Diuretics Flashcards
Typical features of excessive diuresis on the metabolic/electrolyte profile include __________
o ↓K+
o ↓Na+
o ↓Cl-
o ↓Mg2+
o Metabolic alkalosis (↓H+)
o Hypovolemia → prerenal azotemia
What is meant by the term progressive nephron blockade
- Different tubular site of action → additive effect
o Thiazides
o Loop diuretics
o K+ sparing agents
What are potential complications of high-dose diuresis in the animal with CHF
- ↓ 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
How are the mechanisms leading to diuretic resistance
- 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
Goals of diuretics
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
Diuretics should always be combined to what type of drugs
ACEi
Loop diuretics
Furosemide
Torsemide
Bumetanide
Ethacrynic acid
Furosemide: molecule
Sulfonamide derivative
Furosemide: MOA
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
Furosemide: site of action
intraluminal
Drug excreted by proximal tubule
Inhibition of Cl, Na, K and H+ transport
Furosemide: pharmacoK/D
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
Furosemide: dosage
o ↑ if impaired renal function
Furosemide: indications
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
Furosemide: contra indications
o CHF w/o fluid retention
↑ aldosterone levels
↓ LV function
o Anuria → exclude dehydration and hypersensitivity to furosemide/sulfonamide
Furosemide: side effects
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
Furosemide: diuretic resistance
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
Furosemide: drug interaction
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+
Hyperosmolar nonketotic hyperglycemic state
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
Bumetanide: effect/site of action
Similar to furosemide
Bumetanide: dose
o Higher dose can cause significant electrolyte disturbances
Bumetanide: pharmocoK/D
o Oral absorption: 80% or ↑
o 10-50x more potent vs furo
Bumetanide: side effects
o Similar to furosemide
↓ ototoxicity
↑ renal toxicity
* Avoid combination with other nephrotoxic drug (ie aminoglycosides)
* Renal failure: reported myalgia in Hu
Torsemide: dose/pharmacoK/D
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%
Torsemide: side effect and CI
similar to furosemide
Ethacrynic acid: molecule
non-sulfonamide diuretic
o Used in patients with sulfonamide sensitivity
Ethacrynic acid: dose/pharmaco/side effects
- Similar to furosemide for dose, duration, side effects but ↑ ototoxicity
Thiazide diuretics
Hydrochlorothiazide/Chlorothiazide/Bendrofluazide/Hydroflumethiazide
Thiazide diuretics: use
Combination with loop diuretics for chronic CHF
Thiazide diuretics: major difference vs loop diuretics
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
Thiazide diuretics: MOA
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
Thiazide diuretics: dose
PO: onset 1-2h, last 16-24h
Thiazide diuretics: indications
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
Thiazide diuretics: contra indications
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
Thiazide diuretics: side effects
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
Thiazide diuretics: drug interactions
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+
Thiazide-like agents: molecule
Different structure
* Chlorthalidone
* Indapamide
* Metolazone
o Efficacy despite ↓ renal function
K+ sparing diuretics
Amiloride and triamterene
Spironolactone and Eplerenone
Angiotensin Converting Enzyme inhibitor and Aldosterone Receptor blockers
K+ sparing agents: effect on arrhythmias
- ↓ incidence of ventricular arrhythmias
Risk K+ sparing agents
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
Amiloride and triamterene: potency
- Weak diuretics alone
Amiloride and triamterene: MOA
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
Amiloride and triamterene: advantages
o Na+ loss w/o major K+ or Mg2+ loss
Amiloride also help retain Mg2+
o K+ retention independent of aldosterone
Amiloride and triamterene: side effects
o HyperK+ = contra-indication
o Acidosis
Spironolactone: MOA
inhibit action of aldosterone in distal tubule cell
o Aldosterone blockers
Block mineralocorticoid R binding aldosterone, cortisol and deoxycorticosterone
K+ sparing
Eplerenone: MOA
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
Effect of Spironolactone and Eplerenone
- Mild diuretic effect since [aldosterone] is normally low
o Probably more effective in CHF when [aldosterone] ↑
Spironolactone and Eplerenone: pharmaco, structure, site of action
Rapidly metabolized in active product = canrenone
o Structure similar to aldosterone → competitive binding on distal tubule site
Spironolactone and Eplerenone: Advantage
no reflex sympathetic activation
Angiotensin Converting Enzyme inhibitor and Aldosterone Receptor blockers: diuretic effect
- Anti aldosterone effect → mild K+ sparing diuretics
Aquaretics: MOA
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
Aquaretics: drugs
vaptans
o Tolvaptan
o Conivaptan
o Satavaptan
o Lixivaptan
Minor diuretics
Carbonic anhydrase inhibitors
Ca2+ channel blockers
Dopamine
A1-adenosine receptor antagonists
Carbonic anhydrase inhibitors: drug
- Acetazolamide
- Weak diuretics
Carbonic anhydrase inhibitors: MOA
↓ H+ secretion in proximal renal tubule
o ↑ loss of bicarbonate → ↑ loss of Na+
Ca2+ channel blockers: effect
- Mild direct diuretics
Dopamine: effect and MOA
- Direct and indirect diuretic action
- Mechanism: only if fluid retention
o Dopamine stimulates agonists receptors on renal tubular → opposes aldosterone effects
A1-adenosine receptor antagonists: effect and MOA
- ↑ urine flow and natriuresis
- Mechanism:
o Dilation of afferent arteriole → ↑ GFR
o ↑ response to loop diuretics
Prevention of excessive diuresis/complications
- ↓ 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
Causes of diuretic resistance
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
What are the benefits of IV furosemide over those of oral furosemide (at least 3)
- 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
Why might torsemide be preferable to furosemide?
- 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
