Flashcards in Diuretics and RAAS Antagonists Use in Heart Failure Deck (56):
HF Pharmacotherapy Goals
1) Reduction of Congestion- Diuretics
2) Modulate Neurohormonal activation- RAAS antagonists and B-Blockers- Positive Remodeling
3) Improve flow- Vasodilators (difficult to obtain pharmacotherapeutically)
Chronic HFrEF Treatments
Hydralazine / ISDN
Chronic HFpEF Treatments
Control Risk Factors (DM, HTN, obesity)
Control volume status
Acute HFrEF Treatments
No standard treatment
Nitrates (if BP allows)
CPAP (if SOB)
Pressors (if very depressed cardiac output/shock)
Acute HFpEF Treatments
No standard treatment
Nitrates (if BP allows)
Preferred Type of Diuretics. Reason. Specific Drugs.
Loop Diuretics are preferred because of EFFICACY. Can be augmented with a thiazide diuretic. Used Chronically and acutely. Furosemide (lasix) is the most common. Torsemide and bumetanide have more reliable absorption.
Produce vasodilation and decreased aldosterone activation
Plus antiremodeling effect
Used in patients intolerant to ACEIs (most often cough due to Bradykinin breakdown product)
NO apparent benefit from dual therapy with ACEI and ARB
Aldosterone Antagonists. Use and functions?
Added to therapy for LVEF < 30-35%, optimized on ACEI/ARB and β-blocker therapy. Blocks aldosterone effect on kidney. Antiremodeling action plus produces additional Na+ loss at the kidney.
Diuretics (we need to know).
Diuretic general location of action and mechanisms.
Exert effects at lumenal (urine) surface of renal tubule cells.
1) Interactions with membrane transport proteins (thiazides, furosemide)
2) Interactions with enzymes (acetazolamide) or hormone receptors (spironolactone)
3) Osmotic effects preventing water reabsorption (mannitol)
Na+ movement is controlled by?
Na+-K+ ATPase activity at the interstitial (blood) surface. In the kidney, Na+-K+-ATPase produces gradient necessary for Na+ reabsorption from the urine back into the blood. No diuretics work against the Na-K-ATPase.
Loop Diuretic Example(s)
Furosemide (variable bioavailability)
Potassium Wasting Agent(s)
Potassium Sparing Agent(s)
Furosemide Blocks...? Causes increased excretion of...?
NKCC2. Na-K-Cl Cotransporter. Decreases Sodium transport across membrane (Urine to Blood). Also, decreases potassium transport back into Urine (decreased membrane potential) which blocks magnesium and calcium transport. Leads to increased H20 excretion as well.
Thick Ascending Limb of Loop of Henle
Loop Diuretics effect on blood flow and diuretic effects on patients with decreased renal function.
Increase renal blood flow via effect on renin-angiotensin and prostaglandin systems
Retain substantial diuretic effect even if renal function is compromised (CrCl < 50 ml/min)
Handled by glomerular filtration and renal secretion
Loop Diuretics Use? Enhanced by?
-Used in HF patients with volume overload to eliminate symptoms of fluid retention
-Efficacy is enhanced with salt restriction (< 2 g/day)
Pt's with HF have reduced.....
Diuretic Response! Decreased drug delivery to kidney via decreased RBF. Hypoperfusion activates of RAAS and SNS.
Most common use of a thiazide
Refractory Edema! Synergistic effect with Loop Diuretics.
Block distal tubule sodium reabsorption
Aldosterone Antagonist Improves? Functions?
Improves survival of some patients with HF. Enhances diuresis and ameliorates the potassium wasting at the collecting tubule (CT)
Most efficacious diuretic in HF?
LOOP DIURETICS!! (High-ceiling dose drug)
LD's Adverse Reactions
Hypokalemic metabolic alkalosis (predisposes to ectopic pacemakers and arrhythmias)
Hyperuricemia (may precipitate a gout attack)
Loop and Thiazide Potassium effect?
Synergistic Potassium excretion!
NCC cotransporter (Na and Cl). Decreases Sodium transport (increased excretion) and increased Ca2+ reabsorption (decreased serum Ca2+ levels). MODEST diuretic effect (only 5 to 10% of Na is reabsorbed at the distal tubule).
Methods to increase loop diuretic efficacy?
-Increase initial dose of furosemide
-Switch to bumetanide or torsemide = more reliable bioavailability and longer duration of action
-IV administration may be required initially due to congestion-related interference with oral absorption
ACEI Dosing Timeframe?
Started during or after optimization of diuretic therapy
Initiated at low doses and titrated to goal
Aldosterone Antagonist Monitoring? Specific drugs?
Monitor for Hyperkalemia and kidney function.
Spironolactone preferred if tolerated - if endocrine side effects occur, Eplerenone can be used.
Prototypical Thiazide and dose
once or twice daily dose
Thiazide Adverse Reactions
Hypokalemia- predisposition to ectopic pacemakers!
Hyperuricemia- avoid in patients with gout
Allergic reactions: skin rashes occasionally, related to SULFONAMIDE STRUCTURE!
Decreased Blood Volume
Receptor increases concentration of ENaC (channels) in lumenal membrane and Na/K ATPase in interstitium membrane.
Aldosterone Antagonist Blocks...?
Binds Aldosterone receptor, blocks activity and decreases Na/Fluid reabsorption. MILD diuretic effect (only 2-5% Na reabsorption at collecting duct)
Benefit of Eplerenone over Spironolactone?
Decreased Gynecomastia (no man boobs!). Lower affinity for androgen and progesterone receptor.
NO UTILITY IN HF! direct block of Na channels in collecting duct.
1-2 doses/day for both. Must wait for turnover of receptors to become effective.
Most important action of Spironolactone in HF is?
Block of aldo receptors on heart- acts as a RAAS antagonist rather than a diuretic. ANTI-REMODELING action (decreased hypertrophy and fibrosis)! Also, increases potassium to counter arrhythmias from K+ wasting diuretics.
K+ sparing diuretic adverse reactions
1) Hyperkalemia- EKG changes, conduction abnormalities, arrhythmias. Increased risk with age, underlying renal dysfunction, higher dosage, use with ACEI/ARB and usage of NSAIDS.
2) Endocrine Abnormalities (gynecomastia) with spironolactone via block of androgen receptor (not with eplerenone)
Targets of RAAS antagonists
AT-1 receptor, ACE, and Aldosterone receptor.
Angiotensin II from Angiotensin I and inactivates Bradykinin (may cause vasodilation)
AT-1 @ vessels produces vasoconstriction. AT-1 @ kidneys produces increased aldosterone.
Breakdown of Bradykinin may result in?
ACEI's vs ARBs
Same effects but cough won't occur w/ ARBs. (Pril to Sartan with cough). Both RAAS antagonists. Elevated Potassium with both!
Vasodilators vs ACEIs
Vasodilators have less survival benefits than ACEIs in HF.
ACEI/Aldosterone blockers Effect in HF
Moderates myocardial hypertrophy and remodeling
ACEI Bradykinin Effect
Decreases bradykinin inactivation, increasing its vasodilator action
ACEI Prodrug Examples and Mechanism
lisinopril and captopril. De-esterification in liver to active metabolite.
ACEI Potential Side Effects
Decreased Renal Function
Chronic Dry Cough
CATEGORY D DURING PREGNANCY!
Positives of ARBs vs ACEIs
1) More complete inhibition of Ang II (not all pathways are blocked by ACEIs)
2) No side effects due to increased Bradykinin levels (cough, angioedema)
Negatives of ARBs vs ACEIs
1) Loss of increased BK vasodilation seen with ACEIs
2) Only Ang II actions at AT-1 receptors are blocked
Once daily dosing (except losartan x 2 daily)
Decreased losartan dose necessary in hepatic dysfunction
ARB Side Effects
Similar to ACEI, contraindicated in pregnancy
NO angioedema or cough, which are thought to be bradykinin-mediated