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12. Pharmacology > Diuretics > Flashcards

Diuretics Flashcards

1
Q

Typical features of excessive diuresis on the metabolic/electrolyte profile include __________

A

o ↓K+
o ↓Na+
o ↓Cl-
o ↓Mg2+
o Metabolic alkalosis (↓H+)
o Hypovolemia → prerenal azotemia

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1
Q

What is meant by the term progressive nephron blockade

A
  • Different tubular site of action → additive effect
    o Thiazides
    o Loop diuretics
    o K+ sparing agents
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2
Q

What are potential complications of high-dose diuresis in the animal with CHF

A
  • ↓ intravascular volume and ventricular filling → ↓ CO → ↓ tissue perfusion
    o ↑ activation of RAAS and ∑ nervous system
  • More common with diuretic combination → synergy (loop + thiazide diuretic)

o Metabolic alkalosis (↓H+)
o Hypovolemia → prerenal azotemia
Electrolytes derangements

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3
Q

How are the mechanisms leading to diuretic resistance

A
  • Late or as early as after 1 dose
  • Mechanism:
    o Repetitive diuretic administration → ↓ intravascular volume → ↓ renal blood flow → RAAS stimulation → ↑ reabsorption of Na+ in other part of tubular system
     Hypertrophy of distal nephron  from aldosterone induced growth
     ↓ Na+ diuresis
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4
Q

Goals of diuretics

A

alter physiologic renal mechanism
* ↑ urine flow and Na+ excretion
o ↑ renal plasma flow → usually CI in CHF since ↑ venous pressures
o Alter nephron function → ion transport
* In CHF: control pulmonary/peripheral symptoms and signs of congestion
o Rarely used with non congested HF → induce renin activation

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5
Q

Diuretics should always be combined to what type of drugs

A

ACEi

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6
Q

Loop diuretics

A

Furosemide
Torsemide
Bumetanide
Ethacrynic acid

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7
Q

Furosemide: molecule

A

Sulfonamide derivative

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8
Q

Furosemide: MOA

A

o Inhibit Na+/K+/2Cl- cotransporter in ascending loop of Henle
 Can ↑ Na+ fractional excretion up to 23% of filtered load

o Venodilation: ↓ preload w/I 5-15min
 Can help dyspnea prior to diuresis action
 Reactive vasoconstriction may follow

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9
Q

Furosemide: site of action

A

intraluminal
 Drug excreted by proximal tubule
 Inhibition of Cl, Na, K and H+ transport

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10
Q

Furosemide: pharmacoK/D

A

o Oral absorption: 10-100%, average 50%
o Short action duration: 4-5h → frequent doses needed for sustained diuresis
o > earlier absolute Na+ loss (vs thiazide)
 24h Na+ loss is ↓
o Highly protein bound

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11
Q

Furosemide: dosage

A

o ↑ if impaired renal function

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12
Q

Furosemide: indications

A

o Diuretic of choice for severe CHF or acute edema 3 reasons
 ↑ fluid clearance for similar natriuresis (compared to thiazides)
 Work despite renal impairment
 ↑ dose → ↑ diuretic response
* High ceiling diuretics
o After initial IV doses → PO is continued for standard diuretic tx
 Usually twice daily low doses
o Effect limited with ↓CO → ↓ renal perfusion → ↓ delivery of furosemide

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13
Q

Furosemide: contra indications

A

o CHF w/o fluid retention
 ↑ aldosterone levels
 ↓ LV function
o Anuria → exclude dehydration and hypersensitivity to furosemide/sulfonamide

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14
Q

Furosemide: side effects

A

o HypoK+
 Depend on doses and degree of diuresis
 Electrolyte monitoring necessary with IV furosemide
 ↑ risk with high doses

o Hypovolemia and hyperuricemia
 Risk of prerenal azoetmia
 ↓ risk with lower doses

o Hyperosmolar nonketotic hyperglycemic state
o Photosensitive skin eruptions
o Blood dyscrasias
o Ototoxicity: dose related
 Electrolyte disturbance of endolymphatic system
 Avoided with oral doses <1000mg/day
o Excreted in milk (nursing mothers)
o ↑ risk of gout

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15
Q

Furosemide: diuretic resistance

A

o Braking: ↓ diuretic response after 1st dose
 RAAS activation → restore diuretic loss of blood volume
o Long term tolerance: ↑ Na+ reabsorption from distal nephron hypertrophy
 ↑ aldosterone → ↑ growth of nephron cell

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16
Q

Furosemide: drug interaction

A

o Aminoglycosides → ototoxicity
o Probenecid (uric acid reducer) → block secretion of diuretic into urine in proximal tubule
o NSAIDs → ↓ renal response
 Interfere with formation of vasodilatory PGE
o Salicylate (aspirin) → excretion inhibited by furosemide
 Predispose to salicylate poisoning
o Steroids → predidspose to hypoK+

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17
Q

Hyperosmolar nonketotic hyperglycemic state

A

 Reported in Hu
 Related to total body K+ depletion
* Transient postprandial ↓ K+ → impairs effect of insulin →intermittent hyperglycemia
 Can precipitate diabetes
* ↓ hypoK+ should ↓ risk of glucose tolerance

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18
Q

Bumetanide: effect/site of action

A

Similar to furosemide

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19
Q

Bumetanide: dose

A

o Higher dose can cause significant electrolyte disturbances

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20
Q

Bumetanide: pharmocoK/D

A

o Oral absorption: 80% or ↑
o 10-50x more potent vs furo

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21
Q

Bumetanide: side effects

A

o Similar to furosemide
 ↓ ototoxicity
 ↑ renal toxicity
* Avoid combination with other nephrotoxic drug (ie aminoglycosides)
* Renal failure: reported myalgia in Hu

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22
Q

Torsemide: dose/pharmacoK/D

A

longer duration of action
o IV dose: onset 10min, peak 1h
o PO dose: onset 1h, peak 1-2h, duration 6-8h
 Absorption: 80-100%

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23
Q

Torsemide: side effect and CI

A

similar to furosemide

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24
Q

Ethacrynic acid: molecule

A

non-sulfonamide diuretic
o Used in patients with sulfonamide sensitivity

25
Q

Ethacrynic acid: dose/pharmaco/side effects

A
  • Similar to furosemide for dose, duration, side effects but ↑ ototoxicity
26
Q

Thiazide diuretics

A

Hydrochlorothiazide/Chlorothiazide/Bendrofluazide/Hydroflumethiazide

27
Q

Thiazide diuretics: use

A

Combination with loop diuretics for chronic CHF

28
Q

Thiazide diuretics: major difference vs loop diuretics

A

o Longer duration of action
o Different site of action
o Low ceiling diuretics → max response at low dosage
o ↓ capacity to work with renal failure

29
Q

Thiazide diuretics: MOA

A

o Inhibit Na+/Cl- co-transporter in distal part of nephron
 ↑ Na+ excretion by 1-8% of filtered load
 ↑Na+ and Cl- reaching distal tubule → stimulate H+ and K+ secretion
* Especially with activated RAAS
 ↑ active excretion of K+
o Block nephron site where hypertrophy occurs from loop diuretic
 Synergetic combination
 Long term diuretic therapy

30
Q

Thiazide diuretics: dose

A

PO: onset 1-2h, last 16-24h

31
Q

Thiazide diuretics: indications

A

o Hypertension: low dose diuretic used as initial agent
 Lower doses → ↓ biochemical alterations → full antihypertensive
 Variable response rate: depend on age, race, Na+ intake
o Congestive heart failure: higher doses necessary

32
Q

Thiazide diuretics: contra indications

A

o HypoK+ → may precipitate arrhythmias
o Ventricular arrhythmias
o Co-therapy with pro-arrhythmic drug
o Pregnancy: can cross placental barrier → neonatal jaundice
o Renal dysfunction
 Can be exacerbated by thiazides
 Thiazides are ineffective when GFR <30ml/min

33
Q

Thiazide diuretics: side effects

A

rare
o Sulfonamide-type immune side effects
 Intrahepatic jaundice
 Pancreatitis
 Blood dyscrasia
 Angiitis
 Pneumonitis
 Interstitial nephritis
 Photosensitive dermatitis

o Metabolic side effects: similar to loop diuretics and dose dependent
 HypoK+ → can combine with K+ retaining agents (ACEi, ARBs, aldosterone blockers)
* Ventricular arrhythmias
* Avoid hypoK+:
o K+ sparing diuretic
o K+ supplementation: do not correct hypo Mg2+
 HypoMg2+ → can provoke arrhythmias with QT prolongation
 HypoNa+
 Diabetogenic effects
 ↓ urate excretion → ↑ risk of gout
 HyperCa2+ → ↑ proximal tubular reabsorption

34
Q

Thiazide diuretics: drug interactions

A

o Steroids → Na+ retention
 Antagonize effects of thiazides
o NSAIDs → blunt response
o Antiarrhythmics prolonging QT interval (class Ia or III)
 Precipitate Torsade de Pointes if hypoK+

35
Q

Thiazide-like agents: molecule

A

Different structure
* Chlorthalidone
* Indapamide
* Metolazone
o Efficacy despite ↓ renal function

36
Q

K+ sparing diuretics

A

Amiloride and triamterene
Spironolactone and Eplerenone
Angiotensin Converting Enzyme inhibitor and Aldosterone Receptor blockers

37
Q

K+ sparing agents: effect on arrhythmias

A
  • ↓ incidence of ventricular arrhythmias
38
Q

Risk K+ sparing agents

A

hyperK+:
o ↑ if
 Preexisting renal dz
 Diabetes
 concurrent administration of nephrotoxic agent

o Mechanism:
 Prolonged solute driven water loss
 Diuretic driven angiotensin aldosterone activation
 Negative effect of diuretic on nephron fct

39
Q

Amiloride and triamterene: potency

A
  • Weak diuretics alone
40
Q

Amiloride and triamterene: MOA

A

o ↓ Na+ reabsorption in distal and collecting tubules
 Indirectly ↓ K+ loss
o Amiloride: act on renal epithelial Na+ channel
o Triamterene: inhibits Na+/H+ exchanger

41
Q

Amiloride and triamterene: advantages

A

o Na+ loss w/o major K+ or Mg2+ loss
 Amiloride also help retain Mg2+
o K+ retention independent of aldosterone

42
Q

Amiloride and triamterene: side effects

A

o HyperK+ = contra-indication
o Acidosis

43
Q

Spironolactone: MOA

A

inhibit action of aldosterone in distal tubule cell
o Aldosterone blockers
 Block mineralocorticoid R binding aldosterone, cortisol and deoxycorticosterone
 K+ sparing

44
Q

Eplerenone: MOA

A

inhibit action of aldosterone in distal tubule cell
o Eplerenone: more specific blocker of mineralocorticoid R
 Avoid gynecomastia and sexual dysfct in 10% of patients with spiro

45
Q

Effect of Spironolactone and Eplerenone

A
  • Mild diuretic effect since [aldosterone] is normally low
    o Probably more effective in CHF when [aldosterone] ↑
46
Q

Spironolactone and Eplerenone: pharmaco, structure, site of action

A

Rapidly metabolized in active product = canrenone
o Structure similar to aldosterone → competitive binding on distal tubule site

47
Q

Spironolactone and Eplerenone: Advantage

A

no reflex sympathetic activation

48
Q

Angiotensin Converting Enzyme inhibitor and Aldosterone Receptor blockers: diuretic effect

A
  • Anti aldosterone effect → mild K+ sparing diuretics
49
Q

Aquaretics: MOA

A

AVP-2 R antagonists in kidneys (aquaporin-2) in renal collecting ducts
o Promote solute free water clearance
 ↑ urine volume and ↓ osmolality
 ↑ serum Na+
o Chronic CHF: associated w ↑ plasma [vasopressin]
 Fluid retention and hypoNa+
 Arginine Vasopressin (AVP) act on
* V1 R → regulate vascular tone
* V2 R → regulate fluid retention

50
Q

Aquaretics: drugs

A

vaptans
o Tolvaptan
o Conivaptan
o Satavaptan
o Lixivaptan

51
Q

Minor diuretics

A

Carbonic anhydrase inhibitors
Ca2+ channel blockers
Dopamine
A1-adenosine receptor antagonists

52
Q

Carbonic anhydrase inhibitors: drug

A
  • Acetazolamide
  • Weak diuretics
53
Q

Carbonic anhydrase inhibitors: MOA

A

↓ H+ secretion in proximal renal tubule
o ↑ loss of bicarbonate → ↑ loss of Na+

54
Q

Ca2+ channel blockers: effect

A
  • Mild direct diuretics
55
Q

Dopamine: effect and MOA

A
  • Direct and indirect diuretic action
  • Mechanism: only if fluid retention
    o Dopamine stimulates agonists receptors on renal tubular  → opposes aldosterone effects
56
Q

A1-adenosine receptor antagonists: effect and MOA

A
  • ↑ urine flow and natriuresis
  • Mechanism:
    o Dilation of afferent arteriole → ↑ GFR
    o ↑ response to loop diuretics
57
Q

Prevention of excessive diuresis/complications

A
  • ↓ dosage
  • Dietary changes
    o K+ supplementation
     Co administration of Cl- required to fully correct K+ in hypoK+ hypoCl- alkalosis
  • KCl: slow release tablets can cause GI ulcerations, not liquid formula
    o Na+ restriction
58
Q

Causes of diuretic resistance

A

o Inadequate dose
o Nonadherence: not taking drug, high Na+ intake
o PharmacoK factors
 Gut edema: slow absorption
 Impaired secretion in tubule lumen: CKD, age, drugs (NSAID, probenecid)
o Hypoproteinemia
o Hypotension
o Nephrotic syndrome
o Antinatriuretic drugs: NSAID, antihypertensives
o ↓ renal blood flow
o Nephron remodelling
o Neurohormonal activation

59
Q

What are the benefits of IV furosemide over those of oral furosemide (at least 3)

A
  • Anti-inflammatory
  • Venodilation
  • Transient bronchodilator effect
  • Fast acting: onset 5min, peak 20-30min, ½ life 15min, duration 2h
    o PO: onset 30-60min, peak 1-2h, duration 6h
  • ↓ bioavailability of PO → ↓GI absorption (especially with edema)
  • ↓ stress during administration in dyspneic dogs
60
Q

Why might torsemide be preferable to furosemide?

A
  • More potent drug
  • Longer duration of action: longer ½ life
  • ↑ bioavailability
  • Likely achieve greater diuresis vs furosemide
  • Decreased susceptibility to diuretic resistance
  • Adjunctive aldosterone antagonist properties

12. Pharmacology (10 decks)

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