is it a heart failure drug
• Glaucoma
○ Topical admin for this
• Acute mountain sickness
○ Reduces pulmonary edema and cerebral edema b/c decreases formation of and pH of CSF

21

Where does water removal from the lumenal side happen?

• Descending limb, osmotic forces in interstitium
• Opposed by impermeable stuff in lumen INCLUDING OSMOTIC DIURETICS

22

Another name for the Loop of Henle is what?

• Thick, ascending limb

23

What are the adverse effects of Acetazolamide?

• Minor
○ Loss of appetite, drowsiness, confusion, tingling in extremities, hypersensitivity rxns
• Hyperchloremic metabolic acidosis, renal stones (increase urinary pH), potassium wasting

24

What is the ascending limb impermeable to?


• Water

25

What is in the ascending limb that allows for NaCl reabsorption?

• Na/K/2Cl cotransporter - NKCC2
○ On the lumenal side
• Electrically neutra, but eventually leads to lumen positive potential that drives reabsorption of Mg and Ca ions (pushes divalent cations back in the body)

26

Where do High Ceiling Diuretics work?




• Loop of Henle
• Inhibit NaCl transporter
○ Na/k/2Cl cotrasport
• Eventually results in INCREASE Mg and Ca excretion due to a diminished lumen positive potential
• Also increases renal blood flow
○ Renin-angiotensin and prostaglandin effects

27

What are the three loop diuretics we discussed?

• Furosemide, bumetanide, and torsemide

28

Furosemide, bumetanide, and torsemide are examples of what kind of drug?

• Loop diuretics

29

What are the parmacokinetics of loop diuretics?

• Rapidly absorbed orally
• Extremely rapid IV diuretic response
• Handled by renal secretion and filtration
• Effect lasts 2-3hours (furosemide)
○ 4-6 hours (torsemide
○ 6 hours bumetanide

30

Can loop diuretics work in renally compromised patients?

• Yes, these maintain efficacy even in renally compromised patients
• These are loop of henle agents or high ceiling diuretics
• The large capacity of the loop of henle leads to powerful diuretic effect

31

What is the main use of loop diuretics that we should be concerned with?




• Congestive heart failure
• These are the preferred diuretc class because of their greater efficacy
• Used in patients with volume overload by way of Heart Failure
• The goal is eliminating fluid retention (pulmonary congestion and peripheral edema)
* also used in acute pulmonary edema, hypercalcemia and refractory edema

32

Why do HF patients have a reduced diuretic response?

• Decreased drug delivery to kidney
• Reduced renal blood flow and hypoperfusion due to activation of RAAS and SNS

33

Why might the loop diuretic course start IV then move oral?

• Congestion related poor oral bioavailability
• Once congestion is improved by IV drug use then oral bioavailability increases

34

What is the most commonly used loop diuretic for HF patients?

• Furosemide

35

What can be added to the treatment of a CHF patient if there is refractory edema during loop diuretic treatment?


• You can add a thiazide (metolazone in particular)
• Blocks distal tubule Na reabsorption and can counter loop-induced increases in sodium delivery and reabsorption at the distal tubule
• CAN ADD TO LOOP-INDUCED HYPOKALEMIA so you must monitor for serum potassium

36

What must you monitor if you add a thiazide to loop-diuretic treatment in CHF patients?

• You would make this adjustment with refractory edema
• CAN ADD TO LOOP-INDUCED HYPOKALEMIA so you must monitor for serum potassium

37

In some patients with systolic HF, what drug is often used to enhance diuresis and ameliorate the potassium wasting in loop diuretic use?




• Aldosterone antagonist
○ Spironolactone

38

When you see Dizziness, headache, orthostatic hypotension in a loop diuretic patient, what are you concerned about?

• overdose

39

What are the adverse reactions of loop diuretic use should we be concerned with?

• Hypokalemic metabolic alkalosis
• Enhanced secretion of K and H
• Thiazides also produce this, but loop diuretics more so
• Ototoxicity (very special cases like antibiotic use and renal impairment)
• Hyperuricemia/hyperglycemia
• Hypomagnesemia
• Overdose
• Rapid blood volume depletion
○ Dizziness, headache, orthostatic hypotension

40

When might you use spironolactone?

• In some patients with systolic HF
• often used to enhance diuresis and ameliorate the potassium wasting in loop diuretic use
• Aldosterone antagonist
○ Spironolactone

41

The distal convoluted tubule is relatively impermeable to what?


• Water
• NaCl reabsorption occurs via an electrically neutral na/cl cotransporter
○ Distinct from loop cotransporter
• Here is the site of active calcium reabsorption (na/ca exchanger)
○ Regulated by parathyroid hormone
○ Not present in loop of henle so this marks an important distinction in drugs targeting the two sites

42

What is regulated by parathyroid hormone in the kidney?

• Distal convoluted tubule
• Here is the site of active calcium reabsorption (na/ca exchanger)
○ Regulated by parathyroid hormone
○ Not present in loop of henle so this marks an important distinction in drugs targeting the two sites

43


Concerning Calcium, loop diuretics and thiazide diuretics act differently…how?

• In contrast to loop diuretics, thiazides increase reabsorpiton of Calcium by lowering intracellular sodium and riving Ca exchanger

44

Where in the kidney to Thiazide diuretics work?

• Distal convoluted tubule
• Inhibit Na/Cl cotransportor, increasing urinary excretion of NaCl
○ Has a modest diuretic effect as only 5-10% of Na is reabsorbed here
• In contrast to loop diuretics, thiazides increase reabsorpiton of Calcium by lowering intracellular sodium and riving Ca exchanger

45

What are the pharmacokinetic properties of Thiazide diuretics?

• Absorbed well orally
• Best taken early in the day
• Hydrochlorothiazide - prototype that needs twice daily dose
• Chlorthalidone-metolazone - longer durations and need once daily dose
• All secreted by organic acid secretory system, causing competition with uric acid and maybe could cause gout

46

What are the symptoms of hypokalemia?

• Weakness, paresthesias, cardiac sensitization
• Predisposition to ectopic pacemakers
• Not advisable to use thiazide diuretics in arrhythmia patients, or those with previous MIs or pre-infarction angina

47

What are the adverse reactions of Thiazide diuretics?

• Hypokalemia
• Volume contraction leading to secondary hyperaldosteronism
• Impaired carbohydrate tolerance
○ Hyperglycemia, glucosuria
• Hyperuricemia
• Hyperlipidemia
• Allergic reactions (often cross-allergic with sulfonamides)

48

What are the clinical uses of thiazide diuretic agents?

• Congestive heart failure
○ Nees the highest doses and usually loop diuretics are used in combo
• Hypertension
○ First line drug for mild hypertension
• Hypercalcuria
○ Reduced uriniary calcium excretion reduces kidney stone risk

49

A HF pt treated with thiazide diuretics suddenly has a horrible pain in his right big toe…what might cause that?

• Thiazides are All secreted by organic acid secretory system, causing competition with uric acid and maybe could cause gout flare ups

50

Aldosterone acts primarily where in the kidney?

• Collecting tubules
• Weak diuretic action possible here as 2-5% of NaCl reabsorption happens here
• Final urinary sodium and K and H concentration determined here so it's an important regulatory site

51

What is the driving force for Cl and K into urine in the collecting tubules and what is the consequence on diuretic use?







• All diuretics that cause a greater delivery of Na (and greater tubular flow) to this site will enhance K excretion
• K excretion is coupled to Na reabsorption

52

What are the pharmacokinetic properties of Triamterene/amiloride?

• Faster effects (2-4 hrs), but 1-3 days for maximal effect
• Triamterene is liver metabolized
• Amiloride is renally excreted unchanged, given less frequently

53

What are the pharmacokinetic properties of spironolactone?

• 1-2 doses a day, poor oral absorption, slow onset of action

54

What are the pharmacodynamic properties of the aldosterone receptor antagonists?

• Potassium sparing diuretics
• Spironolactone, eplerenone
• Not usually used alone (mild diruesis possible)
• Competetive antagonist at aladosterone receptor
• Eplerenone also has some affinity for androgen and progesterone receptors

55

Spironolactone, eplerenone are examples of what?

• Aldosterone receptor antagonists

56

Triamterene, amiloride are examples of what?

• Sodium channel blockers in collecting tubules

57

What will be the effect of aldosterone receptor antagoists?

• Decresae sodium reabsorption and decrease potassium excretion
• "potassium sparing diuretics", so they do have some water excreting effect
• Spironolactone, eplerenone

58

What will be the effect of a diuretic that blocks the sodium channel in the collecting tubules of the kidney?

• Decresae sodium reabsorption and decrease potassium excretion
• "potassium sparing diuretics", so they do have some water excreting effect
• Triamterene, amiloride

59

What does aldosterone do?

• Increases the transcription and therefore expression of ENaC (sodium channel) and Potassium membrane channel and the Na/K-ATPase

60

What are the pharmacokinetic properties of Eplerenone?

• 1-2 doses a day ORAL
• CYP3A4 metabolized (liver problems? Drug interactions)

61

What are the clinical uses of potassium sparing diuretics?


• Congestive heart failure (primarily)
• Primary hyperaldosteronism
• Hirsuitsm of polycystic ovary syndrome
• Hypertension (with thiazides)

62

What increases the risk of cuasing hyperkalemia through potassium sparing diuretic use?

• Old age
• Underlying renal dysfunction
• Higher doses of drug
• Combined ACEI/ARB use
• NSAID use

63

What are the adverse reactions of potassium sparing diuretics?

• Hyperkalemia
○ EKG changes, conduction abnormalities, arrhythmias
• Endocrine abnormalities (gynecomastia)
○ Block of androgen receptor
• Mild - GI upset, drowsiness

64

What is the most efficacious type of diuretic drug?



• Loop diuretic + Thiazide
• Used for refractory edema

65

What's the one diuretic drug class that messes with magnesium plasma levels?

• Loop diuretics

66

What drugs will increase plasma calcium? Decrease?

• Increase - thiazides
• Decrease - loop diuretics

67

What drugs will result in HYPOkalemia?

• Loop + thiazide combo
• Loop diuretics

68

What drugs will result in HYPERkalemia

• Aldosterone antagonists and collecting tubule sodium channel blockers

69

What drugs increase uric acid plasma levels?

• Loop diuretics
• Thiazides

70

What is the one class of drug that messes with HCO3 plasma levels?

• Carbonic anhydrase inhibitors

71

What is the single most efficacious class of drug?

• Loop diuretic (as opposed to Loop + Thiazide)

72

What's the single most important ACEI?





• Lisinopril

73

What gets rid of ACEIs?

• Primarily renally eliminated
• Requires renal dosing

74

What liver function is important for ACEIs?

• Except lisinoprila nd captopril, all ACEIs are prodrugs that need to pass through liver to be activated

75

Are ACEI given orally?

• Yes, most of the time. Good oral absorption

76

What are the non HF uses of ACEI?

• Hypertension
• Delaying diabetic nephropathy

77

What does ACEI do in heart failure?

• Blocks angiotensin II-induced vasoconstriction
• Decreased preload and afterload
• Decreases release of aldosterone because of angiotensin II action
○ Moderates the cardiac remodeling problem
• Decreases bradykinin inactivation (increases vasodilation)
• Induces endothelial funciton by enhancing NO action
• Reduces sympathetic activity

78

What are the side effects of ACEI use?


• Can't use in pregnancy
• Dry cough
• HYPERkalemia
• Severe hypotension
• Acute renal failure
• Angioedema
• Neutropenia, proteinuria
• Minor effects - altered taste and skin rash

79

What does Valsartan do in HF?

• ARB drug
• Inhibits AT1
• A bit better than ACEI at inhibiting Angiotensin II action
• No bradykinin effects so it gets rid of angioedema and cough
○ But that also means less vasodilation
• Only blocks AT1, not both AT1,2 like ACEIs

80

What is the most important angiotensin II receptor antagonist (ARB)?

• Valsartan