Pharm CIS- Drugs Used in Heart Failure Flashcards Preview

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Heart Failure

Major contributor to morbidity and mortality worldwide
Five million cases of heart failure in the United States
Variety of causes and classifications
This CIS is limited to discussion of low-output failure due to systolic dysfunction
Heart failure occurs when cardiac output is inadequate to provide the oxygen needed by the body


Drug Therapy of Heart Failure

Historic focus on end-point components
- Volume overload (congestion) treated with diuretics
- Myocardial dysfunction (heart failure) treated with positive inotropes
- Stabilize hemodynamic decompensation and reduce symptoms
- Do NOT improve survival

Current therapies target organs other than the heart:
- Renin-angiotensin-aldosterone system
- Sympathetic nervous system
- Goals are to reduce preload and afterload, and reduce maladaptive cardiac remodeling
*** ACE inhibitors, ARBs, aldosterone antagonists, and certain β-blockers have been shown to reduce mortality


Loop Diuretics

Prototypes: furosemide and ethacrynic acid
MOA: inhibit the luminal Na+/K+/2Cl- cotransporter (NKCC2) in the TAL of the loop of Henle
Results in:
↓ intracellular Na+, K+, Cl- in TAL
↓ back diffusion of K+ and positive potential
↓ reabsorption of Ca2+ and Mg2+
↑ diuresis
Ion transport is virtually nonexistent
Relieve the “congestive” aspect of CHF
Improve symptoms, but not mortality


indications for loop diuretics

Heart failure
Acute renal failure
Hypercalcemic states


loop diuretics adverse effects

Sulfonamide hypersensitivity (not all)
May worsen renal function


ACE Inhibitors and ARBs Blockthe Action of Angiotensin II

Angiotensin II:
-Arterial vasoconstrictor
-Increases retention of sodium and water
-Increases aldosterone secretion
-Promotes catecholamine release from the adrenal medulla
-Promotes arrhythmias
-Promotes vascular and cardiac hypertrophy
and remodeling
-Stimulates myocyte death

ACE inhibitors and ARBs reduce mortality


Beta Receptors in HF

- Compensatory sympathetic hyperactivation in patients with HF initially increases CO
- Chronic stimulation of causes downregulation and desensitization of beta receptors, reducing responsiveness of myocardium
- High dose β-blocker therapy can antagonize the supportive effects of catecholamines and worsen heart failure
- Treatment only initiated in stable patients


Rationale for β-blocker Use in HF

Beta blockade upregulates myocardial β1 receptor density; inotropic and chronotropic responsiveness of myocardium is improved
Circulating levels of vasoconstrictors (e.g., NE, renin, endothelin) are reduced
Beneficial remodeling
Reduces myocardial O2 requirement
Improve survival after myocardial infarction


Aldosterone antagonist in HF

(spironolactone, eplerenone)
Reduces mortality and hospitalizations
Beneficial at a variety of LVEF reductions in various HF classes
May be especially useful after MI
Monitor for adequate renal function and normal plasma [K+]


Hydralazine + oral nitrate (usually isosorbide dinitrate)
in HF

Reduces mortality and improves quality of life
Beneficial in patients (particularly blacks) with reduced LVEF who have persistent symptoms despite therapy with ACE inhibitor and beta-blocker


Some drugs that reduce preload

ACE Inhibitors
Angiotensin Receptor Blockers


Some drugs that reduce afterload

ACE Inhibitors
Angiotensin Receptor Blockers


Cardiac Glycosides

Digoxin: only cardiac glycoside available in US
Clinical indications: heart failure, atrial fibrillation
Well absorbed and widely distributed
MOA: inhibits the membrane-bound Na+/K+ ATPase and increases myocardial contractility (50-100% in patients with HF)
Improves symptoms and reduces hospitalizations, but no net effect on mortality
Narrow therapeutic index


Effects of Digoxin: Therapeutic Levels

Brief prolongation of action potential, followed by AP shortening
Increases intracellular calcium
Increases cardiac contractility
Increases parasympathetic tone and reduces sympathetic tone


Effects of Digoxin: Toxic Levels

Depolarization of the resting potential, a marked shortening of the action potential, and the appearance of oscillatory depolarizing afterpotentials following normally evoked action potentials

When afterpotentials reach threshold, they elicit action potentials (premature depolarizations, ectopic beats)
Most common cardiac manifestations of digoxin toxicity is arrhythmia
If allowed to progress, the tachycardia may deteriorate into fibrillation that could be fatal unless corrected
At toxic levels, sympathetic outflow is increased by digoxin


Digoxin: Interactions with K+, Ca2+, and Mg2+

Hyperkalemia can reduce the effects of digoxin, especially the toxic effects
Digoxin and potassium compete for binding to the Na+/K+ ATPase
Hyperkalemia inhibits abnormal cardiac automaticity (i.e., hyperkalemia decreases pacemaker arrhythmogenesis)
Hypokalemia can potentiate the toxic effects of digoxin

Hypercalcemia and hypomagnesemia increase the risk of a digoxin-induced arrhythmia
Hypercalcemia accelerates overloading of intracellular Ca2+ stores


Bipyridines (Inamrinone and Milrinone)

MOA: cause selective inhibition of the PDE3 phosphodiesterase enzyme (PDE3 degrades cAMP)
Increased concentrations of cAMP in the heart result in direct stimulation of myocardial contractility and acceleration of myocardial relaxation
Increased concentrations of cAMP in the vasculature cause balanced arterial and venous dilation
Inotropic agents approved for the SHORT-TERM support of circulation in advanced HF
Chronic therapy does not show any improvement in quality or length of life
Chronic therapy may increase mortality
Other agents that inhibit PDE
Sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra) inhibit PDE5
Caffeine and theophylline are nonspecific PDE inhibitors


Agents shown to improve survival in chronic HF

ACE Inhibitors
Aldosterone antagonists
Hydralazine + nitrate